Life Sciences

BackgroundWhen the skin wound defect is too large, it is difficult for the body to heal itself, and medical treatment is often needed. How to shorten the healing cycle and reduce the incidence of infection is a difficult problem faced by clinicians. Panax notoginseng(PN), a traditional Chinese medicine, can promote the absorption of inflammatory exudates, granulation tissue formation and epidermal proliferation, effectively inhibit the inflammatory reaction of wounds and promote the healing of skin wounds, but its molecular mechanism has not been fully clarified so far. Based on network pharmacology and animal experiments, this study explored the target and molecular mechanism of PN in the treatment of skin wound. MethodsThe active components and potential targets of PN were obtained from the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP) and UniProt database, and the skin wound-related targets were obtained from the GeneCards database. The intersecting targets were filtered using Venny 2.1.0. The intersecting targets were imported into the STRING database to construct a protein-protein interaction (PPI) network. Cluster analysis was performed using the MCODE and CytoHubba plugins in Cytoscape 3.8.2 to obtain core functional network modules and the top 10 key target genes. The intersecting targets were subjected to KEGG and GO enrichment analysis using the DAVID 6.8 database (https://david.ncifcrf.gov/). The component-target-pathway network of PN in the treatment of skin wounds was constructed using Cytoscape 3.8.2 software. In the experimental verification phase, 48 Sprague-Dawley (SD) rats were randomly divided into a control group and a PN group, with 24 rats in each group. A full-thickness skin excision was performed to establish a wound model. The PN group received intraperitoneal injections of the drug, while the control group received an equivalent amount of saline. Wound area measurements were taken on days 1, 4, and 7 after model establishment. Histopathological changes in the injured area and the expression and localization of TNF-, IL-6, and IL-10 were observed through hematoxylin and eosin (HE) staining and immunohistochemical staining. Relative expression levels of the three factors were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). ResultsThis study identified 8 major active components, 156 targets, and 115 signaling pathways involved in the treatment of skin wounds in rats using PN. The top 10 core target genes included TNF, IL-6, and IL-10, primarily enriched in signaling pathways such as NF-{kappa}B, MAPK, and JAK-STAT. Animal experiments revealed that at 4 and 7 days post-injury, the wound area in the PN group was significantly smaller than that in the control group (P<0.05). HE staining showed reduced infiltration of neutrophils and inflammatory cells in the injury area at 7 days in the PN group, accompanied by more pronounced fibroblast proliferation and collagen secretion. Molecular detection indicated that TNF-, IL-6, and IL-10 positive reactants were mainly distributed in the cytoplasm and matrix of epidermal cells, inflammatory cells, and fibroblasts in the skin. qRT-PCR and ELISA results showed that TNF- expression in the PN group was significantly lower than that in the control group at 4 and 7 days (P<0.01). IL-6 expression was lower than that in the control group at all time points, peaking at 4 days and then decreasing (P<0.01). IL-10 expression was significantly lower than that in the control group at 1 and 7 days (P<0.01). ConclusionPN exhibits characteristics such as multi-component, multi-target, multi-pathway synergy, and multiple regulatory pathways in the treatment of skin wounds. It can reshape the dynamic balance of cytokine networks, including TNF-, IL-6, and IL-10, optimize the temporal progression of "inflammation initiation - repair transition - tissue remodeling", and provide a therapeutic effect of "efficient debridement - orderly repair - low scar risk" for skin wounds. It is one of the ideal natural drugs for regulating skin wound healing.

Chikungunya virus (CHIKV) infection is one of the major public health concerns in several countries around the world. CHIKV non-structural protein 2 (nsP2) is a promising drug design target due to the enzymes multifunctional properties that facilities viral replication and propagation. To date, there is an evident lack of preventative and therapeutic developments that can be used against CHIKV. Drug repurposing is a time saving and cost-effective method used for the development of new drugs. In this study, drug repurposing was implemented with the use of HIV/HCV protease inhibitors to inhibit the active site of nsP2. Molecular dynamics simulations and analysis revealed the stability of two drugs, Indinavir and Paritaprevir. Indinavir forms a hydrogen bond with a major residue, which closes the flexible loop, situated in close proximity to the active site. This conformational shift in the orientation of the enzyme prevents accessibility to the active site thus disrupting the nsP2 protein from functioning effectively in viral replication. In conclusion, the findings of this study identified Indinavir was identified as a promising CHIKV nsP2 inhibitor. This study will provide the basis to further facilitate the drug repurposing strategy as an alternative approach for drug design of CHIKV inhibitors as well as other viral families.

Resveratrol, a naturally occurring polyphenol, exhibits anticancer, anti-inflammatory, and antioxidant properties. However, its molecular mechanisms in pancreatic cancer remain incompletely understood, necessitating integrative approaches such as network pharmacology and molecular docking. Potential resveratrol targets were identified using Swiss Target Prediction, while pancreatic cancer-related genes were retrieved from GeneCards and NCBI Gene databases. Overlapping targets were obtained through Venn analysis, followed by protein- protein interaction network construction, hub gene selection, and enrichment analysis. Molecular docking validated compound-target interactions. A total of 100 predicted resveratrol targets and 1,447 pancreatic cancer- associated genes were screened, yielding 39 overlapping genes. Network analysis identified hub genes including EGFR, SRC, MTOR, PIK3CA, PIK3CB, BCL2, and PTGS2. Gene Ontology enrichment indicated roles in cell proliferation, apoptosis regulation, inflammatory response and metabolic regulation while KEGG pathway analysis highlighted the PI3K-Akt, ErbB, and EGFR inhibitor resistance signaling as being closely associated with pancreatic cancer pathway. Docking analysis revealed strong binding of resveratrol with KRAS (-8.2 kcal/mol), EGFR (-7.9 kcal/mol), and MTOR (-7.7 kcal/mol), stabilized by hydrogen bonding. The interaction with KRAS, although not among the predicted targets. Expression profiling validated upregulation of hub genes in tumor samples. Resveratrol exerts multi-targeted effects in pancreatic cancer by modulating oncogenic pathways, particularly KRAS and PI3K/Akt/mTOR signaling. Its favourable safety profile and robust hub gene interactions highlight its potential as a supplementary therapeutic drug, necessitating further preclinical and clinical confirmation.

Sanguinarine (SNG) is a natural component belonging to the benzophenanthridine alkaloids. In recent years, due to its remarkable biological activities, it has gained wide interest in the pharmaceutical industry. Various studies have reported its potential as a therapeutic agent in treating chronic human diseases such as cancer. SNG is widely reported to cause programmed cell death in various cancer cell lines. The mechanism by which SNG triggers apoptosis remains poorly elucidated, especially in vivo. Previous studies reported that sanguinarine induces apoptosis by increasing reactive oxygen species (ROS). In this study, we aimed to characterize the effects of SNG using an in vivo Caenorhabditis elegans (C. elegans) model. Treating C. elegans with various SNG concentrations resulted in apoptotic cell death in the proliferative germline. Interestingly, SNG-induced apoptosis depends on the core apoptotic machinery initiated by the DNA-damage-induced activity of the p53/CEP-1 protein. We have also demonstrated that the increase in germ cell apoptosis is caused by elevated levels of reactive oxygen species (ROS) following SNG treatment. Notably, the apoptotic phenotype induced by SNG was resolved upon treatment with the ROS scavenger. Altogether, our study demonstrates that SNG increases ROS, leading to activation of DNA damage-induced apoptosis in the proliferative germline of C. elegans.

Cannabidiol (CBD) and Cannabigerol (CBG) are non-psychoactive cannabinoids known to affect both cancerous and non-cancerous cells. Autophagy is a critical regulator of cell survival and death; however, the impact of CBD and CBG on cell viability through autophagy remains limited. In this study, we show that low-dose combinations of CBD and CBG synergistically enhance Caco-2 cell proliferation, achieving effects comparable to those observed at higher doses. Both cannabinoids--whether applied individually at high concentrations or in low-dose combinations--activate autophagy. Correlation analyses between cell viability and autophagic flux, along with comparative assessments of wild-type and ATG9-deficient Caco-2 cells, demonstrate that the survival-promoting effects of CBD and CBG are closely associated with autophagy activation. Overall, these findings reveal that both individual and combined treatments significantly modulate Caco-2 cell viability under conditions with or without autophagy activation, emphasizing the substantial role of cannabinoid-regulated autophagy in influencing cell survival. HighlightsO_LILow-dose combinations of CBD and CBG synergistically enhance Caco-2 cell proliferation. C_LIO_LIBoth high-dose individual treatments and low-dose combinations of CBD and CBG activate autophagy. C_LIO_LICBD- and CBG-mediated autophagy paly beneficial role in supporting Caco-2 cell survival. C_LI

Polycystic Ovary Syndrome (PCOS) is known as an endocrine and metabolic disorder; however, emerging molecular evidence suggests a far more complex systems-level pathology. In this study, we performed an integrative transcriptomic and pathway-level analysis of endometrial tissue from women with PCOS to gain a deeper understanding of the underlying mechanism facilitating the disorder. The findings of the study highlighted mitochondrial dysfunction, chronic oxidative stress, and multi-layered immune dysregulation, adding some new insight apart from classical hyperandrogenism and insulin resistance. We identified some novel gene disease associations which involve C15orf48, ODF3B PRR15-DT, LINC01176, and LOC105379193. The upstream regulators such as (NFE2L2, TWNK, ALKBH1, BCOR, SMARCA4) involved in processes including mitochondrial genome, redox balance, and chromatin remodeling provided new insights into regulatory mechanisms. The IPA pathway analysis validated the compromised immune recovery with low grade inflammations and mitochondrial dysfunctionality. The observations emphasize on complex associations discarding its PCOS pure endocrine nature through immunometabolic-mitochondrial dysfunctionalities.

Exposure to cigarette smoke is one of the major risk factors for developing various diseases such as chronic obstructive pulmonary disease (COPD), cardiovascular disorders, and cancer mediated via cellular oxidative stress and organelle dysfunction. To this end, the current study investigated how cigarette smoke extract (CSE) affects vacuole structure and function in Saccharomyces cerevisiae, as vacuole plays a crucial role in handling oxidative stress-induced misfolded proteins. Our results showed that CSE exposure causes transient vacuolar fragmentation up to 1 h to increase its surface area to facilitate microautophagy in clearing CSE-mediated misfolded protein and promoting cell survival. However, excessive fragmentation or vacuolar fusion sensitizes cells towards CSE-mediated cellular toxicity. Towards understanding the underlying mechanism, the current study demonstrated the involvement of PI3P and PI (3,5) P2-mediated signaling and phospholipase-driven remodeling of lipid moieties. Moreover, the current study also showed the importance of mitochondrial activity in CSE-mediated vacuolar fragmentation. Prolonged exposure to CSE impairs mitochondrial function and thus disrupts fragmentation, the adaptive survival strategy against CS. It results in proteostasis collapse, which is a characteristic shared by many inflammatory and degenerative disorders. Taken together, the current study reveals a previously unrecognized cellular protection mechanism induced by cigarette smoke and highlights potential therapeutic targets for mitigating CS-mediated diseases

IntroductionDrug repurposing offers a cost-effective and time-efficient strategy for cancer therapy by leveraging existing drugs with established safety profiles, thus functioning as an alternative therapeutic strategy in demanding diseases such as cancer. Antidiabetic agents, in particular, have demonstrated encouraging anticancer potential. Among them, the non-sulfonylurea insulin secretagogue repaglinide (RPG) has shown emerging anticancer potential, yet its effects on breast and lung cancers remain largely unexplored. Thus, this study investigates the anticancer activity of repaglinide in human breast (MCF-7) and lung (A549) cancer cell lines, focusing on its cytotoxic, pro-apoptotic, anti-proliferative, and anti-migratory effects and the underlying possible molecular mechanisms. Methodology and ResultsMTT cytotoxic assay revealed that RPG reduced cell viability in a dose-/time-dependent manner, with an IC (48h) of 100.8 {+/-} 3.98 {micro}M for MCF-7 and 104 {+/-} 3 {micro}M for A549. Further, the apoptotic effect of RPG on both cell lines was evidenced by double staining assays, comet assay, and western blotting analysis, suggesting that RPG explicitly caused DNA damage and activated intrinsic and extrinsic apoptosis pathways. Additionally, RPG suppressed clonogenicity and enforced G1 arrest in MCF7 and A549 cells by modulating cell cycle regulations as well as cell proliferation pathways. Moreover, RPG markedly suppressed cell motility, as demonstrated by scratch and Transwell migration/invasion assays, which is correlated with reduced MMP-2 and MMP-9 expression, confirmed by gelatin zymography and western blotting. ConclusionConclusively, Repaglinide exerts potent anticancer effects in breast and lung cancer cells by modulating key oncogenic signaling pathways, and thus can be considered a promising candidate for repurposing in cancer therapy.

Marburg virus (MARV) is a highly pathogenic filovirus that causes hemorrhagic fever with a high mortality rate, with very limited treatment options. The urgent need for targeted antiviral agents emphasizes the importance of structure-based drug discovery approaches. The present study aimed to evaluate the antiviral potential of Withaferin A (PubChem CID-265237) against three key proteins of MARV: viral protein 35 (VP35), and nucleoproteins (NP). Three-dimensional structures of these proteins were retrieved from RCSB-Protein Data Bank and docked with Withaferin A using AutoDock Vina. The ligand demonstrated favourable binding affinities towards all three viral targets, indicating strong interaction potential at functionally relevant sites. Drug-likeness and pharmacokinetic properties predicted using SwissADME and pkCSM indicated acceptable ADMET profiles that comply with key drug-like criteria. To validate the stability of the docking, molecular dynamics simulations (GROMACS, 100 nanoseconds) were conducted. The protein-ligand complexes exhibited stable root mean square deviation (RMSD), root mean square fluctuation (RMSF), and consistent hydrogen bonding patterns throughout the simulation. The MM-GBSA binding free energy analysis further supported favorable binding energetics, predominantly driven by van der Waals and electrostatic interactions. Altogether, these findings demonstrate that Withaferin A exhibits promising multi-target inhibitory potential against key MARV proteins. This study provides molecular insights into ligand-protein interactions and supports further experimental validation of Withaferin A as a potential therapeutic candidate against Marburg virus.

Cannabidiol (CBD) and cannabigerol (CBG) are non-psychoactive cannabinoids that exert diverse biological activities in both normal and cancerous epithelial cells. Although autophagy plays a pivotal role in maintaining cellular homeostasis, the effects of combined CBD-CBG treatment on autophagic regulation across epithelial cell types remain largely unexplored. In this study, GFP-LC3-RFP reporter assays and ATG9-deficient cell models were employed to examine the influence of CBD and CBG on autophagy in Ca9-22 and HaCaT cells. Certain concentrations of either compound alone failed to induce autophagy and, in some cases, appeared to suppress autophagic activity. In contrast, their combined administration markedly enhanced autophagic flux in both cell lines. Low-dose CBG or high-dose CBD promoted differential greater cell survival in HaCaT-WT cells compared to their ATG9-KO counterparts. Collectively, these findings provide novel insights into the cooperative regulation of autophagy by CBD and CBG, underscoring their combined effects on cellular autophagic responses in cancer or normal epithelial cells. HighlightsO_LIIn both Ca9-22 and HaCaT cells, certain doses of CBD alone failed to induce autophagy, whereas CBG at some concentrations showed a trend toward autophagy suppression. C_LIO_LISub-effective doses of CBD and CBG in combination enhance autophagic flux in Ca9-22 and HaCaT cells, with some combinations exceeding the flux induced by higher doses of either compound alone. C_LIO_LICBD and CBG exhibit distinct dose-dependent effects on the survival of HaCaT ATG9-deficient cells compared with HaCaT-WT cells, indicating differential ATG9-dependence. C_LI

Parkinsons disease (PD) is the second most progressive degenerative disorder of the brain due to dopaminergic (DA) neuron degenerations and alpha-synuclein (-Syn) accumulations. At present, the disease has no effective treatment. Therefore, the current study objective is to identify a novel anti-PD formula (Zhi-Shi-Huang-Wu Formula, F-2) computed at 8:4:2:1 ratio from HSP 70 promoter activators Valeriana jatamansi (V), Acori talarinowii (A), Scutellaria baicalensis (S), Fructus Schisandrae (F). Traditionally, V is used to cure memory impairments, A treats mental disorders, and chronic mild stress, S for neuroprotection, and F showed multiple therapeutic actions to treat insomnia. This study investigated the neuroprotective potential of the V, A, S, F, formula F-2 and its underlying molecular mechanisms in transgenic Caenorhabditis elegans models. A, S, F, and F-2 successfully restored 6-hydroxydopamine intoxicated DA neuron degenerations, reduced food-sensing behavior disabilities, and attenuated -Syn aggregations. Moreover, activates the lipid deposition and proteasome expressions to confirm -Syn degradations at the cellular level. Reactive oxygen species (ROS) cause oxidative stress, and A, S, F, and F-2 repressed ROS and raised SOD-3 expressions. Overall, these data indicate that V, A, S, F combined into F-2 (22.3%) are more effective against PD progression-like symptom than individual drugs V (0.7%), A (11.4%), S (9.6%), and F (12.6%). These improved neuroprotective actions of F-2 possibly due to following the antioxidative pathway. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/709540v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1a6f1f7org.highwire.dtl.DTLVardef@157a270org.highwire.dtl.DTLVardef@69a238org.highwire.dtl.DTLVardef@1194b5e_HPS_FORMAT_FIGEXP M_FIG C_FIG

Mesenchymal stem cells (MSCs) cultured in hypoxic conditions have been suggested to have more therapeutic efficacy than those cultured under normoxic conditions, and there is growing interest in using hypoxic MSCs for clinical treatment, particularly human umbilical cord (hUC)-MSCs. We investigated how hUC-MSCs and human bone marrow (hBM)-MSCs change from normoxia to hypoxia (1% O2) for 2 weeks of culture. In the growth speed and population doubling time, hUC-MSCs cultured under hypoxia exhibited a significantly higher proliferation rate beyond cancerous cells, such as human glioblastoma and breast cancer cells, while hBM-MSCs did not show a significant difference between normoxia and hypoxia, and were statistically slower than these cancerous cells. Notably, hypoxic hUC-MSCs showed upregulation of genes related to metabolic reprogramming (cholesterol biosynthesis and fatty acid metabolism pathways) and cancer stem cell-like phenotype (factors related to Wnt and Hedgehog signaling pathways, cell proliferation drivers, and apoptosis-resistance), and lesser migration and homing to the traumatic brain injury than normoxic hUC-MSCs after intravenous injection. Thus, whether hUC-MSCs cultured under hypoxia offer clinical benefits and use are safe, given their extremely accelerated proliferation rate and partial cancer stem cell-like traits, requires comprehensive and careful investigation.

Obesity affects millions of people worldwide and has serious complications such as cardiovascular disease and diabetes. Current treatments for obesity target proteins such as the receptors for glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP) and/or glucagon (GCG). These interventions have revolutionized the treatment of obesity and represent first-line pharmacotherapeutic strategies. One major weakness to these strategies is that once drug treatment stops, most patients are unable to maintain the new body weight setpoint, often gaining weight back rapidly. Thus, the identification of new therapies that focus on the ability to maintain homeostatic setpoint are necessary. The glucocorticoid receptor (GR) has been implicated in several pathways including reward-seeking, inflammation, stress and energy balance. Here, we investigated the effects of 30 days treatment with PT150 (40 mg/kg), a novel GR antagonist, alone and in combination with semaglutide (30 nmol/kg) on food intake, glucose homeostasis, body weight and setpoint maintenance using a C57Bl/6 diet-induced obesity (DIO) mouse model. We monitored food intake and body weight throughout treatment and after drug washout for 20 days to evaluate defended body weight maintenance (body weight setpoint). Our results indicate that treatment with PT150 alone does not significantly alter body weight but in combination with semaglutide it shows the most promising effects in body weight reduction and homeostatic setpoint maintenance. Together, these data suggest that PT150, a GR modulator, may be effective as a homeostatic setpoint modulator when combined with semaglutide.

ObjectiveThe objective of this study is to provide a concise overview of the various molecular problems and possible treatment targets that have been linked and associated with the onset of certain psychiatric diseases. MethodsObtaining the data from NCBI, we applied GREIN to analyze our datasets. The protein-protein interaction, gene regulatory network, protein-drug-chemical, gene ontology, and pathway network were constructed using STRING, Funrich and DAVID libraries. In order to display our suggested network, we utilized Cytoscape and R studio, verifying our hub gene using roc analysis. ResultsWe discovered a number of strong candidate hub proteins in significant pathways, namely out of 32 (HLA-DRA, HLA-A, HLA-B, HLA-DOB and BRD2) common genes. We also identified a number of TFs (FOXC1, NFYA, RELA, GATA2, FOXL1, SRF and NFIC); miRNA (hsa-mir-129-2-3p, hsa-mir-148b-3p, hsa-mir-196a-5p, hsa-mir-26a-5p, hsa-mir-27a-3p, hsa-mir-23b-3p, hsa-mir-500a-3p, hsa-mir-423-5p, hsa-miR-142-5p, and hsa-miR-671-5p) and chemicals (Estradiol, Antirheumatic Agents, Valproic Acid, Selenium, Vitamin E, ICG 001, Ifosfamide, Tetrachlorodibenzodioxin, arsenic trioxide, entinostat, sodium arsenite and Hydralazine) may control DEGs in transcription as well as post-transcriptional expression levels. ConclusionIn summary, our computational methods have identified distinct potential biomarkers that demonstrate the impact of PTSD, Schizophrenia, and BD on autoimmune inflammation and infectious diseases. Additionally, we have identified pathways and gene regulators through which these psychiatric disorders may affect biological processes. Graphical AbstractThe graphical abstract demonstrates the thorough strategy of combining systems biology and computational technologies to identify significant markers and pathways in blood tissues impacted by post-traumatic stress disorder, Schizophrenia, and Bipolar disorder. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/708243v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@1cd13bforg.highwire.dtl.DTLVardef@cb6392org.highwire.dtl.DTLVardef@f634cforg.highwire.dtl.DTLVardef@532bd_HPS_FORMAT_FIGEXP M_FIG C_FIG

Mouse models of metabolic dysfunction-associated steatotic liver disease (MASLD) are valuable tools for identifying novel molecular mechanisms that drive progression from MASLD to metabolic dysfunction-associated steatohepatitis (MASH). However, generating a clinically relevant MASLD/MASH mouse model with obesity and peripheral metabolic dysfunction remains a challenge. In this study, we fed two different MASH-inducing diets to male mice with pre-existing high-fat (HF) diet-induced obesity. While a HF diet containing 40% Kcal from fat (mostly corn-oil shortening), 2% cholesterol, and 22% fructose reduced adiposity in these mice, a high-fat diet with 60% Kcal from fat (mostly lard), containing 2% cholesterol and supplemented with 10% fructose in the drinking water (HFC+Fr diet) promoted body weight and fat mass gain. Of note, 24 weeks of the HFC+Fr diet induced obesity, metabolic dysfunction, and liver steatosis in male and female mice, and promoted MASH with fibrosis in male mice. Furthermore, the HFC+Fr diet increased the expression of hepatocyte peroxisome proliferator-activated receptor {gamma} (Pparg), but the knockout of Pparg in hepatocytes (Pparg{Delta}Hep) reduced the development of MASH and fibrosis in male mice. In addition, the expression of key hepatic genes involved in methionine metabolism was downregulated by the HFC+Fr diet and upregulated by Pparg{Delta}Hep only in male mice. Overall, the HFC+Fr diet is obesogenic and promotes MASLD in both male and female mice. However, the HFC+Fr diet promotes MASH in a sex- and hepatocyte Pparg-specific manner, which may be associated with downregulation of hepatic methionine metabolism. New & NoteworthyWe explored how a new dietary intervention with fructose in the drinking water and added cholesterol to a high-fat diet extensively used to induce obesity and insulin resistance, promotes the onset of MASLD with obesity and metabolic dysfunction in male and female mice. This clinically relevant model of MASLD shows increased expression of hepatocyte PPAR{gamma} in both male and female mice, but only male mice have PPAR{gamma}-dependent impaired methionine metabolism and develop MASH with fibrosis.

Metabolic dysfunction-associated steatohepatitis (MASH) is associated with increased expression of peroxisome proliferator-activated receptor gamma (PPAR{gamma}, Pparg) and reduced expression of genes involved in methionine metabolism in the liver. The nuclear receptor PPAR{gamma} is activated by fatty acids, and the knockout of Pparg in hepatocytes (Pparg{Delta}Hep) reduced the negative effects of MASH on methionine metabolism. Here, we sought to determine whether hepatocyte Pparg is required for the transcriptional regulation of genes involved in hepatic methionine metabolism in conditions with altered fatty acid flux to the liver: fasting, refeeding, and high-fat diet (HFD)-induced obesity/steatosis. Fasting induced liver steatosis and increased the expression of key genes involved in the methionine metabolism in the liver, while 6h-refeeding reversed these effects and reduced the expression of phosphatidylethanolamine N-methyltransferase (Pemt) and cystathionine beta synthase (Cbs). Overall, fasting and refeeding did not alter hepatocyte Pparg expression nor Pparg{Delta}Hep affected fasting and refeeding-mediated regulation of methionine metabolism gene expression. Diet-induced steatosis reduced hepatic Pemt expression in control (Pparg-intact) mice, and the thiazolidinedione (TZD)-mediated activation of PPAR{gamma} in diet-induced obese control (Pparg-intact) mice reduced the expression of betaine homocysteine S-methyltransferase (Bhmt) and Cbs. However, diet-induced steatosis increased hepatocyte Pparg expression, and Pparg{Delta}Hep blocked the negative effects of HFD and TZD on hepatic methionine metabolism. The PPAR{gamma}-dependent reduction of hepatic Bhmt and Cbs expression was confirmed in mouse primary hepatocytes. Taken together, hepatocyte Pparg may serve as a negative regulator of hepatic methionine metabolism in diet-induced obese mice and these actions could contribute to promoting the onset of MASH.

Menopausal hormone therapy (MHT) is prescribed for climacteric symptoms including hot flushes and weight gain and contains estrogens such as 17 beta-estradiol (17{beta}E2). However, estrogen receptor activation by MHT may increase reproductive cancers and cardiovascular event risk in some people. As the protective metabolic effects of 17{beta}E2 are partly mediated through the arcuate nucleus of the hypothalamus, restricting 17{beta}E2 actions to the brain could serve as a safer mechanism of MHT. 10{beta},17{beta}-Dihydroxyestra-1,4-dien-3-one (DHED) is a prodrug of 17{beta}E2 which is enzymatically converted to the parent hormone exclusively within the brain. DHED has demonstrated positive benefit in rodent models of centrally-mediated maladies including hot flushes, depression and cognitive decline, without peripheral hormonal burden. Therefore, we hypothesized that DHED treatment in obese female mice would act within the hypothalamus to provide the same beneficial metabolic effects as 17{beta}E2. Female mice were ovariectomized, placed on a high fat diet and split into either control, DHED, or 17{beta}E2 treatment groups. Body weight, uterus weight and glucose tolerance were recorded along with gonadal hormone receptor expression in the brain. Delivery of DHED at a similar dose as 17{beta}E2 failed to improve metabolic parameters or recapitulate the hypothalamic responses induced by 17{beta}E2. Delivery of DHED at higher doses, which elicited estrogen-like actions within the brain, still failed to improve metabolic health. Our findings suggest that peripheral actions, in addition to hypothalamic targets, may be required to mediate 17{beta}E2s protective effects on metabolism and that brain-targeted MHT may be unsuitable for improving metabolic health during menopause.

In siRNA-based applications, cellular delivery remains one of the main hurdles. Many formulations are tested for the same and peptides came up as one of the optimal options. The latter have various advantages like natural biological presence, high specificity, and natural metabolism etc. siRNA in conjugation with peptides have exhibited enhanced mRNA silencing. Peptides aid siRNAs in condensation to smaller volumes, enhance nuclease protection, increase half-life, promote cell specific binding as well as endosomal escape and release in cytosol. Despite its prime importance, no resource is available for the peptide-based delivery of siRNAs, therefore to fill the gap we developed PEPsRNA web server. It includes 2266 entries of 270 different kinds of peptides, 106 different types of siRNAs and shRNAs along with more than 80 conjugate molecules targeting 55 different genes, experimentally tested for the delivery of the siRNAs. To provide the detailed insights of the procedure, we have incorporated analysis of the peptides (e.g. secondary structure, amino acid composition, polarity, hydrophobicity etc.), siRNAs (e.g. secondary structures with minimum free energies etc.) and associated conjugate molecules (e.g. structure, SMILES, Inchl). We have derived these values using various other tools and resources to make the web server comprehensive. We further compared various physicochemical properties with the efficacy of the peptide based on the target gene silencing, but these properties do not shown any distinct conclusive relationship. The data is available for browsing, searching and downloading freely on the web server with URL: http://bioinfo.imtech.res.in/manojk/pepsirna. Highlights PEPsRNA is the first database of experimentally tested peptides for siRNA delivery It comprised of 2266 entries with 270 peptides and about 80 conjugate molecules Analysis of peptides, siRNAs and details of conjugate molecules are provided Browse, search and various tools are incorporated for data retrieval and usage

This study presents a phytochemical and pharmacological investigation of Aruncus dioicus, a medicinal plant collected from the northeastern coastal region of Vietnam. In light of the growing global prevalence of type 2 diabetes mellitus (T2DM), the search for natural compounds capable of modulating key enzymes involved in glucose metabolism, particularly Protein Tyrosine Phosphatase 1B (PTP1B) and -glucosidase, remains an important research objective. The experimental methods employed included: botanical identification, extraction, chromatographic separation, and biological activity evaluation. As a result, eleven pure compounds were isolated. Structural determination via 1H- and 13C-NMR spectroscopy revealed these constituents as phenylpropanoids, phenolic acids, nucleosides, and ester derivatives, thereby establishing a distinctive chemical profile for the Vietnamese population of A. dioicus. In vitro enzyme inhibition tests demonstrated significant biological activity. p-coumaric acid (Compound 3) and cinnamic acid (Compound 4) exhibited effects on PTP1B, with IC{square}{square} values of 0.25 {micro}M and 1.16 {micro}M, respectively, higher than the activity of the reference compound ursolic acid (IC{square}{square} = 3.5 {micro}M). Furthermore, ethylparaben (Compound 7) and cinnamic acid exhibited -glucosidase inhibition, with potencies approximately five- to six-fold greater than that of acarbose. These findings suggest that A. dioicus is a potentially valuable source of antidiabetic agents and emphasize the significance of phenylpropanoid derivatives in enzyme inhibition associated with glucose metabolism, thereby providing a scientific foundation for subsequent pharmacological investigations.

Polyunsaturated fatty acids (PUFAs) are fundamental for different cellular and structural processes, especially regarding the nervous system. However, its incorporation in food has many bioaccessibility limitations, making it important to find new ways of its consumption. In this work, nanoencapsulated PUFAs orally administrated to C57BL/6 elite male mice for 8 weeks showed better bioavailability when compared to administration of free acids, also improving the effects on dentate gyrus neuronal survival as well as on the proneurogenic elements of the Brain derived neurotrophic factor biological pathway also in the hippocampus. In addition, nanoencapsulated PUFAs increased expression of Fabp5, a relevant n-3 fatty acids transporter in the brain. Altogether, our results would mean that the form of administration of the fatty acids can alter not only how much and how preserved they reach the central nervous system, but also have a differential impact in the diverse processes they contribute to.