Hyperglycemia-induced effects on cellular metabolic properties and reactive oxygen species (ROS) generation play pivotal roles in the pathogenesis of malignant melanoma (MM). This study assessed how metabolic states, ROS production, and related gene expression are modulated by antidiabetic agents. The anti-diabetic agents metformin (Met) and imeglimin (Ime), inhibitors of fatty acid-binding proteins 5/7 (MF6) and microphthalmia-associated transcription factor (MITF) (ML329), and siRNA-mediated knockdown of angiopoietin-like protein 4 (ANGPTL4), which affect mitochondrial respiration, ROS production, and related gene expression, were tested in A375 (MM cell line) cells cultured in low (5.5 mM) and high glucose (50 mM) conditions. Cellular metabolic functions were significantly and differently modulated by Met, Ime, MF6, or ML329 and knockdown of ANGPTL4. High glucose significantly enhanced ROS production, which was alleviated by Ime but not by Met. Both MF6 and ML329 reduced ROS levels under both low and high glucose conditions. Knockdown of ANGPTL4 enhanced the change in glucose-dependent ROS production. Gene expression related to mitochondrial respiration and the pathogenesis of MM was significantly modulated by different glucose conditions, antidiabetic agents, MF6, and ML329. These findings suggest that glucose-dependent changes in cellular metabolism and redox status are differently modulated by antidiabetic agents, inhibition of fatty acid-binding proteins or MITF, and ANGPTL4 knockdown in A375 cells.

Cisplatin combined with gemcitabine, a doublet regimen, is the first-line treatment for patients with advanced lung adenocarcinoma (ADC); however, the treatment response remains poor. This study aimed to identify potential biomarkers for predicting response to cisplatin and gemcitabine. Tissue transcriptome and blood proteome analyses were conducted on 27 patients with lung ADC. Blood-derived proteins that reflected tissue-specific biomarkers were obtained using Venn diagrams. The candidate proteins were validated by Western blotting. Lentivirus-mediated short hairpin RNA interference was used to verify the functional roles of the candidate proteins in human A549 cells. We identified 417 differentially expressed genes, including 52 upregulated and 365 downregulated genes, and 31 differentially expressed proteins, including 26 upregulated and 5 downregulated proteins. Integrative analysis revealed the presence of alpha-1-acid glycoprotein 1 (A1AG1) and fibrinogen alpha chain (FGA or FIBA) in both the tissue and serum. FGA levels were elevated in responders compared to non-responders, and reduced serum FGA levels were correlated with resistance to this regimen. Moreover, FGA knockdown in A549 cells resulted in resistance to the doublet regimen. Our findings indicate that FGA is a tissue-specific serum protein that may function as a blood-based biomarker to predict the response of patients with lung ADC to cisplatin plus gemcitabine chemotherapy.

This study investigates the dual role of salicylic acid (SA) in enhancing the production of triterpenes and elucidates its molecular regulatory mechanisms in the fungus Athelia termitophila (TMB), a rich source of bioactive triterpenoids vital to the cosmetics and pharmaceutical industries. Our innovative approach involves the strategic application of SA during the mycelial growth phase, leading to a remarkable 21.87% increase in triterpene yield under optimized conditions of 200 μmol/L SA over 9 days. Pioneering in its methodology, our research employs Spearman correlation analysis to dissect the intricate relationship between triterpene content and gene expression within the mevalonate (MVA) pathway of A. termitophila. This analysis has identified four key genes-Acetyl-Coa Acetyltransferase (AACT), Squalene Epoxidase (SE), Phosphomevalonate Kinase (PMK), and Mevalonate Diphosphate Decarboxylase (MVD)-that are important for triterpene synthesis, providing new insights into the biosynthetic capabilities of A. termitophila. Furthermore, our application of cluster analysis has unveiled unprecedented expression patterns among critical genes, at specific growth intervals. This novel insight into the temporal dynamics of gene transcription during triterpene synthesis provides a comprehensive view of the biosynthetic process, setting the stage for targeted enhancement of triterpene production in A. termitophila. This investigation not only highlights TMB's potential as a biotechnological source of triterpenes but also provides critical insights into the underlying molecular pathways responsible for triterpene synthesis.

Cholangiocarcinoma-associated mortality has been increasing over the past decade. The sodium-glucose cotransporter 2 inhibitor, canagliflozin, has demonstrated anti-tumor effects against several types of cancers; however, studies examining its potential impact on cholangiocarcinoma are lacking. This study investigated the anti-tumor effects of canagliflozin on cholangiocarcinoma and the effects of nicotinamide adenine dinucleotide (NAD)+ salvage pathway activation and sirtuin 1 on tumor growth. We evaluated cell proliferation and gene expression in several cholangiocarcinoma cell lines and analyzed the effects of canagliflozin on cell proliferation, apoptosis, and migration. Canagliflozin treatment decreased the viability of cholangiocarcinoma cells in a concentration-dependent manner but increased the viability at low concentrations in several cell lines. At high concentrations, canagliflozin arrested the cell cycle checkpoint in the G0/G1 phase. In contrast, at low concentrations, it increased the proportion of cells in the S phase. Canagliflozin also reduced the migratory ability of cholangiocarcinoma cells in a concentration-dependent manner. Canagliflozin treatment upregulated nicotinamide phosphoribosyltransferase (NAMPT), NAD+, and sirtuin 1 in cholangiocarcinoma and activated the NAD+ salvage pathway. The growth-inhibitory effect of canagliflozin was enhanced when combined with an NAMPT inhibitor. Canagliflozin inhibits cholangiocarcinoma cell growth and migration and its anti-tumor effect is enhanced when combined with an NAMPT inhibitor. However, further investigation is required because of its potential tumor growth-promoting effect through the activation of the NAD+ salvage pathway.

The glucose metabolism homeostasis in the follicular fluid microenvironment plays an important role in follicular maturation and ovulation, and excessively high or low glucose concentrations have adverse effects on the differentiation of follicular granulosa cells (GCs). However, a limited number of microRNAs (miRNA) have been reported to be involved in glucose-stimulated GCs differentiation. In this study, we characterized the miRNA expression profiles of sheep ovarian GCs cultured in high-glucose and optimal glucose concentrations and focused on a differentially expressed miRNA: miR-17-5p, which may be involved in regulating high-glucose-induced GC apoptosis by targeting KPNA2. We found that overexpression of miR-17-5p significantly promoted GCs proliferation and inhibited cell apoptosis, while downregulated the mRNA and protein expression of apoptosis-related makers (Bax, Caspase-3, Caspase-9, and Bcl-2). In contrast to the classical mechanism of miRNA silencing target gene expression, miR-17-5p overexpression significantly upregulated the expression of target gene KPNA2. A dual luciferase reporter gene assay verified the targeted binding relationship between miR-17-5p and KPNA2 promoter. Meanwhile, overexpression of KPNA2 further promoted the downregulation of apoptosis-related genes driven by miR-17-5p mimics. Knockdown of KPNA2 blocked the inhibitory effect of miR-17-5p mimics on the expression of apoptosis-related genes. Our results demonstrated that miR-17-5p activated the KPNA2 promoter region and upregulated KPNA2 expression, thereby inhibiting GCs apoptosis under high glucose.

Hypoxia is a well-known characteristic of the tumor microenvironment which significantly influences cancer development and is closely linked to unfavorable outcomes. Long noncoding RNAs (lncRNAs), which are part of the noncoding genome, have garnered increasing attention because of their varied functions in tumor metastasis. Long noncoding RNAs (lncRNAs) are defined as noncoding RNAs which are longer than 200 nucleotides, and they regulate diverse cellular processes by modulating gene expression at the transcriptional, post-transcriptional and epigenetic levels. Hypoxia is a well-established environmental factor which enhances the metastasis of solid tumors. Epithelial-mesenchymal transition (EMT) represents one of the key mechanisms triggered by hypoxia which contributes to metastasis. Numerous lncRNAs have been identified as being upregulated by hypoxia. These lncRNAs significantly contribute toward cancer cell migration, invasion and metastasis. Recent studies have identified a crucial role for these hypoxia-induced lncRNAs in chemotherapy resistance. These hypoxia-related lncRNAs can be plausible therapeutic targets for devising effective cancer therapies.

Integrating network pharmacological analysis and bioinformatic techniques, this study systematically investigated the molecular mechanisms of six medicinal food homologous plants (Astragalus membranaceus, Ganoderma lucidum, Dioscorea opposite, Curcuma longa, Glycyrrhiza uralensis, and Pueraria lobata) against colorectal cancer. Through screening the TCMSP database, 303 active compounds and 453 drug targets were identified. By integrating differential expression gene analysis with WGCNA on the GSE41258 dataset from the GEO database, 49 potential therapeutic targets were identified. GO and KEGG enrichment analyses demonstrated that these targets are primarily involved in drug response, fatty acid metabolism, and key cancer-related pathways. Cross-validation using three machine learning algorithms-LASSO regression, SVM-RFE, and Random Forest-pinpointed four critical target genes: CA1, CCND1, CXCL2, and EIF6. Further, CIBERSORT immune infiltration analysis revealed strong associations between these core genes and the tumor immune microenvironment in colorectal cancer patients, notably in modulating M0 macrophage infiltration and mast cell activity. Molecular docking analyses confirmed robust binding interactions between active compounds and core target proteins. This study systematically elucidated the molecular mechanisms of six medicinal food homologous plants against colorectal cancer, providing scientific evidence for their rational clinical application.

Polyphenols are micronutrients found in fruits, vegetables, tea, coffee, cocoa, medicinal herbs, fish, crustaceans, and algae. They can also be synthesized using recombinant microorganisms. Interest in plant-derived natural compounds has grown due to their potential therapeutic effects with minimal side effects. This is particularly important as the aging population faces increasing rates of chronic diseases such as cancer, diabetes, arthritis, cardiovascular, and neurological disorders. Studies have highlighted polyphenols' capacity to reduce risk factors linked to the onset of chronic illnesses. This narrative review discusses polyphenol families and their metabolism, and the cardioprotective effects of polyphenols evidenced from in vitro studies, as well as from in vivo studies, on different animal models of cardiac disease. This study also explores the molecular mechanisms underlying these benefits. Current research suggests that polyphenols may protect against ischemia, hypertension, cardiac hypertrophy, heart failure, and myocardial injury through complex mechanisms, including epigenetic and genomic modulation. However, further studies under nutritionally and physiologically relevant conditions, using untargeted multigenomic approaches, are needed to more comprehensively elucidate these mechanisms and firmly prove the cardioprotective effects of polyphenols.

Exposure to air pollution, especially fine particulate matter (PM2.5), is closely linked to various adverse health effects, particularly in the respiratory system. The present study was designed to investigate the lncRNA-mRNA interactions in PM2.5-induced lung cell injury using weighted gene co-expression network analysis (WGCNA). We downloaded the gene expression data of GSE138870 from the Gene Expression Omnibus (GEO) database and screened for differentially expressed lncRNAs and mRNAs. We constructed co-expression modules with WGCNA. Furthermore, functional enrichment analysis was also performed. We also constructed lncRNA-mRNA co-expression networks and lncRNA-mRNA-pathway networks to identify key regulatory relationships. The results revealed several modules significantly correlated with PM2.5-induced lung injury, such as the turquoise and blue modules. Genes within these modules were enriched in pathways related to signal transduction, metabolism, and cancer. Hub lncRNAs in the turquoise module, including LOC100129034 and CROCCP2, were found to be co-expressed with mRNAs involved in apoptosis and proliferation regulation. In the blue module, lnc-CLVS2-2 and GARS1-DT were connected to genes related to cell migration, invasion, and lung injury. These findings contribute novel perspectives to the molecular mechanisms involved in PM2.5-induced lung injury and suggest that WGCNA could be a valuable tool for predicting and understanding this disease process.

Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterized by insulin resistance and beta cell dysfunction, resulting in hyperglycemia. Olive oil, a cornerstone of the Mediterranean diet, has attracted considerable attention due to its potential health benefits, including reducing the risk of developing T2DM. This literature review aims to critically examine and synthesize existing research regarding the impact of olive oil on the expression of genes relevant to T2DM. This paper also seeks to provide an immunological and genetic perspective on the signaling pathways of the main components of extra virgin olive oil. Key bioactive components of olive oil, such as oleic acid and phenolic compounds, were identified as modulators of insulin signaling. These compounds enhanced the insulin signaling pathway, improved lipid metabolism, and reduced oxidative stress by decreasing reactive oxygen species (ROS) production. Additionally, they were shown to alleviate inflammation by inhibiting the NF-κB pathway and downregulating pro-inflammatory cytokines and enzymes. Furthermore, these bioactive compounds were observed to mitigate endoplasmic reticulum (ER) stress by downregulating stress markers, thereby protecting beta cells from apoptosis and preserving their function. In summary, olive oil, particularly its bioactive constituents, has been demonstrated to enhance insulin sensitivity, protect beta cell function, and reduce inflammation and oxidative stress by modulating key genes involved in these processes. These findings underscore olive oil's therapeutic potential in managing T2DM. However, further research, including well-designed human clinical trials, is required to fully elucidate the role of olive oil in personalized nutrition strategies for the prevention and treatment of T2DM.

A promising approach to accelerating the development of innovative anti-cancer therapies involves the evaluation of natural plant compounds. In this study, we focused on examining the effects of Warbugia ugandensis (W. ugandensis) methanolic root and stem infusions on the activity of five target genes-COX-2, CASPS-9, Bcl-xL, Bcl2, and 5-LOX-using colorectal cancer (CRC) cell lines (Caco-2). The plant extracts were prepared for testing by dissolving them in dimethyl sulfoxide (DMSO) after undergoing a step-by-step extraction process. Caco-2 cells were then treated with different concentrations of the extracts, and RNA was extracted and purified for analysis. Our results demonstrated a dose-dependent relationship between the phytoconstituents of W. ugandensis and the overexpression of CASP9, along with the downregulation of COX-2, 5-LOX, Bcl-xL, and Bcl2 genes. This suggests that W. ugandensis acts as a potent natural inhibitor of CRC progression. Given the potential clinical benefits, we propose the use of W. ugandensis methanolic root and stem extracts as promising organic inhibitors for CRC tumorigenesis, with more in vitro studies warranted to validate and expand on our findings. Additionally, we recommend further studies to identify and characterize the specific metabolites in W. ugandensis that contribute to the modulation of pathways responsible for inhibiting CRC growth.

This study evaluated the effects of a novel Astragalus extract (Keyfobell powder [KFB]) composed of Astragalus membranaceus, red ginseng (Panax ginseng C. A. Meyer), and Cervi Parvum Cornu as a potential growth hormone (GH) alternative. The primary focus was placed on its impact on longitudinal bone growth through the upregulation of circulatory insulin-like growth factor (IGF)-1.

Gundelia tournefortii (Kenger) is a traditional medicinal plant and exhibits potential anticancer properties. This study investigates the cytotoxic and apoptotic effects of its water extract on human lung carcinoma A549 cells.

Cadmium (Cd) pollution significantly hampers cleaner production of peanut (Arachis hypogaea L.). Therefore, exploring of tolerance mechanisms to Cd stress and breeding of low-Cd peanut cultivars are urgently needed and require intense efforts. Herein, multi-omics and physiological studies reveal that multiple biological processes, including melatonin (MT) biosynthesis, are involved in the Cd tolerance in peanut plants. Exogenous MT was applied to peanut plants under Cd stress, which decreased Cd accumulation in roots, shoots and seeds for 40%-60%, and promoted the antioxidant capacity. Integrated investigation reveals that MT-mediated Cd tolerance is mainly attributed to the enhanced metabolism of linolenic acid, glutathione (GSH), and phenylpropanoid (lignin), and development of casparian strip in root cell wall. Defense genes, such as non-race-specific disease resistance gene 1/harpininduced gene 1 (NDR1/HIN1)-like in peanut (AhNHL), were also significantly upregulated by MT under Cd stress. Overexpression of the AhNHL gene in tobacco reduced Cd accumulation for 37%-46%, and alleviated photosynthesis-inhibition induced by Cd stress. Transcriptomic analysis suggested that AhNHL confers the Cd tolerance mainly through promoting phenylpropanoid biosynthesis and GSH metabolism. Additionally, exogenous GSH effectively alleviated the Cd stress through improving Cd sequestration and antioxidant capacity in peanut plants, while apply of the GSH biosynthesis inhibitor (buthionine sulfoximine) exacerbated the Cd phytotoxicity. Transcriptomic analysis reveals that exogenous GSH improves Cd tolerance through affecting the expression of genes involved in transcription regulation, and metal ion binding and transport. Our findings provide novel insights into molecular mechanisms underlying Cd tolerance in plants, which would facilitate breeding of low-Cd peanut cultivars.

This study focuses on the investigation of the antioxidant and anti-inflammatory activities of alcohol extracts from Ribes nigrum leaves on murine BV-2 microglial Wt and Acyl-CoA oxidase 1 deficient (Acox1-/-) cell line models, useful for the investigation of some neurodegenerative disorders.

This study investigated the effects of salinity, ammonia, and stocking density on Nile tilapia (Oreochromis niloticus) fingerlings over a 74-days. In three separate experiments, fingerlings (initial weight 25 ± 2.4 g) were exposed to salinity levels (5, 10, 15, and 20 ppt), ammonia concentrations (0.01, 0.02, 0.1, and 0.2 mg/L), and stocking densities (10, 15, 20, and 25 fish per 96 L aquarium). Survival, growth performance, biochemical parameters, and gene expression changes were assessed. Salinity ≥ 15 ppt and ammonia ≥ 0.1 mg/L significantly impaired growth (final weight, weight gain, specific growth rate, and feed efficiency) and increased mortality rates, reaching 37% and 56% at 20 ppt salinity and 0.2 mg/L ammonia, respectively. Elevated salinity and ammonia also caused significant increases in the activities of ALT, AST, LDH enzymes, along with higher serum glucose levels, while disrupting serum protein and ion concentrations, indicating considerable metabolic and osmoregulatory disturbances. At the molecular level, the expression of the growth-promoting IGF-I gene was down-regulated, while inflammatory marker TNFα was up-regulated, suggesting compromised health. Stocking density had less pronounced effects, though densities ≥ 20 fish/aquarium led to reduced growth, altered biochemical markers, and gene expression changes compared to 10-15 fish/aquarium. These findings establish salinity and ammonia tolerance thresholds for tilapia fingerlings, emphasize optimal stocking density, and provide insights into the physiological and molecular responses to multifactorial stressors. The study contributes to sustainable management strategies for tilapia aquaculture under variable environmental conditions.

Defects in cell wall integrity (CWI) profoundly affect plant growth, although, underlying mechanisms are not well understood. We show that in Arabidopsis mur1 mutant, CWI defects from compromising dimerization of RG-II pectin, a key component of cell wall, attenuate the expression of auxin response factors ARF7-ARF19. As a result, polar auxin transport components are misexpressed, disrupting auxin response asymmetry, leading to defective apical hook development. Accordingly, mur1 hook defects are suppressed by enhancing ARF7 expression. In addition, expression of brassinosteroid biosynthesis genes is down-regulated in mur1 mutant, and supplementing brassinosteroid or enhancing brassinosteroid signaling suppresses mur1 hook defects. Intriguingly, brassinosteroid enhances RG-II dimerization, showing hormonal feedback to the cell wall. Our results thus reveal a previously unrecognized link between cell wall defects from reduced RG-II dimerization and growth regulation mediated via modulation of auxin-brassinosteroid pathways in early seedling development.

Slow-release GnRH agonist implants containing deslorelin (SRI) are registered for temporary suppression of male fertility. The effect of SRI treatment on canine testicular function is well characterised, although the effect of downregulation and subsequent recovery on epididymal function has not been studied yet. Therefore, twenty-nine healthy male dogs were treated with a 4.7 mg SRI for five months. Subsequent to implant removal, groups of 4-5 dogs were surgically castrated either at implant removal (week 0) or 2, 4, 6, or 10 weeks later. Three subgroups were categorised according to pre-surgical testosterone levels. Five healthy untreated dogs served as control. Epididymides were separated into head, body and tail. Epididymal duct diameter and epithelial height were measured using haematoxylin-eosin-stained sections of each dog and part of epididymides. Besides, the presence of spermatozoa, the cilial height, the thickness of the muscle layers and the relative amount of connective tissue were semiquantitatively assessed. The downregulated epididymis was characterised by a reduced epithelial height and epididymal duct diameter, lower cilia and absence of sperm, but more connective tissue, supporting that epididymal function is significantly altered by SRI treatment. At recovery subsequent to implant removal, the histomorphology was comparable with untreated controls. The study indicates that recovery of the epididymal function, like spermatogenesis, depends on testicular testosterone production.

Chronic spontaneous urticaria (CSU) is a debilitating inflammatory skin disease with a prevalence of approximately 1% of the population. It is characterized by recurrent itchy wheals and/or angioedema for more than 6 weeks without known triggers leading to a high quality of life impairment. The pathogenesis of CSU remains not fully understood.

Cadmium (Cd) can adversely damage plant growth. Therefore, understanding the control molecular mechanisms of Cd accumulation will benefit the development of strategies to reduce Cd accumulation in plants. This study performed transcriptomic and metabolomic analyses on the roots of a Cd-tolerant Tartary buckwheat cultivar following 0 h (CK), 6 h (T1), and 48 h (T2) of Cd treatment. The fresh weight and root length were not significantly inhibited under the T1 treatment but they were in the T2 treatment. The root's ultrastructure was seriously damaged in T2 but not in T1 treatment. This was evidenced by deformed cell walls, altered shape and number of organelles. A total of 449, 999 differentially expressed genes (DEGs) and eight, 37 differentially expressed metabolites (DEMs) were identified in the CK versus T1 and CK versus T2 comparison, respectively. DEGs analysis found that the expression of genes related to cell wall function, glutathione (GSH) metabolism, and phenylpropanoid biosynthesis changed significantly during Cd stress. Several WRKY, MYB, ERF, and bHLH transcription factors and transporters also responded to Cd treatment. Our results indicate that Cd stress affects cell wall function and GSH metabolism and that changes in these pathways might contribute to mechanisms of Cd tolerance in Tartary buckwheat.