Han S, Wei Y, Yu G
… +10 more, Jia W, Liao W, He Y, Cheng K, Zhao J, Xiang S, Zhang W, Chen X, Zhang B, Huang Z
Sci China Life Sci
· 2026 Jul · PMID 42026367
·
Publisher ↗
The bidirectional communication between the liver and bone profoundly influences the development and progression of both liver and bone diseases and significantly affects systemic homeostasis. Through the metabolic and i...The bidirectional communication between the liver and bone profoundly influences the development and progression of both liver and bone diseases and significantly affects systemic homeostasis. Through the metabolic and immune crosstalk mediated by hepatokines, osteokines, extracellular vesicles, gut microbiota, and neuroendocrine factors, the liver-bone axis not only affects the progression from chronic liver disease to liver cancer but also modulates the balance of bone formation and resorption as well as bone marrow homeostasis. Furthermore, a dysfunctional liver-bone axis can lead to systemic complications characterized by dyslipidemia and hyperglycemia. In this review, we discuss the pathophysiological changes induced by the dysregulated liver-bone axis and elucidate the specific mediating factors and mechanisms involved. We also summarize the current efforts in translating the liver-bone axis into clinical applications, aiming to provide potential therapeutic strategies for liver and bone diseases.
Chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnea (OSA), induces increased carotid body (CB) activity. Hydrogen sulfide (HS), a critical oxygen sensor in the CB, promotes protein post-translationa...Chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnea (OSA), induces increased carotid body (CB) activity. Hydrogen sulfide (HS), a critical oxygen sensor in the CB, promotes protein post-translational modification via S-sulfhydration. This study investigated whether CIH-induced H₂S production drives CB hyperactivity through Sp1 S-sulfhydration-mediated upregulation of angiotensin II receptor type 1 (AT1). Rats were exposed to CIH for 12 weeks. CB activity, H₂S levels, and AT1/Sp1 expression were analyzed. Pharmacological inhibitors [AOAA (H₂S synthase inhibitor) and DTT (S-sulfhydration inhibitor)] and the AT1 antagonist losartan were used in vivo and in PC12 cells under intermittent hypoxia (IH) to elucidate the underlying mechanisms. CIH significantly increased H₂S production and CB hyperactivity, and these effects were reversed by AOAA. Both AOAA and DTT inhibited Sp1 S-sulfhydration and AT1 upregulation in CB tissue and IH-exposed PC12 cells. AT1 inhibition with losartan normalized CB hyperactivity. Mechanistically, H₂S-mediated Sp1 S-sulfhydration enhanced AT1 transcriptional activation, leading to sustained CB sensitization. CIH enhances CB activity through H₂S-dependent Sp1 S-sulfhydration, which increases AT1 expression. This pathway represents a novel therapeutic target for OSA-associated hypertension.
Heart failure (HF) remains a major global health burden, with high morbidity and mortality closely linked to disturbances in cardiac energy metabolism. Targeting metabolic reprogramming has emerged as a key strategy to o...Heart failure (HF) remains a major global health burden, with high morbidity and mortality closely linked to disturbances in cardiac energy metabolism. Targeting metabolic reprogramming has emerged as a key strategy to overcome the limitations of conventional hemodynamic-based therapies. This review systematically elucidates critical alterations in the cardiac energy metabolism network associated with HF, including mitochondrial dysfunction, aberrant substrate utilization, and dysregulation at both the transcriptional and post-translational levels. It also explores multidimensional therapeutic strategies focused on restoring mitochondrial function, enhancing metabolic flexibility, and modulating the neurometabolic axis. Compounds such as metformin, Omecamtiv Mecarbil (OM), and SGLT2 inhibitors have demonstrated significant clinical benefits by optimizing energy substrate utilization, improving mitochondrial function, and enhancing autophagy. Future research should prioritize optimizing intervention timing, achieving tissue-specific targeting, and integrating systemic metabolic control to advance the evolution of HF management strategies.
Xu H, Wang X, Zhang Y
… +3 more, Zan P, He S, Bo X
Sci China Life Sci
· 2026 Apr · PMID 42024183
·
Publisher ↗
Deep learning has made significant progress in drug-target interaction (DTI) prediction. However, most existing approaches are developed using fixed datasets, which limits their applicability and generalizability due to...Deep learning has made significant progress in drug-target interaction (DTI) prediction. However, most existing approaches are developed using fixed datasets, which limits their applicability and generalizability due to the restricted scale of current datasets. This leads to significant discrepancies across the vast chemical space, particularly affecting model performance for previously unseen drugs or targets. In this study, we introduce ASCENT, an active transfer learning framework for DTI prediction. ASCENT utilizes an adaptive active learning strategy to expand datasets by dynamically selecting and annotating the most representative and uncertain samples based on model performance. To improve transferability, an entropy-based adversarial method was incorporated to align feature spaces between source and target domains during training. These innovations enable ASCENT to efficiently capture patterns across vast chemical spaces, thereby enhancing predictive accuracy while reducing annotation costs. Experimental results validate ASCENT's superiority in cross-domain applications, demonstrating its capacity to rapidly and effectively explore chemical diversity. Notably, ASCENT achieves desired performance levels while decreasing annotation expenditures by approximately 20%. Additionally, four representative case studies underscore ASCENT's potential in novel drug discovery and drug repurposing. These results highlight ASCENT as a valuable methodological advancement that supports accelerated drug development and provides new perspectives on DTI prediction.
Pan J, Zhang Y, Du Z
… +19 more, Huang Y, Wang Y, Su M, Cai Y, Xu W, Chen L, Huang C, Cui D, Chen D, Fu S, Wu Q, Tian C, Tang M, Ji T, Hou J, Zuo J, Li S, Zhang H, Bai L
Sci China Life Sci
· 2026 Jul · PMID 42024180
·
Publisher ↗
TGF-β-activated kinase 1 (TAK1) is a key signaling hub and drug target in inflammatory responses. Although metabolism has been critically linked to immune cell function and inflammation, the metabolic control of TAK1 act...TGF-β-activated kinase 1 (TAK1) is a key signaling hub and drug target in inflammatory responses. Although metabolism has been critically linked to immune cell function and inflammation, the metabolic control of TAK1 activation and intervention strategy remains to be explored. Here, we show that SM934, a derivative of the traditional Chinese medicine artemisinin, inhibits inflammatory responses via targeting α-enolase and inhibiting metabolite phosphoenolpyruvate (PEP) production. PEP directly binds TAK1 and inhibits its ubiquitination at the lysine-72 site, which promotes NF-κB activation and inflammatory responses. Overall, our study demonstrates a metabolic control of TAK1 stabilization and proposes that it could be disrupted by the derivative of the natural product artemisinin.
Yuan Y, Ai J, Chen H
… +12 more, Zhang P, Leng F, Guo K, Qi Z, Liu K, Zhang Y, Li T, Yang L, Nie F, Wei A, Hao C, Li W
Sci China Life Sci
· 2026 Apr · PMID 42024179
·
Publisher ↗
Platelets, derived from megakaryocytes (MKs), are crucial for blood clotting. Identifying genes that regulate MK development and platelet production could advance treatments for blood disorders. We found that KxDL motif-...Platelets, derived from megakaryocytes (MKs), are crucial for blood clotting. Identifying genes that regulate MK development and platelet production could advance treatments for blood disorders. We found that KxDL motif-containing 1 (Kxd1) knockout (KO) mice exhibited doubled platelet counts without impairment of individual platelet function. Kxd1-KO mice showed enhanced MK progenitor differentiation and rapid polyploid MK formation in vivo and in vitro. Mechanistically, KXD1 deficiency increased TSPAN14 levels by disrupting its endolysosomal trafficking, thus activating the ADAM10-Notch axis to drive MK polyploidization. In platelet/MK-specific Tspan14-KO mice, TSPAN14 deficiency impaired MK polyploidization and maturation. Our findings reveal that KXD1 is a key negative regulator of Notch signaling, controlling megakaryopoiesis mediated by TSPAN14. The KXD1-TSPAN14 axis is a promising therapeutic target for platelet disorders, including thrombocytopenia and myeloproliferative neoplasms, and as an interventional pathway for platelet production in transfusion medicine.
The increasing and often indiscriminate use of medications challenges populations with limited access to effective treatments. Natural compounds such as omega-3 fatty acids (FA), including eicosapentaenoic acid (EPA) and...The increasing and often indiscriminate use of medications challenges populations with limited access to effective treatments. Natural compounds such as omega-3 fatty acids (FA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exert immunomodulatory effects by incorporating into macrophage membranes and modulating cytokine production and metabolism. This study evaluated the effects of omega-3 FA on inflammatory responses, metabolic reprogramming, and signaling pathways in bone marrow-derived macrophages (BMDMs) infected with Pseudomonas aeruginosa. BMDMs from C57BL/6 mice were pretreated for 3 h with 26 mg DHA and 36 mg EPA, then stimulated with P. aeruginosa (PA14), heat-killed bacteria (HKPA), or lipopolysaccharide (LPS). Omega-3 FA pretreatment reduced pro-inflammatory mediators, including TNF-α, IL-1β, nitric oxide, and NLRP3 expression in macrophages stimulated with PA14, HKPA and LPS, while IL-10 secretion was also reduced under these stimuli. However, omega-3 FA increased IL-10 production under basal conditions. Gene expression analysis revealed upregulation of M2-associated markers (ARG1 and CD206), without changes in the M1 marker iNOS. Metabolic and transcriptional analyses demonstrated downregulation of glycolysis-related genes and upregulation of genes associated with mitochondrial function and lipid metabolism. Omega-3 FA did not alter P. aeruginosa proliferation but increased bacteria phagocytosis. Molecular docking suggested that omega-3 FA interact with key inflammatory targets, including GPR120 and PPARγ. Consistently, pharmacological antagonism of PPARγ reversed the omega-3 FA suppressive effects on TNF-α and IL-1β production and NLRP3 expression. These results indicate that omega-3 FA modulates macrophage immune responses and metabolism during P. aeruginosa infection, promoting an anti-inflammatory, metabolically adapted phenotype without impairing bacterial clearance.
AIMS: To investigate the role of secreted frizzled-related protein 5 (Sfrp5) in ST-segment elevation myocardial infarction (STEMI) and its protective mechanisms in macrophage-driven plaque instability. MATERIALS AND METH...AIMS: To investigate the role of secreted frizzled-related protein 5 (Sfrp5) in ST-segment elevation myocardial infarction (STEMI) and its protective mechanisms in macrophage-driven plaque instability. MATERIALS AND METHODS: Serum Sfrp5 levels were measured in 89 STEMI and 65 stable angina pectoris (SAP) patients. Foam macrophage models were established using murine RAW264.7 and human THP-1-derived macrophages. Sfrp5 effects on foam cell formation, apoptosis, and M1/M2 polarization were assessed, along with p38-MAPK/JNK/NF-κB signaling modulation using specific activators/inhibitors and RNA sequencing. KEY FINDINGS: STEMI patients showed significantly lower serum Sfrp5 levels (P < 0.0001), negatively correlated with peak troponin T (P = 0.013). Sfrp5 suppressed foam cell formation, apoptosis, and M1 polarization while promoting M2 polarization in vitro. Inhibition of M2 polarization attenuated these effects. Mechanistically, Sfrp5 exerted protection by suppressing the p38-MAPK/JNK/NF-κB signaling axis, confirmed by RNA sequencing showing altered expression of genes involved in lipid metabolism, inflammation, and apoptosis. SIGNIFICANCE: Sfrp5 enhances atherosclerotic plaque stability by inhibiting macrophage foam cell formation and apoptosis via suppression of p38-MAPK/JNK/NF-κB signaling and modulation of macrophage polarization, representing a potential therapeutic target for STEMI.
AIMS: A high-salt diet (HSD) induced excessive sodium intake is a major risk factor for various diseases, including pregnancy disorder. We aim to explore the effects of HSD on uterine endothelial cell and remodeling of s...AIMS: A high-salt diet (HSD) induced excessive sodium intake is a major risk factor for various diseases, including pregnancy disorder. We aim to explore the effects of HSD on uterine endothelial cell and remodeling of spiral artery during pregnancy in mice. MATERIALS AND METHODS: Blood pressure was monitored during pregnancy in control and HSD treated mice. Uterine endothelial were RNA-seq was used to profile the molecular basis for the adaptation of vascular endothelial cell during pregnancy. Salt accumulation in decidual tissue was measured and in vitro cultured endothelial were treated with NaCl to investigate the mechanisms for cell junction change. KEY FINDINGS: HSD impairs the normal pregnancy-associated blood pressure adaptation. Cell junction in the endothelia undergo significant changes for the during the pregnancy adaptation. HSD induced more salt accumulation in the uteri and triggered the disturbed vascular endothelium cytoskeletal remodeling, which was associated impaired trophoblast cell invasion and incorporation into the vascular wall. SIGNIFICANCE: Our study identifies unique roles of decidual endothelium for pregnancy vascular remodeling, and demonstrates that HSD disrupts physiological spiral artery remodeling through endothelial maladaptation, which may concurrently induce systemic endothelial damage in maternal systemic vascular.
INTRODUCTION: Platelet mitochondrial bioenergetics contribute to vascular thrombosis in patients with end-stage renal disease (ESRD). This study aimed to elucidate the effect of pre-hemodialysis exercise training (preHD-...INTRODUCTION: Platelet mitochondrial bioenergetics contribute to vascular thrombosis in patients with end-stage renal disease (ESRD). This study aimed to elucidate the effect of pre-hemodialysis exercise training (preHD-ET) on platelet mitochondrial bioenergetic efficiency in ESRD patients. METHODS: Ninety ESRD patients were enrolled, and eighteen eligible ESRD candidates participated in the preHD-ET program. The ESRD patients underwent 24 weeks of hospital-supervised and 12 weeks of home-based preHD-ET on cycling exercise at 50-60% W for 30 min/day, 3 days/week. Moreover, this study also analyzed 18 age- and gender matched healthy sedentary participants as a healthy sedentary (HS) group. Peak oxygen consumption (VO) and capacities of oxidative phosphorylation (OXPHOS) and electron transport system (ETC), and bioenergetic health index (BHI) in platelets were measured using an automatic gas analyzer and a high-resolution respirometer, respectively. RESULTS: The ESRD group exhibited (i) lower W and VO, (ii) inferior capacities of Complex I and II-dependent OXPHOS and ETC in platelets, and (iii) less platelet BHI, compared to the HS group. However, the preHD-ET significantly (i) elevated W and VO, (ii) enhanced capacities of OXPHOS and ETC by facilitating Complex I and II-linked pathways in platelets, and (iii) raised platelet BHI in the ESRD patients. Moreover, the changes of VO were positively correlated to the changes of OXPHOS, ETC and BHI in platelets following the preHD-ET. CONCLUSIONS: The preHD-ET for 36 weeks improves systemic aerobic capacity in ESRD patients. Moreover, this exercise regimen enhances mitochondrial bioenergetics efficiency in platelets, whose responses are associated with increased VO in ESRD patients. Clinical trials registration No. NCT06417307.
AIMS: This study aims to explore relationship between methionine levels and hepatic steatosis in population, as well as protective effects of a methionine restriction (MR) diet and its underlying mechanisms in preventing...AIMS: This study aims to explore relationship between methionine levels and hepatic steatosis in population, as well as protective effects of a methionine restriction (MR) diet and its underlying mechanisms in preventing hepatic steatosis in alcohol-induced mice. MATERIALS AND METHODS: This study integrated population data analysis based on the National Health and Nutrition Examination Survey (NHANES), and combined with animal experiments to establish mouse model of alcohol-induced hepatic steatosis. KEY FINDINGS: The population data showed a significant positive correlation between methionine intake levels and the risk of hepatic steatosis, with restricted methionine intake linked to a lower risk. Furthermore, the effect of MR on alcoholic liver injury has not been reported. In this study, the alcohol-induced fatty liver (AFL) model mice were used and the results demonstrate that MR significantly attenuated hepatic lipid accumulation. Microbiomics and metabolomics analyses revealed that MR can enhance the production of indole-3-acetic acid (IAA), a metabolite of tryptophan, by increasing the abundance of beneficial bacteria Akkermansia and Bacteroides that promote tryptophan metabolism. Acting as a key signaling messenger in the gut-liver axis, IAA reaches the liver and modulates the hepatic AhR/PPARγ/SREBP-1c pathway, thereby alleviating hepatic steatosis in AFL mice. SIGNIFICANCE: These findings establish a positive correlation between methionine intake and hepatic steatosis and elucidate the role and mechanism by which MR ameliorates alcohol-induced hepatic steatosis. The study provides key insights into the mechanisms underlying the protective effects conferred by the MR diet, and serves as a guide for the prevention and management of AFL.
AIMS: Fatigue in safety-critical occupations is multifactorial and often overlaps with chronic stress-related neurobehavioral impairment. Hyperbaric oxygen therapy (HBOT) may accelerate fatigue recovery, but its efficacy...AIMS: Fatigue in safety-critical occupations is multifactorial and often overlaps with chronic stress-related neurobehavioral impairment. Hyperbaric oxygen therapy (HBOT) may accelerate fatigue recovery, but its efficacy and optimal regimen are unclear. We evaluated HBOT and identified the optimal number of sessions in a mouse chronic multi-stressor-induced fatigue-like phenotype. MATERIALS AND METHODS: C57BL/6 J mice subjected to a multi-stressor paradigm (restraint, noise, forced running, and overcrowding for 15 days) underwent different post-fatigue interventions: natural recovery, normobaric oxygen (NBO, 100% O at 1 ATA, 60 min/session/day), or HBOT(100% O at 2.5 ATA, 60 min/session/day) for 3 days respectively. In parallel, different HBOT frequencies (1, 3, 7, or 14 consecutive days of once-daily HBOT) were compared. Outcomes included physical endurance, cognitive function, mood-related behaviors, biochemical indicators of stress, inflammation and oxidative damage, and histopathology of liver and hippocampus. KEY FINDINGS: Within 3 days, natural rest produced limited improvement and NBO provided only marginal gains. In contrast, HBOT yielded significant improvements in physical, cognitive, and emotional outcomes. Among HBOT regimens, 3 and 7 sessions achieved near-complete recovery across multiple indices, whereas 1 session was insufficient. Fourteen sessions conferred no additional benefit and several readouts suggested attenuation of the early advantage. SIGNIFICANCE: HBOT provides a rapid, short-course intervention that accelerates recovery in this multi-stressor fatigue-like model. A 3-7 session regimen (2.5 ATA, 60 min each) appears sufficient across functional and biological endpoints, supporting further translational evaluation of time-efficient HBOT protocols while avoiding unnecessary prolonged exposure.
Senile plaques consist of Amyloid-β (Aβ) are the pathological hallmark of Alzheimer's disease (AD), which is the most common type of neurodegenerative disorder. Aβ is a small peptide that consists of 38 to 43 amino acids...Senile plaques consist of Amyloid-β (Aβ) are the pathological hallmark of Alzheimer's disease (AD), which is the most common type of neurodegenerative disorder. Aβ is a small peptide that consists of 38 to 43 amino acids. It causes harmful effects through abnormal aggregation, like the formation of oligomers and protofibrils. These aggregates can disrupt normal synaptic function and trigger a series of neuroinflammatory and neurodegenerative changes. The aggregation dynamics of Aβ are modulated by multiple factors, such as conformational transitions, the exposure of hydrophobic segments, liquid-liquid phase separation, and post-translational modifications. These factors can promote the formation of diverse aggregates with distinct conformations. This review summarizes the structural characteristics of various Aβ aggregates, along with related regulatory elements, their effects on cellular processes, and therapeutic strategies targeting Aβ and its aggregates. This overview contributes to a better understanding of the complex mechanisms underlying Aβ aggregation and its pathological consequences, as well as the basis for future therapies targeted to Aβ and aggregates.