Effects of Glycyrrhizae Radix Pharmacopuncture Intravenous Injection on Ischemia-induced Acute Renal Failure in Rabbits

Objectives: The present study was undergone to determine whether Glycyrrhizae Radix pharmacopuncture intravenous injection exerts beneficial effect against the ischemia-induced acute renal failure in rabbits. Methods: Rabbits were treated with Glycyrrhizae Radix pharmacopuncture via i.v., followed by renal ischemia/reperfusion. The fractional excretion of glucose and phosphate were measured and the malondialdehyde content was also determined. The morphological changes of cortical part of kidney also observed with light microscope. Results: Renal ischemia/reperfusion caused increase of the fractional excretion of glucose and phosphate in ischemia-induced animals, which was prevented by Radix Glycyrrhizae extract treatment. Ischemia/reperfusion increased lipid peroxidation, which was prevented and morphological changes also altered by Radix Glycyrrhizae pharmacopuncture administration. Conclusions: These results indicate that lipid peroxidation plays a critical role in ischemia-induced acute renal failure and Glycyrrhizae Radix pharmacopuncture exerts the protective effect against acute renal failure induced by renal ischemia/reperfusion

Efficacy and Safety of Enavogliflozin versus Dapagliflozin as Add-on to Metformin in Patients with Type 2 Diabetes Mellitus: A 24-Week, Double-Blind, Randomized Trial

Background Enavogliflozin is a novel sodium-glucose cotransporter-2 inhibitor currently under clinical development. This study evaluated the efficacy and safety of enavogliflozin as an add-on to metformin in Korean patients with type 2 diabetes mellitus (T2DM) against dapagliflozin. Methods In this multicenter, double-blind, randomized, phase 3 study, 200 patients were randomized to receive enavogliflozin 0.3 mg/day (n=101) or dapagliflozin 10 mg/day (n=99) in addition to ongoing metformin therapy for 24 weeks. The primary objective of the study was to prove the non-inferiority of enavogliflozin to dapagliflozin in glycosylated hemoglobin (HbA1c) change at week 24 (non-inferiority margin of 0.35%) (Clinical trial registration number: NCT04634500). Results Adjusted mean change of HbA1c at week 24 was –0.80% with enavogliflozin and –0.75% with dapagliflozin (difference, –0.04%; 95% confidence interval, –0.21% to 0.12%). Percentages of patients achieving HbA1c <7.0% were 61% and 62%, respectively. Adjusted mean change of fasting plasma glucose at week 24 was –32.53 and –29.14 mg/dL. An increase in urine glucose-creatinine ratio (60.48 vs. 44.94, P<0.0001) and decrease in homeostasis model assessment of insulin resistance (–1.85 vs. –1.31, P=0.0041) were significantly greater with enavogliflozin than dapagliflozin at week 24. Beneficial effects of enavogliflozin on body weight (–3.77 kg vs. –3.58 kg) and blood pressure (systolic/diastolic, –5.93/–5.41 mm Hg vs. –6.57/–4.26 mm Hg) were comparable with those of dapagliflozin, and both drugs were safe and well-tolerated. Conclusion Enavogliflozin added to metformin significantly improved glycemic control in patients with T2DM and was non-inferior to dapagliflozin 10 mg, suggesting enavogliflozin as a viable treatment option for patients with inadequate glycemic control on metformin alone

Erastin Inhibits Septic Shock and Inflammatory Gene Expression via Suppression of the NF-κB Pathway

Sepsis is a life-threatening condition that is caused by an abnormal immune response to infection and can lead to tissue damage, organ failure, and death. Erastin is a small molecule capable of initiating ferroptotic cell death in cancer cells. However, the function of erastin in the inflammatory response during sepsis remains unknown. Here, we showed that erastin ameliorates septic shock induced by cecal ligation and puncture or lipopolysaccharides (LPS) in mice, which was associated with a reduced production of inflammatory mediators such as nitric oxide, tumor necrosis factor (TNF)-&alpha;, and interleukin (IL)-1&beta;. Pretreatment with erastin in bone marrow-derived macrophages (BMDMs) significantly attenuated the expression of inducible nitric oxide synthase, cyclooxygenase-2, TNF-&alpha;, and IL-1&beta; mRNA in response to LPS treatment. Furthermore, we also showed that erastin suppresses phosphorylation of I&kappa;B kinase &beta;, phosphorylation and degradation of I&kappa;B&alpha;, and nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-&kappa;B) in LPS-stimulated BMDMs. Our findings suggest that erastin attenuates the inflammatory response by suppressing the NF-&kappa;B signaling pathway, resulting in inhibition of sepsis development. This study provides new insights regarding the potential therapeutic properties of erastin in sepsis

Functional Cooperation between Vitamin D Receptor and Runx2 in Vitamin D-Induced Vascular Calcification

<div><p>The transdifferentiation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells has been implicated in the context of vascular calcification. We investigated the roles of vitamin D receptor (Vdr) and <i>runt-related transcription</i> factor <i>2</i> (<i>Runx2</i>) in the osteoblastic differentiation of VSMCs in response to vitamin D₃ using <i>in vitro</i> VSMCs cultures and <i>in vivo</i> in <i>Vdr</i> knockout (<i>Vdr</i>^<i>-/-</i>) and <i>Runx2 carboxy-terminus</i> truncated heterozygous (<i>Runx2</i>^<i>+/ΔC</i>) mice. Treatment of VSMCs with active vitamin D₃ promoted matrix mineral deposition, and increased the expressions of Vdr, Runx2, and of osteoblastic genes but decreased the expression of smooth muscle myosin heavy chain in primary VSMCs cultures. Immunoprecipitation experiments suggested an interaction between Vdr and Runx2. Furthermore, silencing <i>Vdr</i> or <i>Runx2</i> attenuated the procalcific effects of vitamin D₃. Functional cooperation between Vdr and Runx2 in vascular calcification was also confirmed in <i>in vivo</i> mouse models. Vascular calcification induced by high-dose vitamin D₃ was completely inhibited in <i>Vdr</i>^<i>-/-</i> or <i>Runx2</i>^<i>+/ΔC</i> mice, despite elevated levels of serum calcium or alkaline phosphatase. Collectively, these findings suggest that functional cooperation between Vdr and Runx2 is necessary for vascular calcification in response to vitamin D₃.</p> </div

Protection from vitamin D₃-induced VC in <i>Runx2</i>^+/ΔC mice.

<p>Eight-week-old Runx2^+/+ and <i>Runx2</i>^+/ΔC mice were injected with vitamin D₃ (6 x 10⁵ IU/kg of body weight). (A) Calcified regions were detected by von Kossa staining. The protein levels of Vdr, Runx2, Mgp, and Smmhc in these regions were assessed by immunohistochemical staining. Original magnification, X400 (Scale bar=10 μm). Experimental groups (n=5-8). N.IgG was used as an internal control. (B) Serum calcium, phosphate, and Alp levels were also measured. Data are group means ± SDs (n=5-8/group). Statistical analysis was analyzed using the unpaired Student’s <i>t</i>-test. *P<0.05; **P<0.01.</p