ISSN / EISSN : 0024-3205 / 1879-0631
Published by: Elsevier BV (10.1016)
Total articles ≅ 33,715
Latest articles in this journal
Life Sciences, Volume 277; doi:10.1016/j.lfs.2021.119625
Iron oxide nanoparticles (IONPs) have been widely used in diagnosis, drug delivery, and therapy. However, the biodistribution and toxicity profile of IONPs remain debatable and incomplete, thus limiting their further use. We predict that coating iron oxide nanoparticles using curcumin (Cur-IONPs) will provide an advantage for their safety profile. In this study, an evaluation of the multidose effect (6 doses of 5 mg/kg Cur-IONPs to male BALB/c mice, on alternating days for two weeks) on the toxicity and biodistribution of Cur-IONPs was conducted. Serum biochemical analysis demonstrated no significant difference in enzyme levels in the liver and kidney between the Cur-IONP-treated and control groups. Blood glucose level measurements showed a nonsignificant change between groups. However, the serum iron concentration was found to initially increase significantly but then decreased at 10 days after the final injection. Histopathological examination of the liver, spleen, kidneys, and brain showed no abnormalities or differences between the Cur-IONP-treated and control groups. There were no abnormal changes in mouse body weight. The biodistribution results showed that Cur-IONPs accumulated mainly in the liver, spleen, and brain, while almost no Cur-IONPs were found in the kidney. The iron content in the liver remained high even 10 days after the final injection, while the iron content in the spleen and brain had returned to normal levels by this time point, indicating their complete clearance. These results are significant and promising for the further application of Cur-IONPs as theragnostic nanoparticles.
Life Sciences, Volume 277; doi:10.1016/j.lfs.2021.119627
Myeloid-derived suppressor cells (MDSCs) are heterogeneous and poorly mature cells of innate immunity that their population is increased substantially in cancer patients. MDSCs represent three subsets including CD14+ monocytic (M), CD15+ granulocytic (G) and Lin− early precursor (e) cells. MDSCs release a number of factors that direct several tumorigenic-related events including immune evasion, angiogenesis and metastasis. Assessment of MDSCs can provide valuable information from cancer immunity state, and it can be an indicator of tumor prognosis. The cells can be targeted in combination with current immunotherapeutic schedules, and the outcomes were promising. The focus of this review is to provide an overview of MDSCs, their involvement in tumor-related immunosuppression, and their impact on cancer immunotherapy. Then, strategies are proposed to boost the power of immune system against MDSCs.
Life Sciences, Volume 277; doi:10.1016/j.lfs.2021.119610
Cadmium (Cd) is a toxic heavy metal that causes severe toxic effects on different tissues including liver and kidney. Therefore the research for alternatives to reduce the damage caused by Cd has substantial importance. This study was performed to examine the possible modulatory effects of carvacrol (CRV) against Cd-induced hepatorenal toxicities and the possible mechanisms underlying these effects. In the present study, 35 male Wistar rats were randomly divided into 5 groups. The rats were treated with Cd (25 mg/kg) and treated with CRV (25 and 50 mg/kg body weight) for 7 consecutive days. CRV could modulate Cd-induced elevations of ALT, ALP, AST, urea, creatinine, MDA and enhance antioxidant enzymes' activities such as SOD, CAT, and GPx, and GSH's level. CRV also reversed the changes in levels of inflammatory biomarker and apoptotic genes that include NF-κB, Bcl-3, MAPK-14, iNOS, COX-2, MPO, PGE2, Bax, Bcl-2, P53, Caspase-9, Caspase-6 and Caspase-3 in both tissues. The levels of 8-OHdG in the Cd-induced liver and kidney tissues were modulated after CRV treatment. Furthermore, CRV treatment considerably lowered Cd, Na, Fe, and Zn content while increased K, Ca, Mg and Cu contents in both tissues as compared to the Cd-exposed rats. The results of the present study revealed that CRV supplementation could be a promising strategy to protect the liver and kidney tissues against Cd-induced oxidative damage, inflammation and apoptosis.
Life Sciences, Volume 277; doi:10.1016/j.lfs.2021.119593
Recent studies have reported a relationship between periodontal disease and hypertension, and previous evidence suggests that the sympathetic nervous system plays an important role in the control of bone metabolism. This study sought to evaluate the effect of the beta-2 adrenergic receptor (β2-AR) blocker butoxamine on experimental periodontitis in a rat model. Wistar-Kyoto and spontaneously hypertensive rats (n = 6 per group) were orally administered butoxamine 1 mg/kg/day and experimental periodontitis was induced by applying an orthodontic ligature wire. The rats were sacrificed after 4 weeks and the residual alveolar bone was measured using micro-computed tomography (micro-CT) imaging analysis software for histological analysis. Micro-CT imaging analysis showed a higher ratio of residual alveolar bone, BV/TV, and Tb.N in both Wistar-Kyoto and spontaneously hypertensive rats treated with butoxamine compared with the corresponding control rats. In histological analysis, compared with the Wistar-Kyoto and spontaneously hypertensive rat control groups, the corresponding butoxamine-treated groups showed a lower ratio of attachment level, lower values of osteoclast number and surface. β2-AR blockers maintained the alveolar bone mass and attachment level by suppressing osteoclast activity. Thus, β2-AR blockers may be effective in preventing periodontitis.
Life Sciences, Volume 277; doi:10.1016/j.lfs.2021.119584
Ferulic acid (FA) is a component found in plants that has free radical scavenging and liver-protective properties. Acute liver injury (ALI) is a serious complication of sepsis and is closely associated with changes in the levels of inflammatory factors. This study was taken to examine the role of FA in cecal ligation and perforation (CLP)-induced murine ALI and lipopolysaccharide (LPS)-induced cellular ALI models. An in vivo ALI model was established by performing CLP surgery on C57BL/6 mice. After the ALI model was established, mice were examined for liver injury, including HE staining to observe tissue sections, the percentage of liver/body weight and inflammatory factor levels. Myeloperoxidase (MPO), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were measured in liver or serum using commercial kits. An in vitro ALI model was established using LPS-stimulated RAW264.7 cells. Cell viability was measured by MTT method and the intracellular levels of IL-10, IL-1β, IL-6, IL-12 and TNF-α inflammatory factors were measured using kits. The expression of GSK-3β, NF-κB and CREB was measured by western blot or immunofluorescence. FA pretreatment significantly reduced liver/body weight ratio, decreased MPO, AST and ALT activity, alleviated the inflammatory responses and improved CLP-induced histopathological changes in liver. In addition, in vitro results showed that FA could dose-dependently increase the viability of RAW264.7 cells and decrease the levels of pro-inflammatory factors. In conclusion, our data suggest that FA can ameliorate ALI-induced inflammation via the GSK-3β/NF-κB/CREB pathway, suggesting that FA can be used to protect the liver against ALI.
Life Sciences, Volume 277; doi:10.1016/j.lfs.2021.119521
Hepatocellular carcinoma (HCC) is one of the most prevalent fatal malignancies in the Chinese population, due to high rates of hepatitis virus infection. Molecular targeted drugs such as sorafenib are the anti-tumor agents of choice for HCC treatment, but their results are generally unsatisfactory. In the present study the use of Pit-Oct-Unc transcription factor 1 (OCT1/POU2F1) as a potential therapeutic target for HCC was investigated, and a novel small molecular inhibitor of OCT1 (SMIO-1) was designed and its therapeutic efficacy against HCC was assessed. OCT1 expression was higher in HCC specimens than in corresponding non-tumor tissues, and higher OCT1 was associated with poorer prognosis in advanced HCC patients undergoing sorafenib treatment. For the first time, the novel SMIO-1 was investigated in conjunction with OCT1 via molecular docking. Interaction between SMIO-1 and OCT1 was confirmed via OCT1 point mutation. Treatment with SMIO-1 repressed OCT1 transcription factor activation by disrupting the interaction between OCT1 and its cofactors. It also repressed the proliferation and metastasis of HCC cells, and inhibited proliferation-related and metastasis-related genes downstream of OCT1. Therefore, SMIO-1 is a promising strategy for HCC treatment.
Life Sciences, Volume 277; doi:10.1016/j.lfs.2021.119497
Gastric cancer is a malignant tumor with a poor prognosis, and the interaction between tumor cells and cancer-associated fibroblasts (CAFs) further contributes to progression and treatment failure. Recent studies have revealed the potential value of melatonin in cancer therapy, but its role in gastric cancer and CAFs requires further exploration. CAFs were isolated using the tissue block method. Cell Counting Kit-8 and cell cycle assays were used to determine the cell proliferation ability, while the cell metastatic capacity was detected by a wound healing assay and Transwell migration/invasion assay. Furthermore, the expression levels of proteins involved were examined using quantitative real-time PCR (qRT-PCR) and western blotting. Melatonin not only inhibits cell proliferation and metastasis by reducing the production of reactive oxygen species (ROS) in gastric cancer cells but also inhibits CAFs-induced gastric cancer cell progression by reducing the production of metalloproteinase 2 (MMP2) and metalloproteinase 2 (MMP9) in CAFs. The direct and indirect inhibitory effects of melatonin on gastric cancer cells are involved in the NF-kB signaling pathways. This study provides insights into the role of melatonin in the tumor microenvironment, further deepens available knowledge regarding the mechanism of action of melatonin in gastric cancer and suggests the potential value of melatonin in gastric cancer treatment.
Life Sciences, Volume 277; doi:10.1016/j.lfs.2021.119505
We aimed to investigate the patterns and prognostic roles of tumor mutation burden and immune microenvironment in pancreatic cancer. The somatic mutation data, transcriptome profiles and clinical information were downloaded from the Cancer Genome Atlas database. Gene expression difference, Gene ontology, KEGG, gene set enrichment analyses and “CIBERSORT” algorithm were performed to screen differentially expressed genes, enriched functions or pathways and immune infiltrates differences between high and low TMB groups. Single sample gene set enrichment and unsupervised consensus clustering analyses were used for immunity grouping. Immune cell infiltration and expressions of HLA and checkpoint genes were investigated. Finally, a nomogram model integrating TMB and immune infiltration was established. A total of 608 differentially expressed genes were identified between high and low TMB groups, KEGG base excision repair and DNA replication pathways were enriched in high TMB group. Infiltration levels of M0 macrophages were higher and dendritic resting cells were lower in high TMB group. The risk model based on TMB-related immune genes, FAM19A2 and SLC22A17 was established and high risk scores indicated poorer prognosis. The expressions of HLA genes and immune checkpoint genes were higher in high immunity group. The nomogram showed remarkable ability for individualized survival estimation with good AUC values (0.794 and 0.800, respectively) for 3- and 5-year survival rates prediction. The characteristics of tumor mutation burden and immune infiltration in pancreatic cancer provide new insights into the tumor microenvironment, immunotherapies and a novel prognostic nomogram model for pancreatic cancer patients.
Life Sciences, Volume 277; doi:10.1016/j.lfs.2021.119504
The role of genetic and epigenetic factors in tumor initiation and progression is well documented. Histone deacetylases (HDACs), histone methyl transferases (HMTs), and DNA methyl transferases. (DNMTs) are the main proteins that are involved in regulating the chromatin conformation. Among these, histone deacetylases (HDAC) deacetylate the histone and induce gene repression thereby leading to cancer. In contrast, histone acetyl transferases (HATs) that include GCN5, p300/CBP, PCAF, Tip 60 acetylate the histones. HDAC inhibitors are potent drug molecules that can induce acetylation of histones at lysine residues and induce open chromatin conformation at tumor suppressor gene loci and thus resulting in tumor suppression. The key processes regulated by HDAC inhibitors include cell-cycle arrest, chemo-sensitization, apoptosis induction, upregulation of tumor suppressors. Even though FDA approved drugs are confined mainly to haematological malignancies, the research on HDAC inhibitors in glioblastoma multiforme and triple negative breast cancer (TNBC) are providing positive results. Thus, several combinations of HDAC inhibitors along with DNA methyl transferase inhibitors and histone methyl transferase inhibitors are in clinical trials. This review focuses on how HDAC inhibitors regulate the expression of coding and non-coding genes with specific emphasis on their anti-cancer potential.
Life Sciences, Volume 277; doi:10.1016/j.lfs.2021.119532
The rise in consumption of dietary supplements containing the trace amines p-tyramine, p-synephrine and p-octopamine has been associated with cardiovascular side effects. Since renal blood flow plays an important role in blood pressure regulation, this study investigated the mechanisms of action of these trace amines on isolated porcine renal arteries. Contractile responses to amines were investigated in noradrenaline-depleted rings of porcine main renal arteries in the absence and presence of the α1-adrenoceptor antagonist, prazosin (1 μM), β-adrenoceptor antagonist, propranolol (1 μM), or the trace amine-associated receptor (TAAR-1) antagonist, EPPTB (RO-5212773; 100 nM or 100 μM). All three amines induced constrictor responses of similar magnitude and potency. However, their mechanisms of action on the renal artery appeared to differ. Depleting endogenous noradrenaline stores significantly reduced maximum responses to tyramine and synephrine, but less for octopamine. When direct responses were examined after depleting tissues of noradrenaline, responses to synephrine and octopamine, but not tyramine, were reduced in the presence of prazosin(1 μM) and potentiated in the presence of propranolol (1 μM) or L-NNA (100 μM). Generally, vasoconstrictor responses remaining after noradrenaline-depletion and α-adrenoceptor blockade were not affected by the TAAR-1 antagonist EPPTB (0.1–100 μM), although responses to low concentration of synephrine and octopamine were enhanced by this antagonist. Tyramine appears to mediate constriction of the renal artery mainly via an indirect sympathomimetic mechanism, whereas synephrine and octopamine exert additional direct effects on α1-adrenoceptors and possibly contractile TAAR (not TAAR-1). The two amines also activate simultaneous inhibitory responses via β-adrenoceptors, TAAR-1 and nitric oxide release.