Research Of New Drugs Research Articles

Design, Synthesis, and Biological Evaluation of Novel Tetrahydroacridin Hybrids with Sulfur-Inserted Linkers as Potential Multitarget Agents for Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disease that can lead to the loss of cognitive function. The progression of AD is regulated by multiple signaling pathways and their associated targets. Therefore, multitarget strategies theoretically have greater potential for treating AD. In this work, a series of new hybrids were designed and synthesized by the hybridization of tacrine (4, AChE: IC50 = 0.223 μM) with pyrimidone compound 5 (GSK-3β: IC50 = 3 μM) using the cysteamine or cystamine group as the connector. The biological evaluation results demonstrated that most of the compounds exhibited moderate to good inhibitory activities against acetylcholinesterase (AChE) and glycogen synthase kinase 3β (GSK-3β). The optimal compound 18a possessed potent dual AChE/GSK-3β inhibition (AChE: IC50 = 0.047 ± 0.002 μM, GSK-3β: IC50 = 0.930 ± 0.080 μM). Further molecular docking and enzymatic kinetic studies revealed that this compound could occupy both the catalytic anionic site and the peripheral anionic site of AChE. The results also showed a lack of toxicity to SH-SY5Y neuroblastoma cells at concentrations of up to 25 μM. Collectively, this work explored the structure-activity relationships of novel tetrahydroacridin hybrids with sulfur-inserted linkers, providing a reference for the further research and development of new multitarget anti-AD drugs.

Abstract 3549: PMed-TRIAL PDX database: Integrated multidimensional information to facilitate new drug development

Abstract PDX models play a crucial role in pre-clinical research for new drugs. In recent years, research based on PDX models has entered the 'Big Data Era.' On the one hand, there are numerous factors influencing drug responses, such as cancer types, genetic backgrounds, clinical treatment histories, and more. Therefore, selecting the appropriate PDX models for drug efficacy testing based on relevant information has become increasingly important. On the other hand, conducting in-depth genomics and transcriptomics analyses on PDX models allows us to gain a deeper understanding of the mechanisms of drug efficacy and drug sensitivity. After years of effort, LIDE have successfully built and maintained over 1800 PDX models from 40 different cancer types. And in this year (2023), we launched LIDE’s PMed-TRIAL PDX database website. As a comprehensive database of PDX models, it includes fundamental PDX clinical information, medication history, growth curves, and standard of care (SOC) data. It also contains whole exome sequencing data and RNA-seq data. Cancer is a complex and heterogeneous disease characterized by tumor heterogeneity, encompassing both inter-tumor diversity (between patients) and intra-tumor variability (within a single patient), thereby complicating drug responsiveness. PDX models preserve heterogeneity of individual patients, and a robust PDX cohort is essential for accurately representing inter-tumor heterogeneity. LIDE’s PDX cohorts effectively capture representative molecular subtypes across various major cancer types, highlighting their potential as a valuable resource for pre-clinical trials. LIDE’s PMed-TRIAL PDX database comes with a concise and efficient web user interface. Users can search and filter models using keywords, such as drug names, gene symbols, and other information. The website can now be accessed via the following URL (https://pmed.lidebiotech.com:8000/). Citation Format: Xinlei Chen, Youbin Guo, Loc Van, Josh Caggiula, Xiaorong Gu, Danyi Wen. PMed-TRIAL PDX database: Integrated multidimensional information to facilitate new drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3549.

Potential application of Nardostachyos Radix et Rhizoma-Rhubarb for the treatment of diabetic kidney disease based on network pharmacology and cell culture experimental verification.

Diabetic kidney disease (DKD) is one of the serious complications of diabetes mellitus, and the existing treatments cannot meet the needs of today's patients. Traditional Chinese medicine has been validated for its efficacy in DKD after many years of clinical application. However, the specific mechanism by which it works is still unclear. Elucidating the molecular mechanism of the Nardostachyos Radix et Rhizoma-rhubarb drug pair (NRDP) for the treatment of DKD will provide a new way of thinking for the research and development of new drugs. To investigate the mechanism of the NRDP in DKD by network pharmacology combined with molecular docking, and then verify the initial findings by in vitro experiments. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to screen active ingredient targets of NRDP. Targets for DKD were obtained based on the Genecards, OMIM, and TTD databases. The VENNY 2.1 database was used to obtain DKD and NRDP intersection targets and their Venn diagram, and Cytoscape 3.9.0 was used to build a "drug-component-target-disease" network. The String database was used to construct protein interaction networks. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Gene Ontology analysis were performed based on the DAVID database. After selecting the targets and the active ingredients, Autodock software was used to perform molecular docking. In experimental validation using renal tubular epithelial cells (TCMK-1), we used the Cell Counting Kit-8 assay to detect the effect of NRDP on cell viability, with glucose solution used to mimic a hyperglycemic environment. Flow cytometry was used to detect the cell cycle progression and apoptosis. Western blot was used to detect the protein expression of STAT3, p-STAT3, BAX, BCL-2, Caspase9, and Caspase3. A total of 10 active ingredients and 85 targets with 111 disease-related signaling pathways were obtained for NRDP. Enrichment analysis of KEGG pathways was performed to determine advanced glycation end products (AGEs)-receptor for AGEs (RAGE) signaling as the core pathway. Molecular docking showed good binding between each active ingredient and its core targets. In vitro experiments showed that NRDP inhibited the viability of TCMK-1 cells, blocked cell cycle progression in the G0/G1 phase, and reduced apoptosis in a concentration-dependent manner. Based on the results of Western blot analysis, NRDP differentially downregulated p-STAT3, BAX, Caspase3, and Caspase9 protein levels (P < 0.01 or P < 0.05). In addition, BAX/BCL-2 and p-STAT3/STAT3 ratios were reduced, while BCL-2 and STAT3 protein expression was upregulated (P < 0.01). NRDP may upregulate BCL-2 and STAT3 protein expression, and downregulate BAX, Caspase3, and Caspase9 protein expression, thus activating the AGE-RAGE signaling pathway, inhibiting the vitality of TCMK-1 cells, reducing their apoptosis. and arresting them in the G0/G1 phase to protect them from damage by high glucose.

Bibliometric analysis of antimalarial drug resistance.

Malaria has always been a serious infectious disease prevalent in the world. Antimalarial drugs such as chloroquine and artemisinin have been the main compounds used to treat malaria. However, the massive use of this type of drugs accelerates the evolution and spread of malaria parasites, leading to the development of resistance. A large number of related data have been published by researchers in recent years. CiteSpace software has gained popularity among us researchers in recent years, because of its ability to help us obtain the core information we want in a mass of articles. In order to analyze the hotspots and develop trends in this field through visual analysis, this study used CiteSpace software to summarize the available data in the literature to provide insights. Relevant literature was collected from the Web of Science Core Collection (WOSCC) from 1 January 2015 to 29 March 2023. CiteSpace software and Microsoft Excel were used to analyze and present the data, respectively. A total of 2,561 literatures were retrieved and 2,559 literatures were included in the analysis after the removal of duplicates. An irrefutable witness of the ever-growing interest in the topic of antimalarial drug resistance could be expressed by the exponentially increased number of publications and related citations from 2015 to 2022, and its sustained growth trend by 2023. During the past 7 years, USA, Oxford University, and David A Fidock are the country, institution, and author with the most publications in this field of research, respectively. We focused on the references and keywords from literature and found that the research and development of new drugs is the newest hotspot in this field. A growing number of scientists are devoted to finding new antimalarial drugs. This study is the first visual metrological analysis of antimalarial drug resistance, using bibliometric methods. As a baseline information, it is important to analyze research output published globally on antimalarial drug resistance. In order to better understand the current research situation and future research plan agenda, such baseline data are needed accordingly.

Chinese expert consensus on evaluation and treatment of advanced non-small cell lung cancer with negative driver genes after first-line immunotherapy resistance (2024 edition)

Immunotherapy has become the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with negative driver genes, which has significantly improved the prognosis of patients. However, there is still a lack of consistent guidelines or consensus on evaluation and treatment regimens after first-line immunotherapy resistance. The Committee of Non-Small Cell Lung Cancer of Chinese Society of Clinical Oncology organized multidisciplinary experts from medical oncology, respiratory medicine, thoracic surgery, radiotherapy, and imaging to conduct an in-depth discussion on the definition and classification of primary resistance and secondary resistance, evaluation criteria of immunotherapy, subsequent treatment strategies of oligo-progression or extensive progression after first-line immunotherapy, re-challenges of immunotherapy and clinical research of new drugs in advanced NSCLC patients with negative driver genes according to the existing evidence. After the consensus meeting, an expert consensus on evaluation and treatment strategy of advanced NSCLC with negative driver genes after first-line immunotherapy resistance was formed, aiming to provide standardized guidance for clinical practice of Chinese clinicians.

Research on the application of computer in drug design

Virtual screening by computer is of great scientific significance for drug research and development. In recent years, a large number of computer simulation methods have been developed and applied to drug development for a variety of diseases. This paper summarized and prospected the application progress of computer aided drug design (CADD) in the research and development of new drugs, focusing on the working principle of CADD, related algorithms, and the advantages and disadvantages of existing methods. Although CADD has been successfully applied to a number of drug development projects, the accuracy of auxiliary drug structure optimization is still not high. Therefore, it is urgent to develop more accurate and efficient CADD models and algorithms to promote the process of new drug discovery.

A Periprosthetic Joint Candida albicans Infection Model in Mouse.

Periprosthetic joint infection (PJI) is one of the common infections caused by Candida albicans (C. albicans), which increasingly concerns surgeons and scientists. Generally, biofilms that can shield C. albicans from antibiotics and immune clearance are formed at the infection site. Surgery involving the removal of the infected implant, debridement, antimicrobial treatment, and reimplantation is the gold standard for the treatment of PJI. Thus, establishing animal PJI models is of great significance for the research and development of new drugs or therapeutics for PJI. In this study, a smooth nickel-titanium alloy wire, a widely used implant in orthopedic clinics, was inserted into the femoral joint of a C57BL/6 mouse before the C. albicans were inoculated into the articular cavity along the wire. After 14 days, mature and thick biofilms were observed on the surface of implants under a scanning electronic microscope (SEM). A significantly reduced bone trabecula was found in the H&E staining of the infected joint specimens. To sum up, a mouse PJI model with the advantages of easy operation, high successful rate, high repeatability, and high clinical correlation was established. This is expected to be an important model for clinical studies of C. albicans biofilm-related PJI prevention.

Research and development strategy of new traditional Chinese medicine drugs for syndromes based on human use experience

Chinese drug registration laws and regulations have always reserved a place for the new traditional Chinese medicine(TCM) drugs for syndromes, but so far no such new drugs have been approved for registration. This paper expounded on the relevant policies, regulations, and technologies of new TCM drugs for syndromes in China and pointed out that the application of the animal model of TCM syndromes to carry out pharmacodynamics research and clinical efficacy evaluation criteria of TCM syndromes were the main technical difficulties in the research and development of new TCM drugs for syndromes. Not all syndromes are suitable for developing new drugs, and the indications for new TCM drugs should be constant syndromes. Among the three research and development models of simple syndrome, syndrome-unified disease, and combined disease and syndrome, the research and development model of combined disease and syndrome is recommended. Clinical positioning is the key to new TCM drugs for syndromes. It is encouraged to conduct high-quality human use experience studies to determine the clinical positioning of new TCM drugs for syndromes, as well as the target population, dose, course of treatment, and initial therapeutic and safety, and apply for exemption from non-clinical effectiveness studies. Clinical trials of new TCM drugs for syndromes should take the target symptoms or signs as the main efficacy index and the efficacy of TCM syndromes as the secondary efficacy index. Clinical research program design should implement the &quot;patient-centered&quot; concept and introduce clinical outcome evaluation indicators. In the clinical safety evaluation, special conditions such as characteristic syndromes and changes should be considered. With the construction of the human use experience technology system and the promotion of the TCM registration and evaluation evidence system featuring the &quot;combination of TCM theory, human use experience, and clinical trials&quot;, it is believed that many high-quality new TCM drugs for syndromes will be developed in the future.

Research progress of targeted therapy regulating Th17/Treg balance in bone immune diseases.

Rheumatoid arthritis (RA) and postmenopausal osteoporosis (PMOP) are common bone-immune diseases. The imbalance between helper (Th17) and regulatory T cells (Tregs) produced during differentiation of CD4+ T cells plays a key regulatory role in bone remodelling disorders in RA and PMOP. However, the specific regulatory mechanism of this imbalance in bone remodelling in RA and PMOP has not been clarified. Identifying the regulatory mechanism underlying the Th17/Treg imbalance in RA and PMOP during bone remodelling represents a key factor in the research and development of new drugs for bone immune diseases. In this review, the potential roles of Th17, Treg, and Th17/Treg imbalance in regulating bone remodelling in RA and PMOP have been summarised, and the potential mechanisms by which probiotics, traditional Chinese medicine compounds, and monomers maintain bone remodelling by regulating the Th17/Treg balance are expounded. The maintenance of Th17/Treg balance could be considered as an therapeutic alternative for the treatment of RA and PMOP. This study also summarizes the advantages and disadvantages of conventional treatments and the quality of life and rehabilitation of patients with RA and PMOP. The findings presented her will provide a better understanding of the close relationship between bone immunity and bone remodelling in chronic bone diseases and new ideas for future research, prevention, and treatment of bone immune diseases.

Myrrh Essential Oil Improves DSS-Induced Colitis by Modulating the MAPK Signaling Pathway: In vitro and in vivo Studies.

To explore the mechanism and active components of the anti-colitis effects of myrrh essential oil (MEO). In this study, we investigated the anti-inflammatory effects and molecular mechanisms of MEO on dextran sulfate sodium (DSS)-induced colitis with in vitro cell experiments, RNA-seq (RNA Sequencing), Weighted gene co-expression network analysis (WGCNA), combined with "weighting coefficient" network pharmacology, as and in vivo pharmacodynamic experiments. A 3% DSS solution was used to induce colitis in BALB/c mice and MEO was administered orally. We performed gas chromatography-mass spectrometry (GC-MS) analysis of the MEO components. The disease activity index (DAI) was evaluated by observing body weight, fecal characteristics, and blood in the stool of mice. The levels of inflammatory cytokines (TNF-α and IL-1β) in mouse serum were measured using ELISA (Enzyme-linked immunosorbent assay) kits. Additionally, the expression of MAPK-related proteins (JNK, p-JNK, ERK, and p-ERK) in mouse colonic tissues was detected by Western blotting and immunohistochemistry. MEO (0.0625-0.125µg/g, p.o). significantly inhibited the expression of the inflammatory mediator Nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. After treatment, there was a significant increase in body weight and alleviation of diarrhea and bloody stools in colitis mice. It also reduced inflammatory cell infiltration. Furthermore, it decreased the serum levels of TNF-α and IL-1β, and reduced the activity of p-JNK and p-ERK in the MAPK pathway. MEO relieved DSS-induced colitis by modulating the MAPK pathway. The experimental results indicate that the MAPK pathway might be inhibited by the synergistic effect of gamma-Muurolene, Curzerene, beta-Elemene, and Furanoeudesma 1.3-diene in MEO, which provides a novel idea for subsequent research and development of new anti-colitis drugs.

Lactobacilli and Klebsiella: Two Opposites in the Fight for Human Health.

The problem of antibiotic resistance is currently very acute. Numerous research and development of new antibacterial drugs are being carried out that could help cope with various infectious agents. One of the promising directions for the search for new antibacterial drugs is the search among the probiotic strains present in the human gastrointestinal tract. This review is devoted to characteristics of one of these probiotic strains that have been studied to date: Limosilactobacillus reuteri. The review discusses its properties, synthesis of various compounds, as well as role of this strain in modulating various systems of the human body. The review also examines key characteristics of one of the most harmful among the currently known pathogenic organisms, Klebsiella, which is significantly resistant to antibiotics existing in medical practice, and also poses a great threat of nosocomial infections. Discussion of characteristics of the two strains, which have opposite effects on human health, may help in creation of new effective antibacterial drugs without significant side effects.

Cellular and DNA Toxicity Study of Triphenyltin Ethyl Phenyl Dithiocarbamate and Triphenyltin Butyl Phenyl Dithiocarbamate on K562, Leukemia Cell Line.

Continuous research for new effective drugs to treat cancer has improved our understanding on the mechanism of action of these drugs and paved new potential for their application in cancer treatments. In this study, organotin compounds known as triphenyltin ethyl phenyl dithiocarbamate and triphenyltin butyl phenyl dithiocarbamate were investigated for their toxicity on leukemia cell line (K562) and non-cancerous cell line (Chang liver cell and lung fibroblast, V79 cell). MTT assay was performed to evaluate the cytotoxic effects of both compounds toward the cells after 24, 48 and 72 hours of exposure or treatment. The alkaline comet assay was conducted to determine the DNA damage on K562 cells after been exposed to both compounds for 30, 60 and 90 minutes. The IC50 values obtained from K562 cells ranged from 0.01 to 0.30 μM, whereas for both Chang liver cell and lung fibroblast V79 cell, the values ranged from 0.10 to 0.40 μM. For genotoxicity evaluation, the percentage of damaged DNA is measured as an average of tail moment, and was found to be within 1.20 to 2.20 A.U while the percentage of DNA intensity ranging from 1.50 to 3.50% indicating no genotoxic effects. Both compounds are cytotoxic toward leukemia cells and non-cancerous cells but do not exert their genotoxic effects towards leukemia cell.

The Structural Basis of DL0410, a Novel Multi-Target Candidate Drug for the Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is a complicated disease for which there are still no ideal one-target drugs, while multi-target drugs are closer to ideal drugs and will provide new solutions for the clinical treatment of AD. DL0410 is a promising multi-target drug candidate for AD treatment that is not only a significant inhibitor against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) but also an antagonist of histamine H3 receptor (H3R), and its therapeutic efficacy in treating cognitive dysfunction has been validated in a series of AD-related animal models, including scopolamine-induced mice, D-galactose-induced and Aβ-induced mice, and APP/PS1 and SAMP8 mice. Although the structure of DL0410 has been analyzed using various detection techniques, such as MS and NMR, its three-dimensional crystal structure still requires further confirmation. In this study, the crystal of DL0410 was grown in aqueous solution, and its structure was detected using the X-ray diffraction method. The crystal data, atomic coordinates, bond lengths, angles, and hydrogen bonds of DL0410 were obtained. Its stability was proven by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Based on this study, the molecular docking of DL0410 with AChE, BuChE, and H3R was performed to uncover their interaction mechanisms and explain their bioactivities. This study provides important information for new multi-target drug design and the research and development of new drugs for AD treatment.

Why and when should be lipoprotein(a) level measured?

Lipoprotein(a) [Lp(a)] is composed of a low-density lipoprotein (LDL) and glycoprotein (a)—apo(a). The size and concentration of Lp(a) in serum can vary among individuals and is determined by genetic factors. The environmental factors, diet, and physical activity have a negligible effect on Lp(a) level. Observational, epidemiological, and genetic studies improved that high levels of Lp(a) &gt; 50 mg/dL (&gt; 125 nmol/L) have been associated with an increased risk of myocardial infarction (MI), stroke, and calcific aortic valve stenosis (CAVS). It is recommended to measure Lp(a) at least once in adults to identify individuals with a high cardiovascular risk. This screening is particularly important in certain populations, including: youth with a history of ischemic stroke or a family history of premature atherosclerotic cardiovascular disease (CVD; ASCVD) or high Lp(a), individuals with recurrent cardiovascular events despite optimal hypolipemic treatment and no other identifiable risk factors or patients with familial hypercholesterolemia (FH). Considering Lp(a) levels in the evaluation of cardiovascular risk can provide valuable information for risk stratification and management decisions. However, it’s important to note that the treatments of elevated level of Lp(a) are limited. In recent years, there has been ongoing research and development of new drugs targeting Lp(a): pelacarsen—antisense oligonucleotide (ASO), and olpasiran—a small interfering RNA (siRNA).

Salvianolic acid A provides neuroprotective effects on cerebral ischemia-reperfusion injury in rats via PKA/CREB/c-Fos signaling pathway

BackgroundCerebral ischemia-reperfusion injury (CIRI) is a phenomenon that pathological injury of ischemic brain tissue is further aggravated after the restoration of blood supply. The complex pathological mechanism of CIRI has led to the failure of multiple neuroprotective agents in clinical studies. Salvianolic acid A (SAA) is a neuroprotective extract from Salvia miltiorrhiza Bge., with significant pharmacological activities in the treatment of brain injury. However, the neuroprotective mechanisms of SAA remain unclear. PurposeTo explore the potential protective effect of SAA on CIRI and its mechanism, and to provide experimental basis for the research of new drugs for CIRI. Study designA model of transient middle cerebral artery occlusion (tMCAO) in rats was used to simulate clinical CIRI, and the neuroprotective effect of SAA on tMCAO rats was investigated within 14 days after reperfusion. The improvement effects of SAA on cognitive impairment of tMCAO rats were investigated by behavioral tests from days 7–14. Finally, the neuroprotective mechanism of SAA was investigated on day 14. MethodsThe neuroprotective effects and mechanism of SAA were investigated by behavioral tests, HE and TUNEL staining, RNA sequence (RNA-seq) analysis and Western blot in tMCAO rats. ResultsThe brain protective effects of SAA were achieved by alleviating cerebral infarction, cerebral edema, cerebral atrophy and nerve injury in tMCAO rats. Meanwhile, SAA could effectively improve the cognitive impairment and pathological damage of hippocampal tissue, and inhibit cell apoptosis in tMCAO rats. Besides, SAA could provide neuroprotective effects by up-regulating the expression of Bcl-2, inhibiting the activation of Caspase 3, and regulating PKA/CREB/c-Fos signaling pathway. ConclusionSAA can significantly improve brain injury and cognitive impairment in CIRI rats, and this neuroprotective effect may be achieved through the anti-apoptotic effect and the regulation of PKA/CREB/c-Fos signaling pathway.

Multi-channel Small Animal Drug Metabolism Real-Time Monitoring Fluorescence System.

The data acquisition of drug metabolism analysis requires a lot of time and animal resources. However, there are often many deviations in the results of pharmacokinetic analysis. Conventional methods cannot measure the blood drug concentration data in multiple tissues at the same time, and the data is obtained by in vitro measurement, which produces time errors, in vitro data errors, and individual differences between animals. In the analysis of pharmacokinetic parameters, it will seriously affect the pass rate of clinical trials of R&D drugs and the accuracy of the dosing schedule. To the best of our knowledge, we have not found the study of in vivo blood drug concentration using multi-channel equipment. Therefore, the purpose of this paper is to build a set of multi-organ monitoring and analysis instruments for synchronously monitoring the metabolism of drugs in various tissues of small animals, so as to obtain real in vivo data of blood drug concentration in real time. Using the fluorescence properties and laser-induced fluorescence principle of drugs, we designed six channels to monitor the changes of fluorescence-labeled drugs in their main metabolic organs, a multi-channel calibration method was proposed to improve the accuracy of the time-division multiplexing, the real-time collection of drug concentration in vivo is realized, and the drug metabolism curve in vivo can be observed. The instrument satisfies the collection of small doses of drugs such as microgram; the detection sensitivity can reach 10 ng/ml, and can monitor and collect the drug metabolism of multiple small animal tissues at the same time, which greatly reduces the use of animals, reduces the differences between individuals, and reduces consumption cost and improve the detection efficiency of parameters, and obtain data information that is closer to the real biology. The real-time continuous monitoring and data collection of the drug metabolism in the plasma of living small animals and the important organs such as kidney, liver, and spleen were realized. The research and development of new drugs and clinical research have higher practical value.

Signaling pathways regulated by natural active ingredients in the fight against exercise fatigue-a review.

Exercise fatigue is a normal protective mechanism of the body. However, long-term fatigue hinders normal metabolism and exercise capacity. The generation and recovery from exercise fatigue involves alterations in multiple signaling pathways, mainly AMPK, PI3K/Akt, Nrf2/ARE, NF-κB, PINK1/Parkin, and BDNF/TrkB, as well as MAPK signaling pathways that mediate energy supply, reduction of metabolites, oxidative stress homeostasis, muscle fiber type switching, and central protective effects. In recent studies, a rich variety of natural active ingredients have been identified in traditional Chinese medicines and plant extracts with anti-fatigue effects, opening up the field of research in new anti-fatigue drugs. In this review we give an overview of the signaling pathways associated with the activity of natural food active ingredients against exercise fatigue. Such a comprehensive review is necessary to understand the potential of these materials as preventive measures and treatments of exercise fatigue. We expect the findings highlighted and discussed here will help guide the development of new health products and provide a theoretical and scientific basis for future research on exercise fatigue.

Advances in virtual screening techniques for anti-viral drug design: A computational perspective

With the outbreak of the novel coronavirus, which has been found to mutate almost once a week, future viruses may mutate faster than we think. To deal with the mutation of the virus as soon as possible, the development of new drugs should be accelerated. The traditional drug research and development cycle is long, the cost is high, and the human resource consumption is large. Virtual screening technology has gradually become an indispensable link in the research and development of new drugs because of its high efficiency and low cost. This paper introduces the discovery, structure, symptoms and pathogenesis of 5 viruses (HIV, HBV, HCV, Ebola Virus, Coronavirus), and summarizes the application cases of virtual screening technology in the research and development of new antiviral drugs in recent years, to provide a reference for researchers.

Flavonoids with Anti-Herpes Simplex Virus Properties: Deciphering Their Mechanisms in Disrupting the Viral Life Cycle.

The herpes simplex virus (HSV) is a double-stranded DNA human virus that causes persistent infections with recurrent outbreaks. HSV exists in two forms: HSV-1, responsible for oral herpes, and HSV-2, primarily causing genital herpes. Both types can lead to significant complications, including neurological issues. Conventional treatment, involving acyclovir and its derivatives, faces challenges due to drug resistance. This underscores the imperative for continual research and development of new drugs, with a particular emphasis on exploring the potential of natural antivirals. Flavonoids have demonstrated promise in combating various viruses, including those within the herpesvirus family. This review, delving into recent studies, reveals the intricate mechanisms by which flavonoids decode their antiviral capabilities against HSV. By disrupting key stages of the viral life cycle, such as attachment to host cells, entry, DNA replication, latency, and reactivation, flavonoids emerge as formidable contenders in the ongoing battle against HSV infections.

Antimicrobial Activities of Substituted 4-N-alkylated-2-trifluoromethylquinoline Analogs Against Nontuberculous Mycobacteria

Background: Many contagious diseases have been caused by a variety of nontuberculous mycobacteria, opportunistic pathogens that can cause disseminated or localized diseases, particularly pulmonary, skin, and soft tissue infections. Objective: In this study fifty-five substituted 4-N-alkylated-2-trifluoromethylquinolines were evaluated against five species of nontuberculous mycobacteria: Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium kansasii, and Mycobacterium avium. Methods: The antimycobacterial activities of all tested compounds were assessed using the microplate procedure with broth microdilution assay. The most actives were selected for their potential cytotoxic activity against Vero cells. Results: Most of the compounds displayed some activity against M. kansaii, of which 12, 15, 34, 37 and 48 were the most active at 3.12 μg/mL. The derivative 8 was the most active against M. fortuitum at 6.25 μg/mL and the most active against M. chelonae at 3.12 μg/mL. The derivative 2 was the most active against M. avium at 12.5 μg/mL, and 9 the most active against M. abscessus at 12.5 μg/mL. All the most active compounds showed MIC values similar to the references drugs used against these species. Conclusion: 47 compounds displayed some activity against some of the species analyzed, highlighting derivatives 12, 15, 34, 37, and 48, which presented the lower MIC values. Compounds 34 and 37 displayed the highest activity and did not show cytotoxicity against Vero cells. These findings have opened new perspectives for the research of new drugs against these mycobacterial species based on the quinoline nucleus.