Frontiers in Pharmacology

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ISSN / EISSN : 1663-9812 / 1663-9812
Published by: Frontiers Media SA (10.3389)
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Lindsey Shapiro, Andrew Escayg,
Published: 26 January 2022
Frontiers in Pharmacology, Volume 13; https://doi.org/10.3389/fphar.2022.815950

Abstract:
Voltage-gated sodium channel genes are an important family of human epilepsy genes. De novo missense mutations in SCN8A (encoding Nav1.6) are associated with a spectrum of clinical presentation, including multiple seizure types, movement disorders, intellectual disability, and behavioral abnormalities such as autism. Patients with SCN8A mutations are often treated with multiple antiepileptic drugs, the most common being sodium channel blockers. Cannabidiol (CBD) has been included as a component of treatment regimens for some SCN8A patients; however, to date, there are no clinical trials that have evaluated the therapeutic potential of CBD in patients with SCN8A mutations. In the current manuscript, we demonstrated a dose-dependent increase in seizure resistance following CBD treatment in mice expressing the human SCN8A mutation R1620L (RL/+). We also found that CBD treatment improved social behavior and reduced hyperactivity in the RL/+ mutants. Our findings suggest that CBD may be beneficial in patients with SCN8A-associated disease.
Lipeng Tang, Tong Li, Bowen Zhang, Zihao Zhang, Xiaoyi Sun, Ying Zhu, Bing Feng, Zuqing Su, Laijun Yang, Hongxia Li, et al.
Published: 26 January 2022
Frontiers in Pharmacology, Volume 13; https://doi.org/10.3389/fphar.2022.817526

Abstract:
Psoriasis is a chronic and inflammatory skin disorder characterized by inflammation and epidermal hyperplasia. Punicalagin (PUN) is a main active ingredient of pomegranate (Punica granatum L.) peel with multiple biological activities, such as antibacterial, antioxidant and anti-tumor effects. However, the potential effect of PUN on psoriasis remains unknown. In this study, we want to investigate the pharmacological effect of PUN on psoriasis by using imiquimod (IMQ)-induced psoriatic mice model in vivo and tumor necrosis factor a (TNF-α) and interleukin-17A (IL-17A)-stimulated HaCaT cells in vitro. Our results showed that PUN can effectively alleviate the severity of psoriasis-like symptoms. Mechanistically, PUN potently suppresses the aberrant upregulation of interleukin-1β (IL-1β) and subsequent IL-1β-mediated inflammatory cascade in keratinocytes by inhibiting the nuclear factor kappa B (NF-κB) activation and cleaved caspase-1 expression in vitro and in vivo. Taken together, our findings indicate that PUN can relieve psoriasis by repressing NF-κB-mediated IL-1β transcription and caspase-1-regulated IL-1β secretion, which provide evidence that PUN might represent a novel and promising candidate for the treatment of psoriasis.
Hang Zhou, Yi Yang, Linwen Deng, Yongqing Yao, Xin Liao
Published: 26 January 2022
Frontiers in Pharmacology, Volume 12; https://doi.org/10.3389/fphar.2021.775245

Abstract:
Background: Kidney-tonifying herbs (KTHs) are widely used to treat unexplained recurrent spontaneous abortion (URSA) based on the theory of traditional Chinese medicine (TCM). However, there is still a lack of systematic evaluation and mechanistic explanation for these treatments.Objective: The purpose of this study was to assess the clinical efficacy, and to investigate the potential mechanisms, of KTH based on TCM for the treatment of URSA.Methods: A systematic literature search was conducted within PubMed, Embase, China Biomedical Literature database, Web of Science (WOS), China National Knowledge Infrastructure (CNKI) database, and the Wanfang database to find articles reporting on the Chinese herbal formula based around KTH for treating URSA, which were published between January 2010 and June 2021. A full bibliometric analysis was carried out; in addition, randomized controlled trial (RCT) articles were selected for systematic evaluation and meta-analysis. The drugs with the highest frequency of KTHs were screened for meta-analysis. Finally, network analysis and molecular docking were used to study the key components and potential pathway of KTHs in the treatment of URSA.Results: The meta-analysis included nine RCTs involving 1,054 subjects. Compared with the control groups, the clinical efficacy of TCM-based KTHs in the treatment of URSA patients significantly improved outcomes. Additionally, a component target pathway network was identified, which included 32 potential blood activating components and 113 main targets. Japonine, sopranol, lysine, and matrine were considered the most important bioactive molecules for KTHs. The key potential therapeutic pathway for URSA was a tumor-related signaling pathway. The target genes for URSA regulated by KTHs were highly similar to tumor biological processes such as the regulation of apoptotic signaling pathways, inflammatory responses, angiogenesis, and epithelial metabolic transition.Conclusion: KTH has great potential for treating URSA. Because the maintenance of pregnancy has a high similarity with tumor invasion, the research relating to tumor mechanisms should also be followed up as it may lead to new ideas and breakthroughs for research into URSA. At the same time, embryonic and decidual cells share a high degree of cellular heterogeneity and spatial structural complexity with tumor cells, and a single cell combined with spatial omics may be the best future approach for validating KTH mechanisms.
Jing Meng, Siyan Qiu, Ling Zhang, Min You, Haizhu Xing, Jing Zhu
Published: 26 January 2022
Frontiers in Pharmacology, Volume 12; https://doi.org/10.3389/fphar.2021.774795

Abstract:
Chemotherapy induced peripheral neuropathy (CIPN) is a severe neurodegenerative disorder caused by chemotherapy drugs. Berberine is a natural monomer compound of Coptis chinensis, which has anti-tumor effect and can improve neuropathy through anti-inflammatory mechanisms. Transient receptor potential vanilloid (TRPV1) can sense noxious thermal and chemical stimuli, which is an important target for the study of pathological pain. In both vivo and in vitro CIPN models, we found that berberine alleviated peripheral neuropathy associated with dorsal root ganglia inflammation induced by cisplatin. We confirmed that berberine mediated the neuroinflammatory reaction induced by cisplatin by inhibiting the overexpression of TRPV1 and NF-κB and activating the JNK/p38 MAPK pathways in early injury, which inhibited the expression of p-JNK and mediated the expression of p38 MAPK/ERK in late injury in vivo. Moreover, genetic deletion of TRPV1 significantly reduced the protective effects of berberine on mechanical and heat hyperalgesia in mice. In TRPV1 knockout mice, the expression of NF-κB increased in late stage, and berberine inhibited the overexpression of NF-κB and p-ERK in late injury. Our results support berberine can reverse neuropathic inflammatory pain response induced by cisplatin, TRPV1 may be involved in this process.
Laura Szalai, András Sziráki, László Sándor Erdélyi, Kinga Bernadett Kovács, Miklós Tóth, András Dávid Tóth, Gábor Turu, Dominique Bonnet, Bernard Mouillac, László Hunyady, et al.
Published: 25 January 2022
Frontiers in Pharmacology, Volume 13; https://doi.org/10.3389/fphar.2022.811836

Abstract:
The urine concentrating function of the kidney is essential to maintain the water homeostasis of the human body. It is mainly regulated by the arginine-vasopressin (AVP), which targets the type 2 vasopressin receptor (V2R) in the kidney. The inability of V2R to respond to AVP stimulation leads to decreased urine concentration and congenital nephrogenic diabetes insipidus (NDI). NDI is characterized by polyuria, polydipsia, and hyposthenuria. In this study, we identified a point mutation (S127F) in the AVPR2 gene of an NDI patient, and we characterized the impaired function of the V2R mutant in HEK293 cells. Based on our data, the S127F-V2R mutant is almost exclusively located intracellularly in the endoplasmic reticulum (ER), and very few receptors were detected at the cell surface, where the receptor can bind to AVP. The overexpressed S127F-V2R mutant receptor has negligible cAMP generation capability compared to the wild-type receptor in response to AVP stimulation. Since certain misfolded mutant proteins, that are retained in the ER, can be rescued by pharmacological chaperones, we examined the potential rescue effects of two pharmacochaperones on the S127F-V2R. We found that pretreatment with both tolvaptan (an established V2R inverse agonist) and MCF14 compound (a cell-permeable high-affinity agonist for the V2R) were capable of partially restoring the cAMP generating function of the receptor in response to vasopressin stimulation. According to our data, both cell permeant agonists and antagonists can function as pharmacochaperones, and serve as the starting compounds to develop medicines for patients carrying the S127F mutation.
, Vera Francisco, Bruno Neves, Joana Liberal, Carlos Cavaleiro, Jorge Canhoto, Lígia Salgueiro, Maria Teresa Cruz
Published: 25 January 2022
Frontiers in Pharmacology, Volume 12; https://doi.org/10.3389/fphar.2021.695911

Abstract:
Lavandulaviridis L´Hér. is an endemic Iberian species with a high essential oil yield and a pleasant lemon scent. Despite these interesting features, this species remains unrecognized and poorly explored by the food and pharmaceutical industries. Nevertheless, it has been valued in traditional medicine being used against flu, circulatory problems and to relieve headaches. Since these disorders trigger inflammatory responses, it is relevant to determine the anti-inflammatory potential of L. viridis L´Hér. essential oil in an attempt to validate its traditional use and concomitantly to increment its industrial exploitation. Therefore, in the present study the chemical composition of this volatile extract as well as the effect on ROS production, inflammatory response and proteasome activity on LPS-stimulated macrophages were disclosed. Also, its safety profile on keratinocytes, hepatocytes and alveolar epithelial cells was depicted, envisioning a future human administration. The essential oil was characterized by high quantities of 1,8-cineole, camphor and α-pinene. From a pharmacological point of view, the essential oil showed a potent antioxidant effect and inhibited nitric oxide production through down-modulation of nuclear factor kappa B-dependent Nos2 transcription and consequently iNOS protein expression as well as a decrease in proteasomal activity. The anti-inflammatory activity was also evidenced by a strong inhibition of LPS-induced Il1b and Il6 transcriptions and downregulation of COX-2 levels. Overall, bioactive safe concentrations of L. viridis L´Hér. essential oil were disclosed, thus corroborating the traditional usage of this species and paving the way for the development of plant-based therapies.
Jin Zhang, Xiaobing Wang, Rick E. Bernardi, Jun Ju, , Zhiting Gong
Published: 25 January 2022
Frontiers in Pharmacology, Volume 13; https://doi.org/10.3389/fphar.2022.821975

Abstract:
Background: Parkinson’s disease (PD) is commonly accompanied with anxiety disorder, however, the mechanisms underlying PD-mediated anxiety remain elusive. The lateral habenula (LHb) is a critical brain region that influences the activity of the monoaminergic system in the midbrain and consequently modulates anxiety. Most neurons in the LHb express AMPA receptors (AMPARs). The PD model for the pharmacological intervention of AMPA receptors was established by the unilateral lesion of the substantia nigra pars compacta (SNc) with 6-hydroxydopamine (6-OHDA).Methods: The AMPAR agonist (S)-AMPA and antagonist NBQX were microinjected into the LHb, respectively, to examine whether anxiety-like behaviors were altered in sham-operated and SNc-lesion rats, measured with the paradigms of the open-field test (OPT) and elevated plus maze (EPM). Furthermore, dopamine (DA) and 5-hydroxytryptamine (5-HT) levels in the basolateral amygdala (BLA) were measured using in vivo microdialysis immediately following the injections of (S)-AMPA and NBQX into the LHb.Results: Activation of LHb AMPA receptors by (S)-AMPA produced anxiolytic-like behaviors and enhanced the extracellular DA and 5-HT in the BLA. Conversely, NBQX induced anxiety-like effects and suppressed the extracellular DA and 5-HT in the BLA. In addition, the minimal doses inducing the effects in the SNc-lesion rats were lower than those in sham-operated rats.Conclusion: These findings suggest that the effects of AMPA receptors in the LHb on anxiety-like behaviors likely involve the extracellular levels of DA and 5-HT in the BLA. The present results may improve our understanding of the neuropathology and/or treatment of PD.
Hong-Li Guo, Jia-Yi Long, Ya-Hui Hu, Yun Liu, Xin He, Ling Li, Ying Xia, Xuan-Sheng Ding, Feng Chen, Jing Xu, et al.
Published: 25 January 2022
Frontiers in Pharmacology, Volume 12; https://doi.org/10.3389/fphar.2021.724145

Abstract:
Standard-dose caffeine citrate has been routinely prescribed for apnea of prematurity (AOP) management; however, some preterm infants respond well to the therapy while others do not. The AOP phenotype has been attributed solely to the immature control of the respiratory system consequent to preterm birth, but there are also important genetic influences. Based on our previous report, we tested the hypothesis that the human circadian locomotor output cycles kaput (CLOCK) gene polymorphisms play a role in the response to caffeine citrate therapy in preterm infants. We also studied the interactions of the circadian clock with aryl hydrocarbon receptor (AHR) signaling pathways in preterm babies who received caffeine citrate. This single-center study collected data from 112 preterm infants (<35 weeks gestational age) between July 2017 and July 2018, including apnea-free (n = 48) and apneic (n = 64) groups. Eighty-eight candidate single nucleotide polymorphisms (SNPs) were tested using the MassARRAY system. Association analysis was performed using the PLINK Whole Genome Data Analysis Toolset and SNPStats software. Linkage disequilibrium (LD) and haplotype analyses were performed using Hapview software. No significant intergroup differences in allele distributions or genotype frequencies of CYP1A2, CYP3A4, CYP3A5, and CYP3A7 were detected in our study on preterm babies. Two more SNPs in AHR were found to be associated with determining the response to caffeine citrate therapy in our pediatric patients. Of the 46 candidate SNPs in the CLOCK gene, 26 were found to be associated with determining the response to caffeine treatment in these babies. Interestingly, a significant association was retained for 18 SNPs in the CLOCK gene after false discovery rate correction. Moreover, strong LD formed in those variants in AHR, ADORA2A, and CLOCK genes was confirmed to be significantly associated with a better response to standard-dose caffeine therapy. In summary, CLOCK gene polymorphisms play a role in determining the response to caffeine therapy in premature neonates with AOP. However, whether the AHR and CLOCK signaling pathways crosstalk with each other during caffeine treatment remains largely unclear. Future clinical studies including more immature babies and basic research are needed to explore the mechanism by which circadian rhythms affect the response to caffeine therapy.
John Villandre, Virginia White, Travis B. Lear, Yanwen Chen, Ferhan Tuncer, Emily Vaiz, Beyza Tuncer, Karina Lockwood, Dan Camarco, Yuan Liu, et al.
Published: 25 January 2022
Frontiers in Pharmacology, Volume 13; https://doi.org/10.3389/fphar.2022.828643

Abstract:
Aquaporin 5 (AQP5) is expressed in several cell types in the lung and regulates water transport, which contributes to barrier function during injury and the composition of glandular secretions. Reduced AQP5 expression is associated with barrier dysfunction during acute lung injury, and strategies to enhance its expression are associated with favorable phenotypes. Thus, pharmacologically enhancing AQP5 expression could be beneficial. Here, we optimized a high-throughput assay designed to detect AQP5 abundance using a cell line stably expressing bioluminescent-tagged AQP5. We then screened a library of 1153 compounds composed of FDA-approved drugs for their effects on AQP5 abundance. We show compounds Niclosamide, Panobinostat, and Candesartan Celexitil increased AQP5 abundance, and show that Niclosamide has favorable cellular toxicity profiles. We determine that AQP5 levels are regulated in part by ubiquitination and proteasomal degradation in lung epithelial cells, and mechanistically Niclosamide increases AQP5 levels by reducing AQP5 ubiquitination and proteasomal degradation. Functionally, Niclosamide stabilized AQP5 levels in response to hypotonic stress, a stimulus known to reduce AQP5 levels. In complementary assays, Niclosamide increased endogenous AQP5 in both A549 cells and in primary, polarized human bronchial epithelial cells compared to control-treated cells. Further, we measured rapid cell volume changes in A549 cells in response to osmotic stress, an effect controlled by aquaporin channels. Niclosamide-treated A549 cell volume changes occurred more rapidly compared to control-treated cells, suggesting that increased Niclosamide-mediated increases in AQP5 expression affects functional water transport. Taken together, we describe a strategy to identify repurposed compounds for their effect on AQP5 protein abundance. We validated the effects of Niclosamide on endogenous AQP5 levels and in regulating cell-volume changes in response to tonicity changes. Our findings highlight a unique approach to screen for drug effects on protein abundance, and our workflow can be applied broadly to study compound effects on protein abundance in lung epithelial cells.
Xueming Fan, Wei Shen, Liuding Wang,
Published: 25 January 2022
Frontiers in Pharmacology, Volume 12; https://doi.org/10.3389/fphar.2021.810297

Abstract:
Background: Poststroke cognitive impairment (PSCI) is a common complication observed after stroke. Current pharmacologic therapies have no definitive evidence for cognitive recovery or disease progression. Recent studies have verified the positive effect of DL-3-n-butylphthalide (NBP). However, the clinical efficacy and safety are still unclear. The aim of this study was to assess the efficacy of NBP and its harmful effect in the treatment of PSCI.Method: Eligible randomized controlled trials (RCTs) were retrieved from inception to June 2021 from seven medical databases and two clinical registries. The revised Cochrane risk of bias tool (RoB 2.0) was used for methodological quality. RevMan v5.4.1 from Cochrane Collaboration was used for statistical analysis, and Hartung-Knapp-Sidik-Jonkman (HKSJ) method was used for post hoc testing depend on the number of studies. This study has been submitted to PROSPERO with registration number is CRD42021274123.Result: We identified 26 studies with a total sample size of 2,571 patients. The results of this study showed that NBP as monotherapy or combination therapy had better performance in increasing the MoCA (monotherapy: SMDN = 1.05, 95% CI [0.69, 1.42], p < 0.00001; SMDP = 1.06, 95% CI [0.59, 1.52], p < 0.00001. combination: SMDO = 0.81, 95% CI [0.62, 1.01], p < 0.00001; SMDN = 0.90, 95% CI [0.46, 1.33], p < 0.0001; SMDD = 1.04, 95% CI [0.71, 1.38], p < 0.00001), MMSE (monotherapy: MDN = 4.89, 95% CI [4.14, 5.63]), p < 0.00001). combination: SMDO = 1.26, 95% CI [0.97, 1.56], p < 0.00001; SMDC = 1.63, 95% CI [1.28, 1.98], p < 0.00001; SMDN = 2.13, 95% CI [1.52, 2.75], p < 0.00001) and BI (monotherapy: MDN = 13.53, HKSJ 95% CI [9.84, 17.22], p = 0.014. combination: SMDO = 2.24, HKSJ 95%CI [0.37, 4.11], p = 0.032; SMDC = 3.36, 95%CI [2.80, 3.93], p < 0.00001; SMDD = 1.48, 95%CI [1.13, 1.83], p < 0.00001); and decreasing the NIHSS (monotherapy: MDN = −3.86, 95% CI [−5.22, −2.50], p < 0.00001. combination: SMDO = −1.15, 95% CI [−1.31, −0.98], p < 0.00001; SMDC = −1.82, 95% CI [−2.25, −1.40], p < 0.00001) and CSS (combination: MDO = −7.11, 95% CI [−8.42, −5.80], p < 0.00001), with no serious adverse reactions observed. The funnel plot verified the possibility of publication bias.Conclusion: NBP maintains a stable pattern in promoting the recovery of cognitive function and abilities of daily living, as well as reducing the symptoms of neurological deficits. However, there is still a need for more high-quality RCTs to verify its efficacy and safety.
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