👤 Haiqiang Sang

Neurodegenerative and mental disorders impose significant global disease burdens and pose serious social and economic challenges. Physical exercise (PE) exerts beneficial effects on brain health, contributing to a reduction in the risk of Alzheimer's disease (AD), Parkinson's disease (PD), depression, anxiety, and post-traumatic stress disorder (PTSD). To understand these effects of PE, a variety of molecules released from various tissues in response to PE have been discovered, which are collectively called 'exerkines'. In particular, the skeletal muscle acts as an endocrine organ, secreting exerkines and is included in the category of myokines that facilitate direct or indirect crosstalk between the muscle and the brain. Although muscles actively interact with organs such as the liver, pancreas, and adipose tissue, the precise mechanisms of muscle-brain communication have yet to be fully elucidated. In the skeletal muscle, the types of exerkines secreted and their effects vary depending on the PE modality. Furthermore, these exerkines can cross the blood-brain barrier (BBB) to exert direct effects or act indirectly Show less

CNS diseases are a prevailing cause of morbidity and mortality worldwide, and are influenced by environmental and biological factors, including genetic risk. Here, we generated genome-wide genetic data on a large cohort of brain tissue donors with in-depth clinical and neuropathological phenotyping, allowing for broad investigations into the risk and mechanisms of these neurological, neurodevelopmental, and psychiatric conditions. This resource consists of 9,663 donors with array-based genotyping and 9,543 donors with whole-genome sequencing completed. The clinical diagnoses of these donors include 148 central nervous system diseases clustered into 15 broad categories by International Classification of Diseases-10 (ICD-10) coding. These donors were collected by six repositories comprising the National Institutes of Health NeuroBioBank, with an average participant age of 60 years. While primarily older individuals of European descent, the cohort also contains younger donors and individuals from non-European backgrounds. Variants were detected in whole-genome sequencing (WGS), normalized and annotated to describe their functional impact, resulting in 171,121,209 unique variants and 1,078,774 non-silent variants. These raw and normalized data have been made available as a neurogenomics resource in the National Institute of Mental Health Data Archive (NIMH NDA) (nda.nih.gov), combined with donor-matched deep demographic and phenotypic data from the NeuroBioBank Portal (neurobiobank.nih.gov). To illustrate applications, we replicated the strong association observed in previous studies between pathogenic CAG nucleotide repeat expansions in the HTT gene with the clinical diagnosis of Huntington's disease, as well as associations of the APOE gene with Alzheimer's disease, and examined the association of polygenic risk scores with the three most common disease diagnoses in the cohort. Show less

Chronic stress is associated with inflammatory activation and oxidative stress responses leading to endothelial dysfunction, which promotes the development of atherosclerosis (AS). SGLT2 inhibitors, such as Dapagliflozin (DAPA), exhibit a protective effect against cardiovascular diseases. However, the effects and mechanisms of DAPA on chronic stress-induced AS are largely unknown. The aim of this study was to determine whether DAPA confers a protective effect against chronic stress-induced AS and to elucidate its further molecular mechanisms. The combined high-fat diet-fed and chronic unpredictable mild stress in ApoE-/- mice and lipopolysaccharides- and corticosterone-induced human umbilical vein endothelial cells (HUVECs) were employed to evaluate the antiatherosclerotic effect of DAPA under chronic stress in vivo and in vitro. Histological staining, western blot analysis, siRNA transfection, reactive oxygen species (ROS) staining, and apoptosis assessment were used to investigate the potential mechanisms of DAPA against AS under chronic stress. The results indicate that DAPA significantly improved plaque size and increased plaque stability in the aorta under chronic stress and reduced inflammation and oxidative stress and inhibited apoptosis in the aorta and HUVECs. Chronic stress upregulated regulated in development and DNA damage response 1 (REDD1) expression, which exacerbated cellular inflammation, oxidative stress, and apoptosis levels, leading to endothelial dysfunction. In contrast, DAPA downregulated REDD1 expression and activated the AKT/FoxO1 pathway. In addition, p53 was a transcriptional regulator of REDD1 under chronic stress. More importantly, p53 agonists prevented DAPA from downregulating REDD1 and inhibited AKT/FoxO1 activation, thereby exacerbating chronic stress-induced endothelial dysfunction. These results suggest that DAPA effectively attenuates chronic stress-induced endothelial dysfunction and AS by downregulating REDD1 to activate the AKT/FoxO1 pathway. Show less

Osteoporosis has emerged as a growing public health concern due to its high prevalence and substantial economic burden on both individuals and society. Recent studies have identified the serum uric acid to high-density lipoprotein cholesterol ratio (UHR) as a novel predictive biomarker for various diseases. However, its association with bone mineral density (BMD) remains unclear. This study evaluated the association of the UHR and forearm BMD (FR-BMD) in a middle-aged and elderly cohort. We also assessed the interaction effects of age, sex, and body mass index (BMI). A total of 4,958 adults aged ≥50 years were enrolled from health examinees at Heze Municipal Hospital (2022-2025). We collected demographic data, serum lipids, and uric acid levels. Measurements of FR-BMD were performed on the left distal radius (1/3 site) utilizing dual-energy X-ray absorptiometry. Multivariate linear regression analyses evaluated the UHR-BMD relationship, supplemented by subgroup analyses and interaction tests. Nonlinear associations were assessed using generalized additive models with smoothing curves. After adjusting for age, sex, BMI, Alb, ALP, ALT, BUN, TP, Scr, Lp(a), TC, GGT and hypertension, a higher UHR was significantly associated with lower FR-BMD [β=-0.076, 95%CI(-0.138~-0.015), P = 0.015]. Significant interaction effects were observed for age and sex ( The association of UHR with FR-BMD is significantly modified by age and sex in middle-aged and elderly populations. Nonlinear relationships exist in males <60 years, females ≥60 years and non-overweight individuals. The potential of UHR as a novel indicator for bone health assessment in select populations is highlighted by our results. Show less

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the effects of simvastatin on the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. The experiment included three groups: C57BL/6 wild-type mice, C57BL/6J SOD1G93A mice treated with PBS (SOD1G93A + PBS), and C57BL/6J SOD1G93A mice treated with simvastatin (SOD1G93A + simvastatin). The primary endpoints were survival rates, body weight changes, performance in pole climbing and suspension tests, and neurological deficit scores. Pathological changes were assessed using hematoxylin and eosin staining, transmission electron microscopy, Nissl staining, and Masson staining. Proteomic and metabolomic analyses were performed to identify differentially expressed proteins (DEPs) and metabolites. Quantitative real-time polymerase chain reaction and western blotting were used to measure gene expression. Although there were no significant differences in survival rates, body weight, pole climbing, and suspension test performance, or neurological deficit scores between the SOD1G93A + simvastatin and SOD1G93A + PBS groups, simvastatin treatment improved axonal organization within the spinal cord, increased the number of neurons, and reduced cytoplasmic swelling and gastrocnemius fibrosis. A total of 47 DEPs and 13 differential metabolites were identified between the SOD1G93A + PBS and SOD1G93A + simvastatin groups. Notably, the expression levels of Apoa4 and Alb were elevated in the SOD1G93A + simvastatin group compared to the SOD1G93A + PBS group. Our results suggest that simvastatin may have potential therapeutic effects in ALS, likely involving the modulation of Apoa4 and Alb expression. Show less

This study aimed to (1) evaluate small dense low-density lipoprotein cholesterol (sdLDL-C) dynamics from prediabetes to type 2 diabetes mellitus (T2DM) with complications, (2) validate existing sdLDL-C estimation formulas (Sampson’s, Srisawasdi’s, Han’s) in Chinese populations, and (3) develop a population-specific formula for enhanced accuracy. A multicenter study recruited 1,944 participants (216 controls, 70 with prediabetes, 212 with newly diagnosed T2DM, 164 with treated T2DM, and 1,286 in validation cohorts). Lipid profiles, including sdLDL-C (measured via enzymatic assays), were analyzed. Formula performance was assessed using spearman correlation, intraclass correlation coefficients (ICC), and multivariable linear regression. A novel formula was derived via multivariable regression. Atherogenic lipid triad manifestations emerged early: sdLDL-C was significantly elevated in participants with prediabetes (1.07 [0.73, 1.40] vs. 0.57 [0.44, 0.72] mmol/L in controls, P < 0.05) and further increased in those with T2DM, correlating strongly with triglycerides (TG; sdLDL-C elevation begins in prediabetes, highlighting its value for early atherosclerotic cardiovascular disease (ASCVD) risk assessment. Current formulas show population-specific limitations, whereas the new model provides improved accuracy for Chinese T2DM patients, enabling cost-effective sdLDL-C estimation and personalized lipid management. The online version contains supplementary material available at 10.1186/s12944-025-02636-0. Show less

Iodine is an essential micronutrient for developmental processes in the early stages; however, data on the effect of maternal iodine nutrition on milk lipids are limited. We aimed to explore the effect of inadequate and excessive iodine intake on milk lipid metabolism and its mechanisms preliminarily. Rats were treated with different concentrations of potassium iodide water to construct animal models of iodine deficiency and excess. Iodine excess reduced serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels during lactation. Iodine deficiency had no significant effect on blood lipid indicators. In early and late lactation, iodine deficiency and excess inhibited triglyceride (TG) levels in milk; in mid-lactation, the inhibitory effect of iodine deficiency was attenuated. Under iodine deficiency and excess, the level of TG and the expression of THRα1, THRβ1, ACC1, FAS, THRSP, BTN1A1, and ADFP proteins in the mammary gland were decreased during lactation; a decrease in LPL protein expression was observed in early and late lactation; and a decline of XOR protein expression was reported in mid and late lactation. Blood lipid metabolism was less sensitive to iodine deficiency during lactation. Iodine excess has a more profound effect on blood lipid metabolism, causing dyslipidemia in lactating rats. Long-term iodine deficiency and excess may have a negative role in the mechanisms regulating milk lipid synthesis and secretion by affecting thyroid hormones to inhibit the milk TG level. Show less

To investigate the genetic etiology of six adult patients with Dilated cardiomyopathy (DCM), and analyze the structure of the identified variants, for providing reference for the diagnosis of DCM. Six adult patients with DCM (patients 1-6) admitted to the Department of Cardiology of Zhumadian Central Hospital from January 2023 to December 2023 were recruited. Clinical data of the patients were retrospectively collected. And 5 mL of peripheral blood was collected from each patient. Pathogenic variants of the patients were detected by whole exome sequencing (WES), and candidate variants were verified by Sanger sequencing. The possible functional significance of the identified missense variants was evaluated using software including SIFT, PolyPhen-2 and Mutation Taster. Specific regions of the MYBPC protein encoded by the MYBPC3 gene from different species were aligned using Mutation Taster. The wild-type and mutant MYBPC proteins were constructed using homologous modeling software MODELLER v10.4 and three-dimensional structures were visualized using PyMOL software. The molecular interaction between MYBPC-C5 domain and myosin with or without the mutation was further analyzed using ZDOCK module in Discovery Studio 2019 software. Pathogenicity ratings for the detected variant sites were performed in accordance with the Standards and Guidelines for the Interpretation of Sequence variants by the American College of Medical Genetics and Genomics (ACMG) (hereafter referred to as the ACMG Guidelines). This study was reviewed and approved by the Ethics Committee of Zhumadian Central Hospital (Approval No. 2022092007). The six DCM patients had typical symptoms of heart failure, and echocardiography showed whole-heart dilation and decreased ventricular wall motion, left ventricular end-diastolic dimension (LVEDD) was 59-74 mm, left ventricular ejection fraction (LVEF) was 35%-43%, and left ventricular fractional shortening (LVFS) was 17%-28%. Variations of the DCM related genes, including a c.98473A>T (p.Lys32825*) variation of the TTN gene and a c.1976T>C (p.Ile659Thr) variation of the MYBPC3 gene, were identified in two patients. Multiple software predicted that both mutations were deleterious. MYBPC3-Ile659Thr mutation affected the highly conserved residue within the C5 domain of MYBPC. Three-dimensional structural analysis of homologous modeling revealed the alterations in amino acid properties and interactions with surrounding amino acids caused by the MYBPC3-Ile659Thr mutation. Further molecular docking analysis showed that the Ile659Thr mutation altered both the hydrogen bond and salt-bridge interactions between the MYBPC-C5 domain and the ligand myosin. Two mutations associated with DCM were identified in this study. The abnormal conformation of the mutant protein further affected its interaction with the ligand myosin, resulting in the phenotype of DCM. Show less

This study aimed to investigate the possible mechanisms by which ANGPTL4 is involved in the pathogenesis of choroidal neovascularization (CNV) and subretinal fibrosis. Differentially expressed genes in retinal pigmented epithelium (RPE)-choroid-sclera complex tissues from nAMD patients and control individuals were identified via the GEO database, followed by GO and KEGG analyses. A Venn diagram was used to identify EndMT-related DEGs. A logistic regression model was constructed to screen for prognostic genes. Laser-induced CNV mouse models were established and validated with FFA and OCTA. The expression of ANGPTL4 and EndMT-related markers in the RPE-choroid-sclera complex was measured via RT‒qPCR and Western blotting. TGF-β2-induced HUVECs were used as EndMT cell models, and specific siRNAs targeting ANGPTL4 (si-ANGPTL4) were designed and screened. The effects of ANGPTL4 knockdown on the migration and invasion of HUVECs were also examined. Laser-induced CNV mouse models were constructed, and an intravitreal injection of cholesterol-modified si-ANGPTL4 was used to knock down ANGPTL4. FFA, OCTA and immunofluorescence staining were used to observe CNV formation and subretinal fibrosis, and the expression of ANGPTL4 and EndMT-related markers was determined. ANGPTL4 expression was significantly increased in mice with CNV and colocalized with IB4. In TGF-β2-induced EndMT, ANGPTL4 was also upregulated, and its knockdown led to the inhibition of EndMT and cell migration and invasion, while its overexpression promoted the EndMT process. ANGPTL4 knockdown reduced the formation of CNV and subretinal fibrosis in mice with CNV by suppressing EndMT. ANGPTL4 may promote CNV and subretinal fibrosis through EndMT, suggesting that ANGPTL4 may be a novel potential target for nAMD therapy. Show less

Carbamoyl phosphate synthetase 1 (CPS1) deficiency (OMIM 237300), an autosomal recessive rare and severe urea cycle disorder, is associated with hyperammonemia and high mortality. Herein we present 12 genetic variants identified in seven clinically well-characterized Chinese patients with CPS1 deficiency who were admitted to the Children's Medical Center of Peking University First Hospital from September 2014 to August 2023. Seven patients (two male and five female patients including two sisters) experienced symptoms onset between 2 days and 13 years of age, and they were diagnosed with CPS1 deficiency between 2 months and 20 years. Peak blood ammonia levels ranged from 160 to 1,000 µmol/L. Three patients showed early-onset CPS1 deficiency, with only one surviving after treatment with sodium phenylbutyrate, N-carbamoyl-L-glutamate, and liver transplantation at 4 months, showing a favorable outcome. The remaining four patients had late-onset CPS1 deficiency, presenting with mental retardation, psychiatric symptoms, and self-selected low-protein diets. Among the 12 CPS1 variants identified in these patients, 10 were novel, with all patients exhibiting compound heterozygosity for CPS1 mutant alleles. Seven variants (c.149T > C, c.616 A > T, c.1145 C > T, c.1294G > A, c.3029 C > T, c.3503 A > T, and c.3793 C > T) resulted in single amino acid substitutions. Three frameshift variations (c.2493del, c.3067dup, and c.3241del) were identified, leading to enzyme truncation. One mutation (c.3506₃₅₀₈del) caused an in-frame single amino acid deletion, while another (c.2895 + 2T > C) resulted in aberrant splicing. Except for two known variants, all other variants were identified as novel. No hotspot variants were observed among the patients. Our data contribute to expanding the mutation spectrum of CPS1. Show less

Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing the detailed mechanisms governing Notch degradation will identify attractive strategies for treating Notch-activated cancers. Here, we report that the long noncoding RNA (lncRNA) Show less

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease often caused by sarcomeric gene mutations. MYBPC3 is one of the most common genes associated with HCM. In this study, we generated a human induced pluripotent stem cell line ZZUNEUi028-A from a 19-year-old male HCM patient with c. 1504C → T in MYBPC3 gene using non-integrative Sendai viral reprogramming technology. This cell line expresses pluripotency markers, exhibits a normal male karyotype (46, XY) and can differentiate into all three germ layers in vitro. ZZUNEUi028-A can serve as a cell disease model in the understanding of HCM pathogenesis. Show less

The role of Tibet kefir milk (TKM) feeding on fat deposition was investigated in high-fat diet (HFD)-fed human flora-associated (HFA) rats. TKM feeding reduced abdominal fat mass from 33.9 g to 24.0 g and serum triglyceride (TG) from 0.75 mmol/L to 0.47 mmol/L, and caused lipoprotein lipase (LPL) to decrease from 395.8 ± 36.0 ng/L to 362.3 ± 64.4 ng/L in fat and increase from 287.3 ± 40.8 ng/L to 329.8 ± 48.5 ng/L and 312.5 ± 22.0 to 375.1 ± 30.8 ng/L in liver and serum, respectively. Likewise, TMK feeding down-regulated Lpl gene expression in fat and Angptl4 (angiopoietin-like protein-4, also known as fasting-induced adipose factor) gene expression in liver, and up-regulated Angptl4 gene expression in fat. Sequence analysis showed that the Firmicutes/Bacteroidetes proportion and Verrucomicrobia at the phylum level, Akkermansia, Escherichia and Oscillospira at the genus level, as well as Escherichia coli at the species level were positively regulated by TKM. The results indicated that TKM decreased abdominal fat deposition and serum TG by regulating Lpl and Angptl4 at the transcriptional level. The microbiota groups mentioned above were regulated by TKM at the same time and may be the potential intervention targets to reduce fat deposition. Show less

The incidence of oral squamous cell carcinoma (OSCC) is continuously increasing while its survival rate has not notably improved. There is a pressing need for improved understanding of the genetic regulation of OSCC tumorigenesis and progression. In this study, the function of miR-448 in the regulation of OSCC growth and its putative target were thoroughly analyzed Show less

Alpinetin is a natural flavonoid abundantly present in the ginger family. Here, we investigated the effect of alpinetin on cholesterol efflux and lipid accumulation in oxidized low-density lipoprotein (ox-LDL)-treated THP-1 macrophages and human peripheral blood monocyte-derived macrophages (HMDMs). After exposing THP-1 macrophages to alpinetin, cholesterol efflux was determined by liquid scintillator. The mRNA and protein levels of peroxisome proliferator-activated receptor gamma (PPAR-γ), liver X receptor alpha (LXR-α), ATP-binding cassette transporter A1 (ABCA1), and ABCG1 and scavenger receptor class B member 1 were determined by reverse-transcriptase PCR (RT-PCR) and Western blot analysis, respectively. Alpinetin promoted apolipoprotein A-I- and high-density-lipoprotein-mediated cholesterol efflux and elevated PPAR-γ and LXR-α mRNA and protein expression in a dose-dependent fashion in ox-LDL-treated THP-1 macrophages and HMDMs. Small interfering RNA-mediated silencing of PPAR-γ or LXR-α dose dependently reversed alpinetin-increased cholesterol efflux in THP-1 macrophages, indicating the involvement of PPAR-γ and LXR-α in alpinetin-promoted cholesterol efflux. Alpinetin inhibited ox-LDL-induced lipid accumulation and enhanced the expression of ABCA1 and ABCG1 mRNA and protein, which was reversed by specific knockdown of PPAR-γ or LXR-α. Taken together, our results reveal that alpinetin exhibits positive effects on cholesterol efflux and inhibits ox-LDL-induced lipid accumulation, which might be through PPAR-γ/LXR-α/ABCA1/ABCG1 pathway. Show less

Both G1 and mitotic cyclins have been implicated in regulating Candida albicans filamentous growth. We have investigated the functions of Grr1 whose orthologue in Saccharomyces cerevisiae is known to mediate ubiquitin-dependent degradation of the G1 cyclins Cln1 and Cln2. Here, we report that deleting C. albicans GRR1 causes significant stabilization of two G1 cyclins Ccn1 and Cln3 and pseudohyphal growth. grr1Delta cells are highly heterogeneous in length and many of them fail to separate after cytokinesis. Interestingly, some isolated rod-like G1 cells of similar sizes are present in the grr1Delta culture. Time-lapse microscopy revealed that the rod-shaped G1 cells first grew exclusively in width before budding and then the bud grew exclusively by apical extension until after cytokinesis, yielding rod-like daughter cells. Consistently, actin patches persistently localize to the bud tip until around the time of cytokinesis. Despite the pseudohyphal phenotype, grr1Delta cells respond normally to hyphal induction. Hyperphosphorylated Cln3 isoforms accumulate in grr1Delta cells, indicating that Grr1 selectively mediates their degradation in wild-type cells. grr1Delta pseudohyphal growth requires neither Hgc1 nor Swel, two important regulators of cell morphogenesis. Furthermore, the cellular level of Hof1, a protein having a role in cytokinesis, is also significantly increased in grr1Delta cells. Show less

It is well known that cultured Sertoli cells secrete plasminogen activators (Lacroix et al., Mol Cell Endocrinol 1977; 9:227-236; Hettle et al., Biol Reprod 1986; 34:895-904). We now show that testicular cells in culture also secrete gelatinolytic metalloproteinases. Gelatin zymographic analysis of concentrated culture medium proteins reveals that Sertoli cells secrete gelatinases of 185 kDa, 110 kDa, 83 kDa, 76 kDa, and 72 kDa in addition to plasminogen activators (PAs). Gelatinase 185 kDa is induced by FSH. Media from Sertoli (epithelial)/peritubular (mesenchymal) cell cocultures contain the Sertoli cell gelatinases and one FSH-stimulated gelatinase of 50 kDa, indicating that gelatinase 50 kDa is regulated by both FSH and cell-cell interactions. A 50-kDa fibronectinolytic activity is also present in the coculture medium from cells grown in the presence of FSH. Casein zymography demonstrates a prominent 30-kDa protease only in media from cocultures. Peritubular cells secrete urokinase-type plasminogen activator (u-PA) and exhibit slight degrading activity at 86 kDa and 74 kDa. The gelatinases are most active in the pH range 7.3-8.5 and are completely or partially inhibited by metal ion chelators indicating that they are metalloproteinases. Our data demonstrate that testicular cells in culture secrete several gelatinases in addition to PAs, and that FSH and coculture conditions regulate some of these secreted proteases. We suggest that the highly regulated secretion of these proteases may well be of physiological importance during testicular development and spermatogenesis. Show less