Clinical science最新文献

The dysregulation of renal sodium metabolism linked to obesity and excessive dietary salt intake is a significant factor in the development of salt-sensitive hypertension. Our previous research has demonstrated that oxidative stress-particularly through the amplification loop of reactive oxygen species (ROS)-plays a critical role in modulating renal sodium handling via Na/K-ATPase signaling. This present study aims to determine whether the antioxidant enzyme heme oxygenase-1 (HO-1) modulates renal sodium metabolism by affecting oxidative stress and the Na/K-ATPase pathway, potentially revealing novel therapeutic avenues. To investigate this, we conducted high-salt dietary interventions and administered Co(III) protoporphyrin IX chloride (CoPP) in both normal and obese C57BL/6J mice. Results indicated that obesity exacerbated oxidative stress and disrupted sodium metabolism. Notably, the induction of HO-1 via CoPP effectively reduced oxidative stress, suppressed inflammatory responses, and modulated mechanisms of renal sodium handling. These observations were corroborated by decreases in protein carbonylation and malondialdehyde (MDA) levels, as well as inhibition of the IL-6/STAT3 inflammatory pathway. Importantly, up-regulation of HO-1 corresponded with a reduction in activated Na/K-ATPase signaling, likely attributable to diminished ROS levels. Furthermore, genetic analyses and urinary metabolite profiles validated the regulatory effects of CoPP on oxidative stress and sodium metabolism. In conclusion, our findings elucidate the dual role of HO-1 as both an antioxidant defense system and a pivotal modulator of sodium excretion. This research underscores the multifaceted physiological functions of HO-1 and its crucial role in regulating renal sodium metabolism, with significant implications for managing salt-sensitive hypertension.

Vascular aging is marked by increased levels of reactive oxygen species in endothelial cells. Reactive oxygen species can, among others, be produced by dysfunctional mitochondria, contributing to acceleration of vascular aging by promoting DNA damage response and senescence. In the aged vasculature, impaired endothelial cell function causes decreased vasodilation, which may also have an impact on peripheral organs such as the kidney. The aim of this study was to investigate the effect of chronic treatment with SUL-138 (30 mg/kg/day), a novel mitochondrial protective compound, on DNA damage-prompted, accelerated endothelial aging and associated kidney dysfunction in mice. Endothelial-specific aging was induced by knock-out (KO) of DNA repair endonuclease Ercc1 in mice [endothelial-cell specific Ercc1 KO (EC-KO) mice]. We showed that impaired endothelium-dependent vasodilation and expression of DNA damage response markers in EC-KO mice were restored after the treatment with SUL-138. The underlying mechanism of improved vasodilation was an increase in endothelium-derived hyperpolarization (EDH). Endothelial-specific aging induced tubular injury, sodium wasting, and increased inflammatory markers in the kidney, which were normalized by the treatment with SUL-138. We conclude that accelerated endothelial aging adversely affects vascular function and causes kidney tubular injury. SUL-138 rescues endothelial aging, restores vasodilation by increasing EDH, and protects the kidney. Thus, preservation of mitochondrial function is a potential pharmacotherapeutic target in aging-related dysfunction provoked by the DNA damage response.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major non-communicable disease with global prevalence of 38% and no early-stage treatment. It has risk factors of insulin resistance, impaired glucose tolerance, type 2 diabetes, and diets rich in glucose and fructose. In this review, we explore evidence of abnormal increased early-stage glycolytic intermediates, glycolytic overload, in the initiation of MASLD and propose a new strategy for improved therapy. Glucose is mainly metabolized to glucose-6-phosphate by glucokinase (GCK) in the human liver. This is slowed by the competitive inhibitor, glucokinase regulatory protein (GKRP), with inhibition potentiated by fructose-6-phosphate and lifted by fructose-1-phosphate. The in situ activity of GCK is predicted to increase up to 3-fold by dietary glucose and over 4-fold with concurrent fructose. Related increased glycolytic intermediates activate carbohydrate response element binding protein (ChREBP), hexosamine pathway, and methylglyoxal-stimulated unfolded protein response (UPR). Activation of ChREBP contributes to enhanced lipogenesis and impaired suppression of hepatic glucose production by down-regulation of insulin receptor substrate-2 (IRS-2). IRS-1 signaling is maintained, contributing to enhanced lipogenesis through activation of sterol response element binding protein-1c and down-regulation of IRS-2. Hexosamine pathway activity stabilizes GCK and ChREBP to proteolysis, and the UPR stimulates inflammation and fibrosis. Hepatocytes then export glucose excessively, increasing fasting plasma glucose and risk of peripheral insulin resistance, type 2 diabetes, and vascular complications. Activators of nuclear factor erythroid 2-related factor 2 (Nrf2) provide a novel strategy for therapy. They divert excess glucose metabolism to the pentosephosphate pathway, decreasing activation of ChREBP and hexosamine pathway and formation of methylglyoxal, and decrease lipogenic gene expression. Nrf2 activator, trans-resveratrol and hesperetin combination, corrected glycolytic overload and insulin resistance clinically and now merits evaluation for early-stage treatment of MASLD.

Panvascular disease, defined by the systemic involvement of multiple vascular beds, poses a growing challenge to contemporary diagnostic and therapeutic paradigms. Despite organ-specific manifestations, these conditions share a convergent pathological basis driven by chronic low-grade inflammation, immune dysregulation, and maladaptive vascular remodeling. Within this immunovascular interface, complement C3 (C3) has emerged as a pivotal regulator. Positioned at the convergence of the classical, lectin, and alternative complement pathways, C3 integrates systemic immune cues with microenvironmental stimuli to orchestrate endothelial activation, smooth muscle cell phenotypic switching, immune cell recruitment, platelet activation, and fibroinflammatory remodeling. This review provides a comprehensive analysis of C3 biology, including its structural domains, activation cascades, and downstream effector functions. We examine the role of C3 across major vascular cell types, endothelial cells, vascular smooth muscle cells, innate and adaptive immune cells, platelets, and fibroblasts, highlighting how C3 signaling dynamically shapes both acute injury responses and chronic vascular adaptation. In disease-specific contexts, we delineate how C3 contributes to the pathogenesis of atherosclerosis, coronary artery disease, aortic aneurysm and dissection, hypertension, pulmonary arterial hypertension, peripheral vascular disease, stroke, and autoimmune- associated vasculitides. Special emphasis is placed on the dual-phase roles of C3, such as its injuryexacerbating effects in the acute phase of stroke versus its reparative functions in neuroregeneration. Finally, we review emerging therapeutic strategies targeting C3, with a focus on compstatin-based inhibitors, their pharmacological profiles, clinical trial progress, and immunological safety considerations. Collectively, this review reframes C3 as a master orchestrator of panvascular pathology and a promising target for precision immunomodulation across vascular systems.

Short-chain fatty acids (SCFAs) are metabolic by-products from microbial fermentation of complex carbohydrates and protein. They have gained clinical interest for their protective effects, including within the lung microenvironment. SCFAs are detectable in circulation and exhaled breath condensate (EBC), posing questions as to whether exhaled SCFAs originate from the gut and/or lung microbiota. Mapping SCFAs from the lung could improve our understanding of microbial activity in respiratory conditions. SCFA measurements in EBC were evaluated using a validated gas chromatography-mass spectrometry assay. Six healthy participants ingested sodium acetate, calcium propionate and sodium butyrate to acutely increase circulating SCFAs. EBC samples were collected alongside venous draws, with circulating and exhaled levels compared. A series of additional respiratory sample matrices from patient samples was investigated to gain novel insights into SCFAs within different respiratory biofluids. Serum SCFAs were increased in line with known responses. However, these increases were not observed in EBC, indicating a lack of correlation between circulating and exhaled SCFAs. SCFAs were detected in all additional respiratory biosamples, with EBC and sputum reporting the highest concentrations. Interestingly, branched-chain moieties were notably abundant in sputum, indicating the potential for their local production by bacterial fermentation of lung mucus proteins. SCFAs in EBC do not reflect circulatory levels and, therefore, are not a suitable surrogate measurement to inform on systemic load. These data suggest that exhaled SCFAs are potentially derived from lung microbial metabolism, supporting the need for further investigation into SCFA production, function and diagnostic utility in respiratory health.

Dietary fibre lowers blood pressure (BP) via short-chain fatty acids, acidic metabolites released from fibre fermentation by bacteria in the large intestine. This acidic microenvironment may activate the pH-sensing receptor GPR68, primarily expressed in immune cells. Here, we aimed to investigate whether GPR68 confers the BP-lowering effects of a high-fibre diet in hypertension by regulating inflammatory responses. Baseline BP parameters were measured using telemetry in C57BL/6J wildtype (WT) and GPR68-deficient (Gpr68-/-) male and female mice. Moreover, male mice were fed a control or high-fibre diet following minipump implantation with saline or angiotensin II (Ang II), where BP was measured weekly by tail-cuff. Cardiac ultrasounds, histological, flow cytometric and gut microbiome (16S) analyses were performed. No BP differences were detected in untreated male and female mice, irrespective of genotype. Similarly to WT mice, Gpr68-/- male mice were susceptible to Ang II-induced hypertension. High-fibre-fed WT mice exhibited blunted elevations in BP and improved cardiac collagen deposition and aortic elastin content compared with control-fed WT mice. These were not observed in high-fibre-fed Gpr68-/- mice. A high-fibre diet decreased pro-inflammatory renal and aortic immune cell counts independently of GPR68. Dietary fibre, rather than GPR68 or Ang II, was the primary factor influencing differences in the gut microbiota. This study provides novel insight into how the pH-sensing receptor GPR68 may be implicated in the protective effects of a high-fibre diet. However, these effects are likely immune-independent.

Allogeneic haematopoietic stem cell transplantation (alloHSCT) is a curative treatment for haematological malignancies. AlloHSCT aims to generate graft-versus-leukaemia immunity, where donor T cells eliminate residual malignant cells. However, graft-versus-host disease (GVHD), where donor T cells attack recipient tissues, is a common and often fatal side effect. Post-transplant cyclophosphamide (PTCy) can reduce GVHD, but the cellular mechanisms through which this occurs are not fully understood, and high doses may be associated with toxicity. This study aimed to determine whether lower doses of PTCy can reduce GVHD and to examine the effects of PTCy doses on human (h) immune cell subsets, T cell exhaustion, and histological GVHD in a humanised mouse model. NOD-scid-IL2Rγnull mice were injected with 2 × 107 human peripheral blood mononuclear cells on day 0, cyclophosphamide (10, 25 or 33 mg/kg) or control diluent on days 3 and 4 and monitored for GVHD development at early and late time points. Low-dose PTCy (10 mg/kg) abrogated clinical signs of GVHD with comparable efficacy to high-dose PTCy (33 mg/kg), delaying GVHD onset and prolonging mouse survival. Proportions of hPD-1+ hCD4+ and hPD-1+hCD8+ T cells were increased with low-dose PTCy but not higher doses, while hPD-1+ hTreg proportions were increased by all PTCy doses. Exhausted hPD-1+hLAG3+hCD8+ T cell proportions were increased with high-dose PTCy, but not lower doses. This study indicates that low-dose PTCy reduces GVHD with similar efficacy to that of high-dose PTCy, but this appears to be associated with differing cellular mechanisms of action.

Sepsis triggers impaired macrophage bacterial phagocytosis, rendering the host more vulnerable to secondary infections, a manifestation termed sepsis-associated immunosuppression. Glutamine (Gln) is a vital nutrient in critical illness that not only supports energy production and biomass synthesis but also potentially exerts immunomodulatory effects. The aim of the present study was to investigate whether supplementation of Gln modulates macrophage phagocytosis and mitigates sepsis-induced immunosuppression. Using a murine model of polymicrobial sepsis, we evaluated the effects of Gln supplementation on bacterial load, cytokine production, and survival. In multiple in vitro assays, we employed molecular and pharmacological approaches to dissect Gln-dependent signaling pathways in recovering the immunosuppressive macrophages. We found that Gln deficiency impaired macrophage phagocytosis and exacerbated sepsis-induced immunosuppression. In contrast, exogenous Gln supplementation restored macrophage function and improved survival in septic mice-effects that were abolished upon macrophage depletion. Mechanistically, Gln promoted glutamine-fructose-6-phosphate transaminase (GFAT)-dependent protein O-GlcNAcylation, leading to dynamin-related protein 1 (DRP1) oligomerization. Concurrently, Gln activated a GFAT-mediated, cyclin-dependent kinase 1-dependent pathway that induced DRP1 phosphorylation at Ser-616 irrelevant of O-GlcNAcylation. These effects enhanced DRP1-mediated mitochondrial fission, increased mitochondrial calcium efflux, and sustained cytosolic calcium levels essential for phagocytosis. In conclusion, our study demonstrates that Gln strengthens macrophage phagocytosis and alleviates immunosuppression in sepsis through a dual GFAT-DRP1 mechanism co-ordinating mitochondrial dynamics and calcium signaling, highlighting the GFAT-DRP1-calcium axis as a potential therapeutic target for treating sepsis-induced immunosuppression.

Sepsis is a life-threatening condition that occurs when infection drives an overwhelming immune response that damages tissues and results in multi-organ dysfunction. Current treatment of sepsis focuses on eliminating the infectious pathogen and supporting the cardiovascular system. However, effective therapeutics for mitigating the dysregulated immune response in sepsis are still lacking. To this end, many sepsis survivors end up with immunoparalysis and an increased risk of recurring infections. Despite the growing body of research revealing the close interplay between the nervous and immune systems, modulating the neuroimmune pathways remains an unexplored route of treatment. The sympathetic arm of the autonomic nervous system, particularly β-adrenergic receptor signalling, is integral in limiting the inflammatory response during bacterial infections. However, our current understanding of the neuroimmune interactions and their impact on sepsis pathophysiology remains limited. In this review, we outline current insights into the neuroimmune response in sepsis, with a particular focus on the role of the sympathetic nervous system in modulating immune responses against bacterial infections. Elucidating the neural signalling pathways that regulate the immune response and recovery in sepsis will reveal new therapeutic targets to reduce disease burden and improve patient outcomes.

Neutrophils are innate immune effector cells that play a vital role in host defense against infection. They exert antimicrobial activities through degranulation, phagocytosis, intracellular killing, production of reactive oxygen species, and neutrophil extracellular traps. Dysregulation of neutrophil abundance, phenotype, and immune activity is a commonly observed inflammatory feature of chronic obstructive pulmonary disease (COPD), a chronic inflammatory disorder of the lungs with no effective cure. Here, we review the clinical association and involvement of neutrophils in COPD pathogenesis, progression, and exacerbation. The association between neutrophilia, airway microbial imbalance (dysbiosis), and clinical manifestations of COPD is described. We summarize the impact (or lack of) of current treatments, including inhaled corticosteroids, macrolide antibiotics, and phosphodiesterase inhibitors, on neutrophilic inflammation or neutrophilia-associated features. Finally, we review potential future therapeutic options to address neutrophilic inflammation in COPD currently in clinical development, including anti-alarmins and inhibitors of neutrophil mediators.