Background: Cadmium, a toxic metal, is widely encountered in diverse environmental contexts. Despite its pervasive exposure, there is limited research on the association between blood cadmium levels and depression, especially among females. This study aimed to investigate the relationship between blood cadmium levels and depression in adult women.
View Article and Find Full Text PDFFront Psychiatry
March 2024
Background And Aim: High-sensitivity C-reactive protein (hs-CRP) is a sensitive measure of low-grade inflammation and appears superior to conventional blood tests in assessing cardiovascular disease. The purpose of this investigation was to explore the link between high-sensitivity CRP and depressive symptoms among adults.
Methods And Results: Multiple logistic regression and smoothed curve fitting were used to investigate the association between hs-CRP and depressive symptoms based on data from the, 2017-2020 National Health and Nutrition Examination Survey (NHANES).
The Stimulator of Interferon Genes (STING) has a crucial role in mediating the immune response against cytosolic double-stranded DNA (dsDNA) and its activation is critically involved in various diseases. STING is synthesized, modified, and resides in the endoplasmic reticulum (ER), and its ER exit is intimately connected with its signaling. The ER, primarily known for its roles in protein folding, lipid synthesis, and calcium storage, has been identified as a pivotal platform for the regulation of a wide range of STING functions.
View Article and Find Full Text PDFDepletion of fat-resident regulatory T cells (T) and group 2 innate lymphoid cells (ILC2s) has been causally linked to obesity-associated insulin resistance. However, the molecular nature of the pathogenic signals suppress adipose T and ILC2s in obesity remains unknown. Here, we identified the soluble isoform of interleukin (IL)-33 receptor ST2 (sST2) as an obesity-induced adipokine that attenuates IL-33 signaling and disrupts T/ILC2 homeostasis in adipose tissue, thereby exacerbates obesity-associated insulin resistance in mice.
View Article and Find Full Text PDFβ Cell apoptosis and dedifferentiation are 2 hotly debated mechanisms underlying β cell loss in type 2 diabetes; however, the molecular drivers underlying such events remain largely unclear. Here, we performed a side-by-side comparison of mice carrying β cell-specific deletion of ER-associated degradation (ERAD) and autophagy. We reported that, while autophagy was necessary for β cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex was required for the maintenance of β cell maturation and identity.
View Article and Find Full Text PDFAberrant T cell development is a pivotal risk factor for autoimmune disease; however, the underlying molecular mechanism of T cell overactivation is poorly understood. Here, we identified NF-κB-inducing kinase (NIK) and IkB kinase α (IKKα) in thymic epithelial cells (TECs) as essential regulators of T cell development. Mouse TEC-specific ablation of either NIK or IKKα resulted in severe T cell-mediated inflammation, injury, and fibrosis in the liver and lung, leading to premature death within 18 d of age.
View Article and Find Full Text PDFCell-cell communication via ligand-receptor signaling is a fundamental feature of complex organs. Despite this, the global landscape of intercellular signaling in mammalian liver has not been elucidated. Here we perform single-cell RNA sequencing on non-parenchymal cells isolated from healthy and NASH mouse livers.
View Article and Find Full Text PDFConsumption of a high-energy Western diet triggers mild adaptive β cell proliferation to compensate for peripheral insulin resistance; however, the underlying molecular mechanism remains unclear. In the present study we show that the toll-like receptors TLR2 and TLR4 inhibited the diet-induced replication of β cells in mice and humans. The combined, but not the individual, loss of TLR2 and TLR4 increased the replication of β cells, but not that of α cells, leading to enlarged β cell area and hyperinsulinemia in diet-induced obesity.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2018
Cell encapsulation has been shown to hold promise for effective, long-term treatment of type 1 diabetes (T1D). However, challenges remain for its clinical applications. For example, there is an unmet need for an encapsulation system that is capable of delivering sufficient cell mass while still allowing convenient retrieval or replacement.
View Article and Find Full Text PDFEndoplasmic reticulum (ER)-associated degradation (ERAD) is a principal mechanism that targets ER-associated proteins for cytosolic proteasomal degradation. Here, our data demonstrate a critical role for the Sel1L-Hrd1 complex, the most conserved branch of ERAD, in early B cell development. Loss of Sel1L-Hrd1 ERAD in B cell precursors leads to a severe developmental block at the transition from large to small pre-B cells.
View Article and Find Full Text PDFInflammatory bowel disease (IBD) is an incurable chronic idiopathic disease that drastically decreases quality of life. Endoplasmic reticulum (ER)-associated degradation (ERAD) is responsible for the clearance of misfolded proteins; however, its role in disease pathogenesis remains largely unexplored. Here we show that the expression of SEL1L and HRD1, the most conserved branch of mammalian ERAD, is significantly reduced in ileal Crohn's disease (CD).
View Article and Find Full Text PDFEndoplasmic reticulum (ER)-associated degradation (ERAD) represents a principle quality control mechanism to clear misfolded proteins in the ER; however, its physiological significance and the nature of endogenous ERAD substrates remain largely unexplored. Here we discover that IRE1α, the sensor of the unfolded protein response (UPR), is a bona fide substrate of the Sel1L-Hrd1 ERAD complex. ERAD-mediated IRE1α degradation occurs under basal conditions in a BiP-dependent manner, requires both the intramembrane hydrophilic residues of IRE1α and the lectin protein OS9, and is attenuated by ER stress.
View Article and Find Full Text PDFCD1d-dependent NKT cells have been extensively studied; however, the function of CD8(+)NKT-like cells, which are CD1d-independent T cells with NK markers, remains unknown. Here, we report that CD1d-independent CD8(+)NKT-like cells, which express both T cell markers (TCRβ and CD3) and NK cell receptors (NK1.1, CD49b and NKG2D), are activated and significantly expanded in mice immunized with GFP-expressing dendritic cells.
View Article and Find Full Text PDFCell encapsulation holds enormous potential to treat a number of hormone deficient diseases and endocrine disorders. We report a simple and universal approach to fabricate robust, hydrogel-based, nanofiber-enabled encapsulation devices (NEEDs) with macroscopic dimensions. In this design, we take advantage of the well-known capillary action that holds wetting liquid in porous media.
View Article and Find Full Text PDFChronic intake of Western diet has driven an epidemic of obesity and metabolic syndrome, but how it induces mortality remains unclear. Here, we show that chronic intake of a high-fat diet (HFD), not a low-fat diet, leads to severe pulmonary damage and mortality in mice deficient in Toll-like receptors 2 and 4 (DKO). Diet-induced pulmonary lesions are blocked by antibiotic treatment and are transmissible to wild-type mice upon either cohousing or fecal transplantation, pointing to the existence of bacterial pathogens.
View Article and Find Full Text PDFSuppressor/Enhancer of Lin-12-like (Sel1L) is an adaptor protein for the E3 ligase hydroxymethylglutaryl reductase degradation protein 1 (Hrd1) involved in endoplasmic reticulum-associated degradation (ERAD). Sel1L's physiological importance in mammalian ERAD, however, remains to be established. Here, using the inducible Sel1L knockout mouse and cell models, we show that Sel1L is indispensable for Hrd1 stability, ER homeostasis, and survival.
View Article and Find Full Text PDFThe transcriptional co-regulator host cell factor-1 (HCF-1) plays critical roles in promoting cell cycle progression in diverse cell types, and in maintaining self-renewal of embryonic stem cells, but its role in pancreatic β-cell function has not been investigated. Immunhistochemistry of mouse pancreas revealed nuclear expression of HCF-1 in pancreatic islets. Reducing HCF-1 expression in the INS-1 pancreatic β-cell line resulted in reduced cell proliferation, reduced glucose-stimulated insulin secretion, and reduced expression of the critical β-cell transcription factor Pdx1.
View Article and Find Full Text PDFHyperglycemia is a result of impaired insulin action on glucose production and disposal, and a major target of antidiabetic therapies. The study of insulin-independent regulatory mechanisms of glucose metabolism may identify new strategies to lower blood sugar levels. Here we demonstrate an unexpected metabolic function for IL-13 in the control of hepatic glucose production.
View Article and Find Full Text PDFHere we identify and characterize a cytoskeletal myosin protein required for IRE1α oligomerization, activation, and signaling. Proteomic screening identified nonmuscle myosin heavy chain IIB (NMHCIIB), a subunit of nonmuscle myosin IIB (NMIIB), as an ER stress-dependent interacting protein specific to IRE1α. Loss of NMIIB compromises XBP1s and UPR target gene expression with no effect on the PERK pathway.
View Article and Find Full Text PDFInflammation in adipose tissue plays an important role in the pathogenesis of obesity-associated complications. However, the detailed cellular events underlying the inflammatory changes at the onset of obesity have not been characterized. Here we show that an acute HFD challenge is unexpectedly associated with elevated alternative (M2) macrophage polarization in adipose tissue mediated by Natural Killer T (NKT) cells.
View Article and Find Full Text PDFInflammasome activation in adipose tissue has been implicated in obesity-associated insulin resistance and type 2 diabetes. However, when and how inflammasome is activated in adipose tissue remains speculative. Here we test the hypothesis that extracellular ATP, a potent stimulus of inflammasome in macrophages via purinergic receptor P2X, ligand-gated ion channel, 7 (P2X(7)), may play a role in inflammasome activation in adipose tissue in obesity.
View Article and Find Full Text PDFThe fields of immunology and metabolism are rapidly converging on adipose tissue. During obesity, many immune cells infiltrate or populate in adipose tissue and promote a low-grade chronic inflammation. Studies to date have suggested that perturbation of inflammation is critically linked to nutrient metabolic pathways and to obesity-associated complications such as insulin resistance and type 2 diabetes.
View Article and Find Full Text PDFNatural killer T (NKT) cells are important therapeutic targets in various disease models and are under clinical trials for cancer patients. However, their function in obesity and type 2 diabetes remains unclear. Our data show that adipose tissues of both mice and humans contain a population of type 1 NKT cells, whose abundance decreases with increased adiposity and insulin resistance.
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