Assessing the contribution of global wildfire biomass burning to BaP contamination in the Arctic.

Polycyclic aromatic hydrocarbons (PAHs) have become cause for growing concern in the Arctic ecosystems, partly due to their stable levels despite global emission reduction. Wildfire is considered one of the primary sources that influence PAH levels and trends in the Arctic, but quantitative investigations of this influence are still lacking. This study estimates the global emissions of benzo[a]pyrene (BaP), a congener of PAHs with high carcinogenicity, from forest and grassland fires from 2001 to 2020 and simulates the contributions of wildfire-induced BaP emissions from different source regions to BaP contamination in the Arctic. We find that global wildfires contributed 29.3% to annual averaging BaP concentrations in the Arctic from 2001 to 2020. Additionally, we show that wildfires contributed significantly to BaP concentrations in the Arctic after 2011, enhancing it from 10.1% in 2011 to 83.9% in 2020. Our results reveal that wildfires accounted for 94.2% and 50.8% of BaP levels in the Asian Arctic during boreal summer and autumn, respectively, and 74.2% and 14.5% in the North American Arctic for the same seasons. The source-tagging approach identified that local wildfire biomass emissions were the largest source of BaP in the Arctic, accounting for 65.7% of its concentration, followed by those of Northern Asia (17.8%) and Northern North America (13.7%). Our findings anticipate wildfires to play a larger role in Arctic PAH contaminations alongside continually decreasing anthropogenic emissions and climate warming in the future.

Effect and mechanism of safranal on ISO-induced myocardial injury based on network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Sympathetic hyperactivation is a significant risk factor in the development of cardiovascular disease. Safranal has shown good myocardial protection in recent studies, but the mechanism of its role in myocardial injury caused by sympathetic hyperactivation remains unclear. AIM OF THE STUDY: The purpose of this study was to investigate whether safranal can effectively reduce isoproterenol (ISO)-induced myocardial injury in rats and H9c2 cells and to reveal its pharmacological action and target in inhibiting myocardial injury caused by sympathetic hyperactivation. MATERIALS AND METHODS: This study was carried out using network pharmacology, molecular docking, and in vitro and in vivo experiments. An in vivo model of myocardial injury was established by subcutaneous injection of ISO, and an in vitro model of H9c2 cell injury was induced by ISO. RESULTS: Safranal ameliorated myocardial injury caused by sympathetic hyperactivation by reducing the level of myocardial apoptosis. According to the results of network pharmacological analysis and molecular docking, the mechanism by which safranal alleviates myocardial injury may be closely related to the TNF signaling pathway, and safranal plays a role by regulating the core targets of the TNF signaling pathway. Safranal significantly inhibited the protein expression of TNF, PTGS2, MMP9 and pRELA. CONCLUSION: Safranal plays a protective role in myocardial injury induced by sympathetic hyperactivation by downregulating the TNF signaling pathway.

[Connexin 43 (Cx43) inhibits autophagy of rat thoracic aortic smooth muscle cells induced by ox-LDL].

Objective To investigate the role of connexin 43 (Cx43) in the autophagy of rat thoracic aortic vascular smooth muscle cells (VSMCs) induced by oxidized low-density lipoprotein (ox-LDL). Methods The primary VSMCs were identified by immunofluorescence cytochemical staining of α-smooth muscle actin (α-SMA). After ox-LDL treatment, the foam cells were identified by oil red O staining; the expression of microtubule associated protein 1 light chain 3 (LC3) protein in VSMCs treated with 0, 40, 80, 160 µg/mL ox-LDL for 0, 6, 12, 24 hours and the expression of Cx43 protein treated with 80 µg/mL ox-LDL for 24 hours were detected by Western blotting. VSMCs were randomly divided into control group, ox-LDL group, and ox-LDL combined with Cx43 specific antagonist Gap26 group to detect the expressions of LC3 and beclin 1 by Western blotting. Results The positive rate of α-SMA in the isolated cells was more than 95%. The oil red O positive cells in ox-LDL treated cells significantly increased, ox-LDL decreased the ratio of LC3II/LC3I and the expression of beclin 1 protein in a concentration- and time-dependent manner, and the expression of Cx43 protein was significantly increased. After administration of Gap26, the ratio of LC3II/LC3I and the expression of beclin 1 protein were up-regulated. Conclusion Cx43 inhibits autophagy of VSMCs induced by ox-LDL. Cx43 inhibits ox-LDL induced autophagy.

Assessing Safety of Market-Sold Fresh Fish: Tracking Fish Origins and Toxic Chemical Origins.

Increasing global and domestic food trade and required logistics create uncertainties in food safety inspection due to uncertainties in food origins and extensive trade activities. Modern blockchain techniques have been developed to inform consumers of food origins but do not provide food safety information in many cases. A novel food safety tracking and modeling framework for quantifying toxic chemical levels in the food and the food origins was developed. By integrating chemicals' multimedia environment exchange, food web, and source tracking systems, the framework was implemented to identify short-chain chlorinated paraffin (SCCP) contamination of fresh hairtail fish sold by a Walmart supermarket in Xi'an, northwestern China, and sourced in Eastern China Sea coastal waters. The framework was shown to successfully predict SCCP level with a mean of 17.8 ng g-1 in Walmart-sold hairtails, which was comparable to lab-analyzed 21.9 ng g-1 in Walmart-sold hairtails. The framework provides an alternative and cost-effective approach for safe food inspection compared to traditional food safety inspection techniques. These encouraging results suggest that the approach and rationale reported here could add additional information to the food origin tracking system to enhance transparency and consumers' confidence in the traded food they consumed.

α1 -Adrenoceptors activate the NLRP3 inflammasome through downregulation of Kir2.1 in cardiac inflammation.

NEW FINDINGS: What is the central question of this study? What is the mechanism of cardiac inflammation induced by α1 -adrenoceptor stimulation by NLRP3 inflammasome activation? What is the main finding and its importance? In the mechanism of cardiac inflammation induced by α1 -adrenoceptor overactivation, Kir2.1 exerts cardioprotective and anti-inflammatory effects by inhibiting the activation of the NLRP3 inflammasome. ABSTRACT: Overstimulation of sympathetic nerves in cardiovascular diseases can lead to impaired cardiomyocyte function and potential heart failure, which activates not only the ß-adrenoceptors but also the α1 -adrenoceptors (α1 -AR). A previous report indicated that NLRP3 inflammasome activation is involved in cardiac inflammation induced by the α1 -AR agonist phenylephrine (PE), but the mechanism is still unknown. Here, we aimed to study whether Kir2.1 is involved in cardiac inflammation caused by PE. The results from in vitro experiments showed that PE upregulated the expression levels of NLRP3, caspase-1, interleukin (IL)-18 and IL-1ß and downregulated the expression level of Kir2.1 in H9C2 cells. The Kir2.1 agonist zacopride downregulated the expression of NLRP3, caspase-1, IL-1ß and IL-18, and the Kir2.1 inhibitor ML133 upregulated their expression. To further explore the mechanism, we found that zacopride downregulated the protein expression level of p-p65 and that ML133 upregulated it. Moreover, the nuclear factor-κB (NF-κB) signalling pathway inhibitor curcumenol reversed the expression of NLRP3 inflammasomes caused by PE in H9C2 cells. In in vivo experiments, the protein expression level of Kir2.1 in the PE group was significantly decreased, and the activation of Kir2.1 by zacopride reduced cardiac inflammation. In short, Kir2.1 is involved in α1 -AR overactivation, which induces cardiac inflammation, through the NF-κB signalling pathway, and activating Kir2.1 can downregulate NLRP3 inflammation and exert cardioprotective effects induced by zacopride.

Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway.

Background: Oxidized low-density lipoproteins (ox-LDL) may induce foam cell formation from the vascular smooth muscle cell (VSMC) by inhibiting VSMC autophagy. This process accelerates the formation of atherosclerosis (AS). Connexin 43 (Cx43), which is the most widely distributed connexin in VSMC is associated with autophagy. However, the mechanism of action and the involvement of Cx43 in ox-LDL-inhibited VSMC autophagy remain unclear. Methods: The primary VSMC were obtained and identified, before primary VSMC were pretreated with an inhibitor (Cx43-specific inhibitor Gap26 and PI3K inhibitor LY294002) and stimulated with ox-LDL. Results: Ox-LDL not only inhibited autophagy in VSMC via downregulation of autophagy-related proteins (such as Beclin 1, LC3B, p62), but also increased Cx43 protein levels. Then we added Gap26 to VSMC in the ox-LDL+Gap26 group, in which autophagy-related proteins were increased and the accumulation of lipid droplets was reduced. These result suggested that an enhanced level of autophagy and an alleviation of lipid accumulation might be caused by inhibiting Cx43 in VSMC. The phosphorylation levels of PI3K, AKT, mTOR were increased by ox-LDL, thus down-regulating autophagy-related proteins. However, this situation was partially reversed by the Gap26. Moreover, Cx43 expression were decreased by LY294002 in ox-LDL-induced VSMCs. Conclusion: Inhibiting Cx43 may activate VSMC autophagy to inhibit foam cell formation by inhibiting the PI3K/AKT/mTOR signaling pathway.

Adiponectin Attenuates Lipopolysaccharide-induced Apoptosis by Regulating the Cx43/PI3K/AKT Pathway.

Cardiomyocyte apoptosis is a crucial factor leading to myocardial dysfunction. Adiponectin (APN) has a cardiomyocyte-protective impact. Studies have shown that the connexin43 (Cx43) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathways play an important role in the heart, but whether APN plays a protective role by regulating these pathways is unclear. Our study aimed to confirm whether APN protects against lipopolysaccharide (LPS)-induced cardiomyocyte apoptosis and to explore whether it plays an important role through regulating the Cx43 and PI3K/AKT signaling pathways. In addition, our research aimed to explore the relationship between the Cx43 and PI3K/AKT signaling pathways. In vitro experiments: Before H9c2 cells were treated with LPS for 24 h, they were pre-treated with APN for 2 h. The cytotoxic effect of APN on H9c2 cells was evaluated by a CCK-8 assay. The protein levels of Bax, Bcl2, cleaved caspase-3, cleaved caspase-9, Cx43, PI3K, p-PI3K, AKT and p-AKT were evaluated by Western blot analysis, and the apoptosis rate was evaluated by flow cytometry. APN attenuated the cytotoxicity induced by LPS. LPS upregulated Bax, cleaved caspase-3 and cleaved caspase-9 and downregulated Bcl2 in H9c2 cells; however, these effects were attenuated by APN. In addition, LPS upregulated Cx43 expression, and APN downregulated Cx43 expression and activated the PI3K/AKT signaling pathway. LPS induced apoptosis and inhibited PI3K/AKT signaling pathway in H9c2 cells, and these effects were attenuated by Gap26 (a Cx43 inhibitor). Moreover, the preservation of APN expression was reversed by LY294002 (a PI3K/AKT signaling pathway inhibitor). In vivo experiments: In C57BL/6J mice, a sepsis model was established by intraperitoneal injection of LPS, and APN was injected into enterocoelia. The protein levels of Bax, Bcl2, cleaved caspase-3, and Cx43 were evaluated by Western blot analysis, and immunohistochemistry was used to detect Cx43 expression and localization in myocardial tissue. LPS upregulated Bax and cleaved caspase-3 and downregulated Bcl2 in sepsis; however, these effects were attenuated by APN. In addition, the expression of Cx43 was upregulated in septic myocardial tissue, and APN downregulated Cx43 expression in septic myocardial tissue. In conclusion, both in vitro and in vivo, the data demonstrated that APN can protect against LPS-induced apoptosis during sepsis by modifying the Cx43 and PI3K/AKT signaling pathways.

Carbenoxolone decreases monocrotaline­induced pulmonary inflammation and pulmonary arteriolar remodeling in rats by decreasing the expression of connexins in T lymphocytes.

The adaptive immune response mediated by T lymphocytes is a well­established factor in the pathogenesis of pulmonary inflammation. Changes in the expression of various connexins (Cxs) or disruption of connexin­mediated cellular communication in T lymphocytes contribute to inflammation or tissue remodeling. The aim of the present study was to investigate the potential therapeutic value of blocking Cxs in a monocrotaline (MCT)­induced pulmonary inflammation rat model. Carbenoxolone (CBX) was used to inhibit connexin­mediated cellular communication. An MCT rat model was established by intraperitoneal (i.p.) injection of a single dose of MCT (60 mg/kg), and CBX treatment (20 µg/kg/day, i.p.) was initiated on the day following MCT treatment for 28 days. Vehicle­treated male Sprague­Dawley rats were used as the negative control. The MCT rat model was evaluated by measuring the pulmonary artery flow acceleration time and right ventricular hypertrophy index (RVHI). Histopathological features of the lung tissues and pulmonary arteriolar remodeling were assessed. The proportions of T lymphocyte subtypes, Cx40/cx43 expression in the T cell subtypes and the cytokine levels in the plasma and the lung tissues were also analyzed. Pharmacological inhibition of Cxs using CBX attenuated MCT­induced right ventricular hypertrophy, pulmonary arteriolar remodeling, lung fibrosis and inflammatory cell infiltration by decreasing the RVHI, pulmonary arterial wall thickening, collagen deposition and pro­inflammatory cytokines production as well as CD3+ and CD4+ T cell accumulation in lung tissues of MCT­treated rats. Furthermore, flow cytometry analysis revealed that CBX may inhibit MCT­induced Cx40 and Cx43 expression in CD4+ and CD8+ T lymphocytes in lung tissues. The present study provides evidence that pharmacological inhibition of Cxs may attenuate MCT­induced pulmonary arteriolar remodeling and pulmonary inflammatory response, at least in part, by decreasing Cx expression. The results highlight the critical role of Cxs in T lymphocytes in the MCT­induced pulmonary inflammatory response and that targeting of Cxs may be a potential therapeutic method for treating pulmonary inflammatory diseases.