Molecular Mechanism Of Action Research Articles

Methylsulfonylmethane induces caspase-dependent apoptosis in acute myeloid leukemia cell lines.

Acute myeloid leukemia (AML) is a heterogeneous ailment in both biological and clinical concepts. Numerous efforts have been devoted to discover natural compounds for combating cancer, which showed great potential in cancer management. Methylsulfonylmethane (MSM), an organosulfur dietary supplement, is utilized for improving various clinical conditions, particularly osteoarthritis. MSM can exert antitumor activity in a wide range of cancers. The molecular mechanisms of action underlying antileukemic activity of MSM remain unclear. In this regard, we aimed to investigate the anticancer properties of MSM on human AML cell lines (U937 and HL60) with focus on underlying cell death mechanism. Anticancer activity of the MSM was examined employing MTT assay, Annexin V-PE/7AAD staining, caspase3/7 activity test, and real-time qPCR. Both cell lines were treated with different concentrations (50-400 mM) of MSM for 24 h. Pretreatment of the cells with a caspase inhibitor (i.e., Z-VAD-fmk) was performed for the assessment of apoptosis induction. The results of MTT assay revealed that in both cell lines, the MSM markedly reduced cell viability in comparison to the control cells. Additionally, findings of Annexin V-7AAD staining revealed that MSM induced apoptosis and activated caspase 3/7 in both cell lines markedly. Real-time quantitative PCR results also supported the induction of apoptosis in AML cells. MSM altered the expression levels of various apoptotic genes (BAX, BAD, and BIM). Overall, our results indicated that MSM could induce apoptosis in AML cell lines in a dose-dependent manner, which therefore could be utilized as anantileukemic agent.

A Family of Cyclic Lipopeptides Found in Human Isolates of Bacillus Ameliorates Acute Colitis via Direct Agonism of Toll-Like Receptor 2 in a Murine Model of Inflammatory Bowel Disease.

The Bacillus-derived cyclic lipopeptides (surfactin, iturin, and fengycin) form potent Heterogeneous Lipopeptide Micelle (HeLM) complexes. HeLM is a small molecule that has been shown to have immunomodulatory effects. However, how HeLM regulates inflammation is not clear, moreover its application to Inflammatory Bowel Disease (IBD), specifically Ulcerative Colitis (UC), has not been tested before. To use a murine model of IBD and determine the effects of HeLM and related molecular mechanisms of action. Colitis was induced in mice by administration of 4% Dextran Sodium Sulfate. Three preparations were tested against negative and positive controls: Purified HeLM, the wild-type strain that produces it, and an isogenic mutant that does not produce HeLM. Clinical, biochemical, and histological scoring systems were used to assess the severity of colitis. RT-qPCR and cell cultures were used to determine the levels of molecular signaling. Fecal samples were processed for metagenomic analysis. Purified HeLM, and the wild-type strain, significantly decreased the severity of colitis as determined by the disease activity index (DAI), mouse colitis histology index (MCHI), fecal calprotectin, and colonic length. This effect was not seen in the mutant. HeLM was found to be an agonist to TLR-2, seemingly activating the Toll-Like Receptor 2/IL-10 pathway, with subsequent downregulation of inflammatory cytokines (TNF-α, IL-1β, and IL-6). At higher concentrations HeLM inhibited lipopolysaccharide ligands from activating TLR-4. The reduction in colitis was not due to microbiome modulation, as had previously been hypothesized. Our results indicate that HeLM ameliorates colitis by TLR-2-induced IL-10 production and possibly via the inhibition of lipopolysaccharide.

Advances in the understanding of androgen receptor structure and function and in the development of next-generation AR-targeted therapeutics

Androgen receptor (AR) and its ligand androgens are important for development and physiology of various tissues. AR and its ligands also play critical role in the development of various diseases, making it a valuable therapeutic target. AR ligands, both agonists and antagonists, are being widely used to treat pathological conditions, including prostate cancer and hypogonadism. Despite AR being studied widely over the last five decades, the last decade has seen striking advances in the knowledge on AR and discoveries that have the potential to translate to the clinic. This review provides an overview of the advances in AR biology, AR molecular mechanisms of action, and next generation molecules that are currently in development. Several of the areas described in the review are just unraveling and the next decade will bring more clarity on these developments that will put AR at the forefront of both basic biology and drug development.

TDMPP activation of estrogen receptor 2a regulates smc2 and p53 signaling to interfere with liver development in zebrafish (Danio rerio)

Tris (2,6-dimethylphenyl) phosphate (TDMPP), a novel organic phosphorus flame retardant (OPFR), has been found to have estrogenic activity. Estrogens are critical in regulating various biological responses during liver development. However, the effects of TDMPP on zebrafish liver development remain largely unexplored. Here, we utilized a chemical genetic screening approach to assess the estrogenic effects of TDMPP on liver development and to elucidate the underlying molecular mechanism. Our findings revealed that zebrafish larvae exposed to environmentally relevant concentrations of TDMPP (0.05 and 0.5 μM) exhibited concentration-dependent liver impairments, including reduced liver size, histopathological changes, and hepatocyte apoptosis. In addition, E2 caused similar adverse effects to TDMPP, but the pharmacological blockade of estrogen synthesis alleviated the effects on liver development. Chemical inhibitors and morpholino knockdown assays indicated that the reduction of esr2a blocked TDMPP-induced liver impairments, which was further confirmed in the esr2a-/- mutant line. Subsequently, transcriptomic analysis showed that the estrogen receptor activated by TDMPP inhibited the expression of smc2, which was linked to the suppression of liver development through p53 activation. Consistently, overexpression of smc2 and inhibition of p53 evidently rescued hepatic damages induced by TDMPP. Taken together, the above findings identified esr2a, downstream smc2, and p53 as important regulators for the estrogenic effects of TDMPP on liver development. Our work fills crucial gaps in the current knowledge of TDMPP's hepatotoxicity, providing new insights into the adverse effects of TDMPP and the molecular mechanisms of action. These findings underscore the need for further ecological risk assessment and regulatory considerations.

PGV-1 causes disarrangement of spindle microtubule organization resulting in aberrant mitosis in HLF and HuH6 cells associated with altered MYCN status

Purpose: The HLF and HuH-6 cell lines represent Hepatocellular carcinoma (HCC) with different characteristics in chromosome content that may give different drug responses. Here, PGV-1 was intended to challenge the growth-suppressing effect on HLF and HuH-6 and trace the molecular target mechanism of action compared to sorafenib. Methods: We applied MTT cytotoxic assay, colony forming assay, flowcytometry analysis, immunofluorescence assay and western blot assay. Results: PGV-1 exhibited cytotoxic effects on HLF and HuH-6 with IC-50 values of 1 µM and 2 µM, respectively, whereas sorafenib showed less cytotoxicity with IC-50 values of 5 µM and 8 µM respectively. PGV-1 suppressed the cell growth permanently but not for sorafenib. Sorafenib did not change the cell cycle profiles on both cells, but PGV-1 arrested the cells at G2/M with the characteristic of senescent cells and mitotic disarrangement. PGV-1 and sorafenib showed the same effect in downregulating p-EGFR, indicating that both compounds have the same target on EGFR activation or as Tyrosine kinase inhibitors. PGV-1 suppressed the MYCN expression in HuH-6 and HLF cells but stabilized cMYC-T58 indicating that even though the MYCN was downregulated, the cells maintained the active form of cMYC. In this regard, PGV-1 also stabilized the expression of PLK-1 and AurA. In summary, PGV-1 elicits stronger cytotoxic properties compared to sorafenib. The lower the MYCN expression, the higher the cytotoxic effect of PGV-1. PGV-1 abrogates cell cycle progression of both cells in mitosis through EGFR inhibition and stabilizes PLK-1 and AurA in correlation with the suppression of MYCN expression.

RG-I-containing sugar domains from Centella Asiatica bind strongly to galectin-3 to inhibit cell–cell interactions

BackgroundCentella Asiatica has been shown to have beneficial value for the treatment of tumors. However, its active ingredients and molecular mechanisms of action have not been fully elucidated. Pectic polysaccharides are the primary active components from medicinal plants. Moreover, these polysaccharides are regarded as potential inhibitors of galectins, such as galectin-1, -3, -7, that generally promote tumor growth. Nevertheless, detailed structural analysis of pectic polysaccharides from Centella Asiatica is sorely lacking, as is knowledge of their interactions with galectins.MethodsWater-soluble pectic polysaccharides (WCAP) isolated from Centella Asiatica were purified into two homogeneous fractions (WCAP-A2b and WCAP-A5b) by a combination of anion-exchange and gel-permeation chromatography. Monosaccharide composition, FT-IR, NMR and enzymatic analyses were used to characterize their structural features. Furthermore, the interactions between galectin-1, -3, -7 and a series of these polysaccharides, including two pectin fractions and their structural domains produced by enzymatic hydrolysis, were evaluated by using hemagglutination and biolayer interferometry.ResultsWCAP-A2b and WCAP-A5b have weight averaged molecular weights of 30.0 kDa and 34.0 kDa, respectively, and both polysaccharides consist of rhamnogalacturonan I (RG-I), rhamnogalacturonan II (RG-II) and homogalacturonan (HG) domains, with mass ratios of 1.3: 1.0: 1.4 and 1.1: 1.0: 2.4, respectively. Their RG-I domains contain arabinan, galactan, and/or arabinogalactan, along with neutral sugar side chains that are more prevalent in WCAP-A2b than in WCAP-A5b. Hemagglutination and biolayer interferometry binding assays indicate that galectin-3 vis-à-vis galectin-1 and -7, binds strongly to the RG-I domain (likely via its neutral side chains) in WCAP-A5b, thereby inhibiting galectin-3-mediated cell–cell interactions.ConclusionsOur study provides structural information on pectin polysaccharides from Centella Asiatica. Results suggest that RG-I domains from WCAP-A5b and WCAP-A2b may be developed as potential inhibitors of galectin-3-mediated cell–cell adhesion and tumor growth.Graphical

How mass spectrometry can be exploited to study AMPK.

AMP-activated protein kinase (AMPK) is a key regulator of metabolism and a recognised target for the treatment of metabolic diseases such as Type 2 diabetes (T2D). Here, we review how mass spectrometry (MS) can be used to study short-term control by AMPK via protein phosphorylation and long-term control due to changes in protein expression. We discuss how MS can quantify AMPK subunit levels in tissues from different species. We propose hydrogen-deuterium exchange (HDX)-MS to investigate molecular mechanisms of AMPK activation and thermoproteomic profiling (TPP) to assess off-target effects of pharmacological AMPK activators/inhibitors. Lastly, because large MS data sets are generated, we consider different approaches that can be used for their interpretation.

Biogenesis of lysosome-related organelles complex-2 is an evolutionarily ancient proto-coatomer complex

Hermansky-Pudlak syndrome (HPS) is an inherited disorder of intracellular vesicle trafficking affecting the function of lysosome-related organelles (LROs). At least 11 genes underlie the disease, encoding four protein complexes, of which biogenesis of lysosome-related organelles complex-2 (BLOC-2) is the last whose molecular action is unknown. We find that the unicellular eukaryote Dictyostelium unexpectedly contains a complete BLOC-2, comprising orthologs of the mammalian subunits HPS3, -5, and -6, and a fourth subunit, an ortholog of the Drosophila LRO-biogenesis gene, Claret. Lysosomes from Dictyostelium BLOC-2 mutants fail to mature, similar to LROs from HPS patients, but for all endolysosomes rather than a specialized subset. They also strongly resemble lysosomes from WASH mutants. Dictyostelium BLOC-2 localizes to the same compartments as WASH, and in BLOC-2 mutants, WASH is inefficiently recruited, accounting for their impaired lysosomal maturation. BLOC-2 is recruited to endolysosomes via its HPS3 subunit. Structural modeling suggests that all four subunits are proto-coatomer proteins, with important implications for BLOC-2's molecular function. The discovery of Dictyostelium BLOC-2 permits identification of orthologs throughout eukaryotes. BLOC-2 and lysosome-related organelles, therefore, pre-date the evolution of Metazoa and have broader and more conserved functions than previously thought.

Molecular Mechanism of the β3AR Agonist Activity of a β-Blocker.

Development of subtype-selective drugs for G protein-coupled receptors poses a significant challenge due to high similarity between subtypes, as exemplified by the three β-adrenergic receptors (βARs). The β3AR agonists show promise for treating the overactive bladder or preterm birth, but their potential is hindered by off-target activation of β1AR and β2AR. Interestingly, several β-blockers, which are antagonists of the β1ARs and β2ARs, have been reported to exhibit agonist activity at the β3AR. However, the molecular mechanism remains elusive. Understanding the underlying mechanism should facilitate the development of β3AR agonist drugs with improved selectivity and reduced off-target effects. In this work, we determined the structures of human β3AR in complex with the endogenous agonist epinephrine or with a synthetic β3AR agonist carazolol, which is also a high-affinity β-blocker. Structure comparison, mutagenesis studies and molecular dynamics simulations revealed that the differences on the flexibility of D3.32 directly contribute to carazolol's distinct activities as an antagonist for the β2AR and an agonist for the β3AR. The process is also indirectly influenced by the extracellular loops (ECL), especially ECL1. Taken together, these results provide key guidance for development of selective β3AR agonists, paving the way for new therapeutic opportunities.

The structural basis of the activation and inhibition of DSR2 NADase by phage proteins

DSR2, a Sir2 domain-containing protein, protects bacteria from phage infection by hydrolyzing NAD+. The enzymatic activity of DSR2 is triggered by the SPR phage tail tube protein (TTP), while suppressed by the SPbeta phage-encoded DSAD1 protein, enabling phages to evade the host defense. However, the molecular mechanisms of activation and inhibition of DSR2 remain elusive. Here, we report the cryo-EM structures of apo DSR2, DSR2-TTP-NAD+ and DSR2-DSAD1 complexes. DSR2 assembles into a head-to-head tetramer mediated by its Sir2 domain. The C-terminal helical regions of DSR2 constitute four partner-binding cavities with opened and closed conformation. Two TTP molecules bind to two of the four C-terminal cavities, inducing conformational change of Sir2 domain to activate DSR2. Furthermore, DSAD1 competes with the activator for binding to the C-terminal cavity of DSR2, effectively suppressing its enzymatic activity. Our results provide the mechanistic insights into the DSR2-mediated anti-phage defense system and DSAD1-dependent phage immune evasion.

Berberine alleviates ulcerative colitis by inhibiting inflammation through targeting IRGM1

BackgroundBerberine (BBR), the main active component of Coptis chinensis Franch., has a variety of pharmacological effects, notably anti-inflammatory, which make it a potential treatment for ulcerative colitis (UC). Nevertheless, the specific target and the mode of action of BBR against UC are still unclear. PurposeHere, we aim to identify BBR's anti-inflammatory target and its mode of action in UC treatment. MethodsThe therapeutic effects of BBR and Coptis chinensis Franch. extract were first assessed in UC mice. Then, stable isotope labeling using amino acids in cell culture-activity-based protein profiling (SILAC-ABPP) was applied to identify the anti-inflammatory target proteins of BBR in an inflammation model of RAW264.7 cells stimulated by LPS. Molecular docking, drug affinity responsive target stability (DARTS), molecular dynamics simulation, cellular thermal shift assay (CETSA), and biological layer interference (BLI) measurement were employed to study the interaction between BBR and its targets. Lentiviral transfection was used to knock down the target protein and investigate BBR's anti-inflammatory mechanism. ResultsBBR and Coptis chinensis Franch. extracts both significantly alleviated UC in mice. SILAC-ABPP identified IRGM1 as BBR's anti-inflammatory target, with its overexpression reduced by BBR treatment in both RAW264.7 cell inflammation models stimulated by LPS and UC mice. BBR significantly reduced inflammatory cytokines in LPS-induced RAW264.7 cells by blocking the PI3K/AKT/mTOR pathway. Knockdown of IRGM1 weakened BBR's effects on cytokine expression and pathway regulation. ConclusionFor the first time, IRGM1 was identified as the direct anti-inflammatory target of BBR. BBR has the potential to inhibit IRGM1 expression in vitro as well as in vivo. The molecular mechanism of BBR's anti-inflammatory activity was inhibiting the PI3K/AKT/mTOR pathway by targeting IRGM1.

Daphnetin alleviates allergic airway inflammation by inhibiting T-cell activation and subsequent JAK/STAT6 signaling

Allergic asthma is a major health burden on society as a chronic respiratory disease characterized by inflammation and muscle tightening around the airways in response to inhaled allergens. Daphne kiusiana Miquel is a medicinal plant that can suppress allergic airway inflammation; however, its specific molecular mechanisms of action are unclear. In this study, we aimed to elucidate the mechanisms by which D. kiusiana inhibits allergic airway inflammation. We evaluated the anti-inflammatory effects of the ethyl acetate (EA) fraction of D. kiusiana and its major compound, daphnetin, on murine T lymphocyte EL4 cells stimulated with phorbol 12-myristate 13-acetate and ionomycin in vitro and on asthmatic mice stimulated with ovalbumin in vivo. The EA fraction and daphnetin inhibited T-helper type 2 (Th2) cytokine secretion, serum immunoglobulin E production, mucus secretion, and inflammatory cell recruitment in vivo. In vitro, daphnetin suppressed intracellular Ca2+ mobilization (a critical regulator of nuclear factor of activated T cells) and functions of the activator protein 1 transcription factor to reduce interleukin (IL)-4 and IL-13 expression. Daphnetin effectively suppressed the IL-4/-13-induced activation of Janus kinase (JAK)/signal transducer and activator of transcription 6 (STAT6) signaling in vitro and in vivo, thereby inhibiting the expression of GATA3 and PDEF, two STAT6-target genes responsible for producing Th2 cytokines and mucins. These findings indicate that daphnetin suppresses allergic airway inflammation by stabilizing intracellular Ca2+ levels and subsequently inactivating the JAK/STAT6/GATA3/PDEF pathway, suggesting that daphnetin is a promising alternative to existing asthma treatments.

Synthesis, characterization and bioactivity of new pyridine-2(H)-one, nicotinonitrile, and furo[2,3-b]pyridine derivatives.

Pyridone heterocycles, such as furo[2,3-b]pyridines, have emerged as prominent scaffolds in medicinal chemistry due to their versatile pharmacological properties, including significant anticancer activity. In this study, we successfully synthesized new pyridine-2(H)-one, nicotinonitrile, and furo[2,3-b]pyridine derivatives from chalcones bearing 4-(benzyloxy)phenyl and dichlorothiophenyl subunits to explore their therapeutic potential against breast cancer. By employing a synthetic strategy involving Claisen-Schmidt condensation followed by sequential cyclizations and functional modifications, we synthesized and characterized four compounds (MI-S0, MI-S1, MI-S2, and MI-S3) using various spectroscopic methods, including FT-IR, 1H-NMR, 13C-NMR, DEPT, H,H- and C,H-COSY, and HRMS. The in vitro cytotoxic activity of these compounds was evaluated against two breast cancer cell lines, MCF-7 and MDA-MB-231, and compared with a noncancerous breast cell line, MCF-10A. All compounds exhibited potent cytotoxic activities with minimal selectivity toward normal cells. Molecular docking studies targeting the serine/threonine kinase AKT1, estrogen receptor alpha (ERα), and human epidermal growth factor receptor 2 (HER2) revealed strong binding affinities, suggesting a mechanism involving the disruption of key cellular signaling pathways. These findings underscore the potential of furo[2,3-b]pyridine derivatives as promising candidates for further development into anticancer agents, laying the groundwork for future investigations into their selective therapeutic efficacy and molecular mechanisms of action.

SGLT2 inhibitors attenuate endothelial to mesenchymal transition and cardiac fibroblast activation

Beneficial effects of sodium glucose co-transporter 2 inhibitors (SGLT2is) in cardiovascular diseases have been extensively reported leading to the inclusion of these drugs in the treatment guidelines for heart failure. However, molecular actions especially on non-myocyte cells remain uncertain. We observed dose-dependent inhibitory effects of two SGLT2is, dapagliflozin (DAPA) and empagliflozin (EMPA), on inflammatory signaling in human umbilical vein endothelial cells. Proteomic analyses and subsequent enrichment analyses discovered profound effects of these SGLT2is on proteins involved in mitochondrial respiration and actin cytoskeleton. Validation in functional oxygen consumption measurements as well as tube formation and migration assays revealed strong impacts of DAPA. Considering that most influenced parameters played central roles in endothelial to mesenchymal transition (EndMT), we performed in vitro EndMT assays and identified substantial reduction of mesenchymal and fibrosis marker expression as well as changes in cellular morphology upon treatment with SGLT2is. In line, human cardiac fibroblasts exposed to DAPA showed less proliferation, reduced ATP production, and decelerated migration capacity while less extensive impacts were observed upon EMPA. Mechanistically, sodium proton exchanger 1 (NHE1) as well as sodium-myoinositol cotransporter (SMIT) and sodium-multivitamin cotransporter (SMVT) could be identified as relevant targets of SGLT2is in non-myocyte cardiovascular cells as validated by individual siRNA-knockdown experiments. In summary, we found comprehensive beneficial effects of SGLT2is on human endothelial cells and cardiac fibroblasts. The results of this study therefore support a distinct effect of selected SGLT2i on non-myocyte cardiovascular cells and grant further insights into potential molecular mode of action of these drugs.

The Antioxidant Properties, Metabolism, Application and Mechanism of Ferulic Acid in Medicine, Food, Cosmetics, Livestock and Poultry.

Ferulic acid is a ubiquitous ingredient in cereals, vegetables, fruits and Chinese herbal medicines. Due to the ferulic phenolic nucleus coupled to an extended side chain, it readily forms a resonant-stable phenoxy radical, which explains its potent antioxidant potential. In addition, it also plays an important role in anti-cancer, pro-angiogenesis, anti-thrombosis, neuroprotection, food preservation, anti-aging, and improving the antioxidant performance of livestock and poultry. This review provides a comprehensive summary of the structure, mechanism of antioxidation, application status, molecular mechanism of pharmacological activity, existing problems, and application prospects of ferulic acid and its derivatives. The aim is to establish a theoretical foundation for the utilization of ferulic acid in medicine, food, cosmetics, livestock, and poultry.

The quassinoids bruceines A-M: pharmacology, mechanism of action, synthetic advance, and pharmacokinetics-a review.

Bruceines A-L are among the quassinoid representatives found in the medicinal plant Brucea javanica (L.). An overview of their pharmacological activities is still unknown. The given research deals with highlights in their pharmacological result, molecular mechanism of action, synthetic progress, and pharmacokinetics. From previous evidence, bruceine derivatives are potential agents for anticancer treatments, as well as they are appropriate to treat inflammation, diabetes, and parasitic infections, and protect the neurons, kidneys, and lungs. Cytokine inhibitions, oxidative stress responses, and various signaling pathways, such as MAPK (mitogen-activated protein kinase) and NF-κB (nuclear factor-kappa B), have been proposed as the underlying mechanisms of action. Synthetic approaches to synthesize new derivatives with enhancement activities are based on free hydroxyl group modifications. Bruceines seem to be promptly absorbed by both oral and intravenous administrations, but their bioavailability is not high (less than 6%). Pre-clinical and clinical studies to prove their anticancer potential and other activities are urgent. Structural modifications, nano-combinations, and synergistic effects are necessary.

DIGEP-Pred 2.0: A web application for predicting drug-induced cell signaling and gene expression changes.

The analysis of drug-induced gene expression profiles (DIGEP) is widely used to estimate the potential therapeutic and adverse drug effects as well as the molecular mechanisms of drug action. However, the corresponding experimental data is absent for many existing drugs and drug-like compounds. To solve this problem, we created the DIGEP-Pred 2.0 web application, which allows predicting DIGEP and potential drug targets by structural formula of drug-like compounds. It is based on the combined use of structure-activity relationships (SARs) and network analysis. SAR models were created using PASS (Prediction of Activity Spectra for Substances) technology for data from the Comparative Toxicogenomics Database (CTD), the Connectivity Map (CMap) for the prediction of DIGEP, and PubChem and ChEMBL for the prediction of molecular mechanisms of action (MoA). Using only the structural formula of a compound, the user can obtain information on potential gene expression changes in several cell lines and drug targets, which are potential master regulators responsible for the observed DIGEP. The mean accuracy of prediction calculated by leave-one-out cross validation was 86.5 % for 13377 genes and 94.8 % for 2932 proteins (CTD data), and it was 97.9 % for 2170 MoAs. SAR models (mean accuracy-87.5 %) were also created for CMap data given on MCF7, PC3, and HL60 cell lines with different threshold values for the logarithm of fold changes: 0.5, 0.7, 1, 1.5, and 2. Additionally, the data on pathways (KEGG, Reactome), biological processes of Gene Ontology, and diseases (DisGeNet) enriched by the predicted genes, together with the estimation of target-master regulators based on OmniPath data, is also provided. DIGEP-Pred 2.0 web application is freely available at https://www.way2drug.com/digep-pred.

Intestinal barrier permeability: the influence of gut microbiota, nutrition, and exercise.

The intestinal wall is a selectively permeable barrier between the content of the intestinal lumen and the internal environment of the body. Disturbances of intestinal wall permeability can potentially lead to unwanted activation of the enteric immune system due to excessive contact with gut microbiota and its components, and the development of endotoxemia, when the level of bacterial lipopolysaccharides increases in the blood, causing chronic low-intensity inflammation. In this review, the following aspects are covered: the structure of the intestinal wall barrier; the influence of the gut microbiota on the permeability of the intestinal wall via the regulation of functioning of tight junction proteins, synthesis/degradation of mucus and antioxidant effects; the molecular mechanisms of activation of the pro-inflammatory response caused by bacterial invasion through the TLR4-induced TIRAP/MyD88 and TRAM/TRIF signaling cascades; the influence of nutrition on intestinal permeability, and the influence of exercise with an emphasis on exercise-induced heat stress and hypoxia. Overall, this review provides some insight into how to prevent excessive intestinal barrier permeability and the associated inflammatory processes involved in many if not most pathologies. Some diets and physical exercise are supposed to be non-pharmacological approaches to maintain the integrity of intestinal barrier function and provide its efficient operation. However, at an early age, the increased intestinal permeability has a hormetic effect and contributes to the development of the immune system.

Intestinal barrier permeability: the influence of gut microbiota, nutrition, and exercise

The intestinal wall is a selectively permeable barrier between the content of the intestinal lumen and the internal environment of the body. Disturbances of intestinal wall permeability can potentially lead to unwanted activation of the enteric immune system due to excessive contact with gut microbiota and its components, and the development of endotoxemia, when the level of bacterial lipopolysaccharides increases in the blood, causing chronic low-intensity inflammation. In this review, the following aspects are covered: the structure of the intestinal wall barrier; the influence of the gut microbiota on the permeability of the intestinal wall via the regulation of functioning of tight junction proteins, synthesis/degradation of mucus and antioxidant effects; the molecular mechanisms of activation of the pro-inflammatory response caused by bacterial invasion through the TLR4-induced TIRAP/MyD88 and TRAM/TRIF signaling cascades; the influence of nutrition on intestinal permeability, and the influence of exercise with an emphasis on exercise-induced heat stress and hypoxia. Overall, this review provides some insight into how to prevent excessive intestinal barrier permeability and the associated inflammatory processes involved in many if not most pathologies. Some diets and physical exercise are supposed to be non-pharmacological approaches to maintain the integrity of intestinal barrier function and provide its efficient operation. However, at an early age, the increased intestinal permeability has a hormetic effect and contributes to the development of the immune system.

Serving up health: How phytochemicals transform food into medicine in the battle against cancer

AbstractThe escalating global cancer burden underscores the urgent need for more effective therapeutic strategies. Phytochemicals, naturally occurring compounds in plants, have garnered attention for their potential in cancer chemoprevention and chemotherapy. Their ability to modulate molecular mechanisms and influence cell signaling pathways offers a promising avenue for cancer management. This review aims to synthesize current knowledge on phytochemicals’ chemopreventive and chemotherapeutic potential, focusing on their molecular mechanisms of action and impacts on cell signaling pathways involved in cancer. A systematic literature search was conducted across major databases, including PubMed/Medline, Web of Science, Scopus, and Google Scholar. The search strategy uses Medical Subject Headings (MeSH) and free‐text terms using Boolean operators to capture relevant studies. Inclusion criteria targeted original research and reviews on the effects of phytochemicals in cancer, with a specific focus on molecular mechanisms. Phytochemicals, including flavonoids, polyphenols, and terpenoids, demonstrated significant anticancer properties by inducing cell cycle arrest, apoptosis, and autophagy. They modulate critical cell signaling pathways, such as cyclooxygenase‐2, nuclear factor kappa B, and various growth factor‐related pathways, and rectify epigenetic alterations, contributing to their chemopreventive and therapeutic effects. Phytochemicals represent a valuable resource for developing novel cancer prevention and treatment strategies; their actions on molecular mechanisms and cell signaling pathways underscore their potential in cancer prevention and combat. Further research is warranted to translate these findings into clinical applications, optimizing phytochemical‐based interventions for cancer management.