👤 Manel Juan

Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) may contribute to Alzheimer's disease (AD) pathogenesis by promoting amyloid-β (Aβ) aggregation. ASC protein is mainly composed of the N-terminal pyrin domain (PYD) and the C-terminal caspase recruitment domain (CARD). This study aims to explore the different roles of the two domains of ASC in AD. The SH-SY5Y-APP695 cells were treated with ASC neutralizing antibodies against the N-terminal domain (anti-ASC N-terminal antibodies) or C-terminal domain(anti-ASC C-terminal antibodies). The cell apoptosis and Aβ production were detected. The eight-month-old APP/PS1 mice received lateral ventricle injections of anti-ASC N-terminal antibodies or anti-ASC C-terminal antibodies. The cognitive function and AD-like pathology of APP/PS1 mice were assessed. The anti-ASC N-terminal and C-terminal antibodies attenuated apoptosis and mitochondrial damage, and reduced Aβ production by inhibiting BACE1 in vitro. Furthermore, intracerebroventricular administration of anti-ASC N-terminal and C-terminal antibodies improved cognitive impairment and reduced Aβ deposition, tau hyperphosphorylation, and neuroinflammation in the APP/PS1 mice. The anti-ASC N-terminal and C-terminal antibodies may have neuroprotective effects, which are manifested as reducing cell apoptosis, improving cognitive function, and alleviating AD-like pathology in AD mice. Immunotherapies targeting ASC are promising for treating AD. Show less

B-cell maturation antigen (BCMA) is the main target for chimeric antigen receptor (CAR)-T cells in multiple myeloma (MM), demonstrating promising outcomes. However, unlike what happens with CART19 in lymphoblastic leukemia and non-Hodgkin's lymphoma, a high proportion of patients will relapse after CAR-T BCMA therapy due to insufficient antigen expression, low CAR-T cell persistence and/or T-cell exhaustion. In other B cell malignancies, second-generation anti-CD19 4-1BB CARs with CD28-transmembrane domain (TMD) have shown high efficacy and a favorable toxicity profile. We have developed a second-generation CD8α-TM BCMA-4-1BBζ CAR-T product, ARI0002h (Cesnicabtagene-autoleucel) for patients with relapsed/refractory MM. We hypothesized that replacing the TMD of ARI0002h with a CD28-TMD could increase efficacy and reduce tumor escape while maintaining a tolerable toxicity profile. We generated CAR-T cells using T-cells isolated from buffy coats and evaluated the efficacy and fitness of CAR-Ts at day 8-10 of expansion against several MM cell lines. In vitro analyses included cytotoxicity, proliferation, cytokine secretion, T-cell subset markers, activation and exhaustion profiling, metabolomic assays, and RNA-seq after multiple tumor challenges. In in vivo xenograft studies using NSG mice, with tumor cells expressing GFP-ffLuc, disease progression was monitored weekly via bioluminescence imaging. Despite showing similar in vitro performance regarding cytotoxicity, proliferation and cytokine production, ARI2h-TM28 outperforms ARI0002h in a low BCMA expression setting and achieves superior in vivo tumor control and survival in relapse models with antigen downregulation. Furthermore, ARI2h-TM28 showed an optimized metabolic profile, more oxidative and energetic compared with ARI0002h, with downregulation of proinflammatory genes in CD8 T cells, contributing altogether both to reduced exhaustion and increased persistence of the CARs, improving their efficacy in preclinical models. Incorporating a CD28-TMD into the ARI0002h CAR enhances tumor control even in relapse models with downregulation of the target antigen, offering improved long-term disease management. This modification increases potency against MM tumor cell lines with both normal and reduced BCMA expression, demonstrating superior metabolic endurance and in vivo activity. Show less

This study aimed to explore the professional quality of life among nursing assistants and identify latent profiling, and examine their relationships with perceived organizational support and self-efficacy. A cross - sectional survey study was conducted. Nursing assistants from two hospitals in Shenzhen, China, were recruited through convenience sampling. Demographic characteristics, perceived organizational support, self-efficacy, and professional quality of life were measured using validated scales. Latent profile analysis (LPA) identified subgroups of professional quality of life, and logistic regression examined the associations of demographic factors, organizational support, and self-efficacy with profile membership. A total of 354 nursing assistants were included in this study. The professional quality of life was classified into three profiles: "adaptive group", "stress group", and "high burden group" comprising 216, 102, and 36 nursing assistants, respectively. Statistical differences were observed among the three groups in terms of demographic characteristics such as gender, ethnicity, certification, and professional title (P < 0.05). Additionally, instrumental support, emotional support, and self - efficacy differed significantly among the groups (P < 0.05). Gender (female), licensure, professional title (primary and mid - level), emotional support, and self - efficacy were predictors of nursing assistants' professional quality of life. These findings may facilitate the identification of different profiles of nursing assistants for targeted training programs aimed at improving their professional quality of life. Furthermore, intervention strategies emphasizing emotional support, and self - efficacy may offer valuable approaches for enhancing professional quality of life. Show less

Angiopoietin-like protein 4 (ANGPTL4) is a hepatokine implicated in fat metabolism regulation. Its genetic inactivation has been associated with improved glucose homeostasis, while elevated plasma ANGPTL4 levels are observed in diabetic and obese individuals. However, the potential link between ANGPTL4 and diabetes- or obesity-related complications remains uncertain. This study aimed to explore whether plasma ANGPTL4 level could serve as a predictor of cancer mortality, cardiovascular mortality, and all-cause mortality in a community-based cohort. A community-based cohort study was conducted, where fasting plasma ANGPTL4 concentrations were measured at baseline, and vital status was ascertained through linkage with the National Health Insurance Research Database in Taiwan. During a 10.46-year follow-up period, 29 (2.49%) of the 1163 participants died. Subjects within the highest tertile of plasma ANGPTL4 levels exhibited the lowest survival rate. In unadjusted models, plasma ANGPTL4 significantly predicted all-cause mortality, cancer mortality, and cardiovascular or cancer-related mortality. Upon adjustment for confounders including age, sex, smoking, body mass index (BMI), hypertension, diabetes mellitus (DM), and renal function, each standard deviation increase in plasma ANGPTL4 was associated with HRs of 1.35 (95% CI: 1.01-1.80, Plasma ANGPTL4 emerges as a promising biomarker capable of predicting 10-year mortality and enhancing risk prediction beyond established risk factors. Show less

The early detection of high-risk individuals is crucial to delay and reduce the incidence of type 2 diabetes. In this study, we aimed to explore the performance of a novel subgroup-specific biomarker strategy in the prediction of incident diabetes. In the Taiwan Lifestyle Cohort Study, adult subjects without diabetes were included and followed for the incidence of diabetes in 2006-2019. The biomarkers measured included blood secretogranin III (SCG3), vascular adhesion protein-1 (VAP-1), fibrinogen-like protein 1 (FGL1), angiopoietin-like protein 6 (ANGPTL6), and angiopoietin-like protein 4 (ANGPTL4). Among the 1,287 subjects, 12.2% developed diabetes during a 6 year follow-up. Blood VAP-1 was significantly associated with incident diabetes in the overall population (HR = 0.724, P < 0.05), participants under 65 years old (HR = 0.685, P < 0.05), those with a BMI of ≥24 kg/m Gender- and BMI-specific biomarker strategy can improve the prediction of incident diabetes. A subgroup-specific biomarker strategy is a novel approach in the prediction of incident diabetes. Show less

To investigate the role of pyroptosis in diabetic nephropathy (DN) and identify potential biomarkers for diagnosis. We analyzed the GEO dataset GSE96804 to identify differentially expressed genes (DEGs) related to pyroptosis in DN. The CIBERSORT method was used to assess M1 macrophage infiltration in the samples. Using weighted gene co-expression network analysis (WGCNA), we identified gene modules associated with M1 macrophages. The least absolute shrinkage and selection operator (LASSO) method was then applied to screen for key genes. The intersection of key genes identified by LASSO and the gene modules obtained from WGCNA resulted in the identification of ten hub genes as potential biomarkers for DN. A total of 366 DEGs were identified, with 310 genes associated with pyroptosis. Increased M1 macrophage infiltration was observed in DN patients. Ten hub genes were identified as potential DN biomarkers: ECM1, LRP2BP, ALKBH7, CDH10, DUSP1, HSPA1A, LPL, NFIL3, PDK4, and TMEM150C. This study highlights the importance of pyroptosis in DN pathophysiology and identifies 10 hub genes as potential biomarkers. These findings may contribute to improved diagnosis and treatment of DN. Show less

Angiopoietin-like protein 4 (ANGPTL4) is a secretory glycoprotein involved in regulating glucose homeostasis in non-pregnant subjects. However, its role in glucose metabolism during pregnancy and the pathophysiology of gestational diabetes mellitus (GDM) remains elusive. Thus, this study aimed to clarify the relationship between ANGPTL4 and GDM and investigate the pathophysiology of placental ANGPTL4 in glucose metabolism. We investigated this issue using blood and placenta samples in 957 pregnant women, the human 3A-sub-E trophoblast cell line, and the L6 skeletal muscle cell line. We found that ANGPTL4 expression in the placenta was higher in obese pregnant women than in lean controls. Palmitic acid significantly induced ANGPTL4 expression in trophoblast cells in a dose-response manner. ANGPTL4 overexpression in trophoblast cells resulted in endoplasmic reticulum (ER) stress, which stimulated the expression and secretion of growth hormone-variant (GH2) but not human placental lactogen. In L6 skeletal muscle cells, soluble ANGPTL4 suppressed insulin-mediated glucose uptake through the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinases 1/2 (ERK 1/2) pathways. In pregnant women, plasma ANGPTL4 concentrations in the first trimester predicted the incidence of GDM and were positively associated with BMI, plasma triglyceride, and plasma GH2 in the first trimester. However, they were negatively associated with insulin sensitivity index ISI Show less

Large-for-gestational-age (LGA) neonates have increased risk of adverse pregnancy outcomes and adult metabolic diseases. We aimed to investigate the relationship between plasma angiopoietin-like protein 4 (ANGPTL4), a protein involved in lipid and glucose metabolism during pregnancy, placental function, growth factors, and the risk of LGA. We conducted a prospective cohort study and recruited women with singleton pregnancies at the National Taiwan University Hospital between 2013 and 2018. First trimester maternal plasma ANGPTL4 concentrations were measured. Among 353 pregnant women recruited, the LGA group had higher first trimester plasma ANGPTL4 concentrations than the appropriate-for-gestational-age group. Plasma ANGPTL4 was associated with hemoglobin A1c, post-load plasma glucose, plasma triglyceride, plasma free fatty acid concentrations, plasma growth hormone variant (GH-V), and birth weight, but was not associated with cord blood growth factors. After adjusting for age, body mass index, hemoglobin A1c, and plasma triglyceride concentrations, plasma ANGPTL4 concentrations were significantly associated with LGA risk, and its predictive performance, as measured by the area under the receiver operating characteristic curve, outperformed traditional risk factors for LGA. Plasma ANGPTL4 is associated with glucose and lipid metabolism during pregnancy, plasma GH-V, and birth weight, and is an early biomarker for predicting the risk of LGA. Show less

Imidacloprid (IMI), the most widely used worldwide neonicotinoid biocide, produces cognitive disorders after repeated and single treatment. However, little was studied about the possible mechanisms that produce this effect. Cholinergic neurotransmission regulates cognitive function. Most cholinergic neuronal bodies are present in the basal forebrain (BF), regulating memory and learning process, and their dysfunction or loss produces cognition decline. BF SN56 cholinergic wild-type or acetylcholinesterase (AChE), β-amyloid-precursor-protein (βAPP), Tau, glycogen-synthase-kinase-3-beta (GSK3β), beta-site-amyloid-precursor-protein-cleaving enzyme 1 (BACE1), and/or nuclear-factor-erythroid-2-related-factor-2 (NRF2) silenced cells were treated for 1 and 14 days with IMI (1 μM-800 μM) with or without recombinant heat-shock-protein-70 (rHSP70), recombinant proteasome 20S (rP20S) and with or without N-acetyl-cysteine (NAC) to determine the possible mechanisms that mediate this effect. IMI treatment for 1 and 14 days altered cholinergic transmission through AChE inhibition, and triggered cell death partially through oxidative stress generation, AChE-S overexpression, HSP70 downregulation, P20S inhibition, and Aβ and Tau peptides accumulation. IMI produced oxidative stress through reactive oxygen species production and antioxidant NRF2 pathway downregulation, and induced Aβ and Tau accumulation through BACE1, GSK3β, HSP70, and P20S dysfunction. These results may assist in determining the mechanisms that produce cognitive dysfunction observed following IMI exposure and provide new therapeutic tools. Show less

Single-cell RNA sequencing (scRNA-seq) approach can broadly and specifically evaluate the individual cells with minimum detection bias. To explore the individual compositional and transcriptional alteration of intestinal leukocytes in the Dual Specificity Phosphatase six knockout (D6KO) mice, we performed a scRNA-seq followed by the cell type annotation based on ImmGen database. Composition assessments found that D6KO-derived intestinal leukocytes tend to stay inactivate or immature status. The enrichment analysis showed that D6KO-derived intestinal leukocytes are less sensitive to microbes. The Show less

Strengthening the gut epithelial barrier is a potential strategy for management of gut microbiota-associated illnesses. Here, we demonstrate that dual-specificity phosphatase 6 (Dusp6) knockout enhances baseline colon barrier integrity and ameliorates dextran sulfate sodium (DSS)-induced colonic injury. DUSP6 mutation in Caco-2 cells enhances the epithelial feature and increases mitochondrial oxygen consumption, accompanied by altered glucose metabolism and decreased glycolysis. We find that Dusp6-knockout mice are more resistant to DSS-induced dysbiosis, and the cohousing and fecal microbiota transplantation experiments show that the gut/fecal microbiota derived from Dusp6-knockout mice also confers protection against colitis. Further culturomics and mono-colonialization experiments show that one gut microbiota member in the genus Duncaniella confers host protection from DSS-induced injury. We identify Dusp6 deficiency as beneficial for shaping the gut microbiota eubiosis necessary to protect against gut barrier-related diseases. Show less

MC4R gene is a hypothalamic satiety control mediator in which mutations cause a monogenic form of obesity. The aim of this study was to perform a genetic screening to identify variations in the entire region of MC4R gene. A total of 236 unrelated and severely obese patients (BMI ≥ 40 kg/m Show less

Polyunsaturated fatty acids (PUFAs) are associated with a lower risk of multiple diseases. Fatty acid desaturase 1 gene (FADS1) polymorphisms and dietary PUFA intake are both established determinants of circulating PUFA proportions. We explored the joint effects of FADS1 polymorphisms and dietary PUFA intake on circulating PUFA proportions. We studied 2288 participants from a nested case-control study of coronary artery disease among participants who provided blood samples in the Nurses' Health Study and the Health Professionals Follow-Up Study. Dietary PUFA intake was obtained from semiquantitative food-frequency questionnaires. FADS1 rs174546 was genotyped by using the Affymetrix 6.0 platform, and circulating PUFA proportions were measured with gas-liquid chromatography. Linear regression models were used to examine the associations between rs174546 and circulating proportions of each fatty acid. Gene-diet interactions were tested by including a cross-product term of dietary intake of each PUFA by rs174546 genotype in the linear regression models. After adjustment for sex and ancestry, each copy of the C allele of rs174546 was associated with higher circulating proportions of arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) and lower proportions of linoleic acid and α-linolenic acid. The magnitude of positive association between higher consumption of dietary EPA or DHA and circulating proportions of EPA increased with each copy of the rs174546_T allele (P-interaction = 0.01 and 0.007, respectively). Each 1-SD increment in EPA intake was associated with an average 3.7% increase in circulating EPA proportions among participants with the rs174546_CC genotype and an average 7.8% increase among participants with the TT genotype. Carriers of the T allele at FADS1 rs174546 may need higher doses of dietary EPA and DHA to achieve the same circulating proportions of EPA as carriers of the C allele. The implications of these findings on disease risk and dietary guidelines require further study. Show less