Journal of physiology and biochemistry最新文献

Food allergy (FA) is an exacerbated immune system response to harmless food antigens following sensitization. The incidence of FA has risen significantly over the past two decades, a trend often attributed to modern lifestyle factors such as dietary patterns, antibiotic use, and urban environments. Sensitization may result from a compromised intestinal barrier caused by inflammatory bowel diseases, genetic predisposition, or a combination of both. These conditions trigger an inflammatory response involving mechanisms such as the activation of Toll-Like Receptors (TLRs), which recognize pathogen-associated molecular patterns. This review examines the intestine's role as a key antigen-sensing organ through three critical components: a) gut-associated lymphoid tissue, b) the mucosal immune system, and, c) the intestinal microbiota in the development of FA. The role of TLRs (particularly TLR2 and TLR4) in recognizing bacterial membrane-derived compounds (e.g., lipopolysaccharides) and how commensal bacteria generate TLR ligands that influence allergen sensitization vs. tolerance is discussed. The importance of candidate gene polymorphisms encoding TLR proteins and other molecules associated with tolerance and sensitization to food antigens is also commented on. Finally, future research directions and preventive strategies to mitigate FA risk and development are suggested.

Cold injury presents a significant health challenge, causing tissue damage due to prolonged exposure to low temperatures. This study examines menthol's protective effects against cold injury, focusing on its activation of transient receptor potential cation channel subfamily M member 8 (TRPM8), a "cold-sensing" receptor, to stimulate thermogenesis in brown adipose tissue (BAT). Male C57BL/6J mice were treated with menthol for 21 days and exposed to -20 °C. Core body temperature, activity levels, and cold injury severity were measured. Network pharmacology methods identified TRPM8 as a potential target, confirmed through molecular docking and pathway analysis. Further experiments inhibited TRPM8 to evaluate its role in menthol-induced thermogenesis and cold tolerance. Menthol significantly raised core body temperature, improved cold tolerance, and reduced cold injury severity in treated mice. Network pharmacology analysis highlighted TRPM8 as a key regulator of BAT thermogenesis through the PKA/UCP1 pathway. TRPM8 inhibition diminished menthol's effect, underscoring its essential role in menthol-mediated thermogenesis. This study demonstrates that menthol activates TRPM8 in BAT, enhancing thermogenesis to prevent cold injury. These findings suggest menthol as a promising natural agent for cold injury prevention, with TRPM8 as a potential therapeutic target.

We have investigated the involvement of K⁺ channels in generating the membrane current in MDA-MB-436 cells, a model of triple-negative breast cancer (TNBC). The membrane current is strongly influenced by the opening of voltage-dependent channels insensitive to the nonspecific K⁺ channel inhibitor 4-aminopyridine (4-AP). Using the cell patch clamp technique, we observed a significant decrease in membrane current after exposure to the generic K⁺ channel inhibitor tetraethylammonium chloride (TEA-Cl), indicating that K⁺ ions contribute to the overall membrane current through K⁺ channels that are insensitive to 4-AP but TEA-Cl-sensitive. RNA-sequencing analysis identified the Big Potassium (BK or Maxi-K or KCa1.1, encoded by KCNMA1) and the Kv2.1 (encoded by KCNB1) channels as putative candidates, both of which are involved in cancer cell proliferation and migration. Iberiotoxin, a specific inhibitor of BK channels, did not affect the total membrane current, just as CdCl₂ did, a potent inhibitor of Ca²⁺ channels involved in BK activation. Using selective inhibitors, stromatoxin and drofenine, we demonstrated that the Kv2.1 channel contributes to the membrane current in MDA-MB-436 cells. Furthermore, drofenine inhibited cell migration as measured by the xCELLigence Real-Time Cell Analyzer System and induced apoptosis. Single-cell analysis revealed that the Kv2.1 channel is expressed in both normal and cancerous tissues, with significant upregulation in brain metastases. This raises the possibility that Kv2.1 could be explored as a potential therapeutic target for controlling advanced stages of the neoplasia.

Hepatocellular carcinoma is the most prevalent form of liver cancer worldwide and has high mortality rates. miRNAs, particularly miR-184, have been implicated in cancer biology, where they regulate gene expression and influence tumorigenesis. This study explored the role of miR-184 in HCC, revealing its dual function as both an oncogene and a tumor suppressor, depending on the target genes. We highlight the regulatory effects of miR-184 on critical genes such as INPPL1, FOXO3a, MTSS, OSGIN1, and SOX7 and its impact on key signaling pathways, including the Wnt/β-catenin and JAK2/STAT3/AKT pathways. Dysregulation of miR-184 expression in HCC tissues compared with normal liver tissue was linked to increased proliferation, reduced apoptosis, and autophagy inhibition. Furthermore, miR-184 shows promise as a diagnostic and prognostic biomarker in HCC because of its altered expression in cancerous tissues and blood. Its regulation through circRNAs and lncRNAs such as lncRNA UCA1, circ_0004913, circ-0001141, circ-102,166, LINC00205, and SNHG11 adds a layer of complexity, challenging us to delve deeper into the intricate mechanisms of miR-184, positioning it as a crucial target for potential therapeutic intervention.

This study aimed at determining the effects of type II collagen (CII)-induced arthritis (CIA) on cardiac homeostasis in the contexts of a laboratory chow (LC) and a Western diet (WD). The influence of dietary docosahexaenoic acid (DHA) was also examined. Sixty female Wistar rats were assigned to five groups. The first two groups were fed the LC and were treated or not with CII (LC + CIA and LC); the third and fourth groups were fed a WD with or without CII treatment (WD + CIA and WD); and the fifth group was treated with CII and it was fed the WD whose 2.5% of the lipid fraction was replaced by DHA (DHA + CIA). Ionic homeostasis, redox status, inflammation markers, and mitochondrial stress were analysed in the heart. CIA reduced the body weight and favoured wasting of the lipid and protein stores. It also reduced cardiac cell density. The CIA subgroups, particularly the WD + CIA rats, showed higher cardiac calcium and lower reduced glutathione to oxidized glutathione ratio. In the LC + CIA rats, no oxidative/nitrosative stress (ONS) was noticed and the mitochondrial extraction yield (MEY) was similar to that measured in the LC subgroup. In contrast, the ONS was higher and the MEY was lower in the WD + CIA subgroup compared to the WD one. The observed differences were not due to inflammation. DHA had little effect on the cardiac consequences of CIA. In conclusion, the WD amplified the deleterious effects of CIA on cardiac homeostasis by weakening the mitochondria via an increased ONS.

Activation of brown adipose tissue (BAT) or subcutaneous adipose tissue (iWAT in mice) is a strategy to regulate metabolic homeostasis. The NAD⁺-dependent deacetylase Sirtuin 1 (SIRT1) plays an essential role in energy metabolism and inflammation and is a promising target to tackle obesity and associated comorbidities. We have previously reported the beneficial effect of moderate SIRT1 overexpression in protecting mice against inflammation-induced insulin resistance and impaired BAT thermogenesis. Here, we investigated the effect of an inflammatory environment on insulin sensitivity and thermogenic capacity in iWAT from wild-type (WT) or SIRT1 overexpressing mice (Sirt1^Tg+). We also analyzed in vitro responses to insulin and norepinephrine (NE) in subcutaneous white adipocytes (iWA) from both genotypes under proinflammatory conditions. Results showed higher UCP-1 levels in iWAT from Sirt1^Tg+ mice under thermoneutral conditions compared to WT mice, an effect also found in vitro in differentiated iWA. Cold-induced UCP-1 expression and insulin-induced Akt phosphorylation levels were reduced in iWAT from WT mice upon in vivo bacterial lipopolysaccharide (LPS) injection. However, these reductions were attenuated in iWAT from Sirt1^Tg+ mice. Likewise, in iWA exposed to the conditioned medium from LPS-stimulated Raw 264.7 macrophages (CM-LPS) both insulin signaling and NE-induced UCP-1 expression levels were preserved only in cells overexpressing SIRT1. LPS or CM-LPS increased SIRT1 levels in iWAT or iWA, respectively, an effect more evident upon SIRT1 overexpression. Collectively, our results suggest a SIRT1-dependent anti-inflammatory compensatory response that likely protects iWAT from the deleterious effects of inflammation.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a worldwide leading cause of liver-related associated morbidities and mortality. Currently, there is a lack of reliable non-invasive biomarkers for an accurate of MASLD. Hence, this study aimed to evidence the functional role of miRNAs as potential biomarkers for MASLD assessment. Data from 55 participants with steatosis (MASLD group) and 45 without steatosis (control group) from the Fatty Liver in Obesity (FLiO) Study (NCT03183193) were analyzed. Anthropometrics and body composition, biochemical and inflammatory markers, lifestyle factors and liver status were evaluated. Circulating miRNA levels were measured by RT-PCR. Circulating levels of miR-122-5p, miR-151a-3p, miR-126-5p and miR-21-5p were significantly increased in the MASLD group. These miRNAs were significantly associated with steatosis, liver stiffness and hepatic fat content. Logistic regression analyses revealed that miR-151a-3p or miR-21-5p in combination with leptin showed a significant diagnostic accuracy for liver stiffness obtaining an area under the curve (AUC) of 0.76 as well as miR-151a-3p in combination with glucose for hepatic fat content an AUC of 0.81. The best predictor value for steatosis was obtained by combining miR-126-5p with leptin, presenting an AUC of 0.95. Circulating miRNAs could be used as a non-invasive biomarkers for evaluating steatosis, liver stiffness and hepatic fat content, which are crucial in determining MASLD. CLINICAL TRIAL REGISTRATION: • Trial registration number: NCT03183193 ( www.clinicaltrials.gov ). • Date of registration: 12/06/2017.