Glucose-induced lipid metabolism is essential for preserving functional β-cells, and its disruption is linked to type 2 diabetes (T2D) development. Lipids are an integral part of the cells playing an indispensable role as structural components, energy storage molecules, and signals. Glucose presence significantly impacts lipid metabolism in β-cells, where fatty acids are primarily synthesized and/or are transported from the bloodstream. This process is regulated by the glycerolipid/free fatty acid cycle, which includes lipogenic and lipolytic reactions producing metabolic coupling factors crucial for insulin secretion. Disrupted lipid metabolism involving oxidative stress and inflammation is a hallmark of T2D. Lipid metabolism in β-cells is complex involving multiple simultaneous processes. Exact compartmentalization and quantification of lipid metabolism and its intermediates, especially in response to glucose or chronic hyperglycemia, are essential. Current research often uses non-physiological conditions, which may not accurately reflect situations. Identifying and quantifying individual steps and their signaling, including redox, within the complex fatty acid and lipid metabolic pathways as well as the metabolites formed during acute chronic glucose stimulation, will uncover the detailed mechanisms of glucose-stimulated insulin secretion. This knowledge is crucial for understanding T2D pathogenesis and identifying pharmacological targets to prevent this disease. 00, 000-000.

Dopamine agonists (DAs) are the first-line treatment for patients with prolactin-secreting pituitary adenoma (PRL adenoma). However, a subset of individuals exhibits poor responses, known as DA resistance. Previous studies have reported that DA resistance is more prevalent in male patients. This study aims to investigate the relationship between androgen receptor (AR) expression and DA resistance, as well as to explore underlying mechanisms of AR-mediated DA resistance. Our results demonstrated that patients with higher AR expression exhibit greater resistance to DA in our cohort of DA-resistant PRL adenoma. Furthermore, AR was found to be involved in cell proliferation, PRL secretion, and resistance to bromocriptine (BRC) both and . Mechanistically, we demonstrated that intracellular reactive oxygen species (ROS) function as upstream mediators of apoptosis and ferroptosis following BRC treatment. As a ligand-dependent transcription factor, AR could translocate to the nucleus and transcriptionally promote NFE2-like bZIP transcription factor 2 (NRF2) expression, which regulates intracellular ROS levels, thereby enhancing cell viability and conferring DA resistance to pituitary adenoma (PA) cells. Finally, AR targeting agents were used to inhibit AR signaling, downregulate NRF2 transcription, and sensitize PA cells to BRC treatment. We demonstrated that AR plays a crucial role in mediating DA resistance in PRL adenoma. Mechanistically, AR promotes cell proliferation and PRL secretion and confers drug resistance by transcriptionally regulating NRF2 expression to maintain redox homeostasis in PA cells. Finally, combining AR targeting agents with BRC shows promise as a therapeutic strategy for treating PRL adenomas. 00, 000-000.

The limited therapeutic options for diabetic tubulopathy (DT) in early diabetic kidney disease (DKD) reflect the difficulty of targeting renal tubular compartment. While renin-angiotensin-aldosterone system (RAS) inhibitors are commonly utilized in the management of DKD, how intrarenal RAS contributes to diabetic tubular injury is not fully understood. Mitochondrial disruption and reactive oxygen species (ROS) overgeneration have been involved in diabetic tubular injury. Herein, we aim to test the hypothesis that angiotensin-converting enzyme (ACE)-dependent intrarenal angiotensin II (AngII) disrupts tubular mitochondrial membranous homeostasis and causes excessive ROS generation in DT. Mice suffered from renal tubular mitochondrial disruption and ROS overgeneration following high-fat diet/streptozocin-type 2 diabetic induction. Intrarenal AngII generation is ACE-dependent in DT. Local AngII accumulation in renal tissues was achieved by intrarenal artery injection. ACE-dependent intrarenal AngII-treated mice exhibit markedly elevated levels of makers of tubular injury. CTP: Phosphoethanolamine cytidylyltransferase (PCYT2), the primary regulatory enzyme for the biosynthesis of phosphatidylethanolamine, was enriched in renal tubules according to single-cell RNA sequencing. ACE-dependent intrarenal AngII-induced tubular membranous disruption, ROS overgeneration, and PCYT2 downregulation. The diabetic ambiance deteriorated the detrimental effect of ACE-dependent intrarenal AngII on renal tubules. Captopril, the ACE inhibitor (ACEI), showed efficiency in partially ameliorating ACE-dependent intrarenal AngII-induced tubular deterioration pre- and post-diabetic induction. This study uncovers a critical role of ACE-dependent intrarenal AngII in mitochondrial membranous disruption, ROS overgeneration, and PCYT2 deficiency in diabetic renal tubules, providing novel insight into DT pathogenesis and ACEI-combined therapeutic targets. 00, 000-000.

Resistance to standard therapeutic methods, including chemotherapy, immunotherapy, and targeted therapy, remains a critical challenge in effective cancer treatment. Redox homeostasis modification has emerged as a promising approach to address medication resistance. This review aims to explore the mechanisms of redox alterations and signaling pathways contributing to treatment resistance in cancer. In this study, a comprehensive review of the molecular mechanisms underlying drug resistance governed by redox signaling was conducted. Emphasis was placed on understanding how tumor cells manage increased reactive oxygen species (ROS) levels through upregulated antioxidant systems, enabling resistance across multiple therapeutic pathways. Key mechanisms identified include alterations in drug efflux, target modifications, metabolic changes, enhanced DNA damage repair, stemness preservation, and tumor microenvironment remodeling. These pathways collectively facilitate tumor cells' adaptive response and resistance to various cancer treatments. Developing a detailed understanding of the interrelationships between these redox-regulated mechanisms and therapeutic resistance holds potential to improve treatment effectiveness, offering valuable insights for both fundamental and clinical cancer research. 00, 000-000.

Silicosis is a lung disease caused by inhalation of silica particles. Both silica-induced oxidative stress and aberrant activation of the Wnt/β-catenin signaling pathway are potential targets in the treatment of pulmonary fibrosis. Dickkopf-1 (Dkk1), an inhibitor of the Wnt/β-catenin signaling pathway, plays regulatory roles in cell fate determination and immune responses. Our previous study demonstrated that adenoviral vector-mediated gene transfer alleviated the silica-induced mouse silicosis. However, the mechanism of therapeutic action of Dkk1 in silicosis is yet completely understood; together with the drawbacks of adenoviral vectors in gene therapy, we investigated the therapeutic effect and mechanisms of Dkk1 by employing an adeno-associated virus (AAV) vector in a silicosis mouse model. The AAV vector could efficiently transduce the gene in silicotic lung during both the early and the late phases of disease, resulting in an alleviation of silicotic lesions, improvement of pulmonary compliance, and radiological findings. Mechanistic studies further demonstrated that the transduction of inhibited the silica-activated Wnt/β-catenin signaling and reduced the silica-induced reactive oxygen species-producing enzyme NADPH oxidase 4, oxidative stress regulator nuclear factor erythroid 2-related factor 2, and signaling molecules binding immunoglobulin protein and C/EBP homologous protein. In addition, shRNA-mediated downregulation of exacerbated the progression of silicosis in mice, whereas the treatment of ROS scavenger n-acetylcysteine showed a comparable mitigation of silicosis that was seen in the AAV-Dkk1 treatment. This study provides an insight into the mechanism by which Dkk1 inhibits the silica-induced Wnt signaling and oxidative stress to mitigate the pathogenesis of lung silicosis and evidence of the potential of AAV-mediated Dkk1 gene transfer as an alternative approach in silicosis treatment. 00, 000-000.

Adaptation to oxidative stress is essential for maintaining protein and redox homeostasis in mammalian cells. Palmitic acid (PA) plays a central role in oxidative stress and immunoproteasome regulation in podocytes and diabetes, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have beneficial impact on diabetes. The role of Nrf2 in adaptation to oxidative stress and regulation of immunoproteasome by PA and EPA/DHA in podocytes and diabetic kidneys is not well defined. The present study describes the effect of PA- and EPA/DHA-induced oxidative stress in regulating Nrf2/immuoproteasome pathway in a model system relevant to diabetic nephropathy (DN). Short PA exposure to podocytes promotes the upregulation of antioxidant proteins and immunoproteasome mediated by Nrf2, leading to acute transient oxidative stress adaptation. Both short- and long-term incubation of EPA or DHA in podocytes induced oxidative stress and activation of Nrf2, causing persistent oxidative stress adaptation. Long PA exposure to podocytes decreased the Nrf2 activity, and EPA/DHA attenuated these effects of PA. In mice, feeding of EPA/DHA-rich fish oil increased oxidative stress in kidneys and induced renal cortical Nrf2 nuclear translocation and immunoproteasome overexpression, inhibiting the progression of DN. We demonstrate an oxidative stress adaptation mechanism by PA and EPA/DHA regulated by Nrf2 in podocytes and kidneys of type 2 diabetes. This work provides an important insight into the pathogenetic mechanisms of DN by PA-induced oxidative stress. We conclude that activation of Nrf2-immunoproteasome signaling pathway by EPA/DHA plays a crucial role in abrogating the proteotoxic stress in DN. 00, 000-000.

Cellular senescence is a critical process underlying aging and is associated with age-related diseases such as Alzheimer's disease. Lipids are implicated in cellular senescence. Fatty acids, particularly eicosanoids, have been associated with various forms of senescence and inflammation, and the associated reactive oxygen species production has been proposed as a therapeutic target for mitigating senescence. When overactivated, calcium-dependent phospholipase A2 (cPLA2) catalyzes the conversion of arachidonic acid into eicosanoids such as leukotrienes and prostaglandins. With a growing understanding of the importance of lipids as mediators and modulators of senescence, cPLA2 has emerged as a compelling drug target. cPLA2 overactivation plays a significant role in several pathways associated with senescence, including neuroinflammation and oxidative stress. Previous cPLA2 inhibitors have shown potential in ameliorating inflammation and oxidative stress, but the dominant hurdles in the central nervous system-targeting drug discovery are specificity and blood-brain barrier penetrance. With the need for more effective drugs against neurological diseases, we emphasize the significance of discovering new brain-penetrant, potent, and specific cPLA2 inhibitors. We discuss how the recently developed Virtual Synthon Hierarchical Enumeration Screening, an iterative synthon-based approach for fast structure-based virtual screening of billions of compounds, provides an efficient exploration of large chemical spaces for the discovery of brain-penetrant cPLA2 small-molecule inhibitors. 00, 000-000.

Lipids, which constitute the highest portion (over 50%) of brain dry mass, are crucial for brain integrity, energy homeostasis, and signaling regulation. Emerging evidence revealed that lipid profile alterations and abnormal lipid metabolism occur during normal aging and in different forms of neurodegenerative diseases. Moreover, increasing genome-wide association studies have validated new targets on lipid-associated pathways involved in disease development. Myelin, the protective sheath surrounding axons, is crucial for efficient neural signaling transduction. As the primary site enriched with lipids, impairments of myelin are increasingly recognized as playing significant and complex roles in various neurodegenerative diseases, beyond simply being secondary effects of neuronal loss. With advances in the lipidomics field, myelin lipid alterations and their roles in contributing to or reflecting the progression of diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and others, have recently caught great attention. This review summarizes recent findings of myelin lipid alterations in the five most common neurodegenerative diseases and discusses their implications in disease pathogenesis. By highlighting myelin lipid abnormalities in neurodegenerative diseases, this review aims to encourage further research focused on lipids and the development of new lipid-oriented therapeutic approaches in this area. 00, 000-000.

The glutathione peroxidase (GPx) family is recognized for its essential function in maintaining cellular redox balance and countering the overproduction of reactive oxygen species (ROS), a process intricately linked to the progression of various diseases including those spurred by viral infections. The modulation of GPx activity by viruses presents a critical juncture in disease pathogenesis, influencing cellular responses and the trajectory of infection-induced diseases. Cutting-edge research has unveiled the GPx family's dynamic role in modulating viral pathogenesis. Notably, GPX4's pivotal function in regulating ferroptosis presents a novel avenue for the antiviral therapy. The discovery that selenium, an essential micronutrient for GPx activity, possesses antiviral properties has propelled us toward rethinking traditional treatment modalities. Deciphering the intricate relationship between viral infections and GPx family members is paramount. Viral invasion can precipitate significant alterations in GPx function, influencing disease outcomes. The multifaceted nature of GPx activity during viral infections suggests that a deeper understanding of these interactions could yield novel insights into disease mechanisms, diagnostics, prognostics, and even chemotherapeutic resistance. This review aims to synthesize current knowledge on the impact of viral infections on GPx activity and expression and identify key advances. By elucidating the mechanisms through which GPx family members intersect with viral pathogenesis, we propose to uncover innovative therapeutic strategies that leverage the antioxidant properties of GPx to combat viral infections. The exploration of GPx as a therapeutic target and biomarker holds promise for the development of next-generation antiviral therapies. 00, 000-000.

Musculoskeletal diseases seriously affect global health, but their importance is greatly underestimated. These diseases often afflict the elderly, leading to disability, paralysis, and other complications. Hydrogen sulfide (HS) plays an important role in the occurrence and development of musculoskeletal diseases, which may have potential therapeutic significance for these diseases. Recently, it has been found that many musculoskeletal diseases, such as osteoporosis, periodontitis, muscle atrophy, muscle ischemia-reperfusion injury, muscle contraction under high fever, arthritis, and disc herniation, can be alleviated by treatment with HS. HS may be conducive to the development of multiple myeloma. The mechanism of action of HS in the musculoskeletal system has been partly elucidated. A variety of HS donors and nano-delivery systems provide promising prospects for HS-based therapies. Related research remains at the level of cell or animal experiments, but clinical research is lacking. The roles of HS in more musculoskeletal disorders remain largely unknown. The serious consequences of musculoskeletal diseases have not been widely concerned. Targeted delivery of HS remains a challenging task in musculoskeletal diseases. Develop therapeutic drugs for musculoskeletal diseases based on HS and test their safety, efficacy, and tolerance. Explore the combination of current drugs for musculoskeletal diseases with HS-releasing components to improve the therapeutic efficacy and avoid side effects. Carry out relevant clinical trials to verify the possibility of its widespread use. 00, 000-000.

Parietal epithelial cells (PECs) are potential stem cells within the glomerulus, migrating into site of podocyte loss to differentiate into podocytes. Little is known about the mechanism mediating differentiation of PECs into podocytes. differentiation of PECs into podocytes led to upregulation of podocyte markers such as Wilms' tumor gene 1 (WT-1), Forkhead box C1 (FOXC1), synaptopodin and podocin, accompanied by increased mitochondrial abundance. Preincubation with a mitochondrial reactive oxygen species (ROS) inhibitor prevented all these events in PECs. , adriamycin (ADR)-treated mice exhibited albuminuria, decreased WT1 positive cells, and claudin-1 expressed in glomerular capillary tuft, as well as peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) overproduction in PECs. Expression of the ROS-related molecule nuclear factor erythroid 2-related factor 2 (Nrf2) and its target protein Brahma-related gene 1 (Brg1) increased during differentiation of PECs into podocytes. Suppressing Nrf2 or Brg1 reduced the differentiation of PECs, whereas overexpression had the opposite effect. Brg1 directly regulated WT-1 transcription in PECs. Activation of Nrf2 with bardoxolone-methyl (CDDO-Me) resulted in less proteinuria and more WT1 positive cells in ADR mice. PECs conditional human Nrf2 knock-in mice showed increased WT1 cell numbers. It concluded that mitochondria-derived ROS mediated differentiation of PECs into podocytes Nrf2 and Brg1 signaling.

Tumor microenvironment (TME) plays a crucial role in sustaining cancer stem cells (CSCs). 4-hydroxynonenal (4-HNE) is abundantly present in the TME of colorectal cancer (CRC). However, the contribution of 4-HNE to CSCs and cancer progression remains unclear. This study aimed to investigate the impact of 4-HNE on the regulation of CSC fate and tumor progression. Human CRC cells were exposed to 4-HNE, and CSC signaling was analyzed using quantitative real-time polymerase chain reaction, immunofluorescent staining, fluorescence-activated cell sorting, and bioinformatic analysis. The tumor-promoting role of 4-HNE was confirmed using a xenograft model. Exposure of CRC cells to 4-HNE activated noncanonical hedgehog (HH) signaling and homologous recombination repair (HRR) pathways in LGR5 CSCs. Furthermore, blocking HH signaling led to a significant increase in the expression of γH2AX, indicating that 4-HNE induces double-stranded DNA breaks (DSBs) and simultaneously activates HH signaling to protect CSCs from 4-HNE-induced damage the HRR pathway. In addition, 4-HNE treatment increased the population of LGR5 CSCs and promoted asymmetric division in these cells, leading to enhanced self-renewal and differentiation. Notably, 4-HNE also promoted xenograft tumor growth and activated CSC signaling . These findings demonstrate that 4-HNE, as a signaling inducer in the TME, activates the noncanonical HH pathway to shield CSCs from oxidative damage, enhances the proliferation and asymmetric division of LGR5 CSCs, and thereby facilitates tumor growth. These novel insights shed light on the regulation of CSC fate within the oxidative TME, offering potential implications for understanding and targeting CSCs for CRC therapy.

Nattokinase (NK), a potent serine endopeptidase, has exhibited a variety of pharmacological effects, including thrombolysis, anti-inflammation, and antioxidative stress. Building on previous research highlighting NK's promise in nerve regeneration, our study investigated whether NK exerted protective effects in transient middle cerebral artery occlusion (tMCAO)-induced cerebral ischemia-reperfusion injury and the underlying mechanisms. The rats were administered NK (5000, 10000, 20000 FU/kg, i.g., 7 days before surgery, once daily). We showed that NK treatment dose dependently reduced the infarction volume and improved neurological symptoms, decreased the proinflammatory and coagulation cytokines levels, and attenuated reactive oxygen species (ROS) in the infarcted area of tMCAO rats. We also found that NK could exert neuroprotective effects in a variety of vitro models, including the microglia inflammation model and neuronal oxygen-glucose deprivation/reperfusion (OGD/R) model. Notably, NK effectively countered OGD/R-induced neuron death, modulating diverse pathways, including autophagy, apoptosis, PARP-dependent death, and endoplasmic reticulum stress. Furthermore, the neuroprotection of NK was blocked by phenylmethylsulfonyl fluoride (PMSF), a serine endopeptidase inhibitor. We revealed that heat-inactive NK was unable to protect against tMCAO injury and other vitro models, suggesting NK attenuated ischemic injury by its enzymatic activity. We conducted a proteomic analysis and found inflammation and coagulation were involved in the occurrence of tMCAO model and in the therapeutic effect of NK. In conclusion, these data demonstrated that NK had multifaceted neuroprotection in ischemic brain injury, and the therapeutic effect of NK was related with serine endopeptidase activity.

Seawater immersion significantly aggravated organ dysfunction following hemorrhagic shock, leading to higher mortality rate. However, the effective treatment is still unavailable in clinic. Mitochondria were involved in the onset and development of multiple organ function disorders; whether mitochondria participate in the cardiac dysfunction following seawater immersion combined with hemorrhagic shock remains poorly understood. Hence, we investigated the role and possible mechanism of mitochondria in seawater immersion combined with hemorrhage shock-induced cardiac dysfunction. Mitochondrial fission protein dynamin-related protein 1 (Drp1) was activated and translocated from the cytoplasm to mitochondria in the heart following seawater immersion combined with hemorrhagic shock, leading to excessive mitochondrial fission. Excessive mitochondrial fission disrupted mitochondrial function and structure and activated mitophagy and apoptosis. At the same time, excessive mitochondrial fission resulted in disturbance of myocardial structure and hemodynamic disorders and ultimately provoked multiple organ dysfunction and high mortality. Further studies showed that the mitochondrial division inhibitor mitochondrial division inhibitor-1 can significantly reverse Drp1 mitochondrial translocation and inhibit mitochondrial fragmentation, reactive oxygen species (ROS) accumulation, mitophagy, and apoptosis and then protect circulation and vital organ functions, prolonging animal survival. Our findings indicate that Drp1-mediated mitochondrial fission could be a novel therapeutic targets for the treatment of seawater immersion combined with hemorrhagic shock. Drp1 mitochondrial translocation played an important role in the cardiac dysfunction after seawater immersion combined with hemorrhage shock. Drp1-mediated excessive mitochondrial fission leads to cardiac dysfunction due to the mitochondrial structure and bioenergetics impairment.

S-propargyl-cysteine (SPRC) is an endogenous hydrogen sulfide (HS) donor obtained by modifying the structure of S-allyl cysteine in garlic. This study aims to investigate the effect of SPRC on mitigating cardiac aging and the involvement of jumonji domain-containing protein 3 (JMJD3), a histone demethylase, which represents the primary risk factor in major aging related diseases, in this process, elucidating the preliminary mechanism through which SPRC regulation of JMJD3 occurs. , SPRC mitigated the elevated levels of reactive oxygen species, senescence-associated β-galactosidase, p53, and p21, reversing the decline in mitochondrial membrane potential, which represented a reduction in cellular senescence. , SPRC improved Dox-induced cardiac pathological structure and function. Overexpression of JMJD3 accelerated cardiomyocytes and cardiac senescence, whereas its knockdown reduced the senescence phenotype. The potential binding site of the upstream transcription factor of JMJD3, sheared X box binding protein 1 (XBP1s), was determined using online software. SPRC promoted the expression of cystathionine γ-lyase (CSE), which subsequently inhibited the IRE1α/XBP1s signaling pathway and decreased JMJD3 expression. This study is the first to establish JMJD3 as a crucial regulator of cardiac aging. SPRC can alleviate cardiac aging by upregulating CSE and inhibiting endoplasmic reticulum stress pathways, which in turn suppress JMJD3 expression. JMJD3 plays an essential role in cardiac aging regulation, whereas SPRC can suppress the expression of JMJD3 by upregulating CSE, thus delaying cardiac aging, which suggests that SPRC may serve as an aging protective agent, and pharmacological targeting of JMJD3 may also be a promising therapeutic approach in age-related heart diseases.

Endothelial cells (ECs) line the entire vasculature system and serve as both barriers and facilitators of intra- and interorgan communication. Positioned to rapidly sense internal and external stressors, ECs dynamically adjust their functionality. Endothelial dysfunction occurs when the ability of ECs to react to stressors is impaired, which precedes many cardiovascular diseases (CVDs). While EC reactive oxygen species (ROS) have historically been implicated as mediators of endothelial dysfunction, more recent studies highlight the central role of ROS in physiological endothelial signaling. New evidence has uncovered that EC ROS are fundamental in determining how ECs interact with their environment and respond to stress. EC ROS levels are mediated by external factors such as diet and pathogens, as well as inherent characteristics, including sex and location. Changes in EC ROS impact EC function, leading to changes in metabolism, cell communication, and potentially disrupted signaling in CVDs. Current endothelial biology concepts integrate the dual nature of ROS, emphasizing the importance of EC ROS in physiological stress adaptation and their contribution to CVDs. Understanding the discrete, localized signaling of EC ROS will be critical in preventing adverse cardiovascular outcomes. Exploring how the EC ROS environment alters EC function and cross-cellular communication is critical. Considering the inherent heterogeneity among EC populations and understanding how EC ROS contribute to this diversity and the role of sexual dimorphism in the EC ROS environment will be fundamental for developing new effective cardiovascular treatment strategies.

Intestinal stem cells (ISCs) are crucial for the continuous renewal and regeneration of the small intestinal epithelium. ISC fate decisions are strictly controlled by metabolism. Mitochondria act as the central hubs of energetic metabolism and dynamically remodel their morphology to perform required metabolic functions. Mitochondrial dysfunction is closely associated with a variety of gastrointestinal diseases. In recent years, several studies have reported that mitochondria are potential therapeutic targets for regulating ISC function to alleviate intestinal diseases. However, how mitochondrial quality control mediates ISCs under physiological conditions and protects against intestinal injury remains to be comprehensively reviewed. In this review, we summarize the available studies about how mitochondrial metabolism, redox state, dynamics, autophagy, and proteostasis impact ISC proliferation, differentiation, and regeneration, respectively. We propose that remodeling the function of mitochondria in ISCs may be a promising potential future direction for the treatment of intestinal diseases. This review may provide new strategies for therapeutically targeting the mitochondria of ISCs in intestinal diseases.

Arterial stiffness, a hallmark of vascular aging, significantly contributes to hypertension and impaired organ perfusion. Vascular smooth muscle cell (VSMC) dysfunction, particularly VSMC senescence and its interaction with stiffness, is crucial in the pathogenesis of arterial stiffness. Although hydrogen sulfide (HS) and its key enzyme cystathionine γ-lyase (CSE) are known to play roles in cardiovascular diseases, their effects on arterial stiffness are not well understood. First, we observed a downregulation of CSE/HS in the aortic media during biological aging and angiotensin II (AngII)-induced aging. The VSMC-specific CSE knockout mice were created by loxp-cre (Tagln-cre) system and which exacerbated AngII-induced aortic aging and stiffness and VSMC senescence and stiffness . Conversely, the CSE agonist norswertianolin mitigated these effects. Next, we identified growth arrest-specific 1 (Gas1) as a crucial target of CSE/HS and found it to be a downstream target gene of forkhead box protein M1 (Foxm1). siRNA knockdown Foxm1 increased Gas1 transcription and reduced the protective effects of HS on VSMC senescence and stiffness. Finally, we demonstrated that CSE/HS sulfhydrates Foxm1 at the C210 site, regulating its nuclear translocation and activity, thus reducing VSMC senescence and stiffness. Our findings highlight the protective role of CSE/HS in arterial stiffness, emphasizing the novel contributions of CSE, Gas1, and Foxm1 to VSMC senescence and stiffness. Endogenous CSE/HS in VSMCs reduces VSMC senescence and stiffness, thereby attenuating arterial stiffness and aging, partly through sulfhydration-mediated activation of Foxm1 and subsequent inhibition of Gas1 signaling pathways.

Succinate, a metabolite in the tricarboxylic acid cycle, is increasingly recognized to play essential roles in inflammation by functioning either as an intracellular or extracellular signaling molecule. However, the role and mechanisms of succinate in inflammation remain elusive. Here, we investigated the mechanism underlying the effects of succinate on neuroinflammation in intracerebral hemorrhage (ICH) models. We unexpectedly found that succinate robustly inhibited neuroinflammation and conferred protection following ICH. Mechanistically, the oxidation of succinate by succinate dehydrogenase (SDH) drove reverse electron transport (RET) at mitochondrial complex I, leading to mitochondrial superoxide production in microglia. Complex I-derived superoxides, in turn, activated uncoupling protein 2 (UCP2). By using mice with specific deletion of UCP2 in microglia/macrophages, we showed that UCP2 was needed for succinate to inhibit neuroinflammation, confer protection, and activate downstream 5'-adenosine monophosphate-activated protein kinase (AMPK) following ICH. Moreover, knockdown of SDH, complex I, or AMPK abolished the therapeutic effects of succinate following ICH. We provide evidence that driving complex I RET to activate UCP2 is a novel mechanism of succinate-mediated intracellular signaling and a mechanism underlying the inhibition of neuroinflammation by succinate.

Reduction-oxidation (redox) regulation is an important biological phenomenon that provides a balance between antioxidants and the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) under pathophysiological conditions. Structural and functional changes in glycans are also important as post-translational modifications of proteins. The integration of glycobiology and redox biology, called Glyco-redox has provided new insights into the mechanisms of epithelial-mesenchymal transition (EMT)/mesenchymal-epithelial transition (MET), cancer, and various diseases including Alzheimer's disease (AD), chronic obstructive lung disease (COPD), type 2 diabetes, interstitial pneumonitis, and ulcerative colitis (UC), .