Mckenziekara1509

The glucose-lowering effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors is reduced in patients with diabetes who have chronic kidney disease (CKD). In the present study, we examined the effect of an SGLT2 inhibitor on the salt sensitivity of blood pressure (BP), circadian rhythm of BP, and sympathetic nerve activity (SNA) in nondiabetic CKD rats. Uninephrectomized Wistar rats were treated with adenine (200 mg/kg/day) for 14 days. After stabilization with a normal-salt diet (NSD, 0.3% NaCl), a high-salt diet (HSD, 8% NaCl) was administered. Mean arterial pressure (MAP) was continuously monitored using a telemetry system. EGFR inhibitor review We also analyzed the low frequency (LF) of systolic arterial pressure (SAP), which reflects SNA. In adenine-induced CKD rats, HSD consumption for 5 days significantly increased the mean MAP from 106 ± 2 to 148 ± 3 mmHg. However, MAP was decreased to 96 ± 3 mmHg within 24 h after switching back to a NSD (n = 7). Treatment with an SGLT2 inhibitor, luseogliflozin (10 mg/kg/day, p.o., n = 7), significantly attenuated the HSD-induced elevation of MAP, which was associated with a reduction in LF of SAP. These data suggest that treatment with an SGLT2 inhibitor attenuates the salt sensitivity of BP, which is associated with SNA inhibition in nondiabetic CKD rats.There is evidence to suggest that hypertension involves a chronic low-grade systemic inflammatory response; however, the underlying mechanisms are unclear. To further understand the role of inflammation in hypertension, we used a rat renovascular model of hypertension in which we administered the TNF-α synthesis inhibitor pentoxifylline (PTX, 30 mg/kg/day) in the drinking water for 60 days. In conscious rats, PTX administration significantly attenuated the development of hypertension (systolic blood pressure, PTX 145 ± 8 vs. vehicle (Veh) 235 ± 11 mmHg, after 38 days of treatment, P  less then  0.05, N = 5/group). This attenuation in hypertension was coupled with a decrease in the low-frequency spectra of systolic blood pressure variability (PTX 1.23 ± 0.2 vs Veh 3.05 ± 0.8 arbitrary units, P  less then  0.05, N = 5/group). Furthermore, systemic PTX administration decreased c-Fos expression within the hypothalamic paraventricular nucleus (PTX 17 ± 4 vs. Veh 70 ± 13 cells, P  less then  0.01, N = 5, PVN) and increased the total number of microglial branches (PTX 2129 ± 242 vs. Veh 1415 ± 227 branches, P  less then  0.05, N = 4/group). Acute central injection of PTX (20 μg) under urethane anesthesia caused a small transient decrease in blood pressure but did not change renal sympathetic nerve activity. Surprisingly, we found no detectable basal levels of plasma TNF-α in either PTX- or vehicle-treated animals. These results suggest that inflammation plays a role in renovascular hypertension and that PTX might act both peripherally and centrally to prevent hypertension.Both hydrostatic and osmotic pressures are altered in the tumour microenvironment. Glioblastoma (GBM) is a brain tumour with high invasiveness and poor prognosis. We hypothesized that physical and osmotic forces regulate glioblastoma (GBM) invasiveness. The osmotic pressure of GBM cell culture medium was adjusted using sodium chloride or water. Alternatively, cells were subjected to increased hydrostatic force. The proteolytic profile and epithelial-mesenchymal transition (EMT) were investigated using zymography and real-time qPCR. The EMT markers assessed were Snail-1, Snail-2, N-cadherin, Twist and vimentin. Invasion was investigated in vitro using extracellular matrix-coated Transwell inserts. In response to osmotic and mechanical pressure, GBM cell lines U87 and U251 and patient-derived neural oncospheres upregulated the expression of urokinase-type plasminogen activator (uPA) and/or matrix metalloproteinases (MMPs) as well as some of the EMT markers tested. The adherent cell lines invaded more when placed in media of increased osmolality. Therefore, GBM respond to osmotic or mechanical pressure by increasing matrix degrading enzyme production, and adopting a phenotype reminiscent of EMT. Better understanding the molecular and cellular mechanisms by which increased pressure promotes GBM invasiveness may help to develop innovative therapeutic approaches.Eutectic high entropy alloys, with lamellar arrangement of solid solution phases, represent a new paradigm for simultaneously achieving high strength and ductility, thereby circumventing this well-known trade-off in conventional alloys. However, dynamic strengthening mechanisms and phase-boundary interactions during external loading remain unclear for these eutectic systems. In this study, small-scale mechanical behavior was evaluated for AlCoCrFeNi2.1 eutectic high entropy alloy, consisting of a lamellar arrangement of L12 and B2 solid-solution phases. The ultimate tensile strength was 1165 MPa with ductility of ~18% and ultimate compressive strength was 1863 MPa with a total compressive fracture strain of ~34%. Dual mode fracture was observed with ductile failure for L12 phase and brittle mode for B2 phase. Phase-specific mechanical tests using nano-indentation and micro-pillar compression showed higher hardness and strength and larger strain rate sensitivity for B2 compared with L12. Micro-pillars on B2 phase deformed by plastic barreling while L12 micro-pillars showed high density of slip steps due to activation of more slip systems and homogenous plastic flow. Mixed micro-pillars containing both the phases exhibited dual yielding behavior while the interface between L12 and B2 was well preserved without any sign of separation or cracking. Phase-specific friction analysis revealed higher coefficient of friction for B2 compared to L12. These results will pave the way for fundamental understanding of phase-specific contribution to bulk mechanical response of concentrated alloys and help in designing structural materials with high fracture toughness.The pathogenesis of DNA mismatch repair (MMR)-deficient endometrial carcinoma (EC) is driven by inactivating methylation or less frequently mutation of an MMR gene (MLH1, PMS2, MSH2, or MSH6). This study evaluated the prognostic and clinicopathologic differences between methylation-linked and nonmethylated MMR-deficient endometrioid ECs. We performed MMR immunohistochemistry and methylation-specific multiplex ligation-dependent probe amplification, and classified 682 unselected endometrioid ECs as MMR proficient (MMRp, n = 438) and MMR deficient (MMRd, n = 244), with the latter subcategorized as methylated (MMRd Met) and nonmethylated tumors. Loss of MMR protein expression was detected in 35.8% of the tumors as follows MLH1 + PMS2 in 29.8%, PMS2 in 0.9%, MSH2 + MSH6 in 1.3%, MSH6 in 2.8%, and multiple abnormalities in 0.9%. Of the 244 MMRd cases, 76% were methylation-linked. MMR deficiency was associated with older age, high grade of differentiation (G3), advanced stage (II-IV), larger tumor size, abundant tumor-infiltrating lymphocytes, PD-L1 positivity in immune cells and combined positive score, wild-type p53, negative L1CAM, ARID1A loss, and type of adjuvant therapy.