Abstract: BACKGROUND: Genetic factors have been found to be associated with the efficacy and adverse reactions of antiseizure medications. BCL11A is an important regulator of the development of neuronal networks. However, the role of BCL11A in epilepsy remains unclear. This study aimed to evaluate the genetic association of BCL11A with the susceptibility to develop epileptic seizures and therapeutic response of patients with epilepsy in Han Chinese. METHODS: We matched 450 epilepsy cases with 550 healthy controls and 131 drug-resistant epilepsy patients with 319 drug-responsive epilepsy patients from two different centers. Genetic association analysis, genetic interaction analysis, expression quantitative trait loci analysis and protein-protein interaction analysis were conducted. RESULTS: Our results showed that rs2556375 not only increases susceptibility to develop epileptic seizures (OR = 2.700, 95% = 1.366-5.338, p = 0.004 and OR = 2.984, 95% = 1.401-6.356, p = 0.005, respectively), but also increases the risk of drug resistance(OR = 21.336, 95%CI =2.489-183.402, p = 0.005). The interaction between rs2556375 and rs12477097 results in increased risk for pharma coresistant. In addition, rs2556375 regulated BCL11A expression in human brain tissues (p = 0.0096 and p = 0.033, respectively). Furthermore, the protein encoded by BCL11A interacted with targets of approved antiepileptic drugs. CONCLUSION: BCL11A may be a potential therapeutic target for epilepsy. Rs2556375 may increase the risks of epilepsy and drug resistance by regulating BCL11A expression in human brain tissues. Moreover, the interaction between rs2556375 and rs12477097 results in increased risk for drug resistance.

Abstract: Coronavirus disease 2019 (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently spreading rapidly around the world. Since SARS-CoV-2 seriously threatens human life and health as well as the development of the world economy, it is very urgent to identify effective drugs against this virus. However, traditional methods to develop new drugs are costly and time-consuming, which makes drug repositioning a promising exploration direction for this purpose. In this study, we collected known antiviral drugs to form five virus-drug association datasets, and then explored drug repositioning for SARS-CoV-2 by Gaussian kernel similarity bilinear matrix factorization (VDA-GKSBMF). By the 5-fold cross-validation, we found that VDA-GKSBMF has an area under curve (AUC) value of 0.8851, 0.8594, 0.8807, 0.8824, and 0.8804, respectively, on the five datasets, which are higher than those of other state-of-art algorithms in four datasets. Based on known virus-drug association data, we used VDA-GKSBMF to prioritize the top-k candidate antiviral drugs that are most likely to be effective against SARS-CoV-2. We confirmed that the top-10 drugs can be molecularly docked with virus spikes protein/human ACE2 by AutoDock on five datasets. Among them, four antiviral drugs ribavirin, remdesivir, oseltamivir, and zidovudine have been under clinical trials or supported in recent literatures. The results suggest that VDA-GKSBMF is an effective algorithm for identifying potential antiviral drugs against SARS-CoV-2.

Abstract: Ginseng and ginsenosides have been reported to have various pharmacological effects, but their efficacies depend on intestinal absorption. Compound K (CK) is gaining prominence for its biological and pharmaceutical properties. In this study, CK-enriched fermented red ginseng extract (DDK-401) was prepared by enzymatic reactions. To examine its pharmacokinetics, a randomized, single-dose, two-sequence, crossover study was performed with eleven healthy Korean male and female volunteers. The volunteers were assigned to take a single oral dose of one of two extracts, DDK-401 or common red ginseng extract (DDK-204), during the initial period. After a 7-day washout, they received the other extract. The pharmacokinetics of DDK-401 showed that its maximum plasma concentration (Cmax) occurred at 184.8 +/- 39.64 ng/mL, Tmax was at 2.4 h, and AUC(0-12h) was 920.3 +/- 194.70 ng h/mL, which were all better than those of DDK-204. The maximum CK absorption in the female volunteers was higher than that in the male volunteers. The differentially expressed genes from the male and female groups were subjected to a KEGG pathway analysis, which showed results in the cell death pathway, such as apoptosis and necroptosis. In cytotoxicity tests, DDK-401 and DDK-204 were not particularly toxic to normal (HaCaT) cells, but at a concentration of 250 mug/mL, DDK-401 had a much higher toxicity to human lung cancer (A549) cells than DDK-204. DDK-401 also showed a stronger antioxidant capacity than DDK-204 in both the DPPH and potassium ferricyanide reducing power assays. DDK-401 reduced the reactive oxygen species production in HaCaT cells with induced oxidative stress and led to apoptosis in the A549 cells. In the mRNA sequence analysis, a signaling pathway with selected marker genes was assessed by RT-PCR. In the HaCaT cells, DDK-401 and DDK-204 did not regulate FOXO3, TLR4, MMP-9, or p38 expression; however, in the A549 cells, DDK-401 downregulated the expressions of MMP9 and TLR4 as well as upregulated the expressions of the p38 and caspase-8 genes compared to DDK-204. These results suggest that DDK-401 could act as a molecular switch for these two cellular processes in response to cell damage signaling and that it could be a potential candidate for further evaluations in health promotion studies.

Abstract: BACKGROUND: Depression is a common disorder that affects patients' quality of life and incurs health system costs. Due to the resistance to treat depression, better understanding of neurophysiology was considered; one of the implications is the glutamatergic system. This study aims to systematically review clinical trials investigating the antidepressant effects of kainate receptor antagonists. METHODS: The study protocol was registered in PROSPERO (CRD42021213912). Scopus, ISI, Embase, PubMed, Cochrane Library, Google Scholar, and two trial registries were searched for randomized controlled trials on the effectiveness of topiramate, phenobarbital, and other ten barbiturates in depression. The difference with control groups in terms of changing depressive symptoms was the primary outcome. RESULTS: Nine trials were identified, in which 784 patients were studied. The efficacy of thiopental was comparable to that of imipramine, with fewer side effects. When administered with electroconvulsive therapy, it had fewer to similar effects and fewer side effects than ketamine. Both monotherapy and adjunctive therapy with topiramate were effective and tolerable in treating depressed patients. Phenobarbital had therapeutic effects compared to imipramine and amitriptyline with fewer side effects. CONCLUSION: Regarding the glutamatergic hypothesis of depression and obtained promising results, further studies of kainate receptor antagonists in high-quality trials are recommended. Given the high prevalence of depression in epileptic patients, more problems with its treatment, and the fact that the studied agents were anticonvulsants, it is recommended that future studies prioritize depressed-epileptic patients.

Abstract: It has been acknowledged that more women suffer from adverse effects of drugs than men globally. A group of drugs targeting serotonin [5-hydroxytryptamine] (5-HT) binding G-protein-coupled receptors (GPCRs) have been reported to preferentially affect women more than men, causing adverse effects such as breast cancer and infertility. 5-HT GPCR-targeted drugs in the central nervous system (CNS) manage psychiatric conditions, such as depression or bipolar and in the peripheral nervous system (PNS) treat migraines. Physiological characteristics such as specific types of hormones, higher body fat density and smaller body mass in women result in disparities in pharmacodynamics of drugs, thus explaining sex-related differences in the observed adverse effects. In this review, we discuss the side effects of drugs targeting 5-HT GPCRs based on serotonin's roles in the CNS and PNS. We have systematically reviewed adverse effects of drugs targeting 5-HT GPCR using information from the Food and Drug Administration and European Medicines Agency. Further information on drug side effects and receptor targets was acquired from the SIDER and DrugBank databases, respectively. These drugs bind to 5-HT GPCRs in the CNS, namely the brain, and PNS such as breasts, ovaries and testes, potentially causing side effects within these areas. Oestrogen affects both the biosynthesis of 5-HT and the densities of 5-HT GPCRs in given tissues and cells. 5-HT GPCR-targeting drugs perturb this process. This is likely a reason why women are experiencing more adverse effects than men due to their periodic increase and the relatively high concentrations of oestrogen in women and, thus a greater incidence of the oestrogen-mediated 5-HT system interference. In addition, women have a lower concentration of serotonin relative to men and also have a relatively faster rate of serotonin metabolism which might be contributing to the former. We discuss potential approaches that could mitigate at least some of the adverse effects experienced by women taking the 5-HT GPCR-targeting drugs.

Abstract: Dental caries is one of the most prevalent and costly biofilm-associated infectious diseases worldwide. Streptococcus mutans (S. mutans) is well recognized as the major causative factor of dental caries due to its acidogenicity, aciduricity and extracellular polymeric substances (EPSs) synthesis ability. The EPSs have been considered as a virulent factor of cariogenic biofilm, which enhance biofilms resistance to antimicrobial agents and virulence compared with planktonic bacterial cells. The traditional anti-caries therapies, such as chlorhexidine and antibiotics are characterized by side-effects and drug resistance. With the development of computer technology, several novel approaches are being used to synthesize or discover antimicrobial agents. In this mini review, we summarized the novel antimicrobial agents targeting the S. mutans biofilms discovery through computer technology. Drug repurposing of small molecules expands the original medical indications and lowers drug development costs and risks. The computer-aided drug design (CADD) has been used for identifying compounds with optimal interactions with the target via silico screening and computational methods. The synthetic antimicrobial peptides (AMPs) based on the rational design, computational design or high-throughput screening have shown increased selectivity for both single- and multi-species biofilms. These methods provide potential therapeutic agents to promote targeted control of the oral microbial biofilms in the near future.

Abstract: Porphyromonas gingivalis is a major pathogenic bacterium involved in the pathogenesis of periodontitis. Citrullination has been reported as the underlying mechanism of the pathogenesis, which relies on the interplay between two virulence factors of the bacterium, namely gingipain R and the bacterial peptidyl arginine deiminase. Gingipain R cleaves host proteins to expose the C-terminal arginines for peptidyl arginine deiminase to citrullinate and generate citrullinated proteins. Apart from carrying out citrullination in the periodontium, the bacterium is found capable of citrullinating proteins present in the host synovial tissues, atherosclerotic plaques and neurons. Studies have suggested that both virulence factors are the key factors that trigger distal effects mediated by citrullination, leading to the development of some non-communicable diseases, such as rheumatoid arthritis, atherosclerosis, and Alzheimer's disease. Thus, inhibition of these virulence factors not only can mitigate periodontitis, but also can provide new therapeutic solutions for systematic diseases involving bacterial citrullination. Herein, we described both these proteins in terms of their unique structural conformations and biological relevance to different human diseases. Moreover, investigations of inhibitory actions on the enzymes are also enumerated. New approaches for identifying inhibitors for peptidyl arginine deiminase through drug repurposing and virtual screening are also discussed.

Abstract: Objective: Neonatal hyperbilirubinemia is caused by the excessive production of bilirubin and decreased excretion ability in the neonatal period. It leads to a concentration of blood bilirubin that exceeds a certain threshold. Yinzhihuang oral liquid (YZH) is a traditional Chinese medicine mixture used in the treatment of neonatal hyperbilirubinemia in China. This article systematically explores the pharmacological mechanisms by which YZH acts in the treatment of neonatal hyperbilirubinemia through network pharmacology at the molecular level. Methods: We adopted the method of network pharmacology, which includes active component prescreening, target gene prediction, gene enrichment analysis, and network analysis. Results: According to the network pharmacological analysis, 8 genes (STAT3, AKT1, MAPK14, JUN, TP53, MAPK3, ESR1, and RELA) may be targets of YZH in the treatment of neonatal hyperbilirubinemia. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that YZH may regulate antioxidation, modulate lipid metabolism, and have anti-infective properties. Conclusion: In this study, the pharmacological action and molecular mechanisms of YZH were predicted as a whole. It was found that YZH is a promising drug for treating oxidative stress due to bilirubin, as it reduces immunosuppression and helps to eliminate virus infection.

Abstract: Since COVID-19 emerged in 2019, significant levels of suffering and disruption have been caused on a global scale. Although vaccines have become widely used, the virus has shown its potential for evading immunities or acquiring other novel characteristics. Whether current drug treatments are still effective for people infected with Omicron remains unclear. Due to the long development cycles and high expense requirements of de novo drug development, many researchers have turned to consider drug repositioning in the search to find effective treatments for COVID-19. Here, we review such drug repositioning and combination efforts towards providing better handling. For potential drugs under consideration, aspects of both structure and function require attention, with specific categories of sequence, expression, structure, and interaction, the key parameters for investigation. For different data types, we show the corresponding differing drug repositioning methods that have been exploited. As incorporating drug combinations can increase therapeutic efficacy and reduce toxicity, we also review computational strategies to reveal drug combination potential. Taken together, we found that graph theory and neural network were the most used strategy with high potential towards drug repositioning for COVID-19. Integrating different levels of data may further improve the success rate of drug repositioning.

Abstract: Background: Heart failure (HF), the final stage of cardiovascular diseases, is a clinical syndrome of cardiac structural or functional abnormalities. QiShenYiQi Dripping Pills (T101), short for QSYQ (T101), showed effectiveness and safety in the treatment of HF according to modern pharmacological research and clinical studies, but the mechanism remains unclear. This study aims to clarify the mechanism of QSYQ (T101) in treating heart failure through the analysis to critical biomarkers, targets and pathways. Materials and Methods: In this study, the efficacies of QSYQ (T101) in non-human primates and rodents were evaluated, and the mechanism was demonstrated by integrating network pharmacology and metabolomics analysis. Furthermore, the targets from network pharmacology and the metabolites from targeted metabolomics were jointly analyzed to screen the critical pathways. Results: In rhesus monkeys with spontaneous chronic heart failure, nasogastric administration of QSYQ (T101) for 12 weeks caused profound improvement of systolic and diastolic function as evidenced by echocardiography detection. Consistently, QSYQ (T101) administration especially with higher dose lowered the blood pressure and improved the ventricular remodeling, collagen deposition and fibrosis markedly in Spontaneous Hypertension Rats (SHR) model. Computational prediction showed that QSYQ (T101) exhibited anti-HF effects possibly through HIF-1 signaling pathway, FoxO signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway and other enriched paths. Metabolomics analysis obtained 23 significantly altered metabolites, revealing that QSYQ (T101) significantly regulated the abnormal levels of fatty acids, carnitines, organic acids pyridines, nucleosides, which were mostly involved in myocardial energy metabolism related pathways. Conclusion: Based on serum and myocardium metabolomics and network pharmacology, the present study revealed that the actions of QSYQ (T101) in treating HF depend on multi-components, multi-targets and multi-pathways.