Acute respiratory distress syndrome (ARDS) is a common respiratory emergency, but current clinical treatment remains at the level of symptomatic support and there is a lack of effective targeted treat Show more
Acute respiratory distress syndrome (ARDS) is a common respiratory emergency, but current clinical treatment remains at the level of symptomatic support and there is a lack of effective targeted treatment measures. Our previous study confirmed that inhalation of hydrogen gas can reduce the acute lung injury of ARDS, but the application of hydrogen has flammable and explosive safety concerns. Drinking hydrogen-rich liquid or inhaling hydrogen gas has been shown to play an important role in scavenging reactive oxygen species and maintaining mitochondrial quality control balance, thus improving ARDS in patients and animal models. Coral calcium hydrogenation (CCH) is a new solid molecular hydrogen carrier prepared from coral calcium (CC). Whether and how CCH affects acute lung injury in ARDS remains unstudied. In this study, we observed the therapeutic effect of CCH on lipopolysaccharide (LPS) induced acute lung injury in ARDS mice. The survival rate of mice treated with CCH and hydrogen inhalation was found to be comparable, demonstrating a significant improvement compared to the untreated ARDS model group. CCH treatment significantly reduced pulmonary hemorrhage and edema, and improved pulmonary function and local microcirculation in ARDS mice. CCH promoted mitochondrial peripheral division in the early course of ARDS by activating mitochondrial thioredoxin 2 (Trx2), improved lung mitochondrial dysfunction induced by LPS, and reduced oxidative stress damage. The results indicate that CCH is a highly efficient hydrogen-rich agent that can attenuate acute lung injury of ARDS by improving the mitochondrial function through Trx2 activation. Show less
Understanding the adaptive evolution of brain function in extreme environments remains a central challenge in evolutionary biology. This study investigates the molecular mechanisms underlying cave ada Show more
Understanding the adaptive evolution of brain function in extreme environments remains a central challenge in evolutionary biology. This study investigates the molecular mechanisms underlying cave adaptation by comparing brain transcriptomes of sympatric cave-dwelling ( Show less
Poly(A) binding protein cytoplasmic 4 (PABPC4) has been regarded as a prognostic marker in many malignancies. In this study, we evaluated PABPC4 expression at both messenger ribonucleic acid (mRNA) an Show more
Poly(A) binding protein cytoplasmic 4 (PABPC4) has been regarded as a prognostic marker in many malignancies. In this study, we evaluated PABPC4 expression at both messenger ribonucleic acid (mRNA) and protein levels. The prognostic value of PABPC4 in patients with prostate cancer (PCa) was also investigated. The Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) database, our analysis of Chinese Prostate Cancer Genome and Epigenome Atlas (CPGEA), and 65 pairs of ribonucleic acid (RNA) sequencing data from our center were employed to detect the expression of PABPC4 in PCa tissues. Tissue microarrays (TMAs) were utilized to detect the expression of the PABPC4 protein, and survival analysis as well as risk factor analysis were conducted. In the 65 pairs of sequencing data, the expression of PABPC4 in tumor tissues was significantly higher than that in paired adjacent tissues (P<0.001), and its expression also presented significant differences among different Gleason groups (P=0.041). In the CPGEA data, the expression of PABPC4 in tumor tissues was significantly higher than that in control tissues (P<0.001), and the expression of PABPC4 in M1 patients was higher than that in M0 patients, although no significant statistical difference was shown (P=0.051). In the TCGA data, the expression of PABPC4 in tumor tissues was significantly higher than that in control tissues (P<0.001). The expression of pT3/4 (pathological tumor stage 3 and pathological tumor stage 4) in high-stage tumor tissues was significantly higher than that in low-stage tumor tissues (pT2) (P=0.02), the expression of pT3/4 in GSE21034 and GSE32571 tumor tissues was significantly higher than that in control tissues (P<0.001), and the expression of pT3/4 in primary tumor tissues was higher than that in metastatic tissues in GSE6752 (P<0.001). The TCGA data revealed that patients with high PABPC4 expression had poorer overall survival (OS) than those with low PABPC4 expression (P=0.04), and the TMA data indicated that patients with high PABPC4 expression had a poor prognosis (P=0.004). Our study demonstrated that PABPC4 was overexpressed at mRNA and protein levels in PCa. We found that patients with high PABPC4 expression had a shorter biochemical recurrence (BCR)-free survival and OS, showing its value as a prognostic biomarker in patients with PCa. Show less
To quantify international variations in lipid-lowering therapies (LLT) use among patients with coronary heart disease (CHD) and attainment of European guideline-recommended lipid goals. INTERASPIRE is Show more
To quantify international variations in lipid-lowering therapies (LLT) use among patients with coronary heart disease (CHD) and attainment of European guideline-recommended lipid goals. INTERASPIRE is an observational study (2020-23) covering 14 countries from all WHO regions. Patients (18-79 years) hospitalized in the preceding 6-36 months with CHD were invited for standardized interviews and examination, with central laboratory analyses for low-density lipoprotein cholesterol (LDL-C), non-HDL-C, and apolipoprotein B (apoB). Valid lipid data meeting quality control standards were available from 13 countries. Lipid goals followed the 2019 guidelines of the European Atherosclerosis Society and the European Society of Cardiology: LDL-C < 1.4 mmol/L, non-HDL-C < 2.2 mmol/L, and apoB <65 mg/dL.Among 4061 patients (78.8% male, mean age 60.3 years), between index event and interview, 66.3% had no change in treatment intensity. LLT use at interview was largely statin monotherapy: 49.6% high-intensity (inter-country range 5.3%-77.3%) and 24.1% low/moderate-intensity (inter-country range 5.1%-70.1%). Otherwise, 12.2% (inter-country range 0.2%-41.1%) were on combination therapy, and 12.7% on no LLT (inter-country range 3.5%-36.7%). Goal attainment for LDL-C was 17.5%. Corresponding non-HDL-C and apoB goals were achieved by 29.9% and 29.2%, respectively. Higher-income countries (defined by the World Bank's 2024-25 classification of income levels) did better in goal attainment than lower-middle-income countries. In this international study, contemporary lipid goals were not achieved in most CHD patients, with lower-middle-income countries having the worst goal attainment. Contributory factors include absence of any LLT use, low use of combinations and a failure to up-titrate LLT to achieve guideline targets. Show less
Haixiong Tang, Lin Fu, Changyun Yang+9 more · 2025 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
Cadherin-11 (CDH11), a specialized cell-cell adhesion protein, plays an essential role in tissue injury, inflammation and repair. This study aimed to investigate the role of CDH11 in severe asthma. Br Show more
Cadherin-11 (CDH11), a specialized cell-cell adhesion protein, plays an essential role in tissue injury, inflammation and repair. This study aimed to investigate the role of CDH11 in severe asthma. Bronchial biopsy specimens were obtained from healthy subjects and patients with severe asthma. Two murine models of severe asthma were established using either TDI (toluene diisocyanate) or OVA (ovalbumin)/CFA (complete Freund's adjuvants). A selective CDH11 antagonist SD133 (100 mg/kg) was given to allergen-exposed mice after airway challenge. The effects of recombinant CDH11 were also tested in vivo, and FGFR1 inhibition was used to explore a possible mechanism for CDH11-induced inflammatory responses in the lung. We detected upregulated expression of CDH11 in the airway mucosa of severe asthma patients when compared with the healthy control. In the OVA/CFA-induced model, though CDH11 expression in the lung remained unchanged, pharmacological antagonism of CDH11 with SD133 dramatically decreased airway neutrophil accumulation, as well as IL-6 production, but had no effect on eosinophilic infiltration, type 2 inflammation (IL-4 and IL-5) nor airway hyperresponsiveness. In the TDI model, pulmonary CDH11 expression was upregulated. Treatment with SD133 inhibited TDI-induced airway hyperresponsiveness and neutrophilic inflammation, decreased IL-6 and TNF-α production, with no effect on airway eosinophil counts and type 2 inflammatory cytokines. In addition, intratracheal instillation of recombinant CDH11 led to neutrophil recruitment in the lungs of mice, which could be attenuated by inhibition of FGFR1 signaling. CDH11 contributes to airway neutrophilic inflammation in severe asthma through the FGFR1 pathway. Show less
Despite the known impacts of weaning on animal health, the underlying molecular mechanisms remain unclear, particularly how psychological and nutritional stress differentially affect gut health and im Show more
Despite the known impacts of weaning on animal health, the underlying molecular mechanisms remain unclear, particularly how psychological and nutritional stress differentially affect gut health and immune function over time. This study hypothesized that early weaning exerts distinct short- and long-term effects on lamb stress physiology, immunity, and gut health, mediated by specific molecular pathways. Twelve pairs of full-sibling male Hu sheep lambs were assigned to control (CON) or early-weaned (EW) groups. Plasma stress/immune markers were dynamically monitored, and intestinal morphology, antioxidant capacity, apoptosis, and transcriptomic profiles were analyzed at 5 and 28 days post-weaning. Early weaning triggered transient psychological stress, elevating hypothalamic-pituitary-adrenal (HPA) axis hormones (cortisol, catecholamines) and inflammatory cytokines (TNF-α) within 1 day ( Show less
Based on the Caco-2 cell heat stress model, the study explored the heat stress preventive regulatory mechanisms of key polyphenol fractions in mung bean by metabolomics and transcriptomics association Show more
Based on the Caco-2 cell heat stress model, the study explored the heat stress preventive regulatory mechanisms of key polyphenol fractions in mung bean by metabolomics and transcriptomics association analysis. Results Mung bean polyphenol intervention before heat stress significantly reduced the elevated expression level of heat shock protein 70 (HSP70) caused by 39 °C temperature. At the metabolic level, mung bean polyphenols could play a role in heat stress regulation by alleviating oxidative stress damage. At the gene level, mung bean polyphenols showed regulation of cell proliferation, differentiation, and DNA damage, with DUSP6 and NEURL3 as key regulatory genes. The correlation analysis showed that nucleotide metabolism, and oxidative phosphorylation metabolism were the key pathways in the regulation of mung bean polyphenols by heat stress. Then mung bean polyphenols can exert heat stress preventive activity through the regulation of cellular oxidative damage and energy metabolism. This study provides a good idea for the research and development of dietary intervention products for heat stress. Show less
Colorectal cancer (CRC) metastasis remains a major cause of mortality, driven by epithelial-to-mesenchymal transition (EMT) and invasion. Programmed cell death 4 (Pdcd4), a tumor suppressor, is known Show more
Colorectal cancer (CRC) metastasis remains a major cause of mortality, driven by epithelial-to-mesenchymal transition (EMT) and invasion. Programmed cell death 4 (Pdcd4), a tumor suppressor, is known to inhibit translation via interaction with eukaryotic initiation factor 4A (eIF4A). Previous studies have established that Pdcd4 suppresses stress-activated protein kinase 1-interacting protein 1 (Sin1) translation through the mTORC2-Akt axis, thereby downregulating Snail expression and EMT in CRC cells. However, whether Pdcd4 directly regulates Slug, another critical EMT transcription factor, remains unexplored. PDCD4 shRNA and SLUG siRNA were used to knock down Pdcd4 and Slug in colorectal cancer cells, respectively. The sucrose gradient fractionation was performed to determine SLUG translation. A luciferase reporter assay was used to determine the role of the SLUG 5' untranslated region (5'UTR) on Pdcd4 inhibition. The effect of Slug on promoting invasion was determined by Matrigel invasion assays. Knockdown of Pdcd4 in colorectal cancer cells increased Slug protein levels without altering SLUG mRNA abundance. Sucrose gradient fractionation revealed that Pdcd4 knockdown elevated the proportion of SLUG mRNA in polysome fractions, demonstrating Pdcd4-mediated suppression of SLUG translation. To validate the mechanism, the SLUG 5'UTR was cloned and fused to a luciferase reporter and named SLUG-5'UTR-Luc. Pdcd4 knockdown markedly enhanced SLUG-5'UTR-Luc activity; whereas, ectopic Pdcd4 expression suppressed it, indicating that the SLUG 5'UTR is critical for Pdcd4-mediated translational repression. Treatment with the eIF4A inhibitor silvestrol substantially reduced Slug protein levels and SLUG-5'UTR-Luc activity. In addition, Pdcd4 overexpression decreased Slug protein abundance and restored E-cadherin expression. Notably, Slug knockdown in Pdcd4-deficient cells rescued E-cadherin expression and abrogated the invasive phenotype. These findings suggest that up-regulation of Slug translation by Pdcd4 knockdown contributes to enhanced invasion. Pdcd4 suppresses colorectal cancer invasion by translationally downregulating Slug expression. Show less
Xiaolei Song, Chenchen Wang, Qin Ding+8 more · 2025 · Journal of controlled release : official journal of the Controlled Release Society · Elsevier · added 2026-04-24
Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder. The vicious circle between amyloid-β peptide (Aβ) overgeneration and microglial dysfunction is an important path Show more
Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder. The vicious circle between amyloid-β peptide (Aβ) overgeneration and microglial dysfunction is an important pathological event that promotes AD progression. However, therapeutic strategies toward only Aβ or microglial modulation still have many problems. Herein, inspired by the Aβ transportation, an Aβ-derived peptide (CKLVFFAED) engineered biomimetic nanodelivery system (MK@PC-R NPs) is reported for realizing BBB penetration and reprogram neuron and microglia in AD lesion sites. This hollow mesoporous Prussian blue-based MK@PC-R NPs carrying curcumin and miRNA-124 can down-regulate β secretase expression, thereby inhibiting Aβ production and reducing Aβ-induced neurotoxicity. Meanwhile, MK@PC-R NPs with excellent antioxidant and anti-inflammatory properties could normalize the microglial phenotype and promote Aβ degradation, providing neuroprotection. As expected, after treatment with MK@PC-R NPs, the Aβ burdens, neuron damages, neuroinflammation, and memory deficits of transgenic AD mice (APP/PS1 mice) are significantly attenuated. Overall, this biomimetic nanodelivery system with anti-Aβ and anti-inflammatory properties provides a promising strategy for the multi-target therapy of early AD. Show less
Highly effective therapies to reduce triglyceride levels are lacking. Olezarsen is an In this phase 3, international, double-blind, randomized, placebo-controlled trial, we enrolled patients with mode Show more
Highly effective therapies to reduce triglyceride levels are lacking. Olezarsen is an In this phase 3, international, double-blind, randomized, placebo-controlled trial, we enrolled patients with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) and randomly assigned them in a 1:3 ratio to a 50-mg or 80-mg cohort. The patients were then randomly assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the least-squares mean percent change in triglyceride level from baseline to 6 months among the patients with moderate hypertriglyceridemia, reported as the difference between each olezarsen dose group and the placebo group (the placebo-adjusted change). A total of 1349 patients (254 in the olezarsen 50-mg group, 766 in the olezarsen 80-mg group, and 329 in the placebo group) were included in the primary efficacy analysis. The median age was 64 years, 40% of the patients were women, and the median triglyceride level at baseline was 238.5 mg per deciliter (interquartile range, 190.5 to 307.5). At 6 months, the placebo-adjusted least-squares mean change in triglyceride level was -58.4 percentage points (95% confidence interval [CI], -65.1 to -51.7; P<0.001) in the olezarsen 50-mg group and -60.6 percentage points (95% CI, -67.1 to -54.0; P<0.001) in the olezarsen 80-mg group. The incidence of serious adverse events appeared to be similar across the trial groups. Among patients with moderate hypertriglyceridemia and elevated cardiovascular risk, treatment with olezarsen resulted in significantly greater reduction in triglyceride levels at 6 months than placebo. (Funded by Ionis Pharmaceuticals; ESSENCE-TIMI 73b ClinicalTrials.gov number, NCT05610280.). Show less
Alzheimer's disease (AD) represents a neurodegenerative condition characterized by steadily increasing prevalence and incidence, arising significant challenge to both patients and social insurance. Ho Show more
Alzheimer's disease (AD) represents a neurodegenerative condition characterized by steadily increasing prevalence and incidence, arising significant challenge to both patients and social insurance. However, the etiology of AD remains controversial so far, and pathogenesis is far more complicated. Presently, no definitive therapeutic methodologies were available for AD, and only partial symptomatic relief can be achieved. Consequently, early diagnosis and intervention are emergently needed for AD patients. The diagnostic criteria for AD are continuously evolving, and biomarker testing is becoming increasingly critical for diagnosis. Currently, the diagnosis of AD primarily relies on the detection of pathological proteins through cerebrospinal fluid (CSF) testing and positron emission tomography (PET). However, factors such as high costs, operational contraindications, and invasiveness limited the application of these technologies, making them particularly challenging to implement in large-scale clinical trials and screenings. Core fluid biomarkers for AD including β-amyloid (Aβ), phosphorylated tau protein (p-tau), total tau protein (t-tau), and their combinations were found in CSF. Although these biomarkers were demonstrated with significant specificity and sensitivity, challenges remain high concerning the collection of CSF. Blood-derived biomarkers for Aβ and tau proteins are essential for preliminary screening, diagnosis, and monitoring of AD. Additionally, other bodily fluids such as saliva, urine, and tears have been investigated for their potential as biomarkers, offering unique characteristics and applications. Emerging biomarkers, including neurofilament light chain (NfL), neurogranin (Ng), Beta-site APP cleaving enzyme 1 (BACE1), synaptosome associated protein 25 (SNAP-25), as well as inflammation-related and gene-related factors, provided valuable insights into the diagnosis and pathogenesis of AD from diverse perspectives. Despite the substantial progress made in AD biomarker research, there are still baskets of limitations concerning the complication of the disease. The current review focused on the reported literature to summarize the biomarkers associated with AD. By critically analyzing studies published over the past decade, we aimed to strengthen the recent research progress, theoretical frameworks, and unresolved challenges related to AD biomarkers. Show less
Calcific aortic valve stenosis (CAVS) can lead to cardiac adverse outcomes; however, currently, no effective pharmacological interventions are available to prevent or delay disease progression. Emergi Show more
Calcific aortic valve stenosis (CAVS) can lead to cardiac adverse outcomes; however, currently, no effective pharmacological interventions are available to prevent or delay disease progression. Emerging evidence has identified significant associations between CAVS and key biomarkers, including Lp(a) (lipoprotein [a]), low-density lipoprotein cholesterol, and PCSK9 (proprotein convertase subtilisin/kexin type 9). However, robust evidence from randomized controlled trials is still lacking to substantiate these associations. The EPISODE (Effect of PCSK9 Inhibitors on Calcific Aortic Valve Stenosis) trial is a prospective, evaluator-blinded, randomized controlled trial designed to assess the therapeutic efficacy of PCSK9 inhibitors in patients with CAVS. A total of 160 patients with mild-to-moderate or asymptomatic severe CAVS will be randomly assigned to receive either statin monotherapy or a combination of statins and PCSK9 inhibitors. Participants will undergo follow-up assessments at 3-month intervals for 24 months, including transthoracic ultrasonic cardiogram, computed tomography, and quality-of-life evaluations using the EuroQol-5 Dimension-3 Level questionnaire. The primary end point is the annualized change in peak aortic jet velocity, whereas secondary end points encompass changes in aortic valve area, calcification score, incidence of heart valve surgery, and quality of life. Safety end points include all-cause mortality and cardiovascular events. The trial aims to evaluate the efficacy of PCSK9 inhibitors in modulating disease progression, reducing adverse cardiovascular events, and improving clinical outcomes in patients with CAVS. The anticipated findings are expected to provide critical insights for developing novel therapeutic strategies for early intervention in CAVS. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04968509. Show less
Familial chylomicronemia syndrome (FCS) is diagnosed by genetic or nongenetic criteria. To assess responses to treatment of apolipoprotein (apo)C-III, triglycerides, and pancreatitis events in patient Show more
Familial chylomicronemia syndrome (FCS) is diagnosed by genetic or nongenetic criteria. To assess responses to treatment of apolipoprotein (apo)C-III, triglycerides, and pancreatitis events in patients with FCS-based diagnostic methods. APPROACH enrolled 66 patients with FCS randomized to volanesorsen or placebo for 12 months. In 50 participants, genetic confirmation of FCS was based on the presence of pathogenic bi-allelic variants in LPL, APOC2, APOA5, GPIHBP1, or LMF1 genes. In 16 participants without a genetic diagnosis, FCS was diagnosed using clinical criteria and postheparin lipoprotein lipase activity ≤20% of normal. Plasma levels of apoC-III, triglycerides and related variables were measured at 3, 6, and 12 months. No significant differences were present in mean apoC-III reductions with volanesorsen at 3, 6, or 12 months in patients with FCS diagnosed either genetically or nongenetically. In contrast, the triglyceride reductions were statistically less robust in patients with genetic diagnosis at each timepoint, with mean (95% CI) percent reduction in triglycerides of -68.7% (-78.7, -58.6) vs -84.0% (-99.4, -68.6), P = .014 at Month 3; -58.2% (-78.1, -38.2) vs -84.5% (-122.4, -46.7), P = .009 at Month 6; and -35.6% (-57.7, -13.4) vs. -69.0% (-105.0, -33.1), P = .005 at Month 12. Patients with a genetic diagnosis had significantly lower response rates for achieved triglycerides <500 mg/dL, <750 mg/dL, <880 mg/dL and <1000 mg/dL than patients with a nongenetic diagnosis. All 5 episodes of acute pancreatitis occurred in patients with a genetic diagnosis. For a similar reduction in apoC-III in response to volanesorsen, triglyceride reduction is attenuated in patients with genetically vs nongenetically diagnosed FCS. Show less
In preliminary research and literature review, we identified a potential link between chronic obstructive pulmonary disease (COPD) and lipid metabolism. Therefore, this study employed Mendelian random Show more
In preliminary research and literature review, we identified a potential link between chronic obstructive pulmonary disease (COPD) and lipid metabolism. Therefore, this study employed Mendelian randomization (MR) analysis to investigate the potential causal connection between blood lipids and COPD. A genome-wide association study (GWAS) on COPD was conducted, encompassing a total of 112,583 European participants from the MRC-IEU. Additionally, extensive UK Biobank data pertaining to blood lipid profiles within European cohorts included measurements for low-density lipoprotein cholesterol (LDL-C) with 440,546 individuals, high-density lipoprotein cholesterol (HDL-C) with 403,943 individuals, triglycerides (TG) with 441,016 individuals, total cholesterol (TC) with 187,365 individuals, apolipoprotein A-I (apoA-I) with 393,193 individuals, and apolipoprotein B (apoB) with 439,214 individuals. Then, MR analyses were performed for lipids and COPD, respectively. The primary analytical technique employed was the inverse-variance weighted (IVW) approach, which included a 95% confidence interval (CI) to calculate the odds ratio (OR). Additionally, a sensitivity analysis was conducted to assess the dependability of the MR analysis outcomes. MR analysis was primarily based on IVW, unveiled a causal link between COPD and LDL-C (OR=0.994, 95% CI (0.989, 0.999), P=0.019), TG (OR=1.005, 95% CI (1.002, 1.009), P=0.006), and apoA-I (OR=0.995, 95% CI (0.992, 0.999), P=0.008), in addition, no causal link was found with HDL-C, TC, apoB. Sensitivity analysis demonstrated the robustness of these causal relationships. However, through multivariate MR(MVMR) and multiple testing correction, LDL-C and TG had no causal effect on the outcome. ApoA-I remained a protective factor for the risk of COPD (OR=0.994, 95% CI (0.990-0.999), P=0.008). Through MR analysis, this study offers evidence of a causal link between apoA-I with COPD. This further substantiates the potential role of lipid metabolism in COPD, and has significant clinical implications for the prevention and management of COPD. Show less
William Stewart, Bin Hu, Fengqiao Li+6 more · 2025 · Journal of controlled release : official journal of the Controlled Release Society · Elsevier · added 2026-04-24
Obesity, a widespread global health issue affecting millions, is characterized by excess fat deposition and metabolic dysfunction, significantly elevating the risk of comorbidities like type 2 diabete Show more
Obesity, a widespread global health issue affecting millions, is characterized by excess fat deposition and metabolic dysfunction, significantly elevating the risk of comorbidities like type 2 diabetes, cardiovascular disease, and certain cancers, all of which contribute to rising rates of preventable morbidity and mortality. Current approaches to obesity, including lifestyle modifications, and pharmacotherapy, often face limitations such as poor long-term adherence, side effects, and insufficient targeting of the complex, multifactorial pathways underlying the disease. Herein we report a dual, RNA-mediated combinatorial approach using targeting lipid nanoparticles (LNP) for the treatment of obesity. LNPs were co-encapsulated with mRNA encoding Interleukin-27 (mIL-27) to coactivate PGC-1α, PPARα, and UCP-1, thereby promoting adipocyte differentiation and enhancing adaptive thermogenesis within adipocytes, and siRNA targeting Dipeptidyl peptidase-4 (siDPP-4) to silence the primary inhibitory enzyme of GLP-1, and GIP within the incretin system, effectively restoring glucose homeostasis. Following post translational silencing of DPP-4 and upregulation of IL-27 in a diet-induced obesity (DIO) mice model, increased expression of thermogenic biomarkers PGC-1α, PPARα, and UCP-1 was observed at the molecular, protein, and tissue level, and insulin sensitivity was restored. Importantly, this gene modulation led to a 21.1 % reduction of bodyweight after treatment in the DIO model. These findings demonstrate for the first time a dual RNA-mediated combinatorial approach, leveraging liver targeting LNP delivery with synergistic effects from incretin system regulation and induction of adipocyte differentiation and thermogenesis after codelivery of siDPP-4 and mIL-27. This innovative strategy provides a promising alternate framework for addressing obesity and its associated metabolic dysfunction. Show less
Recent researches highlight the interdependence of lipoprotein(a) [Lp(a)] and Lp(a)-associated cardiovascular risk with the background inflammatory burden. This study aimed to investigate whether syst Show more
Recent researches highlight the interdependence of lipoprotein(a) [Lp(a)] and Lp(a)-associated cardiovascular risk with the background inflammatory burden. This study aimed to investigate whether systemic inflammation modulates Lp(a)-associated coronary stenosis in chronic coronary syndromes (CCS). A total of 1513 participants undergoing angiography at a tertiary cardiology center in China were included in our retrospective, cross-sectional study. Participants were categorized into normal, mild, and severe groups based on the Gensini Scores, which quantitatively assess stenosis severity. Multinomial logistic models were calculated according to accompanying systemic inflammation concentration. Participants with elevated Lp(a) levels had a high coronary stenosis risk: fully adjusted model odds ratios (ORs) [95% confidence intervals (CIs)] for the mild vs. normal and severe vs. normal groups were 1.47 (1.11-1.96) and 1.68 (1.21-2.33). Notably, the strongest Lp(a)-coronary stenosis associations after multi-variable adjustment persisted only in low inflammation concentration [systemic inflammation response index (SIRI) < 0.64)] [mild vs. normal, OR 2.03, 95% CI 1.17-3.54, Elevated Lp(a) correlates with coronary stenosis only in low inflammation concentration. Considering systemic inflammation in personalized Lp(a)-lowering therapies is more conducive for CCS managements. Show less
In the microenvironment of atherosclerosis (AS), low-density lipoprotein (LDL) accumulates in injured endothelial areas and undergoes oxidation, thereby generating oxidized LDL (ox-LDL). The formation Show more
In the microenvironment of atherosclerosis (AS), low-density lipoprotein (LDL) accumulates in injured endothelial areas and undergoes oxidation, thereby generating oxidized LDL (ox-LDL). The formation of ox-LDL, in turn, not only amplifies endothelial cell (EC) dysfunction but also triggers macrophage polarization into the pro-inflammatory M1 phenotype. This cascade results in increased inflammatory cytokine secretion and exacerbated lipid accumulation. Therefore, a dual-targeting strategy aimed at both ECs and macrophages to inhibit the vicious circle between inflammation and lipids is a promising avenue for AS treatment. Simvastatin (SIM)-loaded nanomicelles (PLA-PEG/SIM) were prepared using the thin-film hydration method. Then, platelet membrane (PM) was coated the nanomicelles via sonication to obtain PM@PLA-PEG/SIM dual-targeting biomimetic nanoparticles. The morphological features of the nanoparticles were assessed by transmission electron microscopy (TEM). Cytotoxicity was evaluated using the CCK-8 assay and live/dead cell staining. Their targeting ability toward ECs and macrophages was assessed by flow cytometry and confocal laser scanning microscopy (CLSM). The biosafety, targeting ability, and therapeutic efficacy of PM@PLA-PEG/SIM against AS were further validated in ApoE PM@PLA-PEG/SIM effectively reduced the drug toxicity of SIM, exhibiting good biocompatibility. In vitro, cell experiment results showed that the nanoparticles inhibited foam cell formation, decreased interleukin-6 (IL-6) expression, and increased interleukin-4 (IL-4) and interleukin-10 (IL-10) expression by promoting macrophage repolarization. In vivo, results indicated that the formulation demonstrated excellent plaque-targeting ability. More importantly, the plaque area and lipid levels in the PM@PLA-PEG/SIM group were lowest, and plaques were most stable, showing its best therapeutic efficiency. PM@PLA-PEG/SIM alleviated progression of AS by co-targeting ECs and macrophages to inhibit the vicious cycle between inflammation and lipids. Our study provides a new strategy for the treatment of the disease by the co-targeting biomimetic nanoparticle. Show less
Despite substantial progress in low-density lipoprotein cholesterol (LDL-C)-lowering strategies, residual cardiovascular risk remains. Apolipoprotein C3 (APOC3) has emerged as a novel target for lower Show more
Despite substantial progress in low-density lipoprotein cholesterol (LDL-C)-lowering strategies, residual cardiovascular risk remains. Apolipoprotein C3 (APOC3) has emerged as a novel target for lowering triglycerides. Multiple clinical trials of small-interfering RNA therapeutics targeting APOC3 are currently underway. To investigate whether genetically predicted lower APOC3 is associated with a reduction in cardiovascular risk and if the combined exposure to APOC3 and LDL-C-lowering variants is associated with a reduction in the risk of coronary heart disease (CHD). This was a population-based genetic association study with 2 × 2 factorial mendelian randomization. Included were participants of European ancestry in the UK Biobank. Data were analyzed from November 2023 to July 2024. Genetic scores were constructed to mimic the effects of APOC3, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors. Plasma lipid and lipoprotein levels, CHD, and type 2 diabetes (T2D). This study included 401 548 UK Biobank participants (mean [SD] age, 56.9 [8.0] years; 216 901 female [54.0%]). Genetically predicted lower APOC3 was associated with a lower risk of CHD (odds ratio [OR], 0.96; 95% CI, 0.93-0.98) and T2D (0.97; 95% CI, 0.95-0.99). Genetically lower APOC3 and PCSK9 were associated with a similar magnitude of risk reduction in CHD per 10-mg/dL decrease in apolipoprotein B (ApoB) level (APOC3: 0.70; 95% CI, 0.59-0.83; PCSK9: 0.71; 95% CI, 0.65-0.77). Combined exposure to genetically lower APOC3 and PCSK9 was associated with an additive lower risk of CHD (APOC3: 0.96; 95% CI, 0.92-0.99; PCSK9: 0.93; 95% CI, 0.90-0.97; combined: 0.90; 95% CI, 0.86-0.93). Genetically lower HMGCR was also associated with a lower risk of CHD, and the risk was further reduced when combined with APOC3 (0.93; 95% CI, 0.90-0.97). Genetically predicted lower APOC3 was associated with a reduced risk of CHD that is comparable with that associated with lower PCSK9 per unit decrease in ApoB. Combined exposure to APOC3 and LDL-C-lowering variants was associated with an additive reduction in CHD risk. Future studies are warranted to investigate the therapeutic potential of these combined therapies, particularly among high-risk patients who cannot achieve therapeutic targets with existing lipid-lowering therapies. Show less
ANGPTL3/4/8 (angiopoietin-like proteins 3, 4, and 8) are important regulators of LPL (lipoprotein lipase). ANGPTL8 forms complexes with ANGPTL3 and ANGPTL4. ANGPTL4/8 complex formation converts ANGPTL Show more
ANGPTL3/4/8 (angiopoietin-like proteins 3, 4, and 8) are important regulators of LPL (lipoprotein lipase). ANGPTL8 forms complexes with ANGPTL3 and ANGPTL4. ANGPTL4/8 complex formation converts ANGPTL4 from a furin substrate to a plasmin substrate, and both cleavages generate similar C-terminal domain-containing (CD)-ANGPTL4 fragments. Whereas several studies have investigated associations of free ANGPTL proteins with cardiovascular risk, there are no data describing associations of the complexes and CD-ANGPTL4 with outcomes or describing the effects of the complexes on LPL bound to GPIHBP1 (glycosylphosphatidylinositol HDL-binding protein 1). Recombinant protein assays were used to study ANGPTL protein and complex effects on GPIHBP1-LPL activity. ANGPTL3/8, ANGPTL3, ANGPTL4/8, and CD-ANGPTL4 were measured with dedicated immunoassays in 2394 LURIC (Ludwigshafen Risk and Cardiovascular Health) study participants undergoing coronary angiography and 6188 getABI study (German Epidemiological Trial on Ankle Brachial Index) participants undergoing ankle brachial index measurement. There was a follow-up for cardiovascular death with a median (interquartile range) duration of 9.80 (8.75-10.40) years in the LURIC study and 7.06 (7.00-7.14) years in the getABI study. ANGPTL3/8 potently inhibited GPIHBP1-LPL activity and showed positive associations with LDL-C (low-density lipoprotein cholesterol) and triglycerides (both ANGPTL3/8 potently inhibited GPIHBP1-LPL enzymatic activity, consistent with its positive association with serum lipids. However, ANGPTL3/8, LDL-C, and triglyceride levels were not associated with cardiovascular death in the LURIC and getABI cohorts. In contrast, concentrations of ANGPTL4/8 and particularly CD-ANGPTL4 were positively associated with inflammation, the prevalence of diabetes, and cardiovascular mortality. Show less
Neonatal piglets possess lysosome-rich foetal-type enterocytes that facilitate uptake and intracellular processing of maternally provided nutrients. However, the role of lysosomes in early-life growth Show more
Neonatal piglets possess lysosome-rich foetal-type enterocytes that facilitate uptake and intracellular processing of maternally provided nutrients. However, the role of lysosomes in early-life growth and intestinal maturation remains unclear. Therefore, this study was conducted to determine the role of lysosomes in the development of neonatal intestine in piglets. For 1-day-old neonatal piglets, a total of 12 piglets (Duroc × (Landrace × Large Yorkshire)) were divided into 2 groups using a split-litter design. To initiate malfunction in lysosomes, newborn piglets were subjected to oral gavage with imipramine (25 mg/kg bodyweight) once daily for 7 days. For 21-day-old piglets, a total of 12 piglets were divided into two groups, and each group received the same treatment as described above. Piglets receiving imipramine demonstrated significantly stunted growth at 7 days of age, but not at 27 days. By postnatal day 7, the foetal-type enterocytes of untreated piglets were restricted in the mid to upper ileal villus and contained several large lysosomal vacuoles. In contrast, marked changes in ileal morphological and histological structure were observed following imipramine treatment, as evidenced by reduced degree of vacuolation, decreased lysosomal count, as well as pronounced mitochondrial swelling; however, no vacuolated enterocytes were found in 27-day-old piglets. Furthermore, signaling pathways associated with lipid transport and metabolism were significantly enriched, and the related hub genes were identified by bioinformatic analysis after imipramine administration. These findings were further confirmed by biochemical analysis demonstrating that serum levels of total cholesterol (TC) and apolipoprotein A1 (ApoA1) were significantly increased while serum ApoB was decreased in 7-day-old piglets receiving imipramine treatment. Additionally, there was an opposite trend in levels of ApoA1and ApoB in ileal mucosa compared to serum. These results demonstrate that lysosome dysfunction induced by imipramine resulted in significant growth retardation, pronounced morphological and ultrastructural alterations in ileal enterocytes, along with disrupted lipid metabolism in early postnatal piglets; however, no such effect was observed in 27-day-old piglets. These findings enhance understanding of lysosomal functions and intestinal maturation in neonatal piglets. Show less
Mesenchymal cells constitute the primary structural support elements within endometriotic lesions, yet their pivotal roles in endometriotic pathogenesis remain largely uncharted. This study aimed to c Show more
Mesenchymal cells constitute the primary structural support elements within endometriotic lesions, yet their pivotal roles in endometriotic pathogenesis remain largely uncharted. This study aimed to construct a single-cell atlas of endometriosis using samples from three ovarian tissues affected by endometriosis and three normal ovarian tissues. Through the utilization of scRNA-seq, we have unveiled six distinct mesenchymal subclusters in normal and endometriosis-afflicted ovaries, elucidating the diverse functions of mesenchymal populations in endometriosis. Our comprehensive analysis has revealed that mesenchymal cells predominantly engage in three key functions: ribosome-mediated protein synthesis and processing, cell adhesion facilitating intercellular support and communication, and a range of metabolic processes. Furthermore, our findings have identified several pivotal differentially expressed genes (e.g. C3, FN1, COL3A1, COL1A1, NRXN3), primarily associated with the complement and coagulation cascades, extracellular matrix (ECM) regulation, ECM receptor interactions, and cell adhesion molecules. In essence, our study provides a comprehensive transcriptomic dataset and novel insights into adhesive molecule and integrin networks within mesenchymal subclusters in endometriosis. This, in effect, has deepened the understanding of the pathomechanisms governing this condition. Show less
Post traumatic stress disorder (PTSD) is a serious and persistent mental diseases. Nowadays, Treatment of PTSD patients in clinical practice is mainly based on drug therapy accompanied by psychologica Show more
Post traumatic stress disorder (PTSD) is a serious and persistent mental diseases. Nowadays, Treatment of PTSD patients in clinical practice is mainly based on drug therapy accompanied by psychological therapy. However, the therapeutic effect is unsatisfactory. It is urgent to detect how to treat PTSD patients. Here, we found that ginsenoside can significantly relieve PTSD symptoms in mice model. Rg3, one of the main pharmacological components of ginsenoside, prevents PTSD by promoting alternatively activated M2 phenotype microglia while inhibiting classically activated inflammatory M1 phenotype microglia. Mechanistically, Rg3 up-regulates fibroblast growth factor receptor 1 (FGFR1) expression in microglia to suppress excessive activation of microglia and reduce neuronal apoptosis. Importantly, knocking down FGFR1 expression in BV2 cells promoted a pro-inflammatory phenotype of BV2 cells, while over-expressing FGFR1 reversed this effect. In vivo PTSD mice model results showed that knockdown FGFR1 prevents the therapeutic effect of Rg3, which indicates that FGFR1 is an essential target of PTSD. Our results reveal that Rg3 may be a potential drug to treat PTSD patients. Show less
R-loop is a common chromatin feature consisting of a displaced single-stranded DNA and an RNA-DNA hybrid, and dysregulation of R-loop surveillance results in genomic and transcriptomic instability. Al Show more
R-loop is a common chromatin feature consisting of a displaced single-stranded DNA and an RNA-DNA hybrid, and dysregulation of R-loop surveillance results in genomic and transcriptomic instability. Although the RNA moiety of most R-loops originates from linear transcripts, circular RNAs (circRNAs), outputs from back-splicing, can also hybridize with the complementary strand of a DNA duplex. However, how circRNA-associated R-loops (ciR-loops) are monitored remains elusive. Here, we identify the DEAD-box RNA helicase Brr2 as an evolutionarily-conserved ciR-loop repressor with dual roles in inhibiting circRNA generation and resolving harmful ciR-loops. Accumulation of ciR-loops caused by loss-of-function of this dual-action factor induces antisense transcription and premature transcription termination for many genes and generates significant DNA damage, which further leads to a series of defects in DNA replication, cell division and cell proliferation. We propose that functional integration of multilayered regulation by a single protein can be an efficient double protection against genome instability. Show less
To explore the correlation between different traditional Chinese medicine (TCM) constitution types and apolipoprotein B (ApoB) in patients with hyperuricemia (HUA) and to investigate the relationships Show more
To explore the correlation between different traditional Chinese medicine (TCM) constitution types and apolipoprotein B (ApoB) in patients with hyperuricemia (HUA) and to investigate the relationships between TCM constitutions, uric acid levels, and various cardiovascular risk factors. A cross-sectional study involving 683 patients diagnosed with HUA was conducted. Patients' TCM constitutions were classified using the standardise "Classification and Determination of TCM Constitution" questionnaire. Serum uric acid (UA), lipid profiles, ApoB, and homocysteine (Hcy) levels were measured. Among 683 HUA patients, phlegm-dampness (22.99% ) and damp-heat constitution (20.06% ) were the most common TCM constitution types. UA, ApoB, and Hcy levels in patients with phlegm-damp constitution were significantly higher than those in other constitutions (P< 0.05). UA levels were negatively correlated with HDL-C (r=-0.472, P= 0.027) and positively correlated with ApoB (r= 0.618, P= 0.012) and Hcy (r= 0.492, P= 0.018). Phlegm-damp and damp-heat constitutions are the most common TCM constitution types in HUA patients and are associated with higher levels of UA, ApoB, and Hcy. These constitutional types are independently associated with increased cardiovascular risk. Show less
Osteoporotic bone defects pose significant clinical challenges. While icariin (ICA) exhibits pro-osteogenic effects in vitro, its capacity to repair osteoporosis (OP)-related bone defects remains unve Show more
Osteoporotic bone defects pose significant clinical challenges. While icariin (ICA) exhibits pro-osteogenic effects in vitro, its capacity to repair osteoporosis (OP)-related bone defects remains unverified. This study investigates ICA' s therapeutic role in bone regeneration and elucidates its molecular mechanisms via the Hippo pathway in bone marrow mesenchymal stem cells (BMSCs) and OP rats. Rat BMSCs were isolated and characterized by flow cytometry (CD29+/CD34-/CD45-). BMSCs were induced under osteogenic conditions with ICA at 25 and 50 mg/L. Osteogenic differentiation and mineralization were assessed by ALP and Alizarin Red staining and by measuring mRNA and protein levels of ALP, Runx2, and OCN. The Hippo/TAZ pathway was evaluated by Western blot and qPCR for MST1, p-MST1, TAZ, and p-TAZ. A rescue experiment employed the Hippo pathway agonist lysophosphatidic acid (LPA). An ovariectomized (OVX) rat model of osteoporosis was established to validate ICA's effects in vivo, examined by micro-CT, histology, and tibial expression analyses of osteogenic markers and Hippo/TAZ signaling components. ICA promoted osteogenic differentiation and mineralization of BMSCs. Mechanistically, ICA did not alter MST1 or TAZ transcripts but markedly reduced MST1 and TAZ phosphorylation, thereby stabilizing total TAZ and enhancing downstream osteogenesis. Co-treatment with LPA abrogated ICA-induced osteogenesis, confirming Hippo/TAZ pathway dependence. In OVX rats, ICA mitigated bone loss, improved trabecular microarchitecture (BMD, BV/TV, Tb.N), and upregulated tibial expression of ALP, Runx2, and OCN. Consistently, ICA reduced p-MST1 and p-TAZ levels and increased total TAZ in bone tissues. ICA promotes bone formation both in vitro and in vivo by inhibiting Hippo kinase activity and stabilizing TAZ, thereby enhancing osteogenic differentiation. Our findings identify the Hippo/TAZ axis as a potential therapeutic target for OP and support further translational exploration of ICA as an anti-osteoporotic agent. Show less
Pork serves as a significant meat commodity, with intramuscular fat (IMF) content being a critical determinant of its quality. However, the epigenetic mechanism of porcine IMF deposition is still uncl Show more
Pork serves as a significant meat commodity, with intramuscular fat (IMF) content being a critical determinant of its quality. However, the epigenetic mechanism of porcine IMF deposition is still unclear. This study integrated proteomics and lactylation profiles from the longissimus thoracis (LT) muscles of pigs with extremely high (IMF_H) and extremely low (IMF_L) IMF content to clarify the association between lactylation and porcine fat deposition. Furthermore, an intramuscular preadipocyte induction and differentiation model was conducted to elucidate the changes in lactylation during adipocyte differentiation. Finally, the regulatory role of lactylation in adipocyte differentiation was explored by modulating lactate production during the induction and differentiation of preadipocytes. Proteomic analysis revealed significantly increased expression of key lipid metabolism related proteins (FASN, APOA4, FABP4, ACLY, PLIN1) in IMF_H pig muscle tissues compared with IMF_L tissues, along with substantial activation of lipid metabolism pathways. Lactylation profiling identified 95 differential lysine sites across 56 proteins, with most showing lower lactylation levels in the IMF_H group. The integrative omics analysis revealed differences in lactylation profiles in porcine LT tissues with varying efficiencies of IMF deposition, highlighted PGK1, PKM, and PYGM as central lactylation-modified proteins in porcine fat deposition regulation. Further in vitro study proved that lactate-mediated lactylation inhibited adipogenic differentiation of porcine intramuscular preadipocytes through PPARγ signaling pathway. This study clarified the changes in the lactylation profile in porcine LT tissues with varying efficiencies of IMF deposition, and demonstrated that lactate-mediated lactylation inhibits the PPARγ signaling pathway and the adipogenic differentiation of porcine intramuscular preadipocyte. This study provided a new insight to understanding the epigenetic regulation mechanisms of lipid deposition in pigs. Show less
Recent advances in human blastoids have opened new avenues for modeling early human development and implantation. Human blastoids can be generated in large numbers, making them well-suited for high-th Show more
Recent advances in human blastoids have opened new avenues for modeling early human development and implantation. Human blastoids can be generated in large numbers, making them well-suited for high-throughput screening. However, automated methods for evaluating and characterizing blastoid morphology are lacking. We developed a deep-learning model-deepBlastoid-for automated classification of live human blastoids using only brightfield images. The model processes 273.6 images per second with an average accuracy of 87%, which is further improved to 97% by integrating a Confidence Rate metric. deepBlastoid outperformed human experts in throughput while matching accuracy in blastoid classification. We demonstrated the utility of the model in two use cases: (i) systematic assessment of the effect of lysophosphatidic acid (LPA) on blastoid formation and (ii) evaluating the impact of dimethyl sulfoxide (DMSO) on blastoid formation. The evaluation results of deepBlastoid using over 10,000 images were consistent with the known drug effects and showed subtle but significant effects that might have been overlooked in manual assessments. The publicly available deepBlastoid model enables researchers to train customized models based on their imaging and protocols, providing an efficient, automated tool for blastoid classification with broad applications in research, drug screening, and Show less
Xiaokun Li, Zhiheng Rao, Wenhao Hu+2 more · 2025 · Obesity reviews : an official journal of the International Association for the Study of Obesity · Blackwell Publishing · added 2026-04-24
Metabolic dysfunction-associated steatohepatitis (MASH) is a condition characterized by hepatosteatosis, inflammation, and tissue damage, with steatosis as the initial stage, which involves chronic, e Show more
Metabolic dysfunction-associated steatohepatitis (MASH) is a condition characterized by hepatosteatosis, inflammation, and tissue damage, with steatosis as the initial stage, which involves chronic, excess deposition of lipids in hepatic lipid droplets. Despite the growing prevalence and serious risks it poses, including liver decompensation, the need for transplantation, and increased patient mortality, MASH currently faces no approved pharmacotherapy. Several promising treatment candidates have emerged from recent clinical trials, including analogs of FGF21 and agonists of the associated FGFR1-KLB complex. These agents were well-tolerated in trials and have demonstrated significant improvements in both histological and biochemical markers of liver fat content, inflammation, injury, and fibrosis in patients with MASH. Endocrine FGF21 plays a vital role in maintaining homeostasis of lipid, glucose, and energy metabolism. It achieves this through pathways that target lipids or lipid droplets in adipocytes and hepatocytes. Mechanistically, pharmacological FGF21 acts as a potent catabolic factor to promote lipid or lipid droplet lipolysis, fatty acid oxidation, mitochondrial catabolic flux, and heat-dissipating energy expenditure, leading to effective clearance of hepatic and systemic gluco-lipotoxicity and inflammatory stress, thereby preventing obesity, diabetes, and MASH pathologies. In this review, we aim to provide an update on the outcomes of clinical trials for several FGF21 mimetics. We compare these outcomes with preclinical studies and offer a lipid-centric perspective on the mechanisms underlying the clinical benefits of these agents for MASH. Show less