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Cellular mechanism of nutritionally induced insulin resistance: the desert rodent Psammomys obesus and other animals in which insulin resistance leads to detrimental outcome.

Animal species with genetic or nutritionally induced insulin resistance, diabetes and obesity (diabesity) may be divided into two broad groups: those with resilient pancreatic beta-cells, e.g. ob/ob mice and fa/fa rats, capable of long-lasting compensatory insulin over-secretion, and those with labile beta-cells in which the secretion pressure leads to irreversible beta-cell degranulation, e.g. db/db mice, Macaca mulatta primates, ZDF diabetic rats. Prominent in this group is the Israeli desert gerbil Psammomys obesus (sand rat), which features low insulin receptor density in liver and muscle.

Morphology of pancreatic islets: a time course of pre-diabetes in Zucker fatty rats.

The Zucker fatty rat (fa/fa; ZR) is considered as a model for pre-diabetes, as characterised by a genetic defect in the leptin receptor, which results in hyperphagia, insulin resistance, hyperinsulinaemia, hyperlipoproteinaemia, and obesity. These animals become glucose intolerant but do not develop type 2 diabetes. As a consequence of increased adiposity and insulin resistance, the endocrine pancreas of ZR undergoes adaptive and compensatory changes. Measurements of the time course of the pathological changes by the histological analysis of the pancreatic islet in combination with metabolic p

Molecular Hydrogen Reverses Sepsis-induced Immunoparalysis: Insights from Longitudinal Deep Immunophenotyping.

BACKGROUND/AIM: Refractory septic shock and post-cardiac arrest syndrome (PCAS) can induce lethal immunoparalysis. However, longitudinal evidence on the effects of molecular hydrogen on deep human immunophenotyping remains scarce. CASE REPORT: We report the case of a 49-year-old man with severe tricuspid regurgitation and Child-Pugh class B alcoholic cirrhosis who developed severe pneumonia, refractory septic shock, and PCAS after high-energy thoracic trauma. At a therapeutic impasse marked by high levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) (>35,000 pg/ml) and profound im

Growth hormone administration reduces circulating proinflammatory cytokines and soluble Fas/soluble Fas ligand system in patients with chronic heart failure secondary to idiopathic dilated cardiomyopathy.

BACKGROUND: Recent studies have shown that an abnormal proinflammatory cytokine expression and apoptotic process contribute to adverse left ventricular remodeling and progress of chronic heart failure. This study investigates the effects of growth hormone (GH) administration on serum levels of representative proinflammatory cytokines and soluble apoptosis mediators in patients with chronic heart failure secondary to idiopathic dilated cardiomyopathy (IDC). METHODS: Serum levels of tumor necrosis factor-alpha (TNF-alpha), its soluble receptors (sTNF-RI, sTNF-RII), interleukin-6 (IL-6), soluble

Lipoprotein-Inspired Nanocarrier Composed of Folic Acid-Modified Protein and Lipids: Preparation and Evaluation of Tumor-Targeting Effect.

BACKGROUND: Reconstituted lipoproteins (rLips) based on endogenous lipid nanostructures has been increasingly regarded as an excellent and promising antitumor drug delivery. However, some problems relating to the main component, apolipoprotein, for instance, rare source, unaffordable price, and low specificity of relevant receptor expression, become chief obstacles to its broad development and application. PURPOSE: The primary aim of this study is to develop biomimetic rLips by utilizing folic acid (FA)-modified bovine serum albumin (BSA) as a replacement for apolipoprotein and demonstrate i

The role of necroptosis in disease and treatment.

Necroptosis, a distinctive type of programmed cell death different from apoptosis or necrosis, triggered by a series of death receptors such as tumor necrosis factor receptor 1 (TNFR1), TNFR2, and Fas. In case that apoptosis process is blocked, necroptosis pathway is initiated with the activation of three key downstream mediators which are receptor-interacting serine/threonine protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL). The whole process eventually leads to destruction of the cell membrane integrity, swelling of organelles, and severe inflammation. Ove

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… Laster et al. found that tumor necrosis factor‐α (TNF‐α) could induce a classical form of apoptosis or a necrotic form of cell death. 1 In 1998, Vercammen et al. found two different Fas receptor‐related pathways: one leads to apoptosis, the other one directs the cells to necrosis when apoptotic is blocked … Dual signaling of the Fas receptor: initiation of both apoptotic and necrotic cell death pathways. J Exp Med. 1998;188(5):919‐930. 3. Holler N, Zaru R, Micheau O, et al. Fas triggers an alternative, caspase‐8‐independent cell death pathway using the kinase RIP as effector molecule. …

Over-expression of C/EBP-alpha induces apoptosis in cultured rat hepatic stellate cells depending on p53 and peroxisome proliferator-activated receptor-gamma.

Hepatic stellate cells (HSCs) play a key role in the pathogenesis of hepatic fibrosis. In our previous studies, CCAAT enhancer binding protein-alpha (C/EBP-alpha) has been shown to be involved in the activation of HSCs and to have a repression effect on hepatic fibrosis in vivo. However, the mechanisms are largely unknown. In this study, we show that the infection of adenovirus vector expressing C/EBP-alpha gene (Ad-C/EBP-alpha) could induce HSCs apoptosis in a dose- and time-dependent manner by Annexin V/PI staining, caspase-3 activation assay, and flow cytometry. Also, over-expression of C/E

Hepatocyte Bcl-3 protects from death-receptor mediated apoptosis and subsequent acute liver failure.

Acute liver failure (ALF) is a rare entity but exhibits a high mortality. The mechanisms underlying ALF are not completely understood. The present study explored the role of the hepatic B cell leukemia-3 (Bcl-3), a transcriptional regulator of nuclear factor-kappa B (NF-κB), in two independent models of ALF. We employed a recently developed transgenic mouse model in a C57BL6/J background comparing wild-type (WT) and transgenic littermates with hepatocyte-specific overexpression of Bcl-3 (Bcl-3Hep) in the ALF model of d-galactosamine (d-GalN) and lipopolysaccharide (LPS). Additionally, the apop

[Effects of Qushi Huayu Decoction in prevention and treatment of fatty liver in rats based on adiponectin-free fatty acid pathway].

OBJECTIVE: To explore the effects of Qushi Huayu Decoction (QSHYD), a compound traditional Chinese herbal medicine, in prevention and treatment of non-alcoholic fatty liver disease (NAFLD) in rats. METHODS: Forty Wistar male rats were used to establish the NAFLD model by subcutaneous injection of carbon tetrachloride (CCl(4)) for 4 weeks (twice weekly) along with high-fat and low-protein diet for 2 weeks. After two-week administration, the rats were randomly divided into four groups: untreated group, high-dose QSHYD group, medium-dose QSHYD group and low-dose QSHYD group. Another six rats wer

Regulation of the extrinsic and intrinsic apoptotic pathways in the prefrontal cortex of short- and long-term human opiate abusers.

Opiate addiction is a chronic medical disorder characterized by drug tolerance and dependence, behavioral sensitization, vulnerability to compulsive relapse, and high mortality. In laboratory animals, the potential effect of opiate drugs to induce cell death by apoptosis is a controversial topic. This postmortem human brain study examined the status of the extrinsic and intrinsic apoptotic pathways in the prefrontal cortex of a large group of well-characterized heroin or methadone abusers. In these subjects (n=36), the immunocontent of apoptosis-1 protein (Fas) death receptor did not differ fr

Dysfunctional immune-privilege in morbid obesity: implications and effect of gastric bypass surgery.

BACKGROUND: Despite the epidemiological evidence linking obesity and cancer, there has never been a causal link. We believe the chronic inflammation present in obesity may predispose the obese to cancer through Fas-receptor over-expression and L-selectin under-expression in leukocytes, and elevated Fas ligand secretion in tumors affecting the morbidly obese. METHODS: Leukocytes from 25 patients having gastric bypass surgery were compared to 15 normal controls preoperatively and at 1, 3, 6, and 12 months postoperatively using flow cytometry to measure CD3, CD4, CD8, CD56, CD62 (L-selectin), CD

An analysis of apoptosis in lymphoid organs and lupus disease in murine systemic lupus erythematosus (SLE).

Apoptosis is a programmed cell death process that helps to regulate both T cell and B cell development. In this study, we have investigated the levels of apoptotic death in cells of the thymuses and spleens (white matter) of autoimmune MRL-lpr/lpr mice with progressive lymphadenopathy and SLE disease activity; we also examined the renal pathology in these animals. Fas is a cell surface receptor, which when activated initiates the sequence of events that lead to apoptosis. In MRL-lpr/lpr mice Fas is defective, so the competency for apoptosis may be reduced. In young animals of advancing age the

Gastric Bypass-Related Effects on Glucose Control, β Cell Function and Morphology in the Obese Zucker Rat.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) may improve beta cell function by mechanisms other than caloric restriction and body weight loss. We aimed to assess the impact of anatomical and hormonal alterations specific to RYGB on glucose homeostasis, β cell function and morphology. METHODS: Male Zucker(fa/fa) rats underwent either RYGB (n = 11) or sham surgeries (n = 10). Five of the shams were then food restricted and body weight matched (BWM) to the RYGB rats. Six male Zucker(fa/+) rats underwent sham surgery and served as additional lean controls. Twenty-seven days after surgery, an oral

Glutamate and GABA receptor dysfunction in the fetal alcohol syndrome.

The brain damaging effects of ethanol, as the most disabling component of the fetal alcohol syndrome FAS), have been recognized for 3 decades, but the mechanism underlying these effects has remained elusive. Recently, we discovered that ethanol triggers widespread apoptotic neurodegeneration throughout the developing brain when administered to infant rodents during the period of synaptogenesis, also known as the brain growth spurt period. These findings provide a more likely explanation than has heretofore been available for the reduced brain mass and lifelong neurobehavioral disturbances asso

Evaluation of the Effect of Menopausal Status and BMI on Polymorphisms in Fas/Fas L and the Risk of Breast Cancer.

BACKGROUND: FAS and FAS ligand play an essential role in cell apoptosis. An identifying feature of malignant cells is the loss of FAS and increased FASL expression. A study analyzing the effects of menopausal status and body mass index (BMI) on functional polymorphisms of FAS-(1377G/A; rs2234767 & 670 A/G; rs1800682) and FASL (-844T/C; rs763110 & Ivs-2nt; rs5030772) in breast cancer evaluated these effects. PATIENTS AND METHODS: 316 blood samples were collected from breast cancer patients and healthy controls in this case/control study. RFLP-PCR was used after DNA extraction to determine geno

TSG-6 Induces Apoptosis of Human Hypertrophic Scar Fibroblasts via Activation of the Fas/FasL Signalling Pathway.

Tumour necrosis factor-stimulated gene 6 (TSG6) is a protective inflammatory reaction gene which is upregulated by inflammatory processes. Recent studies suggest that TSG-6 exhibits anti-scarring effects. However, the mechanism of TSG-6 action in the scar formation remains poorly understood. We investigated whether TSG-6 affects growth of the human hypertrophic scar fibroblasts (HSFs) via Fas/FasL signalling pathway. Cultured HSFs were transfected with a vector carrying the TSG6 gene (pLVX-Puro-TSG-6) or with a vector not containing the TSG6 gene (pLVX-Puro). Untransfected HSFs served as a con

[Expression of Fas and Fas ligand in infiltrating lymphocytes in patients with oral lichen planus].

OBJECTIVE: To examine the expression of Fas and Fas ligand (FasL) in T lymphocytes of oral lichen planus (OLP) and the effects of Fas, FasL and activation-induced cell death (AICD) on OLP. METHODS: The oral mucosa samples from patients with OLP and normal oral mucosa were assessed by in situ terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine-5'-triphosphate (dUTP)-biotin nick end-labelling (TUNEL) assay for nucleosomal DNA fragmentation of apoptotic cells in infiltrating lymphocytes. Immunohistochemical technique was used for detection of expression level of Fas and FasL. Immun

[Molecular pathways of germ cell apoptosis following testicular torsion in rats].

OBJECTIVE: To investigate the molecular mechanism of germ cell apoptosis following testicular torsion in rats. METHODS: Healthy male Sprague-Dawley rats (n = 16) were equally randomized into a control and a torsion group and the models of testicular torsion (720 degrees 2 h) were established. Twenty-four hours later, the apoptosis and count of germ cells were determined by flow cytometry, the expressions of Bax, Fas and Fas ligand (FasL) mRNA semiquantitatively analyzed by RT-PCR and the cytochrome C release detected by Western blot. RESULTS: Compared with the control group, there was an obv

Soluble form of Fas and Fas ligand in serum and bronchoalveolar lavage fluid of individuals infected with human T-lymphotropic virus type 1.

Human T-lymphotropic virus type 1 (HTLV-1) carriers are known to develop pulmonary complications characterized by T-lymphocytic alveolitis. The aim of this study was to determine the profile and role of soluble Fas (sFas) and sFas ligand (sFasL) in the lung of asymptomatic HTLV-1 carriers. We measured sFas and sFasL levels in serum and bronchoalveolar lavage fluid (BALF) of 16 seropositive asymptomatic HTLV-1 carriers and 32 healthy subjects. The serum levels of both sFas and sFasL were significantly higher in HTLV-1 carriers than in the control. In BALF, the percentage of lymphocytes and CD4

Accelerated neutrophil apoptosis in neutropenic patients with hepatosplenic schistosomiasis is induced by serum Fas ligand.

Neutropenia in patients with hepatosplenic (HS) schistosomiasis may stem from enhanced neutrophil apoptosis. However, the molecular mechanism of neutrophil apoptosis has not been clearly defined. Neutrophils harvested from neutropenic patients with HS schistosomiasis (n = 25), non-neutropenic patients with hepatointestinal (HI) schistosomiasis (n = 10), and age- and sex-matched healthy control subjects (n = 10) were examined for the degree of apoptosis after incubation with autologous sera. Neutrophil apoptosis was quantified by flow cytometry through determination of propidium iodide nuclear