Pharmacology
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<b><i>Introduction:</i></b> Doxorubicin (DOX), an anthracycline antitumor agent, has been widely used against various solid tumors and hematological malignancies. However, the clinical application of DOX is restricted by its multiple organ toxicity including nephrotoxicity. This study investigated the protective effects and mechanisms of dexrazoxane (DZR) against DOX-induced nephropathy in rats. <b><i>Methods:</i></b> Male Sprague Dawley rats received 2.5 mg/kg DOX once a week for 5 consecutive weeks. 24-h urinary protein and renal function injury biomarkers were determined to evaluate the renal function. Histopathological changes and glomerulosclerosis were examined by hematoxylin and eosin and periodic acid-Schiff staining. The change of renal ultrastructure in the DOX-induced rats was observed by the electron microscopy. The renal apoptosis was detected by TUNEL staining and measured the protein expression of Caspase-3, Bcl-2, and Bax. Renal interstitial fibrosis was determined by Masson staining and immunohistochemistry examination. The levels of vimentin, alpha-smooth muscle actin (α-SMA), and transforming growth factor β (TGF-β) in kidney tissue were detected by Western blot. <b><i>Results:</i></b> DZR pretreatment markedly raised the survival rate and improved the renal dysfunction in DOX-treated rats. DZR ameliorated DOX-induced histopathological lesion of glomerular and tubular and apoptosis. DZR restored the oxidant/antioxidant balance via regulating the levels of MDA, SOD, and TAC. DZR reduced DOX-induced collagen IV deposition and renal interstitial fibrosis and downregulated the fibrosis-related protein expressions of vimentin, α-SMA, and TGF-β1. <b><i>Conclusion:</i></b> Our results suggest DZR exerted its protective effects against DOX-induced nephropathy through inhibition of lipid peroxidation, apoptosis, and fibrosis.

<b><i>Background:</i></b> Asperulosidic acid (ASP) is a bioactive iridoid exerting broad pharmacological and medicinal properties. However, it is still unknown if ASP has therapeutical effects on gestational diabetes mellitus (GDM). This study aims to evaluate the effects of ASP on GDM as well as its underlying mechanism. <b><i>Methods:</i></b> A mouse model of GDM was established and orally administrated ASP (10, 20, and 40 mg/kg) on gestation day (GD) 0. The mice were sacrificed on GD 18. <b><i>Results:</i></b> Blood glucose and serum insulin were then determined. The inflammatory cytokines including IL-6 and TNF-α and oxidative stress biomarkers including MDA, SOD, GSH, and GPx were determined by using specific ELISAs. In addition, the expressions of NF-κB and MAPK signaling pathway-related proteins were determined by using Western blotting. Treatment with ASP decreased blood glucose in the mouse model of GDM. Besides, ASP also increased serum insulin and attenuated β-cell function. Treatment with ASP suppressed IL-6 and TNF-α and regulated oxidative stress-related biomarkers. Western blotting analysis showed that treatment with ASP suppressed phosphorylation of NF-κB p65, ERK1/2, and p38 in placental tissues. <b><i>Conclusion:</i></b> ASP alleviates placental oxidative stress and inflammatory responses in GDM by the inhibition of the NF-κB and MAPK signaling pathways.

<b><i>Introduction:</i></b> Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel currents of <i>Ih</i> and absence epilepsy seizures are associated, but studies reveal differential results. <b><i>Objective:</i></b> In our study, we aimed to investigate the role of the HCN channels on the expression of spike-and-wave discharges (SWDs) using the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model. <b><i>Methods:</i></b> HCN isoform levels from isolated brains of both naïve nonepileptic Wistar and GAERS groups were evaluated by enzyme-linked immunosorbent assay. ZD7288, an <i>Ih</i> inhibitor as well as an HCN channel antagonist, was administered intracerebroventricularly to the adult GAERS groups, and to evaluate their SWD activities, electroencephalography was recorded. The effect of ZD7288 on the cumulative total duration and number of SWDs and the mean duration of each SWD complex was evaluated. <b><i>Results:</i></b> The HCN2 levels in the cortex and hippocampus of the GAERS group were lower compared to the naïve nonepileptic Wistar group (<i>p</i> &#x3c; 0.05). ZD7288 increased the number of SWDs at the 20th and 120th min with the highest administered dose of 7 μg (<i>p</i> &#x3c; 0.05). <b><i>Conclusion:</i></b> The <i>Ih</i> inhibitor ZD7288 increased the number of SWDs in a genetic absence epilepsy rat model, although this increase may not be significant due to the inconsistent time-dependent effects. In GAERS, the cortical and hippocampal HCN2 channel levels were significantly lower compared to the control group. Further studies are needed with higher doses of ZD7288 to determine if the effects will increase drastically.

<b><i>Introduction:</i></b> Sodium-glucose cotransporter 2 (SGLT2) inhibitors are increasingly utilized in the treatment of diabetes mellitus as well as therapeutic extra-glycemic effects. However, there are still concerns over complications such as amputation events, given the results from the Canagliflozin Cardiovascular Assessment Study (CANVAS) trial. Hence, we conducted a systematic review and meta-analysis of randomized-controlled trials to investigate the effect of SGLT2 inhibitors on amputation events. <b><i>Methods:</i></b> Four electronic databases (PubMed, Embase, Cochrane, and SCOPUS) were searched on November 21, 2020, for articles published from January 1, 2000, up to November 21, 2020, for studies that examined the effect of SGLT2 inhibitors on amputation events. Random-effect pair-wise meta-analysis for hazard ratios and fixed-effect Peto odds ratio meta-analysis were utilized to summarize the studies. <b><i>Results:</i></b> A total of 15 randomized-controlled trials were included with a combined cohort of 63,716 patients. We demonstrated that there was no significant difference in amputation events across different types of SGLT2 inhibitors, different baseline populations, and different duration of SGLT2 inhibitor use. <b><i>Discussion/Conclusions:</i></b> In this meta-analysis, SGLT2 inhibitors were not associated with a significant difference in amputation events.

<b><i>Introduction:</i></b> Sunitinib, a multi-targeted tyrosine kinase receptor inhibitor used to treat renal-cell carcinoma and gastrointestinal stromal tumor, was recently shown to have a beneficial effect on metabolism in type 2 diabetes (T2D). Endothelial dysfunction is a key factor behind macro- and microvascular complications in T2D. The effect of sunitinib on endothelial function in T2D remains, however, unclear. We therefore tested the hypothesis that sunitinib ameliorates endothelial dysfunction in T2D. <b><i>Methods:</i></b> Sunitinib (2 mg/kg/day, by gavage) was administered to T2D Goto-Kakizaki (GK) rats for 6 weeks, while water was given to GK and Wistar rats as controls. Hemodynamic, inflammatory, and metabolic parameters as well as endothelial function were measured. <b><i>Results:</i></b> Systolic, mean arterial blood pressures, plasma tumor necrosis factor α levels, kidney weight to body weight (BW) ratio, and glucose levels were higher, while BW was lower in GK rats than in Wistar rats. Six-week treatment with sunitinib in GK rats did not affect these parameters but suppressed the increase in glucose levels. Endothelium-dependent relaxations were reduced in both aortas and mesenteric arteries isolated from GK as compared to Wistar rats, which was markedly reversed in both types of arteries from GK rats treated with sunitinib. <b><i>Conclusions:</i></b> This study demonstrates that sunitinib has a glucose-lowering effect and ameliorates endothelial dysfunction in both conduit and resistance arteries of GK rats.

Soluble guanylate cyclase (sGC) plays an important role in nitric oxide (NO)-mediated regulation of vascular tone; however, NO bioavailability is often reduced in diseased blood vessels. Accumulating evidence suggests that a shift of sGC from the NO-sensitive form to the NO-insensitive form could be an underlying cause contributing to this reduction. Herein, we investigated the impact of renovascular hypertension on NO-sensitive and NO-insensitive sGC-mediated relaxation in rat aortas. Renovascular hypertension was induced by partially clipping the left renal artery (2-kidneys, 1-clip; 2K1C) for 10 weeks. Systolic, diastolic, and mean arterial pressures were significantly increased in the 2K1C group when compared with the sham group. In addition, plasma thiobarbituric acid reactive substances and aortic superoxide generation were significantly enhanced in the 2K1C group when compared with those in the sham group. The vasorelaxant response of isolated aortas to the sGC stimulator BAY 41-2272 (NO-sensitive sGC agonist) was comparable between the sham and 2K1C groups. Likewise, the sGC activator BAY 60-2770 (NO-insensitive sGC agonist)-induced relaxation did not differ between the sham and 2K1C groups. In addition, the cGMP mimetic 8-Br-cGMP (protein kinase G agonist) induced similar relaxation in both groups. Furthermore, there were no differences in BAY 41-2272-stimulated and BAY 60-2770-stimulated cGMP generation between the groups. These findings suggest that the balance between NO-sensitive and NO-insensitive forms of sGC is maintained during renovascular hypertension. Therefore, sGC might not be responsible for the reduced NO bioavailability observed during renovascular hypertension.

<b><i>Introduction:</i></b> 5-Aminosalicylic acid (5-ASA) is widely used as a key drug in inflammatory bowel disease. It has been recently reported that 5-ASA induces CD4 + Foxp3 + regulatory T cells (Tregs) in the colon via the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that regulates inflammation. However, the role of 5-ASA as an AhR agonist that induces Tregs in the spleen remains unknown. <b><i>Methods:</i></b> In the present study, we investigated these themes using an AhR-mediated transactivation assay and flow cytometry analysis. The experiments were conducted by using DR-EcoScreen cells and C57BL/6 mice. <b><i>Results:</i></b> The DR-EcoScreen cell-based transactivation assay revealed that 5-ASA acted as a weak AhR agonist at concentrations of ≥300 μM (1.31–1.45-fold), and that a typical AhR agonist, 2,3,7,8-tetrachlorodibenzo-<i>p</i>-dioxin (TCDD), activated AhR at a concentration of 0.1 nM (22.8-fold). In addition, the treatment of mouse splenic cells with 300 μM 5-ASA in a primary culture assay significantly induced CD4+CD25 + Foxp3 + Tregs (control vs. 5-ASA: 9.0% vs. 12.65%, <i>p</i> &#x3c; 0.05), while 0.1 nM TCDD also showed significant induction of Tregs (control vs. TCDD: 9.0% vs. 14.1%, <i>p</i> &#x3c; 0.05). Interestingly, this induction was eliminated by co-treatment with an AhR antagonist, CH-223191. <b><i>Discussion:</i></b> These results suggest that 5-ASA is a weak agonist of AhR and thereby induces Tregs in spleen cells. Our findings may provide useful insights into the mechanism by which 5-ASA regulates inflammation.

<b><i>Background:</i></b> The pathobiology of diabetes and associated complications has been widely researched in various countries, but effective prevention and treatment methods are still insufficient. Diabetes is a metabolic disorder of carbohydrates, fats, and proteins caused by an absence of insulin or insulin resistance, which mediates an increase of oxidative stress, release of inflammatory factors, and macro- or micro-circulation dysfunctions, ultimately developing into diverse complications. <b><i>Summary:</i></b> In the last decade through pathogenesis research, epigenetics has been found to affect metabolic diseases. Particularly, DNA methylation, histone acetylation, and miRNAs promote or inhibit diabetes and complications by regulating the expression of related factors. Curcumin has a wide range of beneficial pharmacological activities, including anti-inflammatory, anti-oxidation, anticancer, anti-diabetes, anti-rheumatism, and increased immunity. <b><i>Key Messages:</i></b> In this review, we discuss the effects of curcumin and analogs on diabetes and associated complications through epigenetics, and we summarize the preclinical and clinical researches for curcumin and its analogs in terms of management of diabetes and associated complications, which may provide an insight into the development of targeted therapy of endocrine diseases.

<b><i>Introduction:</i></b> This study aimed to assess the influence of different doses of tadalafil on coronary flow and oxidative stress in isolated rat hearts. <b><i>Methods:</i></b> The hearts of male Wistar albino rats (<i>n</i> = 48) were retrogradely perfused according to the Langendorff technique at gradually increased constant perfusion pressure (CPP) (40–120 mm Hg). Coronary flow and oxidative stress markers: nitrite oxide (NO) outflow and superoxide anion production in coronary effluent were measured. The experiments were performed during control conditions and in the presence of tadalafil (10, 20, 50, and 200 nM) alone or with Nω-nitro-L-arginine monomethyl ester (L-NAME) (30 μM). <b><i>Results:</i></b> Tadalafil administration significantly increased coronary flow at all CPP values at all administered doses. Tadalafil led to an increase in the NO levels, but a statistically significant NO release increase was found only at the highest dose and highest CPP. Tadalafil did not significantly affect the release of O²⁻. After inhibiting the nitrite oxide synthase system by L-NAME, tadalafil-induced changes in cardiac flow and NO levels were reversed. L-NAME administration had no pronounced effect on the O²⁻ release. <b><i>Conclusion:</i></b> Tadalafil causes changes in the heart vasculature in a dose-dependent manner. It does not lead to a significant increase in the production of superoxide anion radicals.

<b><i>Introduction:</i></b> The study sought to assess the effect of treatment with mineralocorticoid receptor antagonists (MRAs) on long-term prognosis of patients with systolic heart failure (HF) surviving index episodes of ventricular tachyarrhythmias. <b><i>Methods:</i></b> A large retrospective registry was used including consecutive HF patients with left ventricular ejection fraction &#x3c;45% and index episodes of ventricular tachyarrhythmias from 2002 to 2015. The primary endpoint was all-cause mortality at 3 years and secondary endpoints were rehospitalization, as well as the composite endpoint consisting of recurrent ventricular tachyarrhythmias, sudden cardiac death and appropriate implantabe cardioverter defibrillator (ICD) therapies at 3 years. <b><i>Results:</i></b> 748 patients were included, 20% treated with MRA and 80% without. At 3 years, treatment with MRA was not associated with improved all-cause mortality (22% vs. 24%, log-rank <i>p</i> = 0.968; hazard ratio (HR) = 1.008; 95% CI 0.690–1.472; <i>p</i> = 0.968). Accordingly, risk of the composite endpoint (28% vs. 27%; HR = 1.131; 95% CI 0.806–1.589; <i>p</i> = 0.476) and first cardiac rehospitalization (24% vs. 22%; HR = 1.139; 95% CI 0.788–1.648; <i>p</i> = 0.489) were not affected by treatment with MRA. <b><i>Conclusion:</i></b> In patients with ventricular tachyarrhythmias, treatment with MRA was not associated with improved all-cause mortality at 3 years. The therapeutic effect of MRA treatment in patients with ventricular tachyarrhythmias needs to be reinvestigated within further randomized controlled trials.