DNA gyrase-inhibitory antimicrobial anthraquinone from the endophytic Sordariomycetes fungus Diaporthe perseae.

Fungi of the order Diaporthales are prolific sources of antimicrobial secondary metabolites. In this paper, we describe antimicrobial and antituberculosis anthraquinones (AQs) from Diaporthe perseae, an endophytic fungus isolated and identified from the endemic Philippine medicinal plant Uvaria alba (Annonaceae). Large-scale rice fermentation of D.

Uncovering a Mutation-Independent Therapeutic Strategy against Inherited Retinal Diseases: Development of Class I HDAC/LSD1 Hybrid Inhibitors.

Among genetic retinal disorders, retinitis pigmentosa (RP) is characterized by degeneration of rod photoreceptors caused by a large number of diverse mutations, most of which act through different pathways to which epigenetic targets also contribute. The eraser enzymes lysine demethylase 1 (LSD1) and histone deacetylase 1 (HDAC1) play major roles in the development of rod photoreceptors, and their inhibitors were shown to block inherited rod degeneration, preserving vision and contributing to a general anti-inflammatory profile at the retinal level. In this work, we proposed the development of polypharmacological agents targeting class I HDAC/LSD1 enzymes with the aim of treating the mice model of RP.

Hydroxyl carboxylic acid receptor-2 (HCAR2) as a potential target in neurometabolic diseases.

Hydroxycarboxylic acid receptor 2 (HCAR2) is a G-protein-coupled receptor initially identified for its role in lipid metabolism. Beyond its classical metabolic functions, HCAR2 plays a pivotal role in chronic inflammatory diseases, neurometabolic disorders, and pain modulation. Evidence from preclinical studies suggest that when endogenously activated by β-hydroxybutyrate and pharmacologically by niacin and its derivatives, HCAR2 attenuates microglial reactivity, suppress pro-inflammatory cytokine release, and modulate neuronal excitability, by offering neuroprotective benefits in neurological disorders and chronic pain.

Novel Antiviral Agents: Synthesis, Molecular Modelling Studies and Biological Investigation, 2nd Edition.

After the success of the Special Issue entitled "" (https://www [...

Synthesis and biological investigation of peptidomimetic SARS-CoV-2 main protease inhibitors bearing quinoline-based heterocycles at P.

In the last few years, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been the cause of a worldwide pandemic, highlighting the need for novel antiviral agents. The main protease (M) of SARS-CoV-2 was immediately identified as a crucial enzyme for viral replication and has been validated as a drug target. Here, we present the design and synthesis of peptidomimetic M covalent inhibitors characterized by quinoline-based P moieties.

Natural Compounds from Alhagi maurorum as Potential HCC and HepG2 Inhibitors: An Integrated Study using Pharmacophore Development, Molecular Docking, MD Simulation, and DFT Approaches.

Background: The rise in the frequency of liver cancer all over the world makes it a prominent area of research in the discovery of new drugs or repurposing of existing drugs.

Methods: This article describes the pharmacophore-based structure-activity relationship (3DQSAR) on the secondary metabolites of Alhagi maurorum to inhibit human liver cancer cell lines Hepatocellular carcinoma (HCC) and hepatoma G2 (HepG2) which represents the molecular level understanding for isolated phytochemicals of Alhagi maurorum. The definite features, such as hydrophobic regions, average shape, and active compounds' electrostatic patterns, were mapped to screen phytochemicals.

Microbial Fermentation in Food and Beverage Industries: Innovations, Challenges, and Opportunities.

Microbial fermentation is a primary method by which a variety of foods and beverages are produced. The term refers to the use of microbes such as bacteria, yeasts, and molds to transform carbohydrates into different substances. Fermentation is important for preserving, enhancing flavor, and improving the nutritional quality of various perishable foods.

Carotenoid Interactions with PCSK9: Exploring Novel Cholesterol-Lowering Strategies.

: This study investigated the potential of green algae-derived carotenoids as natural inhibitors of the proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol metabolism. PCSK9 promotes the degradation of low-density lipoprotein receptors (LDLR), thereby increasing blood cholesterol levels and elevating the risk of cardiovascular diseases. /: We screened the pharmacophore fit score of 27 carotenoids with PCSK9 and identified 14 that were analyzed for binding affinity and molecular interactions.

Antitumor Activity and Multi-Target Mechanism of Phenolic Schiff Bases Bearing Methanesulfonamide Fragments: Cell Cycle Analysis and a Molecular Modeling Study.

Five phenolic Schiff bases (-) incorporating a fragment of methanesulfonamide were synthesized and evaluated for their efficacy as antitumor agents. Compounds and demonstrated the most potent antitumor action, with a positive cytotoxic effect (PCE) of 54/59 and 59/59 and a mean growth percentage (MG%) of 67.3% and 19.

Synthesis, enzyme inhibition assay, and molecular modeling study of novel pyrazolines linked to 4-methylsulfonylphenyl scaffold: antitumor activity and cell cycle analysis.

Antitumor activity using 59 cancer cell lines and enzyme inhibitory activity of a newly synthesized pyrazoline-linked 4-methylsulfonylphenyl scaffold (compounds 18a-q) were measured and compared with those of standard drugs. Pyrazolines 18b, 18c, 18f, 18g, 18h, and 18n possessed significant antitumor activity, with a positive cytotoxic effect (PCE) of 22/59, 21/59, 21/59, 48/59, 51/59, and 20/59, respectively. The cancer cell lines HL60, MCF-7, and MDA-MB-231 were used to measure the IC values of derivatives 18c, 18g, and 18h the MTT assay method, and the results were compared with those of reference drugs.

Intermittent Fasting: Myths, Fakes and Truth on This Dietary Regimen Approach.

Intermittent fasting (IF) has been indicated as a valuable alternative to the classical caloric restriction dietary regimen for lowering body weight and preventing obesity-related complications, such as metabolic syndrome and type II diabetes. However, is it effective? In this review article, we analyzed over 50 clinical studies in which IF, conducted by alternate day fasting (ADF) or time-restricted feeding (TRF), was compared with the caloric restriction approach. We evaluated the different roles of IF in treating and preventing human disorders such as metabolic syndrome, type II diabetes, and some types of cancer, as well as the usefulness of IF in reducing body weight and cardiovascular risk factors such as hypertension.

Targeting Relevant HDACs to Support the Survival of Cone Photoreceptors in Inherited Retinal Diseases: Identification of a Potent Pharmacological Tool with In Vitro and In Vivo Efficacy.

Inherited retinal diseases, which include retinitis pigmentosa, are a family of genetic disorders characterized by gradual rod-cone degeneration and vision loss, without effective pharmacological treatments. Experimental approaches aim to delay disease progression, supporting cones' survival, crucial for human vision. Histone deacetylases (HDACs) mediate the activation of epigenetic and nonepigenetic pathways that modulate cone degeneration in RP mouse models.

Globospiramine Exhibits Inhibitory and Fungicidal Effects against via Apoptotic Mechanisms.

Candidiasis is considered an emerging public health concern because of the occurrence of drug-resistant strains and the lack of an available structurally diverse antifungal drug armamentarium. The indole alkaloid globospiramine from the anticandidal Philippine medicinal plant exhibits a variety of biological activities; however, its antifungal properties remain to be explored. In this study, we report the in vitro anticandidal activities of globospiramine against two clinically relevant species ( and ) and the exploration of its possible target proteins using in silico methods.

Globospiramine from Exerts Robust Cytotoxic and Antiproliferative Activities on Cancer Cells by Inducing Caspase-Dependent Apoptosis in A549 Cells and Inhibiting MAPK14 (p38α): In Vitro and Computational Investigations.

Bisindole alkaloids are a source of inspiration for the design and discovery of new-generation anticancer agents. In this study, we investigated the cytotoxic and antiproliferative activities of three spirobisindole alkaloids from the traditional anticancer Philippine medicinal plant , along with their mechanisms of action. Thus, the alkaloids globospiramine (), deoxyvobtusine (), and vobtusine lactone () showed in vitro cytotoxicity and antiproliferative activities against the tested cell lines (L929, KB3.

Exploring Type II Diabetes Inhibitors from Genus Daphne Plant-species: An Integrated Computational Study.

Background: Plant species of the genus Daphne clasps a historical background with a potential source of bioactive phytochemicals such as flavonoids and daphnodorins. These compounds manifest a significant chemotaxonomic value in drug discovery. Their flair comprehensive pharmacological, phytochemical, biological, catalytic, and clinical utilities make them exclusively unique.

A novel potent class I HDAC inhibitor reverses the STAT4/p66Shc apoptotic defect in B cells from chronic lymphocytic leukemia patients.

Chronic Lymphocytic Leukemia (CLL) patients have a defective expression of the proapoptotic protein p66Shc and of its transcriptional factor STAT4, which evoke molecular abnormalities, impairing apoptosis and worsening disease prognosis and severity. p66Shc expression is epigenetically controlled and transcriptionally modulated by STAT4; epigenetic modifiers are deregulated in CLL cells and specific histone deacetylases (HDACs) like HDAC1, are overexpressed. Reactivation of STAT4/p66Shc expression may represent an attractive and challenging strategy to reverse CLL apoptosis defects.

Natural products as non-covalent and covalent modulators of the KEAP1/NRF2 pathway exerting antioxidant effects.

By controlling several antioxidant and detoxifying genes at the transcriptional level, including NAD(P)H quinone oxidoreductase 1 (NQO1), multidrug resistance-associated proteins (MRPs), UDP-glucuronosyltransferase (UGT), glutamate-cysteine ligase catalytic (GCLC) and modifier (GCLM) subunits, glutathione S-transferase (GST), sulfiredoxin1 (SRXN1), and heme-oxygenase-1 (HMOX1), the KEAP1/NRF2 pathway plays a crucial role in the oxidative stress response. Accordingly, the discovery of modulators of this pathway, activating cellular signaling through NRF2, and targeting the antioxidant response element (ARE) genes is pivotal for the development of effective antioxidant agents. In this context, natural products could represent promising drug candidates for supplementation to provide antioxidant capacity to human cells.

A virtual insight into mushroom secondary metabolites: 3D-QSAR, docking, pharmacophore-based analysis and molecular modeling to analyze their anti-breast cancer potential.

Breast cancer is a major issue of investigation in drug discovery due to its rising frequency and global dominance. Plants are significant natural sources for the development of novel medications and therapies. Medicinal mushrooms have many biological response modifiers and are used for the treatment of many physical illnesses.

Exploring Phytochemicals as Potential Inhibitors for Breast Cancer Genes BRCA1 and BRCA2 Using Pharmacophore Modeling, Molecular Docking, MD Simulations, and DFT Analysis.

Background: Structure-activity relationship (SAR) is considered to be an effective in silico approach when discovering potential antagonists for breast cancer due to gene mutation. Major challenges are faced by conventional SAR in predicting novel antagonists due to the discovery of diverse antagonistic compounds. Methodologyand Results: In predicting breast cancer antagonists, a multistep screening of phytochemicals isolated from the seeds of the plant was applied using feasible complementary methodologies.

Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. SARs, Structural Analysis, and Biological Characterization.

New potent, selective monoacylglycerol lipase (MAGL) inhibitors based on the azetidin-2-one scaffold ((±)--, (±)--, and (±)--) were developed as irreversible ligands, as demonstrated by enzymatic and crystallographic studies for (±)-, (±)-, and (±)-. X-ray analyses combined with extensive computational studies allowed us to clarify the binding mode of the compounds. was identified as selective for MAGL when compared with other serine hydrolases.

Lithocholic acid derivatives as potent modulators of the nuclear receptor RORγt.

Retinoic acid receptor-related orphan receptor γt (RORγt) is a nuclear receptor found in various tissues that plays a crucial role in the differentiation and proliferation of T helper 17 (Th17) cells, as well as in their generation of the pro-inflammatory cytokine IL-17A. RORγt represents a promising therapeutic target for autoimmune diseases, metabolic disorders, and multiple tumors. Despite extensive research efforts focused on the development of small molecule RORγt modulators, no drug candidates have advanced to phase 3 clinical trials owing to a lack of efficacy or safety margin.

Structure-Based High-Throughput Virtual Screening and Molecular Dynamics Simulation for the Discovery of Novel SARS-CoV-2 NSP3 Mac1 Domain Inhibitors.

Since the emergence of SARS-CoV-2, many genetic variations within its genome have been identified, but only a few mutations have been found in nonstructural proteins (NSPs). Among this class of viral proteins, NSP3 is a multidomain protein with 16 different domains, and its largest domain is known as the macrodomain or Mac1 domain. In this study, we present a virtual screening campaign in which we computationally evaluated the NCI anticancer library against the NSP3 Mac1 domain, using Molegro Virtual Docker.

Novel Antiviral Agents: Synthesis, Molecular Modelling Studies and Biological Investigation.

Representing more than 20% of all deaths occurring worldwide, infectious diseases remain one of the main factors in both human and animal morbidity and mortality [...

Developmental landscape of computational techniques to explore the potential phytochemicals from peels for their antioxidant activity in Alzheimer's disease.

Alzheimer's disease (AD) is more commonly found in women than in men as the risk increases with age. Phytochemicals are screened from peels for their antioxidant activity to be utilized for Alzheimer's disease. Alzheimer's disease is inhibited by the hormone estrogen, which protects the brain from the bad effects of amyloid beta and acetylcholine (ACh), and is important for memory processing.