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Several studies have suggested an association between exposure to various metals and the onset of type 2 diabetes (T2D). However, the results vary across different studies. We aimed to investigate the associations between serum metal concentrations and the risk of developing T2D among 8734 participants using a prospective cohort study design. We utilized inductively coupled plasma mass spectrometry (ICP-MS) to assess the serum concentrations of 27 metals. Cox regression was applied to calculate the hazard ratios (HRs) for the associations between serum metal concentrations on the risk of developing T2D. Additionally, 196 incident T2D cases and 208 healthy control participants were randomly selected for serum metabolite measurement using an untargeted metabolomics approach to evaluate the mediating role of serum metabolite in the relationship between serum metal concentrations and the risk of developing T2D with a nested case control study design. In the cohort study, after Bonferroni correction, the serum concentrations of zinc (Zn), mercury (Hg), and thallium (Tl) were positively associated with the risk of developing T2D, whereas the serum concentrations of manganese (Mn), molybdenum (Mo), barium (Ba), lutetium (Lu), and lead (Pb) were negatively associated with the risk of developing T2D. After adding these eight metals, the predictive ability increased significantly compared with that of the traditional clinical model (AUC: 0.791 vs. 0.772, P =8.85×10−5). In the nested case control study, a machine learning analysis revealed that the serum concentrations of 14 out of 1579 detected metabolites were associated with the risk of developing T2D. According to generalized linear regression models, 7 of these metabolites were significantly associated with the serum concentrations of the identified metals. The mediation analysis showed that two metabolites (2-methyl-1,2-dihydrophthalazin-1-one and mestranol) mediated 46.81% and 58.70%, respectively, of the association between the serum Pb concentration and the risk of developing T2D. Our study suggested that serum Mn, Zn, Mo, Ba, Lu, Hg, Tl, and Pb were associated with T2D risk. Two metabolites mediated the associations between the serum Pb concentration and the risk of developing T2D. • Association between metals and type 2 diabetes (T2D) remain inconsistent. • Cohort study and mediation analysis was used to uncover link between metals and T2D. • Level of 8 metals were identified to be associated with incident T2D risk. • 2 metabolites mediated 46.81% and 58.70% of the association between Pb and T2D risk. [ABSTRACT FROM AUTHOR]

Marine benthic dinoflagellate toxins, potent bioactive compounds with wide-ranging presence in marine ecosystems, have surged in response to global climate change and human activities, prompting an urgent and imperative inquiry. This study conducts an in-depth review of contemporary research concerning these toxins, employing meticulous bibliometric analysis. Leveraging a dataset of 736 relevant literatures sourced from the Web of Science (spanning from 2000 to May 2023), our analysis delves comprehensively into the scientific discourse surrounding these toxic compounds. Employing tools such as VOSviewer, co-citation analysis, co-occurrence analysis, and cluster analysis, our study yields nuanced insights into the intricate characteristics and trajectories of the field. The co-citation analysis underscores the pivotal role played by benthic and epiphytic dinoflagellates like Ostreopsis and Gambierdiscus in shaping prevailing research trends. Our study identifies four distinct research directions, encompassing the domains of ecology, toxicology, toxin production, and taxonomy. Moreover, it traces the evolutionary journey of research stages, marking the transition from a focus on taxonomy to an emphasis on unraveling molecular mechanisms. The culmination of our comprehensive analysis yields three pertinent research recommendations: a call for widescale global studies, the advancement of rapid toxin monitoring techniques, and a deeper exploration of the factors influencing toxin synthesis and toxicity. These findings provide invaluable insights to researchers grappling with the complex realm of harmful algal blooms and substantially enrich the understanding of this pivotal and pressing field. • Comprehensive bibliometric analysis of marine benthic dinoflagellate toxins research. • Co-citation analysis spotlights Ostreopsis , Gambierdiscus , and toxicity ecology. • Cluster analysis reveals four research avenues, including ciguatera fish poisoning. • Evolution of research stages from taxonomy to toxicology and molecular mechanisms. • Urgent imperative for global-scale studies and rapid toxin monitoring methods. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the survival of acid stress adapted Listeria monocytogenes Bug600 and ScottA cells in various lethal concentrations of disinfectants in broth and water models. Acid stress adapted cells had significantly greater survival than the non-adapted cells in lethal concentrations of hydrochloric acid, lactic acid, and acetic acid in tryptic soy broth containing yeast extract (TSBYE). Also, acid stress adaptation protected L. monocytogenes cells against lethal sodium hydroxide (NaOH), potassium hydroxide (KOH) and ammonium hydroxide (NH 4 OH). Increased tolerance to lethal concentrations of ethanol and isopropanol was also observed after acid stress adaptation. Acid stress adapted cells also exhibited higher survival in two quaternary ammonium compounds (QAC-1 and QAC-2). Acid stress adapted cells were more susceptible to hydrogen peroxide (H 2 O 2) inactivation. Similar survival patterns were observed for the acid stress adapted and non-adapted cells in both water and broth models, suggesting that the impact of acid adaptation on L. monocytogenes survival in disinfectants was not altered due to the presence of nutrients. Overall, these findings indicate that oxidative based agents are the best choice to decontaminate the food contact surface where acid stress adapted L. monocytogenes cells may be present. • Acid adaptation of L. monocytogenes enhanced the survival in lethal acid/alkali. • Acid adaptation of L. monocytogenes enhanced the survival in lethal QAC. • Acid adaptation of L. monocytogenes caused increased sensitivity to lethal H 2 O 2. • Acid adaptation did not affect the survival of L. monocytogenes in lethal NaOCl. • Survival of acid adapted Lm in lethal disinfectants were similar in broth/water. [ABSTRACT FROM AUTHOR]

Abstract Nobiletin has protective effects on cardiovascular diseases, but the mechanism is not clear. In this study, we examined whether nobiletin affects the expression of miR-590/LPL and its relative effects on lipid accumulation and pro-inflammatory cytokine secretion in human THP-1 macrophages. RT-qPCR analysis showed that nobiletin increased the expression of miR-590. Western blot analysis showed that nobiletin-suppressed LPL expression was enhanced by miR-590 mimic and abrogated by miR-590 inhibitor. Oil Red O staining and high-performance liquid chromatography assays showed that nobiletin attenuated lipid accumulation in macrophages. Treatment with nobiletin and miR-590 mimic decreased cellular lipid accumulation, whereas treatment with miR-590 inhibitor increased cellular lipid accumulation. ELISA illustrated that nobiletin alleviated pro-inflammatory cytokine secretion in macrophages as measured by, which was reduced by miR-590 mimic and increased by miR-590 inhibitor. In conclusion, nobiletin may alleviate lipid accumulation and secretion of pro-inflammatory cytokines by enhancing the inhibitory effect of miR-590 on LPL expression, suggesting a promising strategy for potential drug development for atherosclerosis. Highlights • Nobiletin may alleviate lipid accumulation in human THP-1 macrophages. • Nobiletin may alleviate secretion of pro-inflammatory cytokines in human THP-1 macrophages. • Nobiletin may enhance the inhibitory effect of miR-590 on LPL expression. [ABSTRACT FROM AUTHOR]

Long-term and short-term exposure to carbon nanoparticles (CNPs) can affect fetal development and subsequent adverse outcomes including preterm delivery, intrauterine growth restriction, low birth weight, increased health risk linked to cardiovascular, respiratory and nervous systems in adulthood. The adverse developmental outcomes of CNPs were well known, but the underlying mechanisms remain unresolved. In this study, zebrafish embryos were treated with CNPs of 50,100,200 μg/mL and the toxic effects were observed. Using the RNA-seq analysis approach, we examined the effects of CNPs (200 μg/mL) on gene expression in zebrafish embryos exposed from 4 to 96 h-post-fertilization (hpf). We observed that CNPs-treated embryos exhibited increased malformations and decreased hatching. A total of 236 differentially expressed genes were detected by transcriptome analyses, which were associated with phototransduction, amino acid metabolism, steroid and steroid hormone biosynthesis. Transcriptome results were verified by real-time fluorescence quantitative PCR (RT-qPCR). Our results indicated that CNPs exposure was most likely to lead to differential gene changes in steroid and hormone biosynthesis pathways, thus inducing developmental toxicity such as delayed incubation of zebrafish embryos, increased malformation rate and multiple malformation phenotypes. • Zebrafish embryos were exposed to carbon nanoparticles. • The hatchability and malformation rate of zebrafish embryos were calculated. • CNPs-treated embryos exhibited increased malformations and decreased hatching. • 236 differentially expressed genes were detected by transcriptome analyses. [ABSTRACT FROM AUTHOR]

Agricultural soils derived from black shale are typically enriched in potentially toxic metals. This is a serious problem, both in terms of the ecological environment and human health. To assess the levels of potentially toxic metals, 90 paired soil-crops samples were collected from the Anji Country, western Zhejiang province, a typical exposed black shale area in China. Concentrations and bioavailability of potentially toxic metals in the soil-crops system were measured, and the associated potential risks were further evaluated. Results showed the enrichment of potentially toxic metals (i.e. Cd, Pb, Cu, Zn and Ni) in the soil and crop samples, especially a significant accumulation of Cd. Sequential extraction data indicated that Cd in soils derived from black shale was the second most dominant element in the exchangeable fraction (mean at 33.42%) and possessed high bioavailability, whereas Pb was mostly retained in the residual fraction (mean at 76.34%) and exhibited low mobility. The total concentration as well as mobility and bioavailability of Cd were the highest in the sampled soils. This resulted in a high potential ecological risk in areas with agricultural soils derived from black shale, which could eventually jeopardize the health of local residents through various exposure pathways. Overall, our findings provide a scientific basis for developing suitable management strategies to mitigate the exposure to potentially toxic metals in high risk areas. [Display omitted] • Significant enrichment of potentially toxic elements was found in agricultural soils derived from black shale. • Cd and Pb dominated in the exchangeable and residual fractions, respectively. • Potentially toxic elements pose prominent ecological risks in the study area, especially Cd. • Food consumption produced the highest health risk among various exposure pathways. [ABSTRACT FROM AUTHOR]

Congenital anomalies of the kidney and urinary tract (CAKUT) have been attributed to genetic and environmental factors. However, monogenic and copy number variations cannot sufficiently explain the cause of the majority of CAKUT cases. Multiple genes through various modes of inheritance may lead to CAKUT pathogenesis. We previously showed that Robo2 and Gen1 coregulated the germination of ureteral buds (UB), significantly increasing CAKUT incidence. Furthermore, MAPK/ERK pathway activation is the central mechanism of these two genes. Thus, we explored the effect of the MAPK/ERK inhibitor U0126 in the CAKUT phenotype in Robo2 PB/+ Gen1 PB/+ mice. Intraperitoneal injection of U0126 during pregnancy prevented the development of the CAKUT phenotype in Robo2 PB/+ Gen1 PB/+ mice. Additionally, a single dose of 30 mg/kg U0126 on day 10.5 embryos (E10.5) was most effective for reducing CAKUT incidence and ectopic UB outgrowth in Robo2 PB/+ Gen1 PB/+ mice. Furthermore, embryonic kidney mesenchymal levels of p-ERK were significantly decreased on day E11.5 after U0126 treatment, along with decreased cell proliferation index PHH3 and ETV5 expression. Collectively, Gen1 and Robo2 exacerbated the CAKUT phenotype in Robo2 PB/+ Gen1 PB/+ mice through the MAPK/ERK pathway, increasing proliferation and ectopic UB outgrowth. • Urinary system congenital anomalies are genetically and environmentally complex. • ROBO2 and GEN1 coregulate ureteral bud germination and influence CAKUT incidence. • U0126 treatment reduces CAKUT incidence in mice with Robo2 and Gen1 mutations. • We conclude that ROBO2 and GEN1 influence MAPK/ERK signaling to contribute to CAKUT. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) presents a substantial population health concern. Previous studies have revealed that GDM can ultimately influence nephron endowment. In this study, we established a GDM mouse model to investigate the embryological alterations and molecular mechanisms underlying the development of congenital anomalies of the kidney and urinary tract (CAKUT) affected by GDM. Our study highlights that GDM could contribute to the manifestation of CAKUT, with prevalent phenotypes characterized by isolated hydronephrosis and duplex kidney complicated with hydronephrosis in mice. Ectopic ureteric buds (UBs) and extended length of common nephric ducts (CNDs) were noted in the metanephric development stage. The expression of Ret and downstream p -ERK activity were enhanced in UBs, which indicated the alteration of RET/MAPK/ERK pathway may be one of the mechanisms contributing to the increased occurrence of CAKUT associated with GDM. • GDM could contribute to the manifestation of CAKUT in mice. • Ectopic UBs and extended length of CNDs were noted in the metanephric development stage under GDM. • GDM could alter the RET/MAPK/ERK pathway involved in metanephric development. [ABSTRACT FROM AUTHOR]

In this study, soyasaponin (Ssa), corn oil, and soybean protein isolate (SPI) were used to prepare a water-in-oil-in-water (W/O/W) double emulsion system that can protect Lactobacillus plantarum (L.P) in the upper gastrointestinal tract for delivery to the small intestine and colon. Incorporating different amounts of L.P (0.1–0.6% (w/v)) in the W/O/W double emulsion caused the viscoelastic modulus and droplet size of the L.P-embedded emulsion system to change, and the emulsion system transformed from a non-Newtonian fluid to a "solid-like" gel. These results revealed that L.P encapsulation led to significantly improved stability of the W/O/W emulsion. In addition, different concentrations of L.P had different effects on the survival rate of L.P in simulated digestive fluids, and after in vitro digestion, L.P was naturally delivered from the stomach into the intestines. The optimal concentration of L.P for obtaining a stable emulsion was found to be 0.3%, and the survival rate of the encapsulated L.P in the small intestine was as high as 78.96% after 1 h. Thus, choosing an appropriate amount of L.P was crucial. The W/O/W emulsion system effectively maintained the viability of L.P and successfully delivered it to the small intestine and colon. • Ssa-SPI W/O/W emulsion improves the survival of LP in the gastrointestinal tract. • L.P shows better resistance to gastric acid upon encapsulation in inner phase. • Addition of 0.2–0.4% of L.P resulted higher stability in Ssa-SPI W/O/W emulsions. • The adsorption and film formation of L.P at the interface helps stabilize emulsion. [ABSTRACT FROM AUTHOR]

Nanofirework-like PtRu alloy catalyst has been successfully synthesized and used as an efficient anodic catalyst for glycerol oxidation reaction (GOR) in alkaline medium. [Display omitted] • A class of firework-like bimetallic PtRu alloy nanocatalysts has been successfully fabricated. • The addition of Ru can effectively tune the electronic structure of Pt and greatly improve the performance of the catalyst. • The electrocatalytic properties of bimetallic PtRu catalysts strongly rely on their chemical composition. Electro-oxidation of glycerol is a key anodic reaction in direct alcohol fuel cell (DAFCs). Exploring the cost-effective nanocatalysts for glycerol oxidation reaction (GOR) is very important for the development of DAFC, but it is still challenging. In this paper, nanofirework-like PtRu alloy catalyst was successfully synthesized and used for GOR in alkaline medium. Thanks to the unique nanofirework-like structure and synergetic effects, the activity and stability of the as-prepared PtRu alloy nanofireworks (NFs) toward GOR were significantly improved relative to Pt NFs. In particular, the peak current density of GOR catalyzed by the optimized Pt 1 Ru 3 NFs catalyst reached 2412.0 mA mg−1, surpassing that of commercial Pt/C catalyst. This work has important guidance for the design of advanced anode electrocatalysts for fuel cells. [ABSTRACT FROM AUTHOR]

Soyasaponins (Ssa) have various biological benefits for the human body. However, they are one of the main factors contributing to the bitter taste of certain soybean-based foods. In this study, the case interaction between pectin and Ssa was investigated by us, as well as the impact of pectin addition on the bitter taste of Ssa. The findings revealed that the thermal stability of Ssa–pectin complexes was higher than that of Ssa–mucin complexes. Fluorescence spectroscopy and isothermal titration calorimetry revealed that pectin interferes with the binding of Ssa to mucin by interacting with Ssa, thereby disrupting the Ssa binding process. As the proportion of pectin increases, the comprehensive score also increases. This confirms that pectin can effectively reduce the bitterness and astringency of Ssa, signifying its importance in further exploration of the mechanism by which Ssa–pectin complexes influence the presentation of bitterness. • The thermal stability of Ssa-pectin complexes is stronger than that of Ssa-mucin. • Pectin binding to Ssa mainly through hydrogen bonding. • Hydrogen bonding plays an important role in the interaction with receptors. • Pectin effectively reduces the bitter and astringent flavors of Ssa. [ABSTRACT FROM AUTHOR]

Congenital anomalies of the kidney and urinary tract (CAKUT) are a family of often-concurrent diseases with various anatomical spectra. Null-mutant Gen1 mice frequently develop multiple urinary phenotypes, most commonly duplex kidneys, and are ideal subjects for research on ectopic budding in CAKUT development. The upper and lower kidney poles of the Gen1 PB/PB mouse were examined by histology, immunofluorescence, and immunohistochemistry. The newborn Gen1 PB/PB mouse lower poles were significantly more hypoplastic than the corresponding upper poles, with significantly fewer glomeruli. On embryonic day 14.5, immediately before first urine formation, the upper pole kidney was already larger than the lower pole kidney. In vivo and in vitro, embryonic kidney upper poles had more ureteric buds than lower poles. Gen1 PB/PB embryos exhibited ectopic ureteric buds, usually near the original budding site, occasionally far away, or, rarely, derived from the primary budding site. Therefore, ectopia of the ureteric buds is the core of CAKUT formation. Further studies will be needed to investigate the regulatory roles of these genes in initial ureteric budding and subsequent ontogenesis during metanephros development. • Ectopia of the initial budding is central to the formation of CAKUT. • Three kinds of ectopic bud develop into three duplex kidneys in Gen1 PB/PB mice. • Upper pole kidney of newborn Gen1 PB/PB mice was more hypoplastic than that in lower. • At E14.5, the upper pole kidney was already larger than the lower pole kidney. • Ectopic budding alone results in kidney hypoplasia, not dysplasia in Gen1 mutation. [ABSTRACT FROM AUTHOR]

Oxidative stress caused by the excess of radical oxygen species (ROS) could lead to many kinds of human diseases. Antioxidant peptides, a kind of natural antioxidants, have attracted much attention for their low toxicities and strong antioxidant activities. Food proteins can be regarded as good materials for the production of antioxidant peptides by enzymatic hydrolysis. In this work, we aimed to find novel natural antioxidant peptides derived from Agrocybe aegerita proteins by enzymatic hydrolysis. The method of response surface methodology (RSM) was adopted for optimizing the hydrolysis parameters. Under the optimal condition, antioxidant peptides of Agrocybe aegerita were separated and sequenced. Finally, twenty-five novel antioxidant peptides with high antioxidant scores were identified. These results suggest that the hydrolysates of Agrocybe aegerita proteins could be used as natural antioxidants in functional foods and food processing. • Hydrolysates of Agrocybe aegerita proteins can be used as natural antioxidants in food. • Reaction temperature is an important factor to affect the antioxidant activities of hydrolysates. • Twenty-five novel antioxidant peptides scoring more than 5 were identified. [ABSTRACT FROM AUTHOR]

Proteinuria is an important marker and is closely related to the progressive decline of renal function. Our previous research showed that angiopoietin-like-3 (ANGPTL3) plays a crucial role in proteinuria. In this study, we prepared an antibody against ANGPTL3 coil-coiled domain (ANGPTL3-CCD) and investigated the protective effect of anti -ANGPTL3-CCD antibody in mice with adriamycin-induced nephropathy. Nephropathy was established by adriamycin injection at a dose of 25 mg per kg in 8–12 week-old male mice in the ADR group. Blockade of ANGPTL3 by anti -ANGPTL3-CCD antibody (20 mg per kg) was performed every three days nine times after adriamycin injection in the ADR plus anti -angptl3-antibody group. The anti -ANGPTL3-CCD antibody can specifically recognize ANGPTL3. After anti -ANGPTL3-CCD antibody intervention, the urinary protein level in the ADR plus anti -angptl3-antibody group was significantly lower than that in the ADR group. Serum albumin was higher and triglyceride and total cholesterol were lower in the ADR plus anti -angptl3-antibody group than in the ADR group. The levels of serum creatinine did not significantly differ among the groups. Focal sclerotic glomeruli and podocyte foot processes extensive fusion were found in the renal tissue of the ADR group, whereas no sclerotic glomeruli and only partial fusion were found in the ADR plus anti -angptl3-antibody group. This study demonstrated that the anti -ANGPTL3-CCD antibody ameliorated proteinuria and podocyte dysfunction in adriamycin-induced nephropathy in mice. • ANGPTL3 is considered to be an important molecules involved in proteinuria. • Anti -ANGPTL3-CCD antibody decreased serum lipid levels. • Anti -ANGPTL3-CCD antibody ameliorated proteinuria and podocyte injury in adriamycin-induced nephropathy mice. [ABSTRACT FROM AUTHOR]

Intrauterine low-protein diet can affect kidney development and hence final nephron number. In this study, we reported that intrauterine low-protein diet can cause congenital anomalies of the kidney and urinary tract (CAKUT) phenotypes, which was dominated by the duplicated collecting system phenotype. At the same time, ectopic ureteric buds were increased under intrauterine low-protein diet and the number of UB branches was reduced in the serum-free culture. Intrauterine low-protein diet can change metanephric gene expression. Slit2/Robo2 and Spry1 expression levels were decreased, Ret expression was increased, and downstream p -Akt activity enhanced with apoptosis abnormal in ureteric bud tissue, which may be the mechanisms that intrauterine low-protein diet causes increased incidence of CAKUT in offspring. Thus, we showed correlation between intrauterine low-protein diet and CAKUT in offspring. • Intrauterine low-protein diet can cause CAKUT, which was dominated by the duplicated collecting system phenotype. • Ectopic ureteric buds were increased under intrauterine low-protein diet. • The number of UB branches was reduced in the serum-free culture. • Intrauterine low-protein diet can change metanephric gene expression. [ABSTRACT FROM AUTHOR]

Similar to programmed death-1 (PD-1), B and T lymphocyte attenuator (BTLA) is a co-inhibitory molecule of the CD28 family. PD-1 is involved in T cell exhaustion during chronic viral infection. However, the role of BTLA in virus-specific T cells is poorly defined. Here we investigated the expression and function of BTLA in T cells from patients with chronic hepatitis B virus (HBV) infection. The phenotype of peripheral and intrahepatic HBV-specific T cells from 43 patients with chronic HBV infection was assessed by flow cytometry. Functional evaluation was analyzed by T cell expansion and cytokine secretion after different treatments. In chronic HBV patients, a subset of inefficient interferon-γ producing antigen-specific CD8 + T cells recruited to the liver expressed high BTLA levels. The BTLA + HBV-specific CD8 + T cell suppressive function was antigen-specific, at least in the induction phase, because they were only activated by a pool of HBV peptides but not with a pool of unrelated peptides. Suppression of T cell responses was restored by a BTLA signaling blockade and neutralizing IL-10, indicating that BTLA signaling-mediated IL-10 secretion plays a key role in suppression. This study provides important evidence that there is a subset of liver infiltrated virus-specific CD8 + BTLA + regulatory T cells in patients with chronic HBV infection. This subset of cells plays a pivotal role in controlling hepatic effector CD8 + T cell responses through BTLA signaling mediated regulatory factor IL-10 production. [ABSTRACT FROM AUTHOR]

Abstract: The mechanisms by which mast cells (MCs) regulate immune responses are still largely unknown. Here, we showed that MCs induced interleukin (IL)-10 producing T cells to regulate inflammatory responses. To gain insight into the molecules involved, we set up an in vitro system in which lipopolysaccharide (LPS) stimulated MCs and CD4+ T cells were co-cultured. Induction of IL-10 producing regulatory T cells mainly relied on the inducible costimulator ligand (ICOSL)/ICOS axis. MCs stimulated with LPS for more than 6weeks upregulated ICOSL expression, while icosl −/− BMMCs failed to induce IL-10 producing T cells. The LPS effect was mediated through NF-κB activation via the TLR4 signaling pathway. Ex vivo analysis of bronchoalveolar lavage fluid from mice with LPS-mediated pneumonia revealed ICOSL+ MCs and IL-10 producing T cell induction. Additionally, adaptive transfer of ICOSL+ BMMCs attenuated LPS-mediated inflammation in MC-deficient mice. This study provided new evidence for the regulatory role of MCs. [Copyright &y& Elsevier]

Peroxisome proliferator-activated receptor α (PPARα) activation has been reported to exert protective effects on podocytes, whereas angiopoietin-like 3 (ANGPTL3) has been shown to exert significant pathogenic effects on these cells. This study aimed to investigate the link between the protective effects of PPARα activation and the pathogenic effects of ANGPTL3 in podocytes. Both PPARα and ANGPTL3 were expressed in cultured podocytes. PPARα mRNA and protein levels decreased whereas ANGPTL3 mRNA and protein levels increased in a time-dependent manner in podocytes treated with puromycin aminonucleoside (PAN). Gemfibrozil, a pharmacological agonist of PPARα, increased PPARα levels and activity in podocytes. The drug also decreased ANGPTL3 levels by potentially weakening ANGPTL3 promoter activity in both normal and PAN-treated podocytes. Furthermore, gemfibrozil significantly decreased PAN-induced apoptosis and F-actin rearrangement. Primary podocytes from Angptl3 -knockout mice were cultured. There was no significant difference between Angptl3 −/− podocytes treated with or without gemfibrozil in the lamellipodia numbers after PAN treatment. The results suggested that the protective effects of gemfibrozil on podocytes were not exerted following knockout of the Angptl3 gene. This study identified a novel mechanism of the PPARα agonist gemfibrozil that exerts its protective effects by inhibiting PAN-induced apoptosis and cytoskeleton rearrangements through inhibition of ANGPTL3 expression. [ABSTRACT FROM AUTHOR]

Abstract: Experimental autoimmune myocarditis (EAM) has been used as a model for human myocarditis in relation to the autoimmune mechanism and proved as a T cell-mediated autoimmune disease. Interaction of T cell receptors (TCR) with its ligand peptide-MHC complex on APCs is critical for antigen-specific T cell activation under physiological and pathological conditions. CIITA is a transcriptional coactivator that functions as a key regulatory factor for MHC-II expression. To achieve effective inhibition of interaction of TCR and peptide-MHC-II complex, adenovirus vectors containing antisense CIITA were constructed and their effects in preventing EAM were examined. Ad-CIITA was injected intravenously into mice on days 0–2 or 14–16 after myosin immunization to study the preventive effects on EAM in the T cell activation phase or inflammatory phase. Disease severity was determined by the microscopic grade of heart check, concentration of plasma cTnI, and cellular and humoral immune responses on day 21. Results show that onset of EAM after Ad-CIITA treatment on days 0–2 was almost completely inhibited and antigen-specific lymphocyte proliferation was significantly reduced in adenovirus treatment group, which demonstrate that this adenovirus vector inhibit auto-responsive T cells activation and proliferation. Moreover, compared with EAM mice, even administered on days 14–16, the Ad-CIITA treated mice achieved significant reduction in disease severity. It indicates the therapeutic potential of blocking T cells activation by gene-transfer in myocarditis. [Copyright &y& Elsevier]

Treg is essential to limit the extend and duration of the immune response, but its stability is still under debate. Here we demonstrate that IL-17-producing Treg cells (Th17-like cells) increased in peripheral blood of patients with Systemic Lupus Erythematosus (SLE). Notably, the Th17-like cells from patient with active SLE were characterized with some phenotype and function of Th17 cells. Upon stimulation, Helios-Foxp3 + CD4+ T cells decrease Foxp3 expression but increase expression of IL-17 and RORγt. Damage associated molecule pattern and inflammatory cytokines are important for induction of IL-17 expression in Treg cells. The Th17-like cells from patients with active SLE lose suppressive function and have robust response to stimulation of autoantigens. We also observed that the level of Th17-like cells in peripheral blood is closely associated with the clinical index of SLE. These findings suggest that instability of Treg plays a critical role in pathogenesis of autoimmune diseases. • IL-17-producing Treg cells upregulate in both patients with active SLE and spontaneous lupus model. • IL-17-producing Treg cell originates from Helio− Treg upon stimulation of HMGB1 and IL-6. • IL-17-producing Treg in patients with active SLE responds to autoantigen stimulation, and shows regulatory deficiency. [ABSTRACT FROM AUTHOR]