👤 Xiongchao Cheng

Convergent evolution offers a unique lens through which to explore the molecular underpinnings of significant phenotypic transformations. Similar selective pressures likely drove the evolution of analogous milk traits in sheep and goats. Consequently, the current study aimed to identify common selection signals for milk traits across dairy and non-dairy breeds of sheep and goats worldwide. In this study, a total of 308 whole-genome sequences from diverse sheep (n = 108) and goat (n = 200) breeds, including both dairy and non-dairy types, across the world were utilized. The population structure and genetic diversity of dairy and non-dairy sheep and goat breeds were characterized. Species-specific genes associated with milk traits, such as POU2F1, ABCD2, TRNAC-GCA in sheep and PRPF6, VPS13C, TPD52L2, NFX1 and B4GALT1 in goats, were identified. Further gene annotation and bioinformatics analyses indicated that different biological pathways are important for milk traits in each species: fatty acid oxidation and AMP metabolic process in sheep, the U2-type spliceosomal complex and propanoate metabolism in goats. Additionally, common signatures of selection such as CLASP1, PDS5B, ZNF831, CCDC73 were found in sheep and goats. Haplotype and transcriptional analyses further confirmed the role of these genes in milk production and provided evidence for their analogous evolution in sheep and goats. The CLASP1 gene was identified as a target of convergent selection, representing a promising candidate for genetic improvement programs in dairy species. These results provide insights into the genetic basis of convergent dairy traits, offering valuable targets for improving milk production and advancing dairy sheep and goat breeding programs. Show less

Perioperative neurocognitive disorder (PND) describes a range of cognitive impairments associated with surgery and anaesthesia, often driven by neuroinflammation. This study explored a novel adult mouse model, in which preoperative subclinical infection, induced by low-dose lipopolysaccharide (LPS) in combination with surgery, led to cognitive dysfunction in adult mice. Adult male C57BL/6J mice were treated with 0.75 mg/kg LPS two hours before undergoing tibial fracture fixation or appendicectomy. Spontaneous activity and anxiety-like behaviours were tested by open field test. Cognitive outcomes were evaluated using the novel object recognition test and morris water maze. Inflammatory markers and synaptic proteins in the hippocampus were analysed through ELISA, RT-qPCR, and Western blot, while proteomics provided deeper insights into molecular changes. We found that preoperative LPS sensitised the immune system, leading to heightened neuroinflammation and microglial activation after surgery. This was accompanied by memory and learning impairments. Key synaptic proteins, including PSD-95, GAP-43, SYN and mature BDNF, were significantly reduced, indicating disrupted synaptic function. Proteomics revealed changes in pathways related to immune responses, synaptic organisation, and energy metabolism, providing a potential molecular basis for these cognitive deficits. This study provided a practical adult mouse model for PND, demonstrating that low-dose LPS followed by surgery induced an inflammatory response, leading to postoperative impairments in learning and memory. Show less

Exercise and heat stress have been reported to independently provide benefits to brain health. We tested the hypothesis that 8 weeks of post-exercise local heating, passive local heating only, or exercise training only improves cognitive performance compared to a control group. Sixty young, healthy participants (n = 30 female, age: 23 [3] years) were randomised into one of four groups: control (CON), aerobic exercise (EX), local heating (HEAT), or combined heat and exercise (HEATEX). Participants completed supervised sessions three times per week for 8 weeks. Exercise sessions were completed at 70-75% of maximum heart rate on a cycle ergometer, and local heating sessions involved hot water immersion (42°C) of the feet (both 45 min duration). The HEATEX group performed both the EX and HEAT components sequentially in the same session (90 min total duration). Cognitive performance was measured at baseline and at the end of the 8-week intervention using the digit symbol substitution task (DSST) and the Stroop test. There was a main effect of time (P < 0.001) where DSST performance improved; however, there was no group effect (P = 0.089) or time by group interaction (P = 0.119). There was no effect of the interventions on Stroop cost (baseline: 90 [SD: 70] ms; post-intervention: 84 [SD: 70] ms; time by condition interaction P = 0.205). Similarly, there were no effects of the interventions on circulating plasma concentrations of brain-derived neurotrophic factor (interaction P = 0.189). Eight weeks of exercise training and/or local heating is not sufficient to improve cognitive performance in young, moderately fit individuals. Show less

The Glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) are well-established drug targets for the treatment of diabetes and obesity. Studies have linked GLP-1R agonist to cardiometabolic diseases (CMDs), while the therapeutic potential of the GIPR agonist remains a topic of debate. Using genetic variants as instrumental variables, we performed a two-sample Mendelian randomization (MR) analysis to investigate causal relationships between genetically proxied GIPR agonist and 23 CMD outcomes, and a two-step mediation analysis to identify mediating inflammatory biomarkers. The inverse variance weighted (IVW) method served as the primary analytical approach, supplemented by sensitivity analyses to validate robustness. The genetic mimicry of GIPR enhancement showed significant protective associations with 14 CMDs. Mediation analysis revealed that Fms-related tyrosine kinase 3 ligand (Flt3L) partially mediated the effects of GIPR agonist on angina (OR 0.997 [0.995-0.999], P = 0.0048) and myocardial infarction(MI) (OR 0.998 [0.996-0.999], P = 0.0077), accounting for 15.49% and 16.71% of the total risk reduction, respectively. Our study revealed that GIPR agonist lowers the risk of 14 CMDs. Flt3L is pinpointed as a key mediating factor in reducing angina and MI risk, suggesting a new therapeutic avenue. Show less

Adamantinomatous craniopharyngioma (ACP) is a histologically benign but clinically aggressive tumor arising from Rathke's pouch remnants, which is molecularly distinct from the other subtype, papillary craniopharyngioma (PCP). Despite advancements in surgery and radiotherapy, treatment outcomes remain unsatisfactory due to the tumor's invasiveness and resistance to conventional therapies. This review systematically examines the molecular pathogenesis of ACP and evaluates current and emerging therapeutic strategies to improve clinical management. ACP is driven by CTNNB1 mutations and dysregulated Wnt/β-catenin signaling, alongside inflammatory and senescence-associated pathways. Current pharmacological approaches, including interferon-α, IL-6 inhibitors (e.g., tocilizumab), and intracystic agents (e.g., bleomycin), exhibit limited efficacy. Promising emerging therapies target the angiogenesis (e.g., bevacizumab) and MAPK/ERK pathway, which is activated by somatic BRAF V600E mutations in PCP, has been successfully targeted with BRAF/MEK inhibitors, demonstrating significant efficacy in the majority of treated PCP patients. whereas immune checkpoint inhibitors and SHH pathway modulators face significant challenges. Additionally, ACP-related endocrine dysfunction and hypothalamic obesity require tailored interventions, such as GLP-1 receptor agonists and MC4R-targeted therapies. Precision medicine, informed by molecular subtyping and multi-omics data, holds transformative potential for ACP treatment. Future strategies should focus on combinatorial therapies to address tumor heterogeneity, microenvironment modulation, and senolytic approaches. Collaborative multidisciplinary efforts are crucial to translating these insights into clinical practice, ultimately enhancing patient outcomes and quality of life. Show less

Lactylation, a recently identified post-translational modification, plays a critical role in tumor progression and immune regulation. However, its cellular heterogeneity and functional impact in lung adenocarcinoma (LUAD) remain poorly understood. This study was designed as exploratory biological research to characterize lactylation-associated patterns at the single-cell level and to propose a potential lactylation-related prognostic model. Single-cell transcriptomic data from LUAD and normal lung tissues were analyzed to quantify lactylation activity using AUCell based on 332 lactylation-related genes. Cell-cell communication was inferred using CellChat to identify ligand-receptor interactions among subpopulations. Candidate genes were selected by integrating ligand-receptor pair genes, marker genes from highly lactylated subtypes, and previously reported lactylation-related genes. A total of 101 machine learning model combinations were evaluated to construct the prognostic model. Selected genes were further validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR), and the potential relationship between Lactylation activity was higher in tumor epithelial and stromal cells, with particularly elevated levels in specific epithelial subpopulations. A 12-gene signature was identified, comprising nine risk genes (e.g., This study presents a lactylation-based prognostic model for LUAD and uncovers potential immune-related mechanisms by which highly lactylated epithelial cells may contribute to immune evasion and tumor progression. Show less

How extravillous trophoblast (EVT) invasion is regulated during placental development remains an important question in reproductive biology. This study demonstrates that growth differentiation factor-11 (GDF-11) promotes EVT invasion by upregulating angiopoietin-like 4 (ANGPTL4) via ALK4/ALK5-SMAD3 signaling, revealing a novel mechanism in placental biology. Proper regulation of extravillous trophoblast (EVT) cell invasion is critical for normal placental development and function. Growth differentiation factor 11 (GDF-11), a member of the transforming growth factor-β (TGF-β) superfamily, has been shown to promote EVT cell invasion, yet the underlying molecular mechanisms remain largely unclear. In this study, RNA sequencing identified angiopoietin-like 4 (ANGPTL4), a multifunctional secreted protein, as a novel downstream target of GDF-11. In vitro experiments demonstrated that GDF-11 significantly upregulated ANGPTL4 expression in both HTR-8/SVneo cells and primary human EVT cells. Mechanistically, we found that the type I TGF-β receptors ALK4 and ALK5 were essential for mediating the stimulatory effect of GDF-11 on ANGPTL4 expression. Further analysis revealed that SMAD3, but not SMAD2, was the key transcription factor involved in this process. Using both loss- and gain-of-function approaches, we demonstrated that ANGPTL4 was required for GDF-11-induced EVT cell invasion. Importantly, serum levels of GDF-11 were markedly reduced in patients with preeclampsia (PE), a pregnancy disorder associated with shallow trophoblast invasion and poor placentation. Together, our findings uncover a previously unrecognized GDF-11-ANGPTL4 signaling axis that regulates EVT cell invasion and provides new insight into the pathophysiology of PE. Show less

Hypoglycemia is a commonly neglected complication in elderly diabetic patients, which can lead to cardiovascular events. Endothelial cell dysfunction is the primary inducer of cardiovascular events, and it is associated with hypoglycemia-triggered cytokine release and inflammatory programmed cell death. A comprehensive understanding of lineage-specific variations in pathological vascular changes is essential to mitigate cardiovascular events and ensure therapeutic efficacy. Herein, unbiased clustering analyses and single-nucleus RNA sequencing are performed on cells of the thoracic aorta in db/db and insulin-induced hypoglycemic db/db mice. Comparative analyses show changes in lineage-specific genes, subpopulation composition, intercellular communication, and molecular biology in hypoglycemic diabetic mice. The analyses also revealed the changes of different cells, particularly endothelial cell PANoptosis, macrophage inflammatory polarization, and vascular smooth muscle cell (VSMC) fibrosis. Pseudo-time sequencing, differential expression, and regulation network analyses revealed the association of potential hub genes Klf2, ETS2, Elavl1, C3, and Nr4a1 with the mentioned pathological processes. It is demonstrated that hypoglycemia induces VSMC fibrosis in vivo, whereas Angptl4 knockdown can attenuate VSMC fibrosis in vitro. These findings demonstrate the hypoglycemic macroangiopathy mechanism and provide important references for future disease intervention and treatment. Show less

Proper regulation of extravillous trophoblast (EVT) cell invasion is critical for normal placental development and function. Angiopoietin-like 4 (ANGPTL4), a multifunctional protein, has previously been implicated in promoting EVT cell invasion. Growth differentiation factor-8 (GDF-8), a member of the transforming growth factor-β (TGF-β) superfamily, also stimulates EVT cell invasion. However, it remains unclear whether GDF-8 regulates ANGPTL4 expression and how this regulation contributes to the invasive behavior of human EVT cells. This study aims to explore the role of ANGPTL4 in GDF-8-induced EVT cell invasion and to uncover the underlying molecular mechanisms. The immortalized EVT cell line HTR-8/SVneo and primary human EVT cells were used as in vitro models. The effects of GDF-8 on ANGPTL4 expression and the underlying signaling mechanisms were investigated using RT-qPCR and Western blot analysis. Cell viability was assessed using the MTT assay, and cell invasiveness was examined using a Matrigel-coated transwell invasion assay. Our results demonstrated that GDF-8 increased ANGPTL4 expression. Mechanistically, we found that activin receptor-like kinases 4 and 5 (ALK4 and ALK5) were required for GDF-8-mediated upregulation of ANGPTL4. Additionally, both SMAD2 and SMAD3 were involved in this regulatory pathway. We further showed that GDF-8 treatment promoted cell invasion without affecting cell viability. The pro-invasive effect of GDF-8 was attenuated by ANGPTL4 knockdown, whereas ANGPTL4 overexpression alone enhanced cell invasiveness. This study reveals a novel role for GDF-8 in regulating ANGPTL4 expression and EVT cell invasion, offering new insights into placental development and potential implications for pregnancy-related disorders. Show less

Hypertriglyceridemia, characterized by increased triglyceride (TG) concentrations, is considered the most important risk factor for cardiometabolic disorders, including dyslipidemia, atherosclerotic cardiovascular diseases, and non-alcoholic fatty liver disease (NAFLD). Recently, the angiopoietin-like protein (ANGPTL) family, which comprises ANGPTL1 to ANGPTL8, was confirmed to play an important role in modulating lipoprotein lipase (LPL) activity. However, understanding of the underlying mechanisms remains limited. Importantly, emerging evidence has linked several transcriptional and post-transcriptional factors to the potential alteration of TG metabolism via ANGPTL proteins. This review focused on the similarities and differences in the expression, structural features, and modulatory profile of three ANGPTLs: ANGPTL3, ANGPTL4, and ANGPTL8. In addition, the regulatory functions of those three ANGPTLs in modulating LPL were summarized to provide potential therapeutic and clinical strategies for hypertriglyceridemia and its related cardiometabolic disorders. Show less

Angiopoietin‑like 4 (ANGPTL4), a member of the angiopoietin family, plays critical roles in angiogenesis, lipid metabolism and inflammation. It has been demonstrated that ANGPTL4 has significant influence on various diseases. Accumulating evidence has highlighted the impacts of ANGPTL4 on human malignancies. ANGPTL4 is commonly overexpressed in various types of cancer, such as breast, non‑small cell lung, gastric and colorectal cancer. Its upregulation promotes tumor growth, invasion, metastasis and angiogenesis, as well as metabolic reprogramming and resistance to programmed cell death, radiotherapy and chemotherapy. However, ANGPTL4 has also exhibited antitumor effects under certain conditions, indicating its complex roles in tumor biology. The transcriptional regulation of ANGPTL4 is influenced by multiple factors, such as HIF‑1, PPARs, TGF‑β and long non‑coding RNAs. In terms of signaling pathways, STATs, PI3K/AKT and COX-2/PGE2 are important in regulating cellular processes. The present review summarizes the biological functions of ANGPTL4 in tumors and its association with patient prognosis. Furthermore, the key molecular mechanisms and potential reasons for its dual roles in cancer are also discussed. In conclusion, ANGPTL4 is a valuable diagnostic biomarker and a potential therapeutic target for human cancers. Show less

Despite the high morbidity and mortality, the effective therapies for heart failure with preserved fraction (HFpEF) are limited as the poor understand of its pathophysiological basis. This study was aimed to characterize the cellular heterogeneity and potential mechanisms of HFpEF at single-cell resolution. An HFpEF mouse model was induced by a high-fat diet with N-nitro-L-arginine methyl ester. Cells from the hearts were subjected to single-cell sequencing. The key protein expression was measured with Immunohistochemistry and immunofluorescence staining. In HFpEF hearts, myocardial fibroblasts exhibited higher levels of fibrosis. Furthermore, an increased number of fibroblasts differentiated into high-metabolism and high-fibrosis phenotypes. The expression levels of genes encoding certain pro-angiogenic secreted proteins were decreased in the HFpEF group, as confirmed by bulk RNA sequencing. Additionally, the proportion of the endothelial cell (EC) lineages in the HFpEF group was significantly downregulated, with low angiogenesis and high apoptosis phenotypes observed in these EC lineages. Interestingly, the fibroblasts in the HFpEF heart might cross-link with the EC lineages via over-secretion of ANGPTL4, thus displaying an anti-angiogenic function. Immunohistochemistry and immunofluorescence staining then revealed the downregulation of vascular density and upregulation of ANGPTL4 expression in HFpEF hearts. Finally, we predicted ANGPTL4as a potential druggable target using DrugnomeAI. In conclusion, this study comprehensively characterized the angiogenesis impairment in HFpEF hearts at single-cell resolution and proposed that ANGPTL4 secretion by fibroblasts may be a potential mechanism underlying this angiogenic abnormality. Show less

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease with no effective pharmacological treatments. The causal role of triglycerides (TGs) in AAA development remains unclear and controversial. Mendelian randomization was applied to assess causal relationships between lipoproteins, circulating proteins, metabolites, and the risk of AAA. To test the hypothesis that elevated plasma TG levels accelerate AAA development, we used Mendelian randomization analyses integrating genetic, proteomic, and metabolomic data identified causal relationships between elevated TG-rich lipoproteins, TG metabolism-related proteins/metabolites, and AAA risk. In the angiotensin II infusion AAA model, most These findings identify hypertriglyceridemia as a key contributor to AAA pathogenesis and suggest that targeting TG-rich lipoproteins may be a promising therapeutic strategy for AAA. Show less

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without effective medications. This study integrated genetic, proteomic, and metabolomic data to identify causation between increased triglyceride (TG)-rich lipoproteins and AAA risk. Three hypertriglyceridemia mouse models were employed to test the hypothesis that increased plasma TG concentrations accelerate AAA development and rupture. In the angiotensin II-infusion AAA model, most 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

Pentadecanoic acid (PEA), an odd-chain fatty acid derived from diet by the gut microbiome, has garnered increasing attention for its systemic health-promoting properties. Its potential role in bladder cancer (BC) occurrence and invasion, however, remains unclear. Large-scale cohorts' analyses were performed to assess the association between dietary PEA and BC occurrence and invasion. In vitro and in vivo experiments, including EJ and T24 BC cell assays and a BBN-induced mouse model, were conducted to experimentally assess the impact of PEA on BC. Serum proteomics, gut microbiome, and targeted fecal lipidomics analyses were employed to explore the underlying mechanisms. Dietary PEA was negatively associated with BC occurrence and invasion in cohort analyses. PEA suppressed EJ and T24 BC cell migration, invasion, and proliferation, while inhibiting BC development in a BBN-induced mouse model. In vivo serum proteomics identified differentially expressed lipid-related proteins (e.g., Apoe and Apob) following PEA treatment, implicating its modulation of lipid metabolism pathways. Considering the essential role of the gut-bladder axis, the gut microbiome analysis exhibited that PEA markedly altered bacteria (e.g., g_Alistipes) and fungi (e.g., o_Erysiphales, g_Teberdinia, and g_Gibberella), with concomitant lipid metabolism changes. Furthermore, targeted fecal lipidomics demonstrated the shifts in key lipids, such as phosphatidylethanolamines (PE) involved in essential lipid clusters, suggesting regulation by gut microbiome linked to BC development. Collectively, our findings demonstrate that PEA mitigates BC by reshaping the gut microbiome and modulating lipid metabolism, providing new insights into its molecular and therapeutic potential. Show less

By various assessments, the previous study has unequivocally concluded functional apoB and MTTP (microsomal triglyceride transfer protein) for VLDL production in chicken ovaries. The present study sought to use whole tissue culture to define the role of VLDL secretion by small yellow follicles (SYFs) along their development under normal and heat stress (HS) conditions. Under thermoneutral conditions (39 °C), chicken SYFs increased MTTP activity, apoB expression and VLDL secretion, while underwent cell apoptosis along the time course. Despite relieved ER stress and protein ubiquitinylation, inhibition of VLDL secretion by Lomitapide and Mipomersen greatly increased triglyceride accumulation, impaired estradiol production and cell proliferation, and accelerated cell apoptosis in accordance with upregulated caspase 3/7 activity, JNK activation, protein carbonylation, and MDA accumulation. Exposure to HS at 44 °C boosted cell apoptosis in a duration-dependent manner. Acute HS for 3 h enhanced VLDL secretion, impaired estradiol production and cell proliferation, and promoted IL-1b production, oxidative damages, and cell apoptosis, whereas except MDA content and cell proliferation, the detrimental effects were halted after 13 h recovery. Lomitapide and Mipomersen augmented lipid accumulation, oxidative stress, inflammatory response, and exacerbated transient impairment of estradiol secretion and cell proliferation in SYFs under 3 h HS and after recovery, but failed to rescue cell viability despite relieved ER and proteostatic stress. In conclusion, routine secretion of VLDL by SYFs serves as an intrinsic mechanism to sustain cell viability and functions to support the whole program required for follicle development, while under HS, this mechanism provisionally rescues steroidogenesis and cell proliferation. Show less

Cholesterol is an essential molecule for tumor cell growth and proliferation, and dysregulated cholesterol metabolism has been widely implicated in cancer pathogenesis. However, the specific role and underlying molecular mechanisms of cholesterol metabolism alterations in diffuse large B-cell lymphoma (DLBCL) remain poorly understood. We retrospectively analyzed clinical data from 200 DLBCL patients and 185 healthy controls, focusing on lipid and lipoprotein levels, including triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and apolipoprotein E (ApoE). Univariate and multivariate Cox proportional hazard models were used to evaluate the prognostic value of these markers, and Kaplan-Meier analysis assessed their associations with overall survival (OS). Bioinformatics analysis predicted associations between lipid markers and cholesterol metabolism. Cellular experiments further investigated the expression of cholesterol metabolism-related proteins and the effect of the cholesterol-depleting agent Methyl-β-cyclodextrin (MβCD) on DLBCL cells. We confirmed significant alterations in metabolic markers (such as TC and ApoA1) between the healthy control group and patients, which were significantly associated with patient prognosis and overall OS. Bioinformatics analysis revealed a strong correlation between these markers and elevated CD36 expression. In addition, DLBCL cells exhibited increased expression of cholesterol uptake and synthesis proteins (CD36, SREBP2, and HMGCR) and decreased expression of efflux proteins (APOA1, NR1H2 and ABCG1), consistent with cholesterol metabolic reprogramming. Treatment with MβCD disrupted CD36 expression and cholesterol metabolism, leading to reduced DLBCL cell survival. These findings underscore the pivotal role of cholesterol metabolic reprogramming in DLBCL progression. CD36 and related metabolic markers represent promising therapeutic targets, opening novel avenues for the treatment of this malignancy. Show less

Several protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) levels in statin-intolerant patients, but none have been verified in Chinese patients. This study aimed to evaluate the efficacy and safety of ongericimab, a novel PCSK9 monoclonal antibody, in Chinese statin-intolerant patients with primary hypercholesterolemia or mixed dyslipidemia. This was a randomized, multicenter, double-blind, placebo-controlled phase 3 study designed to enroll 120 statin-intolerant adult patients. Eligible patients were randomly assigned in a 2:1 ratio to receive ongericimab 150 mg or placebo subcutaneously every 2 weeks for 12 weeks in the double-blind treatment period, followed by 40 weeks of ongericimab treatment during the open-label period. The primary endpoint was a percentage change in LDL-C from baseline to week 12. The key secondary endpoints included percentage change from baseline to week 12 in non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol (TC), and lipoprotein(a) [Lp(a)]. From February 6, 2023, to September 23, 2024, a total of 139 patients were enrolled. The least-squares (LS) mean difference between ongericimab and placebo groups in LDL-C from baseline to week 12 was -66.2 % (95 % CI: 74.2 %, -58.2 %; p < 0.0001), with reductions sustained up to week 52. Ongericimab also significantly reduced levels of non-HDL-C, ApoB, TC, and Lp(a). The overall incidence of treatment-emergent adverse events was comparable between the ongericimab and placebo groups. Ongericimab significantly reduced LDL-C as well as other atherogenic lipid levels and was well tolerated in Chinese statin-intolerant patients with primary hypercholesterolemia or mixed dyslipidemia. http://www. gov; Unique Identifier: NCT05621070. Show less

In mammals, tissues other than liver and intestine are known to possess functional MTTP (microsomal triglyceride transfer protein) and apoB (apolipoprotein B) capable of VLDL (very low-density lipoprotein) assembly. Birds are oviparous and possess unique capabilities in lipid biology to accommodate yolk formation through massive deposition of hepatically assembled yolk-targeted VLDLy into ovarian follicles. Following identifications of MTTP and ApoB expression within chicken ovarian stroma, granulosa, theca, and epithelial cells of various classes of follicles, we sought to define the functionality of ovarian MTTP and ApoB in VLDL assembly. In situ hybridization analysis found that ApoB transcripts are most abundant in thecal layers, whereas immunohistochemistry showed that MTTP predominates in the granulosa layers. MTTP lipid transfer activity was greater in small yellow follicles than in hierarchical follicles. Metabolic labeling, electron microscopy, and Western blot studies confirmed the functionality of ovarian apoB and MTTP as newly assembled VLDL around 50-200 nm in diameter and lacking ApoVLDL-II dissimilar to VLDLy, were secreted from cultured follicular cells. Lomitapide and the ApoB-antisense oligonucleotide Mipomersen dose-dependently decreased MTTP activity and VLDL-apoB secretion from cultured follicular cells, while oleate addition or acute heat stress enhanced VLDL-apoB secretion. Ultrastructural images showed VLDL assembly and trafficking toward the secretion route. The findings support the notion that VLDL assembly and secretion within avian ovarian tissues functions as a protective mechanism against fuel and physical stressors to secure follicle development and/or nutritional quality control of yolk for embryo development. Show less

Low-density lipoprotein (LDL) is intricately associated with numerous clinical conditions, including dyslipidemia and metabolic-associated fatty liver disease (MAFLD), and its serum concentration is crucial for diagnostic purposes. However, the sensitive and accurate analysis of "intact" LDL is a significant difficulty, as conventional approaches typically focus solely on the detection of cholesterol or surface proteins of LDL. We developed a proximity ligation-induced DNAzyme motor that facilitates an outstanding amplification reaction for the precise and sensitive detection of LDL through the simultaneous recognition of the target ApoB and cholesterol. This technique facilitates the direct and accurate quantification of the concentration of "intact" LDL particles, as opposed to assessing the cholesterol content or ApoB protein inside LDL. The elevated amplification efficiency of the exponential amplification reaction, in conjunction with the trans-cleavage activity of the Cas14a1/crRNA complex, facilitates sensitive LDL detection with a low limit of detection of 6.12 mg/dL. The unique properties of the proposed method offer significant advantages in selectivity, stability, and sensitivity, rendering it extremely appropriate for diagnostics in MAFLD. 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

To evaluate the efficacy and safety of inclisiran in the treatment of hypercholesterolemia. Randomized controlled trials comparing inclisiran with a placebo were searched until April 2024. Overall, 8 studies involving 4947 patients were included. Inclisiran reduced low-density lipoprotein cholesterol (mean difference [MD]: -46.95 %; 95 % confidence interval [CI]: -53.26 to -40.46; P < 0.05), proprotein convertase subtilisin/kexin type 9 (MD: -70.80 %; 95 % CI: -76.52 to -65.08; P < 0.05), serum total cholesterol (MD: -29.47 %; 95 % CI: -32.56 to -26.39; P < 0.05), non-high-density lipoprotein cholesterol (MD: -40.46 %; 95 % CI: -45.24 to -35.68; P < 0.05), apolipoprotein B (MD: -36.77 %; 95 % CI: -40.94 to -32.61; P < 0.05), and lipoprotein(a) (MD: -20.04 %; 95 % CI: -24.2 to -15.87; P < 0.05) levels but increased high-density lipoprotein cholesterol level (MD: 6.09 %; 95 % CI: 3.63 to 8.55; P < 0.05). The incidences of adverse events, serious adverse events, headache, nasopharyngitis, and muscular adverse reactions were not significantly different between the inclisiran and placebo groups. Inclisiran reduced the incidence of cardiovascular adverse reactions (odds ratio [OR] = 0.79; 95 % CI: 0.65 to 0.96; P = 0.02) and increased the incidence of injection-site reactions (OR = 4.79; 95 % CI: 2.18 to 10.52; P < 0.05). Inclisiran is effective in treating hypercholesterolemia and has a good safety profile. Show less

Aging-related lipid metabolic disorder is related to oxidative stress. Selenium (Se)-enriched Cardamine violifolia (SEC) is known for its excellent antioxidant function. The objective of this study was to evaluate the effects of SEC on antioxidant capacity and lipid metabolism in the liver of aged laying hens. A total of 450 sixty-five-wk-old Roman laying hens were randomly divided into 5 treatments: a basal diet (without Se supplementation, CON) and basal diets supplemented with 0.3 mg/kg Se from sodium selenite (SS), 0.3 mg/kg Se from Se-enriched yeast (SEY), 0.3 mg/kg Se from SEC (SEC), or 0.3 mg/kg Se from SEC and 0.3 mg/kg Se from SEY (SEC + SEY). The experiment lasted for 8 wk. The results showed that dietary SEC + SEY supplementation decreased (P < 0.05) triglyceride (in the plasma and liver) and total cholesterol levels (in the plasma), and increased (P < 0.05) HDL-C concentration in plasma compared to CON diet. Compared with CON diet, SEC and/or SEY supplementation decreased (P < 0.05) the mRNA expression of hepatic ACC, FAS and HMGCR, and increased (P < 0.05) PPARα, VTG-II, Apo-VLDL II and ApoB expression. Dietary SEC + SEY and SEY supplementation increased (P < 0.05) Se content in egg yolk and breast muscle compared to CON diet. Dietary SEC, SEY or SEC + SEY supplementation increased (P < 0.05) the activity of antioxidant enzymes (GSH-PX, T-AOC and T-SOD) in the plasma and liver and decreased (P < 0.05) MDA content in the plasma compared to CON diet. Dietary Se supplementation promoted (P < 0.05) mRNA expression of Nrf2 in the liver. In contrast, dietary SEY and SEC supplementation resulted in a decrease (P < 0.05) of hepatic Keap1 mRNA expression compared to CON diet. Dietary SEC + SEY and/or SEC supplementation increased (P < 0.05) mRNA expression of Selenof, GPX1 and GPX4 in the liver compared with CON diet. In conclusion, dietary SEC (0.3 mg/kg Se) or SEC (0.3 mg/kg Se) + SEY (0.3 mg/kg Se) improved the antioxidant capacity and the lipid metabolism in the liver of aged laying hens, which might be associated with regulating Nrf2/Keap1 signaling pathway. Show less

In view of the favorable effect of hormone replacement therapy (HRT) on the lipid profile in postmenopausal women, and the discrepancies that exist on the effect of medroxyprogesterone acetate (MPA) on lipoprotein concentrations and cardiovascular disease (CVD) risk, we conducted this meta-analysis of randomized controlled trials (RCT) to assess the efficacy of MPA on apolipoprotein and lipoprotein(a) concentrations in healthy postmenopausal women. A systematic search was conducted across multiple databases, including for English-language papers published up to September 2023 comparing the effect of MPA on ApoA-I, Apo-AII, and Lp(a) levels with those of a control group. A meta-analysis was conducted using a random-effects model, reporting the results as the weighted mean difference (WMD) with a 95 % confidence interval (CI). The current meta-analysis included 11 publications. the comprehensive findings indicated a noteworthy reduction in ApoA-I (WMD:-8.70 mg/dL,95 %CI: -12.80, -4.59,P<0.001), a significant increase in Lp(a) concentrations (WMD: 1.36 mg/dL, 95 % CI: 0.10, 2.63, P=0.033), and a non-significant increase in ApoB concentrations (WMD: 0.57 mg/dL, 95 %CI: -1.25, 2.40, P=0.539) after the administration of MPA in postmenopausal women. In addition, a significant reduction in ApoB levels was identified in studies with a mean participant BMI ≥25 kg/m2 (WMD: -4.94 mg/dL, 95 %CI: -5.71 to -4.18,P< 0.001) and a greater impact on ApoA-1 and Lp(a) levels was observed in trials with doses of 5 mg/day compared with 2.5 mg/day. MPA administration resulted in a significant increase in Lp(a) and decrease in ApoA-I levels and a non-significant increase in ApoB levels in healthy postmenopausal women. Show less

Clustered regularly interspaced short palindromic repeats-Cas13 effectors are used for RNA editing but the adeno-associated virus (AAV) packaging limitations because of their big sizes hinder their therapeutic application. Here we report the identification of the Cas13j family, with LepCas13j (529 aa) and ChiCas13j (424 aa) being the smallest and most highly efficient variants for RNA interference. The miniaturized Cas13j proteins enable the development of compact RNA base editors. Chi-RESCUE-S, by fusing dChiCas13j with hADAR2dd, demonstrates high efficiency and specificity in A-to-G and C-to-U conversions. Importantly, this system is compatible with single-AAV packaging without the need for protein sequence truncation. It successfully corrected pathogenic mutations, such as APOC3 Show less

Type 2 diabetes (T2D) and mild cognitive impairment (MCI) are interrelated conditions that significantly impair quality of life. This study aimed to identify a feasible biomarker for assessing T2D-MCI risk and to evaluate a potential therapeutic strategy. We integrated data from the National Health and Nutrition Examination Survey (NHANES) with Mendelian randomization (MR) to investigate genetic causal relationships between T2D, MCI, and their shared biomarkers. Transcriptomic analysis identified T2D-associated genes. Clinical trials evaluated the short-term effects of modified fasting therapy (MFT) on glucose regulation and cognitive function. Cellular assays and patient samples were used to validate the regulatory roles of key genes in biochemical markers and downstream signaling pathways. Among 6,356 T2D and 1,138 MCI subjects, vitamin D, high-density lipoprotein cholesterol (HDL-C), globulin, and creatinine were associated with both conditions. MR analysis showed that higher HDL-C levels reduced T2D risk (0.9059, 95% CI: 0.8666-0.9470) but increased MCI risk (OR = 1.0482, 95% CI: 1.0216-1.0755). Nuclear factor I A ( HDL-C has divergent genetic effects on T2D and MCI. Show less

Metabolic disorders and neurocognitive diseases frequently co-occur, yet the specific mechanisms driving this comorbidity remain elusive. While epidemiological associations are well-documented, the causal links between these conditions are complex and incompletely understood, necessitating a systems-level investigation into their shared biological architecture. This study integrates large-scale human genetics with experimental Network-informed Mendelian randomization identified bidirectional causalities, including a 14% elevated dementia risk from type 2 diabetes and protective effects of obesity against parental Alzheimer's disease (AD). The study identified a signature encompassing key lipid metabolism hubs This multi-modal investigation provides a robust framework that converges on a high-confidence, 13-gene signature of lipid dysregulation as a central mechanistic interface, offering a powerful set of prioritized targets for future functional validation and therapeutic development at the metabolic-neurocognitive nexus. Show less