The prevalence of obesity and its associated diseases has increased dramatically, and they are major threats to human health worldwide. A variety of approaches, such as physical training and drug therapy, can be used to reduce weight and reverse associated diseases; however, the efficacy and the prognosis are often unsatisfactory. It has been reported that natural food-based small molecules can prevent obesity and its associated diseases. Among them, alkaloids and polyphenols have been demonstrated to regulate lipid metabolism by enhancing energy metabolism, promoting lipid phagocytosis, inhibiting adipocyte proliferation and differentiation, and enhancing the intestinal microbial community to alleviate obesity. This review summarizes the regulatory mechanisms and metabolic pathways of these natural small molecules and reveals that the binding targets of most of these molecules are still undefined, which limits the study of their regulatory mechanisms and prevents their further application. In this review, we describe the use of Discovery Studio for reverse pharmacophore screening of related small molecules and provide new insights for target protein prediction, scaffold hopping, and mechanistic studies in the future. These studies will provide a theoretical basis for the modernization of anti-obesity drugs and promote the discovery of novel drugs.

Infections provoked by parasites are among the most prevalent diseases worldwide and generate important health and socioeconomic problems. Despite the enormous amount of work done, the chemotherapy for most of them remains unsolved. Usually, treatments are based on not specific drugs associated, in several cases, with long-term treatments and severe side effects. In addition, drug resistance and different strains susceptibility are further drawbacks of the existing chemotherapy. Considering that 1,4-DHP derivatives constitute an important class of compounds for new drug development, we present in this review an in-depth overview of the work done so far on 1,4-DHPs and their antiparasitic activities. The development of new derivatives or the application of known drugs used for other diseases is described in terms of their potential usefulness for drug design.

BACKGROUND: The Brugada syndrome (BrS) is a heart rhythm condition that is commonly associated with a strong predisposition for sudden cardiac death. Malignant ventricular arrhythmias could occur secondary to the dysfunction of the cardiac sodium voltage-gated Na(v)1.5 channel (SCN5A). OBJECTIVE: This study aimed to perform a multiparametric computational analysis of the physicochemical properties of SCN5A mutants associated with BrS using a set of bioinformatics tools. METHODS: In-house algorithms were calibrated to calculate, in a double-blind test, the Polarity Index Method (PIM) profile and protein intrinsic disorder predisposition (PIDP) profile of each sequence, and computer programs specialized in the genomic analysis were used. RESULTS: Specific regularities in the charge/polarity and PIDP profile of the SCN5A mutant proteins enabled the re-creation of the taxonomy, allowing us to propose a bioinformatics method that takes advantage of the PIM profile to identify this group of proteins from their sequence. CONCLUSION: Bioinformatics programs could reproduce characteristic PIM and PIDP profiles of the BrS-related SCN5A mutant proteins. This information can contribute to a better understanding of these altered proteins.

BACKGROUND: Cantharidin (CTD) is a highly toxic substance which can be used to treat a variety of cancers. However, the clinical application of CTD is restricted due to the serious side effects. In recent years, screening its analogues, exploring the mechanism of action and using combinatory therapy with certain substances are considered to be feasible methods which can reduce side effects and improve the therapeutic activity of CTD. This review aims to describe SAR (structure-activity relationship) of CTD analogues, CTD induction mechanisms, and combinatory therapy exploration. METHODS: We searched for research about CTD by entering the database. Important information was screened and extracted purposefully, including SAR, mechanisms, methods, etc. Finally, these contents were unified into a framework to form a review. RESULTS: Some CTD analogues with imidazolium salt or double bonds at C-5 and C-6 positions demonstrate good anticancer activity. Through introducing methyl and acetoxy groups at the C-1 or C-4 position, the inhibitory effect of PP was weakened or even inactivated. Removing the two methyl groups of C-2 and C-3 can reduce side effects and improve efficacy. Replacing methyl with fluorine can also improve the activity and reduce toxicity. Water solubility and bioavailability could be improved by opening the five five-membered anhydride ring to form carboxylic acid, salt, amide, and ester derivatives. The anticancer mechanism can be divided into the following aspects, including inhibiting cell invasion and metastasis, inducing apoptosis, regulating cell cycle and enhancing immunity. The proper formulation of CTD and its analogues (liposomes, nanoparticles and micelles) can improve the targeting of liver cancer and reduce toxic and side effects. CTD combined with anti-angiogenic therapeutics (Ginsenoside Rg3, Bevacizumab, Apatinib and Endostar) showed additive anti-pancreatic cancer effects. CONCLUSION: It was found that the potential mechanism was closely related to multi-channel and multi-target interactions, which provided a guiding direction for the later exploration of new clinical therapeutic applications. However, some detailed mechanisms are still unclear, and more evidence is required to verify. In addition, the new methods to improve the therapeutic potential of CTD and its analogues still need more clinical trials to be tested in the future. This prospect is very broad and worthy of further study.

BACKGROUND: Statins are the main lipid-lowering drugs and are used in the prevention of cardiovascular diseases (CVDs). Since the results have been, to a certain extent, inconsistent in the clinical trials concerning different types of CVDs, a systematic review and meta-analysis was performed to prove the effect of statins on decreasing elevated levels of total cholesterol, triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in patients with CVDs. METHODS: Literature search was performed on major electronic databases (MEDLINE/PubMed, Scopus, and ISI Web of Science) from inception up to July 2021 to find randomized controlled trials (RCTs) evaluating the effect of different statins on different types of CVDs. The effect size was determined using weighted mean difference (WMD) and corresponding 95% confidence interval (CI). RESULTS: Statin therapy significantly decreased levels of total cholesterol (WMD = -33.37 mg/dl, 95% CI: -45.98 to -20.76, P<0.001), LDL-C (WMD = -29.42 mg/dl, 95% CI: -36.81 to -22.03, P<0.001), and TG (WMD = -15.19 mg/dl, 95% CI = -26.41 to -3.97, P<0.001), and increased levels of HDL-C (WMD = 1.55 mg/dl, 95% CI: 0.20, to 2.90, P=0.02) in patients with different CVDs. CONCLUSION: Statin therapy was found effective in lowering levels of total cholesterol, LDL-C, and TG, and increasing levels of HDL-C in patients with different CVDs.

Sulfonamides, with the general formula R-SO2NR1R2, have attracted great attention since the early discovery of sulfonamide-containing antibacterial drugs. The combinations of certain sulfonamides and other drug molecules to form sulfonamide hybrids are being used to develop novel formulations with greater effectiveness and in a huge range of therapeutic applications such as antimicrobial, antifungal, anti-inflammatory, antitubercular, antiviral, antidiabetic, antiproliferative, carbonic anhydrase inhibitor, antimalarial, anticancer and other medicinal agents. Part C of this review presents recent advances in designing and developing multicomponent sulfonamide hybrids containing more than one biologically active heterocycle, such as coumarin, indole, pyridine, pyrimidine, pyrazole, triazole, oxazole, oxadiazole, triazine, quinazoline, and thiadiazol. This review aims to highlight the status of the hybridization technique in synthesizing biological and computational studies of novel sulfonamide hybrids that were designed and presented between 2016 and 2020.

Sesquiterpene lactones are secondary plant metabolites with a wide variety of biological activities. The process of lactone conjugation to other pharmacophores can increase the efficacy and specificity of the conjugated agent effect on molecular targets in various diseases, including brain pathologies. Derivatives of biogenic indoles, including neurotransmitter serotonin, are of considerable interest as potential pharmacophores. Most of these compounds have neurotropic activity and, therefore, can be used in the synthesis of new drugs with neuroprotective properties. The aim of this experimental synthesis was to generate potential treatment agents for Alzheimer's disease using serotonin conjugated with natural sesquiterpene lactones. Three novel compounds were obtained via the Michael reaction and used for biological testing. The obtained conjugates demonstrated complex neuroprotective activities. Serotonin conjugated to isoalantolactone exhibited strong antioxidant and mitoprotective activities. The agent was also found to inhibit β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), prevent the aggregation of β-amyloid peptide 1-42, and protect SH-SY5Y neuroblastoma cells from neurotoxins such as glutamate and H2O2. In a transgenic animal model of Alzheimer's disease (5xFAD line), the conjugated agent restored declined cognitive functions and improved learning and memory. In conclusion, the obtained results indicate that serotonin conjugates to sesquiterpene lactones are promising agents for the treatment of symptoms associated with Alzheimer's disease.

BACKGROUND: Although radiotherapy is one of the main cancer treatment modalities, exposing healthy organs/tissues to ionizing radiation during treatment can lead to different adverse effects. In this regard, it has been shown that the use of radioprotective agents may alleviate the ionizing radiation-induced toxicities. OBJECTIVE: The present study aims to review the radioprotective potentials of silymarin/silibinin in the prevention/reduction of ionizing radiation-induced adverse effects on healthy cells/tissues. METHODS: Based on PRISMA guideline, a comprehensive and systematic search was performed for identifying relevant literature on the "potential protective role of silymarin/silibinin in the treatment of radiotherapy-induced toxicities" in the different electronic databases of Web of Science, PubMed, and Scopus up to April 2022. Four hundred and fifty-five articles were obtained and screened in accordance with the inclusion and exclusion criteria of the current study. Finally, 19 papers were included in this systematic review. RESULTS: The findings revealed that the ionizing radiation-treated groups had reduced survival rate and body weight in comparison with the control groups. It was also found that radiation can induce mild to severe adverse effects on skin, digestive, hematologic, lymphatic, respiratory, reproductive, and urinary systems. Nevertheless, the administration of silymarin/silibinin could mitigate the ionizing radiation-induced adverse effects in most cases. This herbal agent exerts its radioprotective effects through anti-oxidant, anti-apoptosis, anti-inflammatory activities, and other mechanisms. CONCLUSION: The results of the current systematic review showed that co-treatment of silymarin/silibinin with radiotherapy alleviates the radiotherapy-induced adverse effects in healthy cells/tissues.

Many drugs have adverse absorption, distribution, metabolism, and excretory (ADME) properties that prevent their widespread use or limit their use in some indications. In addition to preparation techniques and prodrug strategies, deuterium modification is a viable method for improving ADME properties. Deuterated drugs have attracted increasing attention from the pharmaceutical industry in recent years. To date, two deuterated drugs have been approved by the FDA. In 2017, austedo was approved by the FDA as a new drug for Huntington's disease in the United States, the first deuterium drug to be marketed worldwide. Recently (June 9, 2021), donafinil has been listed in China; this result has caused major pharmaceutical companies and the pharmaceutical industry to pay attention to deuterium technology again. In addition, BMS-986165, RT001, ALK-001, HC-1119, AVP-786 and other drugs are in phase Ⅲ clinical studies, and some solid deuterium compounds have entered phase I and Ⅱclinical trials. The deuterium strategy has been widely used in pharmaceutical research and has become a hot spot in pharmaceutical research in recent years. In this paper, the research and development of deuterated drugs are reviewed, and the influence of deuterium modification on drugs, the advantages of deuterium strategies and the synthesis strategies of deuterated drugs are mainly introduced. Hoping to provide references for clinical application, the discovery of new deuterium chemical entities and research and development of new deuterated drugs.

More than 10 million people worldwide have Alzheimer's disease (AD), a degenerative neurological illness and the most prevalent form of dementia. AD's progression in memory loss, cognitive deterioration, and behavioral changes are all symptoms. Amyloid-beta 42 (Aβ42), the hyperphosphorylated forms of microtubule-associated tau protein, and other cellular and systemic alterations are all factors that contribute to cognitive decline in AD. Rather than delivering a possible cure, present therapy strategies focus on reducing disease symptoms. It has long been suggested that various naturally occurring small molecules (plant extract products and microbiological isolates, for example) could be beneficial in preventing or treating disease. Small compounds, such as flavonoids, have attracted much interest recently due to their potential to alleviate cellular stress. Flavonoids have been proven helpful in various ways, including antioxidants, anti-inflammatory agents, and anti-apoptotic agents, but their mechanism remains unknown. The flavonoid therapy of Alzheimer's disease focuses on this review, which includes a comprehensive literature analysis.

BACKGROUND: Circulating microRNAs (miRNAs) are now used as non-invasive diagnostic indicators in a variety of malignancies. Our objective is to use a meta-analysis to assess the diagnostic performance of circulating miRNAs in gastric cancer. METHODS: We reviewed databases and methodically obtained papers for analysis up to October 15th, 2021. The random-effect meta-analysis was performed to construct pooled diagnostic parameter. To detect the causes of heterogeneity, spearman threshold effect analysis and subgroup analysis were performed. The I2 and Chi-square test were also used to examine the heterogeneity. The subgroup analyses were conducted based on sample types (serum/plasma/blood), normalized genes (U6, miR-16, and miR-39), qPCR mastermix (SYBR and Taqman), and country. Finally, the publication bias was estimated using Egger's funnel plot asymmetry test. RESULTS: A total of 40 articles covering 73 studies (59 microRNAs) were included, containing 11,022 participants (6,324 cases and 4,698 controls). The overall pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were 0.75 (95% CI: 0.74-0.77), 0.79 (95% CI: 0.78-0.80), 4.081 (95% CI: 3.43-4.85), 0.28 (95% CI: 0.25-0.32), 16.08 (95% CI: 12.34-20.95), and 0.877 (CI: 0.84- 0.90), respectively. We conducted a subgroup analysis of diagnostic value, which revealed that serum type, U6 reference gene, SYBR mastermix, and East Asian Countries (China, Japan, Taiwan) had better diagnostic value. CONCLUSIONS: In consequence, circulating miRNAs can serve as diagnostic biomarkers for gastric cancer. However, specific miRNAs still need to be discovered in diagnosing gastric cancer, especially early screening.

BACKGROUND: G-protein-coupled receptors (GPCRs) are the largest family of membrane receptors and the most intensively studied drug targets. Given the physiological importance of signal transduction by GPCRs and the recent progress in the structure determination of membrane proteins, the development of GPCR antagonists and agonists is expected to continue to be a major area of medicinal chemistry research. METHOD: The structure-property relationship illustrates how the modification of the chemical structure influences the absorption, distribution, metabolism, excretion, and other related properties of drug compounds. Understanding the structure-property relationships of clinically approved GPCR-targeted drugs and their analogues could provide useful information on the lead-to-candidate optimization strategies. RESULTS: Among more than 50 GPCR antagonists and agonists approved in the last decade, the structure-property relationships of 17 drugs are compiled from medicinal chemistry literature, in which detailed pharmacokinetic and toxicological properties are disclosed not only for the final drug candidate but also for key analogues generated during the lead optimization campaign. CONCLUSION: The structure-property relationships hereby summarized demonstrate how in vitro and in vivo properties of the membrane protein-targeted ligands could be effectively optimized, in many cases, without requiring a significant change in the molecular size. This information is expected to provide valuable insights to expedite new GPCR-targeted drug development.

This review covers nanotherapeutic strategies for solving the global problems associated with the Alzheimer disease (AD). The most dramatic factor contributing humanistic, social and economic urgency of the situation is the incurability of the disease, with the drug intervention addressing only AD symptoms and retarding their progress. Key sources behind these challenges are the inability of the early diagnosis of AD, lack of comprehensive information on the molecular mechanism of the pathogenesis, the blood-brain barrier obstacles, and low effectiveness of currently available drugs and therapeutic strategies. Application of nanocarriers allows the part of these problems to be solved, together with the improvement of drug bioavailability, prolonged circulation, and the biological barrier overcoming/bypassing. To this date, numerous types and sub-types of nanocarriers are developed and reviewed, the majority of which can be adapted for the treatment of various diseases. Therefore, herein, nanotherapy strategies are specifically categorized in term of the administration of AD medicines, with the noninvasive, i.e., transdermal, oral, and intranasal routes emphasized. Further, benefits/limitations of various nanocarriers are discussed, and perspectives of their application are highlighted.

Lipid metabolism is a complex biochemical process that regulates normal cell activity and death. Ferroptosis is a novel mode of programmed cell death different from apoptosis, pyroptosis, and autophagy. Abnormal lipid metabolism may lead to lipid peroxidation and cell rupture death, which are regulated by lipoxygenase(LOX), long-chain acyl-coA synthases, and antioxidant enzymes. Alternatively, Fe2+ and Fe3+ are required for the activity of LOXs and ferroptosis, and Fe2+ can significantly accelerate lipid peroxidation in ferroptosis. Abnormal lipid metabolism is a certain risk factor for cardiovascular disease. In recent years, the important role of ferroptosis in developing cardiovascular disease has been increasingly reported. Reducing lipid accumulation could reduce the occurrence of ferroptosis, thus alleviating cardiovascular disease deterioration. This article reviews the relationship of lipid peroxidation to the general mechanism of ferroptosis and highlights lipid peroxidation as the common point of ferroptosis and cardiovascular disease.

Ovarian cancer (OC) is the 3rd common gynecologic cancer. Numerous procedures are involved in the growth of OC, like migration, angiogenesis, proliferation, apoptosis, invasion, and metastasis. Therefore, a better knowledge of the molecular processes complicated in ovarian tumorigenesis can lead to better measures for the prevention and treatment of the disease and its diagnosis. Long non-coding RNAs (LncRNAs), a subclass of non-coding RNAs, are much more diverse than previously thought. It is suggested that these RNAs may play a role in controlling complex cellular signaling mechanisms via binding to proteins and influencing their function. Nevertheless, our acquaintance with the participation of LncRNAs in the pathogenesis of OC is still restricted. Especially, we do not yet recognize how to pharmacologically correct the epi-mutations. Resveratrol, a natural polyphenol mostly derived from grapes, has been evaluated in many studies to find its cancer therapeutic potential. In the current paper, we aimed to review the role of resveratrol as a potential natural product on lncRNAs as novel diagnostic and therapeutic targets in OC and represent new insights for further investigations.