Perioperative neurocognitive disorder (PND) is a common complication following thoracic surgery and often leading to poor outcomes. Despite ongoing research, effective treatments for late PND remain l Show more
Perioperative neurocognitive disorder (PND) is a common complication following thoracic surgery and often leading to poor outcomes. Despite ongoing research, effective treatments for late PND remain limited. Identifying reliable biomarkers for early diagnosis is, therefore, essential. A prospective cohort study was conducted with 60 elderly patients undergoing thoracic surgery. Serum samples were collected within 10 minutes prior to anesthesia and following extubation to measure adiponectin (APN), cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), aquaporin-4 (AQP4) and brain-derived neurotrophic factor (BDNF). Among PND patients, serum APN, PKA, AQP4, and BDNF levels were markedly decreased compared with the normal group. While serum cAMP (HR = 1.087, p = 0.695, 95% CI [0.284-4.166]) and PKA (HR = 0.996, p = 0.09, 95% CI [0.491-0.947]) were not significantly correlated with PND, serum APN (HR = 0.307, 95% CI [0.113-0.835], p = 0.021), AQP4 (HR = 0.204, 95% CI [0.060-0.697], p = 0.011), and BDNF (HR = 0.382, 95% CI [0.177-0.823], p = 0.014) were protective factors against PND. ROC analysis demonstrated that APN (AUC = 0.68, 95% CI [0.51-0.87]), AQP4 (AUC = 0.73, 95% CI [0.59-0.87]), BDNF (AUC = 0.73, 95% CI [0.59-0.87]), and the model of combining those biomarkers (AUC = 0.91, 95% CI [0.83-0.99]) could predict PND. PND patients exhibited a lower protective stress response to surgical trauma. High serum APN, AQP4, and BDNF levels were independent protective factors for PND, and a combined model of these biomarkers showed predictive potential for PND. Show less
Accelerated population aging and rising incidence of bone defects have intensified the need for advanced bone regeneration strategies. While tissue-engineered scaffolds fabricated via 3D printing offe Show more
Accelerated population aging and rising incidence of bone defects have intensified the need for advanced bone regeneration strategies. While tissue-engineered scaffolds fabricated via 3D printing offer promising alternatives to conventional grafts, most techniques fail to replicate the multi-scale fibrous architecture of native bone extracellular matrix, limiting their biofunctionality. To address this, we developed a hybrid manufacturing strategy integrating low-temperature thermally induced phase separation with extrusion-based 3D printing of polylactic acid (PLA) scaffolds. By optimizing solvent ratios (THF: DMF = 3:1) and freezing temperatures (-196 °C-4 °C), we produced scaffolds with tunable micro-nano fibrous surfaces and macroporous structures. Key findings revealed that scaffolds processed at -196 °C (PLA-196) exhibited the highest porosity (pore size: 6.01 ± 2.06 μm), superior hydrophilicity, and enhanced compressive modulus. These scaffolds significantly promoted BMSC adhesion, proliferation, and osteogenic differentiation via activation of Show less
No studies have explored the genetic differences between the Chinese and other ethnic hypertrophic cardiomyopathy (HCM) populations. This cross-sectional study included Chinese patients ( Chinese HCM Show more
No studies have explored the genetic differences between the Chinese and other ethnic hypertrophic cardiomyopathy (HCM) populations. This cross-sectional study included Chinese patients ( Chinese HCM patients have a higher proportion of rare variants (52.8% vs 13.6%, Our findings suggested that patients of Chinese ancestry with HCM have a higher proportion of rare variants but are less likely to be classified as P/LP variants in HCM genes than those of European origin. The variants of c.3624del in Show less
Sustained activation of hepatic stellate cells (HSCs) drives liver fibrosis in response to chronic liver injury and inflammation. It is reported that profibrogenic signals released from stressed/injur Show more
Sustained activation of hepatic stellate cells (HSCs) drives liver fibrosis in response to chronic liver injury and inflammation. It is reported that profibrogenic signals released from stressed/injured hepatocytes evoke fibrogenic responses in HSCs. However, intrahepatocyte players that modulate such cell-to-cell communications remain poorly defined. In this study, hepatic ChREBPα is found to be reduced in mouse models of chemical-induced liver fibrosis as well as in three groups of human patients with liver fibrosis. Chrebpα-LKO mice are highly sensitive to both chemical (CCL4 and TAA) and bile duct ligation (BDL)-induced liver injury and developed more advanced liver fibrosis without affecting liver lipid content. Hepatocyte ChREBPα overexpression suppressed the activation of HSCs in an in vitro medium transfer experiment in part via inhibiting the expression of profibrogenic factors THBS1 and CTGF. RNA-Seq analysis revealed that E2F1, a novel effector of TGFβ-mediated fibrogenic pathway, is highly induced in the liver of Chrebpα-LKO mice. Hepatic knockdown of E2F1 ameliorated the increased liver fibrosis in mice with hepatic Chrebpα deficiency while reducing the expression of hepatic THBS1 and CTGF. Show less
Pancreatic cancer has a complex immunosuppressive tumor microenvironment (TME), which is highly resistant to conventional therapies and emerging cancer immunotherapies. Oncolytic viruses are multiface Show more
Pancreatic cancer has a complex immunosuppressive tumor microenvironment (TME), which is highly resistant to conventional therapies and emerging cancer immunotherapies. Oncolytic viruses are multifaceted killers of malignant tumors, which can selectively infect, replicate in and lyse tumor cells, release tumor-associated antigens to stimulate specific antitumor immune responses, and recruit immune cells into the TME, turning "cold" tumors "hot". Here, we report a novel A novel oncolytic VV with deletion of the TK, N1L, and A41L genes, and expression of the red fluorescent protein (RFP) gene (VVL-TD-RFP) was constructed using CRISPR-Cas9-based homologous recombination. This virus was armed with IL-27, creating VVL-TD-IL-27. The characteristics of these viruses were evaluated VVL-TD-RFP cured 71.4% of tumor-bearing mice, compared with 14.3% of animals treated with VVLΔTKΔN1L that does not have an A41L gene deletion. Efficacy was mainly dependent on elevated dendritic cell (DC) populations, activation of DC, CD86 VVL-TD-mIL-27 is a potential immunotherapy agent for the treatment of pancreatic cancer, and a clinical study of this virus is warranted. Show less
Obesity-induced metabolic inflammation is a key driver of chronic kidney disease (CKD), with immune dysregulation, particularly among lymphocytes, contributing to early disease pathology. To explore t Show more
Obesity-induced metabolic inflammation is a key driver of chronic kidney disease (CKD), with immune dysregulation, particularly among lymphocytes, contributing to early disease pathology. To explore the role of apolipoprotein A4 (Apoa4) in regulating immune cell metabolism and function, we establish high-fat diet-induced obese (DIO) models using wild-type and Show less
Biomarker profiling from biofluids such as blood are widely measured in clinical research, using for example Olink proteomics panels. One such research focus area is cardiovascular disease (CVD), for Show more
Biomarker profiling from biofluids such as blood are widely measured in clinical research, using for example Olink proteomics panels. One such research focus area is cardiovascular disease (CVD), for which chronic sleep restriction (SR) is a risk factor. However, it remains unclear whether blood levels of commonly measured CVD biomarkers are sensitive to acute dynamic factors such as SR, physical exercise (PEx), and time of day. In this crossover design, 16 normal-weight, healthy men underwent three highly standardized in-lab nights of SR (4.25 h/night) and normal sleep (NS, 8.5 h/night) in randomized order, with 88 CVD blood protein biomarkers quantified using the Olink technology (and selected validation using ELISA) in the morning, evening, and immediately before and repeatedly after 30 min of high-intensity exercise. We found significant time-of-day-dependent changes in several CVD biomarkers. Whereas several proteins were exercise-induced across sleep conditions (such as the canonical exerkines IL- 6 and BDNF), exercise-induced proteomic dynamics differed in response to recurrent SR, compared with following NS. Moreover, SR compared with NS resulted in a biomarker profile previously associated with increased prospective risk of several CVDs across large-scale cohorts (such as higher circulating levels of IL-27 and LGALS9). Our findings highlight how dynamic physiology can modulate CVD biomarker levels. These results also underscore the need to consider sleep duration as a key determinant of cardiovascular health-an emphasis reflected in recent American Heart Association guidelines. Further studies in women, older individuals, and patients with prior CVD, and across different chronotypes and dietary schedules are warranted. Show less
Macropinocytosis is a nonselective form of endocytosis that allows cancer cells to largely take up the extracellular fluid and its contents, including nutrients, growth factors, etc. We first elaborat Show more
Macropinocytosis is a nonselective form of endocytosis that allows cancer cells to largely take up the extracellular fluid and its contents, including nutrients, growth factors, etc. We first elaborate meticulously on the process of macropinocytosis. Only by thoroughly understanding this entire process can we devise targeted strategies against it. We then focus on the central role of the MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) in regulating macropinocytosis, highlighting its significance as a key signaling hub where various pathways converge to control nutrient uptake and metabolic processes. The article covers a comprehensive analysis of the literature on the molecular mechanisms governing macropinocytosis, including the initiation, maturation, and recycling of macropinosomes, with an emphasis on how these processes are hijacked by cancer cells to sustain their growth. Key discussions include the potential therapeutic strategies targeting macropinocytosis, such as enhancing drug delivery via this pathway, inhibiting macropinocytosis to starve cancer cells, blocking the degradation and recycling of macropinosomes, and inducing methuosis - a form of cell death triggered by excessive macropinocytosis. Targeting macropinocytosis represents a novel and innovative approach that could significantly advance the treatment of cancers that rely on this pathway for survival. Through continuous research and innovation, we look forward to developing more effective and safer anti-cancer therapies that will bring new hope to patients. Show less
Diabetic cardiomyopathy (DCM) in type 2 diabetes (T2D) may lead to heart failure and patient death. Fibroblast growth factor 21 (FGF21) is a therapeutic candidate for treating this disease. However, o Show more
Diabetic cardiomyopathy (DCM) in type 2 diabetes (T2D) may lead to heart failure and patient death. Fibroblast growth factor 21 (FGF21) is a therapeutic candidate for treating this disease. However, one impediment to its clinical use is its weak ability to activate downstream signaling pathways. In this study, based on our in-depth understanding of the binding properties of fibroblast growth factor receptor 1c (FGFR1c) with paracrine FGF1 and endocrine FGF21, we engineered a novel FGF21 analog named FGF21 Show less
Interleukin-27 receptor alpha (IL27RA), a key subunit of the interleukin-27 receptor, plays an essential role in T cell-mediated immunity. However, its relevance in breast cancer and response to immun Show more
Interleukin-27 receptor alpha (IL27RA), a key subunit of the interleukin-27 receptor, plays an essential role in T cell-mediated immunity. However, its relevance in breast cancer and response to immunotherapy remains unexplored. We integrated bulk and single-cell RNA sequencing data from TCGA, GEO, and scRNA-seq datasets to analyze IL27RA expression, prognosis, immune infiltration, and treatment response. TIDE and immune checkpoint-treated clinical cohorts were used to assess immunotherapy responsiveness. Chemotherapy sensitivity was predicted using GDSC data, and IL27RA protein expression was validated by Western blot. IL27RA was downregulated in breast cancer but high expression correlated with favorable survival. It was primarily expressed in T cells, particularly CD8⁺ subsets, and associated with enriched immune infiltration and elevated checkpoint gene expression. IL27RA high-expression patients showed lower TIDE scores, better outcomes in ICI-treated cohorts, and higher sensitivity to multiple chemotherapeutic agents. IL27RA is a potential immune biomarker that reflects an inflamed tumor microenvironment and predicts benefit from immunotherapy and chemotherapy in breast cancer. These findings provide novel insights into immune-based stratification using single-cell transcriptomic data. Show less
To clarify the possible mechanism of leptin and α-MSH on the onset of puberty in female offspring rats after prenatal androgen exposure. Sixteen 8-week-old specific pathogen free (SPF) healthy Sprague Show more
To clarify the possible mechanism of leptin and α-MSH on the onset of puberty in female offspring rats after prenatal androgen exposure. Sixteen 8-week-old specific pathogen free (SPF) healthy Sprague Dawley (SD) pregnant rats were randomly divided into the testosterone-treated group (TG, female offspring termed PNA group) or the olive oil control group (OOG, female offspring termed VEH group). The female offspring rats of two groups were raised to 21 days (PND21) and weaned. Six female offspring rats at PND21 (VEH:PNA = 3:3) were randomly selected for transcriptome sequencing. Twenty-seven offspring female rats were randomly divided into three groups (VEHI:VEHII:PNA = 9:9:9). VEHI group was observed until the onset of puberty, VEHII and PNA groups were observed until the 8th week. Compared with VEH group, onset of puberty was not observed in PNA group, and hypothalamic Pomc gene expression at PND21 was lower. Compared with the VEHI group, the body weight, abdominal fat, serum testosterone (T), dehydroepiandrosterone (DHEA) and leptin (LEP) levels were upregulated in the PNA group, while serum gonadotropin-releasing hormone (GnRH), mRNA of hypothalamic estrogen receptor α (ERα), α-melanocyte stimulating hormone (α-MSH), melanocortin receptor-4 (MC4R), GnRH and adipose AR, and the protein of androgen receptor (AR) and leptin receptor (LEPR) in the hypothalamic arcuate nucleus (ARC) were decreased. In the PNA group, there were positive correlations between serum DHEA and mRNA of hypothalamic ERα, MC4R and AR, negative correlations between mRNA of adipose AR and serum T and free testosterone (FT). Prenatal androgen exposure delayed the onset of puberty in female offspring, the possible mechanism of which is that prenatal androgen exposure may increase the levels of androgen and LEP, decreases their sensitivity and the expression of AR, LEPR, and MC4R, reducing GnRH secretion. Show less
Tumorigenesis is typically accompanied by cellular dedifferentiation and the acquisition of stem cell-like attributes. However, few studies have comprehensively evaluated the putative relationships be Show more
Tumorigenesis is typically accompanied by cellular dedifferentiation and the acquisition of stem cell-like attributes. However, few studies have comprehensively evaluated the putative relationships between these characteristics and various cancers. Here, we integrated gene expression and DNA methylation quantitative trait loci (cis-eQTL and cis-mQTL) data from the blood to perform multi-omics Mendelian randomization analysis. Our analyses revealed 967 stem cell-associated genes (P < 0.05) and 11,262 methylation sites (P < 0.01) significantly related to 12 cancers. SMAD7 (cg14321542) in colon cancer, IGF2 (cg13508136) in prostate cancer, and FADS1 (cg07005513) in rectal cancer were prioritized as candidate causal genes and regulatory elements. Notably, using cis-eQTL data from the corresponding tissue sites, we detected 16 stem cell-associated genes dramatically causally associated with six cancers (FDR<0.2). The gene THBS3 was particularly common in both blood and stomach tissues and exhibited prognostic significance. Furthermore, it was markedly associated with one microbial metabolic pathway and four immunophenotypes. Functional validation using the ECC12 gastric cancer cell line revealed that the inhibition of its expression could accelerate oxidative phosphorylation and reactive oxygen species production, reduce clonal proliferation ability, and promote the apoptosis of stomach tumor cells. Additionally, based on spatial transcriptomic data from gastrointestinal cancers, the results demonstrated the clusters enriched with the most stem cell-associated genes exhibited significantly enhanced tumor-promoting potency, and the THBS3-expressing cells displayed suppressed oxidative phosphorylation. Overall, this study enhances our understanding of tumorigenic mechanisms and aids in the identification of therapeutic targets. Show less
The existing evidence regarding the impact of tamoxifen on lipoprotein(a) and apolipoproteins remains inconsistent. Therefore, this updated meta-analysis of randomized controlled trials (RCTs) aims to Show more
The existing evidence regarding the impact of tamoxifen on lipoprotein(a) and apolipoproteins remains inconsistent. Therefore, this updated meta-analysis of randomized controlled trials (RCTs) aims to enhance the quality of evidence concerning the effects of tamoxifen on these lipid parameters. Eligible RCTs published up to October 2024 were meticulously selected through a comprehensive search. A meta-analysis was then performed using a random-effects model, and results were presented as the weighted mean difference (WMD) with a 95% confidence interval (CI). Findings from the random-effects model revealed an increase in ApoA-I (WMD: 15.22 mg/dL, 95% CI: 6.43-24.01, P = 0.001), alongside decreases in ApoB (WMD: -9.33 mg/dL, 95% CI: -15.46 to -3.19, P = 0.003) and lipoprotein(a) (WMD: -3.35 mg/dL, 95% CI: -5.78 to -0.91, P = 0.007) levels following tamoxifen treatment in women. Subgroup analyses indicated a more significant reduction in lipoprotein(a) levels in RCTs with a duration of ≤24 weeks (WMD: -3.65 mg/dL) and in studies using tamoxifen doses of ≥20 mg/day (WMD: -4.53 mg/dL). This meta-analysis provides evidence that tamoxifen leads to a decrease in lipoprotein(a) levels, along with reductions in ApoB and increases in ApoA-I among women. Show less
Despite the increasing approval and ongoing clinical trials of FGFR-targeted therapies, accurately detecting FGFR fusions remains a challenge due to limited research, low incidence rates, complex fusi Show more
Despite the increasing approval and ongoing clinical trials of FGFR-targeted therapies, accurately detecting FGFR fusions remains a challenge due to limited research, low incidence rates, complex fusion partner distribution, and unique kinase domain distribution. We conducted a multicenter study to comprehensively profile FGFR fusions in the largest Chinese pan-cancer cohort to date, comprising 118 FGFR fusions from 114 individuals. Both DNA- and RNA-based sequencing approaches were utilized to reveal novel and fundamental features of FGFR fusion. Our research reveals an incidence rate of 0.96% for FGFR rearrangements within this Chinese cohort, including a high incidence rate of FGFR fusions (40%) in parotid gland carcinoma. However, this is based on a small sample size of 5 tumors and should be interpreted cautiously pending validation in larger cohorts. We also uncovered distinct breakpoint distribution patterns across various FGFR rearrangements. For example, a primary breakpoint in intron17 of FGFR2 was predominant (21/22), while FGFR1/3 breakpoints displayed substantial diversity. For the first time, we identified "hot" breakpoints in FGFR1 intron17, exon18, and FGFR3's 3' untranslated region. These findings underline the importance of incorporating these regions in targeted sequencing to ensure comprehensive detection of FGFR1/3 fusions. Notably, we observed a predilection for intrachromosomal distribution in common FGFR1/2/3 fusions. In contrast, most novel fusions (12/15) exhibited an interchromosomal distribution pattern, indicating variations in the fusion formation mechanism. Importantly, our study demonstrates the substantial incremental value of RNA-NGS or other orthogonal methods in confirming the functionality of FGFR rearrangements initially identified by DNA sequencing. In our cohort, 46% (6/13) of rare FGFR1/2/3 fusions lacked detectable RNA transcripts; however, this does not definitively indicate non-functionality as factors such as low RNA quality, expression below detection limits, or nonsense-mediated decay may contribute. Therefore, RNA-based validation is critical for accurately identifying potentially targetable FGFR fusions and guiding therapy. Our findings offer critical novel insights into functional FGFR fusions and bear considerable clinical implications for identifying individuals whose tumors are most likely to respond favorably to FGFR-targeted therapies. Show less
Sow colostrum is rich in lactoferrin (LF), which can be orally administered to protect piglets from porcine epidemic diarrhea virus (PEDV) infection, thereby reducing piglet mortality. Previous study Show more
Sow colostrum is rich in lactoferrin (LF), which can be orally administered to protect piglets from porcine epidemic diarrhea virus (PEDV) infection, thereby reducing piglet mortality. Previous study has shown that sows fed with recombinant B. subtilis expressing 4,4-diaponeurosporene (B.S-Dia) have significantly higher LF levels in their colostrum compared to sows fed with B. subtilis. This suggests that 4,4-diaponeurosporene (DNP) produced by B.S-Dia may influence LF content in sow colostrum. In this study, we first extracted DNP expressed by the recombinant probiotic using acetone-hexane extraction. Flow cytometry, RT-qPCR, and ELISA analyses demonstrated that DNP promoted dendritic cell (DCs) maturation and increased the expression of IL-1β and IL-27. We then established a method for isolating neutrophils from sow colostrum and set up a co-culture system of neutrophils and DCs to investigate factors regulating LF secretion. The results indicated that DCs secretions enhanced LF expression in neutrophils. Finally, the application of IL-27 inhibitors confirmed that IL-27 produced by DCs upregulates LF secretion in neutrophils. These findings elucidate the mechanism by which DNP promotes LF production in colostrum and provide a theoretical foundation for using B.S-Dia to prevent and control PEDV infection in piglets. Show less
The deer antler is a fully regenerable and the fastest-growing osseous organ. Circular RNA (circRNA), a novel member of the non-coding RNA family, has significant research potential and crucial roles Show more
The deer antler is a fully regenerable and the fastest-growing osseous organ. Circular RNA (circRNA), a novel member of the non-coding RNA family, has significant research potential and crucial roles in biological processes. This study aims to explore the impact and mechanisms of circRNA505 on antler chondrocytes. Functional experiments demonstrated that m5C-modified circRNA505 inhibits antler chondrocyte proliferation, enhances osteogenic differentiation, and facilitates cellular glycolysis. Mechanistically, dual luciferase and AGO2-RIP assays revealed a direct binding relationship between circRNA505, miR-127, and p53. Rescue assays further showed that circRNA505 affects cell proliferation and differentiation through the miR-127/p53 axis. Meanwhile, RNA Antisense Purification (RAP) screening and analysis of related proteins binding to circRNA505 demonstrated that circRNA505 binds to LDHA and increases the level of LDHA phosphorylation through FGFR1 to promote cellular glycolysis by FISH-IF, RIP, and Western blot experiments. Additionally, Me-RIP assays confirmed the m5C methylation modification of circRNA505. NSUN2 mediates the m5C modification of circRNA505, affecting its stability, while the m5C reader ALYREF promotes the nuclear export of circRNA505 in an ALYREF-dependent manner. This study provides new insights into the regulatory mechanisms underlying rapid antler development. Show less
Dual-specificity protein phosphatase 6 (DUSP6), also known as mitogenactivated protein kinase phosphatase 3 (MKP-3), was considered as a functional candidate gene for white fat accumulation in mice. H Show more
Dual-specificity protein phosphatase 6 (DUSP6), also known as mitogenactivated protein kinase phosphatase 3 (MKP-3), was considered as a functional candidate gene for white fat accumulation in mice. However, the physiological function of the DUSP6 gene on white adipocyte adipogenesis in farm animals remains unknown. In this study, we aimed to clarify the effect of DUSP6 on porcine subcutaneous preadipocyte proliferation and differentiation. We first make clear that the patterns of DUSP6 expression is associated with fat contents in porcine fat deposition related tissues. Porcine subcutaneous preadipocytes were isolated and induced to differentiation. Small interfering RNAs were applied to deplete DUSP6. MTT assay, CCK-8 analysis, Oil Red O staining, triglyceride determination and reverse transcription quantitative polymerase chain reaction were applied to study the regulatory role of DUSP6 during adipocyte adipogenesis in pigs. We found that the expression levels of DUSP6 were significantly higher in backfat and longissimus dorsi tissues from fat-type pigs than in those from lean-type pigs. Consistently, the significantly induced expression of DUSP6 was also observed in differentiated adipocytes. In addition, knockdown of DUSP6 greatly inhibited preadipocytes proliferation, through the decreased cell viability and downregulated mRNA expressions of cell proliferation-associated genes, including PCNA, CDK1, CDK2. Furthermore, knockdown of DUSP6 significantly inhibited preadipocytes differentiation, as evidenced by markedly reduced lipid droplet formation, attenuated triglyceride accumulation and downregulated expression levels of adipogenic transcription masters (PPARγ, C/EBPβ, FASN and FABP4) in DUSP6 knockdown cells. Our results demonstrate that DUSP6 is required for white adipocyte adipogenesis in pigs. Show less
Infantile hemangioma (IH) is a common benign vascular tumor in infants, often requiring intervention due to potential functional impairment and cosmetic concerns. Propranolol, a nonselective β-adrener Show more
Infantile hemangioma (IH) is a common benign vascular tumor in infants, often requiring intervention due to potential functional impairment and cosmetic concerns. Propranolol, a nonselective β-adrenergic receptor blocker, is the first-line therapy for IH, yet its mechanisms remain incompletely elucidated. This prospective study investigated the systemic angiogenic protein profile changes in response to propranolol in 14 treatment-naïve IH infants compared to 14 healthy controls using antibody array analysis. We identified twenty-six angiogenic proteins significantly downregulated in pretreatment IH patients compared to healthy controls. After 3 months of propranolol treatment, six proteins including HB-EGF, TGFα, ANGPTL4, Follistatin, Tie-1 and PLGF were significantly upregulated. Bioinformatic enrichment analysis revealed that these proteins are involved in key biological processes and signaling pathways, including epithelial cell proliferation, angiogenesis regulation, VEGF signaling, ERBB-EGFR axis, Ras-MAPK, and PI3K-Akt pathways. These results suggest that propranolol treatment is associated with a rebalancing of dysregulated angiogenic proteins in IH, through modulating both pro- and anti-angiogenic factors to rebalance vascular homeostasis. Our study provides novel insights into the systems-level pharmacological actions of propranolol and proposes potential biomarkers for treatment response evaluation. Show less
The prevalence of depression, a common mental disorder in clinical practice, has been continuously increasing in recent years, with its intricate etiology and pathogenesis incompletely understood. Mic Show more
The prevalence of depression, a common mental disorder in clinical practice, has been continuously increasing in recent years, with its intricate etiology and pathogenesis incompletely understood. MicroRNA (miRNA), a highly conserved and widely distributed genetic regulatory factor in eukaryotic organisms, plays a crucial role in the pathophysiology of depression. miR-132, a miRNA molecule specifically enriched in the central nervous system, has emerged as a significant focus in the study of depression. miR-132 is involved in the pathogenesis by modulating critical processes such as dendritic spine remodeling and synaptic efficacy. Current research confirms that the expression profile of miR-132 in peripheral blood and brain tissue samples from animal models of depression shows significant abnormal fluctuations, and its expression level is dose-dependently associated with disease severity, progression, and treatment response. Therefore, this article focuses on a few key elements, including brain-derived neurotrophic factor, neuroinflammatory cascade reactions, neurogenesis, and plasticity, to comprehensively examine the potential role of miR-132 expression in the onset and progression of depression. This review also aims to provide a theoretical foundation for future in-depth research and clinical applications in the field of depression therapy. Show less
Gastric cancer (GC) exhibits marked heterogeneity, patients with identical stage receive divergent outcomes. Metabolic reprogramming and aging are pivotal in reshaping the tumor microenvironment. Howe Show more
Gastric cancer (GC) exhibits marked heterogeneity, patients with identical stage receive divergent outcomes. Metabolic reprogramming and aging are pivotal in reshaping the tumor microenvironment. However, their interplay in GC prognosis remains unexplored. We analyzed RNA-seq and clinical data from The Cancer Genome Atlas Program and Gene Expression Omnibus databases. Using univariate Cox, LASSO, and multivariate Cox regression, we identified candidate genes and constructed a prognostic signature. Immune contexture, genomic alterations and drug sensitivity were compared between high- and low-risk group. The metabolic and aging related risk score, comprising 4 genes (GNAI1, GSTA1, APOC3, and LOX), was developed. Validation across multiple cohorts confirmed its robust prognostic performance. The model also effectively stratified patients into distinct risk subgroups with differential immune profiles and responses to immunotherapy. Notably, high-risk patients showed reduced sensitivity to common chemotherapeutic agents but may benefit from targeting the PI3K/mTOR pathway. Metabolic and aging related risk score serves as a promising tool for individualized risk assessment and therapeutic guidance in GC, warranting further clinical validation. Show less
Altered levels of human plasma metabolites have been implicated in the etiology of bipolar disorder (BD). However, the causality between metabolites and the disease was not well described. We performe Show more
Altered levels of human plasma metabolites have been implicated in the etiology of bipolar disorder (BD). However, the causality between metabolites and the disease was not well described. We performed a bidirectional metabolome-wide Mendelian randomization (MR) analysis to evaluate the potential causal relationships between 871 plasma metabolites and BD. We used DrugBank and ChEMBL to evaluate whether related metabolites are potential therapeutic targets. Finally, Bayesian colocalization analysis was performed to identify shared genomic loci BD and identified metabolites. Our MR results showed that six metabolites were significantly associated with a reduced risk of BD, including arachidonate (20:4n6) (OR: 0.90, 95% CI: 0.84-0.95) and sphingomyelin (d18:2/24:1, d18:1/24:2) (OR: 0.92, 95% CI: 0.87-0.96), while five metabolites were significantly associated with an increased risk of BD, including 1-palmitoyl-2-linoleoyl-GPE (16:0/18:2) (OR: 1.09, 95% CI: 1.05-1.13). However, our reverse MR analysis showed that BD was not associated with the levels of any metabolite. Additionally, the leave-one-out analysis revealed SNPs within chromosome 11 loci harboring MYRF, FADS1, and FADS2 as ones with the potential to influence partial causal effects. Druggability evaluation showed that 10 of the BD-related metabolites, such as sphingomyelin and cytidine, have been targeted by pharmacologic intervention. Colocalization analysis highlighted one colocalized region (chromosome 11q12) shared by 11 metabolites and BD and pointed to some genes as possible players, including FADS1, FADS2, FADS3, and SYT7. Our study supported a causal role of plasma metabolites in the susceptibility to BD, and the identified metabolites may provide a new avenue for the prevention and treatment of BD. Show less
Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer (BC), characterized by limited treatment options and poor clinical outcomes. Aberrant FGFR signaling has been implic Show more
Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer (BC), characterized by limited treatment options and poor clinical outcomes. Aberrant FGFR signaling has been implicated in TNBC; however, the therapeutic potential of targeting FGFRs for TNBC treatment remains unclear. This study investigated the anti-cancer activity of the selective pan-FGFR inhibitor Erdafitinib and its underlying mechanisms using both in vitro and in vivo models. The results demonstrated that Erdafitinib suppressed TNBC tumorigenicity by promoting FGFR1/4 degradation, generating reactive oxygen species (ROS), inducing DNA damage, and ultimately triggering cell death. Mechanistic analyses revealed that Erdafitinib facilitated FGFR1/4 degradation through ubiquitination, enhanced interaction between TRIM25 and FGFR1/4, and subsequent lysosomal degradation. Furthermore, RNA-seq data from the TCGA and GEO databases, along with paired tumor tissues from TNBC patients, indicated that FGFR4 was significantly upregulated in TNBC. Notably, co-knockdown of FGFR1 and FGFR4 induced cytotoxicity in MDA-MB-231 cells, highlighting the therapeutic relevance of FGFR1/4 degradation by Erdafitinib in TNBC. These findings provide novel insights into the mechanisms underlying the anti-cancer efficacy of Erdafitinib, supporting its potential as a promising therapeutic agent for TNBC. Show less
Dyslipidemia has been proved to play a pivotal role in biological aging. Atherogenic Index of Plasma (AIP), derived from serum triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C), is an Show more
Dyslipidemia has been proved to play a pivotal role in biological aging. Atherogenic Index of Plasma (AIP), derived from serum triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C), is an effective biomarker of dyslipidemia. However, whether AIP can be used as an indicator of biological aging remains unclear. This study aims to investigate the relationship between AIP and biological aging in the US adult population. 4,471 American adults with age over 20 years from the National Health and Nutrition Examination Survey (NHANES) database were included in this study. Biological aging was assessed by phenotypic age acceleration (PhenoAgeAccel). Multivariable linear regression models, subgroup analyses and interaction tests were employed to explore the association between AIP and PhenoAgeAccel. Furthermore, adjusted restricted cubic spline (RCS) analyses were employed to assess potential nonlinear relationships, while mediation analysis was utilized to identify the mediating effects of homeostatic model assessment of insulin resistance (HOMA-IR). Besides, network pharmacology was performed to determine the potential mechanisms underlying dyslipidemia-related aging acceleration. A total of 4,471 participants were included in this study, the median chronological age, PhenoAge and PhenoAgeAccel for the overall population were 49 (35-64) years, 42.85 (27.30-59.68) years, and - 6.92 (- 10.52 to -2.46) years, respectively. In the fully adjusted model, one unit increase of AIP was correlated with 1.820-year increase in PhenoAgeAccel (β = 1.820, 95% CI: 1.085-2.556), which was more pronounced among individuals being female, diabetic and hypertensive. Furthermore, RCS analysis revealed a nonlinear relationship between AIP and PhenoAgeAccel, with an inflection point identified at -0.043 for AIP via threshold and saturation effect analysis. AIP demonstrated a positive correlation with PhenoAgeAccel both before (β = 6.550, 95% CI: 5.070-8.030) and after (β = 3.898, 95% CI: 2.474-5.322) this inflection point. Additionally, HOMA-IR was found to mediate 39.21% of the association between AIP and PhenoAgeAccel. Finally, network pharmacology analysis identified INS, APOE, APOB, IL6, IL10, PPARG, MTOR, ACE, PPARGC1A, and SERPINE1 as core targets in biological aging, which were functionally linked to key signaling pathways like AMPK, apelin, JAK-STAT, FoxO, etc. CONCLUSIONS: An elevated AIP was notably and positively correlated with accelerated aging, suggesting that AIP may serve as an effective predictor to evaluate accelerated aging. Show less
Patients with metabolic syndrome and heart failure (HF) often have accompanying kidney dysfunction, which was recently defined as cardiovascular-kidney-metabolic (CKM) syndrome. Prior metabolomics pro Show more
Patients with metabolic syndrome and heart failure (HF) often have accompanying kidney dysfunction, which was recently defined as cardiovascular-kidney-metabolic (CKM) syndrome. Prior metabolomics profiling of metabolic syndrome patients identified a plasma branched chain amino acid (BCAA) signature, and BCAAs themselves are elevated in the myocardium of patients with HF, potentially due to a defect in BCAA catabolic breakdown. The rate limiting step of BCAA catabolism is the decarboxylation by the enzyme branched chain ketoacid dehydrogenase (BCKDH), which is negatively regulated by BCKDH kinase (BCKDK or BDK), and BDK inhibitors improve metabolism and heart failure preclinically. Here, using two pre-clinical CKM models, the hyperphagic ZSF1 obese rat and the uninephrectomized SDT fatty rat with high salt drinking water, we applied unbiased proteomic, transcriptomic and metabolomic profiling to assess overall kidney gene expression and mitochondrial function. We show that BCAA catabolic impairment is associated with and may be causal to CKM and demonstrated impairment in BCAA catabolism within ZSF1 obese rat kidneys. In both CKM animal models, treatment with the BDK inhibitor BT2 improved urine protein content, kidney hypertrophy, and kidney pathology. Furthermore, coadministration of BT2 and the sodium-glucose cotransporter-2 inhibitor empagliflozin demonstrated additive effects to improve kidney parameters, kidney gene expression signatures, and kidney mitochondrial density and function. Our study suggests that in addition to its previously reported beneficial effects on metabolism and cardiac function, BDK inhibition may also improve kidney health and therefore could represent a new therapeutic avenue for CKM. Show less
Reverse Potts shunt is a promising yet high-risk therapy for pediatric pulmonary arterial hypertension. Postoperative hemodynamics is critically influenced by shunt configuration but is difficult to p Show more
Reverse Potts shunt is a promising yet high-risk therapy for pediatric pulmonary arterial hypertension. Postoperative hemodynamics is critically influenced by shunt configuration but is difficult to predict. This study aimed to quantify the effects of shunt size and location on hemodynamics to guide surgical planning. Based on a patient-specific model, four postoperative models with two different shunt locations [left pulmonary artery (LPA)-descending aorta (DAO) and pulmonary artery bifurcation-aortic arch] and three conduit sizes (4, 5, and 6 mm) were created. The direct Potts shunt model was created by a direct side-to-side anastomosis between the LPA and DAO with a 6-mm circular opening. Quantitative parameters including the shunt ratio (SR), which was defined as the percentage of the shunt flow rates to the total pulmonary inflow rate, lower limb oxygen saturation, and pressure were analyzed. Increasing the shunt size from 4 mm to 6 mm elevated the SR from 6.01% to 9.80%, concurrently reducing lower limb oxygen saturation from 89.57% to 86.52%. When taking 11,000 Pa as the threshold, this increased SR resulted in a reduction of the high-pressure area from 17.32% of the total pulmonary artery area to almost zero. Meanwhile, the high-pressure area on the aorta expanded from 8.72% of the total aortic area to 14.94%. These results indicated a reduction in the right ventricular afterload and an increase in the left ventricular afterload. Notably, a 6-mm shunt at the pulmonary artery bifurcation yielded a significantly larger SR than at the LPA (9.80% vs. 2.68%), which is attributed to a higher pressure gradient at the pulmonary artery bifurcation (1,201 Pa vs. 162 Pa). The shunt location had a greater impact on the SR than shunt size within the 4 mm-6 mm range in this specific case. A 6-mm shunt at the pulmonary artery bifurcation yielded a significantly larger SR than at the LPA, which is attributed to the higher preoperative pressure gradient at the bifurcation site. Left heart function is as critical as right heart function in maintaining pressure balance and determining outcomes, as the shunt flow increases the left ventricular afterload. Show less
Acupuncture has been proposed as a therapeutic intervention for stroke recovery, yet the underlying molecular mechanisms remain poorly understood. In this study, we used a mouse model of hemorrhagic s Show more
Acupuncture has been proposed as a therapeutic intervention for stroke recovery, yet the underlying molecular mechanisms remain poorly understood. In this study, we used a mouse model of hemorrhagic stroke induced by autologous blood injection to investigate the effects of acupuncture on post-stroke recovery at the cellular and molecular levels, utilizing single-cell RNA sequencing. Our findings revealed that acupuncture modulates the gene expression of microglia, astrocytes, and oligodendrocytes, three major glial cell types, which may contribute to the improvement of stroke-induced phenotypes. Notably, we identified a potential role of the APOE-TREM2 signaling axis, with ligand-binding interactions enhancing microglia activation and promoting their neuroprotective functions. These findings also suggested that acupuncture may promote microglia-astrocyte interactions, leading to enhanced neuroinflammation resolution and tissue repair. Our study provided new insights into the cellular mechanisms underlying acupuncture's therapeutic effects in stroke recovery and highlighted the potential of targeting glial cell-mediated pathways, including APOE-TREM2, as a strategy for improving post-stroke rehabilitation. Show less
Vaccinia-related kinase 1 (VRK1) is involved in numerous cellular processes, including DNA repair, cell cycle and cell proliferation. However, its roles and molecular mechanism underlying the progress Show more
Vaccinia-related kinase 1 (VRK1) is involved in numerous cellular processes, including DNA repair, cell cycle and cell proliferation. However, its roles and molecular mechanism underlying the progression of hepatocellular carcinoma (HCC) are yet largely unexplored. Here, we demonstrated that VRK1 expression is elevated in HCC tumor tissues, which is associated with high tumor stage and poor prognosis in HCC patients. In vitro and in vivo experiments manifested that VRK1 overexpression significantly promotes cell proliferation, colony formation, migration and tumor growth of HCC by inducing epithelial-mesenchymal transition (EMT) program. Mechanistically, immunoprecipitation combined with mass spectrometry analysis determined that VRK1 interacts with CHD1L, which mediates the phosphorylation of CHD1L at serine 122 site. RNA-seq revealed that one of the key downstream target genes of VRK1 is SNAI1, by which VRK1 promotes EMT process and HCC progression. Furthermore, VRK1 upregulates SNAI1 expression through phosphorylating CHD1L. In conclusion, these findings suggested that VRK1/CHD1L/SNAI1 axis acts as a cancer-driving pathway to promote the proliferation and EMT of HCC, indicating that targeting VRK1 may be an attractive therapeutic strategy of HCC. Show less
Homologous recombination repair (HRR) is crucial for maintaining genomic stability by repairing DNA damage. Despite its importance, HRR's role in cancer progression is not fully elucidated. Here, this Show more
Homologous recombination repair (HRR) is crucial for maintaining genomic stability by repairing DNA damage. Despite its importance, HRR's role in cancer progression is not fully elucidated. Here, this work shows that nuclear-localized branched-chain α-ketoacid dehydrogenase kinase (BCKDK) acts as a modulator of HRR, promoting cell resistance against DNA damage-inducing therapy in breast cancer. Mechanistically, this work demonstrates that BCKDK is localized in the nucleus and phosphorylates RNF8 at Ser157, preventing the ubiquitin-mediated degradation of RAD51, thereby facilitating HRR-mediated DNA repair under replication stress. Notably, aberrant expression of the BCKDK/p-RNF8/RAD51 axis correlates with breast cancer progression and poor patient survival. Furthermore, this work identifies a small molecule inhibitor of BCKDK, GSK180736A, that disrupts its HRR function and exhibits strong tumor suppression when combined with DNA damage-inducing drugs. Collectively, this study reveals a new role of BCKDK in regulating HRR, independent of its metabolic function, presenting it as a potential therapeutic target and predictive biomarker in breast cancer. Show less