👤 Xiuyi Ai

Dyslipidemia was a hallmark of metabolic disturbances in coronary heart disease (CHD), metabolic syndrome (MetS), and nephrotic syndrome (NS), yet the specific lipid profile patterns characteristic of each disease remained insufficiently defined. This study aimed to clearly characterize and compare the qualitative features of lipid profiles across patients with CHD, MetS, and NS, and to identify key lipid markers associated with disease classification using multinomial logistic regression. A total of 180 patients were enrolled and classified into three groups (CHD, MetS, NS) based on established diagnostic criteria. 60 healthy controls were concurrently enrolled. Lipidomic profiles and additional laboratory parameters were measured using validated analytical methods. Multinomial logistic regression was used to evaluate the associations between lipid parameters and disease categories. Lipid profile analysis revealed distinct qualitative trends across the disease groups. The CHD group demonstrated notably higher levels of TC and sdLDL, the MetS group exhibited prominent increases in TG and ApoE, while the NS group showed a broad and pronounced elevation across most measured lipid parameters. By contrast, the healthy control group consistently presented uniformly lower lipid levels. LASSO-guided multinomial logistic regression identified TC, TG, ApoB, ApoE, and sdLDL-C as independent predictors of disease classification. Distinct patterns of dyslipidemia were observed in CHD, MetS, and NS. TC and sdLDL-C might serve as robust markers for CHD, while ApoB demonstrated disease-specific variability with diagnostic potential. These findings underscored the importance of detailed lipid profiling for improved risk stratification and targeted management. Show less

Atherosclerosis serves as the fundamental pathological process underlying numerous cardiovascular disorders, and the change of macrophage polarisation is the key to regulate the inflammatory response of AS. SIRT6 plays a protective effect in AS, but whether it regulates macrophage polarisation in AS remains uncertain. We aimed to characterise the mechanistic role of SIRT6 in atherosclerosis development mediated by macrophage polarisation. ApoE Show less

The apolipoprotein E ε4 (APOE ε4) allele is a major genetic risk factor for Alzheimer's disease, but its relevance to cognition in intracranial atherosclerosis (ICAS) remains unclear. We investigated the association between APOE ε4 and cognition in ICAS. Baseline data from a multicenter cohort were analyzed. Patients with radiologically confirmed ICAS underwent APOE genotyping, plasma biomarker assays, magnetic resonance imaging assessment of cerebral small vessel disease (CSVD) and brain atrophy, and standardized cognitive testing. Among 409 patients (mean age 60 years, 55% male), 16% carried APOE ε4. Carriers showed more frequent cognitive impairment (63% vs 48%), greater stenosis burden, and lower plasma amyloid beta (Aβ)42/40 ratios, whereas other Alzheimer's biomarkers, CSVD burden, and atrophy scores showed no difference. After adjustment, APOE ε4remained associated with cognitive impairment (odds ratio [OR] 1.86). The association was pronounced in women (OR 4.43) but absent in men. APOE ε4 is linked to cognitive impairment in ICAS, particularly in women, through mechanisms beyond Alzheimer's pathology. In patients with ICAS, cognitive impairment was more prevalent in carriers than in non-carriers. Carriers showed greater stenosis burden and lower plasma Aβ42/40 ratios. After full adjustment (stroke, CSVD, and AD biomarkers), APOE ε4 remained associated with cognitive impairment. Female carriers had substantially higher odds of cognitive impairment. Show less

Oscillatory shear stress (OSS), resulting from disturbed blood flow, is implicated in atherosclerotic plaque formation by incompletely understood mechanisms. This study aims to elucidate the involvement of death-associated protein kinase (DAPK) 2 in OSS-induced endothelial cell (EC) activation and atherosclerosis. Publicly available resources, including genome-wide microarray, RNA sequencing, and single-cell RNA sequencing, were utilized to identify key OSS-sensitive regulatory factors. Techniques such as mass spectrometry, immunoprecipitation, proximity ligation assay, and RNA sequencing were employed to identify pyruvate kinase M2 (PKM2) as the binding protein of DAPK2 and determine the specific site of PKM2 phosphorylation by DAPK2. To assess the role of Dapk2 in vivo, EC-specific DAPK2 expression was elevated in OSS-exposed regions of human and murine arteries. Mechanistically, Krüppel-like factor 2 (KLF2) suppressed DAPK2-driven phosphorylation of PKM2 at threonine 45 orchestrates endothelial inflammatory responses to disturbed flow, identifying a novel mechanistic axis and potential therapeutic target in atherosclerosis. Show less

Chronic cerebral hypoperfusion (CCH), a subclinical state underlying mild cognitive impairment (MCI), triggers multiple pathological changes associated with Alzheimer's disease (AD) and vascular dementia (VaD), including amyloid-β (Aβ) deposition, tau phosphorylation, microglial activation and neural circuit dysfunction. Developing multitarget therapeutics to effectively prevent the transition from MCI to AD and/or VaD remains an urgent challenge. Herein, we engineered a brain-targeted dual-modified PEGylated nanoliposome (LipTM@miR-195), incorporating mannose (MAN) and the trans-activating protein of HIV type 1 (TAT), which encapsulates polyethyleneimine (PEI) complesed microRNA-195 (miR-195). In a CCH rat model, tail-vein administration of LipTM@miR-195 (0.112 mg/kg) efficiently crossed the blood-brain barrier (BBB) without detectable side effects. Treatment reversed CCH-induced spatial learning and memory deficits, rescued neural circuit dysfunction, and suppressed elevated APP, BACE1, AT8 and CD68 levels. Collectively, these findings provide compelling evidence that LipTM@miR-195 nanoliposome holds therapeutic potential for CCH-induced cognitive impairment, thereby preventing the progression from MCI to AD and/or VaD. Show less

Ovarian cancer (OC) is an aggressive gynecological malignancy with poor prognosis, largely due to late-stage diagnosis and high metastatic potential. However, the functional role and regulatory mechanisms of fibroblast growth factor receptor 1 (FGFR1) in OC remain incompletely understood. In this study, we investigated the expression pattern and biological function of FGFR1 in OC and explored its underlying molecular mechanisms. FGFR1 expression was analyzed using TCGA, GTEx, and tissue microarray datasets, and its prognostic significance was evaluated by Kaplan-Meier survival analysis. Functional assays were performed in OVCAR-3 and SK-OV-3 cells following FGFR1 knockdown or overexpression to assess cell proliferation, migration, invasion, and metabolic activity, including extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Lactate production and histone lactylation were measured by biochemical assays and Western blotting. Protein interaction between FGFR1 and SIRT3 was examined by co-immunoprecipitation and immunofluorescence, and rescue experiments were conducted to determine SIRT3 dependency. In vivo subcutaneous xenograft models were used to evaluate the role of FGFR1 in tumor growth. We found that FGFR1 expression was significantly reduced in OC tissues and that low FGFR1 levels were associated with unfavorable clinical outcomes. Functionally, FGFR1 silencing promoted OC cell proliferation, migration, invasion, and metabolic activity, whereas FGFR1 overexpression exerted inhibitory effects. Mechanistically, FGFR1 interacted with SIRT3 and stabilized its protein expression. Importantly, SIRT3 knockdown abrogated the FGFR1-mediated reductions in lactate production, glycolytic enzyme expression, ATP levels, and histone lactylation, indicating that FGFR1 regulates metabolic reprogramming through a SIRT3-dependent mechanism. Consistently, FGFR1 knockdown promoted the formation of larger and more invasive tumors in vivo. Collectively, these findings demonstrate that FGFR1 functions as a context-dependent tumor suppressor in OC by modulating SIRT3-mediated metabolic reprogramming and histone lactylation, suggesting that targeting the FGFR1-SIRT3 axis may represent a potential therapeutic strategy for ovarian cancer. Show less

Fibroblast growth factor 19 (FGF19) is a key intestinally secreted factor in mammals, its physiological role in teleost remains largely unclear. This study aimed to investigate the function and underlying mechanisms of FGF19 in the regulation of lipid metabolism in large yellow croaker. Results revealed that FGF19 was predominantly expressed in the liver. Treatment with recombinant FGF19 protein significantly reduced triglyceride (TG) levels in hepatocytes in a dose-dependent manner. Both in vitro treatment and in vivo injection of FGF19 significantly downregulated lipogenic genes and upregulated lipolytic genes expression in hepatocytes and liver tissue. Further investigation demonstrated that FGFR1 inhibition attenuated the TG-lowering effects of FGF19 and reversed the suppression of lipogenic gene expression. Additionally, FGF19 treatment enhanced the phosphorylation of ERK, P38, AMPK, and AKT. Inhibition of P38, AMPK, or AKT significantly increased triglyceride levels which were reduced by FGF19. Inhibition of ERK, P38, and AKT impaired the FGF19-mediated regulation of lipolysis-related genes, whereas AMPK inhibition predominantly affected the regulation of lipogenic genes. Moreover, results showed that high linoleic acid (LA) intake induced endoplasmic reticulum stress and elevated expression of FGF19. The expression of XBP1s protein was significantly increased by LA treatment, while co-expression of XBP1s significantly induced the promoter activity of FGF19. In summary, these results suggest that FGF19 is primarily expressed in the liver and plays a crucial role in regulating lipid metabolism to prevent excessive lipid accumulation in large yellow croaker, while high LA intake can increase FGF19 expression through ER stress-induced XBP1s. This study will enhance the understanding of FGF19 in lipid metabolism, offering insights into the evolution of these processes in vertebrates. Show less

An 8-week experiment was conducted to evaluate the effects of dietary phosphatidylserine (PS) supplementation on juvenile large yellow croaker (Larimichthys crocea) fed high soybean oil (SO) diets. A fish oil control, an SO control, and four SO-based diets supplemented with 0.002%, 0.006%, 0.018%, or 0.054% PS were formulated. Results showed that weight gain exhibited quadratic responses to increasing PS levels. PS supplementation alleviated hepatic lipid deposition and reduced serum and hepatic lipid concentrations. At the molecular level, PS downregulated hepatic lipogenic gene expression including sterol regulatory element-binding protein 1 (srebp1), fatty acid synthase (fas), stearoyl-CoA desaturase 1 (scd1), and acetyl-CoA carboxylase 1 (acc1). Conversely, it upregulated hepatic lipid catabolism genes: peroxisome proliferator-activated receptor a (ppara), lipoprotein lipase (lpl), carnitine palmitoyltransferase 1 (cpt1), and diacylglycerol O-acyltransferase 1 (dgat1). Additionally, PS restored antioxidant enzyme activities and the expression of superoxide dismutase (sod1, sod3), glutathione peroxidase (gpx), and catalase (cat) in the liver. Furthermore, PS reduced hepatic pro-inflammatory cytokine mRNA levels: tumor necrosis factor α(tnf-α), cyclooxygenase 2 (cox-2), and interleukins (il-6, il-1β). In conclusion, dietary inclusion of 0.006%-0.018% PS effectively enhanced growth and antioxidant capacity, modulated lipid metabolism, and influenced inflammatory responses. Show less

Leptin resistance limits anti-obesity efficacy. We identified a leptin-sensitizing mechanism through tirzepatide (TZP), a glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) dual-agonist. Our tirzepatide clinical trial revealed that circulating leptin levels at baseline correlated with weight loss efficacy in patients with obesity, suggesting leptin and tirzepatide could interact to achieve stronger effects on weight loss. Next, we utilized the diet-induced obesity (DIO) mice and demonstrated the synergistic effects of tirzepatide and leptin combination (TZP+Lep) on weight loss. TZP+Lep treatment further improved hepatic insulin sensitivity and upregulated thermogenetic gene expression in brown adipose tissue. Metabolic profiling under thermoneutrality revealed TZP+Lep treatment further reduced food intake and increased energy expenditure. Tirzepatide sensitized leptin signaling in hypothalamic pro-opiomelanocortin (POMC) and GLP-1R expressing neurons. TZP+Lep synergistically increased POMC neuronal firing by decreasing the inhibitory postsynaptic input. Together, our work showed combining tirzepatide and leptin as a potential way for better maintenance of metabolic homeostasis in obesity management. Show less

Dual glucagon-like peptide-1 receptor and glucose-dependent insulinotropic polypeptide receptor agonists (GLP1RA and GIPRA, respectively) synergise to reduce body weight. Though this synergy depends on receptors within the brain, where and how this occurs is unclear. We employed a combination of neuroanatomical approaches in the mouse to investigate access of the dual GLP1RA/GIPRA, tirzepatide, and study the central targets engaged by single agonist, dual agonist and combined agonist treatments. Genetic manipulations were then used to further investigate the functional significance of specific brain regions and distinct neuronal subtypes. We recorded penetration of fluorescently labelled tirzepatide limited mainly to circumventricular organs and confirmed the importance both GLP1R and GIPR in the dorsal vagal complex for the actions of systemically administered agonists. Receptor expression indicates GIPRA alone activates a distinct population of GABA neurons in the area postrema directly, but also neurotensin neurons in the central amygdala (Nts As with selective GLP1RA, the actions of dual GLP1RA/GIPA appear to be dependent on the dorsal vagal complex for their action, probably most importantly by gaining access through the area postrema. Downstream targets include the central amygdala where signals following dual receptor agonism interact. Specifically, Nts Show less

Glucagon-like peptide-1 receptor (GLP-1R)/glucose-dependent insulinotropic peptide receptor (GIPR) agonistic analogs have yielded superior results in enhancing glycemic control and weight management compared to GLP-1R agonism alone. Intriguingly, GIPR agonism appears to induce antiemetic effects, potentially alleviating part of the nausea and vomiting side effects common to GLP-1R agonists like semaglutide. Here, we show in rats and shrews that GIPR agonism blocks emesis and attenuates other malaise behaviors elicited by GLP-1R activation while maintaining reduced food intake and body weight loss and improved glucose tolerance. The GLP-1R/GIPR agonist tirzepatide induced significantly fewer side effects than equipotent doses of semaglutide. These findings underscore the therapeutic potential of combined pharmaceutical strategies activating both incretin systems, leading to enhanced therapeutic index and reduced occurrence of nausea and vomiting for obesity and diabetes treatments. Show less

Some individuals are more susceptible to developing or suffering from pain states than others. However, the brain mechanisms underlying the susceptibility to pain responses are unknown. In this study, we defined pain susceptibility by recapitulating inter-individual differences in pain responses in mice exposed to a paradigm of socially transferred allodynia (STA), and with a combination of chemogenetic, molecular, pharmacological and electrophysiological approaches, we identified GABA-ergic neurons in the dorsal raphe nucleus (DRN) as a cellular target for the development and maintenance of STA susceptibility. We showed that DRN GABA-ergic neurons were selectively activated in STA-susceptible mice when compared with the unsusceptible (resilient) or control mice. Chemogenetic activation of DRN GABA-ergic neurons promoted STA susceptibility; whereas inhibiting these neurons prevented the development of STA susceptibility and reversed established STA. In in vitro slice electrophysiological analysis, we demonstrated that melanocortin 4 receptor (MC4R) enriched in DRN GABA-ergic neurons was a molecular target for regulating pain susceptibility, possibly by affecting DRN GABA-ergic neuronal activity. These results establish the DRN GABA-ergic neurons as an essential target for controlling pain susceptibility, thus providing important information for developing conceptually innovative and more accurate analgesic strategies. Show less

Duchenne muscular dystrophy (DMD) is a serious, progressive neuromuscular condition that predominantly impacts male individuals, marked by progressive muscle weakness resulting from mutations in the dystrophin gene (DMD) encoding dystrophin. DMD is a primary muscle disorder that often presents with secondary abnormalities in lipid metabolism and decreased bone mineral density. Although disturbances in circulating lipid profiles and skeletal health have been observed in individuals with DMD, their relationship remains underexplored.This study aimed to investigate the potential association between lipid metabolic disturbances and spinal bone mineral density in patients with DMD by combining clinical lipid levels and bone density with transcriptomic pathway analysis of DMD muscle tissue. Retrospective analysis was performed on 219 genetically confirmed DMD patients and 99 age-matched healthy controls. Healthy controls with a family history of genetic disorders were excluded. Clinical data included lipid profiles (triglycerides [TGs], remnant cholesterol [RC]); bone mineral density of the lumbar spine was evaluated using Dual-energy X-ray absorptiometry (DXA); and corticosteroid use, including treatment status, dose, and duration. Patients were stratified by corticosteroid exposure. Restricted cubic splines and multivariable regression models were applied to explore potential relationships between lipid parameters and bone mineral density. Bioinformatic analyses were performed on RNA sequencing data from muscle biopsy samples from patients with DMD (GSE38417 dataset) and an independent validation cohort (GSE6011 dataset), focusing on pathways related to lipid metabolism and osteoclast differentiation. Patients with DMD had higher TG, RC, and apolipoprotein B (ApoB) levels and lower high-density lipoprotein cholesterol (HDL-C) levels than healthy controls (P < 0.05). Elevated TG and RC levels were associated with reduced spine bone mineral density, independent of corticosteroid use. The bioinformatic analyses identified key pathways, including sphingolipid metabolism and osteoclast differentiation, as well as hub genes such as FCGR2B, C1QA, which are involved in lipid regulation and bone remodeling. Lipid abnormalities, particularly elevated TG and RC levels, were significantly associated with lower bone mineral density in patients with DMD. These findings suggest that lipid abnormalities are involved in bone health impairment in DMD, warranting further studies to confirm the association. Show less

This study aimed to explore the effects of chili meal (CM), a by-product of chili pepper oil extraction, on the productive performance, intestinal health, and lipid metabolism of laying hens fed low-protein (LP) diets. A total of 384 Hy-Line brown laying hens (32 weeks old) were divided into six groups: control (CON) diet with 16.5 % crude protein (CP), LP diet with 15 % CP, and LP diets supplemented with 3 %, 5 %, 7 %, and 9 % CM. Results showed that dietary CM supplementation of up to 5 % did not negatively affect the productive performance of laying hens fed LP diets. However, the groups receiving 7 % and 9 % CM exhibited a significant increase in the feed-to-egg ratio (P < 0.05). Additionally, dietary CM supplementation effectively enhanced egg yolk color in a dose-dependent manner (P < 0.05). Intestinal morphology analysis indicated that the 5 % CM group had a higher villus height-to-crypt depth ratio than the LP and 9 % CM groups (P < 0.05), with no significant differences among the other groups. Dietary supplementation with 3 %-7 % CM did not significantly affect serum and jejunal antioxidant capacity, and the 9 % CM group exhibited the highest levels of serum and jejunal malondialdehyde among the groups (P < 0.05). Dietary CM supplementation significantly increased anti-inflammatory cytokines (IL-4 and IL-10) and decreased pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in the serum and jejunal tissue of laying hens (P < 0.05). Moreover, CM supplementation significantly altered the cecal microbiota composition in laying hens, increasing the abundance of beneficial bacteria, such as Desulfovibrio and Megamonas. Furthermore, dietary CM supplementation significantly decreased serum triglyceride levels; downregulated liver mRNA levels of ACC, FAS, and SREBP-1C/2; and upregulated the mRNA levels of ACOX1, PPAR-α, Apob, and CPT in laying hens fed LP diets. In conclusion, CM supplementation should not exceed 5 % to avoid negative impacts on performance while supporting intestinal health and lipid metabolism. Show less

Alpha-enolase (ENO1), the enzyme catalyzing 2-phosphoglycerate conversion to phosphoenolpyruvate, is highly expressed in diffuse large B-cell lymphoma (DLBCL) and correlates with adverse clinical outcomes. Thus, understanding the relationship between ENO1-related gene (ERG) network and DLBCL is imperative. Here, we integrated multi-omics profiling (RIP-seq, RNA-seq, and protein interactome analysis) to identify ERGs and established a prognostic model by machine learning algorithms. We identified eleven hub genes (CHERP, SYNE2, INTS1, FAP, MMP9, LRP5, RBM8A, PRMT5, SLC25A6, PABPC4, PSTPIP2) using RNA sequencing, RNA immunoprecipitation sequencing, and protein interaction profiling. A prognostic model was constructed using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression in the GSE10846 dataset and validated in two independent cohorts. DLBCL patients were stratified into high- and low-risk groups based on the model, and clinical characteristics were compared. The tumor immune microenvironment (TIME) was analyzed using CIBERSORT and xCell algorithms to explore correlations with the ERG score. Drug sensitivity assays in DLBCL cell lines were performed to validate the model's predictive capacity for chemotherapy response. Furthermore, the functional role of PABPC4, a key gene in the scoring system, was investigated through A prognostic model including 11 hub genes was established. Patients in the high-risk group exhibited worse clinical outcomes and an immunosuppressive TIME, characterized by altered expression of immune checkpoint-related proteins. This group demonstrated increased sensitivity to vincristine, etoposide, and oxaliplatin. Knockdown of PABPC4 significantly inhibited cell proliferation, reduced colony formation, and delayed tumor growth The ERG scoring system offers a robust and precise tool for predicting survival and guiding personalized treatment in DLBCL patients. Show less

With the rapid progress in deciphering the pathogenesis of Alzheimer's disease (AD), it has been widely accepted that the accumulation of misfolded amyloid β (Aβ) in the brain could cause the neurodegeneration in AD. Although much evidence demonstrates the neurotoxicity of Aβ, the role of Aβ in the nervous system are complex. However, more comprehensive studies are needed to understand the physiological effect of Aβ Show less

Guhan Yangshengjing (GHYSJ) is an effective prescription for delaying progression of Alzheimer's disease (AD) based on the ancient Chinese medical classics excavated from Mawangdui Han Tomb. Comprising a combination of eleven traditional Chinese herbs, the precise protective mechanism through which GHYSJ acts on AD progression remains unclear and has significant implications for the development of new drugs to treat AD. To investigate the mechanism of GHYSJ in the treatment of AD through network pharmacology and validate the results through in vitro experiments. Chemical composition-target-pathway network and protein-protein interaction network were constructed by network pharmacology to predict the potential targets of GHYSJ for the treatment of AD. The interaction relationship between active ingredients and targets was verified by molecular docking and molecular force. Furthermore, the chemical constituents of GHYSJ were analyzed by LC-MS and HPLC, the effects of GHYSJ on animal tissues were analyzed by H&E staining. An Aβ-induced SH-SY5Y cellular model was established to validate the core pathways and targets predicted by network pharmacology and molecular docking. The results of the network pharmacology analysis revealed a total of 155 bioactive compounds capable of crossing the blood-brain barrier and interacting with 677 targets, among which 293 targets specifically associated with AD, which mainly participated in and regulated the amyloid aggregation pathway and PI3K/Akt signaling pathway, thereby treating AD. In addition, molecular docking analysis revealed a robust binding affinity between the principal bioactive constituents of GHYSJ and crucial targets implicated in AD. Our findings were further substantiated by in vitro experiments, which demonstrated that Liquiritigenin and Ginsenosides Rh4, crucial constituents of GHYSJ, as well as GHYSJ pharmaceutic serum, exhibited a significant down-regulation of BACE1 expression in Aβ-induced damaged SH-SY5Y cells. This study provides valuable data and theoretical underpinning for the potential therapeutic application of GHYSJ in the treatment of AD and secondary development of GHYSJ prescription. Through network pharmacology, molecular docking, LC-MS, and cellular experiments, GHYSJ was initially confirmed to delay the progression of AD by regulating the expression of BACE1 in Amyloid aggregation pathway. Our observations provided valuable data and theoretical underpinning for the potential therapeutic application of GHYSJ in the treatment of AD. Show less

Germinal center (GC) B cells segregate into three subsets that compartmentalize the antagonistic molecular programs of selection, proliferation, and somatic hypermutation. In bone marrow, the epigenetic reader BRWD1 orchestrates and insulates the sequential stages of cell proliferation and Show less

Small extracellular vesicles (sEVs) act as a critical mediator in intercellular communication. Compared to sEVs derived from in vitro sources, tissue-derived sEVs can reflect the in vivo signals released from specific tissues more accurately. Currently, studies on the role of sEVs in the cochlea have relied on studying sEVs from in vitro sources. This study evaluates three cochlear tissue digestion and cochlear tissue-derived sEV (CDsEV) isolation methods, and first proposes that the optimal approach for isolating CDsEVs using collagenase D and DNase І combined with sucrose density gradient centrifugation. Furthermore, it comprehensively investigates CDsEV contents and cell origins. Small RNA sequencing and proteomics are performed to analyze the miRNAs and proteins of CDsEVs. The miRNAs and proteins of CDsEVs are crucial for maintaining normal auditory function. Among them, FGFR1 in CDsEVs may mediate the survival of cochlear hair cells via sEVs. Finally, the joint analysis of single CDsEV sequencing and single-cell RNA sequencing data is utilized to trace cellular origins of CDsEVs. The results show that different types of cochlear cells secrete different amounts of CDsEVs, with Kölliker's organ cells and supporting cells secrete the most. The findings are expected to enhance the understanding of CDsEVs in the cochlea. Show less

Fish physiological health is often negatively impacted by high-temperature environments and there are few studies on how dietary lipids affect fish growth and physiology when exposed to heat stress. The main objective of this research was to examine the impact of dietary lipid levels on growth and physiological status of juvenile turbot (Scophthalmus maximus L.) and determine if dietary lipid concentration could alleviate the possible adverse effects of heat stress. Five diets containing 6.81%, 9.35%, 12.03%, 14.74%, and 17.08% lipid, respectively, were formulated and fed to turbot (initial weight 5.13 ± 0.02 g) under high-temperature conditions (24.0-25.0 °C). Meanwhile, the diet with 12.03% lipid (considered by prior work to be an optimal dietary lipid level) was fed to turbot of the same size at normal temperature. Results suggested that, among the different dietary lipid levels under high-temperature conditions, fish fed the optimal lipid (12.03%) exhibited better growth compared to non-optimal lipid groups, as evidenced by higher weight gain and specific growth rate. Simultaneously, the optimal lipid diet may better maintain lipid homeostasis, as attested by lower liver and serum lipid, along with higher liver mRNA levels of lipolysis-related genes (pgc1α, lipin1, pparα, lpl and hl) and lower levels of synthesis-related genes (lxr, fas, scd1, pparγ, dgat1 and dgat2). Also, the optimal lipid diet might mitigate oxidative damage by improving antioxidant enzyme activity, decreasing malondialdehyde levels, and up-regulating oxidation-related genes (sod1, sod2, cat, gpx and ho-1). Furthermore, the optimal lipid may enhance fish immunity, as suggested by the decrease in serum glutamic-oxalacetic/pyruvic transaminase activities, down-regulation of pro-inflammatory genes and up-regulation of anti-inflammation genes. Correspondingly, the optimal lipid level suppressed MAPK signaling pathway via decreased phosphorylation levels of p38, JNK and ERK proteins in liver. In summary, the optimal dietary lipid level facilitated better growth and physiological status in turbot under thermal stress. Show less

Patent foramen ovale (PFO) is a congenital defect between the atria, resulting in abnormal hemodynamics. We conducted a genome-wide association study (GWAS) to identify common genetic variants associated with PFO. We performed a whole genome sequencing in a discovery cohort of 3,227 unrelated Chinese participants screened for PFO via contrast transthoracic echocardiography (cTTE). Single-nucleotide polymorphisms (SNPs) associated with PFO were further validated by Sanger sequencing and subsequently were evaluated in a validation cohort. Expression quantitative trait loci (eQTL) analysis was conducted using the GTEx database. Single-cell sequencing analyses with pseudotime trajectory modeling were employed to evaluate their expression in human fetal hearts. The case-control GWAS of discovery cohort ultimately included 517 cases and 517 demographically matched controls. Of the 7,040,407 variants assessed, we identified rs1227675732 (OR = 2.903; 95% CI, 1.961 to 4.297; The identification of susceptible loci for PFO might provide insights into the pathogenesis of PFO and contribute to understanding heart development. https://www.chictr.org.cn/showproj.html?proj=40590, identifier ChiCTR1900024623. Show less

Circulating exosome-enriched extracellular vesicles (EVs) have drawn considerable importance in obesity-related insulin-resistance (IR). We sought to compare the proteomics profile of serum exosomes from normal individuals and those with obesity and IR. We isolated serum exosomes from male subjects with obesity and insulin resistance (Ob-IR, HOMA-IR > 2.0) and lean/overweight insulin-sensitive (Normal (N), HOMA-IR < 2.0) individuals. The differential protein expression between the two groups was detected by a label-free quantitative mass spectrometry analysis followed by GO annotation and ingenuity pathway analysis (IPA). We identified 23 upregulated and 46 downregulated proteins between Ob-IR and N groups. Some of these proteins are involved in altering insulin signaling (VPS13C, TBC1D32, TTR, and ADIPOQ), inflammation (NFκB and CRP), and B-cell proliferation/activation (IGLV4-69, IGKV1D-13, and IGHV4-28). GO analysis revealed that the differentially expressed proteins (DEPs) are mainly involved in regulating immune cell activation and are located in extracellular space. IPA analysis showed that top molecules mediating IR, inflammation and B-cell activation were upregulated in Ob-IR subjects compared to N subjects. Serum exosomal proteins can be used as biomarkers to identify the future risk of diabetes and a therapeutic target to prevent or slow down the progression of diabetes in high-risk individuals. Show less

Nausea and vomiting remain life-threatening obstacles to successful treatment of chronic diseases, despite a cadre of available antiemetic medications. Our inability to effectively control chemotherapy-induced nausea and vomiting (CINV) highlights the need to anatomically, molecularly, and functionally characterize novel neural substrates that block CINV. Behavioral pharmacology assays of nausea and emesis in 3 different mammalian species were combined with histological and unbiased transcriptomic analyses to investigate the beneficial effects of glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism on CINV. Single-nuclei transcriptomics and histological approaches in rats revealed a topographical, molecularly distinct, GABA-ergic neuronal population in the dorsal vagal complex (DVC) that is modulated by chemotherapy but rescued by GIPR agonism. Activation of DVCGIPR neurons substantially decreased behaviors indicative of malaise in cisplatin-treated rats. Strikingly, GIPR agonism blocks cisplatin-induced emesis in both ferrets and shrews. Our multispecies study defines a peptidergic system that represents a novel therapeutic target for the management of CINV, and potentially other drivers of nausea/emesis. Show less

Yi-Shen-Hua-Shi (YSHS) granule is an effective prescription widely used in traditional Chinese medicine to treat diabetic kidney disease (DKD), its exact efficacy in treating DKD has been confirmed but the underlying regulatory mechanism has not been fully elucidated. To explore the mechanism by which YSHS granule regulates intestinal flora and serum metabolites and then regulates renal mRNA expression through the "gut-kidney axis", so as to improve DKD. 40 rats were divided into five groups: Normal group (N) (normal saline), model group (M) (STZ + normal saline), YSHS granule low-dose group (YL) (STZ + 2.27 g kg In group M, blood glucose, blood lipid and proteinuria were increased, inflammation, oxidative stress and renal function were aggravated, with the proliferation of mesangial matrix, vacuolar degeneration of renal tubules, accumulation of collagen and lipid, and increased intestinal permeability, and YSHS granule and valsartan improved these disorders to varying degrees. High dose of YSHS granule improved the diversity and abundance of flora, decreased the F/B value, greatly increased the abundance of Lactobacillus and Lactobacillus_murinus, and decreased the abundance of Prevoella UCG₀₀₁. 14 target metabolites of YSHS granule were identified, which were mainly enriched in 20 KEGG pathways, such as Glycerophospholipid metabolism, Sphingolipid metabolism and Phenylalanine, tyrosine and tryptophan biosynthesis. 96 target mRNAs of YSHS granule were also identified. The enriched top 20 pathways were closely related to glucose and lipid metabolism, of which a total of 21 differential mRNAs were expressed. Further correlation analysis revealed that Lactobacillus, Lactobacillus_murinus and Prevotella UCG₀₀₁ were highly correlated with Glycerophospholipid metabolism, Sphingolipid metabolism and Phenylalanine, tyrosine and tryptophan biosynthesis pathways. At the same time, 6 pathways including Glycerophospholipid metabolism, Arachidonic acid metabolism, Purine metabolism, Primary bile acid biosynthesis, Ascorbate and aldarate metabolism and Galactose metabolism were co-enriched by the target metabolites and the target mRNAs of YSHS granule, including 7 differential metabolites such as phosphatidylethanolamine and 7 differential genes such as Adcy3. The 7 differential metabolites had high predictive value of AUC, and the validation of 7 differential genes were highly consistent with the sequencing results. YSHS granule could improve DKD through the "gut-kidney axis". Lactobacillus and Lactobacillus_murinus were the main driving forces. 6 pathways related to glucose and lipid metabolism, especially Glycerophospholipid metabolism, may be an important follow-up response and regulatory mechanism. Show less

Colon adenocarcinoma is the most common type of colorectal cancer. The prognosis of advanced colorectal cancer patients who received treatment is still very poor. Therefore, identifying new biomarkers for prognosis prediction has important significance for improving treatment strategies. However, the power of biomarker analyses was limited by the used sample size of individual database. In this study, we combined Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases to expand the number of healthy tissue samples. We screened differentially expressed genes between the GTEx healthy samples and TCGA tumor samples. Subsequently, we applied least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox analysis to identify nine prognosis-related immune genes: Show less

Angiopoietin-like 4 (ANGPTL4) is a potent regulator of TAG metabolism, but knowledge of the mechanisms underlying ANGPTL4 transcription in response to fatty acids is still limited in teleost. In the current study, we explored the molecular characterisation of ANGPTL4 and regulatory mechanisms of ANGPTL4 in response to fatty acids in large yellow croaker ( Show less

Hypertrophy and fiber transformation are two prominent features of postnatal skeletal muscle development. However, the role of epigenetic modifications is less understood. ATAC-seq, whole genome bisulfite sequencing, and RNA-seq were applied to investigate the epigenetic dynamics of muscle in Hu sheep at 3 days, 3 months, 6 months, and 12 months after birth. All 6865 differentially expressed genes were assigned into three distinct tendencies, highlighting the balanced protein synthesis, accumulated immune activities, and restrained cell division in postnatal development. We identified 3742 differentially accessible regions and 11799 differentially methylated regions that were associated with muscle-development-related pathways in certain stages, like D3-M6. Transcription factor network analysis, based on genomic loci with high chromatin accessibility and low methylation, showed that ARID5B, MYOG, and ENO1 were associated with muscle hypertrophy, while NR1D1, FADS1, ZFP36L2, and SLC25A1 were associated with muscle fiber transformation. Taken together, these results suggest that DNA methylation and chromatin accessibility contributed toward regulating the growth and fiber transformation of postnatal skeletal muscle in Hu sheep. Show less

The induction of nausea and emesis is a major barrier to maximizing the weight loss profile of obesity medications, and therefore, identifying mechanisms that improve tolerability could result in added therapeutic benefit. The development of peptide YY (PYY)-based approaches to treat obesity are no exception, as PYY receptor agonism is often accompanied by nausea and vomiting. Here, we sought to determine whether glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) agonism reduces PYY-induced nausea-like behavior in mice. We found that central and peripheral administration of a GIPR agonist reduced conditioned taste avoidance (CTA) without affecting hypophagia mediated by a PYY analog. The receptors for GIP and PYY (Gipr and Npy2r) were found to be expressed by the same neurons in the area postrema (AP), a brainstem nucleus involved in detecting aversive stimuli. Peripheral administration of a GIPR agonist induced neuronal activation (cFos) in the AP. Further, whole-brain cFos analyses indicated that PYY-induced CTA was associated with augmented neuronal activity in the parabrachial nucleus (PBN), a brainstem nucleus that relays aversive/emetic signals to brain regions that control feeding behavior. Importantly, GIPR agonism reduced PYY-mediated neuronal activity in the PBN, providing a potential mechanistic explanation for how GIPR agonist treatment reduces PYY-induced nausea-like behavior. Together, the results of our study indicate a novel mechanism by which GIP-based therapeutics may have benefit in improving the tolerability of weight loss agents. Show less

Metastasis is the leading cause of death in patients with colorectal cancer (CRC). The 5-year survival rate of CRC patients in whom the cancer has spread to distant sites is 13.5%. The most common sites of CRC metastasis are liver and lung. The principal therapies for CRC metastatic disease are surgery, but its benefits are limited. This study aimed to reveal the regulatory mechanism of berberine on secondary homing of CRC cells to form metastatic focus. This was more valuable than the previous direct study of the migration and metastasis characteristics of CRC cells. In this study, we used the functional enrichment analysis of differentially expressed genes after berberine treatment and investigated co-expression modules related with CRC metastasis by WGCNA. PPI and survival analyses of significant modules were also conducted. The biological functions of berberine in CRC lung and liver metastasis were investigated by a series of in vitro and in vivo experiments: MTT, colony formation and mouse tail vein injection. And we scanned through the entire extracellular domain of HEY2 protein for autodocking analysis with berberine. We found the differentially expressed genes (DEGs) after berberine treatment were related with cancer progression and metastasis related pathways. Through WGCNA analysis, four cancer progression and metastasis related modules were detected. After PPI and survival analysis, we identified and validated HEY2 as a hub gene, high expression and poor survival at the metastatic stage. Functionally, berberine inhibited the survival, invasion and migration of CRC cells in vitro and in vivo. Mechanistically, berberine treatment down-regulated the expression of HEY2, metastasis related protein E-cadherin, β-catenin and Cyclin D1 during Mesenchymal epithelial transformation (MET). Berberine and HEY2 showed a significant interaction, and berberine binded to HEY2 protein at the residue HIS-99 interface with a hydrogen-bond distance of 1.9A. We revealed that berberine could significantly inhibit the expression of hub gene HEY2 and metastasis related proteins E-cadherin and β-catenin and Cyclin D1 during MET in CRC lung and liver metastases. In total, HEY2 was a promising candidate biomarker for prognosis and molecular characteristics in CRC metastasis. Show less

To study the significance of interleukin-6 (IL-6) and interleukin-27 (IL-27) in the differential diagnosis of acute respiratory distress syndrome (ARDS) and neonatal respiratory distress syndrome (NRDS) in preterm infants. The preterm infants with the manifestation of respiratory distress who were treated in the Neonatal Diagnosis and Treatment Center, Children's Hospital of Chongqing Medical University, from March to November 2021, were enrolled in this prospective study. According to the diagnosis results, they were divided into two groups: ARDS group ( The ARDS group had significantly higher plasma levels of IL-6 and IL-27 than the NRDS group ( Plasma IL-6 and IL-27 can be used as biological indicators for early differential diagnosis of ARDS and NRDS in preterm infants. Show less