Molecular Mechanism Of Action Research Articles

Consumption of Plant-Derived Phenolic Acids Modulates Hunger and Satiety Responses Due to Chemical Interactions with Enteroendocrine Mediators

Energy-dense foods are commonly rich in fat and simple sugars and poor in dietary fiber and micronutrients; regularly consuming them decreases the concentration and/or effect of anorexigenic hormones and may increase that of orexigenic ones, thereby decreasing satiety. In contrast, plant-derived phenolic-rich foods exert positive effects on satiety. In silico, in vitro, and in vivo investigations on some of most representative phenolic acids like chlorogenic acid (CGA), gallic acid (GA), ferulic acid (FA), and protocatechuic acid (PCA) have shown that they are able to modulate various hunger and satiety processes; however, there are few studies that show how their chemical structure contributes to achieve such effects. The objective of this review is to summarize how these phenolic acids can favorably modulate hormones and other satiety mediators, with emphasis on the chemical interactions exerted between the core of these compounds and their biological targets. The evidence suggests that they form interactions with certain hormones, their receptors, and/or enzymes involved in regulating hunger and satiety, which are attributed to their chemical structure (such as the position of hydroxyl groups). Further research is needed to continue understanding these molecular mechanisms of action and to utilize the knowledge in the development of health-promoting foods.

Biochemical and proteomic approaches to investigating effects of IAA-aspartate in pea (Pisum sativum L.) seedlings during osmotic shock.

Osmotic shock is the first step of high salt or drought action that involves biochemical and molecular changes during plant response to these unfavorable conditions. Indole-3-acetyl-aspartate (IAA-aspartate, IAA-Asp) is the main amide conjugate of auxin in pea (Pisum sativum L.) tissues. Although the exact molecular mechanism of the IAA-Asp action is unknown, this conjugate's indole-3-acetic acid (IAA)-independent biological activity has been observed during physiological and stress conditions. In this work, we investigated the effect of IAA-Asp alone, as well as in combination with NaCl or polyethylene glycol (PEG) (osmotic shock) on reduced/oxidized glutathione (GSH/GSSG) ratio, activities of enzymes modulating glutathione concentration, protein S-glutathionylation, and IAA homeostasis. We did not observe the hydrolysis of IAA-Asp to IAA in pea seedlings, which, together with other results, suggests that IAA-Asp modulates plant response to abiotic stimuli independently of IAA. Moreover, despite the effect of IAA-Asp on the enzymes responsible for IAA conjugation, no changes in this phytohormone level were visible. Furthermore, 3h plant treatment with IAA-Asp increased the activity of glutathione reductase (GR), which correlates with an elevated GSH/GSSG ratio. On the contrary, more extended (48h) incubation with IAA-Asp diminished the GSH/GSSG ratio and increased the activity of glutathione peroxidase (GPX). IAA-Asp reduced GR activity during salt treatment but did not affect the GSH/GSSG ratio. Similarly, under plant incubation with PEG, IAA-Asp did not change the GSH/GSSG ratio but increased glutathione S-transferase (GST) activity. We also analyzed the effect of IAA-Asp on pea protein S-glutathionylation. Increased S-glutathionylation of heat shock 70 kDa protein (HSP70) was observed after plant treatment with IAA-Asp, PEG, or IAA-Asp combined with PEG. The proteomic analysis also revealed that IAA-Asp diminished S-glutathionylation of lipoxygenase during plant incubation with PEG. Thus, we suggest that IAA-Asp modulates redox status in pea during oxidative stress and under normal physiological conditions.

The decline in the clinical relevance of pilocarpine and physostigmine monitored in pharmacology textbooks from 1878 to 2023: nine take-home messages for future (pharmacology) textbook authors.

In a recent study, using hydrogen cyanide as paradigm, we have shown that pharmacological knowledge evolves non-linearly ( https://pubmed.ncbi.nlm.nih.gov/38900251/ ). The aim of this study was to investigate the changes in the presentation of the drugs pilocarpine and physostigmine in textbooks from 1878 to 2023. The categories of structure, molecular mechanism of action, pharmacokinetics, effects, indications, adverse drug reactions, interactions, and contraindications were evaluated. The pharmacological knowledge on the molecular mechanism, chemical structure, and pharmacokinetics of pilocarpine and physostigmine changed the most during the period of 150 years. Until 1944, textbooks did not mention a molecular mechanism of action of pilocarpine and from 1951 onwards they described the activation of muscarinic acetylcholine receptors as the molecular basis of pilocarpine's effect. Until 1944, most textbooks on physostigmine also did not mention the molecular mechanism of action. From 1951 onwards, the reversible inhibition of acetylcholinesterase is mentioned as the mechanism of action of physostigmine. In contrast, in the categories effects, indications, adverse drug reactions, interactions, and contraindications, the detected changes in the pharmacological knowledge presented were comparatively smaller. Older pharmacology textbooks were better than newer ones at discussing changes in knowledge and scientific errors. We noted substantial differences in the presentation of pilocarpine and physostigmine among German and US pharmacology textbooks. We show a decline of the clinical relevance of both drugs and their presentation in pharmacological textbooks with physostigmine being virtually irrelevant. But modern textbooks still discuss physostigmine substantially, fitting to studies on the obsolete drug reserpine ( https://pubmed.ncbi.nlm.nih.gov/38103060/ ). Thus, textbooks often far lag clinical practice. Google Scholar conveys the incorrect impression that physostigmine is clinically more relevant than it is. An exponential decline in prescription numbers is a robust indicator of clinical obsolescence. From our study, we extract nine easily implementable take-home messages for future (pharmacology) textbook authors to ensure that this traditional teaching format will prevail against the competition of allegedly more "modern" teaching media.

CSIG-32. MODULATION OF HALLMARKS OF GLIOBLASTOMA MULTIFORME BY BIOACTIVE PHYTOCHEMICALS: A PRECLINICAL MECHANISTIC EVALUATION

Abstract Glioblastoma multiforme (GBM) is an aggressive malignancy with extensive neovascularization, an immunosuppressive tumor microenvironment, and high recurrence rates. Bioactive plant secondary metabolites (phytochemicals), many from fruits and vegetables, have been extensively studied for GBM prevention and treatment. The objective of this study is to determine the effects of phytochemicals on GBM hallmarks and associated molecular mechanisms of action through evaluation of in vitro and in vivo studies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to collect articles using PubMed, ScienceDirect and Scopus. While 1,344 articles were screened, 115 in vitro and 36 in vivo studies met our inclusion criteria. The Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) review of bias tool assessed in vivo study bias. In vitro, 49 alkaloids, 10 phenolics, 2 sulfur- compounds, and 5 terpenoids modulated GBM hallmarks of cell growth, invasion, cell cycle progression, neovascularization, and apoptosis. The PI3K/Akt/mTOR pathway was suppressed by 13 phytochemicals. Apoptosis was induced by 15 phytochemicals activating caspase-3, whereas 11 compounds inhibited Bcl-2. Cell cycle modulation occurred through decreased cyclin-dependent kinases and increased p53, p21, and p27. In vivo, 17 alkaloids, 5 phenolics, 2 sulfur-compounds, and 2 terpenoids had effects on GBM hallmarks. Invasion and neovascularization were inhibited through MMP, HIF-1α, and VEGF modulation. Six phytochemicals induced apoptosis in vivo through caspases and Bcl-2. Utilizing the SYRCLE review of bias tool, the average score quality of animal studies is 10% with many indicators of bias unclear. Various phytochemicals show promise to prevent and treat GBM due to their effects on numerous GBM hallmarks. Study limitations include the inclusion of literature reporting effects of single agents and lack of clinical studies. Future research is warranted to fill gaps in our analysis before recommending phytochemicals for prevention and treatment of GBM, a perilous malignancy.

Therapeutic Potential of Quercetin Analogous: Prospective and Advances.

The purpose of the article is to investigate the therapeutic potential of quer-cetin and related compounds by elucidating their pharmacological characteristics and molecular mechanisms of action. The potential benefits of quercetin and its analogs for cardiovascular health, disorders of the brain, metabolic disorders, and more are discussed in the discussion part of this page. Concerns about their clinical efficacy due to issues with bioavailability and distribution are also discussed. This region of the paper emphasizes the importance of researchers and clinicians working together to maximize the incorporation of these chemicals into real-world therapeutic approaches. In conclusion, quercetin, along with related substances, shows great potential in a wide range of therapeutic settings. Potentially useful for the management of a wide variety of illnesses, their multiple methods of action include the regulation of pathways for cell signaling and interaction with different enzymes. However, additional clinical tri-als are needed to verify their efficacy and safety.

Exploring the potential pharmacological mechanism of aripiprazole against hyperprolactinemia based on network pharmacology and molecular docking

The current primary therapeutic approach for schizophrenia is antipsychotic medication, and antipsychotic-induced hyperprolactinemia occurs in 40–80% of patients with schizophrenia. Aripiprazole, an atypical antipsychotic belonging to the quinolinone derivative class, can reduce the likelihood of developing hyperprolactinemia, but the pharmacological mechanisms of this reduction are unknown. This study aimed to explore the molecular mechanism of action of aripiprazole in treating hyperprolactinemia based on network pharmacology and molecular docking techniques. This study identified a total of 151 potential targets for aripiprazole from the DrugBank, TCMSP, BATMAN-TCM, TargetNet, and SwissTargetPrediction databases. Additionally, 71 hyperprolactinemia targets were obtained from the PharmGKB, DrugBank, TTD, GeneCards, OMIM, and DisGENET databases. Utilizing Venny 2.1.0 software, an intersection of 27 genes was identified between aripiprazole and hyperprolactinemia. To construct a common target protein–protein interaction (PPI) network, the common targets obtained from both sources were input into the STRING database. The resulting PPI network was then imported into Cytoscape 3.7.2 software, which identified eight core targets associated with aripiprazole’s treatment of hyperprolactinemia. Subsequently, a PPI network was established for these targets. Enrichment analysis of the key targets was conducted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes in the DAVID database. Additionally, molecular docking verification of the interaction between aripiprazole and the core targets was performed using AutoDock Vina software. Aripiprazole’s intervention in hyperprolactinemia primarily targets the following core proteins: Solute Carrier Family 6 Member 3 (SLC6A3), monoamine oxidase (MAO-B), Dopamine D2 receptor (DRD2), 5-hydroxytryptamine (serotonin) receptor 2A (HTR2A), 5-hydroxytryptamine (serotonin) receptor 2C (HTR2C), cytochrome P450 2D6 (CYP2D6), Dopamine D1 receptor (DRD1), Dopamine D4 receptor (DRD4). These targets are predominantly involved in biological processes such as the adenylate cyclase-activating adrenergic receptor signaling pathway, G-protein coupled receptor signaling pathway coupled to cyclic nucleotide second messenger, phospholipase C-activating G-protein coupled receptor signaling pathway, chemical synaptic transmission, and response to xenobiotic stimulus. Primary enrichment occurs in signaling pathways such as the neuroactive ligand-receptor interaction and serotonergic synapse pathways. Molecular docking results demonstrate a favorable affinity between aripiprazole and the core target proteins MAO-B, DRD2, SLC6A3, HTR2C, HTR2A, CYP2D6, DRD4, and DRD1. Network pharmacology predicted potential targets and signaling pathways for aripiprazole’s intervention in hyperprolactinemia, offering theoretical support and a reference basis for optimizing clinical strategies and drug development involving aripiprazole.

A comprehensive and systematic review on Curcumin as a promising candidate for the inhibition of melanoma growth: From pre-clinical evidence to molecular mechanisms of action

BackgroundMelanoma, a highly malignant skin tumor, can develop systemic metastases during the early stage. Several studies of melanoma animal models indicate that curcumin, a natural plant extract, inhibits melanoma growth through various mechanisms. To evaluate the relationships among different experimental conditions, curcumin itself, its derivatives, and special formulations, it is necessary to conduct a systematic review and meta-analysis. PurposeThis meta-analysis aims to evaluate the potential of Curcumin as a drug for inhibiting the growth of melanoma and to determine the optimal dosage range and treatment duration for Curcumin administration. MethodsA systematic search of studies published from inception to December 2023 was conducted across six databases (PubMed, Web of Science, Embase, China National Knowledge Infrastructure, Wanfang Data, and VIP). Methodological quality was assessed using SYRCLE's RoB tool. Study heterogeneity was assessed using Cochran's Q test and I2 statistics. Publication bias risk was evaluated using a funnel plot. All analyses were performed using R (version 4.3.3). Additionally, three-dimensional effect analysis and machine learning techniques were utilized to determine the optimal dosage range and treatment duration for Curcumin administration. ResultsForty studies involving 989 animals were included. The results demonstrated that, relative to the control group, administration of Curcumin resulted in a significant reduction in tumor volume. [SMD=−3.44; 95 % CI (−4.25, −2.63); P<0.01; I2 = 79 %] and tumor weight [SMD=−1.93; 95 % CI (−2.41, −1.45); P<0.01; I2 = 75 %]. Additionally, Curcumin demonstrated a significant capacity to decrease the number of lung tumor nodules and microangiogenesis, as well as to extend survival time, in animal models. The results from three-dimensional effect analysis and machine learning emphasize that the optimal dosage range for Curcumin is 25–50 mg/kg, with an intervention duration of 10–20 days. ConclusionCurcumin can inhibit the growth of melanoma, and the dose-response relationship is not linear. However, further large-scale animal and clinical studies are required to confirm these conclusions.

Protective mechanism of Prim-O-glucosylcimifugin in the treatment of osteoarthritis: Based on lncRNA XIST regulation of Nav1.7

LncRNA XIST and Nav1.7 have been identified to be significantly associated with the onset of osteoarthritis. Prim-O-glucosylcimifugin (POG) has antiinflammatory and analgesic effects in treating osteoarthritis (OA). However, its molecular mechanism of action remains unclear. This research investigated whether POG inhibits OA cartilage degeneration by regulating Nav1.7 through lncRNA XIST. We observed the relationship between lncRNA XIST and Nav1.7 through in vivo and in vitro experiments, and utilized lentiviral plasmids for XIST overexpression to further validate the protective effect of POG against OA. In vivo experiments revealed the close association of improving OA cartilage morphological changes by POG with lncRNA XIST and Nav1.7 downregulation and related proteins expression. In vitro experiments demonstrated significantly up-regulated lncRNA XIST and Nav1.7 expression in IL1β-induced chondrocytes, and their levels and related protein expression decreased after POG intervention. FISH indicated that POG attenuated the fluorescence intensity of lncRNA XIST in chondrocytes. RT-PCR and Western blot assays revealed the positive correlation of lncRNA XIST and Nav1.7 expression in chondrocytes. Additionally, flow cytometry results revealed that POG intervention reduced OA chondrocyte apoptosis. Therefore, we conclude that POG can mediate lncRNA XIST to regulate Nav1.7 to delay cartilage degeneration, which is an effective way to treat OA. However, lncRNA XIST is not the only target for regulation, and further discussion is needed.

Design, in silico studies and biological evaluation of novel chalcones tethered triazolo[3,4-a]isoquinoline as EGFR inhibitors targeting resistance in non-small cell lung cancer

A novel series of six [1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-(1,3-diphenyl-1H-pyrazol-4-yl)prop-2-en-1-ones (3a–3f) was designed and synthesized. They were characterized based on spectral and elemental analyses. In silico studies were also committed to provide insights and a better understanding of their structural features. The six compounds were screened for their antiproliferative activity using the MTT assay against five human cancer cell lines, namely, A549, HCT116, PC3, HT29, and MCF-7 in parallel with the non-cancerous human lung cell line WI-38. The results showed that 3e and 3f have potential cytotoxic activities, especially on A549 cells with IC50 = 2.3 µM and 1.15 µM, respectively. Meanwhile, they recorded a minimal cytotoxic effect on WI-38 cells. Concerning the molecular mechanism of action, the present study showed the inhibitory effect of the six compounds against total EGFR. The most potent EGFR inhibitors were 3e and 3f with IC50 = 0.031 µM and 0.023 µM, respectively. The selectivity index of 3f for EGFRT790M was 1.81 times more selective than that of lapatinib. In addition, 3e and 3f initiated cell cycle arrest at the G2/M and pre-G1 phases along with the downregulation of anti-apoptotic protein Bcl2 and the upregulation of pro-apoptotic proteins: p53, Bax, and caspases 3, 8, and 9. Further studies are recommended to evaluate animal models’ promising anticancer activity and molecular mechanism of triazolo[3,4-a]isoquinoline derivatives 3e and 3f.

Mechanistic study of Nidus Vespae inhibiting gastric cancer in vitro through the JAK2/STAT3 signaling pathway

Ethnopharmacological relevanceNidus Vespae, an animal-derived traditional Chinese medicine, has a long-standing history in treating inflammatory conditions and tumor-related diseases. Notably, Nidus Vespae decoction (NVD) has been shown to inhibit the proliferation of gastric cancer cells, although the underlying mechanisms remain unclear. ObjectiveThis study aimed to elucidate the efficacy and mechanisms by which NVD exerts its therapeutic effects on gastric cancer. Materials and methodsWe employed the Cell Counting Kit-8 (CCK-8) assay to assess the impact of NVD on gastric cancer cell proliferation, while flow cytometry was utilized to evaluate cell cycle arrest and apoptosis. Differentially expressed proteins (DEPs) were identified by proteomics analysis, which were further analyzed through Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Protein-protein interaction (PPI) analysis was conducted to identify the hub genes. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were conducted to assess mRNA and protein levels related to apoptosis, cell cycle regulation, and the JAK2/STAT3 pathway. Rescue experiments with Colivelin TFA confirmed the role of NVD in inhibiting gastric cancer cell proliferation. UPLC-HRMS and HS-SPME-GC-MS technologies were performed to analyze the composition of NVD, and the bioinformatics tool called BATMAN-TCM database was used for functional analyses. ResultsOur results demonstrated that NVD significantly hindered the proliferation of gastric cancer cells, initiated programmed cell death, and induced cell cycle arrest in G2/M or G0/G1 phases in various gastric carcinoma cells in vitro. The identified DEPs were involved in several cancer-related pathways and signal transduction processes, notably the JAK-STAT receptor signaling pathway. NVD was found to down-regulate the JAK2/STAT3 signaling cascade, and reactivation of STAT3 diminished its anti-gastric cancer effects. Finally, the ingredient-target-disease network analysis also verified the anti-tumor effect of NVD. ConclusionThis study highlights the potential of Nidus Vespae as a therapeutic agent for gastric cancer, providing insights into its molecular mechanisms of action.

Charge-Transfer Interactions Between Antibiotics and Small Organic Acids: Spectroscopic Characterization and Computational Investigation

Six new charge-transfer complexes using ofloxacin (OFL) and sulfamethazine (SMR) as electron donors and coumaric acid (COA), cinnamic acid (CNA), and salicylic acid (SAA) as acceptors via equimolar mixture have been synthesized. The experiment used UV-vis spectroscopy to determine the formation of the complex in methanol through the presence of a new broad absorption band with a maximum wavelength in the 200-400 nm range. The molecular composition of the charge-transfer complexes was determined by the spectrophotometric titration method and found to be 1:1 (donor: acceptor). These complexes have been characterized by infrared (FTIR) and scanning electron microscopy (SEM). In the FTIR spectra, the CT complexes showed a wavelength shift compared to the reactants. The complexes exhibited various morphologies by SEM, including spherical particles, short rods, and flattened shapes. Additionally, quantum chemical calculations at the DFT/B3LYP level of theory investigated the complexes' steady-state structures, energies, and charge densities. The intermolecular binding energies was negative, indicating that the reactions of the six complexes proceeded spontaneously. There was strong van der Waals forces and hydrogen bonds between the donor and acceptor, which contributed to the complexes' strong molecular stability. The C-N and N-H groups in the donor molecule, and the -COOH group in the acceptor molecule, played key roles in the complexation process. DFT calculation results were appropriate to support our experimental results. This study highlights the molecular mechanisms of donor and acceptor action in charge-transfer interactions, providing a theoretical basis for the synthesis of antibiotic complexes and the removal of antibiotics.

20(R)-ginsenoside Rg3 Alleviates Diabetic Retinal Injury in T2DM Mice by Attenuating ROS-mediated ER Stress Through the Activation of the Nrf2/HO-1 Axis

BackgroundAlthough our previous work confirmed 20(R)-ginsenoside Rg3 (R-Rg3), which is an active ingredient in the Panax Ginseng C.A. Meyer, to have good anti-diabetic activity, its beneficial effect on diabetic retinal injury was found to be limited. PurposeThis study aims to investigate the protective effects of R-Rg3 on diabetes-induced retinal injury and the associated molecular mechanisms of action. MethodsDiabetic retinal injury was induced in mice using a combination of a high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). R-Rg3 (10 and 20 mg/kg) was subsequently administered for 6 weeks. The human retinal endothelial cells (HRECs) were subjected to high glucose (HG)-induced injury for the in vitro analysis and treated with R-Rg3 (4, 8, 16 μM), antioxidant N-Acetylcysteine (NAC, 1 mM) and Nrf2 inhibitor ML385 (5 μM). The mice retinas then underwent functional and histopathological analysis. Expression levels of proteins related to the Nrf2/HO-1 axis, tight junction proteins, endoplasmic reticulum (ER) stress and the apoptosis in retinal tissue and HRECs were determined by western blot. Expressions of ZO-1 and Nrf2 in the retina and HRECs were assessed by immunofluorescence. Additional evaluations included measuring body weights, fasting blood glucose (FBG), lipid levels and oxidative markers. ResultsThe results showed 6 weeks of R-Rg3 treatment significantly restored the functional changes and redox system imbalance that was induced by HFD/STZ in mice. R-Rg3 was also found to significantly reduce retinal barrier damage and thickness changes resulting from hyperglycaemia exposure. At the same time, R-Rg3 also protected HRECs from HG-induced damage. R-Rg3 could also activate Nrf2/HO-1 axis and inhibit endoplasmic reticulum stress as a means of alleviating retinal endothelial cells apoptosis. The molecular docking results also demonstrated that R-Rg3 had a good binding ability with Nrf2. ConclusionOur study suggested Nrf2/HO-1 axis might be crucial for the ability of R-Rg3 to prevent diabetic retinal injury.

Chemopreventive potential of goniothalamin in diethylnitrosamine-induced hepatocellular carcinoma through the suppression of P13K/AKT signalling pathway.

Liver cancer is the most lethal form of cancer and carries a high risk of death around the world. Goniothalamin (GTN) is a styryl-lactone that possesses antiproliferative and apoptotic activity. The molecular action of GTN is not yet fully evaluated. Thus, our research has been intended to assess the chemopreventive and apoptotic activities of diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in rats. Rats were separated into 4 groups: control, DEN only, DEN + GTN (30 mg/kg bw), and GTN (30 mg/kg bw) alone. We evaluated body weight, liver weight, tumor incidence, hepatic toxic markers, antioxidants, inflammatory cytokines, histopathology, immunohistochemistry, and Western blot studies. DEN lessened body weight, antioxidants, and apoptosis, whereas it elevated tumor incidence, toxic markers, cytokines, and Bcl-2 expression. GTN treatment maintains body weight, liver weight, and antioxidant levels, and it also prevents tumor incidence, oxidative stress, toxic markers, pro-inflammatory cytokines, and histological changes. It triggers apoptosis by constraining Bcl-2 and elevating caspase-3 levels. GTN also attenuated the P13K/ AKT signaling which enhanced apoptosis. These findings revealed that GTN subdues the P13K/AKT pathway and has auspicious chemopreventive and apoptotic actions in DEN-induced HCC. Therefore, GTN would be suggested as a new medicine in natural remedies for liver cancer.

In-vitro antibacterial and antibiofilm activities and in-silico analysis of a potent cyclic peptide from a novel Streptomyces sp. strain RG-5 against antibiotic-resistant and biofilm-forming pathogenic bacteria.

The proliferation of multidrug-resistant and biofilm-forming pathogenic bacteria poses a serious threat to public health. The limited effectiveness of current antibiotics motivates the search for new antibacterial compounds. In this study, a novel strain, RG-5, was isolated from desert soil. This strain exhibited potent antibacterial and antibiofilm properties against multidrug-resistant and biofilm-forming pathogenic bacteria. Through phenotypical characterizations, 16S rRNA gene sequence and phylogenetic analysis, the strain was identified as Streptomyces pratensis with 99.8% similarity. The active compound, RG5-1, was extracted, purified by reverse phase silica column HPLC, identified by ESI-MS spectrometry, and confirmed by 1H and 13C NMR analysis as 2,5-Piperazinedione, 3,6-bis(2-methylpropyl), belonging to cyclic peptides. This compound showed interesting minimum inhibitory concentrations (MICs) of 04 to 15µg/mL and minimum biofilm inhibitory concentrations (MBICs 50%) of ½ MIC against the tested bacteria. Its molecular mechanism of action was elucidated through a molecular docking study against five drug-protein targets. The results demonstrated that the compound RG5-1 has a strong affinity and interaction patterns with glucosamine-6-phosphate synthase at - 6.0kcal/mol compared to reference inhibitor (- 5.4kcal/mol), medium with penicillin-binding protein 1a (- 6.1kcal/mol), and LasR regulator protein of quorum sensing (- 5.4kcal/mol), confirming its antibacterial and antibiofilm activities. The compound exhibited minimal toxicity and favorable physicochemical and pharmacological properties. This is the first report that describes its production from Streptomyces, its activities against biofilm-forming and multidrug-resistant bacteria, and its mechanism of action. These findings indicate that 2,5-piperazinedione, 3,6-bis(2-methylpropyl) has the potential to be a promising lead compound in the treatment of antibiotic-resistant and biofilm-forming pathogens.

α-Mangostin: A Xanthone Derivative in Mangosteen with Potent Anti-Cancer Properties

α-Mangostin, a xanthone derivative extracted from the pericarp of the mangosteen fruit (Garcinia mangostana L.), has garnered significant attention for its potential as a natural anti-cancer agent. This review provides a comprehensive analysis of the current literature on the anti-cancer properties of α-mangostin across various cancer types. Through an extensive analysis of in vitro and in vivo studies, this review elucidates the multifaceted mechanisms underlying α-mangostin’s cytotoxicity, apoptosis induction through both intrinsic and extrinsic pathways, and modulation of key cellular processes implicated in cancer progression in a diverse array of cancer cells. It causes mitochondrial dysfunction, activates caspases, and regulates autophagy, endoplasmic reticulum stress, and oxidative stress, enhancing its anti-cancer efficacy. Moreover, α-mangostin exhibits synergistic effects with conventional chemotherapeutic agents, suggesting its utility in combination therapies. The ability of α-mangostin to inhibit cell proliferation, modulate cell cycle progression, and induce apoptosis is linked to its effects on key signaling pathways, including Akt, NF-κB, and p53. Preclinical studies highlight the therapeutic potential and safety profile of α-mangostin, demonstrating significant tumor growth inhibition without adverse effects on normal cells. In summary, understanding the molecular targets and mechanisms of action of α-mangostin is crucial for its development as a novel chemotherapeutic agent, and future clinical investigations are warranted to explore its clinical utility and efficacy in cancer prevention and therapy.

Molecular mechanisms of action of DIM and its clinical application

Optimal nutrition requires complete provision of the human needs not only for energy, macro- and micronutrients, but also for minor biologically active substances. Some of the most promising chemoprotectors are glucosinolates and their active derivatives, such as 3,3’-diindolylmethane (DIM). DIM has the ability to inhibit the development and progression of neoplasia by regulating multiple intracellular signaling pathways. Currently, the clinical efficacy of DIM is being studied in breast and prostate cancer, and the possibility of using DIM’s antioxidant and anti-inflammatory properties in neurodegenerative, metabolic and immune diseases is being investigated.

An epigenetic editor targeting human PCSK9 efficiently and durably lowers Low Density Lipoprotein Cholesterol (LDL-C) in non-human primates

Abstract Background Reducing the risk of atherosclerotic cardiovascular disease is dependent on both the magnitude and cumulative duration of LDL-C lowering. However, in clinical practice achieving treatment goals is often hampered by low adherence to standard of care. Although PCSK9 inhibitors represent an effective option for LDL-C lowering, they require chronic life-long treatment. Epigenetic editing is a new therapeutic approach designed to durably silence genes by leveraging nature’s endogenous cellular mechanism for gene regulation via CpG methylation without the inherent genotoxic risks of genome editing approaches that nick or cut the DNA. We are developing a PCSK9 epigenetic editor (PCSK9-EE) to durably silence PCSK9, with the promise of lifelong reduction in LDL-C. Methods Here, we describe the development of an epigenetic editor targeting human PCSK9. This epigenetic editor consists of a DNA targeting component fused to a transcriptional repressor domain and a DNA methyltransferase domain. PCSK9-EE was first screened and evaluated for specificity and efficacy in primary human hepatocytes (PHH). In vivo efficacy and durability were then evaluated in a transgenic mouse carrying the human PCSK9 genomic locus (hPCSK9-Tg mouse) and non-human primates (NHP). Results Our initial screen of PCSK9-EEs identified several hits that efficiently suppressed secreted PCSK9 levels in immortalized liver cells. We confirmed that our top PCSK9-EE candidates robustly decreased PCSK9 secretion in PHH and were found to be highly specific at targeting PCSK9 as assessed by RNA-seq, methylation array, and whole-genome methylation sequencing. To examine in vivo activity, we treated hPCSK9-Tg mice with a single administration of a lipid nanoparticle delivering mRNA encoding our PCSK9-EE and observed &amp;gt;97% reduction in liver PCSK9 mRNA, and &amp;gt;98% reduction in plasma PCSK9 for the duration of the study (one year). We then delivered PCSK9-EE in NHP and observed a robust reduction in plasma PCSK9 with a concomitant reduction in LDL-C. These effects were found to be durable for at least 6 months following a single administration of PCSK9-EE in NHP. To establish a mechanistic relationship between PCSK9-EE’s molecular action and durable PCSK9 silencing, we performed serial liver biopsies in each NHP approximately 2 months apart. Robust CpG methylation at the PCSK9 genomic locus was observed in the first liver biopsy and was comparable to that observed in the second liver biopsy suggesting that PCSK9-EE induced stable CpG methylation in NHP livers. Conclusions We believe PCSK9-EE may offer an effective, safe, and durable approach to suppress hepatic PCSK9 expression and achieve long-lasting reduction in LDL-C. Furthermore, epigenetic editing may hold promise for one-and-done approaches for the treatment of atherosclerotic cardiovascular disease without cutting, nicking, or altering the DNA sequence.

Modulation of Albumin Esterase Activity by Warfarin and Diazepam.

Data are accumulating on the hydrolytic activity of serum albumin towards esters and organophosphates. Previously, with the help of the technology of proton nuclear magnetic resonance (1H NMR) spectroscopy, we observed the yield of acetate in the solution of bovine serum albumin and p-nitrophenyl acetate (NPA). Thus, we showed that albumin possesses true esterase activity towards NPA. Then, using the methods of molecular docking and molecular dynamics, we established site Sudlow I as the catalytic center of true esterase activity of albumin. In the present work, to expand our understanding of the molecular mechanisms of albumin pseudoesterase and true esterase activity, we investigated-in experiments in vitro and in silico-the interaction of anticoagulant warfarin (WRF, specific ligand of site Sudlow I) and benzodiazepine diazepam (DIA, specific ligand of site Sudlow II) with albumins of different species, and determined how the binding of WRF and DIA affects the hydrolysis of NPA by albumin. It was found that the characteristics of the binding modes of WRF in site Sudlow I and DIA in site Sudlow II of human (HSA), bovine (BSA), and rat (RSA) albumins have species differences, which are more pronounced for site Sudlow I compared to site Sudlow II, and less pronounced between HSA and RSA compared to BSA. WRF competitively inhibits true esterase activity of site Sudlow I towards NPA and does not affect the functioning of site Sudlow II. Diazepam can slow down true esterase activity of site Sudlow I in noncompetitive manner. It was concluded that site Sudlow I is more receptive to allosteric modulation compared to site Sudlow II.

Applications, impacts and consequences of botulinum toxin usage in medicine

Introduction Botulinum toxin is a neurotoxin produced by the gram-positive bacteria Clostridium botulinum. Botulinum toxin has found great interest in the field of aesthetic medicine, but it has many other applications in other areas of medicine. Aim of the study The aim of this comprehensive review is to provide an overview of the usage of botulinum toxin in medicine, with a focus on specific areas of medicine. Attention will be paid to the safety of the use of this substance, taking into account its molecular structure and mechanism of action. Materials and methods An analysis of the scientific articles available in the Pubmed, Google Scholar and web of science databases was performed. Recent publications which most appropriately encompassed the issues under discussion have been selected for the purpose of this study. The process of search was carried out with the following keywords: neurotoxin, botulinum toxins, botulism, muscle paralysis. Summary Despite numerous studies, there is ample room for further research into the safety of using botulinum toxin in patients as well as new therapies with this substance. Botulinum toxin is a neurotoxin that is widely used in medicine, but has many side effects.

A Comprehensive Review of Pedunculagin: Sources, Chemistry, Biological and Pharmacological Insights.

Pedunculagin is a widely abundant ellagitannin found in the plant kingdom, with a chemical structure featuring two hexahydroxydiphenoyl units linked to a glucose core. It has demonstrated various biological activities, including anti-cancer, anti-inflammatory, and anti-bacterial effects. This review aims to summarize the bioactivities, chemistry, and health-promoting properties of pedunculagin and plant preparations containing it. It is the first comprehensive summary covering pedunculagin's chemistry, sources, metabolism, and other relevant research. The search databases were Google Scholar, EBSCO Discovery Service, REAXYS Database, SCILIT, SCOPUS, PubMed, MEDLINE, Web of Science, Wiley Online Library, Science Direct/ELSEVIER, WordCat, and Taylor and Francis Online. All the databases were methodically searched for data published from 1911 until 2024. Various biological effects were proven in vitro for pedunculagin; however, due to the limited availability of the isolated compound, they have not been so far directly confirmed on more advanced in vivo and clinical models. However, its bioactivity can be deduced from studies conducted for plant preparations containing this ellagitannin as a dominant constituent, consequently indicating beneficial health effects. Further studies are needed to determine the molecular mechanism of action following topical application as well as the contribution of gut microbiota postbiotic metabolites- urolithins-being formed following the oral ingestion of preparations containing pedunculagin.