👤 Chunhui Nian

Depression is one of the most prevalent and disabling non-motor symptoms in Parkinson's disease (PD), forming a bidirectional relationship with motor dysfunction that worsens quality of life. Pharmacological treatments exhibit limited and inconsistent efficacy, and may lead to adverse interactions. Acupuncture may improve both depressive and motor symptoms by regulating the neuro-immune-endocrine network, but high-quality evidence remains insufficient. This study aims to evaluate the efficacy and safety of acupuncture as an adjunctive therapy for depression in PD and to explore potential biological correlates of clinical changes using predefined serum biomarkers. In this single-center, evaluator-blinded, randomized controlled trial, 88 patients with PD and comorbid depression will be randomly assigned to an acupuncture group or a waitlist control group. The primary outcome is the change in the Montgomery-Asberg Depression Rating Scale (MADRS) score. Secondary outcomes include motor function, anxiety, sleep quality, and overall quality of life. Exploratory analyses will assess serum inflammatory cytokines, brain-derived neurotrophic factor (BDNF), and kynurenine/tryptophan (KYN/TRP) ratio. We hypothesize that adjunctive acupuncture may improve depressive and motor symptoms compared with the control. Exploratory analyses will examine whether clinical changes are associated with changes in relevant biomarkers. This study will provide rigorous evidence for acupuncture as an adjunctive therapy, offering a non-pharmacological strategy to optimize the comprehensive management of PD and disrupt the bidirectional emotion-motor interplay. https://www.chictr.org.cn/, identifier ChiCTR2500113443. Show less

Carboxymethylcellulose (CMC), a common food emulsifier, induces microbiota dysbiosis and systemic inflammation; however, its impact on transplant immunity remains unclear. Allogenic heart rejection was observed in CMC-fed recipient mice, with increased abundance of lysophosphatidic acid (LPA)-producing bacteria and increased serum LPA concentration. CMC-induced transplant rejection was caused by the gut microbiota, as confirmed by fecal microbiota transplantation and gut microbiota depletion. Furthermore, LPA-treated macrophages demonstrated a proinflammatory ability to accelerate allograft rejection in cytotoxic T lymphocyte-associated protein 4 immunoglobulin-induced allograft survival by upregulating glycolysis. Conversely, the administration of a glycolysis inhibitor resulted in allograft survival and abrogated the detrimental effect of LPA. Mass spectrometry and single-cell RNA sequencing confirmed that transplant patients with rejection showed significantly elevated serum LPA levels and LPA receptor 6 (LPAR6) expression in graft-infiltrate macrophages. Mechanistically, LPA preferentially promoted LPAR6 expression, which interacted with Rho-associated protein kinase 2 to activate the mammalian target of rapamycin/hypoxia-inducible factor 1-alpha pathway, thereby enhancing glycolysis and inducing proinflammatory macrophage polarization. Treatment with Ki16425, an LPAR antagonist, prolonged allograft survival in CMC-fed recipients. Our findings reveal a major detrimental effect of CMC on macrophage physiology and suggest that controlling LPAR6 expression or glycolysis in macrophages may improve allograft survival in transplant recipients. Show less

Mercury (Hg) is a widespread environmental pollutant with known neurotoxic and cardiometabolic effects, and its influence on lipid metabolism during childhood remains insufficiently understood. Mitochondrial dysfunction is proposed as a potential mechanism linking Hg exposure to metabolic disruption. Mitochondrial DNA copy number (mtDNA-CN) is regarded as an indicator of mitochondrial biogenesis and functional capacity, where lower levels generally suggest mitochondrial damage or dysfunction. In contrast, ribosomal DNA (rDNA) and relative telomere length (RTL) reflect genomic stability and cellular aging. This study investigated the associations between blood Hg levels and serum lipid profiles in children and adolescents and assessed the mediating roles of mtDNA-CN, rDNA, and RTL. A cross-sectional study was performed among 352 children and adolescents aged 6–17 years in eastern China. Blood Hg levels were determined using inductively coupled plasma mass spectrometry (ICP-MS), and serum lipid markers, namely total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein(a), were assessed along with the genomic indicators such as mtDNA-CN, rDNA, and RTL. Multivariable linear regression and mediation analyses were conducted. Higher Hg levels were significantly related with increased TC (β = 0.144, Hg exposure in children and adolescents is linked to an atherogenic lipid profile, potentially through mitochondrial dysfunction. MtDNA-CN appears to be a sensitive molecular mediator of Hg-induced lipid disturbances, which highlights the relevance of mitochondrial health in early-life environmental epidemiology and cardiovascular risk prevention. The findings support early prevention strategies and environmentally focused health policies that reduce toxicant exposure and thus promote long-term cardiometabolic health in young populations. Show less

Per- and polyfluoroalkyl substances (PFAS) pose potential health risks to lipid metabolism, but the effects of emerging PFAS alternatives, particularly in children, remain unclear. This cross-sectional study investigated the association between emerging PFAS exposure and lipid levels in 294 Chinese children aged 7-10 years, analyzing blood samples for 14 PFAS and lipid profiles, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB). Exposure to 6:2 Cl-PFESA, PFO4DA, and PFO5DoDA was associated with higher TC, TG, and LDL levels, with PFO4DA increasing the TC by 1.7% and PFO5DoDA increasing the TG by 10.7%. Weighted quantile sum (WQS) regression showed mixed PFAS exposure positively associated with TG (0.08, 95% CI: 0.007, 0.153). PFO4DA had the highest weight for TC (0.468), TG (0.327), LDL (0.57), ApoA1 (0.243), and ApoB (0.466), while PFMOAA had the highest weight for HDL (0.332). Bayesian Kernel Machine Regression (BKMR) analysis confirmed positive associations between the PFAS mixture and TC, TG, LDL, and ApoA1. Mediation analysis revealed that mtDNAcn significantly mediated PFAS exposure's effect on TG levels, explaining 27.2-74.2% of the total effect. These findings highlight the need for regulatory action to address the emerging PFAS risks. Show less

Obesity is becoming a worldwide pandemic. Interfacial engineering of food lipid is expected to inhibit diet-induced obesity without damage to the eating enjoyment brought by high-fat diets. Unfortunately, this strategy has not been achieved yet. After screening different plant proteins, bromelain and papain were found to form wormlike and long-straight protein fibrils, respectively. The conversion of long-straight amyloid-like fibrils to wormlike fibrils was demonstrated in the fibrillation of bromelain. Using oil-in-water high internal phase emulsions (HIPEs) as a proof of concept, bromelain fibrils showed dramatically stronger interfacial stabilization capabilities than papain fibrils with high application potentials in the real-world formulation of high-fat food products such as mayonnaise. Compared with papain fibrils, oral administration of HIPEs stabilized by bromelain fibrils resulted in substantially higher fecal lipid contents and significantly decreased expression levels of the genes related to lipid absorption and transport in the intestine, including Show less

Bis-chalcone compounds with symmetrical structures, either isolated from natural products or chemically synthesized, have multiple pharmacological activities. Asymmetric Bis-chalcone compounds have not been reported before, which might be attributed to the synthetic challenges involved, and it remains unknown whether these compounds possess any potential pharmacological activities. The aim of this study is to investigate the synthesis route of asymmetric bis-chalcone compounds and identify potential candidates with efficient anti-tumor activity. The two-step structural optimization of the bis-chalcone compounds was carried out sequentially, guided by the screening of the compounds for their growth inhibitory activity against gastric cancer cells by MTT assay. The QSAR model of compounds was established through random forest (RF) algorithm. The activities of the optimal compound J3 on growth inhibition, apoptosis, and apoptosis-inducing protein expression in gastric cancer cells were investigated sequentially by colony formation assay, flow cytometry, and western blotting. Further, the inhibitory effects of J3 on the FGFR1 signaling pathway were explored by Western Blotting, shRNA, and MTT assays. Finally, the 27 asymmetric bis-chalcone compounds, including two types (N and J) were sequentially designed and synthesized. Some N-class compounds have good inhibitory activity on the growth of gastric cancer cells. The vast majority of J-class compounds optimized on the basis of N3 exhibit excellent inhibitory activity on gastric cancer cell growth. We established a QSAR model (R In summary, this study outlines a viable method for the synthesis of novel asymmetric bischalcone compounds. Furthermore, the compound J3 demonstrates substantial promise as a potential candidate for an anti-tumor drug. Show less

Fourteen novel compounds were prepared and their antagonistic activities against liver X receptors (LXR) α/β were tested in vitro. Compound 26 had an IC50 value of 6.4 µM against LXRα and an IC50 value of 5.6 µM against LXRβ. Docking studies and the results of structure-activity relationships support the further development of this chemical series as LXRα/β antagonists. Show less

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that also plays a regulatory role in fat metabolism. In 3T3-L1 cells, resistin was demonstrated to be a key mediator of GIP stimulation of lipoprotein lipase (LPL) activity, involving activation of protein kinase B (PKB) and reduced phosphorylation of liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK). The current study was initiated to determine whether resistin has additional roles in GIP-regulated adipocyte functions. Analysis of primary adipocytes isolated from Retn(-/-), Retn(+/-), and Retn(+/+) mice found that GIP stimulated the PKB/LKB1/AMPK/LPL pathway and fatty acid uptake only in Retn(+/+) adipocytes, suggesting that GIP signaling and/or GIP responsiveness were compromised in Retn(+/-) and Retn(-/-) adipocytes. GIP receptor (GIPR) protein and mRNA were decreased in Retn(+/-) and Retn(-/-) adipocytes, but resistin treatment rescued LPL responsiveness to GIP. In addition, genes encoding tumor necrosis factor (TNF), TNF receptor 2 (TNFR2), and the signaling proteins stress-activated protein kinase (SAPK)/Jun NH(2)-terminal kinase (JNK), were downregulated, and phosphorylated levels of SAPK/JNK/c-Jun were decreased in Retn(-/-) mice. Chromatin immunoprecipitation assays were used to identify a 12-O-tetradecanoylphorbol-13-acetate (TPA)-response element (TRE-III) responsible for c-Jun-mediated transcriptional activation of Gipr. Blunted GIP responsiveness in Retn(+/-) and Retn(-/-) adipocytes was therefore largely due to the greatly reduced GIPR expression associated with decreased c-Jun-mediated transcriptional activation of Gipr. Show less

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone that exerts insulinotropic and growth and survival effects on pancreatic β-cells. Additionally, there is increasing evidence supporting an important role for GIP in the regulation of adipocyte metabolism. In the current study we examined the molecular mechanisms involved in the regulation of GIP receptor (GIPR) expression in 3T3-L1 cells. GIP acted synergistically with insulin to increase neutral lipid accumulation during progression of 3T3-L1 preadipocytes to the adipocyte phenotype. Both GIPR protein and mRNA expression increased during 3T3-L1 cell differentiation, and this increase was associated with upregulation of nuclear levels of sterol response element binding protein 1c (SREBP-1c) and peroxisome proliferator-activated receptor γ (PPARγ), as well as acetylation of histones H3/H4. The PPARγ receptor agonists LY171883 and rosiglitazone increased GIPR expression in differentiated 3T3-L1 adipocytes, whereas the antagonist GW9662 ablated expression. Additionally, both PPARγ and acetylated histones H3/H4 were shown to bind to a region of the GIPR promoter containing the peroxisome proliferator response element (PPRE). Knockdown of PPARγ in differentiated 3T3-L1 adipocytes, using RNA interference, reduced GIPR expression, supporting a functional regulatory role. Taken together, these studies show that GIP and insulin act in a synergistic manner on 3T3-L1 cell development and that adipocyte GIPR expression is upregulated through a mechanism involving interactions between PPARγ and a GIPR promoter region containing an acetylated histone region. Show less

The hormone glucose-dependent insulinotropic polypeptide (GIP) potently stimulates insulin secretion and promotes beta-cell proliferation and cell survival. In the present study we identified Forkhead (Foxo1)-mediated suppression of the bax gene as a critical component of the effects of GIP on cell survival. Treatment of INS-1(832/13) beta-cells with GIP resulted in concentration-dependent activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB)/Foxo1 signaling module. In parallel studies, GIP decreased bax promoter activity. Serial deletion analysis of the bax promoter demonstrated that the region -682 to -320, containing FHRE-II (5AAAACAAACA), was responsible for GIP-mediated effects. Foxo1 bound to FHRE-II in gel mobility shift assays, and Foxo1-FHRE-II interactions conferred GIP responsiveness to the bax promoter. INS-1 cells incubated under proapoptotic and glucolipotoxic conditions demonstrated increased nuclear localization of Foxo1 and bax promoter activity and decreased cytoplasmic phospho-PKB/Foxo1. GIP partially restored expression PKB/Foxo1 and bax promoter activity. Similar protective effects were found with dispersed islet cells from C57BL/6 mice, but not with those from GIP receptor knock-out (GIPR(-/-)) mice. GIP treatment reduced glucolipotoxicity-induced cell death in C57 BL/6 and Bax(-/-) islets, but not GIPR(-/-) mouse islets. Chronic treatment of Vancouver diabetic fatty Zucker rats with GIP resulted in down-regulation of Bax and up-regulation of Bcl-2 in pancreatic beta-cells. The results show that PI3K/PKB/Foxo1 signaling mediates GIP suppression of bax gene expression and that this module is a key pathway by which GIP regulates beta-cell apoptosis in vivo. Show less