Physiological health is governed by redox signaling networks, whose dysregulation is central to numerous pathological conditions. Exercise, as a powerful physiological stimulus, can finely regulate this network. Moderate activity boosts tissue resilience through adaptive oxidative signaling, while intense, prolonged exertion can cause multi-organ damage by overwhelming antioxidant defenses. Although the biphasic response to exercise is widely recognized, the precise threshold where benefits turn detrimental remains elusive due to individual variability. This review examines these dose-dependent effects on oxidative stress and their implications for skeletal muscle, cardiovascular and respiratory systems, gut barrier integrity, and neurological performance, providing a framework for personalized exercise and nutrition.

Allergic asthma is characterized by immune dysregulation, and deficiencies in regulatory T-cell (Treg) function are a hallmark of the disease. However, mechanisms of Treg impairment for their therapeutic correction remain poorly defined. The results showed that patient Tregs exhibited a senescent phenotype, including shortened telomeres, increased SA-β-gal activity, and heightened apoptosis. Functionally, they were compromised, showing reduced suppressive capacity and a pro-inflammatory cytokine shift. KQS-1 treatment robustly reversed these defects, restoring FOXP3- and IL-10-dependent Treg suppressive capacity and the production of anti-inflammatory cytokines. This functional rescue centered on these two core Treg signature genes was dependent on Dectin-1 binding and a downstream Raf-1/ROS signaling axis, which drove a sustained epigenetic program characterized by increased H3K4me3 and H3K27ac at the FOXP3 and IL10 loci, focal hypomethylation, and chromatin remodeling at these specific loci. CRISPR-mediated deletion of Dectin-1 abrogated all beneficial effects of KQS-1. As proof of principle that KQS1 is protective, we demonstrate attenuation of airway hyperresponsiveness, inflammation, and remodeling in dust mite-sensitized mice and in recipient mice upon adoptive transfer of KQS-1-trained human Tregs.

BACKGROUND:Gastric intestinal metaplasia (GIM) represents a critical precancerous condition in the progression from chronic gastritis to gastric cancer, with limited therapeutic options. Emerging evidence suggests that taurine, a cytoprotective amino acid, may modulate gastric epithelial dysfunction. However, its application and efficiency in the context of GIM remain poorly understood. AIM:To investigate the therapeutic effects of taurine on GIM using patient-derived organoids and Atp4a -/- mouse models. METHODS:Patient-derived GIM organoids (n = 3) and Atp4a -/- mice, which spontaneously develop GIM, were used as experimental models. Morphological changes were assessed via Alcian blue-periodic acid Schiff staining. The expression levels of the gastric epithelial marker mucin 5AC (MUC5AC) and GIM-associated markers (caudal type homeobox 2 [CDX2], MUC2, Trefoil factor family 3 [TFF3]) were quantified via quantitative PCR, Western blotting, and immunohistochemistry. RESULTS:We confirmed that taurine treatment significantly attenuated pathological changes, including glandular hypertrophy and vacuolar dilation, in Atp4a -/- mice. It also reduced GIM severity compared with that in the untreated model group. Under taurine treatment, MUC5AC expression was significantly increased, whereas the intestinal-specific markers CDX2, MUC2, and TFF3 were reduced (P < 0.05). In parallel, in patient-derived GIM organoids, taurine treatment significantly ameliorated GIM features, as evidenced by increased MUC5AC expression and decreased CDX2, MUC2, and TFF3 expression. CONCLUSION:This study highlights the potential application of taurine as a therapeutic agent for treating GIM, offering a promising strategy for its clinical management.

Gastric intestinal metaplasia (GIM) is a progressive lineage reprogramming process characterized by loss of gastric identity and acquisition of intestinal features. Although disruption of NAD+ (nicotinamide adenine dinucleotide) homeostasis is closely linked to chronic inflammation, its role in gastric metaplastic conversion remains unclear. Here, we establish the first human-derived organoid model of type III incomplete GIM recapitulating goblet cell differentiation, alongside four complementary mouse models representing distinct etiologies of metaplasia. Across human tissues, organoids, and in vivo models, we identify consistent upregulation of the NAD+-consuming enzyme CD38, resulting in chronic NAD+ depletion. We also confirm NAD+ loss reduces SIRT1 activity and increases acetylation of the gastric lineage regulator SOX2 at lysine 73, promoting its nuclear export and functional inactivation. The acute NAD+ depletion disrupts gastric lineage maintenance programs without immediately inducing CDX2, while sustained metabolic erosion permits stable intestinal commitment, defining a hierarchical model of lineage conversion. In parallel, the supplementation with nicotinamide mononucleotide (NMN) restores NAD+ pools, rescues SIRT1 activity, reduces SOX2 acetylation, and reverses metaplastic phenotypes in both human-derived organoids and mouse models. Our findings reveal a CD38-NAD+-SIRT1-SOX2 axis that metabolically drives gastric epithelial identity and position NAD+ homeostasis as a potential strategy for intercepting early gastric tumorigenesis.

TAR DNA-binding protein 43 (TDP-43) is a nuclear RNA-binding protein. It has emerged as a key regulator of RNA processing, such as alternative splicing events, which are essential for cellular homeostasis. The mislocalization and aggregation of TDP-43 are closely associated with mitochondrial dysfunction. However, the mechanisms by which the formation TDP-43 contributes to mitochondrial impairment remain poorly understood. In this study, we confirmed that the TDP-43 loss leads to dramatic alterations in mitochondrial morphology and a significant reduction in respiratory capacity. Further analysis of oxidative phosphorylation (OXPHOS) complex assembly revealed a selective disruption of complex III activity. Notably, the core complex III subunit UQCRC2 was significantly decreased as long as TDP-43 was knocked down. The transcript analysis showed that the loss of TDP-43 results in aberrant alternative splicing of the nuclear-encoded UQCRC2 transcript. In parallel, this mis-splicing event was consistently observed in both dividing cells, including HEK293T, and in the neuroblastoma cell line SH-SY5Y, suggesting that TDP-43-mediated regulation of UQCRC2 splicing can be potentially conserved across a wide range of cell types. These findings indicate a novel role for TDP-43 in maintaining mitochondrial integrity via regulation of UQCRC2 expression and splicing, providing mechanistic insight into how dysregulated RNA processing contributes to mitochondrial bioenergetic deficits.

BackgroundMitochondrial function is essential for biology, particularly in cancer. However, cell-type-specific expression patterns of conserved mitochondrial genes in gastric cancer (GC) remain unclear. We herein raised and tested a novel hypothesis of “mitochondrial conserved gene expression homeostasis imbalance” in GC cohorts with single-cell resolution.MethodsThis work analyzed an open-accessed scRNA-seq dataset (GSE206785, 24 GC patients, 48 samples) with Seurat and defined 43 clusters grouped into 15 cell subtypes. In parallel, Pseudobulk profiles were generated to simulate bulk RNA-seq. A mitochondrial conserved gene score was computed by Seurat AddModuleScore, GSVA, and AUCell. Mitochondria-related biomarkers were also screened, validated, and incorporated into a mitochondria-dependent prognostic model that was further evaluated.ResultsWithout considering cell-type-specific expression patterns, Pseudobulk analysis showed no significant differences in mitochondrial conserved gene expression between GC and control samples. In contracst, single-cell analysis found a cell-type-specific imbalance, under which tumor-associated epithelial cells displayed relatively elevated mitochondrial conserved gene expression, while non-epithelial cells showed reduced. Notably, survival analyses identified gene KRT7 and KLRC1 as robust prognostic biomarkers for early GC.ConclusionOur findings support a mitochondrial conserved gene expression homeostasis imbalance in GC, which is characterized by compartment-specific mtGene expression imbalance. Also, KRT7 and KLRC1 emerge as prognostic markers for therapies aimed at restoring mitochondrial homeostasis in GC.

Classical activation of macrophage and monocyte differentiation induced by β-glucan is accompanied with metabolic change in glucose. However, the role of the metabolic rewiring in monocyte/macrophage activation remains elusive. In this study, we show that berberine induces aerobic glycolysis by blocking the tricarboxylic acid cycle and modulates cytokine responses in bone marrow-derived macrophages (BMDMs) from mice and human PBMC. 13-Methyberberine had activities on glucose metabolism and BMDM activation similar to those of berberine, whereas other tested derivatives lost both activities. Glucose transporter (GLUT)1 expression and total cellular hexokinase activity increased gradually in BMDMs in the presence of berberine. In the contrast, LPS upregulated GLUT1 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) levels in 6 h. Extracellular glucose levels and replacing glucose with galactose in culture medium affected the cytokine secretion of BMDMs. Berberine alleviated enteritis of Salmonella typhimurium infection and protected mice against endotoxic shock. In mice i.p. injected with LPS, the increase of serum TNF-α and the drop of blood glucose were attenuated by berberine treatment. These data together demonstrated that macrophage activation was closely related with glucose metabolism.

A new coumarin-based fluorescent probe CMOH was easily synthesized for detection of Cu2+ and S2- in aqueous media and living cells. CMOH displayed high sensitivity (detection limit = 3.2 nM) and selectivity to Cu2+ with a non-fluorescence complex CMOH-Cu2+ formation via a 1:1 binding mode. According to displacement approach, the fluorescence of CMOH-Cu2+ was recovered in the presence of S2- and acted as a sensitive sensor with a low detection limit of 11.4 nM. This "on-off-on" process can be accomplished within 1 min and repeated at least 5 times. What's more, CMOH exhibited good permeability, low cytotoxicity and can be used as a suitable tool to detect changes of Cu2+ and S2- in biosystem. (C) 2019 Elsevier Ltd. All rights reserved.

Herein, a novel quinoline-based fluorescent probe DQPH has been developed for ratiometric detection of subtle pH fluctuation in biosystem. Upon altering the pH from 4.50 to 9.00, the emission spectra exhibit a large hypsochromic shift (57 nm) and the ratio of fluorescence intensity (F-531 nm/F-588 nm) changes from 0.30 to 1.36 with an ideal pK(a) value of 7.18 and a linear pH variation range of 6.35-8.00. The ratiometric response is attributed to the protonation-activable resonance charge transfer (PARCT) process, which has been proved by H-1 NMR and NOESY experiment. This probe displayed good solubility, low cytotoxicity, anti-interference capability and reversible pH sensing. Furthermore, DQPH was successfully applied for monitoring pH changes in living cells.

A new on-off-on fluorescent probe, CMOS, based on coumarin was developed to detect the process of hypochlorous acid (HOCl) oxidative stress and cysteine/homocysteine (Cys/Hcy) reduction. The probe exhibited a fast response, good sensitivity and selectivity. Moreover, it was applied for monitoring the redox process in living cells.

BACKGROUND:This study was designed to research the potential function of lncRNA ANRIL in osteosarcoma (OS). MATERIALS AND METHODS:Quantitative real-time PCR, cell counting kit-8, wound healing assay, Transwell assay, flow cytometric analysis, caspase activity analysis, and Western blot were carried out. RESULTS:ANRIL was remarkably upregulated in human OS tissues and cells, and knockdown of ANRIL significantly suppressed MG63 cell proliferation, migration, and invasion and promoted apoptosis. Moreover, our mechanistic research findings verified that ANRIL-influenced growth and apoptosis may be partly through regulation of caspase-3 and Bcl-2. Migration and invasion were influenced via ANRIL-mediated regulation of MTA1, TIMP-2, and E-cadherin. CONCLUSION:Our finding demonstrates that ANRIL plays vital roles in OS growth and metastasis.