The natural compound pterostilbene (PTE) has multiple cardiovascular protective effects. However, its effects on pulmonary arterial hypertension (PAH)-associated vascular remodeling remain to be eluci Show more
The natural compound pterostilbene (PTE) has multiple cardiovascular protective effects. However, its effects on pulmonary arterial hypertension (PAH)-associated vascular remodeling remain to be elucidated. This study investigated the effects of PTE on monocrotaline (MCT)-induced PAH in rats Experimental PAH was established by subcutaneous injection of MCT (50 mg/kg) in Sprague-Dawley rats, which were then randomly divided into vehicle or PTE (15 mg/kg via gavage) treatment groups. Endothelial-to-mesenchymal transition (EndMT) was modeled in hPAECs by treating with transforming growth factor-β, tumor necrosis factor-α, and interleukin-1β in combination. In rats with MCT-induced PAH, administration of PTE resulted in a reduction in right ventricular systolic pressure, thereby alleviating right ventricular hypertrophy. This was accompanied by mitigation of the remodeling of pulmonary arteries. PTE mitigates MCT-induced PAH and vascular remodeling in rats, at least in part, by inhibiting HMGA-mediated EndMT, suggesting that PTE may be a useful complementary medicine in the treatment of PAH. Show less
Graphical Abstract Lipoprotein lipase (LPL) mediates peripheral tissue triglyceride (TG) uptake. Hepatic ANGPTL3 (A3) and ANGPTL8 (A8) form a complex and inhibit LPL activity in the white adipose tiss Show more
Graphical Abstract Lipoprotein lipase (LPL) mediates peripheral tissue triglyceride (TG) uptake. Hepatic ANGPTL3 (A3) and ANGPTL8 (A8) form a complex and inhibit LPL activity in the white adipose tissue (WAT) via systematic circulation. ANGPTL4 (A4) is expressed in WAT and inhibits LPL activity locally. Feeding increases hepatic A8 expression and increases its inhibition for WAT LPL activity together with A3, while feeding suppresses WAT A4 expression and releases its inhibition on LPL. At room temperature, the feeding-suppressed A4 overrides the feeding-increased A3/A8, resulting in increased LPL activity in WAT by food intake. Browning improves hepatic insulin sensitivity and increases postprandial A8 expression. The feeding-increased A3/A8 overrides the feeding-suppressed A4, resulting in suppressed LPL activity in WAT by food intake. This reprogrammed LPL regulation plays an important role in reprogramming TG metabolism during adipose tissue browning. Show less
Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disorder characterized by left ventricular hypertrophy and an elevated risk of sudden cardiac death. Cardiac myosin binding protein C ( Show more
Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disorder characterized by left ventricular hypertrophy and an elevated risk of sudden cardiac death. Cardiac myosin binding protein C (MYBPC3) is the most frequently mutated gene leading to HCM. In this study, peripheral blood mononuclear cells isolated from an HCM patient harboring a heterozygous MYBPC3 missense mutation (c.3072C > A; p.S1024R) were reprogrammed via Sendai virus vectors to generate a patient-specific induced pluripotent stem cell (iPSC) line. The iPSC line exhibits normal morphology and karyotype, alongside definitive hallmarks of pluripotency, including trilineage differentiation potential. Show less
The melanocortin system centrally regulates energy homeostasis, with key components such as melanocortin-4 receptor (MC4R) and adenylyl cyclase 3 (ADCY3) in neuronal primary cilia. Mutations in
This study aimed to analyse the relationship of the blood lipid profile and interleukin-6 (IL-6) with osteoporosis and osteopenia and to explore the predictive value of the combined application of the Show more
This study aimed to analyse the relationship of the blood lipid profile and interleukin-6 (IL-6) with osteoporosis and osteopenia and to explore the predictive value of the combined application of these biomarkers in osteoporosis and osteopenia. Data from 276 patients treated in the orthopaedics department were retrospectively analysed. Their general information was collected, and the relationships among the blood lipid profile, IL-6 with bone turnover markers, and bone mineral density (BMD) were analysed. Patients were categorized based on their T scores for intergroup comparisons. Finally, the diagnostic efficiency of lipid metabolism markers and IL-6 for osteoporosis and osteopenia was assessed using receiver operating characteristic (ROC) curves. (1) In both males and females, a negative relationship was observed between BMD and several biomarkers, including total cholesterol (TC), apolipoprotein B (ApoB), low-density lipoprotein cholesterol (LDL-C), free fatty acids (FFAs), and IL-6. Additionally, apolipoprotein A1 (ApoA1) was negatively correlated with BMD only in females, and the ApoA1/ApoB ratio was positively correlated with BMD only in males. (2) FFAs and IL-6 were positively correlated with β-CrossLaps peptide in males. However, for females, TC, ApoB, LDL-C, and IL-6 were negatively correlated with 25-hydroxyvitamin D. FFAs, IL-6, and age were negatively correlated with osteocalcin in males and females. (3) According to the T scores for the lumbar spine, the TC, ApoA1, ApoB, HDL-C, LDL-C, FFA, and IL-6 levels in the osteoporosis group and the TC, ApoB, LDL-C, and FFA levels in the osteopenia group were significantly greater than those in the normal bone mass group. Additionally, the osteoporosis group presented substantially higher levels of ApoA1, FFAs, and IL-6 than the osteopenia group. (4) IL-6 was positively correlated with FFAs, while a negative correlation was observed with TC, ApoA1, ApoB, HDL-C, and LDL-C. (5) The ROC curve revealed that the areas under the curve (AUCs) of TC, FFAs, IL-6, ApoA1, and the ApoA1/ApoB ratio for predicting osteoporosis or osteopenia were 0.634, 0.713, 0.670, 0.628, and 0.516, respectively, whereas the AUC of the combination of TC, FFAs, IL-6, and ApoA1 was 0.846, and the AUC of the combination of TC, FFAs, IL-6, and the ApoA1/ApoB ratio was 0.842. In the sex stratification analysis, in males, the AUCs of TC, FFAs, IL-6, and the ApoA1/ApoB ratio for the prediction of osteoporosis or osteopenia were 0.596, 0.688, 0.739, and 0.539, respectively. In contrast, the AUC of the combination of TC, FFAs, IL-6, and the ApoA1/ApoB ratio was 0.838. In females, the AUCs of TC, FFAs, IL-6, ApoA1, and the ApoA1/ApoB ratio for predicting osteoporosis or osteopenia were 0.620, 0.728, 0.653, 0.611, and 0.502, respectively, whereas the AUC of the combination of TC, FFAs, IL-6, and ApoA1 was 0.841, and the AUC of the combination of TC, FFAs, IL-6, and the ApoA1/ApoB ratio was 0.828. The levels of TC, FFAs, IL-6, ApoA1, and ApoB could contribute to changes in bone metabolism, moreover, FFAs could induce an increase in IL-6 further aggravating bone mass loss and leading to osteoporosis. Based on the comparison of the AUC results, the combination of TC, FFAs, and IL-6 with ApoA1 or the ApoA1/ApoB ratio can better predict osteoporosis or osteopenia in patients, and the diagnostic efficiency is significantly better than that of any individual indicator. The regulation of blood lipid levels should become a new target for clinicians to treat osteoporosis and osteopenia. Show less
GLP-1 has become a prime target for medical treatment due to its significant therapeutic efficacy. However, the activation mechanisms of class B1 GPCRs, including glucagon-like peptides (GLP-1) and gl Show more
GLP-1 has become a prime target for medical treatment due to its significant therapeutic efficacy. However, the activation mechanisms of class B1 GPCRs, including glucagon-like peptides (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), remain poorly understood. This study focuses on understanding the activation mechanisms of the GLP-1 receptor (GLP-1R) by investigating its conformational changes from activated/inactivated to inactivated/activated states. By analyzing the dynamic conformational changes of the receptor during activation, a closure-open transition in the extracellular domain (ECD) and a movement trend of the transmembrane helices are observed, which indicates a similarity to the activation mechanism of class A GPCRs. Furthermore, the binding characteristics of a dual agonist Tirzepatide (LY3298176) is studied in detail and it is revealed that the conserved residues contribute in a similar fashion toward binding to both GLP-1R and GIPR. Mutations in non-conserved residues in Tirzepatide affect the binding affinity, with C-terminal mutations weakening the binding affinity toward GLP-1R, while N-terminal mutations enhancing the affinity to GIPR, resulting in a biased binding mode. These findings enriched our fundamental understanding of GLP-1R/GIPR activation and provided theoretical guidance for the design and development of future peptide-based agonists and offer insights into the optimization of other dual or multi-target agonists. Show less
Rubia cordifolia L. (RCL) is a widely used medicinal with a long history. It exhibits anti-inflammatory and antioxidant properties and prevents apoptosis. While there is growing evidence that exhauste Show more
Rubia cordifolia L. (RCL) is a widely used medicinal with a long history. It exhibits anti-inflammatory and antioxidant properties and prevents apoptosis. While there is growing evidence that exhausted exercise (EE) might cause cardiac damage, RCL has been shown to provide cardioprotective effects. The effects and mechanisms of RCL on exercise-induced myocardial injury remain unclear. In this study, we tested the RCL extract using a rat model of exhausted swimming. We evaluated the therapeutic effect of RCL on exercise-induced myocardial damage using PCR, ELISA, hematoxylin-eosin (H&E) staining, DHE staining, and other methods. UPLC-Q-TOF-MS was employed to identify the components of the RCL extract and its blood-entry components, and network pharmacology was constructed. LC-MS was utilized to investigate left ventricular metabolomics. These two approaches were combined to predict the possible metabolic pathways regulated by RCL. Finally, the targets of the metabolic pathway were verified using molecular docking and western blot analysis. The findings suggest that rubioncolin B, 4-hydroxy-2-carbexyanthraquinone, and 9-Oxo-9H-xanthene-4-carboxylic acid may be the primary active compounds of RCL. RCL promotes the degradation pathway of branched-chain amino acids (BCAA), including valine, leucine, and isoleucine, regulates the proteins BCAT2 and BCKDK, reduces pathological injuries, inflammation, oxidative stress, and collagen deposition, and mitigates the effects of exhaustion-induced myocardial injuries by influencing the key target AKR1C1 and the metabolite L-Valine. This study provides a foundation for the development of RCL as a sports supplement to alleviate EE-induced myocardial injury. Show less
Many patients are suffering from atherosclerosis without typical risk factors, which can cause severe cardiovascular complications. Trimethylamine N-oxide (TMAO), derived from gut microbes, is a key u Show more
Many patients are suffering from atherosclerosis without typical risk factors, which can cause severe cardiovascular complications. Trimethylamine N-oxide (TMAO), derived from gut microbes, is a key unconventional contributor to the development of atherosclerosis. Here we present a strategy performed by orally administered nano-functionalized probiotics (PDMF@LGG) to inhibit TMAO through the gut microbiota-trimethylamine (TMA)-TMAO axis. PDMF@LGG, composed of polydopamine-coated Lacticaseibacillus rhamnosus GG and nanoparticles based on a reactive oxygen species (ROS)-responsive polymeric prodrug of fluoromethylcholine (FMC), can promote the retention of probiotics and nanoparticles in the intestine to persistently scavenge elevated ROS and release drugs. This process suppresses TMA production and absorption, lowering plasma TMAO levels. The therapeutic effects on male ApoE Show less
Signal-induced proliferation-associated 1 like 3 (SIPA1L3) is a member of the protein family. Very limited data are currently available regarding the role of SIPA1L3 in human carcinoma. Therefore, in Show more
Signal-induced proliferation-associated 1 like 3 (SIPA1L3) is a member of the protein family. Very limited data are currently available regarding the role of SIPA1L3 in human carcinoma. Therefore, in this study, we investigated the expression pattern and function of SIPA1L3 in non-small cell lung cancer (NSCLC). We analyzed the distribution of SIPA1L3 in NSCLC specimens by immunohistochemistry, the relationship between SIPA1L3 expression and patient clinicopathological features, and investigated the effect of SIPA1L3 on cell growth and invasion in vivo and in vitro using small interfering RNA. Western blotting and immunoprecipitation were performed to demonstrate the interaction between SIPA1L3 and tight junction-associated angiomotin (AMOT) and Pals1-associtated tight junction protein. We found that SIPA1L3 was overexpressed in NSCLC clinical tissue samples and was associated with several clinicopathological factors. SIPA1L3 affects the proliferation and invasion of cancer cells both in vivo and in vitro. Using a SIPA1L3 mutant, we found that SIPA1L3 interacts with AMOT through its PDZ domain, which inhibits the binding of AMOT to Pals1-associtated tight junction protein and further decreases AMOT anchoring to tight junctions. Our findings suggested that SIPA1L3 promotes tumorigenesis in lung cancer cells through its PDZ domain-mediated interaction with AMOT, suggesting that SIPA1L3 is a novel candidate gene that contributes to the malignant phenotype of lung cancer. Show less
Biomolecular condensates, membrane-less assemblies formed by phase separation, are implicated in neurodegenerative disease, but their role in Alzheimer's disease (AD) remains unclear. Here, we report Show more
Biomolecular condensates, membrane-less assemblies formed by phase separation, are implicated in neurodegenerative disease, but their role in Alzheimer's disease (AD) remains unclear. Here, we report that in the brain of AD patients and animal models, an elevation of poly(C)-binding protein 2 (PCBP2) correlates with biomolecular condensation that involves phase separation. These condensates sequester large numbers of mitochondrial and mRNA-binding proteins, leading to the outside impairment of mitochondrial morphology and function, and BACE1 mRNA decay relative to amyloid deposition. We then identify a small molecule CN-0928 that inhibits the condensates by reducing PCBP2 protein level and mitigates AD pathology and cognitive decline, in which CN-0928 binding to a target protein integrator complex subunit 1 (INTS1) allows to regulate PCBP2 expression. Our findings place PCBP2 condensates as a key player that cooperates the seemingly disparate but important pathways, and show pharmacological modulation of PCBP2 as an effective approach for treating AD. Show less
Current evidence suggests that apolipoprotein E (APOE) is associated with lipid metabolism, cardiovascular diseases, and neurodegenerative disorders. However, the physiological pathways of APOE-mediat Show more
Current evidence suggests that apolipoprotein E (APOE) is associated with lipid metabolism, cardiovascular diseases, and neurodegenerative disorders. However, the physiological pathways of APOE-mediated inflammation remain incompletely elucidated, and a specific inflammatory marker that captures the pro-inflammatory activity of the APOE ε4 allele remains elusive. As a composite peripheral blood biomarker, Systemic immune-inflammation index (SII) is a novel marker of inflammation. This study aimed to investigate the association between APOE alleles and Systemic Immune-Inflammation Index. A total of 13,926 participants (9,098 males and 4,828 females) were recruited from The People’s Liberation Army General Hospital (November 2017 to July 2019). APOE alleles (ε2, ε3, and ε4) were determined by genotyping rs429358 and rs7412 SNPs. SII was calculated as (platelet count × neutrophil count)/lymphocyte count. Multivariable linear regression models (adjusted for demographics, lifestyle, and clinical covariates) and subgroup analyses were performed to assess the APOE-SII associations, with ε3 as the reference. The frequencies of APOE alleles ɛ3, ɛ2, and ɛ4 were70.7%, 13.8%, and 15.5% respectively in 13,926 Chinese patients. The mean SII was lower in ɛ2 carriers than in ɛ3 (373.74*10⁹/L vs. 403.53*10⁹/L, APOE contributes to elevated disease risk by inducing a state of chronic low-grade inflammation, resulting from modulation of both adaptive and innate immune responses. Show less
The precise involvement of Guanine Nucleotide-Binding Protein-Like 3-Like Protein (GNL3L) in lung cancer progression and invasion remains unclear. In this study, we explored the impact and underlying Show more
The precise involvement of Guanine Nucleotide-Binding Protein-Like 3-Like Protein (GNL3L) in lung cancer progression and invasion remains unclear. In this study, we explored the impact and underlying mechanisms of GNL3L on the proliferation, migration, and invasion of lung adenocarcinoma (LUAD), and evaluated the therapeutic potential of targeting GNL3L. Inhibition of GNL3L expression led to a notable decrease in the in vitro proliferation, migration, and invasion of A549 and H1299 non-small cell lung cancer (NSCLC) cells. Meanwhile, GNL3L silencing could significantly reduce the tumor volume of the nude mice and improve the outcomes of tumor-bearing mice in vivo. Additionally, inhibition of GNL3L expression dramatically suppressed NF-κB activation and Slug, MMP2, and MMP9 expression. Overexpression of Slug or treatment of the GNL3L-deficient cells with NF-κB activator can partially restore the growth suppressed by GNL3L deficiency, and combined treatment with Slug overexpression and NF-κB activator could totally restore the suppressed cell growth caused by GNL3L deficiency. Moreover, the overexpression of MMP2 or MMP9 could partially enhance the reduced migration and invasion caused by GNL3L deficiency, and this GNL3L-deficiency-caused suppression of migration and invasion can be totally restored by the overexpression of MMP2 and MMP9 together. These results strongly indicated that GNL3L has the capability to activate the NF-κB and increase Slug, MMP2, and MMP9 expression, which in turn could stimulate the proliferation, migration, and invasion of lung cancer cells. NF-κB activation and Slug, MMP2, and MMP9 expression enhanced by GNL3L, leading to the promotion of proliferation, migration, and invasion of lung cancer cells, indicating the therapeutic implications and potential significance of these pathways in the progression and invasion of NSCLCs that overexpress GNL3L protein. Show less
The highly organized structures of the immunological synapse (IS) are crucial for T cell activation. PDZ domains might be involved in the formation of the IS by serving as docking sites for protein in Show more
The highly organized structures of the immunological synapse (IS) are crucial for T cell activation. PDZ domains might be involved in the formation of the IS by serving as docking sites for protein interactions. In this study, we investigate the role of the PALS1-associated tight junction protein (PATJ), which contains 10 PDZ domains, in the formation of IS and its subsequent impact on T cell activation. To elucidate the function of PATJ, we generated murine models with conditional T cell-specific knockout of We observed a rapid increase in PATJ expression during T cell activation. Conditional knockout of Our study reveals an important role of PATJ in the formation of IS and provides an approach to improve the efficacy of CAR-T therapy. Show less
Alzheimer's disease (AD) presents significant challenges due to its intricate pathogenic mechanisms and the limited efficacy of single-target therapies. In this study, we investigated the potential of Show more
Alzheimer's disease (AD) presents significant challenges due to its intricate pathogenic mechanisms and the limited efficacy of single-target therapies. In this study, we investigated the potential of chlorogenic acid (CHA), a multifunctional natural active compound, in AD therapy by developing a trifunctional nanocarrier (MC-H/R/si). CHA was effectively conjugated with iron-based metal-organic frameworks (MIL/Fe-100) through chelation interaction. The resulting nanocomplex (MC) not only enhances the bioavailability of CHA but also facilitates a synergistic antioxidant effect between CHA and MIL/Fe-100. Importantly, CHA can chelate Zn Show less
Physical fitness in preschoolers, encompassing muscular strength, speed-agility, balance, and cardiorespiratory fitness, serves as a key health indicator. While preschools are ideal settings for promo Show more
Physical fitness in preschoolers, encompassing muscular strength, speed-agility, balance, and cardiorespiratory fitness, serves as a key health indicator. While preschools are ideal settings for promoting physical fitness, the association between preschool-based movement behaviors and physical fitness remains unclear. This cross-sectional study included 1144 Chinese preschoolers aged 3-6 years. Preschool-based movement behaviors including moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), and sedentary behavior (SB), were measured using ActiGraph GT9X accelerometers. Physical fitness was assessed via the PREFIT battery, which includes handgrip strength, standing long jump, 4 × 10 m shuttle run, one-leg stance, and 20 m shuttle run. Compositional linear regression and isotemporal substitution modeling were employed to examine associations and time-reallocation effects, respectively. Greater amounts of MVPA during preschool hours were positively associated with better performance in muscular strength, speed-agility, and cardiorespiratory fitness. Reallocating time from SB or LPA to MVPA enhanced physical fitness, whereas substituting MVPA with SB or LPA reduced fitness levels, demonstrating an asymmetric effect. Moderate-to-vigorous physical activity during preschool hours significantly enhances physical fitness. Prioritizing the implementation of physical activity programs to increase MVPA in preschool settings is crucial for improving physical fitness and addressing insufficient MVPA in this age group. First large-scale study (N = 1144) demonstrating preschool-based moderate-to-vigorous physical activity (MVPA) is essential for developing preschoolers' muscular strength, speed-agility, and cardiorespiratory fitness, complementing existing 24-h movement behavior research. Reveals critical asymmetry: Reducing MVPA time significantly harms fitness, with losses exceeding the benefits from equivalent MVPA increases. Provides objective evidence to guide policymakers in optimizing preschool schedules to prioritize MVPA for enhancing children's physical fitness. Show less
While anticounterfeiting systems based on long persistent luminescence (LPL) materials demonstrate a mature trend, the integration of tunable luminescent lifetimes and emission colors in LPL-based ant Show more
While anticounterfeiting systems based on long persistent luminescence (LPL) materials demonstrate a mature trend, the integration of tunable luminescent lifetimes and emission colors in LPL-based anticounterfeiting systems remains a challenge. Herein, we propose a temporal and spatial anticounterfeiting strategy utilizing novel zero dimensional (0D) metal halides, specifically (PBA) Show less
The prognosis for colorectal cancer (CRC) patients with liver metastasis remains poor, and the molecular mechanisms driving CRC liver metastasis are not fully understood. Tumor-derived hypoxia-induced Show more
The prognosis for colorectal cancer (CRC) patients with liver metastasis remains poor, and the molecular mechanisms driving CRC liver metastasis are not fully understood. Tumor-derived hypoxia-induced extracellular vesicles have emerged as key players in inducing angiogenesis by transferring noncoding RNAs. However, the specific role of CRC-derived hypoxic extracellular vesicles (H-EVs) in regulating premetastatic microenvironment (PMN) formation by inducing angiogenesis remains unclear. Our study demonstrates that H-EVs induce angiogenesis and liver metastasis. Through microRNA microarray analysis, we identified a reduction in miR-6084 levels within H-EVs. We found that miR-6084 inhibited angiogenesis by being transferred to endothelial cells via EVs. In endothelial cells, miR-6084 directly targeted angiopoietin like 4 (ANGPTL4) mRNA, thereby suppressing angiogenesis through the ANGPTL4-mediated JAK2/STAT3 pathway. Furthermore, we uncovered that specificity protein 1 (SP1) acted as a transcription factor regulating miR-6084 transcription, while hypoxia-inducible factor 1A (HIF1A) decreased miR-6084 expression by promoting SP1 protein dephosphorylation and facilitating ubiquitin-proteasome degradation in SW620 cells. In clinical samples, we observed low expression of miR-6084 in plasma-derived EVs from CRC patients with liver metastasis. In summary, our findings suggest that CRC-derived H-EVs promote angiogenesis and liver metastasis through the HIF1A/SP1/miR-6084/ANGPTL4 axis. Additionally, miR-6084 holds promise as a diagnostic and prognostic biomarker for CRC liver metastasis. Show less
We investigated the association between lipoprotein(a) [Lp(a)] levels and stroke recurrence in type 2 diabetes mellitus (T2DM) patients with recent acute ischemic stroke or transient ischemic attack ( Show more
We investigated the association between lipoprotein(a) [Lp(a)] levels and stroke recurrence in type 2 diabetes mellitus (T2DM) patients with recent acute ischemic stroke or transient ischemic attack (TIA). This study included 3,311 T2DM patients with recent acute ischemic stroke or TIA and complete Lp(a) data from the Third China National Stroke Registry. The patients were categorized into three groups based on the 40th and 70th percentiles of the Lp(a): ≤13.1, 13.1 to 29.2 and ≥ 29.2 mg/dL. The primary outcome was stroke recurrence within one year, with incident cases further classified as either ischemic or hemorrhagic. Cox proportional hazards regression and restricted cubic splines were used to evaluate these associations. A total of 3311 patients (2142 men, 64.69%, median age 63) were analyzed. Restricted cubic spline analysis revealed a U-shaped relationship between Lp(a) levels and the risk of stroke recurrence. After adjusting for cardiovascular risk factors, patients with Lp(a) levels ≤ 13.1 mg/dL or ≥ 29.2 mg/dL had hazard ratios of 1.34 (95% confidence interval (CI), 1.02-1.76) and 1.35 (95% CI, 1.01-1.79), respectively, for total stroke compared to those with Lp(a) levels between 13.1 and 29.2 mg/dL. The corresponding hazard ratios were 1.36 (95% CI, 1.02-1.81) and 1.36 (95% CI, 1.01-1.83) for ischemic stroke and 0.88 (95% CI, 0.37-2.09) and 0.77 (95% CI, 0.31-1.94) for hemorrhagic stroke, respectively. Both low and high levels of Lp(a) are associated with an increased risk of stroke recurrence in T2DM patients with a recent history of acute ischemic stroke or TIA, demonstrating a U-shaped relationship. Show less
Liver X receptor α (LXRα) plays an important role in inflammatory immune response induced by hepatic ischemia-reperfusion injury (IRI) and acute rejection (AR). Macrophage M1-polarization play an impo Show more
Liver X receptor α (LXRα) plays an important role in inflammatory immune response induced by hepatic ischemia-reperfusion injury (IRI) and acute rejection (AR). Macrophage M1-polarization play an important role in the occurrence and development of AR. Although the activation of LXR has anti-inflammatory effects, the role of LXRα in AR after liver transplantation (LT) has not been elucidated. We aimed to investigate LXRα anti-inflammatory and macrophage polarization regulation effects and mechanisms in acute rejection rat models. LXRα anti-inflammatory and liver function protective effects was initially measured in primary Kupffer cells and LT rat models. Subsequently, a flow cytometry assay was used to detect the regulation effect of LXRα in macrophage polarization. HE staining, TUNEL and ELISA were used to evaluate the co-treatment effects of TO901317 and tacrolimus on hepatic apoptosis and liver acute rejection after LT. In this study, we found that LPS can inhibit the expression of LXRα and activate MAPK pathway and PI3K/AKT/mTOR. We also found that LXRα agonist (TO901317) could improve liver function and rat survival after LT by activating the level of ABCA1 and inhibiting MAPK. TO901317 could inhibit macrophage M1-polarization by activating PI3K/AKT/mTOR signal pathway to improve the liver lesion of AR rats after liver transplantation. Additionally, co-treatment with TO901317 and tacrolimus more effectively alleviated the damaging effects of AR following LT than either drug alone. Our results suggest that the activation of LXRα can improve liver function and rat survival after LT by regulate ABCA1/MAPK and PI3K/AKT/mTOR signaling axis in macrophages. Show less
To develop and evaluate a predictive model for myocardial injury in patients with advanced gastric cancer treated with fluorouracil plus platinum-based chemotherapy, incorporating baseline characteris Show more
To develop and evaluate a predictive model for myocardial injury in patients with advanced gastric cancer treated with fluorouracil plus platinum-based chemotherapy, incorporating baseline characteristics and inflammatory, nutritional, and atherosclerotic factors. A total of 268 patients with advanced gastric cancer who received this treatment between April 2020 and September 2024 were selected and divided into a training set ( In the training set, 56 patients (29.79%) developed myocardial injury, while 23 patients (28.75%) in the validation set developed myocardial injury, with no statistically significant difference in the incidence or clinical characteristics between the two sets ( This predictive model aids in the early identification of myocardial injury, guiding clinical decision-making and improving prognosis. Show less
Hyperlipidemia is a common metabolic disorder and a risk factor for cardiovascular disease. The traditional medicine herb, Hippophae rhamnoides L., known as sea buckthorn, has anti-obesity and lipid-l Show more
Hyperlipidemia is a common metabolic disorder and a risk factor for cardiovascular disease. The traditional medicine herb, Hippophae rhamnoides L., known as sea buckthorn, has anti-obesity and lipid-lowering effects, while Silybum marianum (L.) Gaertn, known as milk thistle, has hepatoprotective properties and exhibits antioxidant effects. To evaluate the effect of sea buckthorn and milk thistle solid beverage (H-S solid beverage) in alleviating hyperlipidemia in rats and explore the underlying mechanisms by analyzing plasma and liver metabolomics, lipidomics, and liver transcriptomics. A hyperlipidemic rat model was established after 2 weeks of high-fat diet (HFD) feeding in Sprague Dawley rats. The administered doses of H-S solid beverage were 0.30 g/kg/d, 0.15 g/kg/d and 0.075 g/kg/d. Serum biochemical parameter detection, histopathological section analysis, untargeted plasma and liver metabolomics, lipidomics, and liver transcriptomics were performed to determine the therapeutic effects of H-S solid beverage and predict the related pathways in rats with hyperlipidemia. Changes in genes and proteins related to lipid metabolism were detected using real-time quantitative polymerase chain reaction and western blotting. Eighty-nine components were identified in H-S solid beverage using ultra-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry, with flavonoids being the major constituents. The H-S solid beverage significantly reduced body weight, liver index, body fat percentage, lipid accumulation, and liver injury in HFD-fed rats. Fatty acids (FA), bile acid, phosphatidyl ethanolamine, phosphatidylcholine, triglyceride, cholesterol ester, diglyceride and phosphatidylinositol levels were significantly altered in the liver and plasma. Moreover, the transcriptomic analysis suggested that H-S solid beverage significantly altered the hepatic gene expression of cholesterol synthesis (Pdk4, Hmgcs1, and Dhcr24), lipogenesis (Scd, Angptl4, and Angptl8), and FA β-oxidation (Cpt1α, Pparδ, Acsl, Pgc-1α, and Pla2g2d). The solid beverage of sea buckthorn and milk thistle was firstly demonstrated to ameliorate HFD-induced hyperlipidemia. The lipid-lowering and hepatoprotective effects of H-S solid beverage significantly regulated cholesterol synthesis and de novo lipogenesis, as well as FA β-oxidation. In summary, this study highlights the potential of H-S solid beverages for the treatment of hyperlipidemia. Show less
Atherosclerosis (AS) remains a leading cause of cardiovascular morbidity and mortality, characterized by intricate interactions between immune dysregulation and lipid metabolism abnormalities-identify Show more
Atherosclerosis (AS) remains a leading cause of cardiovascular morbidity and mortality, characterized by intricate interactions between immune dysregulation and lipid metabolism abnormalities-identifying key mediators in its pathogenesis is critical for improving diagnostics and therapies. This study focuses on Transmembrane Protein 106A (TMEM106A) to clarify its role and clinical relevance in AS progression. Public transcriptomic datasets (GSE43292, GSE100927, GSE28829) were analyzed to assess TMEM106A expression and diagnostic value; single-cell RNA-seq data (GSE159677) defined its cellular localization. Immune infiltration (ssGSEA, Cibersort, xCell) and CellChat (intercellular communication) analyses explored its immune associations. TMEM106A was significantly upregulated in AS samples across datasets, with strong diagnostic efficacy (AUC 0.80-0.95). Single-cell analysis confirmed its specific enrichment in macrophages, with functional links to immune-related pathways. TMEM106A promoted macrophage infiltration, foam cell formation, oxidative stress, and inflammatory responses, while regulating PLCB2 in chemokine signaling; silencing TMEM106A alleviated these pro-atherosclerotic effects. TMEM106A contributes to AS progression by modulating macrophage-mediated immune responses and chemokine signaling, as validated in experimental models. These findings support its potential as a clinically relevant biomarker and promising therapeutic target for AS intervention. Show less
Diabetic kidney disease (DKD), a common diabetes complication, often progresses to end-stage renal disease (ESRD) Lipid accumulation is crucial in DKD progression, and its dysregulation causes ectopic Show more
Diabetic kidney disease (DKD), a common diabetes complication, often progresses to end-stage renal disease (ESRD) Lipid accumulation is crucial in DKD progression, and its dysregulation causes ectopic fat distribution, inflammation, and renal damage. Soyasapogenol C (SSC) has various therapeutic potentials. However, its effect on DKD and the underlying mechanisms are unknown. This study explores SSC's role in improving DKD, especially in db/db mice, an ideal DKD research model. We hypothesize that by modulating lipid metabolism, especially cholesterol metabolism, SSC could treat DKD. Results show SSC inhibits cholesterol accumulation, interstitial fibrosis, and renal inflammation in db/db mice. In vitro, it suppresses cholesterol accumulation in HK2 cells and increases ABCA1 and ABCG1 levels. Mechanistically, SSC upregulates ABCA1 and ABCG1 via liver X receptor α (LXRα), and this is inhibited by LXRα inhibitor or siRNA knockdown. Our findings offer new insights into SSC's role in cholesterol metabolism and lipid deposition, and new DKD treatment targets. Show less
The entorhinal cortex (ERC) is implicated in early progression of Alzheimer's disease (AD). Here we investigated the impact of established biological risk factors for AD, including
Sudden sensorineural hearing loss (SSNHL) has serious harm to human hearing health, where blood lipid and inflammatory levels may play a key role in it. Thus, the purpose of this investigation was to Show more
Sudden sensorineural hearing loss (SSNHL) has serious harm to human hearing health, where blood lipid and inflammatory levels may play a key role in it. Thus, the purpose of this investigation was to assess the connection between inflammatory and lipid variables and SSNHL. Patients diagnosed with SSNHL had an analysis of serum lipid parameters, such as total cholesterol (TC), triglycerides, HDL-C, LDL-C, apolipoprotein A (apo A), apolipoprotein B (apo B), and lipoprotein A (Lp(a)), as well as inflammatory factors like TNF-α and IL-10. After that, risk factor analysis was carried out utilizing univariate, multivariate regression, and LASSO retrospective modeling. In all, 72 SSNHL patients and 67 healthy control individuals were involved. The LDL/HDL, total cholesterol, ApoB, LP(a), IL-10, TNF-α, and IFN-γ considerably higher in the SSNHL group than in the healthy control group, however, nervonic acid and coenzyme Q were decreased significantly in SSNHL than Control group. The multivariate logistic regression model's analysis using multifactorial retrospective modeling revealed significant changes in LDL, LDL/HDL, IL-10, and TNF-α. In addition, in the LASSO regression model, the model demonstrated high discrimination, as evidenced by the C-index for the cohort's prediction nomogram, which was 0.998 (95% CI, 0.154-1.115) and confirmed to be 0.925 following bootstrapping validation. Finally, IL-10 and LDL/HDL were the main risk factors in SSNHL. LDL/HDL and IL-10 may be closely related to SSNHL's progress and should be evaluated promptly before treating patients with SSNHL. Show less
Traumatic defects or non-union fractures presents a substantial challenge in the fields of tissue engineering and regenerative medicine. Although synthetic calcium phosphate-based biomaterials (CaPs) Show more
Traumatic defects or non-union fractures presents a substantial challenge in the fields of tissue engineering and regenerative medicine. Although synthetic calcium phosphate-based biomaterials (CaPs) such as dibasic calcium phosphate anhydrate (DCPA) are commonly employed for bone repair, their inadequate cellular immune responses significantly impede sustained degradation and optimal osteogenesis. In this study, drawing inspiration from the key structure of an acidic non-collagenous protein-CaP complex (ANCPs-CaP) essential for natural bone formation, we prepared biomimetic mineralized dibasic calcium phosphate (MDCPA). This preparation utilized plant-derived non-collagenous protein Zein as the organic template and acidic artificial saliva as the mineralization medium. Physicochemical property analysis revealed that MDCPA is a complex of Zein and DCPA, which mimics the composite of the natural ANCP-CaP. Moreover, MDCPA exhibited enhanced biodegradability and osteogenic potential. Mechanistic insight revealed that MDCPA can be phagocytized and degraded by macrophages via the FCγRIII receptor, leading to the release of interleukin 27 (IL-27), which promotes osteogenic differentiation by osteoimmunomodulation. The critical role of IL-27 in osteogenesis is further confirmed using IL-27 gene knockout mice. Additionally, MDCPA demonstrates effective healing of critical-sized defects in rat cranial bones within only 4 w, providing a promising basis and valuable insights for critical-sized bone defects regeneration. Show less
Cadmium (Cd) contamination in plants and soil poses significant risks to livestock, particularly sheep. Cd exposure often leads to severe gastrointestinal diseases in sheep that are difficult to treat Show more
Cadmium (Cd) contamination in plants and soil poses significant risks to livestock, particularly sheep. Cd exposure often leads to severe gastrointestinal diseases in sheep that are difficult to treat. Milk-derived exosomes, particularly those from sheep milk (SM-Exo), have shown potential in treating gastrointestinal disorders, though their efficacy in Cd-induced colitis remains unclear. In this study, we investigated the therapeutic potential of SM-Exo in a Cd-induced colitis model. Hu sheep were exposed to Cd, and their fecal microbiota were collected to prepare bacterial solutions for fecal microbiota transplantation (FMT) in mice. The changes in gut microbiota and gene expression were analyzed through microbiome and transcriptomics. Our results showed that prior to treatment, harmful bacteria (e.g., Show less