The Attenuation of Moutan Cortex on Oxidative Stress for Renal Injury in AGEs-Induced Mesangial Cell Dysfunction and Streptozotocin-Induced Diabetic Nephropathy Rats

Oxidative stress (OS) has been regarded as one of the major pathogeneses of diabetic nephropathy (DN) through damaging kidney which is associated with renal cells dysfunction. The aim of this study was to investigate whether Moutan Cortex (MC) could protect kidney function against oxidative stress in vitro or in vivo. The compounds in MC extract were analyzed by HPLC-ESI-MS. High-glucose-fat diet and STZ (30 mg kg−1) were used to induce DN rats model, while 200 μg mL−1 AGEs were for HBZY-1 mesangial cell damage. The treatment with MC could significantly increase the activity of SOD, glutathione peroxidase (GSH-PX), and catalase (CAT). However, lipid peroxidation malondialdehyde (MDA) was reduced markedly in vitro or in vivo. Furthermore, MC decreased markedly the levels of blood glucose, serum creatinine, and urine protein in DN rats. Immunohistochemical assay showed that MC downregulated significantly transforming growth factor beta 2 (TGF-β2) protein expression in renal tissue. Our data provided evidence to support this fact that MC attenuated OS in AGEs-induced mesangial cell dysfunction and also in high-glucose-fat diet and STZ-induced DN rats

Concurrent Intrathecal and Intravenous Nivolumab in Leptomeningeal Disease: Phase 1 Trial Interim Results

There is a critical need for effective treatments for leptomeningeal disease (LMD). Here, we report the interim analysis results of an ongoing single-arm, first-in-human phase 1/1b study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in patients with melanoma and LMD. The primary endpoints are determination of safety and the recommended IT nivolumab dose. The secondary endpoint is overall survival (OS). Patients are treated with IT nivolumab alone in cycle 1 and IV nivolumab is included in subsequent cycles. We treated 25 patients with metastatic melanoma using 5, 10, 20 and 50 mg of IT nivolumab. There were no dose-limiting toxicities at any dose level. The recommended IT dose of nivolumab is 50 mg (with IV nivolumab 240 mg) every 2 weeks. Median OS was 4.9 months, with 44% and 26% OS rates at 26 and 52 weeks, respectively. These initial results suggest that concurrent IT and IV nivolumab is safe and feasible with potential efficacy in patients with melanoma LMD, including in patients who had previously received anti-PD1 therapy. Accrual to the study continues, including in patients with lung cancer. ClinicalTrials.gov registration: NCT03025256

Astilbin Inhibits High Glucose-Induced Inflammation and Extracellular Matrix Accumulation by Suppressing the TLR4/MyD88/NF-κB Pathway in Rat Glomerular Mesangial Cells

Diabetic nephropathy (DN) is characterized by inflammatory responses and extracellular matrix (ECM) accumulation. Astilbin is an active natural compound and possesses anti-inflammatory activity. The aim of this study was to evaluate the anti-inflammatory effect of astilbin on high glucose (HG)-induced glomerular mesangial cells and the potential mechanisms. The results showed that HG induced cell proliferation of HBZY-1 cells in a time-dependent manner, and astilbin inhibited HG-induced cell proliferation. The expression and secretion of inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), and ECM components, including collagen IV (Col IV) and fibronectin (FN), were induced by HG. Moreover, TGF-β1 and CTGF were also induced by HG. The induction by HG on inflammatory response and ECM accumulation was inhibited after astilbin treatment. Astilbin treatment also attenuated HG-induced decrease in expression of matrix metalloproteinase (MMP)-2 and MMP-9. The TLR4/MyD88/NF-κB pathway was activated by HG, and the inhibitor of TLR4 exhibited the same effect to astilbin on reversing the induction of HG. TLR4 overexpression attenuated the effect of astilbin on HG-induced inflammatory cytokine production and ECM accumulation. The results suggested that astilbin attenuated inflammation and ECM accumulation in HG-induced rat glomerular mesangial cells via inhibiting the TLR4/MyD88/NF-κB pathway. This work provided evidence that astilbin can be considered as a potential candidate for DN therapy

Recent Advances in the Synthesis and Antioxidant Activity of Low Molecular Mass Organoselenium Molecules

Selenium is an essential trace element in living organisms, and is present in selenoenzymes with antioxidant activity, like glutathione peroxidase (GPx) and thioredoxin reductase (TrxR). The search for small selenium-containing molecules that mimic selenoenzymes is a strong field of research in organic and medicinal chemistry. In this review, we review the synthesis and bioassays of new and known organoselenium compounds with antioxidant activity, covering the last five years. A detailed description of the synthetic procedures and the performed in vitro and in vivo bioassays is presented, highlighting the most active compounds in each series

Effects of Qijin granules on high glucose-induced proliferation, apoptosis and expression of nuclear factor- κB and MCP-1 in rat glomerular mesangial cells

Purpose: To investigate the effects of Qijin granules on high glucose-induced proliferation and apoptosis in rat glomerular mesangial cells (MC).Methods: MC cells from rats were passaged and cultured, and randomly divided into control group (CNG), high glucose group (HGG), Western medicine group (WMG, high glucose + Benazepril + Gliquidone), and Qijin granules 1/2/3 group (high glucose + different doses of Qijin granules). Mesangial cells proliferation was measured using MTT assay. The NF-κB, MCP-1 and inflammatory factors in supernatant were determined by ELISA. Apoptosis rate and cell cycle were assessed by flow cytometry. The apoptosis-related TGF-β1/Smad signaling pathway-related protein expressions were measured by Western blot.Results: The A-value and early apoptosis rate, apoptosis rate and S-phase percentage, and protein expressions of NF-κB, MCP-1, IL-6, IL-2, TNF-ɑ, Bax, Cyt-C, caspase-3, TGF-β1, and p-Smad3 of MC cells in the HGG at 12 h, 24 h and 48 h were higher than those in the CNG. The above indices were lower in the WMG, and Qijin granules 1/2/3 groups than in the HGG. The Bcl-2, Smad7 protein expression level and the percentage of G1 and G2/M phase were lower in the HGG than in the CNG, and the above indeices were higher in the WMG and Qijin granules 1/2/3 group than in HGG.Conclusion: Qijin granules can dose-dependently inhibit high glucose-induced proliferation and apoptosis in rat MC cells, block the cell cycle and reduce inflammatory responses. This may be related to the regulation of NF-κB, MCP-1 and TGF-β1/Smad signaling pathways. These findings provide theoretical and experimental basis for the clinical treatment of early diabetic nephropathy

Novel Local Characteristic Decomposition Based Path-Conservative Central-Upwind Schemes

We introduce local characteristic decomposition based path-conservative central-upwind schemes for (nonconservative) hyperbolic systems of balance laws. The proposed schemes are made to be well-balanced via a flux globalization approach, in which source terms are incorporated into the fluxes: This helps to enforce the well-balanced property when the resulting quasi-conservative system is solved using the local characteristic decomposition based central-upwind scheme recently introduced in [{\sc A. Chertock, S. Chu, M. Herty, A. Kurganov, and M. Luk\'{a}\v{c}ov\'{a}-Medvi{\softd}ov\'{a}}, J. Comput. Phys., 473 (2023), Paper No. 111718]. Nonconservative product terms are also incorporated into the global fluxes using a path-conservative technique. We illustrate the performance of the developed schemes by applying them to one- and two-dimensional compressible multifluid systems and thermal rotating shallow water equations.Comment: arXiv admin note: text overlap with arXiv:2307.1638

Regulation of the Renin-Angiotensin-Aldosterone System by Reactive Oxygen Species

Angiotensin II (Ang II), the major effector of the renin-angiotensin-aldosterone system (RAAS), stimulates the production of reactive oxygen species (ROS) which are critically involved in Ang II-induced effects. Noteworthy, accumulating evidence indicates that ROS also regulate the activation of RAAS, contributing to the fine-tuning of this system under physiological conditions or to the amplification of the deleterious signaling in several pathologies. This chapter aims at giving an overview of the role of ROS in the regulation of expression, secretion and/or activity of several RAAS components

A Well-Balanced Central-Upwind Scheme for the Thermal Rotating Shallow Water Equations

We develop a well-balanced central-upwind scheme for rotating shallow water model with horizontal temperature and/or density gradients---the thermal rotating shallow water (TRSW). The scheme is designed using the flux globalization approach: first, the source terms are incorporated into the fluxes, which results in a hyperbolic system with global fluxes; second, we apply the Riemann-problem-solver-free central-upwind scheme to the rewritten system. We ensure that the resulting method is well-balanced by switching off the numerical diffusion when the computed solution is near (at) thermo-geostrophic equilibria. The designed scheme is successfully tested on a series of numerical examples. Motivated by future applications to large-scale motions in the ocean and atmosphere, the model is considered on the tangent plane to a rotating planet both in mid-latitudes and at the Equator. The numerical scheme is shown to be capable of quite accurately maintaining the equilibrium states in the presence of nontrivial topography and rotation. Prior to numerical simulations, an analysis of the TRSW model based on the use of Lagrangian variables is presented, allowing one to obtain criteria of existence and uniqueness of the equilibrium state, of the wave-breaking and shock formation, and of instability development out of given initial conditions. The established criteria are confirmed in the conducted numerical experiments