Inhibition of sodium glucose cotransporter 2 (SGLT2) has been reported as a new therapeutic strategy for treating diabetes. However, the effect of SGLT2 inhibitors on the kidney is unknown. In ...addition, whether SGLT2 inhibitors have an anti-inflammatory or antioxidative stress effect is still unclear. In this study, to resolve these issues, we evaluated the effects of the SGLT2 inhibitor, dapagliflozin, using a mouse model of type 2 diabetes and cultured proximal tubular epithelial (mProx24) cells. Male db/db mice were administered 0.1 or 1.0 mg/kg of dapagliflozin for 12 weeks. Body weight, blood pressure, blood glucose, hemoglobin A1c, albuminuria and creatinine clearance were measured. Mesangial matrix accumulation and interstitial fibrosis in the kidney and pancreatic β-cell mass were evaluated by histological analysis. Furthermore, gene expression of inflammatory mediators, such as osteopontin, monocyte chemoattractant protein-1 and transforming growth factor-β, was evaluated by quantitative reverse transcriptase-PCR. In addition, oxidative stress was evaluated by dihydroethidium and NADPH oxidase 4 staining. Administration of 0.1 or 1.0 mg/kg of dapagliflozin ameliorated hyperglycemia, β-cell damage and albuminuria in db/db mice. Serum creatinine, creatinine clearance and blood pressure were not affected by administration of dapagliflozin, but glomerular mesangial expansion and interstitial fibrosis were suppressed in a dose-dependent manner. Dapagliflozin treatment markedly decreased macrophage infiltration and the gene expression of inflammation and oxidative stress in the kidney of db/db mice. Moreover, dapagliflozin suppressed the high-glucose-induced gene expression of inflammatory cytokines and oxidative stress in cultured mProx24 cells. These data suggest that dapagliflozin ameliorates diabetic nephropathy by improving hyperglycemia along with inhibiting inflammation and oxidative stress.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Conophylline (CNP) is a vinca alkaloid extracted from the
Tabernaemontana divaricata
plant. It has been reported that CNP induces autophagy in a mammalian target of rapamycin–independent manner, and ...thereby inhibits protein aggregation. However, the mode of action of CNP in inducing autophagy remains unknown. In this study, we identified glutathione peroxidase 4 (GPX4) as a CNP-binding protein by using thermal proteome profiling. The technique exploits changes in the thermal stability of proteins resulting from ligand interaction, which is capable of identifying compound-binding proteins without chemical modification. GPX4, an antioxidant protein that uses reduced glutathione as a cofactor, directly catalyzes the reduction of hydrogen peroxide, organic hydroperoxides, and lipid peroxides. GPX4 suppresses lipid peroxide accumulation, and thus plays a key role in protecting cells from oxidative damage. We found that treatment with CNP caused accumulation of lipid reactive oxygen species (ROS) in cultured cells. Furthermore, similarly with CNP treatment, GPX4 deficiency caused accumulation of lipid ROS and induced autophagy. These findings indicate that GPX4 is a direct target of CNP involved in autophagy induction.
It is unclear whether the improvement in diabetic nephropathy by sodium glucose cotransporter 2 (SGLT2) inhibitors is caused by a direct effect on SGLT2 or by the improvement in hyperglycemia. Here, ...we investigated the effect of dapagliflozin on early‐stage diabetic nephropathy using a mouse model of type 1 diabetes and murine proximal tubular epithelial cells. Eight‐week‐old Akita mice were treated with dapagliflozin or insulin for 12 weeks. Body weight, urinary albumin excretion, blood pressure, as well as levels of blood glucose and hemoglobin A1c were measured. Expansion of the mesangial matrix, interstitial fibrosis, and macrophage infiltration in kidneys were evaluated by histology. Oxidative stress and apoptosis were evaluated in kidneys and cultured proximal tubular epithelial cells. Compared with nontreated mice, dapagliflozin and insulin decreased blood glucose and hemoglobin A1c levels equally. Urine volume and water intake increased significantly in the dapagliflozin‐treated group compared with those in the insulin‐treated group, but there were no differences in body weight or blood pressure between the two groups. Macrophage infiltration and fibrosis in renal interstitium improved significantly in the dapagliflozin group compared with the insulin group. Oxidative stress was attenuated by dapagliflozin, and suppression occurred in a dose‐dependent manner. RNAi knockdown of SGLT2 resulted in reduced oxidative stress. Dapagliflozin ameliorates diabetic nephropathy by suppressing hyperglycemia‐induced oxidative stress in a manner independent of hyperglycemia improvement in Akita mice. Our findings suggest that dapagliflozin may be a novel therapeutic approach for the treatment of diabetic nephropathy.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Oxidative stress and inflammation play important roles in diabetic complications, including diabetic nephropathy. Metallothionein (MT) is induced in proximal tubular epithelial cells as an ...antioxidant in the diabetic kidney; however, the role of MT in renal function remains unclear. We therefore investigated whether MT deficiency accelerates diabetic nephropathy through oxidative stress and inflammation. Diabetes was induced by streptozotocin injection in MT-deficient (MT(-/-)) and MT(+/+) mice. Urinary albumin excretion, histological changes, markers for reactive oxygen species (ROS), and kidney inflammation were measured. Murine proximal tubular epithelial (mProx24) cells were used to further elucidate the role of MT under high-glucose conditions. Parameters of diabetic nephropathy and markers of ROS and inflammation were accelerated in diabetic MT(-/-) mice compared with diabetic MT(+/+) mice, despite equivalent levels of hyperglycemia. MT deficiency accelerated interstitial fibrosis and macrophage infiltration into the interstitium in the diabetic kidney. Electron microscopy revealed abnormal mitochondrial morphology in proximal tubular epithelial cells in diabetic MT(-/-) mice. In vitro studies demonstrated that knockdown of MT by small interfering RNA enhanced mitochondrial ROS generation and inflammation-related gene expression in mProx24 cells cultured under high-glucose conditions. The results of this study suggest that MT may play a key role in protecting the kidney against high glucose-induced ROS and subsequent inflammation in diabetic nephropathy.
Nuclear hormone receptors (NHRs) are transcription factors that regulate carbohydrate and lipid metabolism, immune responses, and inflammation. Although several NHRs, including peroxisome ...proliferator-activated receptor-γ (PPARγ) and PPARα, demonstrate a renoprotective effect in the context of diabetic nephropathy (DN), the expression and role of other NHRs in the kidney are still unrecognized. To investigate potential roles of NHRs in the biology of the kidney, we used quantitative real-time polymerase chain reaction to profile the expression of all 49 members of the mouse NHR superfamily in mouse kidney tissue (C57BL/6 and db/m), and cell lines of mesangial (MES13), podocyte (MPC), proximal tubular epithelial (mProx24) and collecting duct (mIMCD3) origins in both normal and high-glucose conditions. In C57BL/6 mouse kidney cells, hepatocyte nuclear factor 4α, chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and COUP-TFIII were highly expressed. During hyperglycemia, the expression of the NHR 4A subgroup including neuron-derived clone 77 (Nur77), nuclear receptor-related factor 1, and neuron-derived orphan receptor 1 significantly increased in diabetic C57BL/6 and db/db mice. In renal cell lines, PPARδ was highly expressed in mesangial and proximal tubular epithelial cells, while COUP-TFs were highly expressed in podocytes, proximal tubular epithelial cells, and collecting duct cells. High-glucose conditions increased the expression of Nur77 in mesangial and collecting duct cells, and liver x receptor α in podocytes. These data demonstrate NHR expression in mouse kidney cells and cultured renal cell lines and suggest potential therapeutic targets in the kidney for the treatment of DN.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Japanese government at present is implementing international health and medical growth strategies mainly from the viewpoint of business. However, the United Nations is set to resolve the ...Post-2015 Development Agenda in the fall of 2015; the agenda will likely include the achievement of universal health coverage (UHC) as a specific development goal. Japan's healthcare system, the foundation of which is its public, nationwide universal health insurance program, has been evaluated highly by the Lancet. The World Bank also praised it as a global model. This paper presents suggestions and problems for Japan regarding global health strategies, including in regard to several prerequisite domestic preparations that must be made. They are summarized as follows. (1) The UHC development should be promoted in coordination with the United Nations, World Bank, and Asian Development Bank. (2) The universal health insurance system of Japan can be a global model for UHC and ensuring its sustainability should be considered a national policy. (3) Trade agreements such as the Trans-Pacific Partnership (TPP) should not disrupt or interfere with UHC, the form of which is unique to each nation, including Japan. (4) Japan should disseminate information overseas, including to national governments, people, and physicians, regarding the course of events that led to the establishment of the Japan's universal health insurance system and should make efforts to develop international human resources to participate in UHC policymaking. (5) The development of separate healthcare programs and UHC preparation should be promoted by streamlining and centralizing maternity care, school health, infectious disease management such as for tuberculosis, and emergency medicine such as for traffic accidents. (6) Japan should disseminate information overseas about its primary care physicians (kakaritsuke physicians) and develop international human resources. (7) Global health should be developed in integration with global environment problem management. (8) Support systems, such as for managing large-scale disasters of international scale or preventing the spread of infectious diseases, should be developed and maintained. (9) International healthcare policy, which the Japanese government is trying to promote in accordance with international trends, and international development of Japanese healthcare industry should be reconsidered.
This research was carried out from the perspective that the damage to the people of Fukushima and others from the Fukushima Daiichi Nuclear Power Station (NPS) accident was an "information disaster." ...It evaluated the critical problems raised by and actual condition analysis on the process of events in the Fukushima Daiichi NPS disaster and responses of the governments and others, notification of the occurrence of the accident and evacuation order by the national and local governments and the evacuation of residents, and guidance for distribution and intake of stable iodine tablets. The research aimed to provide a basis for the implementation of effective distribution and intake of stable iodine tablets and responses to the "information disaster" in the nuclear power disaster. On March 15 at the time that the most radioactive substances were dispersed, even when the average wind speed at the site area was 1.6 m/s, the radioactive substances had reached the outer boundary of Urgent Protective action planning Zone (UPZ, the region with a radius of 30 km) within about five hours. Because of this, every second counted in the provision of information about the accident and the issuance of evacuation orders. This study evaluated the actual condition of information provision by the national government and others from the perspective of this awareness of the importance of time. On the basis of the results of this kind of consideration, we come to the following recommendations: The Nuclear Emergency Response Guidelines and the system for communication of information to medical providers should be revised. The national government should make preparations for the effective advance distribution and intake of stable iodine tablets.
To determine if 'Defocus Incorporated Multiple Segments' (DIMS) spectacle lenses slow childhood myopia progression.
A 2-year double-masked randomised controlled trial was carried out in 183 Chinese ...children aged 8-13 years, with myopia between -1.00 and -5.00 D and astigmatism ≤1.50 D. Children were randomly assigned to wear DIMS (n=93) or single vision (SV) spectacle lenses (n=90). DIMS lens incorporated multiple segments with myopic defocus of +3.50 D. Refractive error (cycloplegic autorefraction) and axial length were measured at 6month intervals.
160 children completed the study, n=79 in the DIMS group and n=81 in the SV group. Average (SE) myopic progressions over 2 years were -0.41±0.06 D in the DIMS group and -0.85±0.08 D in the SV group. Mean (SE) axial elongation was 0.21±0.02 mm and 0.55±0.02 mm in the DIMS and SV groups, respectively. Myopia progressed 52% more slowly for children in the DIMS group compared with those in the SV group (mean difference -0.44±0.09 D, 95% CI -0.73 to -0.37, p<0.0001). Likewise, children in the DIMS group had less axial elongation by 62% than those in the SV group (mean difference 0.34±0.04 mm, 95% CI 0.22 to 0.37, p<0.0001). 21.5% children who wore DIMS lenses had no myopia progression over 2 years, but only 7.4% for those who wore SV lenses.
Daily wear of the DIMS lens significantly retarded myopia progression and axial elongation in myopic children. Our results demonstrated simultaneous clear vision with constant myopic defocus can slow myopia progression.
NCT02206217.
Dry gene powder is a novel non-viral gene-delivery system, which is inhalable with high gene expression. Previously, we showed that the transfection of p16
or TP53 by dry gene powder resulted in ...growth inhibitions of lung cancer and malignant pleural mesothelioma (MPM) in vitro and in vivo. Here, we report that dry gene powder containing p53- expression-plasmid DNA enhanced the therapeutic effects of cisplatin (CDDP) against MPM even in the presence of endogenous p53. Furthermore, our results indicated that the safe transfection with a higher plasmid DNA (pDNA) concentration suppressed MPM growth independently of chemotherapeutic agents. To develop a new therapeutic alternative for MPM patients without safety concerns over "vector doses", our in vitro data provide basic understandings for dry gene powder.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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