Fatty acid desaturase 1 (FADS1) is significantly and specifically upregulated following diabetic corneal injury. However, its role in diabetic keratopathy remains unclear. This study aimed to investig Show more
Fatty acid desaturase 1 (FADS1) is significantly and specifically upregulated following diabetic corneal injury. However, its role in diabetic keratopathy remains unclear. This study aimed to investigate the impact of FADS1 on wound healing and functional recovery of the diabetic corneal epithelium and explore its potential mechanisms. Using high-glucose-induced corneal epithelial cells and a streptozotocin-induced type 1 diabetic mouse model, FADS1 expression was suppressed via FADS1 small interfering RNA (siRNA). Cell migration was assessed using scratch and transwell assays. Wound healing and functional recovery of the corneal epithelium were evaluated using sodium fluorescein staining, anterior segment optical coherence tomography, hematoxylin and eosin staining, and immunofluorescence staining. FADS1 knockdown promoted wound healing and functional recovery of the diabetic corneal epithelium both in vivo and in vitro. Suppression of FADS1 enhanced high-glucose-induced corneal epithelial cell migration, which was dependent on elevated levels of the upstream metabolite γ-linolenic acid. This effect was mediated through the activation of the mitogen-activated protein kinase signaling pathway and the accumulation of autophagosomes. After diabetic corneal epithelial injury, FADS1 expression is specifically upregulated. Knockdown of FADS1 promotes wound healing and functional recovery, suggesting a novel therapeutic strategy for diabetic keratopathy. Show less
Insulin supply is the golden standard for type 1 diabetes mellitus (T1DM) therapy. Is there a drug-reduction application for reversing glucose metabolism disabled and diabetic neuropathy (DN), and is Show more
Insulin supply is the golden standard for type 1 diabetes mellitus (T1DM) therapy. Is there a drug-reduction application for reversing glucose metabolism disabled and diabetic neuropathy (DN), and is it suitable for the young and elderly populations? Reducing T1DM-associated DN, and maintaining glucose metabolism require using the anti-aging gene Klotho to regulate specific signaling cascades. This study applied five 16:8 intermittent fasting (16-h fasting, 8-h eating; 168if) protocols by different executing times to young and elderly diabetic mice to evaluate whether 168if is age-dependent and how it alters Klotho-related signaling molecules. Blood glucose levels were efficiently reduced when 168if was implemented in the early stage of T1DM onset (DNf group) of young and elderly mice. Another four groups failed to reduce blood sugar. However, the DNf protocol was unsuitable for diabetic elderly mice because it posed a higher mortality risk for this population. Young DNf mice exhibited reduced thermal hyperalgesia and mechanical allodynia and reversed Klotho downregulation and protein kinase C epsilon (PKCε) upregulation compared with DN mice. Furthermore, young DNf mice exhibited normalization of fibroblast growth factor receptor 1 (FGFR1) and nuclear factor κB (NF-κB) expression, which is involved in Klotho-related glucose metabolism and anti-inflammation. The expression densities of PKCε, Klotho, FGFR1, and NF-κB were linear to neuropathic manifestations. This study demonstrated the effectiveness of 168if application in the early stage of T1DM onset, a straightforward and convenient dietary control method, as a blood glucose control for achieving pharmaceutical reduction and relieving neuropathic pain in young T1DM patients. Show less
Cerebral palsy (CP) is a neurodevelopmental disorder that has been linked to gut microbiota dysbiosis. Although Tuina has shown neuroprotective effects, it remains unclear whether these benefits invol Show more
Cerebral palsy (CP) is a neurodevelopmental disorder that has been linked to gut microbiota dysbiosis. Although Tuina has shown neuroprotective effects, it remains unclear whether these benefits involve regulation of the gut-brain axis. This study aimed to evaluate the therapeutic effects of Tuina in CP rats, with emphasis on its potential regulation of the gut-brain axis. CP was induced in 7-day-old Sprague-Dawley rats through hypoxia-ischemia. Beginning on postnatal day 8 (P8), the Tuina group received daily Tuina therapy for 32 consecutive days. Motor function was assessed using the negative geotaxis test (P6-P12), the beam balance test (P36-P39), and the modified neurological severity score on P40. Gut microbiota composition was analyzed using 16S rRNA sequencing. Brain and intestinal histopathology were evaluated histologically via hematoxylin-eosin and Luxol fast blue staining. Protein expression of BDNF, Nrf2, GPX4, ZO-1, and occludin was assessed via western blotting and immunofluorescence. Serum short-chain fatty acids (SCFAs) were measured by mass spectrometry, whereas oxidative stress and intestinal barrier markers (superoxide dismutase, malondialdehyde, glutathione peroxidase, lipopolysaccharide [LPS], diamine oxidase [DAO], and D-lactate [D-LA]) were detected using enzyme-linked immunosorbent assay. In CP models induced by hypoxic-ischemic encephalopathy, significant brain injury and motor dysfunction were observed, accompanied by gut microbiota dysbiosis and impaired intestinal barrier function. Tuina intervention improved motor function and growth, regulated gut microbiota, and increased serum SCFA levels. It also enhanced intestinal barrier proteins (occludin, ZO-1), reduced serum levels of LPS, DAO, and D-LA, and increased the expression of brain-derived BDNF, Nrf2, and GPX4. Tuina significantly alleviated brain injury and improved motor function in CP rats. These effects were associated with modulation of the gut microbiota and restoration of intestinal barrier integrity, suggesting that the gut-brain axis may mediate the neuroprotective effects of Tuina. Show less
Cholesterol (CH) plays a crucial role in enhancing the membrane stability of drug delivery systems (DDS). However, its association with conditions such as hyperlipidemia often leads to criticism, over Show more
Cholesterol (CH) plays a crucial role in enhancing the membrane stability of drug delivery systems (DDS). However, its association with conditions such as hyperlipidemia often leads to criticism, overshadowing its influence on the biological effects of formulations. In this study, we reevaluated the delivery effect of CH using widely applied lipid microspheres (LM) as a model DDS. We conducted comprehensive investigations into the impact of CH on the distribution, cell uptake, and protein corona (PC) of LM at sites of cardiovascular inflammatory injury. The results demonstrated that moderate CH promoted the accumulation of LM at inflamed cardiac and vascular sites without exacerbating damage while partially mitigating pathological damage. Then, the slow cellular uptake rate observed for CH@LM contributed to a prolonged duration of drug efficacy. Network pharmacology and molecular docking analyses revealed that CH depended on LM and exerted its biological effects by modulating peroxisome proliferator-activated receptor gamma (PPAR-γ) expression in vascular endothelial cells and estrogen receptor alpha (ERα) protein levels in myocardial cells, thereby enhancing LM uptake at cardiovascular inflammation sites. Proteomics analysis unveiled a serum adsorption pattern for CH@LM under inflammatory conditions showing significant adsorption with CH metabolism-related apolipoprotein family members such as apolipoprotein A-V (Apoa5); this may be a major contributing factor to their prolonged circulation Show less
Roshni Jaffery, Yuhang Zhao, Sarfraz Ahmed+11 more · 2025 · bioRxiv : the preprint server for biology · Cold Spring Harbor Laboratory · added 2026-04-24
Mutations in the Leucine-rich repeat kinase 2 ( We investigated the levels of soluble immune regulators in the serum (n=651) and cerebrospinal fluid (CSF, n=129) of In this extensive discovery cohort, Show more
Mutations in the Leucine-rich repeat kinase 2 ( We investigated the levels of soluble immune regulators in the serum (n=651) and cerebrospinal fluid (CSF, n=129) of In this extensive discovery cohort, we identified several elevated serum immune regulatory factors associated with This study highlights distinct immune profiles associated with LRRK2 mutations and PD in the periphery and CNS. Serum levels of SDF-1alpha and TNF-RII were elevated in LRRK2 mutation carriers, while CSF immune markers were reduced. In PD, irrespective of LRRK2 status, reduced CSF inflammatory analytes and weak serum signals were observed. These results provide insight into immune dysregulation linked to LRRK2 mutations. If replicable in independent datasets, they offer potential avenues for biomarker and therapeutic exploration. Show less
(1) Background: the epigenetic mechanisms underlying the progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remain poorly understood; (2) Methods: to investigate this process, Show more
(1) Background: the epigenetic mechanisms underlying the progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remain poorly understood; (2) Methods: to investigate this process, we conducted genome-wide DNA methylation sequencing to map the epigenetic changes during the AKI-CKD transition in a mouse model. By integrating DNA methylome and transcriptome analyses, we identified genes and signaling pathways regulated by DNA methylation throughout this progression; (3) Results: our analysis identified four candidate genes- Show less
Atherosclerosis, a progressive inflammatory disease and the leading cause of cardiovascular disease (CVD), remains a global health burden due to the lack of effective early therapeutic interventions. Show more
Atherosclerosis, a progressive inflammatory disease and the leading cause of cardiovascular disease (CVD), remains a global health burden due to the lack of effective early therapeutic interventions. Although growing evidence highlights the involvement of plasma proteins in atherogenesis, their causal contributions to disease pathogenesis are poorly understood. To address this gap, we conducted a proteome-wide Mendelian randomization (MR) analysis using cis-pQTLs (cis-protein quantitative trait loci) from the deCODE and UKB-PPP cohorts (~90,000 individuals) as instrumental variables. We integrated colocalization analysis, summary-data-based MR (SMR), and HEIDI tests to systematically prioritize causal plasma proteins. Key findings were replicated in the CARDIOGRAMplusC4D (coronary artery disease, CAD) and FinnGen (CVD) cohorts. Functional validation was performed through phenome-wide association studies (PheWAS), single-cell transcriptomics, histological staining, and ELISA assays to characterize protein expression patterns in specific cell types and tissues. Among 2,711 plasma proteins analyzed, 28 showed strong genetic associations with atherosclerosis. Of these, five proteins (ADK, ANGPTL4, CD4, MGAT1, SYT11) met strict validation criteria through colocalization (posterior probability of colocalization, PP.H4 > 0.8) and SMR. Subsequent replication using MR and PheWAS further confirmed the causal roles of ADK, CALB2, and COMT in CAD and other CVD outcomes. Notably, CALB2 was specifically enriched in mast cells within atherosclerotic plaques and adipose tissue, and plasma levels were significantly elevated in patients with severe carotid artery stenosis (CAS). This study identifies 28 novel therapeutic targets for atherosclerosis using a rigorous multi-omics approach. Our findings establish CALB2 as a promising biomarker and therapeutic target, particularly in severe CAS, by linking genetic evidence to cell-type-specific expression and clinical phenotypes. These insights pave the way for precision medicine approaches in the prevention and treatment of CVD. The online version contains supplementary material available at 10.1186/s12967-025-07269-6. Show less
Adolescence is a developmental period characterized by heightened plasticity. Yet, how ongoing development affects sensory processing and cognitive function is unclear. We investigated how adolescent Show more
Adolescence is a developmental period characterized by heightened plasticity. Yet, how ongoing development affects sensory processing and cognitive function is unclear. We investigated how adolescent (postnatal day 20-42) and adult (postnatal day 60-82) mice differ in performance on a pure tone Go/No-Go auditory discrimination task of varying difficulty. Using dense electrophysiological recordings, we measured spiking activity at single neuron resolution in the auditory cortex while mice were engaged in the task. As compared to adults, adolescent mice showed lower auditory discrimination performance in a difficult task. This difference in performance was due to higher response variability and weaker cognitive control expressed as higher lick bias. Adolescent and adult neuronal responses differed only slightly in representations of pure tones when measured outside the context of learning and the task. However, cortical representations after learning within the context of the task were markedly different. We found differences in stimulus- and choice-related activity at the single neuron level representations, as well as lower population-level decoding of the difficult task in adolescents. Overall, cortical decoding in adolescents was lower and slower, especially for difficult sound discrimination, reflecting immature cortical representations of sounds and choices. Notably, we found age-related differences, which were more pronounced after learning, reflecting the combined impact of age and learning. Our findings highlight distinct neurophysiological and behavioral profiles in adolescence, underscoring the ongoing development of cognitive control mechanisms and cortical plasticity during this sensitive developmental period. Show less
To optimize livestock production of integrated farms, dietary crude fat levels are often increased, making efficient fat utilization crucial. Bile acids are known to improve fat utilization, but their Show more
To optimize livestock production of integrated farms, dietary crude fat levels are often increased, making efficient fat utilization crucial. Bile acids are known to improve fat utilization, but their impact on growth performance and breast muscle development in Zhijiang ducks remains unclear. In this study, a total of 360 twenty-day-old Zhijiang ducks with similar body weights were divided into three groups: the control group (CN) received a basal diet; the high-fat group (FA) received the basal diet plus 1.25 % rapeseed oil; and the high-fat plus bile acids compound (BA) group (FB) received the FA diet supplemented with 250 mg/kg BA for 30 days. Results indicated that the addition of rapeseed oil and BA significantly increased (P < 0.05) average daily gain (ADG) and reduced (P < 0.05) feed conversion ratio (FCR). Slaughter data showed that BA significantly enhanced (P < 0.05) breast muscle weight and percentage while decreasing (P < 0.05) abdominal fat weight. Additionally, BA increased (P < 0.05) the cross-sectional area of breast muscle fibers, total bile acid content, and levels of insulin-like growth factors 1/2 (IGF1/2). Transcriptomic analysis further revealed that BA significantly upregulated (P < 0.05) the levels of PPARα, CPT1α, NR1H4, and CETP in breast muscle. 16S rRNA analysis showed a significant increase (P < 0.05) in the relative abundances of genera Enorma, [Eubacterium nodatum group], Rikenellaceae RC9 gut group, and SP3-e08. Additionally, the Spearman correlation suggested a positive correlation between the genera Olsenella, SP3-e08, Enorma, Rikenellaceae_RC9_gut_group, and [Eubacterium_nodatum_group] with PPARα, CETP, NR1H4, and CPT1α. In contrast, the genera Christensenellaceae_R₇_group and Sutterella exhibited negative correlations with PPARα. These findings provide new insights into the role of BA in promoting growth performance and skeletal muscle development in Zhijiang ducks fed a high-fat diet, with this effect potentially linked to changes in the gut microbiota. Show less
Despite advancements in treatment, coronary artery disease (CAD) remains a significant global health concern. Although lipoprotein(a) [Lp(a)] is recognized as a crucial cardiovascular risk factor asso Show more
Despite advancements in treatment, coronary artery disease (CAD) remains a significant global health concern. Although lipoprotein(a) [Lp(a)] is recognized as a crucial cardiovascular risk factor associated with increased risk, the prognostic value of using Lp(a) levels in patients with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention (PCI) remains debatable. This review aimed to investigate the association between Lp(a) levels and recurrent ischemic events in patients with ACS undergoing PCI. This systematic review included studies with individuals aged ≥18 years diagnosed with ACS who underwent PCI and had Lp(a) measurements. The included studies were sourced from the PubMed database, with a focus on articles published between January 2020 and January 2025. Keywords related to Lp(a) and cardiovascular diseases were used in the search. Data extraction involved a review of titles and abstracts followed by quality assessment using the QUADAS-2 tool. The final analysis included 10 studies with a combined population of 20,896 patients from diverse regions, including Japan, India, Egypt, China, and South Korea. Key findings indicate that elevated Lp(a) levels are significantly associated with adverse cardiovascular outcomes, including myocardial infarction and mortality, both in hospital and during long-term follow-up. This review highlights Lp(a) as a critical biomarker for predicting recurrent cardiovascular events in ACS patients post-PCI. The consistent correlation between elevated Lp(a) levels and adverse outcomes underscores the necessity of routine monitoring and targeted management of Lp(a) to mitigate residual cardiovascular risk. Show less
Acetylcholinesterase (AChE) inhibitors are crucial for the symptomatic management of Alzheimer's disease (AD), with natural products-particularly botanical sources like Yellow Gastrodia elata (YGE)-se Show more
Acetylcholinesterase (AChE) inhibitors are crucial for the symptomatic management of Alzheimer's disease (AD), with natural products-particularly botanical sources like Yellow Gastrodia elata (YGE)-serving as promising reservoirs of such inhibitors. Nevertheless, comprehensive screening and mechanistic characterization of their inhibitory potential remain limited. This study sought to identify potent AChE inhibitors from YGE, investigate their mechanisms of action, and assess their therapeutic prospects for AD. Methodologically, an integrated approach was employed, combining ultrafiltration-liquid chromatography (UF-LC) for rapid inhibitor screening, molecular docking and dynamics simulations for mechanistic insight, two-stage high-speed countercurrent chromatography for compound isolation, enzyme kinetics to delineate inhibition modalities, and network pharmacology to uncover relevant AD-related targets. The findings identified seven active constituents with notable AChE inhibition, among which parishins A and G were obtained at high purity (98.26% and 97.26%, respectively) and exhibited mixed-type inhibition with low IC Show less
The intricate involvement of the histaminergic system, encompassing histamine and histamine receptors, in the progression of diverse neoplasias has attracted considerable scrutiny. Histamine receptor Show more
The intricate involvement of the histaminergic system, encompassing histamine and histamine receptors, in the progression of diverse neoplasias has attracted considerable scrutiny. Histamine receptor H1 (HRH1) was reported to be overexpressed in several cancer types, but its specific functional implications in oral squamous cell carcinoma (OSCC) predominantly remain unexplored. Our findings indicate that dysregulated high levels of HRH1 were correlated with lymph node (LN) metastasis and poor prognoses in OSCC patients. We identified a disintegrin and metalloprotease 9 (ADAM9) as a critical downstream target of HRH1, promoting protumorigenic and prometastatic characteristics both in vitro and in vivo. Molecular investigations revealed that the cyclic increase in the HRH1-ADAM9-Snail/Slug axis promoted progression of the epithelial-to-mesenchymal transition (EMT). Clinical analyses demonstrated significant correlations of HRH1 expression with ADAM9 and with EMT-related markers, with elevated ADAM9 also associated with LN metastasis in OSCC patients. Regarding therapeutic aspects, we discovered that activated STAT3 acts as a compensatory pathway for the long-term HRH1 signaling blockade in OSCC cells. Combining inhibition of HRH1 and STAT3 using their respective inhibitors or short hairpin (sh)RNAs enhanced the tumor-suppressive effects compared to HRH1 inhibition/depletion alone in OSCC cells and a xenograft model. In summary, HRH1 has emerged as a valuable biomarker for predicting OSCC progression, and combined targeting of HRH1 and STAT3 may represent a promising strategy for preventing OSCC progression. Show less
Previous experiments have demonstrated that BGM0504, a GLP-1R/GIPR dual agonist drug by molecular dynamics-guided optimization, had enhanced agonistic activity compared to tirzepatide. This study aims Show more
Previous experiments have demonstrated that BGM0504, a GLP-1R/GIPR dual agonist drug by molecular dynamics-guided optimization, had enhanced agonistic activity compared to tirzepatide. This study aims to investigate its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in Chinese healthy volunteers. A randomized, double-blind, placebo-controlled and dose-escalation Phase I study was conducted as follows: a single dose (2.5 mg) and once-weekly administration for 2 weeks to reach target doses (5, 10 and 15 mg) by titration. A total of 40 volunteers received at least one dose of BGM0504 or placebo. The PK profile of BGM0504 was investigated over a wide dose range and supported once-weekly administration. It was observed that C BGM0504 was generally safe and well tolerated with favourable PK profile and potential role in weight loss was also confirmed. These findings support subsequent development of BGM0504 for type 2 diabetes mellitus (T2DM) and obesity. Show less
Adenomyosis (AM), a gynecological disorder that severely affects female reproductive health. AM-associated macrophage (AAM) polarization-induced epithelial-mesenchymal transition (EMT) is a key driver Show more
Adenomyosis (AM), a gynecological disorder that severely affects female reproductive health. AM-associated macrophage (AAM) polarization-induced epithelial-mesenchymal transition (EMT) is a key driver of AM progression. In this study, we investigated the role and underlying mechanisms of endometrial mesenchymal stem cell (eMSC)-derived exosomes in regulating AAM polarization and the subsequent EMT of endometrial epithelial cells (EECs). In vitro coculture studies revealed that AM eutopic eMSCs markedly induced M2 macrophage polarization via exosomes and promoted EMT of EECs. Differentially expressed microRNAs (DE-miRNAs) between exosomes derived from normal eMSCs (N-eMSCs) and AM eutopic eMSCs (A-eMSCs) were identified using miRNA sequencing and miR-4669 was found to be the most significantly upregulated miRNA. Internalization of exosomal miR-4669 by macrophages induced their polarization toward the M2 phenotype and promoted the EMT of EECs. Mechanistic analysis using luciferase assay, mRNA sequencing, and rescue experiments revealed that miR-4669 induced M2 macrophage polarization via downregulation of DUSP6 and activation of MAPK/ERK signaling. The polarized M2 macrophages promoted the EMT of ISK cells via TGF-β1 secretion. In an AM xenograft mouse model, miR-4669 depletion inhibited AM progression by targeting the DUSP6/ERK1/2 pathway in macrophages. Overall, AM A-eMSC-derived exosomal miR-4669 facilitates M2 macrophage polarization by targeting the DUSP6/ERK signaling pathway, thereby promoting EMT of EECs via TGF-β1 secretion. These findings open avenues for developing novel preventive and therapeutic strategies for AM. Show less
Amyloid deposition of human islet amyloid polypeptide (hIAPP) is closely linked to the pathogenesis and progression of type 2 diabetes mellitus (T2DM). Developing effective inhibitors to suppress hIAP Show more
Amyloid deposition of human islet amyloid polypeptide (hIAPP) is closely linked to the pathogenesis and progression of type 2 diabetes mellitus (T2DM). Developing effective inhibitors to suppress hIAPP aggregation holds significant therapeutic potential for the prevention and treatment of T2DM. Recent researches indicate that both heme and lithospermic acid (LPA) can inhibit hIAPP aggregation. However, heme is prone to induce protein damage under oxidative stress, while LPA exhibits limited inhibitory efficacy despite its antioxidant properties. To overcome these limitations, we aimed to develop a dual-component inhibitor comprising heme and LPA. thioflavin T (ThT) fluorescence, transmission electron microscopy (TEM), circular dichroism (CD) and gel electrophoresis were combined to observe the inhibitory efficacy of heme-LPA co-formulation on hIAPP aggregation. The results demonstrate that LPA and heme can synergistically inhibit hIAPP aggregation. The inhibitory effect of heme-LPA co-formulation on hIAPP aggregation is significantly stronger than that of either component alone. The heme-LPA not only prevents the complete conversion of hIAPP into β-sheet fibrillar structures but also maintains its active monomeric conformation for extended periods. Furthermore, peroxidase activity assays revealed that the presence of LPA significantly reduces the peroxidase activity of heme in a concentration-dependent manner and attenuates peptide nitration damage under H₂O₂-NO₂ Show less
To identify the connections between lipid biomarkers and the anti-VEGF therapy response in patients with neovascular age-related macular degeneration (nAMD). A bidirectional and multivariable Mendelia Show more
To identify the connections between lipid biomarkers and the anti-VEGF therapy response in patients with neovascular age-related macular degeneration (nAMD). A bidirectional and multivariable Mendelian randomization study. The summary statistics for anti-VEGF nAMD treatment response included a total of 128 responders, 51 nonresponders, and 6 908 005 genetic variants available for analysis. The sample size of lipid biomarkers is 441 016 and 12 321 875 genetic variants available for analysis. Two-sample Mendelian randomization (MR) method was conducted to exhaustively appraise the causalities among 13 lipid biomarkers and the risk of different anti-VEGF treatment responses (including visual acuity [VA] and central retinal thickness [CRT]) for nAMD subtypes. Thirteen lipid biomarkers, VA, and CRT. A positive causal relationship was identified between triglycerides (TGs), apolipoproteins (Apos) E2, ApoE3, total cholesterol (TC), and VA response to anti-VEGF therapy in patients with nAMD, as confirmed by MR-Egger, weighted median, and weighted mode models. The MR-Egger model yielded statistically significant results for TC, ApoA-I, ApoB, and ApoA-V in relation to the CRT response to anti-VEGF treatment in patients with nAMD. In the reverse MR, the MR-Egger model identified significant causal relationships between ApoA-I, low-density lipoprotein cholesterol (LDL-c), ApoE3, and ApoF and the VA response. However, this was not the case in the weighted median and weighted mode models. In the MR-Egger model, ApoB, LDL-c, ApoE3, and ApoM were identified as significantly influencing the CRT response. In the multisample MR analysis, TC, high-density lipoprotein cholesterol, LDL-c, and TG were found to be causally related to VA response, and TC was also identified as being causally related to the CRT response to anti-VEGF therapy in patients with nAMD. This MR study suggests unidirectional causality between TG and ApoE3 and the response to anti-VEGF treatment in patients with nAMD. The author(s) have no proprietary or commercial interest in any materials discussed in this article. 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 contr Show more
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
Ovarian cancer (OC), a common fatal malignancy in women, has a poor prognosis. RNA modifications are associated with the development of OC. In this study, we aimed to identify and verify RNA modificat Show more
Ovarian cancer (OC), a common fatal malignancy in women, has a poor prognosis. RNA modifications are associated with the development of OC. In this study, we aimed to identify and verify RNA modifications-related prognostic genes in OC by integrating bulk and single-cell RNA sequencing (scRNA-seq) data. Transcriptome data came from public databases and RNA modifications-related genes (RMRGs) were obtained from literature. Candidate genes were identified by intersecting RMRGs with differentially expressed genes (DEGs) in OC patients. Prognostic genes were gained via machine learning techniques, particularly LASSO regression. A risk model was built to predict the prognosis. OC patients were divided into high-risk and low-risk groups according to risk score. Subsequent analyses covered enrichment analysis, immune microenvironment, mutation analysis, and chemotherapeutic drug sensitivity. In addition, scRNA-seq data was assessed for key cells and gene expression in them. Finally, RT-qPCR was applied to identify the expression of prognostic genes. We constructed an RNA modifications-related prognostic signature that can effectively predict clinical outcomes and therapeutic responses in patients with OC. Show less
Cancer is one of the major diseases threatening human health in the world. According to the latest global cancer statistics from the International Agency for Research on Cancer (IARC), there were appr Show more
Cancer is one of the major diseases threatening human health in the world. According to the latest global cancer statistics from the International Agency for Research on Cancer (IARC), there were approximately 20 million new cancer cases and 10 million cancer deaths worldwide. Amidst this global health concern, branched chain amino acids have emerged as key players, playing an important role in the occurrence and development of cancer. In certain malignancies like colorectal cancer, the average level of BCAA in tumor tissues is twice that in normal tissues. BCAA metabolism is intricately associated with the progression of multiple tumors and is modulated by diverse enzymes, including BCAT, BCKDH, and BCKDK. The metabolism of BCAA involves multiple enzymes and biochemical processes via signaling pathways such as PI3K/AKT/mTOR and AMPK/mTOR, etc. In addition, mTOR inhibitors show potential value in cancer treatment by regulating the metabolism and signaling pathways of tumor cells, which provides a new direction for anticancer efforts. Simultaneously, BCAAs are closely associated with tumor immunity, including NK cells, CD4 Show less
Ischemic stroke (IS) remains a leading cause of mortality and disability, with limited therapeutic options due to poor drug delivery to ischemic lesions. To address this challenge, an engineered Salmo Show more
Ischemic stroke (IS) remains a leading cause of mortality and disability, with limited therapeutic options due to poor drug delivery to ischemic lesions. To address this challenge, an engineered Salmonella based therapeutic method for targeted drug delivery and long-term treatment is herein designed to mitigate ischemic damage. We engineered an attenuated luminescent Salmonella typhimurium (S.t -ΔpG) strain with an L-arabinose-inducible pBAD system to secrete bioactive FGF21. C57BL/6 mice were used to to measure neuron apoptosis and the activity of immune cells following IS induction plus S.t-ΔpG injection. Bioluminescence imaging was applied for bacterial colonization. ELISA and glucose uptake assays were performed to detect FGF21 secretion and the bioactivity. Neurological tests, TTC staining, and TUNEL labeling were used to assess the therapeutic effects of barterially secreted FGF21. Immunofluorescence assay of FGF21/FGFR1 dominant pathway was explored to investigate neuroprotective mechanism, while IBA-1 staining, CD3/CD68 immunostaining, cytokine profiling, and hepatorenal histopathology were detected to evaluate biosecurity. S.t-ΔpG Our study presents a novel, Salmonella - based platform for targeted and sustained FGF21 delivery, offering a promising therapeutic strategy for ischemic stroke with robust efficacy and minimal systemic toxicity. Show less
Sepsis arises from a dysregulated host response to infection, leading to multiorgan inflammatory injury. Early diagnosis and treatment necessitate the identification of reliable immune biomarkers. Thi Show more
Sepsis arises from a dysregulated host response to infection, leading to multiorgan inflammatory injury. Early diagnosis and treatment necessitate the identification of reliable immune biomarkers. This study investigated the relationship between aging, immunity, and sepsis by analyzing six human aging-related gene sets (656 genes). We identified 16 aging-related differentially expressed genes (DEGs) in sepsis. Among these, ATP11B, RBBP7, DOCK10, and NUP160 demonstrated the strongest connectivity with other genes and exhibited significant predictive power. Functional enrichment analysis (GO and KEGG) revealed distinct signaling pathway profiles between high-risk and low-risk sepsis groups (stratified based on risk scores). These dysregulated pathways, associated with multiple immune cells, were primarily linked to transcriptional dysregulation in cellular processes and cancer-related pathways. Experimental validation assays corroborated the roles of ATP11B and RBBP7. Collectively, our bioinformatic and experimental findings indicate that ATP11B, RBBP7, DOCK10, and NUP160 are implicated in the pathogenesis and progression of sepsis. But their potential for sepsis biomarkers still requires further verification. Show less
G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery and development, yet the design of protein agonists and antagonists has been challenging as Show more
G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery and development, yet the design of protein agonists and antagonists has been challenging as GPCRs are integral membrane proteins and conformationally dynamic. Here we describe computational Show less
Yunqi Xie, Haochen Wang, Yajie Zhang+5 more · 2025 · Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association · Elsevier · added 2026-04-24
Smoking is harmful to health. Cigarette smoke (CS) contains a variety of toxic substances. Studies have found that nicotine, tar, polycyclic aromatic hydrocarbons, etc. in CS can pass through the bloo Show more
Smoking is harmful to health. Cigarette smoke (CS) contains a variety of toxic substances. Studies have found that nicotine, tar, polycyclic aromatic hydrocarbons, etc. in CS can pass through the blood-brain barrier and enter the brain to exert their effects. Moreover, some existing studies have pointed out that CS exposure is closely related to the accelerated pathology of Alzheimer's disease (AD). Transgenic mice with the five familial AD mutations (5xFAD), which are 1-month-old, were used for chronic CS exposure for 100 days. Subsequently, cognitive function and behavioral changes were evaluated through morris water maze and new object recognition tests. The acceleration of pathological changes due to CS exposure was assessed by HE, Tunel and Aβ immunohistochemical staining. Differential expression proteins and metabolites were screened through hippocampal proteomics and metabolomics analyses. Finally, the expression levels of key proteins were verified by Western blot. Compared with unexposed 5xFAD mice, the behavioral results of mice showed that FAD mice after CS exposure exhibited poorer cognitive abilities, with longer latencies in the Morris water maze, and decreased time spent and entries in the target quadrant. The results of pathological sections indicated that the total nuclei density in the DG and CA3 regions of the hippocampus of 5xFAD mice decreased significantly after chronic CS exposure, the number of TUNEL-positive cells increased, and the expression of Aβ42 increased. Multi - omics analysis revealed that CS exposure up - regulated the expression of 46 proteins and down - regulated the expression of 80 proteins in the hippocampus of 5xFAD mice, and caused changes in 92 metabolites. Analysis of the correlation between differential proteins and differential metabolites revealed six key cross-node proteins: Kng1, Hbb-b1, Fabp3, Apoa1, Ilk, and Apoa4. CS exposure may accelerate pathological changes and cognitive impairment in 5xFAD mice by affecting energy metabolism through the PPAR signaling pathway. Show less
Patients with schizophrenia (SCZ) face multiple health challenges due to the complication of chronic diseases and psychiatric disorders. Among these, cardiovascular comorbidities are the leading cause Show more
Patients with schizophrenia (SCZ) face multiple health challenges due to the complication of chronic diseases and psychiatric disorders. Among these, cardiovascular comorbidities are the leading cause of their life expectancy being 15-20 years shorter than that of the general population. Identifying comorbidity patterns and uncovering differences in immune and metabolic function are crucial steps toward improving prevention and management strategies. A retrospective cross-sectional study was conducted using electronic medical records of inpatients discharged between 2015 and 2024 from a municipal psychiatric hospital in China. The study included patients diagnosed with Schizophrenia, Schizotypal, and Delusional Disorders (SSDs) (ICD-10: F20-F29). Comorbidity patterns were identified through latent class analysis (LCA) based on the 20 most common comorbid conditions among SSD patients. To investigate differences in peripheral blood metabolic and immune function, linear regression or generalized linear models were applied to 44 laboratory test indicators collected during the acute episode. The Benjamini-Hochberg method was used for p-value correction, and the false discovery rate (FDR) was calculated, with statistical significance set at FDR < 0.05. Among 3,697 inpatients with SSDs, four distinct comorbidity clusters were identified: SSDs only (Class 1), High-Risk Metabolic Multisystem Disorders (Class 2, n = 39), Low-Risk Metabolic Multisystem Disorders (Class 3, n = 573), and Sleep Disorders (Class 4, n = 205). Compared to Class 1, Class 2 exhibited significantly elevated levels of apolipoprotein A (ApoA; β = 90.62), apolipoprotein B (ApoB; β = 0.181), mean platelet volume (MPV; β = 0.994), red cell distribution width-coefficient of variation (RDW-CV; β = 1.182), antistreptolysin O (ASO; β = 276.80), and absolute lymphocyte count (ALC; β = 0.306), along with reduced apolipoprotein AI (ApoAI; β = -0.173) and hematocrit (HCT; β = -35.13). Class 3 showed moderate increases in low-density lipoprotein cholesterol (LDL-C; β = 0.113), MPV (β = 0.267), white blood cell count (WBC; β = 0.476), and absolute neutrophil count (ANC; β = 0.272), with decreased HCT (β = -9.81). Class 4 was characterized by elevated aggregate index of systemic inflammation (AISI; β = 81.07), neutrophil-to-lymphocyte ratio (NLR; β = 0.465), and systemic inflammation response index (SIRI; β = 0.346), indicating a heightened inflammatory state. The comorbidity patterns of patients with SCZ can be distinctly classified. During the acute episode, those with comorbid metabolic disorders exhibit a higher risk of cardiovascular diseases and immune system abnormalities, while patients with comorbid sleep disorders present a pronounced systemic inflammatory state and immune dysfunction. This study provides a basis for the chronic disease management and anti-inflammatory treatment, while also offering objective biomarker insights for transdiagnostic research. Show less
Multi-target peptide therapeutics targeting glucagon receptor (GCGR), glucagon-like peptide-1 receptor (GLP1R), and glucose-dependent insulinotropic polypeptide receptor (GIPR) represent a promising a Show more
Multi-target peptide therapeutics targeting glucagon receptor (GCGR), glucagon-like peptide-1 receptor (GLP1R), and glucose-dependent insulinotropic polypeptide receptor (GIPR) represent a promising approach for treating diabetes and obesity. Triple agonist peptides demonstrate promising therapeutic potential compared to single-target approaches, yet rational design remains computationally challenging due to complex sequence-structure activity relationships. Existing methods, primarily based on convolutional neural networks, impose limitations including fixed sequence lengths and inadequate representation of molecular topology. Graph Attention Networks (GAT) offer advantages in capturing molecular structures and variable-length peptide sequences while providing interpretable insights into receptor-specific binding determinants. A dataset of 234 peptide sequences with experimentally determined binding affinities was compiled from multiple sources. Peptides were represented as molecular graphs with seven-dimensional node features encoding physicochemical properties and positional information. The GAT architecture employed a shared encoder with task-specific prediction heads, implementing transfer learning to address limited GIPR training data. Performance was evaluated using 5-fold cross-validation and independent validation on 24 literature-derived sequences. A genetic algorithm framework was developed for peptide sequence optimization, incorporating multi objective fitness evaluation based on predicted binding affinity, biological plausibility, and sequence novelty. Cross-validation demonstrated robust GAT performance across all receptors, with GCGR achieving high accuracy (AUC ROC: 0.915 ± 0.050), followed by GLP1R (AUC-ROC: 0.853 ± 0.059), and GIPR showing acceptable performance despite limited data (AUC-ROC: 0.907 ± 0.083). Comparative analysis revealed receptor-specific advantages: GAT significantly outperformed CNN for GCGR prediction (RMSE: 0.942 vs. 1.209, p = 0.0013), while CNN maintained superior GLP1R performance (RMSE: 0.552 vs. 0.723). Genetic algorithm optimization measurable improvement over baseline, with 4.0% fitness Enhancement and generation of 20 candidates exhibiting mean binding probabilities exceeding 0.5 across all targets. The GAT-based framework provides a computational approach in computational peptide design, demonstrating receptor-specific advantages and robust optimization capabilities. Genetic algorithm optimization enables systematic exploration of sequence space within existing agonist scaffolds while maintaining biological constraints. This approach provides a rational framework for prioritizing experimental validation efforts in triple agonist development. Show less
Fish oil supplements (FOS) are known to alter circulating levels of polyunsaturated fatty acids (PUFAs) but in a heterogeneous manner across individuals. These varied responses may result from unident Show more
Fish oil supplements (FOS) are known to alter circulating levels of polyunsaturated fatty acids (PUFAs) but in a heterogeneous manner across individuals. These varied responses may result from unidentified gene-FOS interactions. To identify genetic factors that interact with FOS to alter the circulating levels of PUFAs, we performed a multi-level genome-wide interaction study (GWIS) of FOS on 14 plasma measurements in 200,060 unrelated European-ancestry individuals from the UK Biobank. From our single-variant tests, we identified genome-wide significant interacting SNPs (p < 5 × 10 Show less
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases, with a range of manifestations, such as hepatic steatosis. Our previous study showed that Kaili Sour Soup Show more
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases, with a range of manifestations, such as hepatic steatosis. Our previous study showed that Kaili Sour Soup (KSS) significantly attenuated hepatic steatosis in rats. This study explored the main components of KSS and the mechanisms by which it exerts its protective effects against NAFLD. Twenty-four 6-week-old male Sprague-Dowley (SD) rats were randomly assigned to three treatments: feeding a normal standard diet, a high-fat diet, or a high-fat diet plus gavage KSS. The effects of KSS treatment on hepatic lipid accumulation were assessed using biochemical, histological, and molecular experiments. The amounts of KSS ingredients were measured using biochemical assays. Network pharmacology analyses were performed to identify the hub genes of KSS targets and enriched pathways. CCK-8 assay was used to determine the effect of free fatty acids (FFA), lycopene, and estrogen on HepG2 viability. Quantitative Real-Time polymerase chain reaction (qRT-PCR) and Western blot assays were performed to determine the effect of KSS or lycopene on estrogen signaling and expression of lipid metabolism-related molecules. Statistical analyses were performed using GraphPad Prism and SPSS. KSS alleviated fat deposition in rat liver tissue and affected the expression of hepatic lipid synthesis, catabolism, and oxidative molecules. Lycopene was identified as the ingredient with the highest amount in KSS. Network pharmacology analyses showed that the hub genes were enriched in the estrogen signaling pathway. Cellular experiments showed that lycopene increased the expression of Estrogen Receptor α (ERα), Carnitine palmitoyltransferase 1 A ( KSS ameliorated abnormal lipid metabolism in patients with NAFLD. Lycopene was the major component of KSS, and it affected estrogen signaling and the expression of lipid metabolism molecules. In short, both KSS and LYC could change lipid metabolism by lowering lipid accumulation and raising lipolysis. Show less