Gentidelasides A-G (1-7) seven unreported loganin derivatives and fourteen known compounds (8-21) were isolated from the flowers of Gentiana delavayi Franch. Their structures including absolute config Show more
Gentidelasides A-G (1-7) seven unreported loganin derivatives and fourteen known compounds (8-21) were isolated from the flowers of Gentiana delavayi Franch. Their structures including absolute configurations were unambiguously elucidated by analysis of extensive NMR spectroscopy, ECD, and HRESIMS, as well as enzymatic hydrolysis. In vitro bioassay, compound 7 showed obvious inhibitory effects on the production of Aβ40 and Aβ42, with IC 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
Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompl Show more
Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompletely defined. Here, we found that BAF60a functions as a chromatin regulator that sustains biphasic GSIS and preserves β cell function under metabolic stress conditions. BAF60a was downregulated in β cells from obese and diabetic mice, monkeys, and humans. β cell-specific inactivation of BAF60a in adult mice impaired GSIS, leading to hyperglycemia and glucose intolerance. Conversely, restoring BAF60a expression improved β cell function and systemic glucose homeostasis. Mechanistically, BAF60a physically interacted with Nkx6.1 to selectively modulate chromatin accessibility and transcriptional activity of target genes critical for GSIS coupling in islet β cells. A BAF60a V278M mutation associated with decreased β cell GSIS function was identified in human donors. Mice carrying this mutation, which disrupted the interaction between BAF60a and Nkx6.1, displayed β cell dysfunction and impaired glucose homeostasis. In addition, GLP-1R and GIPR expression was significantly reduced in BAF60a-deficient islets, attenuating the insulinotropic effect of GLP-1R agonists. Together, these findings support a role for BAF60a as a component of the epigenetic machinery that shapes the chromatin landscape in β cells critical for glucose sensing and insulin secretion. 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
The Huainan pig (HN) is known for its impressive litter size and exquisite meat quality. However, it also exhibits certain drawbacks such as excessive fat deposition, a relatively low percentage of le Show more
The Huainan pig (HN) is known for its impressive litter size and exquisite meat quality. However, it also exhibits certain drawbacks such as excessive fat deposition, a relatively low percentage of lean meat percentage, and a slower growth rate. Crossbreeding with lean-type breeds, such as Large White, Landrace, and Berkshire can enhance offspring traits, and increase genetic diversity. In this study we employed RNA-seq technology to identify differentially expressed genes (DEGs) in subcutaneous adipose tissue (SAT) samples from HN pigs and their crosses with multiple breeds (with three replicates per group). In the SAT of Huainan × Berkshire pigs (BH), Huainan × Yorkshire pigs (YH), and Huainan × Landrace pigs (LH), numerous key functional genes were identified, including In conclusion, these findings offer valuable insights and provide a foundation for future research on the molecular mechanisms underlying fat deposition in pigs. Show less
To clarify the anatomical characteristics of the lateral plantar ligament (LPL) of the transverse metatarsal arch (TMA) in the population of southwest Shandong Province, so as to complement the anatom Show more
To clarify the anatomical characteristics of the lateral plantar ligament (LPL) of the transverse metatarsal arch (TMA) in the population of southwest Shandong Province, so as to complement the anatomical structures of the midfoot and Lisfranc joint complexes. A total of 100 adult lower limbs were dissected and the types of LPL were divided according to their insertions, among them, 63 were (63%) and 37 were female (37%); 50 were on the left side (50%) and 50 were on the right side (50%). The fiber bundle length, origin width, insertion width, and thickness of the LPL were measured. (1) According to the insertions of the LPL, they were divided into: ① Type I, the LPL was inserted at the base of the second metatarsal (M2) in 47 cases; ② Type II, the LPL was inserted at the base of M2 and fused with tibialis posterior tendon (TPT) in 16 cases; ③ Type III, the LPL was absent in 16 cases; ④ Type IV, the LPL was inserted at TPT in 6 cases; ⑤ Type V, the LPL was inserted at the intermediate cuneiform (IC) in 1 case; ⑥ Type VI, bifid LPL with one bundle inserted at the base of M2, and the other bundle inserted at the medial cuneiform (MC) in 4 cases; ⑦ Type VII, two bundles of LPL inserted at the base of M2 in 8 cases; ⑧ Type VIII, the LPL consisted of 3 bundles; the distal, middle and proximal bundles was inserted at the base of M2, the TPT and the lateral side of navicular bone in 2 cases, respectively. (2) There was a statistical significance in the length of LPL between male (31.62 ± 3.83) mm and female (28.07 ± 3.46) mm (t=-3.050, P = 0.003). There was no statistical significance in the types of LPL between male and female (Z=-1.721, P > 0.05), and no statistical significance in the types between left and right sides (Z=-0.026, P > 0.05). According to our research, LPL originates from M5 and is divided into 8 types according to its insertion location, of which insertion at the base of M2 is the most common. In addition, we found that LPL has fibrous fusion with the long plantar ligament and the TPT, which may be involved in maintaining arch stability. The classification of LPL in this study is a supplement to the anatomical structure of the middle foot and Lisfranc joint complex, providing a new direction for the diagnosis and treatment of middle foot and arch injury in the future. Show less
Bladder cancer (BC) is one of the most common urological malignancies, ranking as the eleventh most common cause of cancer-related deaths worldwide. The lack of specific and sensitive prognostic bioma Show more
Bladder cancer (BC) is one of the most common urological malignancies, ranking as the eleventh most common cause of cancer-related deaths worldwide. The lack of specific and sensitive prognostic biomarkers presents a significant challenge in the early diagnosis and treatment of BC. We used the Gene Expression Omnibus (GEO) dataset GSE13507 and the Cancer Genome Atlas (TCGA) database to screen differentially expressed genes related to BC. By using Weighted Gene Co-expression Network Analysis (WGCNA), two modules associated with BC were investigated in GSE13507 and TCGA. Hub genes were identified through Protein-Protein Interaction (PPI) network analysis and their functions were validated through multiple approaches, including Gene Expression Profiling Interactive Analysis (GEPIA), Western Blotting (WB) assay, Human Protein Atlas (HPA), Oncomine analysis, and quantitative Real-Time PCR (qRTPCR) analysis. Additionally, miRNAs associated with hub gene expression were identified using various databases to predict the progression and prognosis of BC. WCGNA and differential gene expression analysis identified 171 common genes as target genes. Ten genes (MYH11, ACTA2, TPM2, ACTG2, CALD1, MYL9, TPM1, MYLK, SORBS1, and LMOD1) were identified using the PPI tool and the CytoHubba plugin of Cytoscape. The CALD1 and MYLK genes showed a significant prognostic value for overall survival and diseasefree survival in patients with BC. According to the HPA and Oncomine databases, CALD1 and MYLK expression levels were significantly lower in BC tissues than in normal tissues. Additionally, qRT-PCR analysis, WB assay, and immunohistochemical analysis confirmed CALD1 and MYLK as tumor suppressor genes in BC. Furthermore, miR-155 showed a significant positive correlation with MYLK. This study established MYLK as a direct target gene of miR-155, functioning as an actionable survival-related gene correlated with BC development. Show less
Ruotong Li, Wenye Zhao, Jiaxin Zhang+7 more · 2025 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
The global increase in muscle weakness poses a critical public health concern. Nutritional interventions that improve muscular function hold promise as a therapeutic potential. Vitamin A (VA) and its Show more
The global increase in muscle weakness poses a critical public health concern. Nutritional interventions that improve muscular function hold promise as a therapeutic potential. Vitamin A (VA) and its active metabolites have been implicated in muscle development and the transformation of muscle fiber types. However, conventional VA formulations are restricted by poor stability and low bioavailability. In this study, a stable Nano VA was utilized to systematically evaluate its effects on muscle development and exercise performance in mice, as well as to explore its underlying mechanisms. A total of 44 male C57BL/6J mice were randomly divided into four groups: (i) normal control (NC), (ii) 5 mg/kg Nano VA (5 NVA), (iii) 10 mg/kg Nano VA (10 NVA), and (iv) 10 mg/kg VA (10 VA). The 10 NVA group demonstrated significantly improved muscle strength and swimming endurance, compared with the NC group. Further examination suggested a significant increase in myofiber diameter, cross-sectional area, and the content of fast-twitch fibers. Additionally, Nano VA treatment improved glucose tolerance and insulin sensitivity. To elucidate the mechanism by which Nano VA enhances muscle locomotor ability, transcriptomics and metabolomics data identified 111 differentially expressed genes and 253 differential metabolites. Of these, Angptl4, Ppp1r3a, and Cyp26b1 were identified as candidate regulators of muscle development and myofiber type transformation. In conclusion, Nano VA regulates muscle development and promotes muscle fiber type conversion, thus improving muscle strength and endurance in mice. Moreover, Nano VA facilitates mitigating and improving myasthenia gravis-related conditions. Show less
Disrupting liver immune homeostasis drives inflammation. Recent evidence shifts immunoregulatory focus to hepatocytes, though the mechanisms remain poorly defined. Forkhead box O1 (FoxO1) is a critica Show more
Disrupting liver immune homeostasis drives inflammation. Recent evidence shifts immunoregulatory focus to hepatocytes, though the mechanisms remain poorly defined. Forkhead box O1 (FoxO1) is a critical homeostasis regulator, but its function in liver immune homeostasis is unknown. We aimed to clarify the role of hepatocyte FoxO1 in liver immune homeostasis and inflammation. Human liver FoxO1 expression and its association with inflammation were analyzed in patients with various inflammation-related liver diseases. Hepatocyte-specific Foxo1 knockout (FoxO1 △hepa ) mice were established. Hepatocyte-specific gene interference was employed in alcoholic hepatitis and hepatic schistosomiasis murine models. Transcriptomic, single-cell RNA sequencing, and CUT&Tag analyses were performed to elucidate the underlying mechanisms. Hepatocyte FoxO1 levels in human inflammatory livers declined prevalently and were inversely correlated with inflammation and fibrosis. Around 15-18 weeks after birth, FoxO1 △hepa mice exhibited mild spontaneous hepatic inflammation with natural killer T (NKT) cell and neutrophil accumulation. NKT cell depletion in FoxO1 △hepa mice with alcoholic hepatitis or hepatic schistosomiasis (HS) significantly reduced neutrophil accumulation and protected against liver inflammation and damage. Mechanistically, FoxO1 promoted retinoic acid synthesis to induce hepatocyte CD1d expression, which is necessary for regulating NKT cell apoptosis. Innovatively, decreased JMJD1C expression in hepatocytes caused histone H3 lysine 9 (H3K9) dimethylation at the Foxo1 promoter, repressing its transcription and disrupting local immune homeostasis. Our findings uncover a hitherto unrecognized mechanism for hepatocyte-based control of liver inflammation, in which hepatocyte FoxO1 maintained by JMJD1C restrains local NKT cells and neutrophils via CD1d induction, providing promising targets for inflammatory liver diseases. Show less
Sepsis is associated with high morbidity and high mortality and has strongly motivated intense studies into its mechanisms. Antibiotics, aimed to eradicate bacteria, have some impact on the immune sys Show more
Sepsis is associated with high morbidity and high mortality and has strongly motivated intense studies into its mechanisms. Antibiotics, aimed to eradicate bacteria, have some impact on the immune system due to anti-inflammatory properties. Tigecycline, an antibiotic of the glycylcycline class, is commonly used for severe infections. This study aimed to investigate tigecycline's mechanism on the inflammatory response of sepsis to find new targets for sepsis treatment. The objective included (i) to observe the changes in inflammatory factors in LPS (lipopolysaccharide) induced septic mice after tigecycline administration, (ii) to detect the effect of tigecycline on macrophages NF-κB (nuclear factor kappa B) signalling. For LPS-induced sepsis in mice and intervention with tigecycline, mice were first injected with tigecycline (6.5 mg/kg) via tail vein followed by LPS (15 mg/kg). Luminex analysis was performed on 16 mediators. NF-κB signalling pathway antibody chip detected the expression of target sites in macrophages of the LPS group and tigecycline + LPS group. Tigecycline has inhibitory effects on LPS-induced inflammatory response in septic mice, decreasing the concentrations of IL (interleukin)-6, IL-27, TNF-α (tumour necrosis factor-α), TNF RII, IFN-γ (interferon-gamma), CCL5/RANTES (CC Motif Chemokine Ligand) while increasing IL-6Rα, IL-10, and TWEAK (TNF-related weak inducer of apoptosis). Tigecycline downregulated phosphorylation levels of key sites JNK (c-Jun N-terminal kinase)1/2/3, p-p65 (s468) and p-p105/p50 (s907) in NF-κB signalling. Tigecycline may inhibit the excessive immune response induced by LPS in sepsis, which may cause a potential protective effect on the host through immune regulation. Show less
The current study aimed to clarify the roles of apolipoprotein A5 (ApoA5) and milk fat globule-epidermal growth factor 8 (Mfge8) in regulating myocardial lipid deposition and the regulatory relationsh Show more
The current study aimed to clarify the roles of apolipoprotein A5 (ApoA5) and milk fat globule-epidermal growth factor 8 (Mfge8) in regulating myocardial lipid deposition and the regulatory relationship between them. The serum levels of ApoA5 and Mfge8 in obese and healthy people were compared, and the obesity mouse model induced by the high-fat diet (HFD) was established. In addition, primary cardiomyocytes were purified and identified from the hearts of suckling mice. The 0.8 mmol/L sodium palmitate treatment was used to establish the lipid deposition cardiomyocyte model 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
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular bacterial pathogen that grows within a specialized membrane-bound compartment known as the Salmonella-containing Show more
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular bacterial pathogen that grows within a specialized membrane-bound compartment known as the Salmonella-containing vacuole (SCV). The molecular composition and regulatory mechanisms governing SCV dynamics remain incompletely understood. In this study, we employed proximity-dependent biotin identification (BioID) to analyze the SCV proteome during infection. For this, we targeted the UltraID biotin ligase to the SCV by fusing it to a type 3 secreted effector. We demonstrate that the bacteria express and translocate the effector-UltraID fusion protein directly into host cells for labeling of the cytosolic face of the SCV surface. Proteomic analysis of biotinylated proteins revealed previously undescribed proteins associated with the SCV, including regulators of vesicular trafficking, cellular metabolism and lipid transport. Among these, VPS13C, a lipid transporter and membrane contact site protein, was identified as a critical regulator of SCV morphology and fission. Functional studies revealed that VPS13C also promotes ER-SCV contact formation, controls SCV positioning in host cells, and facilitates cell-to-cell spread by the bacteria. Together, our findings highlight the utility of BioID as a tool to study host-pathogen interactions in the context of infection and characterize VPS13C as a novel modulator of the intracellular life cycle of S. Typhimurium. Show less
Long noncoding RNAs (lncRNAs), non-protein-coding transcripts exceeding 200 nucleotides, are critical regulators of gene expression through chromatin remodeling, transcriptional modulation, and post-t Show more
Long noncoding RNAs (lncRNAs), non-protein-coding transcripts exceeding 200 nucleotides, are critical regulators of gene expression through chromatin remodeling, transcriptional modulation, and post-transcriptional modifications. While ionizing radiation (IR) induces cellular damage through direct DNA breaks, reactive oxygen species (ROS)-mediated oxidative stress, and bystander effects, the functional involvement of lncRNAs in the radiation response remains incompletely characterized. Here, through genome-wide CRISPR activation (CRISPRa) screening in non-small cell lung cancer (NSCLC) cells, we identified LOC401312 as a novel radiosensitizing lncRNA, the stable overexpression of which significantly enhanced IR sensitivity. Transcriptomic profiling revealed that LOC401312 transcriptionally upregulates carbamoyl-phosphate synthase 1 (CPS1), a mitochondrial enzyme involved in pyrimidine biosynthesis. Notably, CPS1 overexpression recapitulated the radiosensitization phenotype observed with LOC401312 activation. Mechanistic investigations revealed that CPS1 suppresses the phosphorylation of ATM kinase (Ser1981) protein, which is a key mediator of DNA damage checkpoint activation. This study established the LOC401312-CPS1-ATM axis as a previously unrecognized regulatory network governing radiation sensitivity, highlighting the potential of lncRNA-directed metabolic rewiring to impair DNA repair fidelity. Our findings not only expand the functional landscape of lncRNAs in DNA damage response but also provide a therapeutic rationale for targeting the LOC401312-CPS1 axis to improve radiotherapy efficacy in NSCLC. Show less
Symptom burden in primary brain tumor patients varies, emphasizing the need for comprehensive understanding to improve patient care. This study aims to identify distinct symptom clusters among brain t Show more
Symptom burden in primary brain tumor patients varies, emphasizing the need for comprehensive understanding to improve patient care. This study aims to identify distinct symptom clusters among brain tumor patients in Shanghai, China, using Latent Profile Analysis (LPA) to guide personalized diagnosis, treatment, and supportive care. A longitudinal study was conducted among 161 patients with primary brain tumors in Shanghai. Participants completed the MD Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) at three intervals: the day of admission (T1), three days after surgery (T2), and two weeks after surgery (T3). Latent Profile Analysis (LPA) was used to identify subgroups with unique symptom patterns. Six distinct subgroups were identified (entropy = 0.964), ranging from low-burden to persistently severe patterns. Subgroup membership was partially associated with age, tumor grade, and diagnosis. These subgroups were: transient postoperative burden group, stable symptom with cognitive emergence group, distress-predominant, low burden group, elderly-high grade, persistently severe group, nausea-dominant recovery group, and distress-plus-nausea, younger urban group. Our findings reveal substantial heterogeneity in perioperative symptom experiences among brain tumor patients. Identifying subgroups with high and persistent symptom burden may help clinicians target interventions such as enhanced education, proactive monitoring, rehabilitation, psychological support, and antiemetic management. This subgroup-based approach may improve quality of life, reduce morbidity, and guide precision supportive care in neuro-oncology. Show less
Jessica Blumenfeld, Yaqiao Li, Min Joo Kim+12 more · 2025 · bioRxiv : the preprint server for biology · Cold Spring Harbor Laboratory · added 2026-04-24
Apolipoprotein E4 (APOE4), the strongest genetic risk factor for late-onset Alzheimer's disease (AD), exacerbates tau tangles, amyloid plaques, neurodegeneration, and neuroinflammation-the pathologica Show more
Apolipoprotein E4 (APOE4), the strongest genetic risk factor for late-onset Alzheimer's disease (AD), exacerbates tau tangles, amyloid plaques, neurodegeneration, and neuroinflammation-the pathological hallmarks of AD. While astrocytes are the primary producers of APOE in the CNS, neurons increase APOE expression under stress and aging. Prior work established that neuronal APOE4 is essential for AD pathogenesis, but whether it is sufficient to drive disease remained unknown. We generated a PS19 tauopathy mouse model selectively expressing APOE4 in neurons. Neuronal APOE4 alone proved sufficient to promote pathological tau accumulation and propagation, neurodegeneration, and neuroinflammation to levels comparable to a tauopathy model with human APOE4 knocked-in globally. Single-nucleus RNA sequencing further revealed similar transcriptomic changes in neurons and glia of both models. Together, these findings demonstrate that neuronal APOE4 alone can initiate and propagate AD pathologies, underscoring its pivotal role in disease pathogenesis and its potential as a therapeutic target. Show less
Qianzhu Jiang, Huiting Li · 2025 · Journal of bioenergetics and biomembranes · Springer · added 2026-04-24
Myocardial fibrosis (MF) is a key pathological process driving heart failure, characterized by excessive extracellular matrix (ECM) deposition and impaired cardiac function. Although myocyte-specific Show more
Myocardial fibrosis (MF) is a key pathological process driving heart failure, characterized by excessive extracellular matrix (ECM) deposition and impaired cardiac function. Although myocyte-specific enhancer factor 2 A (MEF2A) is implicated in cardiac fibroblast activation, its role in MF remains unclear. We manipulated MEF2A expression in cardiac fibroblasts (CFs) through knockdown and overexpression, and assessed fibrosis markers, migration, and RhoA signaling. Binding of MEF2A to the Snail1 promoter was predicted using JASPAR and validated by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. Rescue experiments with Snail1 overexpression and RhoA inhibition were performed. An angiotensin II (Ang II)-induced MF mouse model was used to evaluate cardiac function by echocardiography and to assess collagen deposition through picrosirius red (PSR) staining. MEF2A was significantly upregulated in Ang II-induced fibrotic hearts and CFs. MEF2A knockdown reduced α-SMA and Col1a1 expression, inhibited CF migration, and suppressed activation of the Snail1/RhoA/α-SMA pathway. ChIP and luciferase assays confirmed the direct binding of MEF2A to the Snail1 promoter. Inhibition of RhoA signaling reversed MEF2A-induced myofibroblast activation and migration. Rescue experiments showed that Snail1 overexpression restored the fibrotic phenotype suppressed by MEF2A knockdown. In vivo, MEF2A knockdown improved left ventricular function, reduced collagen deposition (PSR staining), and lowered heart weight/tibia length ratios. MEF2A promotes myocardial fibrosis by directly activating Snail1 and engages the RhoA/α-SMA pathway. Targeting MEF2A offers a promising therapeutic strategy to attenuate MF and improve heart function. Show less
The association between low-density lipoprotein (LDL) cholesterol and increased mortality risk has been well-documented, yet apolipoprotein B (apoB) is regarded as a more precise risk indicator. Howev Show more
The association between low-density lipoprotein (LDL) cholesterol and increased mortality risk has been well-documented, yet apolipoprotein B (apoB) is regarded as a more precise risk indicator. However, a comprehensive analysis integrating both markers in relation to mortality risk remains unreported. This study aimed to investigate the relationship between LDL cholesterol levels and mortality across varying apoB concentrations within the general population. Data from 15,380 participants in the 2005-2016 National Health and Nutrition Examination Survey (NHANES) were utilized to construct Cox regression models and apply restricted cubic splines, assessing the association between LDL cholesterol and mortality across distinct apoB stratifications. The study cohort had a median (IQR) age of 46.0 (32.0, 60.0) years, with 7949 (51.8%) males. During a median follow-up of 101.0 months (IQR: 67-137), 1771 (8.8%) all-cause mortality events were observed; 443 (2.1%) deaths were attributed to cardiovascular diseases, while 109 (0.5%) resulted from cerebrovascular diseases. Low apoB and LDL-cholesterol levels were independently linked to an elevated risk of all-cause and cardiovascular mortality. Compared with participants having apoB <90 mg/dL and LDL-cholesterol levels between 100-129 mg/dL, those with LDL-cholesterol <70 mg/dL (HR, 1.81; 95%CI: 1.39-2.36) and 70-99 mg/dL (HR, 1.28; 95%CI: 1.01-1.62) demonstrated a higher risk of all-cause mortality. Additionally, reduced apoB levels contributed to an increased risk of cardiovascular mortality among individuals with low LDL-cholesterol levels. Low apoB and LDL-cholesterol levels were associated with heightened all-cause and cardiovascular mortality risk in the general population. Conversely, high apoB and low LDL-cholesterol levels did not correlate with increased mortality risk. Show less
Two-coordinate coinage metal complexes have been exploited for various applications. Herein, a new donor-metal-acceptor (D-M-A) complex PZI-Au-TOT, using bulky pyrazine-fused N-heterocyclic carbene (P Show more
Two-coordinate coinage metal complexes have been exploited for various applications. Herein, a new donor-metal-acceptor (D-M-A) complex PZI-Au-TOT, using bulky pyrazine-fused N-heterocyclic carbene (PZI) and trioxytriphenylamine (TOT) ligands, was synthesized. PZI-Au-TOT displays decent thermally activated delayed fluorescence (TADF) with a quantum yield of 93 % in doped film. The crystals of PZI-Au-TOT show simultaneous TADF, polymorphism, and linearly polarized luminescence (LPL). The polymorph-dependent emission properties with widely varied peaks from 560 to 655 nm are attributed to different packing modes in terms of isolated monomers, discrete π-π stacked dimers or dimer PLUS. Two well-defined microcrystals of PZI-Au-TOT exhibit linearly polarized thermally activated delayed fluorescence with a degree of polarization up to 0.64. This work demonstrates that the molecular rotational flexibility of D-M-A type complexes endows an integration of multiple functions into one complex through manipulation of supramolecular aggregation. This type of complexes is expected to serve as a versatile platform for the fabrication of crystal materials for advanced photonic applications. Show less
Limited identification of insulin resistance-associated loci hinders understanding of its role in cardiometabolic health, impeding therapeutic strategies. We apply three multivariate genome-wide assoc Show more
Limited identification of insulin resistance-associated loci hinders understanding of its role in cardiometabolic health, impeding therapeutic strategies. We apply three multivariate genome-wide association study approaches on homeostatic model assessment for insulin resistance, insulin resistance index, fasting insulin, and ratio of triglycerides to high-density lipoprotein cholesterol from MAGIC and UK Biobank to develop a comprehensive phenotype ('mvIR'), and identify 217 independent loci, including 24 novel loci. The mvIR is causally associated with higher risks of 17 cardiometabolic diseases and five aging phenotypes, independent of adiposity and sarcopenia. We outline 21 of 2644 druggable genes for insulin resistance by Mendelian randomization and colocalization, where six genes (AKT1, ERBB3, FCGR1A, FGFR1, LPL, NR1H3) encode targets for approved drugs with consistent directions in alleviating insulin resistance, with no significant side effects revealed by phenome-wide association study. This study uncovers novel loci and therapeutic targets to inform strategies promoting insulin resistance-centered cardiometabolic health and longevity. Show less
To establish an The 6-8-week-old C57BL/6N female mice and BALB/c female mice were used as the donor and recipient mice of the aGVHD model, respectively. Bone marrow transplantation (BMT) mouse model ( Show more
To establish an The 6-8-week-old C57BL/6N female mice and BALB/c female mice were used as the donor and recipient mice of the aGVHD model, respectively. Bone marrow transplantation (BMT) mouse model ( An The adipogenic differentiation capacity of MSCs is inhibited by aGVHD mouse serum. Show less
no PDFDOI: 10.19746/j.cnki.issn.1009-2137.2025.01.038
Nolan Priedigkeit, Beth Harrison, Robert Shue+27 more · 2025 · Clinical cancer research : an official journal of the American Association for Cancer Research · added 2026-04-24
Inflammatory breast cancer (IBC) is a rare and clinically distinct form of breast cancer associated with poor outcomes. The biological mechanisms driving IBC remain poorly understood, partly due to li Show more
Inflammatory breast cancer (IBC) is a rare and clinically distinct form of breast cancer associated with poor outcomes. The biological mechanisms driving IBC remain poorly understood, partly due to limited large-scale genomic studies that directly compare IBC with non-IBC cases. We conducted a retrospective analysis of 140 patients with IBC (68 primary tumors and 72 metastatic tumors) and 2,317 patients with non-IBC (700 primary tumors, 65 local recurrences, and 1,552 metastases). We compared clinicopathologic features, single-nucleotide variants, copy-number variants, tumor mutational burden, and exploratory survival outcomes between IBC and non-IBC tumors. The most frequent somatic alterations in IBC were detected in TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%), and GATA3 (8%). Multivariate logistic regression revealed a significant enrichment of TP53 single-nucleotide variants in IBC, particularly in HER2+ and hormone receptor-positive disease. Tumor mutational burden did not differ between IBC and non-IBC cases. In HER2+ disease, a pathway analysis revealed an enrichment of NOTCH pathway alterations. TP53, CCND1, and RB1 alterations were associated with poor outcomes in IBC. This study provides a comprehensive resource of somatic alterations in a large cohort of patients with metastatic IBC and non-IBC, highlighting genomic features associated with worse outcomes. Our findings reveal a significant enrichment of TP53 mutations, reinforcing its critical role in IBC pathogenesis. Few other distinct differences in IBC were observed, suggesting further investigations-beyond bulk sequencing of the somatic genome-are required to better understand the biology driving this aggressive disease. Show less
Melatonin (MLT) can improve mitophagy, thereby ameliorating cognitive deficits in Alzheimer's disease (AD) patients. Hence, our research focused on the potential value of MLT-related genes (MRGs) in A Show more
Melatonin (MLT) can improve mitophagy, thereby ameliorating cognitive deficits in Alzheimer's disease (AD) patients. Hence, our research focused on the potential value of MLT-related genes (MRGs) in AD through bioinformatic analysis. First, the key cells in the single-cell dataset GSE138852 were screened out based on the proportion of annotated cells and Fisher's test between the AD and control groups. The differentially expressed genes (DEGs) in the key cell and GSE5281 datasets were identified, and the MRGs in GSE5281 were selected via weighted gene coexpression network analysis. After intersecting two sets of DEGs and MRGs, we performed Mendelian randomization analysis to identify the MRGs causally related to AD. Biomarkers were further ascertained through receiver operating characteristic curve (ROC) and expression analysis in GSE5281 and GSE48350. Furthermore, gene set enrichment analysis, immune infiltration analysis and correlation analysis with metabolic pathways were conducted, as well as construction of a regulator network and molecular docking. According to the Fisher test, oligodendrocytes were regarded as key cells due to their excellent abundance in the GSE138852 dataset, in which there were 281 DEGs between the AD and control groups. After overlapping with 3,490 DEGs and 550 MRGs in GSE5281, four genes were found to be causally related to AD, namely, G protein-coupled receptor, family C, group 5, member B (GPRC5B), Methyltransferase-like protein 7 A (METTL7A), NF-κB inhibitor alpha (NFKBIA) and RAS association domain family 4(RASSF4). Moreover, GPRC5B, NFKBIA and RASSF4 were deemed biomarkers, except for METTL7A, because of their indistinctive expression between the AD and control groups. Biomarkers might be involved in oxidative phosphorylation, adipogenesis and heme metabolism. Moreover, T helper type 17 cells, natural killer cells and CD56dim natural killer cells were significantly correlated with biomarkers. Transcription factors (GATA2, POU2F2, NFKB1, etc.) can regulate the expression of biomarkers. Finally, we discovered that all biomarkers could bind to MLT with a strong binding energy. Our study identified three novel biomarkers related to MLT for AD, namely, GPRC5B, NFKBIA and RASSF4, providing a novel approach for the investigation and treatment of AD patients. Show less
Dominant follicular development and atresia are governed by the proliferation of granulosa cells (GCs), a process influenced by the delicate balance between apoptosis and autophagy. Oxidative stress, Show more
Dominant follicular development and atresia are governed by the proliferation of granulosa cells (GCs), a process influenced by the delicate balance between apoptosis and autophagy. Oxidative stress, a pivotal catalyst of GCs apoptosis, modulates gene expression through epigenetic mechanisms, including chromatin remodeling. Nevertheless, the regulatory mechanisms underpinning GCs functionality in relation to prolificacy remain inadequately elucidated. In this study, we discovered that the chromatin accessibility of nuclear receptor subfamily 1 group D member 1 (NR1D1) was markedly enhanced in dominant follicular GCs from low-prolificacy sheep, as evidenced by Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq), which correlated with elevated NR1D1 transcript levels. Remarkably, NR1D1 emerged as a novel regulator of follicular development, exhibiting heightened expression in dominant follicles. The overexpression of NR1D1 induced cell cycle arrest, autophagy activation, and mitochondrial dysfunction via the AMPK pathway, while its knockdown fostered GCs survival and functionality. Furthermore, NR1D1 inhibits the transcription of HSD17B12, thereby contributing to oxidative stress (ROS)-induced apoptosis, as demonstrated by CUT&Tag-qPCR and dual luciferase assays. The downregulation of HSD17B12 partially alleviated the effects of NR1D1 knockdown on GCs functionality. These findings indicate that NR1D1 orchestrates GCs proliferation and apoptosis through the suppression of HSD17B12 and the activation of the AMPK pathway, establishing NR1D1 as a novel transcription factor implicated in follicular development and ovarian function, with significant implications for prolificacy. Show less
Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection te Show more
Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection techniques. Herein, a unique hydrogel incorporating extracellular matrix from fish swim bladder (FSB-ECM), which has distinct advantages over mammalian derived ECM, such as low antigenicity, bioactivity, and source safety, is developed. It consists of collagen, glycoproteins, and proteoglycans, including 13 proteins common in the myocardial matrix and three specific proteins: HSPG, Col12a1, and vWF. This hydrogel enhances cardiac cell adhesion and stretching while promoting angiogenesis and M2 macrophage polarization. In addition, its storage modulus (G') increases over time, reaching about 1000 Pa after 5 min, which facilitates transcatheter delivery and in situ gelling. Furthermore, this hydrogel provides sustained support for cardiac contractions, exhibiting superior longevity. In a rat model of ischemic heart failure, the ejection fraction significantly improves with FSB-ECM treatment, accompanied by increased angiogenesis, reduced inflammation, and decreased infarct size. Finally, RNA sequencing combined with in vitro assays identifies ANGPTL4 as a key protein involved in mediating the effects of FSB-ECM treatment. Overall, this new injectable hydrogel based on FSB-ECM is suitable for transcatheter delivery and possesses remarkable reparative capabilities for treating heart failure. 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
The incidence of silent myocardial infarction (SMI) is increasing. Meanwhile, due to the atypical clinical symptoms and signs associated with SMI, the prognosis for patients is often poor. This predic Show more
The incidence of silent myocardial infarction (SMI) is increasing. Meanwhile, due to the atypical clinical symptoms and signs associated with SMI, the prognosis for patients is often poor. This prediction model used the least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression analyses to screen variables. Predictive accuracy was assessed using the area under the receiver operating characteristic (ROC) curve (AUC). The clinical decision curve analysis (DCA), alongside the calibration curve and clinical impact curve (CIC) analyses, were used to assess model validity. This study included 174 patients, 64 (36.8%) of whom experienced SMI; logistic regression analysis identified six variables: gender, age, high-density lipoprotein cholesterol (HDL-C), apolipoprotein B/apolipoprotein A1 (ApoB/A1), uric acid (UA), and triglyceride glucose-body mass index (TyG-BMI). The results identified the TyG-BMI as a predictor of SMI (odds ratios (OR) = 1.02, 95% CI: 1.01-1.03; The TyG-BMI is an independent predictor of SMI. A prediction model based on the TyG-BMI showed good predictive ability for SMI. Show less
Phosphorylation is a crucial post-translational modification mechanism that enhances proteomic diversity, and its malfunction has been confirmed to be associated with complex traits, especially brain Show more
Phosphorylation is a crucial post-translational modification mechanism that enhances proteomic diversity, and its malfunction has been confirmed to be associated with complex traits, especially brain disorders. One of the factors contributing to this malfunction is the missense mutations given that they may alter the peptides flanking the phosphorylated residues. However, the specific effects of these missense mutations on phosphorylation remain unclear. To ascertain these, a deep learning phosphorylation prediction model (DeepMEP), which is the first to be developed on a Chinese-brain-specific phosphorylation dataset (CBMAP), was established to bridge the phosphorylation and peptides. The impact of each missense mutation on phosphorylation was subsequently quantified based on the differences between the outputs of reference and mutant protein sequences. A permutation test adjusting for the confounding factors was finally employed to estimate the enrichment for high-impact mutations in disease-associated genomic loci. DeepMEP achieved superior predictive performance compared with other existing tools on both CBMAP and publicly available datasets. Enrichment analysis revealed the high-impact mutations were significantly enriched in GWAS signals for Alzheimer’s disease (AD) and Parkinson’s disease (PD). The corresponding genes of those missense mutations overlapping with GWAS included Our study demonstrated that DeepMEP effectively captured the impact of missense mutations on phosphorylation and highlighted an enrichment of high-impact mutations in AD- and PD-associated genomic loci. The online version contains supplementary material available at 10.1186/s40246-025-00898-4. Show less
To investigate the influence of MEK5/ERK5 pathway on mitophagy in osteosarcoma (OS), as well as the involved molecular mechanisms. The overlapped genes of mitophagy-related genes from MSigDB database Show more
To investigate the influence of MEK5/ERK5 pathway on mitophagy in osteosarcoma (OS), as well as the involved molecular mechanisms. The overlapped genes of mitophagy-related genes from MSigDB database and DEGs between metastatic and primary OS groups from GSE32981 were identified. GSVA of mitophagy-related pathways between the metastatic and primary groups were analyzed. The relationships between Nur77 and mitophagy-related pathways, prognosis, immune infiltrating cells, immune response gene sets were investigated. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blotting were utilized to assess the expression levels of MEK5, ERK5, Nur77, PINK1, and Parkin. Cellular behaviors and mitochondrial potential were evaluated via CCK-8, Transwell assay and JC-1 staining. Total 4 overlapped genes were obtained as mitophagy-related DEGs, including GABARAPL1, HIF1A, PINK1, and RB1CC1. The activity scores of 3 mitophagy-related pathways exhibited significant differences between metastatic and primary groups. Importantly, Nur77 was significantly negatively correlated with a mitophagy-related pathway (GOBP MITOPHAGY: R = - 0.48, P = 0.02). The Nur77 expression in metastatic group was remarkedly higher than that in the primary group (P < 0.001). Patients with high Nur77 expression had poor prognosis, with AUC values all above 0.615 in predicting 1-, 3-, and 5-year survival. In addition, Nur77 was closely related to numerous immune cells, including activated dendritic cells, activated mast cells and M0 macrophages, and immune response gene sets chemokines and cytokines (all P < 0.05). In addition, MEK5/ERK5 pathway is activated in OS, and Nur77 is overexpressed in OS, and MEK5/ERK pathway promotes Nur77 expression, tumorigenesis and mitochondrial function in U2OS cells. Cytosporone B implement significantly increased the tumorigenesis of U2OS cells in sh-MEK5 group, and inhibited the weaken in mitochondrial membrane potential caused by MEK5 downregulation, and reversed the protein levels of mitophagy markers PINK1 and Parkin in sh-MEK5 group. MEK5-ERK5 pathway mediates mitophagy by regulating Nur77 to promote tumorigenesis of OS cells. These findings offered promising therapeutic targets for OS. Show less