FcRn-dependent IgG accumulation in adipose tissue unmasks obesity pathophysiology.

Immunoglobulin G (IgG) is traditionally recognized as a plasma protein that neutralizes antigens for immune defense. However, our research demonstrates that IgG predominantly accumulates in adipose tissue during obesity development, triggering insulin resistance and macrophage infiltration. This accumulation is governed by neonatal Fc receptor (FcRn)-dependent recycling, orchestrated in adipose progenitor cells and macrophages during the early and late stages of diet-induced obesity (DIO), respectively.

Estrogen: the forgotten player in metaflammation.

Metaflammation is low-grade inflammation triggered by chronic metabolic imbalance and caused by dysregulated metabolites in metabolic inflammatory syndrome (MIS), which includes four diseases: obesity, type 2 diabetes mellitus (T2DM), atherosclerosis (AS), and nonalcoholic fatty liver diseases (NAFLD, recently proposed to be replaced by metabolic dysfunction-associated steatotic liver disease, MASLD). These diseases exhibit apparent sex dimorphism as regards MIS. Estrogen not only plays a crucial role in gender differences in adults but also possesses an anti-inflammatory effect on many metabolic diseases.

Mechanism of RSL3-induced ferroptotic cell death in HT22 cells: crucial role of protein disulfide isomerase.

Protein disulfide isomerase (PDI) was recently shown to be an upstream mediator of erastin-induced, glutathione depletion-associated ferroptosis through its catalysis of nitric oxide synthase (NOS) dimerization and nitric oxide (NO) accumulation. A recent study reported that RSL3, a known ferroptosis inducer and glutathione peroxidase 4 (GPX4) inhibitor, can inhibit thioredoxin reductase 1 (TrxR1). The present study seeks to test the hypothesis that RSL3 may, through its inhibition of TrxR1, facilitate PDI activation ( .

Protection of HT22 neuronal cells against chemically-induced ferroptosis by catechol estrogens: protein disulfide isomerase as a mechanistic target.

Ferroptosis is a form of regulated cell death, characterized by excessive iron-dependent lipid peroxidation. Biochemically, ferroptosis can be selectively induced by erastin through glutathione depletion or through inhibition of glutathione peroxidase 4 by RSL3, which leads to accumulation of cytotoxic lipid reactive oxygen species (ROS). Protein disulfide isomerase (PDI) was recently shown to mediate erastin/RSL3-induced ferroptosis and thus also become a new target for protection against chemically-induced ferroptosis.

Raloxifene Prevents Chemically-Induced Ferroptotic Neuronal Death In Vitro and In Vivo.

Ferroptosis, a regulated form of cell death characterized by excessive iron-dependent lipid peroxidation, can be readily induced in cultured cells by chemicals such as erastin and RSL3. Protein disulfide isomerase (PDI) has been identified as an upstream mediator of chemically induced ferroptosis and also a target for ferroptosis protection. In this study, we discovered that raloxifene (RAL), a selective estrogen receptor modulator known for its neuroprotective actions in humans, can effectively inhibit PDI function and provide robust protection against chemically induced ferroptosis in cultured HT22 neuronal cells.

Protein disulfide isomerase plays a crucial role in mediating chemically-induced, glutathione depletion-associated hepatocyte injury in vitro and in vivo.

Recently we have shown that protein disulfide isomerase (PDI or PDIA1) is involved in mediating chemically-induced, glutathione (GSH) depletion-associated ferroptotic cell death through NOS activation (dimerization) and NO accumulation. The present study aims to determine the role of PDI in mediating chemically-induced hepatocyte injury in vitro and in vivo and whether PDI inhibitors can effectively protect against chemically-induced hepatocyte injury. We show that during the development of erastin-induced ferroptotic cell death, accumulation of cellular NO, ROS and lipid-ROS follows a sequential order, i.

Role of mitochondrial reactive oxygen species in chemically-induced ferroptosis.

Ferroptosis is a form of iron-dependent regulated cell death which is different from apoptosis. Chemically-induced ferroptosis is characterized by an accumulation of lipid reactive oxygen species (ROS) in the cells. A number of earlier studies have suggested the involvement of mitochondrial ROS in ferroptosis, and the present study seeks to further investigate the role of mitochondrial ROS in the induction of chemically-induced ferroptotic cell death.

Strong Protection by 4-Hydroxyestrone against Erastin-Induced Ferroptotic Cell Death in Estrogen Receptor-Negative Human Breast Cancer Cells: Evidence for Protein Disulfide Isomerase as a Mechanistic Target for Protection.

Ferroptosis is a recently identified form of regulated cell death, characterized by excessive iron-dependent lipid peroxidation. Recent studies have demonstrated that protein disulfide isomerase (PDI) is an important mediator of chemically induced ferroptosis and also a new target for protection against ferroptosis-associated cell death. In the present study, we identified that 4-hydroxyestrone (4-OH-E), a metabolic derivative of endogenous estrogen, is a potent small-molecule inhibitor of PDI, and can strongly protect against chemically induced ferroptotic cell death in the estrogen receptor-negative MDA-MB-231 human breast cancer cells.

Attenuation of amyloid-β-induced mitochondrial dysfunction by active components of anthocyanins in HT22 neuronal cells.

Alzheimer's disease (AD) is a common form of neurodegenerative disease in the elderly. Amyloid- (A)-associated neurotoxicity is an important component of the neurodegenerative change in AD. Recent studies have revealed a beneficial effect of anthocyanins in improving learning and memory in AD animal models.

Biochemical mechanism of erastin-induced ferroptotic cell death in neuronal cells.

Ferroptosis is a new form of nonapoptotic cell death closely associated with glutathione (GSH) peroxidase 4 inhibition and/or GSH depletion, resulting in the accumulation of cellular iron and lipid peroxides. The exact mechanism by which GSH depletion causes the accumulation of reactive oxygen species (ROS) and lipid-ROS and subsequent ferroptotic cell death in neuronal cells remains unclear. In the present study, using immortalized HT22 mouse hippocampal neuronal cells as a model, we show that nitric oxide (NO) accumulation via protein disulfide isomerase (PDI)-mediated neuronal nitric oxide synthase (nNOS) activation plays a critical role in chemically-induced ferroptosis.

: A Web Server for Machine Learning-Based Prediction of Protein-Protein and Antibody-Protein Antigen Binding Affinities.

Protein-Protein binding affinity reflects the binding strength between the binding partners. The prediction of protein-protein binding affinity is important for elucidating protein functions and also for designing protein-based therapeutics. The geometric characteristics such as area (both interface and surface areas) in the structure of a protein-protein complex play an important role in determining protein-protein interactions and their binding affinity.

Binding affinity prediction for antibody-protein antigen complexes: A machine learning analysis based on interface and surface areas.

Specific antibodies can bind to protein antigens with high affinity and specificity, and this property makes them one of the best protein-based therapeutics. Accurate prediction of antibody‒protein antigen binding affinity is crucial for designing effective antibodies. The current predictive methods for protein‒protein binding affinity usually fail to predict the binding affinity of an antibody‒protein antigen complex with a comparable level of accuracy.

Biochemical mechanism underlying the pathogenesis of diabetic retinopathy and other diabetic complications in humans: the methanol-formaldehyde-formic acid hypothesis.

Hyperglycemia in diabetic patients is associated with abnormally-elevated cellular glucose levels. It is hypothesized that increased cellular glucose will lead to increased formation of endogenous methanol and/or formaldehyde, both of which are then metabolically converted to formic acid. These one-carbon metabolites are known to be present naturally in humans, and their levels are increased under diabetic conditions.

Mechanism of Erastin-Induced Ferroptosis in MDA-MB-231 Human Breast Cancer Cells: Evidence for a Critical Role of Protein Disulfide Isomerase.

Ferroptosis is a form of regulated cell death resulting predominantly from catastrophic accumulation of lipid reactive oxygen species (ROS). While the antioxidant systems that counter ferroptosis have been well characterized, the mechanism underlying ferroptosis-associated accumulation of lipid ROS remains unclear. In this study, we demonstrated that protein disulfide isomerase (PDI) is a novel mediator of ferroptosis, which is responsible for the accumulation of lipid ROS and ultimately ferroptosis in MDA-MB-231 human breast cancer cells.

Protection against glutathione depletion-associated oxidative neuronal death by neurotransmitters norepinephrine and dopamine: Protein disulfide isomerase as a mechanistic target for neuroprotection.

Oxidative stress is extensively involved in neurodegeneration. Clinical evidence shows that keeping the mind active through mentally-stimulating physical activities can effectively slow down the progression of neurodegeneration. With increased physical activities, more neurotransmitters would be released in the brain.

Importance of interface and surface areas in protein-protein binding affinity prediction: A machine learning analysis based on linear regression and artificial neural network.

Protein-protein interaction plays an important role in all biological systems. The binding affinity between two protein binding partners reflects the strength of their association, which is crucial to the elucidation of the biological functions of these proteins and also to the design of protein-based therapeutic agents. In recent years, many studies have been conducted in an effort to improve the ability to predict the binding affinity of a protein-protein complex.

Pathogenic Mechanism of Autoimmune Diabetes Mellitus in Humans: Potential Role of Streptozotocin-Induced Selective Autoimmunity against Human Islet -Cells.

Human type 1 diabetes mellitus is a chronic autoimmune disease characterized by the selective loss of insulin-producing -cells in pancreatic islets of genetically susceptible individuals. In this communication, a new hypothesis is postulated which is based on the observations that streptozotocin (STZ), a chemically reactive and cytotoxic compound produced by certain gram-positive bacteria, can be preferentially taken up into islet -cells and induce cytotoxicity and autoimmunity. It is hypothesized that humans might be occasionally exposed to STZ through opportunistic infections with the STZ-producing bacteria and/or through ingestion of certain food products that contain STZ.

Modulation of Enzyme-Catalyzed Synthesis of Prostaglandins by Components Contained in Kidney Microsomal Preparations.

In the kidney, prostaglandins formed by cyclooxygenase 1 and 2 (COX-1 and COX-2) play an important role in regulating renal blood flow. In the present study, we report our observations regarding a unique modulatory effect of renal microsomal preparation on COX-1/2-mediated formation of major prostaglandin (PG) products in vitro. We found that microsomes prepared from pig and rat kidneys had a dual stimulatory-inhibitory effect on the formation of certain PG products catalyzed by COX-1 and COX-2.

The Use of Chinese Yang/Qi-Invigorating Tonic Botanical Drugs/Herbal Formulations in Ameliorating Chronic Kidney Disease by Enhancing Mitochondrial Function.

Chronic kidney disease (CKD) is a leading cause of morbidity and mortality. Mitochondrial dysfunction has been implicated as a key factor in the development of CKD. According to traditional Chinese medicine (TCM) theory, many Chinese Yang/Qi-invigorating botanical drugs/herbal formulations have been shown to produce promising outcomes in the clinical management of CKD.

17β-Estradiol-Induced Conformational Changes of Human Microsomal Triglyceride Transfer Protein: A Computational Molecular Modelling Study.

Human microsomal triglyceride transfer protein (hMTP) plays an essential role in the assembly of apoB-containing lipoproteins, and has become an important drug target for the treatment of several disease states, such as abetalipoproteinemia, fat malabsorption and familial hypercholesterolemia. hMTP is a heterodimer composed of a larger hMTPα subunit and a smaller hMTPβ subunit (namely, protein disulfide isomerase, hPDI). hPDI can interact with 17β-estradiol (E), an endogenous female sex hormone.

Mechanism of reactivation of the peroxidase catalytic activity of human cyclooxygenases by reducing cosubstrate quercetin.

Our earlier studies show that the peroxidase activity of cyclooxygenase 1 and 2 (COX-1 and COX-2) can be reactivated in vitro and in vivo by the presence of certain naturally-occurring flavonoids such as quercetin and myricetin, which serve as reducing cosubstrates. These compounds can activate COX at nanomolar concentrations. In the present study, quercetin is used as a representative model compound to investigate the chemical mechanism by which the peroxidase activity of human COX-1 and COX-2 is reactivated after each catalytic cycle.

Mechanism underlying resveratrol's attenuation of paclitaxel cytotoxicity in human breast cancer cells: Role of the SIRT1-FOXO1-HER3 signaling pathway.

Resveratrol (RES), a dietary phenolic compound, was reported to have cancer chemoprotective and chemotherapeutic effects. Earlier we unexpectedly observed that RES has a growth-enhancing effect in some breast cancer cells and can diminish the susceptibility of MDA-MB-231 and SKBR-3 cells to paclitaxel-induced cell death, but this phenomenon is not observed in MCF-7 cells. The present study seeks to determine the mechanism underlying RES's attenuation of paclitaxel cytotoxicity in cancer cells.

Insulin-induced conformational changes in the full-length insulin receptor: structural insights gained from molecular modeling analyses.

Insulin receptor plays an important role in the regulation of energy metabolism. Dysfunction of insulin receptor (IR) can lead to many disease states, such as diabetes mellitus. Deciphering the complex dynamic structures of human IR and its mechanism of activation would greatly aid in understanding IR-mediated signaling pathways and also in designing new drugs (including nonpeptidal insulin analogs) to treat diabetes mellitus.

Inhibition of cyclooxygenase by blocking the reducing cosubstrate at the peroxidase site: Discovery of galangin as a novel cyclooxygenase inhibitor.

Earlier we have shown that certain flavonoids (e.g., quercetin) are high-affinity reducing cosubstrates for cyclooxygenase (COX) 1 and 2.