IL-1β-secreting nucleotide-binding oligomerization domain protein 3 (NLRP3) inflammasomes play a pivotal role in triggering innate immune responses in metabolic disease. We investigated the role of soluble uric acid in NLRP3 inflammasome activation in macrophages to demonstrate the effect of systemic hyperuricemia on progressive kidney damage in type 2 diabetes. THP-1 cells, human acute monocytic leukemia cells, were cultured to obtain macrophages, and HK-2 cells, human renal proximal tubule cells, were cultured and stimulated with uric acid. In vivo, we designed four rat groups as follows: 1) Long-Evans Tokushima Otsuka (LETO); 2) Otsuka Long-Evans Tokushima Fatty (OLETF); 3) OLETF+high-fructose diet (HFD) for 16 wk; and 4) OLETF+HFD+allopurinol (10 mg/dl administered in the drinking water). Soluble uric acid stimulated NLRP3 inflammasomes to produce IL-1β in macrophages. Uric acid-induced MitoSOX mediates NLRP3 activation and IL-1β secretion. IL-1β from macrophages activates NF-κB in cocultured proximal tubular cells. In vivo, intrarenal IL-1β expression and macrophage infiltration increased in HFD-fed OLETF rats. Lowering the serum uric acid level resulted in improving the albuminuria, tubular injury, macrophage infiltration, and renal IL-1β (60% of HFD-fed OLETF) independently of glycemic control. Direct activation of proximal tubular cells by uric acid resulted in (C-X-C motif) ligand 12 and high mobility group box-1 release and accelerated macrophage recruitment and the M1 phenotype. Taken together, these data support direct roles of hyperuricemia in activating NLRP3 inflammasomes in macrophages, promoting chemokine signaling in the proximal tubule and contributing to the progression of diabetic nephropathy through cross talk between macrophages and proximal tubular cells.

A subset of human growth hormone (GH)-secreting pituitary tumors contains the gsp oncogene that encodes an activation mutation of the alpha-subunit of the stimulatory GTP-binding protein (G(S) alpha). This study was undertaken to investigate the frequency of the gsp oncogene in GH-secreting pituitary tumors in Korean acromegalic patients and to elucidate the clinical characteristics of these patients to endocrine testing. Direct polymerase chain reaction sequencing revealed the gsp oncogene mutation in 9 out of 21 tumors (43%) at amino acid 201 of the G(S) alpha protein. A single nucleotide mutation in the tumors carrying the gsp oncogene was observed, which replaced an arginine (CGT) in the normal protein with cysteine (TGT) in eight tumors and serine (AGT) in one tumor. The patients with the gsp oncogene mutation (group 1) were older (54 +/- 10 vs 41 +/- 11 years, p = 0.0085) than those without the mutation (group 2). Sex, tumor size and grade, basal GH and prolactin levels, the GH response to oral glucose loading, the GH fluctuation and the paradoxical response to thyrotropin-releasing hormone or gonadotropin-releasing hormone did not differ between the groups. The gsp oncogene was found mostly in somatotroph adenomas. The octreotide-induced GH suppression was significantly higher in group 1 than in group 2 (95 +/- 5% vs 81 +/- 17%, p = 0.0335). The GH response to bromocriptine did not differ between the groups. These results suggest that the G(S) alpha mutations of GH-secreting tumor are observed in Korean acromegalic patients with similar frequency to those of western countries. The patients with gsp oncogene are likely to be older than those without the oncogene, and show excellent response of GH suppression to octreotide.

AMP-activated protein kinase (AMPK) is tightly regu-Mammalian AMP-activated protein kinase (AMPK) 1 plays a key role in the regulation of energy homeostasis and is highly conserved among animals, plants, and fungi (reviewed in Refs.

Controlling the crystal phase of a material using solution-based method is a challenging task and has significant consequence to the material’s properties. Herein we report the phase and size-controlled synthesis of tungsten oxide hydrates at room temperature via a simple precipitation method. In the absence and presence of oxalic acid, orthorhombic WO3·H2O and monoclinic WO3·2H2O nanoplates of size in the range of 200–600 (thickness <50 nm) and 40–200 nm (thickness <20 nm) were respectively synthesized. Oxalic acid is found to play the central role in the phase transition due to its chelating nature that facilitates bonding of oxalate ions to tungsten cations leading to formation of WO3·2H2O. Upon annealing at 400 °C for 2 h under air, both WO3·H2O and WO3·2H2O nanoplates were converted to monoclinic WO3 nanoplates. These nanoplates were demonstrated to be highly efficient for the photocatalytic detoxification of toxic Cr­(VI) in the acidic pH under the visible light irradiation. The best Cr­(VI) reduction performance was obtained with WO3·2H2O nanoplates due to its smaller band gap and larger effective surface area. In addition, a lower pH value is found to facilitates the Cr­(VI) reduction. Furthermore, highly concentrated methylene blue was efficiently removed (>95%) by adsorption on the nanoplates within a minute, suggesting the importance and potential of a material that can be synthesized at room temperature.

This study demonstrated that the response of RPE cells to MMC was bi-directional: 1) partial arrest of the cell cycle at S, G2/M phase, and 2) induction of apoptotic cell death.

Background: The pivotal role of transforming growth factor-β₁ (TGF-β₁)-induced tubulointerstitial fibrosis in the progression of chronic kidney disease is an active topic of research. Recent evidence indicates that hyperuricemia is associated with increased TGF-β₁ and progressive tubulointerstitial injury. We examined the hypothesis that lowering serum uric acid attenuates TGF-β₁-induced profibrogenic tubular change in type 2 diabetic nephropathy. Methods: KK-A^y/Ta mice, an animal model of type 2 diabetes, were provided access to either regular drinking water or drinking water containing 10 mg/dl of allopurinol. Normal rat kidney epithelial cells were cultured and stimulated with 5 mM uric acid with or without allopurinol. Results: Type 2 diabetic mice that received allopurinol exhibited smaller increases in urinary albumin:creatinine ratio than diabetic control mice, as well as attenuated TGF-β₁ and Smad pathway-induced profibrogenic tubular changes in diabetic kidneys. Allopurinol attenuated TGF-β₁-induced Smad pathway activation in tubular cells. These findings were related to increases in E-cadherin, and decreases in vimentin and α-smooth muscle actin. Uric acid-induced upregulation of TGF-β₁ depends on mitogen-activated protein kinase signaling. Conclusions: This is the first study to demonstrate that reducing serum uric acid has preventive effects against to profibrogenic progression in type 2 diabetic kidney disease. These findings suggest that lowering serum uric acid may be an effective therapeutic intervention to prevent the progression of type 2 diabetic kidney disease.

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