Knockdown of NR4A1 alleviates doxorubicin-induced cardiotoxicity through inhibiting the activation of the NLRP3 inflammasome.

Doxorubicin (DOX) is a widely used antitumor drug, but its clinical applicability is hampered by the unfortunate side effect of DOX-induced cardiotoxicity (DIC). In our current study, we retrieved three high-throughput sequencing datasets related to DIC from the Gene Expression Omnibus (GEO) datasets. We conducted differential analysis using R (DESeq2) to pinpoint differentially expressed genes (DEGs, and identified 11 genes that were consistently altered in both the control and DOX-treated groups. Notably, our Random Forest analysis of these three GEO datasets highlighted the significance of nuclear receptor subfamily 4 group A member 1 (NR4A1) in the context of DIC. The DOX-induced mouse model and cell model were used for the in vivo and in vitro studies to reveal the role of NR4A1 in DIC. We found that silencing NR4A1 by adeno-associated virus serotype 9 (AAV9) contained shRNA in vivo alleviated the DOX-induced cardiac dysfunction, cardiomyocyte injury and fibrosis. Mechanistically, we found NR4A1 silencing was able to inhibit DOX-induced the cleavage of NLRP3, IL-1ß and GSDMD in vivo. Further in vitro studies have shown that inhibition of NR4A1 suppressed DOX-induced cytotoxicity and oxidative stress through the same molecular mechanism. We prove that NR4A1 plays a critical role in DOX-induced cardiotoxicity by inducing pyroptosis via activation of the NLRP3 inflammasome, and it might be a promising therapeutic target for DIC.

Efficacy of High-Voltage Pulsed Radiofrequency in Zoster-Associated Pain: A Meta-Analysis and Systematic Review.

Background: Zoster-associated pain (ZAP) is often refractory to conventional treatments and can seriously affect patients' physical and mental health. High-voltage pulsed radio frequency (H-PRF) is a new method for treating ZAP with pulse voltages above 60 V or even up to 100 V. The purpose of this paper was to conduct a systematic review and meta-analysis to evaluate the efficacy of H-PRF in the management of ZAP. Methods: PubMed, Embase, and the Cochrane library were searched from their inception to June 2022 to identify controlled trials which evaluated the effectiveness of H-PRF compared with standard PRF and sham operations. The primary outcome was pain scores at different treatment times. The secondary outcomes included SF-36 scores, rescue analgesic dose, and side effects. Results: We reviewed 6 randomized controlled trials involving 428 patients. There was no significant difference between the H-PRF and standard PRF pain scores at 1 week after surgery and the sham operation group at 1 month. At 1, 3, and 6 months, the H-PRF group had better pain score than the standard PRF group, and at 3 months, the pain score was better than the sham operation group. The H-PRF group showed improvement in the SF-36 score, and there were no significant complications in the H-PRF group. Conclusions: H-PRF is an effective and safe treatment method that has better effects in relieving pain and improving the quality of life and physical and mental health. Although H-PRF provides pain relief rates comparable to those of the control group in the early stages, it remains the preferred and alternative treatment for relieving herpes zoster-related pain.

Discovery of 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as potent and selective CDK9 inhibitors that enable transient target engagement for the treatment of hematologic malignancies.

Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and a potential therapeutic target in hematologic malignancies. Selective and transient CDK9 inhibition reduces Mcl-1 expression and induces apoptosis in Mcl-1-dependent tumor cells for survival. Here, we describe our efforts to discover a novel series of 2H-benzo[b][1,4]oxazin-3(4H)-one as CDK9 inhibitors. Compound 32k was identified as a selective CDK9 inhibitor with short pharmacokinetic and physicochemical properties suitable for intravenous administration. Short-term treatment with 32k resulted in a rapid dose-dependent decrease in cellular p-Ser2-RNAPII, Mcl-1 and c-Myc, leading to apoptosis in the MV4-11 cell line. Correspondingly, significant in vivo antitumor efficacy was observed in xenograft models derived from multiple hematological tumors with intermittent 32k dosing. These results provide evidence that selective transient CDK9 inhibitors could be used for the treatment of hematologic malignancies.

Rational Engineering of the Nonheme Iron- and 2-Oxoglutarate-Dependent Oxygenase SptF.

The Fe- and 2-oxoglutarate-dependent oxygenase SptF is a promising powerful biocatalys with unusual catalytic versatility and promiscuity. The site-specific random substitution of N150, I63, and N65, which are involved in substrate interactions, generated three compounds that were not produced by the SptF wild type. The substrate binding mode was dramatically altered by the introduction of only one or two substitutions. These results provide insights into the engineering of Fe- and 2-oxoglutarate-dependent oxygenases for chemoenzymatic syntheses of bioactive compounds.

Evaluation of Left Ventricular Systolic Function in Patients with Coronary Microvascular Dysfunction by Three-Dimensional Speckle-Tracking Imaging.

INTRODUCTION: The objective of this study is to evaluate the left ventricular systolic function of patients with coronary microvascular dysfunction (CMD) using the three-dimensional speckle-tracking imaging (3D-STI) technique. METHODS: From June 2018 to June 2019,72 subjects from Huzhou Central Hospital were enrolled, including 42 CMD in-patients with typical chest pain or chest tightness and positive treadmill exercise stress test, but without coronary stenosis on coronary angiography, (the CMD group) and another 30 healthy individuals who were undergoing physical examinations in an outpatient clinic (the control group). Using 3D-STI technique, the global longitudinal strain (GLS), global radial strain (GRS), global circumferential strain (GCS), global area strain (GAS), and left ventricle were measured. RESULTS: Compared with the control group, GLS and GAS were significantly reduced in the CMD group (P<0.05), while GRS and GCS were similar in both groups (P>0.05). Univariate logistic regression analysis showed that GLS and GAS were the influencing factors of CMD. For the diagnosis of CMD, the area under the receiver operating characteristic (ROC) curve of GLS was 0.883, and the area under the ROC curve of GAS was 0.875. GAS of -29.3% (log-rank test chi-square=34.245, P<0.001) was a strong predictor of major adverse cardiac events. CONCLUSION: 3D-STI technique has obvious advantages in the evaluation of the left ventricular systolic function for CMD patients. Moreover, 3D-STI parameters, especially GLS and GAS, can detect the early abnormal changes in the ischaemic myocardium. Being timelier and more sensitive than echocardiography, 3D-STI should be recommended for clinical application.

Unraveling prevalence and public health risks of arsenic, uranium and co-occurring trace metals in groundwater along riverine ecosystem in Sindh and Punjab, Pakistan.

The current study focuses on the understanding of contamination status, distribution, source apportionment and health perspectives of arsenic (As), uranium (U) and other co-occurring trace metals in the groundwater samples collected along the major rivers in Sindh and Punjab provinces, Pakistan. ICP-MS analysis revealed that the concentrations of As in the groundwater in Sindh and Punjab ranged from 0.2 to 81.1 µg/L (n = 38) and 1.1 to 501.1 µg/L (n = 110), respectively. Importantly, this study is the first evidence of U contamination in the groundwater samples in Pakistan, which revealed the concentrations of U at from 0.8 to 59.0 and 0.1 to 556.0 µg/L respectively, in Sindh and Punjab. Moreover, the concentrations of Sr and Mn exceeded the WHO limits in the current study area. Anthropogenic activities such as urbanization, direct dispose of industrial, agricultural waste into waterways and extensive use of pesticides and fertilizers might be the main sources of elevated levels of total dissolved solids and electrical conductivity, which increased the mobilization of As, U and Sr in the groundwater samples. Human health risk assessment parameters such as average daily dose, hazard quotient (HQ) and cancer risk indicated severe risks of As and U in the study area. The HQ values of As and U in Punjab were observed at 69.6 and 7.7, respectively, implying the severity of the health risks associated with consumption of contaminated groundwater for drinking purposes. In a nutshell, proactive control and rehabilitation measures are recommended to eradicate trace metals associated groundwater contamination in the targeted areas to avoid future worst scenarios.