Facial nerve injury (FNI) is a common peripheral neuropathy that severely impairs facial function and quality of life. Qianzheng Powder (QZP) is a traditional Chinese herbal formula used to treat faci Show more
Facial nerve injury (FNI) is a common peripheral neuropathy that severely impairs facial function and quality of life. Qianzheng Powder (QZP) is a traditional Chinese herbal formula used to treat facial paralysis clinically, yet its neuroprotective mechanisms remain unclear. This study aims to evaluate the therapeutic effects of QZP on FNI and potential underlying mechanisms. A FNI model was established in male C57BL/6 mice by performing facial nerve crush surgery. QZP (3.51 g/kg) was administered orally once daily for 14 days post-surgery. Facial function was assessed behaviorally. Tissue samples were collected on day 21 for histological evaluation, qPCR and Western blotting. Liver and kidney safety were also assessed via H&E staining and serum biochemical markers. QZP significantly improved facial motor function from day 7 post-injury. Additionally, QZP treatment mitigated neuronal loss in the facial motor nucleus, attenuated buccinator muscle atrophy, and enhanced myelin regeneration, as evidenced by increased MPZ and MBP expression. These were consistent with the increace of the BDNF, TrkB, and QZP promotes structural and functional recovery of facial nerve following injury, likely through activation of the BDNF/TrkB/CREB axis, and demonstrates a favorable safety profile. These findings support its potential as a therapeutic adjunct in peripheral nerve repair. Show less
Vascular stiffness and aging are critical contributors to cardiovascular diseases. Whether betulinic acid (BA), a natural triterpenoid, alleviates vascular aging remains unclear. Mouse aortic smooth m Show more
Vascular stiffness and aging are critical contributors to cardiovascular diseases. Whether betulinic acid (BA), a natural triterpenoid, alleviates vascular aging remains unclear. Mouse aortic smooth muscle cells (MASMCs) with oleic acid (OA)-induced lipotoxic senescence were treated with BA (30 μM). Transcriptomic analysis and functional assays were conducted. Show less
The international consensus classification or the World Health Organization classifications underrepresented driver alterations enriched in pediatric acute myeloid leukemia (AML). To address this, we Show more
The international consensus classification or the World Health Organization classifications underrepresented driver alterations enriched in pediatric acute myeloid leukemia (AML). To address this, we retrospectively characterized the genomic landscape of 105 pediatric patients with AML of East Asian ancestry using transcriptome and whole-exome sequencing (WES). In addition to the common recurrent fusions such as RUNX1::RUNX1T1 and CBFB::MYH11, we identified rearrangements involving KMT2A, NUP98, GLIS, as well as FLT3 and UBTF tandem duplications. The median somatic mutation rate in AML was 0.97 per megabase, as estimated by WES. Frequently mutated pathways included signaling: 68.6% (72/105), transcription: 37.1% (39/105), epigenetic regulation: 26.7% (28/105), cohesin: 7.6% (8/105), RNA binding: 3.8% (4/105), and protein modification: 5.7% (6/105). When analyzed together, high-risk genetic subtypes including GLISr, UBTF tandem duplications, PICALM::MLLT10, and HOXr were significantly associated with poorer 5 year overall survival (OS) in multivariable analysis (p-value = 0.037). Although FLT3 internal tandem duplications were significantly associated with inferior 5 year OS in univariable analysis, this effect was not significant in multivariable analysis (p-value = 0.382). Patients with RUNX1 mutations had inferior 5 year OS in multivariable analysis (p-value = 0.009). These findings suggest specific genomic alterations that may refine risk stratification and guide future therapeutic protocols in Taiwanese pediatric patients with AML. Show less
Acute hepatitis is a major pathological process underlying acute liver injury (ALI) and acute liver failure (ALF), both of which are associated with high mortality. Yet, no effective treatment is curr Show more
Acute hepatitis is a major pathological process underlying acute liver injury (ALI) and acute liver failure (ALF), both of which are associated with high mortality. Yet, no effective treatment is currently available, underscoring the pressing need for novel therapeutic targets. By integrating multiple transcriptomic datasets, this study finds that the expression of brain-derived neurotrophic factor (BDNF) is consistently downregulated in hepatocytes across various ALI/ALF models. Mechanistically, this downregulation is attributed to transcriptional repression of BDNF by RE1-silencing transcription factor. Restoration of endogenous BDNF or exogenous administration of recombinant BDNF significantly alleviates LPS/DGal-induced ALI/ALF. Correlation analysis and proteomic profiling reveal that BDNF exerts potent anti-inflammatory effects by directly binding to and antagonizing Toll-like receptor 4 (TLR4) on macrophages. Structural analysis identifies amino acids 233-244 of BDNF as the key functional domain responsible for this effect. A synthetic 12-mer peptide derived from this region, termed BDP12, retains TLR4-antagonizing ability, demonstrating strong anti-inflammatory efficacy and a favorable safety profile in cultured macrophages and mouse ALI/ALF models. In conclusion, this study identifies hepatocyte-derived BDNF as an endogenous antagonist of TLR4 and a critical immune checkpoint in acute hepatitis. BDNF and its mimetic peptide BDP12 represent promising therapeutic candidates for treating acute hepatitis-mediated ALI/ALF. Show less
We aimed to identify key molecules that can moderately enhance the compensatory capacity of beta cells during obesity. Single-cell RNA-seq was used to profile the RNA expression of islet cells from di Show more
We aimed to identify key molecules that can moderately enhance the compensatory capacity of beta cells during obesity. Single-cell RNA-seq was used to profile the RNA expression of islet cells from diet-induced obese mice and pregnant mice. The gene and protein expression levels of ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) were verified by quantitative PCR and immunofluorescence, respectively. The roles of ENPP2 were investigated using gain-of-function and loss-of-function approaches in Min6 beta cells, global Enpp2-knockout mice and beta cell Enpp2-overexpressing transgenic (Enpp2-Tg) mice. Using single-cell RNA-seq, we demonstrated that proliferation is the primary and common mechanism for compensating for beta cell numbers during both mouse obesity and pregnancy, with proliferation being more pronounced in pregnancy than in obesity. Additionally, many differentially expressed genes were co-regulated in both conditions. Among these, the pro-proliferative phosphodiesterase ENPP2 showed the highest increase in beta cells of pregnant mice and a moderate increase in beta cells of obese mice. Overexpression or knockdown of ENPP2 in Min6 beta cells revealed that ENPP2 promoted beta cell proliferation, inhibited apoptosis and enhanced high-glucose-stimulated insulin secretion. These effects of ENPP2 were further validated in vivo using Enpp2-Tg mice. In Enpp2-knockout mice fed a high-fat diet, the deficiency of ENPP2 resulted in insufficient compensation of beta cells during obesity. The pro-proliferative role of ENPP2 in beta cells was mediated through the lysophosphatidic acid (LPA)-Akt/mammalian target of rapamycin (mTOR) signalling pathway via LPA receptor 2. However, the expression of ENPP2 was reduced in the mouse model of diabetes and in human participants with type 2 diabetes compared with non-diabetic control groups. Furthermore, ENPP2 was co-upregulated by a synergy of oestradiol and progesterone. ENPP2 may serve as a key regulator in beta cell compensation during obesity, and modulating its levels in beta cells could be a potential therapeutic target for mitigating beta cell deterioration in diabetes. Show less
Effective real-time monitoring and tracking of lipid droplets (LDs) are essential for the precise diagnosis of atherosclerotic plaques and the assessment of pathological progression. However, viable s Show more
Effective real-time monitoring and tracking of lipid droplets (LDs) are essential for the precise diagnosis of atherosclerotic plaques and the assessment of pathological progression. However, viable strategies for Show less
Glycolysis-derived lactate serves as a substrate for lysine lactylation, an epigenetic modification playing critical transcriptional regulatory roles in inflammatory diseases. Endothelial inflammation Show more
Glycolysis-derived lactate serves as a substrate for lysine lactylation, an epigenetic modification playing critical transcriptional regulatory roles in inflammatory diseases. Endothelial inflammation, characterized by upregulated glycolysis, initiates atherosclerosis, yet the contribution of histone lactylation remains undefined. Although narciclasine exhibits anti-inflammatory and antioxidant properties, its impact on endothelial inflammation in atherosclerosis is unknown. Connectivity Map (CMap) analysis predicted narciclasine as an inhibitor of oscillatory shear stress and TNF-α-induced endothelial inflammation. In vitro, treatment of human umbilical vein endothelial cells (HUVECs) with 20 nM narciclasine significantly suppressed ox-LDL-induced expression of VCAM1, ICAM1, SELE, and CCL2, reduced reactive oxygen species (ROS) production, and inhibited monocyte adhesion and migration. In vivo, administration of narciclasine (0.02 mg/kg) attenuated carotid artery endothelial inflammation and macrophage infiltration, consequently reducing early atherogenesis in partial carotid ligation model in ApoE Show less
Pregnant women have a high incidence of perinatal mood and anxiety disorders (PMADs). To explore the influence factor on perinatal psychology, we analysed the SCFAs, lipids, cognition, emotion, and cy Show more
Pregnant women have a high incidence of perinatal mood and anxiety disorders (PMADs). To explore the influence factor on perinatal psychology, we analysed the SCFAs, lipids, cognition, emotion, and cytokines in the late pregnant women. The mood, cognition, SCFAs of the non-pregnant group were compared to those in the late pregnancy. The differences in SCFAs, lipids, cognition, and cytokines between the high-risk and low-risk groups for affective disorders among women in the late pregnancy were analysed, and the risk factors were sought. Compared with the non-pregnant group, the pregnant group scored lower on the SDMT (P < 0.001), DST (P = 0.035), VRT (P = 0.001), and VFT (P < 0.001), and took longer on the TMTA (P = 0.004). Acetate (P = 0.001) and butyrate (P = 0.002) were higher, while propionate (P < 0.001) and isobutyrate (P = 0.001) were lower in the pregnant group than in the non-pregnant group. Among the pregnant women, CRP was higher in the high-risk group for mood disorders than in the low-risk group (P = 0.048). Meanwhile, HDL was positively associated with DST (P = 0.000), VRT (P = 0.015), and VFT (P < 0.001). Longer TMTA completion times were associated with reduced propionate (P = 0.072) and LPa (P = 0.022). Longer TMTB completion time was associated with lower life satisfaction (P = 0.037), as well as decreased cholesterol (P = 0.026). Pregnant women experience changes in cognition and SCFAs. CRP is a sensitive indicator for monitoring affective disorder. Regulation of SCFAs and lipids may be beneficial for cognition and affect. Show less
Improving the patency rate of small-diameter vascular grafts in a pathological environment is the key to achieving their clinical translation and application. The current approach to in vivo implantat Show more
Improving the patency rate of small-diameter vascular grafts in a pathological environment is the key to achieving their clinical translation and application. The current approach to in vivo implantation evaluations of small-diameter vascular grafts is predominantly based on healthy animal models. However, the majority of patients who undergo vascular transplantation are afflicted with vascular diseases, such as hyperlipidaemia or atherosclerosis. In this study, we constructed an ApoE gene knockout atherosclerotic mouse model and investigated the patency and regenerative performance of small-diameter vascular grafts in a diseased environment. We prepared heparinized Poly (ε-caprolactone) (PCL) vascular grafts (PCL-Hep) using electrospinning technology. By taking advantage of the physical adsorption of heparin, rapamycin (RM) was loaded onto the surface of grafts to obtain PCL-Hep-RM vascular grafts, which exhibited exceptional mechanical properties and drug sustained-release characteristics. Subsequently, the PCL-Hep-RM vascular grafts were implanted into the carotid arteries of atherosclerotic mice. The results demonstrated that PCL-Hep-RM significantly enhanced the patency rate and suppressed intimal hyperplasia in comparison with the PCL control group. This study offers novel concepts and methodologies for addressing challenges such as the low long-term patency rate and luminal stenosis of vascular grafts in a diseased environment, thereby promoting the translational medicine research of small-diameter vascular grafts. Show less
Breast cancer is the most frequently diagnosed cancer, with metastasis accounting for the majority of cancer-related deaths. The mechanisms of early-stage breast cancer metastasis to regional immune s Show more
Breast cancer is the most frequently diagnosed cancer, with metastasis accounting for the majority of cancer-related deaths. The mechanisms of early-stage breast cancer metastasis to regional immune sites like lymph nodes remain elusive. Here, we performed an in-depth proteomic and phosphoproteomic analysis of a substantial series of breast cancer samples, alongside genomic and transcriptomic evaluations. This cohort encompasses 195 specimens: 65 primary breast tumors, their corresponding normal tissues, and metastatic axillary lymph nodes. We offer an overview of the molecular alterations at the transcriptomic, proteomic, and phosphoproteomic levels during lymph node metastasis. Notably, the findings indicate that regional lymph node metastasis is primarily influenced by proteomic and phosphoproteomic alterations, rather than genomic or transcriptomic changes. We found the ANGPTL4 and HMGB1 could serve as the biomarker of lymph node metastasis. Data analysis and cell experiments involving silencing of the alternative splicing factor HNRNPU demonstrated that alternative splicing plays a significant role in modulating protein expression, phosphorylation profiles and cell proliferation. The key phosphorylation sites, including MARCKSL1-S104 and FKBP15-S320, as well as the upstream kinase PRKCB, were identified as playing crucial roles in breast cancer lymph node metastasis. Targeted intervention of the kinase PRKCB resulted in effectively suppressing the proliferation and metastasis of breast cancer tumor cells. Immune profiling analysis and experimental validation of breast cancer cell cocultured with CD8+ T cell reveals correlations between phosphorylation of MARCKSL1-S104 and FKBP15-S320 with immune checkpoint PD-L1 expression, and their impact on tumor cell apoptosis, suggesting a potential mechanism of immune evasion in metastasis. This study systematically characterizes the molecular landscape and features of primary breast tumors and their matched metastatic lymph nodes. These insights enhance our understanding of early-stage breast cancer metastasis and may pave the way for improved diagnostic tools and targeted therapeutic strategies. Show less
Genetic variants near LYPLAL1 are associated with Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) in humans, but their impact on LYPLAL1 function is unknown. We identified LYPLAL1 los Show more
Genetic variants near LYPLAL1 are associated with Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) in humans, but their impact on LYPLAL1 function is unknown. We identified LYPLAL1 loss-of-function variants from UK BioBank (UKBB) whole-exome sequencing data that had AlphaMissense or GPN-MSA scores in the top 20% of LYPLAL1 variants for being disruptive. We aggregated these variants and carried out burden analysis for effects on MRI Proton Density-Fat Fraction (MRI-PDFF) and ICD-based MASLD in UKBB. Rare loss-of-function LYPLAL1 variants were associated with reduced MRI-PDFF and ICD diagnosed MASLD across sexes. We used CRISPR to knockout and overexpress LYPLAL1 in human hepatoma cells (HuH-7), measuring lipid content, lipid uptake/export, and changes in de novo lipogenesis and mitochondrial β-oxidation. LYPLAL1 subcellular localization was determined by overexpressing LYPLAL1-HA tagged protein. We purified GST tagged human LYPLAL1 protein and conducted in vitro tests for esterase and depalmitoylase activity. Knocking out LYPLAL1 reduced triglycerides biochemically as well as lipid intensity after oleic (18:1, n-9) acid treatment. LYPLAL1 KO cells had increased expression of PPARα and MLXIPL, increased mitochondrial β-oxidation, and reduced capacity to both import fatty acids (FAs) and export lipoproteins. Overexpression of LYPLAL1 increased lipid droplet accumulation and decreased PPARα and MLXIPL. LYPLAL1-HA is partly localized to mitochondria when treated with oleic acid. Biochemical analyses showed that LYPLAL1 has strong esterase activity but lacks depalmitoylase activity. Reduction of LYPLAL1 esterase function likely increases β-oxidation of FAs in mitochondria through PPARα and MLXIPL and decreases FA import to protect against lipid accumulation in human liver cancer cells. Together, our results indicate that LYPLAL1 loss-of-function protects against MASLD in Europeans and in vitro, LYPLAL1 is an esterase for short-chain substrates which is involved in the regulation of mitochondrial β-oxidation and uptake of fatty acids, influencing lipid accumulation in the liver. Show less
Aniridia, driven by PAX6 mutations, causes aniridia-associated keratopathy (AAK), a progressive condition linked to limbal stem cell deficiency. A major hurdle to developing targeted therapies for AAK Show more
Aniridia, driven by PAX6 mutations, causes aniridia-associated keratopathy (AAK), a progressive condition linked to limbal stem cell deficiency. A major hurdle to developing targeted therapies for AAK is the incomplete understanding of the molecular abnormalities in affected corneas. To address this, we leveraged Pax6± (Pax6 het) mice, a model of AAK, and applied single-cell RNA sequencing (scRNA-seq) to profile the transcriptomic changes at a single-cell resolution. ScRNA-seq of corneal/limbal tissues of wild type (WT) and Pax6 het mice were conducted. Immunostaining was performed to examine the expression of specific markers for stem cells. ScRNA-seq identified a quiescent limbal epithelial stem cell (LESC)-like cell cluster and an early transient amplifying cell (eTAC)-like cluster. An increase in the cell numbers in these two clusters in the Pax6 het mouse corneas was observed. Immunostaining detected a marked increase in markers for these two clusters including Tmem176b, Apoe, and Krt15 in the corneal epithelium of Pax6 het mice, suggesting an increase of these LESC/eTA-like cells into the corneal epithelium. The Pax6 deficiency inhibited the expression of genes involved in cell proliferation in the eTAC-like cluster as well as the expression of genes related to corneal epithelial cell fate and differentiation compared with WT mice. Our single cell transcriptome of the limbus and cornea of Pax6 het mice indicates that AAK may be due to the increase of dysfunctional stem/eTACs with defects in committing to a corneal epithelial cell fate and differentiation. Show less
C1q/TNF-related proteins (CTRPs) belong to the adipokine family. Here, we aimed to assess the relation of CTRP4 levels in serum and perivascular adipose tissue (PVAT) with coronary artery disease (CAD Show more
C1q/TNF-related proteins (CTRPs) belong to the adipokine family. Here, we aimed to assess the relation of CTRP4 levels in serum and perivascular adipose tissue (PVAT) with coronary artery disease (CAD), and investigate the effect of CTRP4 on atherosclerosis and the underlying mechanisms. CTRP4 levels were examined in serum and epicardial adipose tissue (a major PVAT) from patients with CAD. Atherosclerotic lesions were analysed in CTRP4 CTRP4 levels were lower in serum and epicardial adipose tissue of patients with CAD compared to non-CAD controls. CTRP4 knockout promoted atherosclerosis in ApoE Decreased CTRP4 levels in serum and epicardial adipose tissue are associated with CAD in patients. CTRP4 deficiency promotes the development of atherosclerosis in ApoE Show less
This study investigated the impact of This retrospective case-control study involved 628 CAD patients and 628 matched controls without CAD. ApoE genotyping was conducted using PCR-chip technology, and Show more
This study investigated the impact of This retrospective case-control study involved 628 CAD patients and 628 matched controls without CAD. ApoE genotyping was conducted using PCR-chip technology, and genotype and allele frequencies were compared between groups. Multivariate logistic regression analyzed the link between ApoE polymorphisms and CAD risk in populations at middle and high altitudes. The data revealed significant differences in These findings validated that the Show less
Carotid atherosclerosis is a significant risk factor for cardiovascular and cerebrovascular diseases. Maintaining plaque stability can prevent plaque rupture and thrombus formation, slow disease progr Show more
Carotid atherosclerosis is a significant risk factor for cardiovascular and cerebrovascular diseases. Maintaining plaque stability can prevent plaque rupture and thrombus formation, slow disease progression, and is critically important for preventing cerebrovascular events (such as stroke, transient ischemic attack (TIA), and similar events). Mechanisms influencing plaque stability are still unclear. In this study, stable plaques (n = 5) and unstable plaques (n = 5) were collected from patients and analyzed using RNA-sequencing. 594 differently expressed genes were found by RNA-seq. Pathways enriched by KEGG analysis of differentially expressed genes included inflammation related pathway, cell adhesion related pathway and TGFβ signaling pathway. Especially, we found AMIGO1 was significantly upregulated in stable plaques. Functional assays including cell adhesion, and inflammation-related factor detection revealed that AMIGO1 significantly promotes endothelial cell adhesion while downregulating inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α) production, thereby mitigating inflammatory responses. Co-immunoprecipitation (Co-IP) experiments further found that AMIGO1 interacts with transforming growth factor beta receptor II (TGFRII), stabilizing TGFRII protein levels and subsequently activating the TGFβ signaling pathway. AMIGO1 overexpression with AAV9 virus tail vein injection markedly stabilized plaques in ApoE Show less
To investigate the connection betweenischemic stroke (IS) patients' risk of dying after being discharged and their residual cholesterol (RC) levels uponadmission. 2021 IS patients between the ages of Show more
To investigate the connection betweenischemic stroke (IS) patients' risk of dying after being discharged and their residual cholesterol (RC) levels uponadmission. 2021 IS patients between the ages of 35 and 80were chosen as the study's subjects, and data on deathendpoints following discharge were gathered. The doseresponse association between the risk of death and the RCat admission was examined using restricted cubic spline(RCS) regression. The hazard ratio (HR) and 95% CI werecalculated via Cox regression to analyse the associationbetween the RC level at admission and the risk of deathafter discharge in patients with IS. According to the RCS model, RC levels were nonlinearly associated with deaths from IS and other causes(P<0.001). With the median RC level as the cutoff value,the subjects were divided into two groups: a low RC group(RC<0.72 mmol/L) and a high RC group (RC≥0.72mmol/L). Compared with those in the high RC group, theage and male ratio in the low RC group were significantlygreater. The fasting blood glucose (GLU), total cholesterol(TC), triglyceride (TG), low-density lipoprotein cholesterol(LDL-C), non-high-density lipoprotein cholesterol (nonHDL-C), apolipoprotein A-1 (ApoA-1), and apolipoproteinB (ApoB) levels, as well as diabetes rates, were lower (P=0.01). Cox regression analysis revealed that withoutadjusting for covariates, the high-level RC group presenteda lower risk of all-cause death than the low-level RC group(HR=0.765, 95% CI: 0.619~0.946, P=0.013) and alower risk of death from IS (HR = 0.638, 95% CI:0.435~0.936, P=0.022). After adjusting for sex, age,smoking status, drinking status, hypertension status, anddiabetes status, the high-level group still had a lower risk ofall-cause death (HR = 760, 95% CI: 0.614~0.941,P=0.012) and a lower risk of death from IS (HR=0.653,95% CI: 0.444-0.961, P=0.031). Male sex (HR=0.753,95% CI: 0.572~0.990, P=0.042). Age ≥65 years (HR=0.598, 95% CI: 0.391~0.916, P=0.018), nonsmokingstatus (HR=0.628, 95% CI: 0.408~0.967, P=0.035),nonalcoholic status (HR=0.656, 95% CI: 0.439~0.979,P=0.039), not complicated with hypertension (HR=0.321, 95% CI: 0.108~0.957, P=0.041), no diabetesmellitus (HR=0.607, 95% CI: 0.389~0.947, P=0.028).Compared with those in the high RC group, the IS patientsin the low RC group had a lower incidence of all-causedeath, IS death and other causes of death and a higher survival rate. An RC<0.72 mmol/L at admission is associated with an increased risk of all-cause death and longterm IS death after discharge. Show less
This study aims to investigate the role of DUSP6 in thyroid cancer metastasis and elucidate its underlying molecular mechanisms. Immunohistochemistry were performed to explore the expression of DUSP6, Show more
This study aims to investigate the role of DUSP6 in thyroid cancer metastasis and elucidate its underlying molecular mechanisms. Immunohistochemistry were performed to explore the expression of DUSP6, IL-8 and PAD4 in papillary thyroid carcinoma (PTC) tissues and adjacent non-cancerous thyroid tissues. Effects of DUSP6 on the proliferation, apoptosis, migration, and invasion of thyroid cancer cell lines TPC-1 and IHH4 were performed through in vitro experiments. A rescue experiment was performed to verified DUSP6 regulated the migration and invasion of thyroid cancer cells TPC-1 and IHH4 through IL-8 and neutrophil extracellular traps (NETs) formation. In addition, in vitro cell experiments were conducted to analyze the regulation of NETs formation by DUSP6 through IL-8. Finally, the effect of sh-DUSP6 on the growth of thyroid cancer tumors in mice were conducted through in vivo experiments. DUSP6 expression was significantly upregulated in PTC tissues. Moreover, the expression of DUSP6 in tumor tissues of TPC patients is positively correlated with the expression of IL-8 and PAD4. Overexpression of DUSP6 promotes the proliferation, migration, and invasion of thyroid cancer cells (TPC-1 and IHH4) while inhibiting apoptosis. Conversely, silencing DUSP6 exerts opposing effects. Knockdown of IL-8 reverses the enhanced migratory and invasive capabilities induced by DUSP6 overexpression in these cell lines. NETs treatment enhances the migration and invasion of TPC-1 and IHH4 cells, whereas the application of sh-DUSP6 or sh-IL-8 counteracts this NETs-mediated promotion. Furthermore, DUSP6 overexpression facilitates NETs formation by upregulating IL-8 expression. In vivo experiments demonstrate that sh-DUSP6 suppresses thyroid cancer tumor growth in mouse models. Conclusion: DUSP6 promotes the metastasis of thyroid cancer by facilitating the formation of neutrophil extracellular traps via IL-8. Show less
In premature infants, patent ductus arteriosus (PDA) can lead to hemodynamic instability and prematurity-related complications. The conventional left atrial-to-aortic (LA/Ao) ratio for evaluating hemo Show more
In premature infants, patent ductus arteriosus (PDA) can lead to hemodynamic instability and prematurity-related complications. The conventional left atrial-to-aortic (LA/Ao) ratio for evaluating hemodynamically significant PDA (hsPDA) has demonstrated limited accuracy. We aimed to investigate the correlation between mitral inflow E-wave velocity, left pulmonary artery (LPA) end-diastolic velocity, and hsPDA in preterm infants. Single-center, retrospective cohort study included neonates born at a gestational age (GA) between 24 and 30 weeks. The echocardiographic parameters, including mitral E-wave velocity, LPA end-diastolic velocity and LA/Ao ratio were assessed with hsPDA requiring treatment. Forty-nine infants were included, of whom 30 were diagnosed with hsPDA. The mitral E-wave (95% CI: 4.6-18.2, p = 0.0016) and LPA end-diastolic velocities (95% CI: 4.14-15.15, p = 0.0010) were significantly higher in infants with hsPDA, while the LA/Ao ratio exhibited no difference. Multivariate analysis revealed that lower GA, higher mitral E-wave, and LPA end-diastolic velocities were predictive of hsPDA. The receiver operating characteristic (ROC) analysis showed that these parameters offered better diagnostic accuracy than the LA/Ao ratio. Our findings suggest that mitral E wave and LPA end-diastolic velocities are more reliable echocardiographic markers for evaluating hsPDA in preterm infants than the conventional LA/Ao ratio. Assessment of dynamic blood flow is more reliable than the left atrium chamber size in evaluating the hemodynamic status of a PDA. Our result provides new criteria for assessing the hemodynamic significance of PDA. Utilizing this technique may yield evidence to assist clinical decision-making regarding PDA treatment. Multifactorial assessment, including birth gestational age and increased intracardiac or pulmonary blood flow velocity, provides more accurate prediction for a hsPDA. Show less
Alzheimer's disease is a common neurodegenerative disease characterized by progressive memory loss, cognitive decline, and behavioral changes. Blood-based biomarkers have recently gained significant a Show more
Alzheimer's disease is a common neurodegenerative disease characterized by progressive memory loss, cognitive decline, and behavioral changes. Blood-based biomarkers have recently gained significant attention due to their accessibility and cost-effectiveness. This review highlights the latest progress in multiple key areas of bloodbased biomarkers for Alzheimer's disease. For early diagnosis, blood-based biomarkers such as amyloid-β and phosphorylated tau can identify Alzheimer's disease even before clinical symptoms emerge. Dynamic changes in blood-based biomarkers, including p-tau217 and neurofilament light chain, reflect disease progression and correlate with cognitive decline, enabling continuous monitoring of Alzheimer's disease progression. Additionally, bloodbased biomarkers such as p-tau181 and glial fibrillary acidic protein aid in differential diagnosis by distinguishing Alzheimer's disease from other dementias such as frontotemporal dementia. Blood-based biomarkers related to nerve repair have opened up new avenues for tracking nerve regeneration and therapeutic response, especially brain-derived neurotrophic factor. Furthermore, advanced detection technologies such as single-molecule array and immunoprecipitation-mass spectrometry have significantly improved the sensitivity and specificity of bloodbased biomarkers, facilitating their clinical translation. In summary, blood-based biomarkers hold strong potential to improve early diagnosis, monitor progression, differential diagnosis, and evaluate therapies in Alzheimer's disease. This review provides a comprehensive and updated evaluation of the translational potential of bloodbased biomarkers, emphasizing their practical utility in clinical settings and offering insights into future directions for large-scale application. This review emphasizes the need to prioritize the allocation of scientific resources, expedite the transition of blood-based biomarkers to clinical implementation, and ultimately achieve precise treatment of Alzheimer's disease using these biomarkers. Show less
Coronary artery calcification (CAC) signifies advanced atherosclerosis and portends increased cardiovascular risk. Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerosis; however, its asso Show more
Coronary artery calcification (CAC) signifies advanced atherosclerosis and portends increased cardiovascular risk. Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerosis; however, its association with in vivo lesion morphology and clinical outcomes in patients with symptomatic, advanced CAC remains incompletely characterized. This study aimed to investigate the association between elevated Lp(a) levels and both in vivo lesion morphology and clinical outcomes in this high-risk population. In this retrospective cohort, 292 patients with intravascular ultrasound(IVUS)-confirmed CAC were stratified into elevated (≥50 mg/dL,n = 77) or low (<50 mg/dL,n = 215) Lp(a) groups. The primary endpoint was major adverse cardiovascular events (MACEs). Associations were assessed via multivariable Cox models adjusted for clinical covariates. Patients in the elevated Lp(a) group presented a greater incidence of aortic valve calcification (p < 0.001). IVUS revealed constrictive remodeling with a smaller lumen and vessel dimensions. During a median follow-up of 17.2 months, the elevated Lp(a) cohort had a significantly higher MACE rate (37.7% vs. 15.8%; adjusted hazard ratio [aHR] 2.60, 95% CI 1.55-4.35, p < 0.001). Elevated Lp(a) independently predicted increased risks of ischemic stroke (aHR 7.14) and in-stent restenosis (aHR 2.78). In symptomatic patients with IVUS-confirmed CAC, elevated Lp(a) identifies a high-risk phenotype characterized by constrictive vascular remodeling and a markedly increased risk of MACEs, driven particularly by ischemic stroke and in-stent restenosis. These findings support the integration of routine Lp(a) testing into the risk stratification of patients with severe CAC, thereby identifying a precise high-risk phenotype that warrants intensified monitoring and represents an ideal target for emerging Lp(a)-lowering therapies. Show less
Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. T Show more
Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. This study investigated the complex tumour microenvironment (TME) in HCC and explored interactions between various cell types and their roles in disease recurrence. Using a multi-omics approach on multi-region samples of surgically resected HCC from the PLANet 1.0 cohort (NCT03267641), we performed spatial transcriptomics on 17 tissue samples from four patients and bulk RNA sequencing on 329 sectors from 90 patients. Findings were validated using immunofluorescence and multiplex immunohistochemistry. Our analysis revealed extensive intra- and intertumour gene expression heterogeneity and identified a specific subset of endothelial cells (ECs), INTS6 INTS6 The spatial co-localisation of cell types plays a significant role in the recurrence of hepatocellular carcinoma. In this study, we have pinpointed a particular group of endothelial cells, known as INTS6+ endothelial cells, which are spatially colocalised with tumour cells and enriched in microvascular invasion regions in patients experiencing recurrence. These discoveries highlight novel therapeutic targets that focus on endothelial cell interactions within the tumour microenvironment to prevent recurrence and enhance overall patient survival. Show less
Aging is asynchronous across cells and organs, but whether plasma proteins can capture cell type-specific aging and predict disease and mortality remains unknown. We developed machine learning models Show more
Aging is asynchronous across cells and organs, but whether plasma proteins can capture cell type-specific aging and predict disease and mortality remains unknown. We developed machine learning models to estimate the biological age of more than 40 distinct cell types-spanning neuronal, immune, glial, endocrine, epithelial, and musculoskeletal origins-using over 7,000 plasma proteins measured in 60,000 individuals across three cohorts, comprising the largest human plasma proteomics aging study to date. Individuals showed heterogeneous aging profiles, with 20-25% exhibiting accelerated aging in a single cell type and 1-3% across ten or more cell types. APOE genotype showed antagonistic aging effects in different cell types: APOE4 carriers exhibited older astrocytes but younger macrophages, while APOE2 carriers showed the inverse. Cellular aging signatures were uniquely associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Amyotrophic lateral sclerosis (ALS) showed the strongest association with skeletal myocyte aging (hazard ratio = 12.7 for extreme accelerated versus youthful aging). In Alzheimer's disease (AD), prevalent cases showed accelerated aging across multiple neural and peripheral cell types, with extreme astrocyte aging conferring AD risk comparable to APOE4 carrier status. Moreover, extreme astrocyte aging increased AD risk in APOE4/4 carriers threefold, while youthful astrocytes strikingly reduced risk. Beyond neurodegeneration, respiratory cell aging identified smokers at 58% higher lung cancer risk, and myeloid aging identified normoglycemic individuals at higher diabetes risk. Both specific cellular vulnerabilities and cumulative aging burden influenced survival, wherein youthful immune or neuronal profiles were protective. A polycellular aging risk score provided robust mortality risk stratification across platforms and cohorts. These findings establish a framework for quantifying biological aging at the cellular resolution using plasma proteomics, revealing heterogeneity in aging trajectories and their impact on disease susceptibility and resilience. Show less
Prior studies indicate that allyl isothiocyanate (AITC) alleviates metabolic dysfunction-associated steatotic liver disease (MASLD). The vitamin D receptor (VDR) is known to exert protective effects i Show more
Prior studies indicate that allyl isothiocyanate (AITC) alleviates metabolic dysfunction-associated steatotic liver disease (MASLD). The vitamin D receptor (VDR) is known to exert protective effects in MASLD; however, whether AITC alleviates MASLD through VDR remains unclear. To clarify the function and underlying mechanisms of AITC in MASLD AML-12 cells were exposed to 300 μM palmitate acid (PA) for 24 hours to establish an To establish an AITC provides a robust molecular basis for improving MASLD by activating hepatic VDR and driving the downstream HNF-4α/MTTP/ApoB signaling pathway. This pathway reduces hepatic lipid accumulation, promotes FA β-oxidation, and improves insulin resistance, establishing AITC as a promising treatment for MASLD. Show less
Methotrexate (MTX) is a widely used chemotherapy drug, but its neurotoxicity can lead to cognitive impairments, particularly through effects on hippocampal function. Nevertheless, the underlying molec Show more
Methotrexate (MTX) is a widely used chemotherapy drug, but its neurotoxicity can lead to cognitive impairments, particularly through effects on hippocampal function. Nevertheless, the underlying molecular mechanisms are not fully understood. Deciphering MTX-induced cognitive impairment-linked molecular mechanisms in cells of the hippocampus could uncover novel therapeutic targets. In this study, we established a mouse model of cognitive impairment induced by the chemotherapy drug MTX. We applied single-nucleus RNA sequencing (snRNA-seq) to analyze the transcriptomic alterations in hippocampal cells of mice following MTX treatment, with a focus on neuron-specific gene expression changes. MTX chemotherapy led to a decrease in excitatory neurons but an increase in inhibitory neurons, altering the excitatory-inhibitory balance of neural networks and thus mediate cognitive dysfunction. Furthermore, MTX significantly disrupted the transcriptional regulatory network and potential trajectory of GABAergic neurons. It enhanced the Nrg1-Erbb4 pathway while attenuating the Nrxn3-Lrrtm4 pathway, destabilizing trans-synaptic signaling and causing abnormalities in excitatory and inhibitory synaptic functions. These disruptions may ultimately lead to neural network imbalance and cognitive dysfunction. This study highlights the specific effects of MTX chemotherapy on hippocampal cellular function and provides valuable insights into the molecular mechanisms underlying cognitive deficits and potential therapeutic targets. Show less
This study explores the influence of congruence and incongruence in father-mother co-parenting on adolescent depression, as well as the mediating effect of self-esteem. A total of 1389 adolescents com Show more
This study explores the influence of congruence and incongruence in father-mother co-parenting on adolescent depression, as well as the mediating effect of self-esteem. A total of 1389 adolescents completed questionnaires assessing their levels of depression and self-esteem, while their fathers and mothers correspondingly reported on their own co-parenting behaviors using the Parental Co-parenting Scale in this cross-sectional study. Dates were analyzed using LPA, RSA, and mediation consecutively. The results show that: (1) We identified three distinct co-parenting profiles: positive parental co-parenting, negative parental co-parenting, and mixed parental co-parenting. (2) In cases of congruent parental co-parenting, high positive parental co-parenting was associated with lower adolescent depression, whereas high negative parental co-parenting was linked to higher depression, and the difference manifests in different forms among boys and girls. Girls showed nonlinear changes in depression while boys exhibited linear trends. (3) In cases of incongruence in parental co-parenting, mothers' co-parenting exerted a stronger influence on boys' depression, while girls were not affected by mothers' and fathers' discrepancies. (4) Self-esteem mediated the relationship between parental co-parenting (in)congruence and depression across both genders. This study provides evidence for the mechanism through which parental coparenting influences adolescent depression and offers a basis for future interventions targeting adolescent depression. Show less
To evaluate the current status and latent profiles of caregiver self-care contributions for patients with chronic obstructive pulmonary disease (COPD) and examine the associations between demographic Show more
To evaluate the current status and latent profiles of caregiver self-care contributions for patients with chronic obstructive pulmonary disease (COPD) and examine the associations between demographic characteristics, health literacy, confidence in self-care contributions, family intimacy, and profile membership. We recruited 275 dyads of patients with COPD and their family caregivers from five tertiary hospitals between May and November 2022 using convenience sampling. Latent profile analysis (LPA) was used to identify distinct profiles of caregiver self-care contributions. Univariate analysis and multinomial logistic regression were subsequently conducted to examine associations between participant characteristics and profile membership. LPA identified four distinct profiles of caregiver self-care contributions: low-contributing, under-monitored, maintenance-prioritized, and high-contributing. Significant differences were observed across these profiles in terms of patients' symptom severity, exacerbation frequency, number of hospitalizations, caregivers' education levels, caregiving duration, health literacy, confidence in self-management contributions, and family intimacy using univariate analysis. Multinomial logistic regression analysis revealed that caregivers' education levels, caregiving duration, confidence in self-management contributions, and health literacy were significant predictors of profile membership. Caregiver self-care contributions for patients with COPD can be characterized by four distinct profiles, with caregivers' educational level, health literacy, and confidence in self-management identified as key factors associated with profile membership. Show less
Chronic heart failure (CHF) impairs cognitive function. Xijiaqi Formula (XJQ), a traditional Chinese medicine (TCM) used clinically to treat CHF, demonstrates potential for improving cognition in CHF Show more
Chronic heart failure (CHF) impairs cognitive function. Xijiaqi Formula (XJQ), a traditional Chinese medicine (TCM) used clinically to treat CHF, demonstrates potential for improving cognition in CHF patients. However, its precise mechanism in treating post-CHF cognitive dysfunction remains unclear. This study systematically investigates XJQ's effects on post-CHF cognitive dysfunction and the underlying mechanisms. The components of XJQ were identified through liquid chromatography-mass spectrometry. CHF was induced in rats via ligation of the left anterior descending coronary artery, followed by six weeks of XJQ treatment. Cardiac function was evaluated through echocardiography and hemodynamic parameters, while cognitive function was assessed using Morris water maze (MWM) and open field tests (OFT). XJQ treatment enhanced both cardiac and cognitive functions in CHF rats. Network pharmacology identified 12 core active components of XJQ and indicated its effect on cognitive dysfunction involved regulating synapses, inflammation, and phosphodiesterase 4 (PDE4)-dependent cyclic adenosine monophosphate (cAMP) signaling. XJQ inhibited microglial and astrocyte activation, decreased proinflammatory cytokines, and mitigated neuronal damage. Notably, XJQ promoted synaptic repair and dendritic growth by downregulating PDE4 and upregulating cAMP, protein kinase A (PKA), cAMP-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), PSD95, and synapsin I levels. Molecular docking and Bio-layer interferometry assays confirmed direct binding of quercetin, kaempferol, isorhamnetin, and darutoside to PDE4. In conclusion, XJQ alleviates neuroinflammation and enhances synaptic plasticity to improve cognitive dysfunction in CHF rats via the PDE4/cAMP/PKA/CREB signaling pathway. These findings provide valuable insight into the heart-brain axis. Show less
Sai Wu, Wanxia Wu, Jun Zhou+8 more · 2026 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
The mechanisms underlying individual variability in acupuncture analgesia among patients with chronic pain remain unclear. This randomized controlled trial investigated the core mechanisms of differen Show more
The mechanisms underlying individual variability in acupuncture analgesia among patients with chronic pain remain unclear. This randomized controlled trial investigated the core mechanisms of differential responses to acupuncture from genetic, neuroimaging, and transcriptomic perspectives in patients with chronic pain due to knee osteoarthritis (KOA). A total of 180 KOA chronic knee pain patients were randomly assigned to verum acupuncture (VA), sham acupuncture (SA), celecoxib (SC), placebo (PB), or waiting list (WL) groups (36 each). Over 2 weeks, VA/SA received 10 sessions, SC/PB oral medication for 14 days, and WL no intervention. Baseline 3.0T MRI 3D-T1 scans and genotyping (GABRB3 rs4906902, OPRM1 rs1799971, COMT rs4680, BDNF rs6265) were performed. Efficacy was assessed via VAS and WOMAC; responders/non-responders were defined by minimally clinically important difference. Chi-square test, logistic regression, voxel-based morphometry (VBM), and Allen Human Brain Atlas-based partial least squares regression were used. No significant difference in primary outcomes was observed between VA and SA, so they were combined as the acupuncture group (AG) to enhance statistical power. Only AG had a significant association between GABRB3 rs4906902 AG/GG genotype and acupuncture response (p < 0.05); other loci showed no correlation. AG/GG carriers in AG had lower gray matter volume in caudate head, putamen, and ventral striatum, with higher GABRB3 expression in these regions. Genetic polymorphisms at GABRB3 rs4906902 could influence the analgesic effect of acupuncture treatment in patients with KOA chronic knee pain, with AG/GG genotype carriers exhibiting superior analgesic effects. This finding may be associated with pain-modulating brain regions' gray matter volume reduction and upregulation of GABRB3 gene expression. Show less
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by excessive amyloid-β (Aβ) accumulation, neuroinflammation, and oxidative stress. Exosomes derived from human umbili Show more
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by excessive amyloid-β (Aβ) accumulation, neuroinflammation, and oxidative stress. Exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSC@Exo) represent promising nanoscale carriers for targeted drug delivery. In this study, Baicalein (Bac), a potent antioxidant and anti-inflammatory flavonoid, was encapsulated into hUC-MSC-derived exosomes (Exo@Bac) to enhance its therapeutic efficacy. The neuroprotective potential of Exo@Bac was evaluated in a rat model of Aβ1-42-induced AD. Rats received intraperitoneal injections of Bac, hUC-MSC@Exo, or Exo@Bac, and cognitive performance was assessed using the passive avoidance test and Morris water maze. Exo@Bac treatment significantly improved memory deficits and elevated brain-derived neurotrophic factor (BDNF) expression compared to controls. Histopathological analyses revealed reduced neuronal damage and apoptosis, alongside decreased Aβ1-42 deposition in Exo@Bac-treated rats. Furthermore, Exo@Bac enhanced antioxidant defense (increased SOD), attenuated pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and lowered lipid peroxidation (MDA). Mechanistically, Exo@Bac promoted AMPK phosphorylation while suppressing NF-κB p65 signaling, indicating modulation of both oxidative stress and neuroinflammatory pathways. These findings demonstrate that Exo@Bac acts as a nanotherapeutic agent capable of mitigating AD pathology, highlighting its potential as a novel strategy for Alzheimer's disease therapy. Show less
Influenza vaccination coverage among older adults in China is low. We sought to identify latent vaccine-hesitancy profiles and their correlates. This community-based cross-sectional survey from May to Show more
Influenza vaccination coverage among older adults in China is low. We sought to identify latent vaccine-hesitancy profiles and their correlates. This community-based cross-sectional survey from May to July 2025 involved 1773 older adults from various areas in Jiangsu province. Data were collected via Wenjuanxing and included demographics, the Influenza Vaccine Hesitancy Scale, and the vaccine literacy scale. Group differences were examined using chi-square tests and one-way ANOVA; latent profile analysis (LPA) identified vaccine hesitancy subgroups, and multinomial logistic regression estimated correlates of profile membership. Three profiles emerged: Low Hesitancy (23.0%), Moderate Hesitancy (35.0%), and High Hesitancy (42.0%). Rural residence predicted Moderate (OR = 2.030) and High (OR = 2.993) hesitancy. Lower household income and chronic disease were associated with the Moderate Hesitancy profile, whereas male sex was associated with the High Hesitancy profile. Higher interactive (OR = 0.686) and critical (OR = 0.599) vaccine literacy were inversely associated with High hesitancy.Concerns about vaccine quality predicted both Moderate (OR = 1.433) and High (OR = 1.376) groups; knowledge gaps and fear of adverse reactions concentrated in the High group. Older adults show heterogeneous vaccine hesitancy phenotypes. Uptake efforts should move beyond one-size-fits-all messaging toward segmented strategies. These strategies should integrate cost-related measures with literacy-sensitive, trust-oriented communication, prioritizing rural residents, older men, and those with chronic conditions. The reported proportions of hesitancy profiles reflect our sample only and should not be viewed as nationally representative. Show less