Effect of Paraquat-Induced Oxidative Stress on Insulin Regulation of Insulin-Like Growth Factor-Binding Protein-1 Gene Expression

Oxidative stress is thought to play a role in the development of insulin resistance. In order to elucidate the molecular effect of oxidative stress on liver insulin signaling, we analyzed the effect of paraquat (1,1-dimethyl-4,4-dipyridynium; PQ)-derived oxidative stress on the expression of insulin-dependent genes and activation of liver insulin signaling pathway. Incubation of primary cultured rat hepatocytes with 2 mM PQ for 6 h impaired the suppressive effect of insulin on insulin-like growth factor-binding protein-1 (IGFBP-1) gene expression, but did not influence glucose-6-phosphatase gene expression. Insulin-dependent phosphorylation or activation of insulin receptor, insulin receptor substrate-1 and -2, phosphatidylinositol 3-kinase, Akt and forkhead in rhabdomyosarcoma were not affected by PQ pre-treatment. In contrast, PQ treatment impaired insulin-dependent phosphorylation of mammalian target of rapamycin (mTOR). These results indicate that PQ-induced oxidative stress impairs insulin-dependent mTOR activation and that this impairment probably causes inhibition of insulin-dependent repression of IGFBP-1 expression

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

SPECT measurement of regional cerebral blood flow, blood volume, and hematocrit in stroke

The clinical importance of measurement of the regional cerebral hemodynamics, using positron emission tomography (PET) or single-photon emission computed tomography (SPECT), is to ascertain the viability of the ischemic tissue or to predict the functional outcome after ischemic cerebral vascular diseases. Specifically, the following aspects may be considered important: I) to determine the state of the hemodynamics in regions of the brain identified from clinical signs and symptoms as ischemic or infarcted, 2) to determine whether the local flow is sufficient or at risk, 3) to estimate the prognosis with or without intervention and 4) to assess whether the risk of a second post-acute infarction has been reduced after treatment. In addition to investigations of the regional cerebral blood flow (CBF), there is now a growing interest in the role of the cerebral blood volume (CBV) and blood viscosity in the pathophysiology of cerebral ischemia. Recent studies have focused on the effectiveness of hemorheological approaches, including hemodilution ther­ apy, in the treatment of cerebral vascular diseases [1]. Employing PET, Gibbs et al. [2] and Powers et al. [3] suggested that the cerebral mean transit time derived from the ratio between CBF and CBV might serve as a sensitive parameter for estimating the circulatory reserve in the ischemic tissue. In the present study, SPECT was used to measure the regional CBF, CBV and cerebral hematocrit in normals and patients with occlusive cerebral vascular dis­ eases. Based on these three cerebral hemodynamic parameters, the regional patho­ physiology during the acute stages of cerebral infarction and of transient ischemic attack (TIA) was evaluated

Hard and soft tissue responses to three different implant materials in a dog model

The aim of this study was to assess hard and soft tissue responses using three dental implants made of different materials. Implants made of titanium (Ti), yttria-stabilized tetragonal zirconia polycrystals (Y-TZP) and ceria partially stabilized zirconia/alumina nanocomposite (Ce-TZP/Al2O3) were used in a dog model. Five male beagles were sacrificed at three months after implantation, and harvested mandible were observed and analyzed. Histological observations were similar in all groups. There were no significant differences in any histomorphometric parameters. Our results suggested the possibility of Ce-TZP/Al2O3 as a dental implant material, similar to Ti and Y-TZP

Serum Autotaxin Concentrations Reflect Changes in Liver Stiffness and Fibrosis After Antiviral Therapy in Patients with Chronic Hepatitis C

The purpose of this study was to determine whether serum autotaxin concentrations reflect liver stiffness in patients with chronic hepatitis C virus (HCV) treated with direct‐acting antiviral agents. Adult patients with chronic HCV were enrolled from January 2016 to August 2017. Autotaxin concentrations in these patients were compared with those of a control group consisting of healthy individuals. Liver stiffness was determined by transient elastography. The relationship between fibrosis markers and fibrosis scores was evaluated before and after treatment. Data from 155 HCV patients and 56 control subjects were analyzed. Autotaxin concentrations were significantly higher in HCV patients with liver stiffness scores less than or equal to 7.4 kPa versus controls. Autotaxin concentrations at the end of treatment and beyond were significantly lower than those prior to treatment. Pretreatment and posttreatment autotaxin concentrations in male and female patients with liver stiffness scores greater than 14.9 kPa changed significantly (P < 0.01 and P < 0.01, respectively). From the start of treatment to 6 months following treatment, the fibrosis marker/liver stiffness score ratios changed as follows: autotaxin: 0.189 (95% confidence interval [CI]: 0.169‐0.209) to 0.191 (95% CI: 0.166‐0.216; P= 0.88); Wisteria floribundaagglutinin‐positive Mac‐2‐binding protein: 0.294 (95% CI: 0.256‐0.332) to 0.223 (95% CI: 0.191‐0.255; P< 0.001); hyaluronic acid: 19.05 (95% CI: 14.29‐23.81) to 13.92 (95% CI: 11.16‐16.70; P = 0.044); and type IV collagen 7S: 0.560 (95% CI: 0.515‐0.604) to 0.546 (95% CI: 0.497‐0.895; P = 0.052). Conclusion: Autotaxin concentrations reflect liver stiffness before and after antiviral treatment in patients with chronic HCV infection