Introduction: The pathological progression of non-alcoholic fatty liver disease (NAFLD) is driven by multiple factors, and non-alcoholic steatohepatitis (NASH) represents its progressive form. In our previous studies, we found that bicyclol had beneficial effects on NAFLD/ NASH. Here we aim to investigate the underlying molecular mechanisms of the bicyclol effect on NAFLD/NASH induced by high-fat diet (HFD) feeding.Methods: A mice model of NAFLD/NASH induced by HFD-feeding for 8 weeks was used. As a pretreatment, bicyclol (200 mg/kg) was given to mice by oral gavage twice daily. Hematoxylin and eosin (H&E) stains were processed to evaluate hepatic steatosis, and hepatic fibrous hyperplasia was assessed by Masson staining. Biochemistry analyses were used to measure serum aminotransferase, serum lipids, and lipids in liver tissues. Proteomics and bioinformatics analyses were performed to identify the signaling pathways and target proteins. Data are available via Proteome X change with identifier PXD040233. The real-time RT-PCR and Western blot analyses were performed to verify the proteomics data.Results: Bicyclol had a markedly protective effect against NAFLD/NASH by suppressing the increase of serum aminotransferase, hepatic lipid accumulation and alleviating histopathological changes in liver tissues. Proteomics analyses showed that bicyclol remarkably restored major pathways related to immunological responses and metabolic processes altered by HFD feeding. Consistent with our previous results, bicyclol significantly inhibited inflammation and oxidative stress pathway related indexes (SAA1, GSTM1 and GSTA1). Furthermore, the beneficial effects of bicyclol were closely associated with the signaling pathways of bile acid metabolism (NPC1, SLCOLA4 and UGT1A1), cytochrome P450-mediated metabolism (CYP2C54, CYP3A11 and CYP3A25), biological processes such as metal ion metabolism (Ceruloplasmin and Metallothionein-1), angiogenesis (ALDH1A1) and immunological responses (IFI204 and IFIT3).Discussion: These findings suggested that bicyclol is a potential preventive agent for NAFLD/NASH by targeting multiple mechanisms in future clinical investigations.

Background: The social restrictions among coronavirus disease 2019 (COVID-19) pandemic have posed a thoughtful risk to mental health and have implications in the use of drugs, including antidepressants, anxiolytics and other psychotropics.Objective: This study analyzed the sales data of the psychotropics prescribed in Brazil, in order to verify the change in consumption trends of these drugs during the COVID-19 pandemic.Methods: This interrupted time-series analyzed psychotropic sales data, between January 2014 and July 2021, using the National System of Controlled Products Management from The Brazilian Health Regulatory Agency. The monthly mean DDDs per 1,000 inhabitants per day of psychotropic drugs was evaluated by analysis of variance (ANOVA) followed by Dunnett Multiple Comparisons Test. The changes in monthly trends in the use of the psychotropic studied were evaluated by Joinpoint regression.Results: During the period studied, clonazepam, alprazolam, zolpidem and escitalopram were the most sold psychotropic drugs in Brazil. According to Joinpoint regression, an upward trend was observed in sales during the pandemic of pregabalin, escitalopram, lithium, desvenlafaxine, citalopram, buproprion and amitriptyline. An increase in psychotropic consumption was noted throughout the pandemic period, with the maximum consumption (2.61 DDDs) occurring in April 2021, with a downward trend in consumption that accompanied the drop in the number of deaths.Conclusions: The increase in sales, mainly of antidepressants during the COVID-19 pandemic, draws attention to issues related to the mental health of the Brazilian population and on the need for greater monitoring in the dispensing of these drugs.

Introduction: It has been proven that hydrogen has obvious anti-inflammatory effects in animal experiments and clinical practice. However, the early dynamic process of the inflammatory response caused by lipopolysaccharide (LPS) and the anti-inflammatory effect of hydrogen has not been definitively reported. Methods: Inflammation in male C57/BL6J mice or RAW264.7 cells was induced with LPS, for which hydrogen was immediately administered until samples were taken. Pathological changes in lung tissue were assessed using hematoxylin and eosin (HE) staining. Levels of inflammatory factors in serum were determined using liquid protein chip. The mRNA levels of chemotactic factors in lung tissues, leukocytes, and peritoneal macrophages were measured by qRT-PCR. The expression levels of IL-1α and HIF-1α were measured by immunocytochemistry. Results: Hydrogen alleviated LPS-induced inflammatory infiltration in the lung tissues of mice. Among the 23 inflammatory factors screened, LPS-induced upregulation of IL-1α etc. was significantly inhibited by hydrogen within 1 hour. The mRNA expression of MCP-1, MIP-1α, G-CSF, and RANTES was inhibited obviously by hydrogen at 0.5 and 1 h in mouse peritoneal macrophages. In addition, hydrogen significantly blocked LPS or H2O2-induced upregulation of HIF-1α, and IL-1α in 0.5 h in RAW264.7 cells. Discussion: The results suggested that hydrogen is potentially inhibitive against inflammation by inhibiting HIF-1α and IL-1α release at early occurrence. The target of the inhibitive LPS-induced-inflammatory action of hydrogen is chemokines in macrophages in the peritoneal cavity. This study provides direct experimental evidence for quickly controlling inflammation with the translational application of a hydrogen-assisted protocol.

Background: Lamotrigine may cause severe skin reactions. There is a known interaction between lamotrigine and valproic acid with an increase in lamotrigine levels and lamotrigine toxicity risk. Few cases of severe rash and systemic reactions in bipolar patients using lamotrigine and valproate have been reported. Here, we report a rare case of severe skin rash and lymphadenopathy associated with lamotrigine−valproic acid combination.Case presentation: An 18-year-old female adolescent with bipolar disorder type I was treated with lamotrigine, magnesium valproate, and perospirone for 12 days. After the last dose of lamotrigine, she abruptly developed generalized rash and swollen lymph nodes, which continued to progress over the next 3 days. This finally subsided after stopping valproate and with glucocorticoid treatment.Conclusion: This case suggests that lamotrigine−valproic acid combination may cause not only rash but also lymphadenopathy. Even though the aforementioned reactions appear after the last dose of lamotrigine, it cannot be ruled out as suspicious. We recommend caution during titration of lamotrigine and valproate and early withdrawal of both when signs of hypersensitivity appear.

Objective: This study aimed to explore the prevalence and associated factors of medication adherence among infertile women undergoing frozen-thawed embryo transfer (FET) cycle.Methods: A cross-sectional study was conducted with 556 infertile women undergoing FET cycle in total. The Self-efficacy for Appropriate Medication Use Scale (SEAMS), Herth Hope Index (HHI) scale, and Social Support Rating Scale (SSRS) were used to evaluate the patients. Data were described by univariate and multivariate analyses. Logistic regression method was performed to analyse the factors potentially associated with medication adherence.Results: The average score of Self-efficacy for Appropriate Medication Use Scale (SEAMS) was 30.38 ± 6.65, and 65.3% of participants showed non-adherence. Multiple regression analysis indicated that first-time FET cycle, treatment stage, methods of daily medication, social support and hope level were the main associated factors of the medication adherence among infertile women undergoing FET cycle (p < 0.001).Conclusion: This study revealed the medication adherence is at medium level among infertile women undergoing FET cycle, especially in patients with repeated FET cycles. The study also suggested that improving the hope level and social support of infertile women undergoing FET cycle may increase medication adherence.

Background: We previously found that modified 5-aminolevulinic acid photodynamic therapy (M-PDT) is painless and effective in cutaneous squamous cell carcinoma (cSCC) treatment, however, the regulatory mechanism of M-PDT in cSCC is still unclear.Objective: To clarify the effect and relevant regulatory mechanism of M-PDT in cSCC.Methods: The cSCC apoptosis was examined by flow cytometry, TUNEL staining and Cleaved-caspase-3 immunofluorescence, respectively. The autophagy-related characterization was detected by monodansylcadaverine (MDC) staining, transmission electron microscopy (TEM), GFP-LC3B autophagic vacuoles localization and mRFP-EGFP tandem fluorescence-tagged LC3B construct, respectively. The expression of autophagy-related proteins and Akt/mTOR signaling molecules were examined by Western blot. ROS generation was measured by DCFH-DA probe.Results: We found that M-PDT induced cSCC apoptosis in a dose-dependent manner, and this result was related to autophagic flux blockage. The phenomenon is confirmed by the results that M-PDT could induce autophagosomes accumulation and upregulate LC3-II and p62 expression. M-PDT elevated co-localization of RFP and GFP tandem-tagged LC3B puncta in cSCC cell, reflecting autophagic flux blockage, and this was confirmed by transmission electron microscopy. Furthermore, we noticed that M-PDT induced accumulated autophagosomes-dependent apoptosis via targeting ROS-mediated Akt/mTOR signaling. Suppression of Akt potentiated M-PDT-induced upregulation of LC3-II and p62 levels, whereas Akt activation and ROS inhibition rendered resistance to these events. In addition, we observed that lysosomal dysfunction was involved in M-PDT-triggered accumulated autophagosomes-dependent cSCC apoptosis.Conclusion: Our data demonstrates that M-PDT inhibits cSCC through blocking Akt/mTOR-mediated autophagic flux.

Menthol, a widely used natural, active compound, has recently been shown to have anticancer activity. Moreover, it has been found to have a promising future in the treatment of various solid tumors. Therefore, using literature from PubMed, EMBASE, Web of Science, Ovid, ScienceDirect, and China National Knowledge Infrastructure databases, the present study reviewed the anticancer activity of menthol and the underlying mechanism. Menthol has a good safety profile and exerts its anticancer activity via multiple pathways and targets. As a result, it has gained popularity for significantly inhibiting different types of cancer cells by various mechanisms such as induction of apoptosis, cell cycle arrest, disruption of tubulin polymerization, and inhibition of tumor angiogenesis. Owing to the excellent anticancer activity menthol has demonstrated, further research is warranted for developing it as a novel anticancer agent. However, there are limitations and gaps in the current research on menthol, and its antitumor mechanism has not been completely elucidated. It is expected that more basic experimental and clinical studies focusing on menthol and its derivatives will eventually help in its clinical application as a novel anticancer agent.

Exosomes are extracellular vesicles (EVs) containing various ingredients such as DNA, RNA, lipids and proteins, which play a significant role in intercellular communication. Numerous studies have demonstrated the important role of exosomes in bone regeneration through promoting the expression of osteogenic-related genes and proteins in mesenchymal stem cells. However, the low targeting ability and short circulating half-life of exosomes limited their clinical application. In order to solve those problems, different delivery systems and biological scaffolds have been developed. Hydrogel is a kind of absorbable biological scaffold composed of three-dimensional hydrophilic polymers. It not only has excellent biocompatibility and superior mechanical strength but can also provide a suitable nutrient environment for the growth of the endogenous cells. Thus, the combination between exosomes and hydrogels can improve the stability and maintain the biological activity of exosomes while achieving the sustained release of exosomes in the bone defect sites. As an important component of the extracellular matrix (ECM), hyaluronic acid (HA) plays a critical role in various physiological and pathological processes such as cell differentiation, proliferation, migration, inflammation, angiogenesis, tissue regeneration, wound healing and cancer. In recent years, hyaluronic acid-based hydrogels have been used as an exosome delivery system for bone regeneration and have displayed positive effects. This review mainly summarized the potential mechanism of HA and exosomes in promoting bone regeneration and the application prospects and challenges of hyaluronic acid-based hydrogels as exosome delivery devices in bone regeneration.

Objective: Based on the 4D label-free phosphoproteomic technique, we examined the differences in cognitive function and hippocampal phosphorylated protein expression in high-fat diet-induced obese mice after the intervention of semaglutide and empagliflozin, as well as the effects of both on protein activity and function in obese mice’s hippocampal tissues and the signaling pathways involved.Methods: Thirty-two C57BL/6JC male mice were assigned to two groups randomly: A control group (group C, 10% of energy is from fat, n = 8) and a high-fat diet group (group H, 60% of energy is from fat, n = 24). The high-fat diet-induced obese mice were screened after 12 weeks of feeding based on the criterion that the bodyweight of mice in fat rich diet group was greater than or equal to 20% of the average body weight of the mice in the blank control group. Group H separate into group H (n = 8), group Semaglutide (group S, n = 8), and group empagliflozin (group E, n = 8). For a total of 12 weeks, group S received 30 nmol/kg/d bodyweight of semaglutide intraperitoneally, group E received 10 mg/kg/d bodyweight of empagliflozin via gavage, and groups C and H received equal amounts of saline by intraperitoneal injection and gavage. At the end of treatment, the mice were appraised for cognitive function employing the Morris water maze (MWM), and serum fasting glucose, lipids, and inflammatory parameters were measured. The 4D label-free phosphoproteomics method was employed to screen the differential phosphoproteins and loci in hippocampal tissues of mice in different treatment groups, and bioinformatics was used to analyze the biological processes, signaling pathways, and related protein–protein interaction (PPI) network analysis of these differentially phosphorylated proteins.Results: In comparison to normal controls, The escape latency of obese mice induced by high-fat diet was prolonged, the percentage of swimming time in the target quadrant was reduced, and the number of times of crossing the platform was reduced, whereas semaglutide and empagliflozin treatment reduced escape latency, increase the percentage of swim time in the target quadrant and increase the frequency of passing through the platform area, although there is little difference in the effect of the two drugs. The phosphoproteomic results showed 20,493 unique phosphorylated peptides, representing 21,239 phosphorylation sites and 4,290 phosphorylated proteins. Further analysis revealed that the proteins corresponding to these differentially phosphorylated sites are jointly distributed in signaling pathways such as dopaminergic synapses and axon guidance, and are involved in biological processes such as neuronal projection development, synaptic plasticity, and axonogenesis. Notably, the key factors voltage-dependent L-type calcium channel subunit alpha-1D (CACNA1D), voltage-dependent P/Q-type calcium channel subunit alpha-1A (CACNA1A), and voltage-dependent N-type calcium channel subunit alpha-1B (CACNA1B) were all found to be involved in the dopaminergic synapse pathway, and their expression was upregulated by semaglutide and empagliflozin.Conclusion: We found for the first time that a high-fat diet decreased CACNA1D, CACNA1A, and CACNA1B protein serine phosphorylation, which may affect neuronal development, synaptic plasticity, and cognitive function in mice. Notably, semaglutide and empagliflozin increased the phosphorylation of these proteins.

Introduction:Cinnamomi ramulus (CR) is one of the most widely used traditional Chinese medicine (TCM) with anti-cancer effects. Analyzing transcriptomic responses of different human cell lines to TCM treatment is a promising approach to understand the unbiased mechanism of TCM.Methods: This study treated ten cancer cell lines with different CR concentrations, followed by mRNA sequencing. Differential expression (DE) analysis and gene set enrichment analysis (GSEA) were utilized to analyze transcriptomic data. Finally, the in silico screening results were verified by in vitro experiments.Results: Both DE and GSEA analysis suggested the Cell cycle pathway was the most perturbated pathway by CR across these cell lines. By analyzing the clinical significance and prognosis of G2/M related genes (PLK1, CDK1, CCNB1, and CCNB2) in various cancer tissues, we found that they were up-regulated in most cancer types, and their down-regulation showed better overall survival rates in cancer patients. Finally, in vitro experiments validation on A549, Hep G2, and HeLa cells suggested that CR can inhibit cell growth by suppressing the PLK1/CDK1/ Cyclin B axis.Discussion: This is the first study to apply transcriptomic analysis to investigate the cancer cell growth inhibition of CR on various human cancer cell lines. The core effect of CR on ten cancer cell lines is to induce G2/M arrest by inhibiting the PLK1/CDK1/Cyclin B axis.

Editorial on the Research Topic Targeting triple negative breast cancer by natural compounds Breast cancer is the most prevalent cancer in women globally and a major global health concern. One in every twelve women worldwide will be diagnosed with this malignancy at some point in their lifetime. Breast cancer is a heterogeneous disease with diverse clinical and molecular characteristics. Treatment decisions for advance-stage breast cancer are guided by the expression of three major therapeutic targets, viz. estrogen receptor-α (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2) (Shuaib et al., 2022). While ER-positive breast cancers are treated with ER antagonists such as tamoxifen and aromatase inhibitors, HER2-positive tumors are treated with HER2 inhibitors such as herceptin. Triple-negative breast cancers (TNBC) that do not express these receptors account for 15%–24% of all breast cancers. The prevalence of TNBC seems to be on the rise in developing nations (Thakur et al., 2018). TNBC treatment is difficult because of disease’s aggressiveness, poor clinical prognosis, and propensity for relapse. It has been extremely difficult to develop more effective treatments for TNBC because of the lack of actionable targets (Diana et al., 2020). Although chemotherapy with taxanes is still a standard-of-care treatment for advanced-stage TNBC, the response is typically short, linked to chemo-resistance, and has a dismal prognosis, with a median overall survival of 9–12 months. As such, strategies for early prevention and/or treatment are needed. Natural agents are known for their role in disease prevention and therapeutic potential, which substantiates the importance of these molecules in human life (Prajapati et al., 2022). Natural products are well known for their minimal side-effect and cost effectiveness. Natural compound-based standalone or combination therapy could be utilized for the better management of triple-negative breast cancer (Kushwaha et al., 2019). The present Research Topic, “Targeting Triple Negative Breast Cancer by Natural Compounds,” has assembled four articles, including original research articles contributed by researchers working in the area of triple-negative breast cancer and its treatment by natural compounds. In the present research article Wei et al. studied the effect of Cordycepin (an active phyto-constituent present in Cordyceps mushroom) on metastasis modulation in mouse TNBC model. The study highlighted that Cordycepin inhibits cellular growth and decreases migration and invasion potential in TNBC cells (BT549 and 4T1 cells) at micromolar concentrations. Mechanistically the study showed that Cordycepin treatment of TNBC cells reversed the expression profile of epithelial to mesenchymal transition markers E-cadherin (increased) and N-cadherin (decreased) in concentration dependent manner. Further, the study showed that Cordycepin treatment reduces the expression of EMT-related transcription factors (SNAIL, SLUG, TWIST1, ZEB1, and ZEB2) in TNBC cells significantly compared to non-treated cells. Furthermore, the authors utilize the 4T1 mouse allogenic tumor model to study the metastasis inhibition potential of Cordycepin in vivo. The immune system plays an important role in cancer metastasis and thus selection of the animal experimental model with the intact immune system provides decent translational pre-clinical data on the anti-metastatic potential of Cordycepin. Overall, the study highlights Cordycepin as a natural lead compound managing metastasis and invasion in mouse TNBC model. In the next research article Wang et al. studied the effect of Ailanthone (phytochemical isolated from Ailanthus altissima) on bone metastasis in TNBC and attempted to search for the underlying mechanism(s). Interaction between breast cancer cells (by secreting osteolytic factors) and bone microenvironment is largely involved in breast cancer metastasis. Interestingly, the study focused on the effect of Ailanthone on osteoclast differentiation which was induced by TNBC cells mediated cytokine secretion. The study reported that Ailanthone treatment can potentially inhibit osteoclasts production by inhibiting the osteolytic factors secretion in RANKL-dependent manner, thereby inhibiting the downstream molecular signaling pathways (PI3K/AKT, NF-κB, and MAPK) involved in TNBC cell metastasis. Overall, these findings reveal a natural compound mediated novel therapeutic strategy for managing breast cancer metastases. In the following article, Zhou et al. studied the effect of Polyphyllin III or dioscin (Paris polyphylla rhizome saponin) in vitro TNBC model. The study also explored the underlying anticancer mechanism(s) of this natural compound. Polyphyllin III has the potential to induce ferroptosis in TNBC cells at micromolar concentration. Studies were performed using the transmission electron microscopy-based morphological assessment of the mitochondrial membrane/cristae density ratio in TNBC cells. Further examination of hallmarks of ferroptosis, including accumulation of cellular lipid reactive oxygen species and decrease in GSH levels in Polyphyllin III, treated TNBC cells, substantiates these findings. The study proposed that increasing the expression of Acyl-CoA synthetase, a long chain family member 4 (ACSL4), by Polyphyllin III treatment might be a possible ferroptosis inducing mechanism in TNBC cells. In an important observation, the study pointed out that KLF4-mediated overexpression of xCT in TNBC cells acts as a protective response during ferroptosis in TNBC cells in response to therapeutic drugs and may result in enhancing drug resistance. The study proposed that this protective response could be diminished by using xCT inhibitors combined with Polyphyllin III to counter balance the protective response in TNBC cells during ferroptosis. The study also...

Editorial on the Research Topic Computational chemogenomics: In silico tools in pharmacological research and drug discovery Chemogenomics aims towards the systematic identification of small molecules that interact with protein targets and modulate their function (Quinlan et al., 2021). This research field is a crucial discipline in pharmacological research and drug discovery, as it allows the identification of novel bioactive compounds and therapeutic targets, as well as the elucidation of the mechanism of action of known drugs. In principle, the final goal of chemogenomics is identifying small molecules that can interact with any biological target. However, considering the number of existing small molecules and biological targets, this task is basically impossible to achieve experimentally. Developments in computer science-related disciplines, such as cheminformatics, molecular modelling, and artificial intelligence (AI) have made possible the in silico analysis of millions of potential interactions between small molecules and biological targets, prioritizing on a rational basis the experimental tests to be performed, reducing with that the time and costs associated with them. These computational approaches represent the toolbox of computational chemogenomics (Mestres, 2004; Jacoby et al., 2018). Methods from computational chemogenomics have become crucial in pharmacological research and drug discovery. Advances in computer science and AI, as well as the growing availability of experimental data, have opened the door to the development and refinement of new computational models. These models require thorough validation and dissemination within the scientific community. The present Research Topic brings together experts that discuss, in five original research papers, recent advances and applications of computational chemogenomics in pharmacological research and drug discovery. Hu et al. presents the identification of novel inhibitors of a mutant of Isocitrate dehydrogenase (IDH), IDH1-R132C, an oncogenic metabolic enzyme. The inhibitors were identified by means of docking-based virtual screening of a commercial synthetic library with 1.5 million compounds and cellular inhibition assays. The most promising compound (with the identifier T001-0657) showed high selectivity for cancer cells with the IDH1-R132C mutation and could be further developed as a tool compound to further investigate the biological role of the mutant IDH1-R132C. The authors explored the potential molecular mechanism of the newly identified compound and structural domain of IDH1-R132C with molecular dynamics simulations and free energy calculations. Ghosh et al. discuss the computational characterization of thirty aryl benzoyl hydrazide derivatives with experimental evaluations as inhibitors of the RNA-dependent RNA polymerase enzyme of the H5N1 influenza virus. The authors investigated the structural requirements for antiviral properties of the compounds with 2D-quantitative structure-activity relationship (2D-QSAR), 3D-QSAR, structure-based pharmacophore modeling, molecular docking, and molecular dynamics simulations. Specifically, molecular docking was employed to generate a structure-based pharmacophore mapping. Molecular dynamics was conducted to assess the dynamic stability of the docked ligands at the proposed binding site of the receptor. The binding interactions obtained from the molecular dynamics simulations had a good agreement with the findings of the 2D-QSAR, 3D-QSAR, and pharmacophore modeling. Cofas-Vargas et al. explore the binding of the fungal antibiotic aurovertin, which is an exogenous allosteric inhibitor of the enzyme FOF1-ATP synthase. This enzyme carries out several major regulatory functions in the cell membrane so that its malfunction has been associated with a growing number of human diseases. It is also a promising drug target to combat antibiotic resistance. To characterize the protein-ligand interactions, the authors employed mixed-solvent molecular dynamics, end-point binding free energy calculations, and free energy calculations. The findings of this work helped to provide insights for the structure-based design of novel allosteric drugs targeting FOF1-ATP synthase sites of exogenous inhibitors. Yang et al. identify dodoviscin A as an inhibitor of the extracellular signal-regulated protein kinase 2 (ERK2). Toward this goal, authors conducted docking-based virtual screening of a natural product collection prefiltered with estimated ADMETox properties. As part of the structure-based virtual screening, the authors compared the calculated binding energies of the screening collection with desirable pharmacokinetic characteristics with magnolipin, a known inhibitor of ERK2. The putative binding mode and stability of dodoviscin A with the binding site of ERK2 were explored with molecular dynamics simulations. Liu et al. introduce the free web-based database of pharmaco-omics for cancer precision medicine (DBPOM). The database provides the reversed and adverse effects of 19,406 small-molecules and drugs and 509 drug combinations on the patients of five cancer types based on the genomics and transcriptomics information of 28 kinds of cell lines and 3078 cancer samples. In their work, the authors also describe a methodology to predict the drug’s efficacy to reverse or enhance their cancer-associated gene expression change. Liu et al. anticipate that the webserver DBPOM will become a valuable platform for drug development, drug mechanism studies and the discovery of new therapies. In conclusion, the authors, the Research Topic Editors, and the journals of Frontiers in Pharmacology and Frontiers in Drug Discovery anticipate that this Research Topic contributes to illustrate the progress made in the development, validation, and successful applications of in silico approaches to pharmacological research and drug discovery. It is expected that the article collection will...

Liver fibrosis, a compensatory repair response to chronic liver injury, is caused by various pathogenic factors, and hepatic stellate cell (HSC) activation and phenotypic transformation are regarded as key events in its progression. Ferroptosis, a novel form of programmed cell death, is also closely related to different pathological processes, including those associated with liver diseases. Here, we investigated the effect of doxofylline (DOX), a xanthine derivative with potent anti-inflammatory activity, on liver fibrosis as well as the associated mechanism. Our results indicated that in mice with CCl₄-induced liver fibrosis, DOX attenuated hepatocellular injury and the levels of liver fibrosis indicators, inhibited the TGF-β/Smad signaling pathway, and significantly downregulated the expression of HSC activation markers, both in vitro and in vivo. Furthermore, inducing ferroptosis in activated HSCs was found to be critical for its anti-liver fibrosis effect. More importantly, ferroptosis inhibition using the specific inhibitor, deferoxamine (DFO) not only abolished DOX-induced ferroptosis, but also led to resistance to the anti-liver fibrosis effect of DOX in HSCs. In summary, our results showed an association between the protective effect of DOX against liver fibrosis and HSC ferroptosis. Thus, DOX may be a promising anti-hepatic fibrosis agent.

Background: Immunotherapy has been a key option for the treatment of many types of cancer. A positive response to immunotherapy is heavily dependent on tumor microenvironment (TME) interaction. However, in pancreatic adenocarcinoma (PAAD), the association between TME mode of action and immune cell infiltration and immunotherapy, clinical outcome remained unknown.Methods: We systematically evaluated 29 TME genes in PAAD signature. Molecular subtypes of distinct TME signatures in PAAD were characterized by consensus clustering. After this, we comprehensively analyzed their clinical features, prognosis, and immunotherapy/chemotherapy response using correlation analysis, Kaplan-Meier curves analysis, ssGSEA analysis. 12 programmed cell death (PCD) patterns were acquired from previous study. Differentially expressed genes (DEGs) were acquired based on differential analysis. Key genes affecting overall survival (OS) of PAAD were screened by COX regression analysis and used to develop a RiskScore evaluation model. Finally, we assessed the value of RiskScore in predicting prognosis and treatment response in PAAD.Results: We identified 3 patterns of TME-associated molecular subtypes (C1, C2, C3), and observed that clinicopathological characteristics, prognosis, pathway features and immune features, immunotherapy/chemosensitivity of patients were correlated with the TME related subtypes. C1 subtype was more sensitive to the four chemotherapeutic drugs. PCD patterns were more likely to occur at C2 or C3. At the same time, we also detected 6 key genes that could affect the prognosis of PAAD, and 5 genes expressions were closely associated to methylation level. Low-risk patients with high immunocompetence had favorable prognostic results and high immunotherapy benefit. Patients in the high-risk group were more sensitive to chemotherapeutic drugs. RiskScore related to TME was an independent prognostic factor for PAAD.Conclusion: Collectively, we identified a prognostic signature of TME in PAAD patients, which could help elucidate the specific mechanism of action of TME in tumors and help to explore more effective immunotherapy strategies.

Inhibition of epithelial ferroptosis in colonic tissues relieved clinical symptoms and improved endoscopic presentations in inflammatory bowel disease (IBD). Kumatakenin, the main ingredient of traditional Chinese medicinal cloves and Alpinia purpurata, is reported to possess therapeutic benefits. However, whether kumatakenin could inhibit ferroptosis and further alleviate colitis remains unclear. Here, we measured the effects of kumatakenin on ferroptosis of colonic epithelial cells from colitis mice. The colitis model was induced in mice by oral intake of 2.5% dextran sulfate sodium in drinking water. RNA sequencing was performed to investigate the mechanism underlying kumatakenin-mediated effects on colitis. The results showed that different doses of kumatakenin significantly alleviated symptoms and suppressed intestinal inflammation in the colitis mouse model. Kumatakenin supplementation decreased cellular iron levels and suppressed ferroptosis in epithelial cells from colitis mice. RNA sequencing, qPCR, and pharmacological inhibition assays showed that kumatakenin reduced cellular iron levels and suppressed ferroptosis in epithelial cells from colitis mice at least partially by upregulating expression of enolase (Eno-3). Furthermore, kumatakenin decreased iron levels in epithelial cells by modulating the Eno3-iron regulatory protein (IRP1) axis. Molecular docking results revealed that kumatakenin could bind Eno3 via hydrogen bonding with the amino acid residues Thr208, Val206, and Pro203. This work will provide a scientific basis for the clinical use of kumatakenin in the treatment of colitis.

Background: Long Mu Qing Xin Mixture (LMQXM) has shown potentially positive effects in alleviating attention deficit hyperactivity disorder (ADHD); however, the action mechanism is still not fully understood. This study aimed to predict the potential mechanism of LMQXM for ADHD using network pharmacology and molecular docking, which were then validated using animal experiments.Methods: Network pharmacology and molecular docking techniques were used to predict the core targets and potential pathways of LMQXMQ for ADHD, and KEGG pathway enrichment analysis revealed the potential significance of dopamine (DA) and cyclic adenosine monophosphate (cAMP) signaling pathways. To verify the hypothesis, we conducted an animal experiment. In the animal experiment, the young spontaneously hypertensive rats (SHRs) were randomly divided into the model group (SHR), the methylphenidate hydrochloride group (MPH, 4.22 mg/kg), and 3 LMQXM groups (low-dose (LD) group, 5.28 ml/kg; medium-dose (MD) group, 10.56 ml/kg; and high-dose (HD) group, 21.12 ml/kg), and administered by gavage for 4 weeks; the WKY rats were set as the control group. The open field test and Morris water maze test were used to evaluate the behavioral performance of rats, high performance liquid chromatography mass spectrometry (LC-MS) was used to analyze DA levels in the prefrontal cortex (PFC) and striatum of rats, ELISA was used to detect cAMP concentrations in the PFC and striatum, and immunohistochemistry and qPCR were used to analyze positive cell expression and mRNA expression for indicators related to DA and cAMP pathways.Results: The results showed that beta-sitosterol, stigmasterol, rhynchophylline, baicalein, and formononetin might be key components of LMQXM for ADHD and that these components bind well to the core targets, DA receptors (DRD1 and DRD2). Furthermore, LMQXM might act through the DA and cAMP signaling pathways. In the animal experiment, we found that MPH and LMQXM-MD controlled hyperactivity and improved learning and memory in SHRs, while LMQXM-HD only controlled hyperactivity in SHRs; meanwhile, MPH and LMQXM-MD upregulated DA and cAMP levels, mean optical density (MOD) of cAMP, and MOD and mRNA expression of DRD1 and PKA in the prefrontal cortex (PFC) and striatum of SHRs, while LMQXM-LD and LMQXM-HD upregulated DA and cAMP levels in the striatum, MOD of cAMP in the PFC, and mRNA expression of PKA in the PFC. However, we did not find a significant regulatory effect of LMQXM on DRD2.Conclusion: To sum up, this study demonstrated that LMQXM may increase DA levels mainly by activating the cAMP/PKA signaling pathway through DRD1, thereby controlling the behavioral disorders of SHRs, which is most effective at moderate doses, and this may be a key mechanism for LMQXM in the treatment of ADHD.

Cinobufacini injection (CI), an aqueous extract of Cutis Bufonis, is clinically used for cancer therapy in China, but its molecular mechanism for the treatment of osteosarcoma (OS) remains unclear. We constructed U2OS ectopic subcutaneous tumor model to verify the anti-OS effect of CI in vivo. Meanwhile, cell proliferation of U2OS and MG63 cells was monitored in vitro using the CCK-8 assay, colony formation and morphological changes. Cell cycle arrest and apoptosis were detected by flow cytometry and western blot, which showed that CI significantly inhibited proliferation, induced cell cycle arrest and apoptosis in human OS cells. The further RNA-seq results identified that the Hippo signaling pathway was involved in the anti-OS effect of CI. YAP/TAZ are two major components of the Hippo pathway in breast cancer and are positively regulated by prolyl isomerase PIN1, we assessed their role in OS using both clinicopathological sections and western blots. CI also inhibited PIN1 enzyme activity in a dose-dependent manner, which resulted in impaired PIN1, YAP, and TAZ expression in vitro and in vivo. Additionally, 15 potential compounds of CI were found to occupy the PIN1 kinase domain and inhibit its activity. In summary, CI plays an anti-OS role by down-regulating the PIN1-YAP/TAZ pathway.

Background: B cell lymphoma 6 (BCL6) is an important transcription factor of T follicular helper (Tfh) cells, which regulate the humoral response by supporting the maturation of germinal center B cells and plasma cells. The aim of this study is to investigate the expansion of T follicular helper cells and the effect of the BCL6 inhibitor FX1 in acute and chronic cardiac transplant rejection models.Methods: A mouse model of acute and chronic cardiac transplant rejection was established. Splenocytes were collected at different time points after transplantation for CXCR5⁺PD-1⁺ and CXCR5⁺BCL6⁺ Tfh cells detection by flow cytometry (FCM). Next, we treated the cardiac transplant with BCL6 inhibitor FX1 and the survival of grafts was recorded. The hematoxylin and eosin, Elastica van Gieson, and Masson staining of cardiac grafts was performed for the pathological analysis. Furthermore, the proportion and number of CD4⁺ T cells, effector CD4⁺ T cells (CD44⁺CD62L⁻), proliferating CD4⁺ T cells (Ki67⁺), and Tfh cells in the spleen were detected by FCM. The cells related to humoral response (plasma cells, germinal center B cells, IgG1⁺ B cells) and donor-specific antibody were also detected.Results: We found that the Tfh cells were significantly increased in the recipient mice on day 14 post transplantation. During the acute cardiac transplant rejection, even the BCL6 inhibitor FX1 did not prolong the survival or attenuate the immune response of cardiac graft, the expansion of Tfh cell expansion inhibit. During the chronic cardiac transplant rejection, FX1 prolonged survival of cardiac graft, and prevented occlusion and fibrosis of vascular in cardiac grafts. FX1 also decreased the proportion and number of splenic CD4⁺ T cells, effector CD4⁺ T cells, proliferating CD4⁺ T cells, and Tfh cells in mice with chronic rejection. Moreover, FX1 also inhibited the proportion and number of splenic plasma cells, germinal center B cells, IgG1⁺ B cells, and the donor-specific antibody in recipient mice.Conclusion: We found BCL6 inhibitor FX1 protects chronic cardiac transplant rejection and inhibits the expansion of Tfh cells and the humoral response, which suggest that BCL6 is a potential therapeutic target of the treatment for chronic cardiac transplant rejection.

Major depressive disorder is one of the most common neuropsychiatric diseases and it is a global public health problem that leads to disabilities. Currently, there is a growing need to explore novel strategy to cure major depressive disorder due to the limitation of available treatments. Rannasangpei (RSNP) is a traditional Tibetan medicine which acts as a therapeutic agent in various acute or chronic diseases, including cardiovascular diseases and neurodegenerative diseases. Crocin-1 a coloring ingredient of saffron which exhibited anti-oxidative and anti-inflammatory properties. Here, we aimed to illustrate whether RSNP and its active ingredient crocin-1 rescue depressive-like phenotypes in chronic unpredictable mild stress (CUMS) induced mouse model of depression. Our results showed that peripheral administration of RSNP or crocin-1 ameliorated the depressive-like behaviors in CUMS-treated mice, as demonstrated by the forced swimming test and tail suspension test. Furthermore, RSNP or crocin-1 treatment reduced oxidative stress in the peripheral blood and hippocampus of the CUMS-treated mice. Additionally, the dysregulated immune system response, as demonstrated by the increased expression of the pro-inflammatory factors (tumor necrosis factor-α and interleukin-6) and the decreased expression of the anti-inflammatory factor-interleukin-10 in the prefrontal cortex and/or hippocampus of CUMS-treated mice, were at least partially restored by RSNP or crocin-1 treatment. RSNP or crocin-1 also restored apoptotic protein marker (Bcl-2 and Bax) levels in the prefrontal cortex and hippocampus of the CUMS-treated mice. Moreover, our data indicated that RSNP or crocin-1 increased astrocyte number and brain-derived neurotrophic factor levels in the hippocampus of CUMS-treated mice after RSNP or crocin-1 administration. Taken together, our study for the first time revealed an anti-depressant effect of RSNP and its active ingredient crocin-1 in a mouse model of depression, with involvement of oxidative stress, inflammatory response and apoptotic pathway.

Diabetes, the ninth leading cause of death globally, is expected to affect 642 million people by 2040. With the advancement of an aging society, the number of patients with diabetes having multiple underlying diseases, such as hypertension, obesity, and chronic inflammation, is increasing. Thus, the concept of diabetic kidney disease (DKD) has been accepted worldwide, and comprehensive treatment of patients with diabetes is required. Receptor for advanced glycation endproducts (RAGE), a multiligand receptor, belonging to the immunoglobulin superfamily is extensively expressed throughout the body. Various types of ligands, including advanced glycation endproducts (AGEs), high mobility group box 1, S100/calgranulins, and nucleic acids, bind to RAGE, and then induces signal transduction to amplify the inflammatory response and promote migration, invasion, and proliferation of cells. Furthermore, the expression level of RAGE is upregulated in patients with diabetes, hypertension, obesity, and chronic inflammation, suggesting that activation of RAGE is a common denominator in the context of DKD. Considering that ligand–and RAGE–targeting compounds have been developed, RAGE and its ligands can be potent therapeutic targets for inhibiting the progression of DKD and its complications. Here, we aimed to review recent literature on various signaling pathways mediated by RAGE in the pathogenesis of diabetic complications. Our findings highlight the possibility of using RAGE–or ligand–targeted therapy for treating DKD and its complications.

Editorial on the Research Topic Advances in antimicrobial therapy and combating resistance The progression of microbial resistance and consequent failure to eradicate infections, clinically opposes one of the major human strides in medicine, which is the discovery of antimicrobials. The rapidly evolving microbial defense systems are paralleled by relentless efforts of scientists and clinicians to prolong the era of effective antimicrobials. Design of novel molecular entities, rational clinical use, optimization of pharmacokinetic exposure, and adherence to stewardship principles are examples of strategies to halt the development of microbial resistance. In this Research Topic we called upon researcher to publish their endeavors in this arena. The rediscovery of older effective antibiotics has recently gained a momentum probably due to the dwindling number of new antibiotics joining the therapeutic armamentarium and diminishing industry investment. Jia et al. retrospectively studied the salvage treatment of a group of Chinese children infected with carbapenem resistant Gram-negative bacteria with polymyxin B. The antibiotic (mostly used in combination with other regimens) demonstrated efficacy in 52.7% of the cases. However, this efficacy was accompanied with 27.3% acute kidney injury (AKI). The authors also highlighted that appropriate dose and therapy duration may improve outcomes. Furthermore, the loading dose did not improve efficacy and avoiding electrolyte imbalances may mitigate toxicity. In a prospective clinical pharmacokinetic study investigating polymyxin B optimal exposure, Zhewei Zu et al., 2022, reported that fAUC_ss,24h/MIC of ≥22.8 was associated with eradication of blood stream infections caused by carbapenem resistant Klebsiella pneumoniae (CRKP) with MIC≤ 1 mcg/mL. A Monte Carlo simulation revealed that a dose of 1.25 mg/kg every 12 h was efficacious against CRKP with such MIC. Polymyxin B—consistent with in vitro studies-demonstrated rapid concentration-dependent bactericidal effect achieving microbiological clearance around day 3 of therapy. The study also emphasized that the pharmacokinetics of the drug in patients with blood stream infections are quite distinctive from these in healthy subjects which could be related to the pathologic changes (Cl; 0.028 ± 0.007 L/kg/h and0.026 ± 0.004 L/kg/h—VD; 0.490 ± 0.142 L/kg and 0.204 ± 0.026 L/kg—T_1/2; 12.5 ± 3.11 vs 5.55 ± 0.942 h, respectively). Finally, the authors attributed the incidence of 55.6% AKI at day 7 of therapy, to the high daily dose and cumulative exposure. Furthermore, they observed a 70% incidence of neurotoxicity and an overlap between exposures responsible for efficacy and emergence of adverse events. A summary of studies discussing the need for dose adjustment in renally impaired patients, Nie et al., argued that polymyxin B is non-renally excreted as evidenced by urine recovery of 0.04%–0.86% of the dose in unchanged form. A case report of renal-impaired patients showed that the drug had comparable half-life of11.5 h similar to those with normal renal function. In a population PK study, there was a lack of correlation between polymyxin B and creatinine clearance. Additionally, in another PK study, the authors found comparable total polymyxin B exposures in both intact and impaired renal function patients who received administered comparable doses. Furthermore, another two studies illustrated no significant difference in incidence of adverse events, microbiological cure or 30-day mortality. On the other hand, several studies based on Monte Carlo simulations, demonstrated that creatinine clearance is a significant covariate in polymyxin B clearance, and the dose should be adjusted based on renal function. The authors of this opinion paper concluded that the evidence is insufficient to reach consensus recommendation. Continuing with polymyxins, Xu-ben Yu et al., 2022, studied the pharmacokinetics of polymyxin E (colistin sulfate, administered as active form) in critically ill patients. The authors found that the drug clearance is similar to polymyxin B and dependent on creatinine clearance. Of the patients infected with carbapenem resistant organisms, 60% achieved clinical cure with analogous to polymyxin B. The study showed that colistin sulfate achieved comparable clinical cure rate similar to polymyxin B despite of the use of significantly lower doses which could be attributed to lower pharmacokinetic target based on higher potency and fraction of unbound drug. The above studies provided insights into the clinical use of polymyxins with respect to optimizing dosing and minimizing untoward effects which becomes particularly beneficial when treating carbapenem resistant bacteria in critically ill patients with multi-drug resistant organisms. Tackling another Research Topic, the emergence of multi drug resistant Mycobacterium tuberculosis (MDR-TB), Azimi et al., conducted a systematic review and meta-analysis of the literature pertaining to the prevalence of TB resistance to linezolid (LNZ). The meta-analysis calculated prevalence (4.2%) of LNZ resistance among all MDR-TB isolate peaking in Spain (22%) and troughing (0.2%) in United States of America LNZ resistance to LND develops as a consequence of several genetic mutations leading to changes in the target binding site (23S rRNA). Combination of LNZ with other anti-tubercular medications can produce synergism, shorten treatment duration, and obliterate latent infections. Since irrational prolonged antibiotic administration could promote the emergence of resistance, He et al., investigated the risk factors associated with prolonged antibiotic use in pediatrics with bacterial meningitis. The study revealed that even with use of guidelines recommended regimens, the augmented renal clearance (ARC) was an independent risk factor...

Introduction: Clinical studies on the effectiveness of Baclofen in alcohol use disorder (AUD) yielded mixed results possibly because of differential effects of the enantiomers and sex-related differences. Here we examined the effect of the different Baclofen enantiomers on alcohol intake and on evoked dopamine release in the core of the nucleus accumbens (NAcc) in male and female Long Evans rats.Methods: Rats were trained to chronically self-administer 20% alcohol solution in daily binge drinking sessions and were treated with the different forms of Baclofen [RS(±), R(+) and S(−)]. The effects on the evoked dopamine release within the core of the nucleus accumbens were measured in brain slices from the same animals and the alcohol naïve animals using the fast scan cyclic voltammetry technique.Results: RS(±)-Baclofen reduced alcohol intake regardless of sex but more females were non-responders to the treatment. R(+)-Baclofen also reduced alcohol intake regardless of sex but females were less sensitive than males. S(−)-Baclofen did not have any effect on average but in some individuals, especially in the females, it did increase alcohol intake by at least 100%. There were no sex differences in Baclofen pharmacokinetic but a strong negative correlation was found in females with a paradoxical effect of increased alcohol intake with higher blood Baclofen concentration. Chronic alcohol intake reduced the sensitivity to the effect of Baclofen on evoked dopamine release and S(−)-Baclofen increased dopamine release specifically in females.Discussion: Our results demonstrate a sex-dependent effect of the different forms of Baclofen with no or negative effects (meaning an increase in alcohol self-administration) in subgroup of females that could be linked to a differential effect on dopamine release and should warrant future clinical studies on alcohol use disorder pharmacotherapy that will deeply analyze sex difference.

Objective: Our aim was to systematically investigate the efficacy of Tanreqing (TRQ) injection on in-hospital outcomes among inpatients with frequent or infrequent AECOPD.Methods: In this ongoing, nationwide multicenter registry designed to investigate clinical characteristics, management, and prognoses of Chinese patients admitted for AECOPD in real-world settings, we collected characteristics, comorbidities, in-hospital prognoses, and information on the COPD assessment test (CAT) questionnaire, PEACE questionnaire, and modified British Medical Research Council (mMRC) questionnaire from each enrolled patient. Frequent AECOPD was determined as being admitted to the hospital ≥1 time or visiting the emergency room (ER) ≥ 2 times due to AECOPD within a year. A propensity match method and univariable and multivariable regression models were performed to analyze the efficacy of TRQ on clinical outcomes for inpatients with frequent AECOPD.Results: A total of 4135 inpatients were involved in the analysis, including 2179 administered with TRQ and 1956 not administered with TRQ. Among those administered with TRQ, 493 had frequent AECOPD and 358 had infrequent AECOPD. After a propensity score match, a significant reduction of CAT score at discharge (TRQ median 12, IQR 8.0–16.0; non-TRQ median 13, IQR 9.0–18.0, p = 0.0297), a lower rate of ICU admission (TRQ 0.8% vs. non-TRQ 2.6%, p = 0.0191), and a shorter length of stay (LOS) (TRQ median 11, IQR 9.0–14.0; non-TRQ median 11, IQR 8.0–14.0, p = 0.004) were observed in the TRQ group, compared with the non-TRQ group among frequent AECOPD patients. In the subgroup analysis, for those with a PEACE score >7 on admission, TRQ contributed to a significantly lower CAT score at discharge (p = 0.0084) and a numerically lower ICU admission rate with a marginal statistical significance. Among those with phlegm-heat symptom complex on admission ≥2, a lower CAT score at discharge and a lower ICU admission were also observed in the TRQ group.Conclusion: TRQ injection had better efficacy in patients with frequent AECOPD in reducing ICU admission and alleviating respiratory symptoms, especially for those with higher severity on admission or more phlegm-heat symptoms.

Synthetic cannabinoids have exhibited unpredictable abuse liabilities, especially self-administration (SA) responses in normal rodent models, despite seemingly inducing addiction-like effects in humans. Thus, an efficient pre-clinical model must be developed to determine cannabinoid abuse potential in animals and describe the mechanism that may mediate cannabinoid sensitivity. The Cryab knockout (KO) mice were recently discovered to be potentially sensitive to the addictive effects of psychoactive drugs. Herein, we examined the responses of Cryab KO mice to JWH-018 using SA, conditioned place preference, and electroencephalography. Additionally, the effects of repeated JWH-018 exposure on endocannabinoid- and dopamine-related genes in various addiction-associated brain regions were examined, along with protein expressions involving neuroinflammation and synaptic plasticity. Cryab KO mice exhibited greater cannabinoid-induced SA responses and place preference, along with divergent gamma wave alterations, compared to wild-type (WT) mice, implying their higher sensitivity to cannabinoids. Endocannabinoid- or dopamine-related mRNA expressions and accumbal dopamine concentrations after repeated JWH-018 exposure were not significantly different between the WT and Cryab KO mice. Further analyses revealed that repeated JWH-018 administration led to possibly greater neuroinflammation in Cryab KO mice, which may arise from upregulated NF-κB, accompanied by higher expressions of synaptic plasticity markers, which might have contributed to the development of cannabinoid addiction-related behavior in Cryab KO mice. These findings signify that increased neuroinflammation via NF-κB may mediate the enhanced addiction-like responses of Cryab KO mice to cannabinoids. Altogether, Cryab KO mice may be a potential model for cannabinoid abuse susceptibility.

Non-alcoholic fatty liver disease (NAFLD) is common chronic metabolic liver disorder which is associated with fat accumulation in the liver. It causes a wide range of pathological effects such as insulin resistance, obesity, hypertension, diabetes, non-alcoholic steatohepatitis (NASH) and cirrhosis, cardiovascular diseases. The molecular mechanisms that cause the initiation and progression of NAFLD remain fully unclear. Inflammation is regarded as a significant mechanism which could result in cell death and tissue injury. Accumulation of leukocytes and hepatic inflammation are important contributors in NAFLD. Excessive inflammatory response can deteriorate the tissue injury in NAFLD. Thus, inhibition of inflammation improves NAFLD by reducing intrahepatic fat content, increasing β-oxidation of fatty acids, inducing hepato-protective autophagy, overexpressing peroxisome proliferator-activated receptor- γ (PPAR-γ), as well as attenuating hepatocyte apoptosis and increasing insulin sensitivity. Therefore, understanding the molecules and signaling pathways suggests us valuable information about NAFLD progression. This review aimed to evaluate the inflammation in NAFLD and the molecular mechanism on NAFLD.

Introduction: The P2X3 receptor (P2X3R), an ATP-gated non-selective cation channel of the P2X receptor family, is expressed in sensory neurons and involved in nociception. P2X3R inhibition was shown to reduce chronic and neuropathic pain. In a previous screening of 2000 approved drugs, natural products, and bioactive substances, various non-steroidal anti-inflammatory drugs (NSAIDs) were found to inhibit P2X3R-mediated currents.Methods: To investigate whether the inhibition of P2X receptors contributes to the analgesic effect of NSAIDs, we characterized the potency and selectivity of various NSAIDs at P2X3R and other P2XR subtypes using two-electrode voltage clamp electrophysiology.Results: We identified diclofenac as a hP2X3R and hP2X2/3R antagonist with micromolar potency (with IC₅₀ values of 138.2 and 76.7 µM, respectively). A weaker inhibition of hP2X1R, hP2X4R, and hP2X7R by diclofenac was determined. Flufenamic acid (FFA) inhibited hP2X3R, rP2X3R, and hP2X7R (IC₅₀ values of 221 µM, 264.1 µM, and ∼900 µM, respectively), calling into question its use as a non-selective ion channel blocker, when P2XR-mediated currents are under study. Inhibition of hP2X3R or hP2X2/3R by diclofenac could be overcome by prolonged ATP application or increasing concentrations of the agonist α,β-meATP, respectively, indicating competition of diclofenac and the agonists. Molecular dynamics simulation showed that diclofenac largely overlaps with ATP bound to the open state of the hP2X3R. Our results suggest a competitive antagonism through which diclofenac, by interacting with residues of the ATP-binding site, left flipper, and dorsal fin domains, inhibits the gating of P2X3R by conformational fixation of the left flipper and dorsal fin domains. In summary, we demonstrate the inhibition of the human P2X3 receptor by various NSAIDs. Diclofenac proved to be the most effective antagonist with a strong inhibition of hP2X3R and hP2X2/3R and a weaker inhibition of hP2X1R, hP2X4R, and hP2X7R.Discussion: Considering their involvement in nociception, inhibition of hP2X3R and hP2X2/3R by micromolar concentrations of diclofenac, which are rarely reached in the therapeutic range, may play a minor role in analgesia compared to the high-potency cyclooxygenase inhibition but may explain the known side effect of taste disturbances caused by diclofenac.

Background: Proton pump inhibitors (PPI) are generally considered to be one of the well-established prescription drug classes and are commonly used to treat most acid-related diseases. However, a growing body of literature showing an association between gastric and colorectal cancer risk and PPI use continues to raise concerns about the safety of PPI use. Therefore, we aimed to investigate the association between proton pump inhibitor use and risk of gastric and colorectal cancer.Methods: We collected relevant articles using PubMed, Embase, Web of Science and Cochrane library from 1 January 1990 to 21 March 2022. The pooled effect sizes were calculated based on the random-effects model. The study was registered with PROSPERO (CRD42022351332).Results: A total of 24 studies (n = 8,066,349) were included in the final analysis in the screening articles. Compared with non-PPI users, PPI users had a significantly higher risk of gastric cancer (RR = 1.82, 95% CI: 1.46–2.29), but not colorectal cancer (RR = 1.22, 95% CI: 0.95–1.55). Subgroup analysis showed that there was a significant positive correlation between the use of PPI and the risk of non-cardiac cancer (RR = 2.75, 95% CI: 2.09–3.62). There was a significant trend between the duration dependent effect of PPI use and the risk of gastric cancer (3 years RR = 2.32, 95% CI: 1.15–4.66), but not colorectal cancer (≤1 year RR = 1.00, 95% CI: 0.78–1.28; >1 year RR = 1.18, 95% CI: 0.91–1.54; ≥5 years RR = 1.06, 95% CI: 0.95–1.17).Conclusion: We found that PPI use increased gastric cancer risk, but not colorectal cancer risk. This result may be biased due to confounding factors. More prospective studies are needed to further validate and support our findings.Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022351332], identifier [CRD42022351332].

The voltage-gated sodium (Na_V) channel subtype Na_V1.7 plays a critical role in pain signaling, making it an important drug target. Here we studied the molecular interactions between μ-Conotoxin KIIIA (KIIIA) and the human Na_V1.7 channel (hNa_V1.7). We developed a structural model of hNa_V1.7 using Rosetta computational modeling and performed in silico docking of KIIIA using RosettaDock to predict residues forming specific pairwise contacts between KIIIA and hNa_V1.7. We experimentally validated these contacts using mutant cycle analysis. Comparison between our KIIIA-hNa_V1.7 model and the cryo-EM structure of KIIIA-hNa_V1.2 revealed key similarities and differences between Na_V channel subtypes with potential implications for the molecular mechanism of toxin block. The accuracy of our integrative approach, combining structural data with computational modeling, experimental validation, and molecular dynamics simulations, suggests that Rosetta structural predictions will be useful for rational design of novel biologics targeting specific Na_V channels.

Background: Oxycodone/acetaminophen has been reported for misuse for many times in China. To cope with that, Chinese national authorities jointly issued a policy, requiring that oxycodone/acetaminophen should be managed as a psychotropic medicine starting 1 September 2019. This paper aimed to evaluate the effect of this policy in medical institutions.Methods: We used interrupted time-series analysis to examine the immediate level and slope changes in the mean number of tablets prescribed, proportion of oxycodone/acetaminophen prescription exceeding 30 pills, days supplied per prescription and the proportion of days supplied exceeding 10 days with prescription data from 5 tertiary hospitals in Xi’an city between 1 January 2018 and 30 June 2021 (42 months). We divided the prescriptions into two groups, one for long-term drug users, and the other for short-term drug users.Results: In total, 12,491 prescriptions were included in the final study, with 8,941 and 3,550 prescriptions for the short-term and long-term drug users, respectively. Significant differences in the proportion of prescriptions issued by various departments, were observed between pre- and post-implementation of the policy for both short-term and long-term drug users (p < 0.001). For short-term drug users, the policy implementation was only associated with an immediate level decrease in proportion of prescriptions exceeding 30 tablets (−4.09%, p < 0.001). For long-term drug users, after the policy, the mean number of tablets prescribed and the mean proportion of prescriptions exceeding 30 tablets experienced a level decrease of 22.96 tablets (p < 0.001) and a level decrease of 41.13% (p < 0.001), respectively; the mean number of days supplied showed a significant level decrease (6.88 days per prescription) and slope increase (0.19 days per month), and the mean proportion of days supplied exceeding 10 days showed a significant level decrease (−10.51% per prescription) and a slope increase (0.27% per month).Conclusion: Implementation of stricter management for oxycodone/acetaminophen achieved its goal of reducing the risk of misuse in short-term drug users. For those long-term drug users, policy needed to be strengthened as the prescription exceeding 10 days was still at a high level after the intervention. Policies targeting patients with different drug demands are needed. Many other strategies can be implemented, including establishing specific guidelines/principles and conducting training programs.

Introduction: The human organic cation transporter 2 (OCT2) is involved in the transport of endogenous quaternary amines and positively charged drugs across the basolateral membrane of proximal tubular cells. In the absence of a structure, the progress in unraveling the molecular basis of OCT2 substrate specificity is hampered by the unique complexity of OCT2 binding pocket, which seemingly contains multiple allosteric binding sites for different substrates. Here, we used the thermal shift assay (TSA) to better understand the thermodynamics governing OCT2 binding to different ligands.Methods: Molecular modelling and in silico docking of different ligands revealed two distinct binding sites at OCT2 outer part of the cleft. The predicted interactions were assessed by cis-inhibition assay using [³H]1-methyl-4-phenylpyridinium ([³H]MPP⁺) as a model substrate, or by measuring the uptake of radiolabeled ligands in intact cells. Crude membranes from HEK293 cells harboring human OCT2 (OCT2-HEK293) were solubilized in n-Dodecyl-β-D-Maltopyranoside (DDM), incubated with the ligand, heated over a temperature gradient, and then pelleted to remove heat-induced aggregates. The OCT2 in the supernatant was detected by western blot.Results: Among the compounds tested, cis-inhibition and TSA assays showed partly overlapping results. Gentamicin and methotrexate (MTX) did not inhibit [³H]MPP⁺ uptake but significantly increased the thermal stabilization of OCT2. Conversely, amiloride completely inhibited [³H]MPP⁺ uptake but did not affect OCT2 thermal stabilization. [³H]MTX intracellular level was significantly higher in OCT2-HEK293 cells than in wild type cells. The magnitude of the thermal shift (ΔT_m) did not provide information on the binding. Ligands with similar affinity showed markedly different ΔT_m, indicating different enthalpic and entropic contributions for similar binding affinities. The ΔT_m positively correlated with ligand molecular weight/chemical complexity, which typically has high entropic costs, suggesting that large ΔT_m reflect a larger displacement of bound water molecules.Discussion: In conclusion, TSA might represent a viable approach to expand our knowledge on OCT2 binding descriptors.

Acori Tatarinowii Rhizoma (ATR, Shi Chang Pu in Chinese), a natural product with multiple targets in various diseases. This review provides the comprehensive summary of the chemical composition, pharmacological effects, pharmacokinetics parameters and toxicity of ATR. The results indicated that ATR possesses a wide spectrum of chemical composition, including volatile oil, terpenoids, organic acids, flavonoids, amino acids, lignin, carbohydrates and so on. Accumulating evidence from various studies has shown that ATR exerts a wide range of pharmacological properties, including protecting nerve cells, alleviating learning and memory impairment, anti-ischemic, anti-myocardial ischemia, anti-arrhythmic, anti-tumor, anti-bacterial, and anti-oxidant activities. Currently, ATR is widely used in the central nervous system, cardiovascular system, gastrointestinal digestive system, respiratory system in China, and for the treatment of epilepsy, depression, amnesia, consciousness, anxiety, insomnia, aphasia, tinnitus, cancers, dementia, stroke, skin diseases, and other complex diseases. Pharmacokinetic studies indicated that β-asarone, α-asarone, cis-methylisoeugenol, and asarylaldehyde, the active components of ATR, were absorbed slowly after oral administration of ATR. Moreover, toxicity studies have suggested that ATR has no carcinogenic, teratogenic and mutagenic toxicity. Nevertheless, long term or high-dose toxicity testing in animals to explore the acute and chronic toxicity of acori Tatarinowii Rhizoma is still lacking. In view of good pharmacological activities, ATR is expected to be a potential drug candidate for the treatment of Alzheimer’s disease, depression, or ulcerative colitis. However, further studies are needed to elucidate its chemical composition, pharmacological effects, molecular mechanisms and targets, improve its oral bioavailability, and clarify its potential toxicity.

Background: A systematic review and meta-analysis was performed to investigate the efficacy and safety of isoniazid (INH) prophylaxis to prevent tuberculosis (TB) infection in kidney transplant recipients (KTRs).Methods: Web of Science, SCOPUS, and PubMed were searched to identify relevant studies that compared the effects among patients who received INH prophylaxis after transplantation.Results: A total of 13 studies (involving 6,547 KTRs) were included in our analysis. We found that the risk of active TB infection (RR: 0.35, 95%CI 0.27–0.45, p < 0.01) for KTRs was lower in the INH treatment group than in those without prophylaxis. However, there was no significant difference between the two groups in mortality (RR: 0.93, 95%CI 0.67–1.28, p = 0.64), acute rejection (RR: 0.82, 95%CI 0.44–1.51, p = 0.52), and hepatotoxicity (RR: 1.25, 95%CI 0.94–1.65, p = 0.12).Conclusion: Isoniazid prophylaxis is a safe and effective for KTRs on reactivation of latent TB infection.

Editorial on the Research Topic Phytochemical-based nanoformulations to tackle drug resistance in cancer A significant problem in medical oncology is chemoresistance. Resistance developed during treatments is a major cause of fatalities in cancer patients. Conventional chemotherapeutic agents have also been revealed to cause damage to normal cells in addition to resistance, suggesting that treatment interruption may be necessary. Phytochemicals might protect healthy tissues via their antioxidant activities and can avoid the emergence of resistance. Their low solubility and short half-life, however, limit their use. Currently, phytonanotechnology is being developed to offer the advantages of increased solubility and availability of phytochemicals. Phytochemicals can reach cancer cells after being attached to nanovehicle surfaces or combined with substances that target tumors. Micelles, liposomes, and nanoparticles are examples of nanoformulations that have the potential to be highly loaded with phytochemicals, including weakly soluble and poorly stable phytochemicals. It will boost the phytochemical bioavailability to local tumors and lower the chances of unfavorable side effects in neighboring or distant organs. Singh et al. offer an insightful overview of clinical updates on tyrosine kinase inhibitors in HER2-positive breast cancer, with a focus on therapeutic advancements such as the use of nanotechnological interventions. To overcome drug resistance and limited efficacy in current treatment options, nanoformulations can be used in patients receiving HER2⁺ BC treatment. Anti-HER2 ligands can be used in various nanoformulations to target HER2 receptors. Here, the authors discuss targeted TKIs in patients with HER2⁺ BC, clinical studies of HER2⁺-targeted TKIs, mechanisms of resistance to HER2-directed therapies with new implications of TKIs in HER2⁺ MBC (metastatic breast cancer), and anti-HER2 ligands in various nanoformulations to target HER2 receptors. Another interesting advancement is the popularization of network pharmacology as an approach to screening new therapeutic targets and moieties. The research work shared by Ahmed et al. sheds light on the exploration of MARK4 as a target for the management of hepatocellular carcinoma and establishes the role of phytoconstituents in regulating the expression of proteins and interactions with altered genes. An intriguing study by Upadhyay et al. focuses on the therapeutic potentials of yeast-derived β-1,3-glucan particles as a safe and effective approach to ameliorating cervical cancer. A need to explore alternative therapeutic strategies to improve therapeutic outcomes and the quality of life of patients has been identified. Using instrumental techniques, the authors characterize the particles and establish an effective dosage. The authors also highlight the need for further research in order to develop a deeper understanding of the spectrum of actions and potentials for the clinical use of the agent studied. The review article by Sindhoor et al. investigates the role of alkaloid nanoformulations for lung cancer therapy as an approach to tackling commonly associated problems with the delivery of conventional therapeutic agents for disease management. The review explores the mechanism of different alkaloids with reference to the pathways targeted, discusses the drawbacks associated with conventional treatment strategies, and highlights the need for nanoformulations, moving forward. Kaur et al. analyze the efficacy of Frankincense oil-loaded nanoemulsion formulation of paclitaxel and erucin, focusing on drug resistance in breast cancer. The study explores the rationale for the selection of the constituents, signaling pathways targeted, and studies that involved evaluation in an animal model to elucidate the synergistic role of the active components in overcoming drug resistance. The study offers an in-depth overview of the formulation considerations and due modulations, effects on various biomarkers, and prospects for further research and development. Singh et al. explore the domain of Ehrlich-ascites carcinoma, proposing the development and use of nanoparticles loaded with erucin, a dietary isothiocyanate isolated from Eruca sativa. The authors discuss the antioxidant property of the phytoconstituent, established using a variety of in vitro assay techniques, and its effects on cellular proliferation. A novel approach to erucin delivery, through the designing of cubosomes, is elucidated, which shall pave the way for further advancements and applications in clinical settings. We sincerely hope you enjoy reading the articles in this Research Topic, which address a subject that is likely to become even more decisive in the coming years. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Keywords: chemoprevention, phytochemicals, nanotherapeutic, drug resistance, cell signaling Citation: Tuli HS, Kaur G and Yerer MB (2023) Editorial: Phytochemical-based nanoformulations to tackle drug resistance in cancer. Front. Pharmacol. 14:1165596. doi: 10.3389/fphar.2023.1165596 Received: 14 February 2023; Accepted: 06 March 2023; Published: 16 March 2023. Edited and reviewed by: Copyright © 2023 Tuli, Kaur and Yerer. This is an open-access article distributed under the...

Macroautophagy (hereafter referred to as autophagy), a highly conserved metabolic process, regulates cellular homeostasis by degrading dysfunctional cytosolic constituents and invading pathogens via the lysosomal system. In addition, autophagy selectively recycles specific organelles such as damaged mitochondria (via mitophagy), and lipid droplets (LDs; via lipophagy) or eliminates specialized intracellular pathogenic microorganisms such as hepatitis B virus (HBV) and coronaviruses (via virophagy). Selective autophagy, particularly mitophagy, plays a key role in the preservation of healthy liver physiology, and its dysfunction is connected to the pathogenesis of a wide variety of liver diseases. For example, lipophagy has emerged as a defensive mechanism against chronic liver diseases. There is a prominent role for mitophagy and lipophagy in hepatic pathologies including non-alcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC), and drug-induced liver injury. Moreover, these selective autophagy pathways including virophagy are being investigated in the context of viral hepatitis and, more recently, the coronavirus disease 2019 (COVID-19)-associated hepatic pathologies. The interplay between diverse types of selective autophagy and its impact on liver diseases is briefly addressed. Thus, modulating selective autophagy (e.g., mitophagy) would seem to be effective in improving liver diseases. Considering the prominence of selective autophagy in liver physiology, this review summarizes the current understanding of the molecular mechanisms and functions of selective autophagy (mainly mitophagy and lipophagy) in liver physiology and pathophysiology. This may help in finding therapeutic interventions targeting hepatic diseases via manipulation of selective autophagy.

Respiratory diseases remain a major health concern worldwide because they subject patients to considerable financial and psychosocial burdens and result in a high rate of morbidity and mortality. Although significant progress has been made in understanding the underlying pathologic mechanisms of severe respiratory diseases, most therapies are supportive, aiming to mitigate symptoms and slow down their progressive course but cannot improve lung function or reverse tissue remodeling. Mesenchymal stromal cells (MSCs) are at the forefront of the regenerative medicine field due to their unique biomedical potential in promoting immunomodulation, anti-inflammatory, anti-apoptotic and antimicrobial activities, and tissue repair in various experimental models. However, despite several years of preclinical research on MSCs, therapeutic outcomes have fallen far short in early-stage clinical trials for respiratory diseases. This limited efficacy has been associated with several factors, such as reduced MSC homing, survival, and infusion in the late course of lung disease. Accordingly, genetic engineering and preconditioning methods have emerged as functional enhancement strategies to potentiate the therapeutic actions of MSCs and thus achieve better clinical outcomes. This narrative review describes various strategies that have been investigated in the experimental setting to functionally potentiate the therapeutic properties of MSCs for respiratory diseases. These include changes in culture conditions, exposure of MSCs to inflammatory environments, pharmacological agents or other substances, and genetic manipulation for enhanced and sustained expression of genes of interest. Future directions and challenges in efficiently translating MSC research into clinical practice are discussed.

Background and objective: IBS-D is a common functional bowel disease with complex etiology and without biomarker. The pathological and physiological basis of IBS-D focuses on visceral hypersensitivity. However, its epigenetic mechanism remains elusive. Our study aimed to integrate the relationship between differentially expressed miRNAs, mRNAs and proteins in IBS-D patients in order to reveal epigenetic mechanism of visceral hypersensitivity from transcription and protein levels and provide the molecular basis for discovering biomarkers of IBS-D.Methods: The intestinal biopsies from IBS-D patients and healthy volunteers were obtained for high-throughput sequencing of miRNAs and mRNAs. The differential miRNAs were selected and verified by q-PCR experiment followed by target mRNA prediction. Biological functions were respectively analyzed for target mRNAs, differential mRNAs and the previously identified differential proteins in order to explore the characteristic involved visceral hypersensitivity. At last, interaction analysis of miRNAs, mRNAs and proteins was performed for the epigenetic regulation mechanism from transcription and protein levels.Results: Thirty-three miRNAs were found to be differentially expressed in IBS-D and five of them were further confirmed, including upregulated hsa-miR-641, hsa-miR-1843, hsa-let-7d-3p and downregulated hsa-miR-219a-5p, hsa-miR-19b-1-5p. In addition, 3,812 differential mRNAs were identified. Thirty intersecting molecules were found from the analysis on the target mRNAs of miRNAs and mRNAs. Fourteen intersecting molecules were obtained from the analysis on the target mRNAs and proteins, and thirty-six intersecting molecules were identified from analysis on the proteins and different mRNAs. According to the integrated analysis of miRNA-mRNA-protein, we noticed two new molecules COPS2 regulated by hsa-miR-19b-1-5p and MARCKS regulated by hsa-miR-641. Meanwhile some critical signaling pathways in IBS-D were found such as MAPK, GABAergic synapse, Glutamatergic synapse, and Adherens junction.Conclusion: The expressions of hsa-miR-641, hsa-miR-1843, hsa-let-7d-3p, hsa-miR-219a-5p, and hsa-miR-19b-1-5p in the intestinal tissues of IBS-D patients were significantly different. Moreover, they could regulate a variety of molecules and signaling pathways, which were involved in the multifaceted and multilevel mechanism of visceral hypersensitivity of IBS-D.

Polysubstance use (PSU), involves the consumption of more than one drug within a period of time and is prevalent among cocaine users. Ceftriaxone, a beta-lactam antibiotic, reliably attenuates reinstatement of cocaine seeking in pre-clinical models by restoring glutamate homeostasis following cocaine self-administration but fails to do so when rats consume both cocaine and alcohol (cocaine + alcohol PSU). We previously found that cocaine + alcohol PSU rats reinstate cocaine seeking similarly to cocaine-only rats, but demonstrate differences in reinstatement-induced c-Fos expression throughout the reward system, including a lack of change upon ceftriaxone treatment. Here, we used this model to determine if previous findings were caused by tolerance or sensitization to the pharmacological effects of cocaine. Male rats underwent intravenous cocaine self-administration immediately followed by 6 h of home cage access to water or unsweetened alcohol for 12 days. Rats subsequently underwent 10 daily instrumental extinction sessions, during which time they were treated with either vehicle or ceftriaxone. Rats then received a non-contingent cocaine injection and were perfused for later immunohistochemical analysis of c-Fos expression in the reward neurocircuitry. c-Fos expression in the prelimbic cortex correlated with total alcohol intake in PSU rats. There were no effects of either ceftriaxone or PSU on c-Fos expression in the infralimbic cortex, nucleus accumbens core and shell, basolateral amygdala, or ventral tegmental area. These results support the idea that PSU and ceftriaxone alter the neurobiology underlying drug-seeking behavior in the absence of pharmacological tolerance or sensitization to cocaine.

Entomoceuticals define a subset of pharmaceuticals derived from insects. The therapeutic effect of insect-derived drugs has been empirically validated by the direct use of various folk medicines originating from three sources in particular: the glandular secretions of insects (e.g., silk, honey, venom), the body parts of the insect or the whole used live or by various processing (e.g., cooked, toasted, ground), and active ingredients extracted from insects or insect-microbe symbiosis. Insects have been widely exploited in traditional Chinese medicine (TCM) relative to other ethnomedicines, especially in the prospect of insect species for medicinal uses. It is noticeable that most of these entomoceuticals are also exploited as health food for improving immune function. In addition, some edible insects are rich in animal protein and have high nutritional value, which are used in the food field, such as insect wine, health supplements and so on. In this review, we focused on 12 insect species that have been widely used in traditional Chinese herbal formulae but have remained less investigated for their biological properties in previous studies. We also combined the entomoceutical knowledge with recent advances in insect omics. This review specifies the underexplored medicinal insects from ethnomedicine and shows their specific medicinal and nutritional roles in traditional medicine.

A brain tumor is an uncontrolled cell proliferation, a mass of tissue composed of cells that grow and divide abnormally and appear to be uncontrollable by the processes that normally control normal cells. Approximately 25,690 primary malignant brain tumors are discovered each year, 70% of which originate in glial cells. It has been observed that the blood-brain barrier (BBB) limits the distribution of drugs into the tumour environment, which complicates the oncological therapy of malignant brain tumours. Numerous studies have found that nanocarriers have demonstrated significant therapeutic efficacy in brain diseases. This review, based on a non-systematic search of the existing literature, provides an update on the existing knowledge of the types of dendrimers, synthesis methods, and mechanisms of action in relation to brain tumours. It also discusses the use of dendrimers in the diagnosis and treatment of brain tumours and the future possibilities of dendrimers. Dendrimers are of particular interest in the diagnosis and treatment of brain tumours because they can transport biochemical agents across the BBB to the tumour and into the brain after systemic administration. Dendrimers are being used to develop novel therapeutics such as prolonged release of drugs, immunotherapy, and antineoplastic effects. The use of PAMAM, PPI, PLL and surface engineered dendrimers has proven revolutionary in the effective diagnosis and treatment of brain tumours.

N6-methyladenosine (m6A) methylation is the most prevalent mRNA modification in eukaryotes, and it is defined as the methylation of nitrogen atoms on the six adenine (A) bases of RNA in the presence of methyltransferases. Methyltransferase-like 3 (Mettl3), one of the components of m6A methyltransferase, plays a decisive catalytic role in m6A methylation. Recent studies have confirmed that m6A is associated with a wide spectrum of biological processes and it significantly affects disease progression and prognosis of patients with gynecologic tumors, in which the role of Mettl3 cannot be ignored. Mettl3 is involved in numerous pathophysiological functions, such as embryonic development, fat accumulation, and tumor progression. Moreover, Mettl3 may serve as a potential target for treating gynecologic malignancies, thus, it may benefit the patients and prolong survival. However, there is a need to further study the role and mechanism of Mettl3 in gynecologic malignancies. This paper reviews the recent progression on Mettl3 in gynecologic malignancies, hoping to provide a reference for further research.

Background: Respiratory diseases are common and frequent diseases. Due to the high pathogenicity and side effects of respiratory diseases, the discovery of new strategies for drug treatment is a hot area of research. Scutellaria baicalensis Georgi (SBG) has been used as a medicinal herb in China for over 2000 years. Baicalin (BA) is a flavonoid active ingredient extracted from SBG that BA has been found to exert various pharmacological effects against respiratory diseases. However, there is no comprehensive review of the mechanism of the effects of BA in treating respiratory diseases. This review aims to summarize the current pharmacokinetics of BA, baicalin-loaded nano-delivery system, and its molecular mechanisms and therapeutical effects for treating respiratory diseases.Method: This review reviewed databases such as PubMed, NCBI, and Web of Science from their inception to 13 December 2022, in which literature was related to “baicalin”, “Scutellaria baicalensis Georgi”, “COVID-19”, “acute lung injury”, “pulmonary arterial hypertension”, “asthma”, “chronic obstructive pulmonary disease”, “pulmonary fibrosis”, “lung cancer”, “pharmacokinetics”, “liposomes”, “nano-emulsions”, “micelles”, “phospholipid complexes”, “solid dispersions”, “inclusion complexes”, and other terms.Result: The pharmacokinetics of BA involves mainly gastrointestinal hydrolysis, the enteroglycoside cycle, multiple metabolic pathways, and excretion in bile and urine. Due to the poor bioavailability and solubility of BA, liposomes, nano-emulsions, micelles, phospholipid complexes, solid dispersions, and inclusion complexes of BA have been developed to improve its bioavailability, lung targeting, and solubility. BA exerts potent effects mainly by mediating upstream oxidative stress, inflammation, apoptosis, and immune response pathways. It regulates are the NF-κB, PI3K/AKT, TGF-β/Smad, Nrf2/HO-1, and ERK/GSK3β pathways.Conclusion: This review presents comprehensive information on BA about pharmacokinetics, baicalin-loaded nano-delivery system, and its therapeutic effects and potential pharmacological mechanisms in respiratory diseases. The available studies suggest that BA has excellent possible treatment of respiratory diseases and is worthy of further investigation and development.

N-methylsansalvamide (MSSV), a cyclic pentadepsipeptide, was obtained from a strain of Fusarium solani f. radicicola. The current study investigated the anti-colorectal cancer effect of MSSV. MSSV exhibited the inhibition of the proliferation in HCT116 cells via induction of G0/G1 cell cycle arrest by downregulating CDK 2, CDK6, cyclin D, and cyclin E, and upregulating p21WAF1 and p27KIP1. Decreased phosphorylation of AKT was observed in MSSV-treated cells. Moreover, MSSV treatment induced caspase-mediated apoptosis through elevating the level of cleaved caspase 3, cleaved PARP, cleaved caspase 9, and pro-apoptotic Bax. MSSV revealed the declined MMP-9 level mediated by reduction in the binding activity of AP-1, Sp-1, and NF-κB motifs, which led to the migration and invasion of HCT116 cells. In vitro metabolism with rat liver S9 fractions was performed to examine the effect of MSSV metabolites. The metabolic process enhanced the inhibitory effect of MSSV on the HCT116 cell proliferation via decline of cyclin D1 expression and AKT phosphorylation. Finally, oral administration of MSSV inhibited the tumor growth of HCT116 xenograft mice. These results suggest that MSSV is a potential anti-tumor agent in colorectal cancer treatment.

Background: Given the limitations of traditional pharmacology pedagogical method, diverse novel teaching methods have been widely explored. In this study, we performed a network meta-analysis (NMA) to evaluate the effects of different strategies in pharmacology education.Methods: Literature databases were searched from their inception to November 2022, and the studies were screened according to predefined inclusion and exclusion criteria to extract important information. Outcomes, including theoretical test scores, experimental test scores, subjective test scores, satisfaction scores, and the proportion of satisfaction, were analyzed using R software (version 3.6.1) and STATA (version 15). The NMA was conducted with a random-effects model under the Bayesian framework to calculate odds ratios (ORs) or mean differences (MDs) with associated 95% credible intervals (95% CIs). Surface under the cumulative ranking curve (SUCRA) probability values were calculated to rank the teaching methods examined.Results: A total of 150 studies involving 21,269 students were included. This NMA systematically evaluated 24 teaching strategies, such as problem-based learning (PBL), team-based learning (TBL), case-based learning (CBL) and flipped classrooms (FC), etc., The results of the NMA showed that, PBL combined with CBL was most likely to improve students’ theoretical and subjective test scores (SUCRA = 75.49 and 98.19%, respectively), TBL was most likely to improve the experimental test score (SUCRA = 92.38%) and the satisfaction score (SUCRA = 88.37%), while FC had the highest probability of being the best option for improving the proportion of satisfaction (SUCRA = 84.45%).Conclusion: The current evidence indicates that TBL, PBL combined with CBL, and FC might be optimal strategies for pharmacology education since they have a more beneficial effect on students.

Background: Pneumocystis jirovecii pneumonia (PJP) has been reported with ICIs but limited to case reports. The clinical features of PJP with ICIs remain mostly unknown. This study aims to investigate the association of PJP with ICIs and describe clinical features.Methods: Reports of PJP recorded in FAERS (January 2004–December 2022) were identified through the preferred term “Pneumocystis jirovecii pneumonia”. Demographic and clinical features were described, and disproportionality signals were assessed through the Reporting Odds Ratio (ROR) and Information Component (IC), using traditional chemotherapy and targeted therapy as comparators, and adjusting signals by excluding contaminant immunosuppressive drugs and pre-existing diseases. A systematic literature review was conducted to describe clinical features of published PJP reports with ICIs. Bradford Hill criteria was adopted for global assessment of the evidence.Results: We identified 677 reports of PJP associated with ICIs, in which 300 (44.3%) PJP cases with fatal outcome. Nivolumab (IC₀₂₅ 2.05), pembrolizumab (IC₀₂₅ 1.88), ipilimumab (IC₀₂₅ 1.43), atezolizumab (IC₀₂₅ 0.36), durvalumab (IC₀₂₅ 1.65), nivolumab plus ipilimumab (IC₀₂₅ 1.59) have significant signals compared to other drugs in FAERS database. After excluding pre-existing diseases and immunosuppressive agents which may increase susceptibility of PJP, the signals for PJP associated with nivolumab, pembrolizumab, durvalumab, nivolumab plus ipilimumab remained robust (IC₀₂₅ > 0). When compared to other anticancer regimens, although all ICIs showed a lower disproportionate signal for PJP than chemotherapy, nivolumab (IC025 0.33, p < 0.001), pembrolizumab (IC025 0.16, p < 0.001), both PD-1 inhibitors, presented a higher signal for PJP than targeted therapy. Male gender (IC₀₂₅ 0.26, p < 0.001) and age >65 years (IC₀₂₅ 0.38, p < 0.001) were predominant in PJP cases associated with across all ICIs. In literature, 15 PJP cases associated with ICIs were reported in 10 published case reports. 12 of 15 (80.0%) of cases received PD-1 inhibitors before PJP was diagnosed.Conclusion: By the combined analysis of post-marketing data from FAERS and published case reports, we identified ICIs may be associated with PJP, especially in males aged >65years. After accounting for confounders, PD-1 inhibitors emerged with a robust disproportionality signal when compared to PD-L1/CTLA-4 inhibitors as well as targeted therapy. Further research is warranted to validate our findings.

Nanoconstructs are made up of nanoparticles and ligands, which can deliver the loaded cargo at the desired site of action. Various nanoparticulate platforms have been utilized for the preparation of nanoconstructs, which may serve both diagnostic as well as therapeutic purposes. Nanoconstructs are mostly used to overcome the limitations of cancer therapies, such as toxicity, nonspecific distribution of the drug, and uncontrolled release rate. The strategies employed during the design of nanoconstructs help improve the efficiency and specificity of loaded theranostic agents and make them a successful approach for cancer therapy. Nanoconstructs are designed with a sole purpose of targeting the requisite site, overcoming the barriers which hinders its right placement for desired benefit. Therefore, instead of classifying modes for delivery of nanoconstructs as actively or passively targeted systems, they are suitably classified as autonomous and nonautonomous types. At large, nanoconstructs offer numerous benefits, however they suffer from multiple challenges, too. Hence, to overcome such challenges computational modelling methods and artificial intelligence/machine learning processes are being explored. The current review provides an overview on attributes and applications offered by nanoconstructs as theranostic agent in cancer.

Objective: In this study, alterations in oxidative stress-related indicators were evaluated in drug-naïve, first-episode schizophrenia (SCZ) patients, and the effectiveness of blood serum glucose, superoxide dismutase (SOD), bilirubin in the objective assistive diagnosis of schizophrenia was explored.Materials and methods: We recruited 148 drug-naïve, first-episode SCZ patients and 97 healthy controls (HCs). Blood biochemical indexes including blood glucose, SOD, bilirubin and homocysteine (HCY) in participants were measured, the indexes were compared between patients with SCZ and HCs. The assistive diagnostic model for SCZ was established on the basis of the differential indexes.Results: In SCZ patients, the blood serum levels of glucose, total (TBIL), indirect bilirubin (IBIL) and homocysteine (HCY) were significantly higher than those in HCs (p < 0.05), and the serum levels of SOD were significantly lower than those in HCs (p < 0.05). There was a negative correlation between SOD with the general symptom scores and total scores of PANSS. After risperidone treatment, the levels of uric acid (UA) and SOD tended to increase in patients with SCZ (p = 0.02, 0.19), and the serum levels of TBIL and HCY tended to decrease in patients with SCZ (p = 0.78, 0.16). The diagnostic model based on blood glucose, IBIL and SOD was internally cross-validated, and the accuracy was 77%, with an area under the curve (AUC) of 0.83.Conclusion: Our study demonstrated an oxidative state imbalance in drug-naïve, first-episode SCZ patients, which might be associated with the pathogenesis of the disease. Our study proved that glucose, IBIL and SOD may be potential biological markers of schizophrenia, and the model based on these markers can assist the early objective and accurate diagnosis of schizophrenia.

The patients with kidney diseases are increasing rapidly all over the world. With the rich abundance of mitochondria, kidney is an organ with a high consumption of energy. Hence, renal failure is highly correlated with the breakup of mitochondrial homeostasis. However, the potential drugs targeting mitochondrial dysfunction are still in mystery. The natural products have the superiorities to explore the potential drugs regulating energy metabolism. However, their roles in targeting mitochondrial dysfunction in kidney diseases have not been extensively reviewed. Herein, we reviewed a series of natural products targeting mitochondrial oxidative stress, mitochondrial biogenesis, mitophagy, and mitochondrial dynamics. We found lots of them with great medicinal values in kidney disease. Our review provides a wide prospect for seeking the effective drugs targeting kidney diseases.

Acute kidney injury (AKI) is a severe and frequent complication of sepsis that occurs in intensive care units with inflammation and rapid decline in renal function as the main pathological features. Systemic inflammation, microvascular dysfunction, and tubule injury are the main causes of sepsis-induced AKI (SI-AKI). The high prevalence and death rate from SI-AKI is a great challenge for clinical treatment worldwide. However, in addition to hemodialysis, there is no effective drug to improve renal tissue damage and alleviate the decline in kidney function. We conducted a network pharmacological analysis of Salvia miltiorrhiza (SM), a traditional Chinese medicine, which is widely used for the treatment of kidney disease. Then, we combined molecular docking and a dynamics simulation to screen for the active monomer dehydromiltirone (DHT) that has therapeutic effects on SI-AKI and investigated its potential mechanism of action through experimental validation. The components and targets of SM were obtained by searching the database, and 32 overlapping genes were screened by intersection analysis with AKI targets. GO and KEGG data showed that the functions of a common gene were closely related to oxidative stress, mitochondrial function, and apoptosis. The molecular docking results combined with molecular dynamics simulations provide evidence for a binding model between DHT and cyclooxygenase-2 (COX2), both of which are mainly driven by van der Waals interactions and a hydrophobic effect. In vivo, we found that mice pretreated with an intraperitoneal injection of DHT (20 mg/kg/d) for 3 days ameliorated CLP surgery-induced renal function loss and renal tissue damage and inhibited inflammatory mediators IL-6, IL-1β, TNF-α, and MCP-1 production. In vitro, the DHT pretreatment decreased LPS-induced expression of COX2, inhibited cell death and oxidative stress, alleviated mitochondrial dysfunction, and restrained apoptosis in HK-2 cells. Our research indicates that the renal preventive effect of DHT is related to maintaining mitochondrial dynamic balance, restoring mitochondrial oxidative phosphorylation, and inhibiting cell apoptosis. The findings in this study provide a theoretical basis and a novel method for the clinical therapy of SI-AKI.

Introduction: Antimicrobial resistance and the rapid spread of multiresistant bacteria represent one of the main public health problem in limited resources countries. This issue is significantly worsening since the COVID-19 pandemic due to the unreasonably increased antibiotics prescription to patients with confirmed SARS-CoV-2 infection. The aim of this study was to examine whether COVID-19 pandemic (2020, 2021) was associated with increased antibiotic consumption in inpatient and outpatient settings in the middle size urban region (Republic of Srpska/Bosnia and Herzegovina) in comparison to period before the pandemic (2019). Additionally, we aimed to determine antimicrobial resistance and the presence of multiresistant bacteria in the regional hospital (“Saint Apostol Luka” Hospital Doboj) in 2021.Methodology: The consumption of antibiotics in inpatient was calculated as Defined Daily Dose per one hundred of patient-days. The consumption of antibiotics in outpatient was calculated as Defined Daily Dose per thousand inhabitants per day. Resistance of bacteria to antibiotics is expressed as a rates and density for each observed antibiotic. The rate of resistance was calculated as a percentage in relation to the total number of isolates of individual bacteria. The density of resistance of isolated bacteria against a specific antibiotic was expressed as the number of resistant pathogens/1000 patient days.Results: Antibiotic consumption in hospital setting registered during 2019, 2020 and 2021 was as follows: carbapenems (meropenem: 0.28; 1.91; 2.33 DDD/100 patient-days, respectively), glycopeptides (vancomycin: 0.14; 1.09, 1.54 DDD/100 patient-days, respectively), cephalosporins (ceftriaxone: 6.69; 14.7; 14.0 DDD/100 patient-days, respectively) and polymyxins (colistin: 0.04; 0.25; 0.35 DDD/100 bed-days, respectively). Consumption of azithromycin increased drastically in 2020, and dropped significantly in 2021 (0.48; 5.61; 0.93 DDD/100 patient-days). In outpatient setting, an increase in the consumption of oral forms of azithromycin, levofloxacin and cefixime, as well as parenteral forms of amoxicillin-clavulanic acid, ciprofloxacin and ceftriaxone, was recorded. In 2021, antimicrobial resistance to reserve antibiotics in hospital setting was as follows: Acinetobacter baumanii to meropenem 66.0%, Klebsiella spp to cefotaxime 67.14%, Pseudomonas to meropenem 25.7%.Conclusion: Recent COVID-19 pandemic was associated with increased antibiotic consumption in inpatient and outpatient settings, with characteristic change of pattern of azithromycin consumption. Also, high levels of antimicrobial resistance to reserve antibiotics were registered in hospital setting with low prevalence of identified pathogen-directed antimicrobial prescription. Strategies toward combat antimicrobial resistance in the Doboj region are urgently needed.

Introduction:A. truncatum Bunge (Sapindaceae or formerly Aceraceae) is a tall deciduous tree native to China. Traditionally, the leaves of A. truncatum are decocted and used by Chinese Mongolians, Koreans, and Tibetans to treat skin itching, dry cracks, and other skin ailments, which indicates A. truncatum leaves may have a potential inhibitory effect on various skin inflammations.Methods: To examine the protective effect against skin inflammations of A. truncatum leaf extract (ATLE), an in vitro dermatitis model was established using sodium dodecyl sulfate (SLS)-induced HaCaT cells. The anti-inflammatory effect of ATLE was evaluated by analyzing cell viability, apoptosis, reactive oxygen species (ROS), interleukin 6 (IL-6), and prostaglandin E2 (PGE2) levels.Results: Orthogonal experiments showed that the pretreatment with ATLE can reduce the IL-6 levels, PGE2 levels, and apoptosis increased in SLS-stimulated HaCaT cells, which indicates that ATLE has positive efficacy for dermatitis. Furthermore, three flavonoid compounds kaempferol-3-O-α-L-rhamnoside, quercetin-3-O-α-L-rhamnopyranoside, kaempferol-3,7-di-O-α-L-rhamnoside, and 1,2,3,4,6-Penta-O-galloyl-β-D-glucopyranose (PGG) were isolated and identified. Among them, kaempferol-3,7-di-O-α-L-rhamnoside was isolated from this plant for the first time. These compounds have been proven to have an anti-inflammatory effect. They may contribute to the efficacy of A. truncatumin treating skin inflammation.Discussion: The results revealed that ATLE has the potential to be used as an additive in various skin care products to prevent skin inflammations and may be incorporated in formulations for topical application as a therapeutic approach against dermatitis.