NLRP3 expression and its predictive role in preserved ejection fraction among non-valvular atrial fibrillation patients.

INTRODUCTION: To investigate the expression and predictive value of NOD-like receptor thermoprotein domain-related protein 3 (NLRP3) in patients with nonvalvular atrial fibrillation (NVAF) with ejection fraction preserved heart failure (HFpEF). METHODS: A retrospective analysis of 121 patients diagnosed with NVAF. According to the occurrence of HFpEF, 81 patients was assigned in the NVAF group and 40 patients in the NVAF/HFpEF group. The levels of NLRP3, B natriuretic peptide (BNP), and interleukin-1ß were determined using enzyme-linked immunosorbent assay (ELISA). Independent predictors for HFpEF in NVAF was determined using logistic regression. The receiver operating characteristic curve (ROC) was used to evaluate the predictive value of each factor. RESULTS: Expression levels of NLRP3, BNP, and IL-1ß in the NVAF/HFpEF group, as well as the H2FPEF score was significantly higher than those in the NVAF group. Pearson analysis showed that NLRP3, BNP, and IL-1ß expression levels in NVAF patients and H2FPEF score was positively correlated (r=0.409, r=0.244, r=0.299, p < 0.001). Multivariate logistic regression analysis showed that NLRP3, BNP, or H2FPEF score can be used as independent factor for predicting the occurrence of HFpEF in NVAF. ROC curves showed that the area under the curve (AUC) of NLRP3, BNP, and H2FPEF score for predicting the occurrence of HFpEF in NVAF patients were 0.856, 0.831 and 0.811, respectively. CONCLUSION: NLRP3 level is elevated in the peripheral blood of NVAF patients with HFpEF and is positively correlated with the H2FPEF score. NLRP3 may serve as a potential predictor of HFpEF in patients with NVAF.

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.

Development of a PBPK model to quantitatively understand absorption and disposition mechanism and support future clinical trials for PB-201.

PB-201 is the second glucokinase activator in the world to enter the phase III clinical trials for the treatment of type 2 diabetes mellitus (T2DM). Combined with the efficacy advantages and the friendly absorption, distribution, metabolism, and excretion characteristics, the indication population of PB-201 will be broad. Because the liver is the primary organ for PB-201 elimination, and the elderly account for 20% of patients with T2DM, it is essential to estimate PB-201 exposure in specific populations to understand the pharmacokinetic characteristics and avoid hypoglycemia. Despite the limited contribution of CYP3A4 to PB-201 metabolism in vivo, the dual effects of nonspecific inhibitors/inducers on PB-201 (substrate for CYP3A4 and CYP2C9 isoenzymes) exposure under fasted and fed states also need to be evaluated to understand potential risks of combination therapy. To grasp the unknown information, the physiologically-based pharmacokinetic (PBPK) model was first developed and the influence of internal and external factors on PB-201 exposure was evaluated. Results are shown that the predictive performance of the mechanistic PBPK model meets the predefined criteria, and can accurately capture the absorption and disposition characteristics. Impaired liver function and age-induced changes in physiological factors may significantly increase the exposure under fasted state by 36%-158% and 48%-82%, respectively. The nonspecific inhibitor (fluconazole) and inducer (rifampicin) may separately increase/decrease PB-201 systemic exposure by 44% and 58% under fasted state, and by 78% and 47% under fed state. Therefore, the influence of internal and external factors on PB-201 exposure deserves attention, and the precision dose can be informed in future clinical studies based on the predicted results.

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.

Heavy Metal Bioaccumulation in Rice from a High Geological Background Area in Guizhou Province, China.

Long-term exposure to high levels of heavy metals can lead to a variety of diseases. In recent years, researchers have paid more attention to mining and smelting areas, industrial areas, and so forth, but they have neglected to report on high geological background areas where heavy metal levels are higher than China's soil environmental quality standard (GB 15618-2018). In our study, an investigation of heavy metals in paddy soil and rice in the high background area of Guizhou Province was carried out, and the factors affecting the absorption and utilization of heavy metals in rice were discussed. A total of 52 paddy soil and rice samples throughout the high geological background of Guizhou, China, were collected, and concentration(s) of arsenic, cadmium, copper, lead, and zinc were analyzed. The arithmetic mean values of paddy soil heavy metals were 19.7 ± 17.1, 0.577 ± 0.690, 40.5 ± 32.8, 35.5 ± 32.0, and 135 ± 128 mg kg-1 for arsenic, cadmium, copper, lead, and zinc, respectively. Most of the heavy metals' contents in the soil were above the soil standard value. The highest content of cadmium was 15.5 times that of the soil standard value. The concentration(s) of arsenic, cadmium, copper, lead, and zinc in rice were 0.09 ± 0.03, 0.01 ± 0.01, 1.57 ± 0.69, 0.002 ± 0.003, and 11.56 ± 2.61 mg kg-1, respectively, which are all lower than those specified by Chinese food safety standards (GB 2762-2017). The results and discussion show that the bioavailability, pH, and soil organic matter are important factors that affect the absorption of heavy metals by rice. According to the consumption of rice in Guizhou Province, the risk of eating rice was considered. The results revealed that the hazard quotient is ranked in the order of copper > zinc > cadmium > arsenic > lead, and there is little risk of eating rice in the high geological background area of Guizhou Province. These findings provide impetus for the revision and improvement of this Chinese soil environmental quality standard.

LiV3O8/Polytriphenylamine Composites with Enhanced Electrochemical Performances as Cathode Materials for Rechargeable Lithium Batteries.

LiV3O8/polytriphenylamine composites are synthesized by a chemical oxidative polymerization process and applied as cathode materials for rechargeable lithium batteries (RLB). The structure, morphology, and electrochemical performances of the composites are characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, galvanostatic discharge/charge tests, and electrochemical impedance spectroscopy. It was found that the polytriphenylamine particles were composited with LiV3O8 nanorods which acted as a protective barrier against the side reaction of LiV3O8, as well as a conductive network to reduce the reaction resistance among the LiV3O8 particles. Among the LiV3O8/polytriphenylamine composites, the 17 wt % LVO/PTPAn composite showed the largest d100 spacing. The electrochemical results showed that the 17 wt % LVO/PTPAn composite maintained a discharge capacity of 271 mAh·g-1 at a current density of 60 mA·g-1, as well as maintaining 236 mAh·g-1 at 240 mA·g-1 after 50 cycles, while the bare LiV3O8 sample retained only 169 and 148 mAh·g-1, respectively. Electrochemical impedance spectra (EIS) results implied that the 17 wt % LVO/PTPAn composite demonstrated a decreased charge transfer resistance and increased Li⁺ ion diffusion ability, therefore manifesting better rate capability and cycling performance compared to the bare LiV3O8 sample.

[Bioaccumulation of Heavy Metals in Twigs and Leaves of Abies fabri at Mount Gongga in China: A Comparison Study Between 1999 and 2014].

The rapid economy growth led to the environmental carrying capacity reaching the maximum level.Given that the time changing trend of heavy metal pollution in the remote forest ecosystems has rarely been reported, we reported the differences of Pb, Hg, Cd, As, Cr, Mn, Cu, Zn and bioaccumulation in twigs and leaves of fir(Abies fabri) between samples collected in 1999 and 2014 at the Mt. Gongga, which was located at eastern Tibet Plateau. Our results suggested that the concentrations of Pb, Hg, As, Cd, Mn and Cu in the samples collected in 1999 were significantly higher than those collected in 2014, while the concentrations of Cr, Zn and Ba in samples collected in 2014 were higher than those collected in 1999. The correlation analysis indicated that concentrations of Pb, Hg, Cr, As, Cd, Mn, Cu, Zn and Ba in leaves were positive correlated to the age of the leaves. In addition, Hg was apt to enrich in leaves while the other metals were prone to enrich in twigs. According to the multiple linear regression result, about 70.6% of Hg in leaves and twigs was from air, while the other heavy metals, including Pb, Cr, As, Cd, Cu, Zn, and Ba, were mainly from soil(42.3%-92.2%). These results suggest that there may be different accumulation mechanisms in forest ecosystems between Hg and the other heavy metals.