Search Results (397)

Beyond their established role in lipid digestion, bile acids function as key metabolic and immune signaling molecules. This review synthesizes recent advances in bile acid metabolism within the context of gout and hyperuricemia, proposing a gut–liver–joint crosstalk framework. Dysregulated bile acid metabolism—characterized by a reduced total bile acid pool, decreased hydrophobic secondary bile acids, elevated 12α-hydroxy bile acids, and impaired enterohepatic circulation—has been mechanistically linked to both hepatic urate overproduction via the PPAR-α/xanthine oxidase pathway and monosodium urate crystal-induced NLRP3 inflammasome activation, although human causal evidence remains to be established. The nuclear receptor FXR suppresses NLRP3 at the transcriptional level, while the membrane receptor TGR5 acts post-translationally through Cyclic adenosine monophosphate/Protein Kinase A (cAMP/PKA) and Glucagon-like peptide-1 (GLP-1) signaling. Gut microbiota dysbiosis amplifies these abnormalities through a vicious cycle of reduced bile acid signaling, increased intestinal permeability, and systemic endotoxemia. Based on these insights, we summarize five therapeutic strategies: FXR modulators, TGR5 agonists, microbiota-based interventions, natural products, and ursodeoxycholic acid replacement therapy. Future research should prioritize gout-specific preclinical models, clinical trials of TGR5 agonists, standardized microbiota-based therapies, dual-target molecules, and personalized patient stratification based on bile acid profiles. Full article

Mitochondrial diseases have traditionally been viewed as energy deficiencies, but current evidence positions mitochondria as central regulators of multiple cell death pathways. This review systematically analyzes the molecular mechanisms of apoptosis and ferroptosis in the context of both primary mitochondrial diseases—caused by mutations in mtDNA or nuclear DNA directly affecting oxidative phosphorylation—and secondary mitochondrial dysfunction associated with broader pathological conditions. Apoptosis is an energy-dependent process characterized by mitochondrial outer membrane permeabilization, cytochrome c release, and caspase cascade activation, whereas ferroptosis involves iron-dependent lipid peroxidation, glutathione depletion, and inactivation of glutathione peroxidase 4 (GPX4), leading to accumulation of oxidized phospholipids predominantly in endoplasmic reticulum and plasma membranes; mitochondrial ultrastructural changes—including volume reduction and cristae loss—represent characteristic morphological features of ferroptosis rather than its primary site of initiation. Key findings reveal that reactive oxygen species overproduction, disruption of reducing equivalent metabolism, iron dyshomeostasis, and calcium overload simultaneously prime cells for both death pathways. Cytochrome c, p53, and BCL-2 family proteins serve as integration hubs, with cardiolipin peroxidation and phospholipid composition influencing pathway switching. Tissue specificity is pronounced in primary mitochondrial diseases: retinal ganglion cells in Leber’s hereditary optic neuropathy, cardiomyocytes in mtDNA-associated cardiomyopathies, and hepatocytes in mtDNA depletion syndromes exhibit distinct dominant death pathways. It should be noted, however, that for many conditions discussed, the evidence for ferroptosis involvement relies on indirect markers—such as lipid peroxidation products, decreased GPX4, and iron deposition—rather than on pharmacological rescue with ferrostatin-1 or liproxstatin-1 and rigorous exclusion of alternative death modalities; this limitation is discussed critically throughout the review. Diagnostic criteria combining morphological, biochemical, and pharmacological tools enable differentiation of death pathways. The review concludes that combined inhibition—using mitochondria-targeted antioxidants, GPX4 modulators, iron chelators, and mPTP blockers—together with personalized diagnostic algorithms offers the most promising therapeutic strategy. Understanding the apoptosis–ferroptosis crosstalk is essential for developing targeted interventions in mitochondrial diseases. Full article

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are critical modulators of male reproductive health, influencing sperm function, hormonal regulation, and overall fertility. While physiological levels of ROS and RNS are essential for processes such as sperm capacitation and acrosome reaction, their overproduction leads to oxidative and nitrosative stress, contributing to male infertility. Excessive ROS and RNS can damage sperm DNA, proteins, and lipids, impairing motility, viability, and fertilizing capacity. Moreover, these reactive species disrupt the hypothalamic-pituitary-gonadal (HPG) axis, leading to hormonal imbalances that further compromise reproductive function. Environmental factors, lifestyle choices, and underlying health conditions exacerbate the production of ROS and RNS, highlighting the need for preventive and therapeutic strategies. Clinically, ROS- and RNS-mediated redox imbalance has been implicated in several male reproductive disorders, including varicocele, genital tract infection and inflammation, obesity, diabetes and other metabolic disorders, and toxicant-related reproductive dysfunction. Antioxidant supplementation has shown promise in mitigating oxidative stress; however, its efficacy varies, and further research is necessary to establish standardized treatment protocols. These findings underscore the clinical relevance of integrating oxidative stress assessment with conventional semen analysis to improve risk stratification and guide targeted interventions in male infertility. This review synthesizes current knowledge on the molecular mechanisms by which ROS and RNS affect male reproduction and discusses potential clinical interventions to address oxidative and nitrosative stress in male infertility. Full article

Severe acute pancreatitis (SAP) is a life-threatening inflammatory disorder characterized by high mortality and limited therapeutic options. Alginate oligosaccharide (AOS), a marine-derived bioactive polysaccharide, exhibits prebiotic, anti-inflammatory and antioxidant properties that are effective against various inflammatory diseases. In this study, a mouse model of SAP was established by intraperitoneal injection of cerulein (100 μg/kg) and lipopolysaccharide (5 mg/kg), and the mice were pretreated with AOS (200 mg/kg) by gavage for 4 consecutive weeks to explore the potential protective efficacy and underlying mechanisms. The results shown that AOS attenuated the severity of SAP, as evidenced by reduced serum amylase and lipase levels, as well as alleviated histopathological injury in both pancreatic and ileal tissues. AOS suppressed the overproduction of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) in serum, pancreas, and ileum at protein or mRNA levels. Moreover, AOS effectively diminished pancreatic and ileal inflammatory infiltration and oxidative stress in SAP mice, accompanied by inhibited the TLR4/MyD88/NF-κB pathway and activated the Nrf2/HO-1 antioxidant axis. Furthermore, AOS restored intestinal barrier integrity, as manifested by upregulated expression of tight junction proteins (claudin-1, occludin, ZO-1), reduced serum diamine oxidase, and decreased bacterial translocation from the gut to the pancreas. It was revealed by 16S rRNA sequencing that AOS ameliorated SAP-induced gut dysbiosis by restoring microbial diversity, normalizing the Firmicutes/Bacteroidetes ratio, enriching beneficial genera (Lactobacillus, Blautia), and enhancing cecal short-chain fatty acid (acetic, propionic, butyric acid) production. Collectively, our findings demonstrate that AOS exerts comprehensive protective effects against SAP through suppression of inflammatory signaling and oxidative stress, as well as restoring gut homeostasis. These results suggest that AOS may serve as a promising prebiotic-based nutritional strategy for the management of SAP. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent global health concern. Although pharmacotherapies such as Resmetirom and semaglutide have recently gained approval by FDA/EMEA, therapeutic options remain limited, necessitating the exploration of novel natural compounds. Our previous research indicated that lycopene exerts protective effects against MASLD; however, its underlying molecular mechanisms remain incompletely understood. The present study aimed to investigate whether lycopene alleviates MASLD by modulating mitophagy, with a focus on the PINK1/Parkin pathway. C57BL/6J mice were fed with high-fat diet for 12 weeks to induce MASLD and daily gavage of lycopene (10/40 mg/kg). In vitro, AML12 cells were treated with lycopene and Mdivi-1 to assess the role of PINK1/Parkin-mediated mitophagy against lipid accumulation, oxidative stress, and apoptosis. The results found that lycopene supplementation significantly ameliorated HFD-induced weight gain, dyslipidemia, hepatic steatosis, pathological liver injury, and elevated serum liver enzymes. It reduced hepatic reactive oxygen species (ROS) overproduction and suppressed the mitochondrial apoptotic pathway, as evidenced by decreased cytochrome c release and caspase cascade activation. Concurrently, lycopene restored ATP levels and mitochondrial membrane potential, improved ultrastructural integrity, and balanced mitochondrial dynamics by downregulating DRP1 and upregulating MFN2 and OPA1. Crucially, lycopene activated PINK1/Parkin-mediated mitophagy, leading to an increased LC3-II/LC3-I ratio and Beclin1 expression, alongside decreased levels of mitochondrial proteins TOM20 and COX IV. In vitro, the lycopene partially reversed the exacerbating effects of Mdivi-1 on lipid accumulation, ROS generation, apoptosis, and the suppression of the PINK1/Parkin pathway. Collectively, lycopene ameliorates MASLD by activating PINK1/Parkin-mediated mitophagy and improving mitochondrial homeostasis, thereby reducing hepatic lipid accumulation and attenuating hepatocyte apoptosis. Full article

Oxidative stress is one of the few defined causes of male infertility affecting at least one third of patients attending infertility clinics. Human spermatozoa are vulnerable to this form of attack because their stripped-down architecture means that they possess limited antioxidant protection and little capacity for biochemical repair. They also compound their vulnerability by being active generators of reactive oxygen species (ROS) and possessing multiple substrates for oxidative damage. The major sources of ROS in these cells are their mitochondria, an L-amino acid oxidase (IL4I1) and a calcium-dependent NADPH oxidase (NOX5). Spermatozoa tolerate the risks associated with ROS generation because their biology is heavily dependent on redox regulation. ROS are important mediators of sperm capacitation, stimulating the generation of cAMP and prostaglandins, inhibiting protein phosphatases and encouraging removal of cholesterol from the plasma membrane. Furthermore, during fertilization, the ability of ROS to activate metalloproteinases facilitates penetration of the zona pellucida and sperm–oocyte fusion. While ROS are physiologically important for sperm function, the over-production of these metabolites can impair sperm function. Antioxidants have therefore assumed some importance as a possible therapy for the infertile male. However, before this potential can be realized, we need to optimize the composition and dose of reagents used in such formulations and develop improved methods of diagnosing oxidative stress within the patient population. Full article

Background: Unhealthy expansion of adipose tissue (AT) due to excessive dietary intake of omega-6 or overnutrition stimulates the overaccumulation of the extracellular matrix (ECM), resulting in AT metabolic dysregulation. Hypertrophic conditions, excessive adipose depots, and hypoxia stimulate the overproduction of collagenous and non-collagenous proteins, which pathophysiologically initiate the pro-fibrotic signaling pathway associated with fibrosis progression, resulting in atherosclerosis and cardiovascular diseases. Methods: We aimed to investigate adipocyte plasticity in response to a varying ratio of omega-3 (ω3) to omega-6 (ω6) supplementation during the chemically induced adipogenic differentiation of human mesenchymal stem cells. Additionally, changes in lipid accumulation, adipocyte hypertrophy and hyperplasia, active lipid metabolites, and inflammatory cytokine profiles were evaluated. Furthermore, conditioned media from adipocytes treated with different ω3/ω6 ratios were applied to platelets to assess inflammatory responses through prostaglandin and thromboxane measurements. Results: A 1:3 ratio of ω3/ω6 (20:60 µM) significantly reduced lipid accumulation, promoted brown-like adipocyte morphology, and decreased apoptosis and reactive oxygen species (ROS) generation, as confirmed via FACS analysis. Transcriptional control of adipose tissue expansion was confirmed by the downregulation of LIPIN1 and COL1A1 mRNA expression and p-prostaglandin12-R protein levels in a 1:3 ratio when compared with 1:1, 1:2, 1:4, or 2:6 ratios of ω3/ω6. Notably, a 1:3 ratio of fatty-acid-treated adipocyte-conditioned media-treated platelets significantly reduced platelet activation and aggregation, as evidenced by lower p-thromboxane A2 protein levels. Conclusions: Supplementation with a 1:3 (20:60 µM) ω3/ω6 ratio favored the development of lean adipocytes, evidenced by the decreased lipid storage achieved by mitochondrial thermogenesis, which attenuated minimal adipocyte expansion and metabolic inflammation. Full article

The complement system is the primary defense mechanism against pathogens, acting through opsonization, the membrane attack complex, and classical, lectin, or alternative pathways. These pathways result in the production of key complement components, including C3a (complement component), C5a, and C3b, which recruit inflammatory cells. Complement dysregulation leads to renal disease through the overproduction of anaphylatoxins or inappropriate formation of the membrane attack complex. The levels of complement components have been shown to be useful as predictive markers in acute kidney injury, especially in conditions of alternative pathway activation, and in diseases of immune complex pathology such as lupus nephritis and IgA nephropathy. Genetic defects in complement regulatory proteins result in diseases such as C3 glomerulopathy or atypical hemolytic uremic syndrome, in which uncontrolled C3 convertase activity results in renal failure. Therapeutic interventions targeting complement components, including eculizumab or pegcetacoplan, improve patient outcomes in atypical hemolytic uremic syndrome and C3 glomerulopathy, respectively, while other interventions improve renal function in IgA nephropathy. These findings underscore the dual role of the complement system, which is not only implicated in the progression of renal diseases but also provides the potential for the development of therapeutic interventions for the treatment of various forms of nephropathy. Full article

The 3-nitropropionic acid (NPA) promotes neurological alterations in the striatum, hippocampus and vicinal motor and pre-motor cortical areas, and in the cerebellum. The neurological alterations induced by systemic NPA administration resemble those found in Huntington’s disease. In previous works, we have shown that intraperitoneal (i.p.) administration of kaempferol can efficiently protect against striatum degeneration and against motor neurological dysfunctions induced by NPA. In this work, we show that i.p. administration of kaempferol also protects against the increase in pro-inflammatory cytokines that potentiate the activation of complement C3 protein (a biomarker of A1-type reactive astrocytes generation) and overproduction of neurotoxic amyloid β (Aβ) peptides in the cerebellum of rats treated with acute i.p. administration of NPA. In NPA-treated rats, large multipolar neurons of cerebellar nuclei and Purkinje neurons of the cerebellar cortex are the cells that are most intensely stained by anti-C3 and by anti-Aβ antibodies. In addition, we found that kaempferol also protects against the NPA-induced increase in phospho-tau 217 and phospho-tau 181 in the cerebellum, and our results pointed out that the NPA-induced phospho-tau 217 colocalizes with Aβ(1-42) more closely than phospho-tau 181, both in dentate nucleus and cerebellar cortex. Also, our results unveil another novel brain-protective action of i.p. kaempferol co-administration: namely, its ability to prevent microhemorrhages induced in the cerebellar nuclei area by acute NPA administration. In conclusion, the results of this work show a potent protection of kaempferol against the NPA-induced increase in degeneration biomarkers in the cerebellum. Full article

The edible tree peony (Paeonia suffruticosa Andrews) flowers are rich in bioactive components with potential health benefits, but the skin-health-promoting effects of their protein hydrolysates remain understudied. The present research sought to evaluate the antioxidant, anti-wrinkle, moisturizing, and whitening properties of tree peony flower protein hydrolysate (TPFP). TPFP was prepared via enzymatic hydrolysis and ultrafiltration, and its peptide sequences were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), revealing 54 unique small-molecule peptides with an average amino acid length of 8.2 residues and a molecular weight of 914.51 Da. In vitro safety evaluation using CCK-8 assay showed TPFP (20–100 μM) did not induce substantial cytotoxic effects in either HaCaT keratinocytes or B16F10 melanoma cell lines. Functional assays demonstrated that TPFP dose-dependently inhibited UVB-induced reactive oxygen species (ROS) overproduction and restored superoxide dismutase (SOD) and catalase (CAT) activities in HaCaT cells, exerting antioxidant effects. Additionally, TPFP protected pro-collagen I from UVB-induced loss, suppressed the expression of matrix metalloproteinase 1 (MMP-1), and restored hyaluronic acid (HA) content, showing anti-wrinkle and moisturizing potentials. In α-MSH-stimulated B16F10 cells, TPFP suppressed melanin synthesis by downregulating the protein expression of tyrosinase (TYR), tyrosinase-related protein 1 (TRP-1), and TRP-2, achieving a whitening effect. These findings indicate that TPFP possesses comprehensive skin-health-promoting activities with good biocompatibility, highlighting its potential as a natural functional ingredient in cosmetics and functional foods. Full article

Reactive oxygen species (ROS) are an essential component for the maintenance of cellular function. However, if produced in excess, ROS can drive cellular dysfunction and compromise cell viability. Indeed, uncontrolled ROS production plays a pivotal role in the pathogenesis of type 2 diabetes (T2D), contributing to the loss of β-cell function and the impairment in insulin signalling, as well as driving the development of diabetic complications, which can severely compromise quality of life. T2D is characterised by persistent hyperglycaemia, which is a leading contributor to ROS overproduction in this disease state. This enhanced, almost uncontrolled, increase in glucose metabolism upregulates several ROS-producing pathways, including the hexosamine pathway, protein kinase C, NADPH oxidase and the mitochondrial electron transport chain. There is accumulating evidence to suggest that in a bid to preserve redox homeostasis, ROS acts to suppress glucose metabolism by inactivating several enzymes involved in the regulation of glycolytic flux, including glucokinase, glyceraldehyde 3-phosphate dehydrogenase, phosphofructokinase-1 and pyruvate kinase. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a multi-faceted transcription factor, with a central role in ROS signalling and redox homeostasis. Whilst NF-κB mediates the transcriptional regulation of many pro-oxidants, NF-κB activity is also regulated by the oxidative status, with ROS having both inhibitory and stimulatory roles in these signalling pathways. Interestingly, NF-κB is also involved in controlling the delicate balance between glycolytic flux and mitochondrial respiration. This review will summarise the interplay linking hyperglycaemia with ROS formation, emphasising the role of glucose metabolism in the process, and the crosstalk of these pathways with NF-κB. Full article

Background/Objectives: Maternal immune activation (MIA) increases the risk of Autism Spectrum Disorders (ASD). Experimental models demonstrate that maternal exposure to bacterial endotoxin or the viral mimic polyinosinic:polycytidylic acid [poly (I:C)] reliably recapitulates ASD-like behavioral abnormalities in offspring, yet the underlying neurobiological mechanisms linking MIA to altered neurodevelopment remain incompletely understood. Increasing evidence highlights the placenta as a critical mediator in shaping fetal brain development through immunological and hormonal regulation. Likewise, disruption of placental regulatory functions upon MIA may therefore represent a mechanistic pathway. Here, we investigated how alterations in placental cytokine profiles, innate immune cell composition, and endocrine outputs relate to neuroinflammation and neurogenesis in the offspring. Methods: Pregnant mice at gestational day 12.5 received a single intraperitoneal injection of poly (I:C). Placental macrophages, neutrophils, inflammatory cytokines, and nerve growth factor (NGF) expression were examined 72 h later. Neurodevelopmental outcomes, including microglial activity and neurogenic markers, were evaluated in mouse offspring at postnatal day (P) 1 and 6. Results: MIA induced a significant accumulation of monocytes and neutrophils in the placenta, which was associated with elevated levels of a broad spectrum of inflammatory mediators, including Th17-biased proinflammatory cytokines, chemokines, and adhesion proteins, in the placenta and amniotic fluid. In contrast, the placenta-derived NGF levels were significantly reduced. MIA induced strong and sustained microglial activation in the fetal and neonatal brain. This inflammatory milieu was accompanied by disrupted cortical neurogenesis, characterized by a marked increase in Ki67+ neuronal progenitor cells (NPCs) in the subventricular zone (SVZ), overproduction of early-born Tbr1+ neurons at P1, later-born Satb2+ neurons at P6. Conclusions: Collectively, these findings suggest that heightened Th17 inflammatory signaling, coupled with impaired placental endocrine function, contributes to dysregulated cortical neurogenesis in the offspring. Full article

Background: Acacetin, a naturally occurring flavone present in various plants, is known as a promising drug candidate for cardiovascular disorders. Our previous study demonstrated that acacetin ameliorates atherosclerosis through endothelial cell protection; however, its pharmacological effects on vascular smooth muscle cells (VSMCs) remain unexplored. This study investigates the therapeutic potential of acacetin against lysophosphatidylcholine (LysoPC)-induced VSMC injury and elucidates the underlying molecular mechanisms. Methods and Results: Multiple biochemical techniques were employed in the present study. The results showed that acacetin significantly attenuated LysoPC-induced apoptosis and reactive oxygen species (ROS) generation in cultured VSMCs. Western blot analysis revealed that the cytoprotection of acacetin was associated with upregulated expression of antioxidant defense proteins, including nuclear factor erythroid 2-related factor 2 (Nrf2), catalase (CAT), NADPH quinone oxidoreductase 1 (NQO-1), and superoxide dismutase 1 (SOD1). Nrf2 silencing completely abolished these protective effects. Mechanistically, siRNA-silencing of Sirtuin 1 (Sirt1) abrogated acacetin-induced modulation of the Nrf2/Keap1/p62 signaling. In vivo validation using aortic tissues from high-fat-diet-fed ApoE^−/− mice confirmed that acacetin effectively suppressed VSMC apoptosis and ROS overproduction associated with restoring the downregulated Sirt1 expression levels. Conclusions: These findings establish a novel mechanistic paradigm wherein acacetin confers protection against LysoPC-induced VSMC apoptosis and oxidative stress through Sirt1-dependent activation of the Nrf2/p62 signaling pathway, suggesting that acacetin is a promising therapeutic drug candidate for atherosclerotic plaque stabilization. Full article

Manganese (Mn) is a crucial micronutrient for plants. The impaired function of the oxygen-evolving complex in Photosystem II (PSII) due to Mn deficiency is believed to result in the overproduction of reactive oxygen species and the induction of an enzymatic antioxidant system. In our study, we investigated the effects of progressive Mn deficiency (the difference in Mn content between the needles of control and Mn-deficient plants increased from 17-fold at the beginning of the experiment to 59-fold at the end) on the activities of superoxide dismutase (SOD), catalase, ascorbate peroxidase, and guaiacol peroxidase in the roots and needles of Scots pine seedlings. We found that the soluble protein content in plant organs under Mn deficiency was maintained at a level comparable to that of the control. Regardless of the severity of Mn deficiency, the needles of the Mn-deficient plants presented twofold lower SOD activity than the needles of the control plants. These differences were observed even when Mn deficiency did not negatively affect plant growth. Additionally, the total SOD activity in the needles of both plant groups was determined solely by the activity of the Cu/Zn-containing SOD isozymes. Compared with the control plants, Mn deficiency did not result in an increase in any of the studied H₂O₂-degrading enzymes in the needles of the seedlings. In contrast, the needles of the Mn-deficient plants presented a lower level of guaiacol peroxidase activity. Despite the inhibition of root growth, Mn deficiency led to changes in the balance of the enzymatic antioxidant system in plant roots. The data obtained suggest that the lack of activation of SOD and other antioxidant enzymes in Scots pine seedlings against the background of progressive Mn deficiency is due to the reduced ability of PSII to generate ROS under these conditions. Full article

Pediatric hydrocephalus results from the overproduction, obstruction, or inability to resorb cerebrospinal fluid (CSF), which may lead to ventricular enlargement. Hydrocephalus may be secondary to other pathologies, including intraventricular hemorrhage (IVH). Surgical intervention may include a ventricular access device or a ventriculosubgaleal shunt in premature infants who are too small for permanent CSF diversion. Hydrocephalus, an inflammatory pathology, involves activation of the inflammasome. Elevation in pro-inflammatory proteins is often associated with worsening clinical outcomes in pediatric pathologies. Whether inflammasome proteins are reliable biomarkers for pediatric hydrocephalus has not been established. We analyzed CSF samples via an ELLA assay from pediatric hydrocephalic patients with IVH of prematurity vs. controls and compared changes in inflammasome protein concentrations post-reservoir surgery at different time points. The area under the curve was calculated using receiver operator characteristic curves. The levels of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin-18 were significantly elevated in pediatric hydrocephalic patients with IVH vs. controls. Thus, these proteins are reliable biomarkers of the inflammatory response in pediatric hydrocephalus following ROC analysis, with an AUC of 1.0 and high sensitivity and specificity at the corresponding cut-off points. Ongoing work seeks to validate these findings in a larger cohort of pediatric hydrocephalic patients with varying etiologies. Full article