Association of air pollution and risk of chronic kidney disease: A systematic review and meta-analysis.

Although epidemiological studies have evaluated the association between ambient air pollution and chronic kidney disease (CKD), the results remain mixed. To clarify the nature of the association, we conducted a comprehensive systematic review and meta-analysis to assess the global relationship between air pollution and CKD. The Web of Science, PubMed, Embase and Cochrane Library databases systematically were searched for studies published up to July 2023 and included 32 studies that met specific criteria. The random effects model was used to derive overall risk estimates for each pollutant. The meta-analysis estimated odds ratio (ORs) of risk for CKD were 1.42 (95% confidence interval [CI]: 1.31-1.54) for each 10 µg/m3 increase in PM2.5 ; 1.20 (95% CI: 1.14-1.26) for each 10 µg/m3 increase in PM10 ; 1.07 (95% CI: 1.05-1.09) for each 10 µg/m3 increase in NO2 ; 1.03 (95% CI: 1.02-1.03) for each 10 µg/m3 increase in NOX ; 1.07 (95% CI: 1.01-1.12) for each 1 ppb increase in SO2 ; 1.03 (95% CI: 1.00-1.05) for each 0.1 ppm increase in CO. Subgroup analysis showed that this effect varied by gender ratio, age, study design, exposure assessment method, and income level. Furthermore, PM2.5 , PM10 , and NO2 had negative effects on CKD even within the World Health Organization-recommended acceptable concentrations. Our results further confirmed the adverse effect of air pollution on the risk of CKD. These findings can contribute to enhance the awareness of the importance of reducing air pollution among public health officials and policymakers.

Autophagy-dependent lysosomal calcium overload and the ATP5B-regulated lysosomes-mitochondria calcium transmission induce liver insulin resistance under perfluorooctane sulfonate exposure.

Perfluorooctane sulfonate (PFOS), an officially listed persistent organic pollutant, is a widely distributed perfluoroalkyl substance. Epidemiological studies have shown that PFOS is intimately linked to the occurrence of insulin resistance (IR). However, the detailed mechanism remains obscure. In previous studies, we found that mitochondrial calcium overload was concerned with hepatic IR induced by PFOS. In this study, we found that PFOS exposure noticeably raised lysosomal calcium in L-02 hepatocytes from 0.5 h. In the PFOS-cultured L-02 cells, inhibiting autophagy alleviated lysosomal calcium overload. Inhibition of mitochondrial calcium uptake aggravated the accumulation of lysosomal calcium, while inhibition of lysosomal calcium outflowing reversed PFOS-induced mitochondrial calcium overload and IR. Transient receptor potential mucolipin 1 (TRPML1), the calcium output channel of lysosomes, interacted with voltage-dependent anion channel 1 (VDAC1), the calcium intake channel of mitochondria, in the PFOS-cultured cells. Moreover, we found that ATP synthase F1 subunit beta (ATP5B) interacted with TRPML1 and VDAC1 in the L-02 cells and the liver of mice under PFOS exposure. Inhibiting ATP5B expression or restraining the ATP5B on the plasma membrane reduced the interplay between TRPML1 and VDAC1, reversed the mitochondrial calcium overload and deteriorated the lysosomal calcium accumulation in the PFOS-cultured cells. Our research unveils the molecular regulation of the calcium crosstalk between lysosomes and mitochondria, and explains PFOS-induced IR in the context of activated autophagy.

Lysosomal iron accumulation and subsequent lysosomes-mitochondria iron transmission mediate PFOS-induced hepatocyte ferroptosis.

Perfluorooctane sulfonate (PFOS) is known as a persistent organic pollutant. A significant correlation between PFOS and liver ferroptosis has been unveiled, but the precise mechanism needs to be elucidated. In prior research, we found that PFOS treatment provoked mitochondrial iron overload. In this study, we observed a gradual increase in lysosomal iron in L-O2 cells after exposure to PFOS for 0.5-24 h. In PFOS-exposed L-O2 cells, suppressing autophagy relieved the lysosomal iron overload. Inhibiting transient receptor potential mucolipin 1 (TRPML1), a calcium efflux channel on the lysosomal membrane, led to a further rise in lysosomal iron levels and decreased mitochondrial iron overload during PFOS treatment. Suppressing VDAC1, a subtype of voltage-dependent anion-selective channels (VDACs) on the outer mitochondrial membrane, had no impact on PFOS-triggered mitochondrial iron overload, whereas restraining VDAC2/3 relieved this condition. Although silencing VDAC2 relieved PFOS-induced mitochondrial iron overload, it had no effect on PFOS-triggered lysosomal iron overload. Silencing VDAC3 alleviated PFOS-mediated mitochondrial iron overload and led to an additional increase in lysosomal iron. Therefore, we regarded VDAC3 as the specific VDACs subtype that mediated the lysosomes-mitochondria iron transfer. Additionally, in the presence of PFOS, an enhanced association between TRPML1 and VDAC3 was found in mice liver tissue and L-O2 cells. Our research unveils a novel regulatory mechanism of autophagy on the iron homeostasis and the effect of TRPML1-VDAC3 interaction on lysosomes-mitochondria iron transfer, giving an explanation of PFOS-induced ferroptosis and shedding some light on the role of classic calcium channels in iron transmission.

The phosphorylation of Smad3 by CaMKIIγ leads to the hepatocyte pyroptosis under perfluorooctane sulfonate exposure.

Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant and accumulated in the liver of mammals. PFOS exposure is closely associated with the development of pyroptosis. Nevertheless, the underlying mechanism is unclear. We found here that PFOS induced pyroptosis in the mice liver and L-02 cells as demonstrated by activation of the NOD-like receptor protein 3 inflammasome, gasdermin D cleavage and increased release of interleukin-1ß and interleukin-18. The level of cytoplasmic calcium was accelerated in hepatocytes upon exposure to PFOS. The phosphorylated/activated form of calcium/calmodulin-dependent protein kinase II (CaMKII) was augmented by PFOS in vivo and in vitro. PFOS-induced pyroptosis was relieved by CaMKII inhibitor. Among various CaMKII subtypes, we identified that CaMKIIγ was activated specifically by PFOS. CaMKIIγ interacted with Smad family member 3 (Smad3) under PFOS exposure. PFOS increased the phosphorylation of Smad3, and CaMKII inhibitor or CaMKIIγ siRNA alleviated PFOS-caused phosphorylation of Smad3. Inhibiting Smad3 activity was found to alleviate PFOS-induced hepatocyte pyroptosis. This study puts forward that CaMKIIγ-Smad3 is the linkage between calcium homeostasis disturbance and pyroptosis, providing a mechanistic explanation for PFOS-induced pyroptosis.

Sodium arsenite induces hepatic stellate cells activation by m6A modification of TGF-ß1 during liver fibrosis.

The compound known as Sodium arsenite (NaAsO2), which is a prevalent type of inorganic arsenic found in the environment, has been strongly associated with liver fibrosis (LF), a key characteristic of nonalcoholic fatty liver disease (NAFLD), which has been demonstrated in our previous study. Our previous research has shown that exposure to NaAsO2 triggers the activation of hepatic stellate cells (HSCs), a crucial event in the development of LF. However, the molecular mechanism is still unknown. N6-methyladenosine (m6A) modification is the most crucial post-transcriptional modification in liver disease. Nevertheless, the precise function of m6A alteration in triggering HSCs and initiating LF caused by NaAsO2 remains unknown. Here, we found that NaAsO2 induced LF and HSCs activation through TGF-ß/Smad signaling, which could be reversed by TGF-ß1 knockdown. Furthermore, NaAsO2 treatment enhanced the m6A modification level both in vivo and in vitro. Significantly, NaAsO2 promoted the specific interaction of METTL14 and IGF2BP2 with TGF-ß1 and enhanced the TGF-ß1 mRNA stability. Notably, NaAsO2-induced TGF-ß/Smad pathway and HSC-t6 cells activation might be avoided by limiting METTL14/IGF2BP2-mediated m6A modification. Our findings showed that the NaAsO2-induced activation of HSCs and LF is made possible by the METTL14/IGF2BP2-mediated m6A methylation of TGF-ß1, which may open up new therapeutic options for LF brought on by environmental hazards.

The VDAC1 oligomerization regulated by ATP5B leads to the NLRP3 inflammasome activation in the liver cells under PFOS exposure.

As a persistent organic pollutant, perfluorooctane sulfonate (PFOS) has a serious detrimental impact on human health. It has been suggested that PFOS is associated with liver inflammation. However, the underlying mechanisms are still unclear. Here, PFOS was found to elevate the oligomerization tendency of voltage-dependent anion channel 1 (VDAC1) in the mice liver and human normal liver cells L-02. Inhibition of VDAC1 oligomerization alleviated PFOS-induced nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome activation. Cytoplasmic membrane VDAC1 translocated to mitochondria was also observed in response to PFOS. Therefore, the oligomerization of VDAC1 occurred mainly in the mitochondria. VDAC1 was found to interact with the ATP synthase beta subunit (ATP5B) under PFOS treatment. Knockdown of ATP5B or immobilization of ATP5B to the cytoplasmic membrane alleviated the increased VDAC1 oligomerization and NLRP3 inflammasome activation. Therefore, our results suggested that PFOS induced NLRP3 inflammasome activation through VDAC1 oligomerization, a process dependent on ATP5B to transfer VDAC1 from the plasma membrane to the mitochondria. The findings offer novel perspectives on the activation of the NLRP3 inflammasome, the regulatory mode on VDAC1 oligomerization, and the mechanism of PFOS toxicity.

Perfluorooctane sulfonate induces ferroptosis-dependent non-alcoholic steatohepatitis via autophagy-MCU-caused mitochondrial calcium overload and MCU-ACSL4 interaction.

The incidence of nonalcoholic steatohepatitis (NASH) is related with perfluorooctane sulfonate (PFOS), yet the mechanism remains ill-defined. Mounting evidence suggests that ferroptosis plays a crucial role in the initiation of NASH. In this study, we used mice and human hepatocytes L-02 to investigate the role of ferroptosis in PFOS-induced NASH and the effect and molecular mechanism of PFOS on liver ferroptosis. We found here that PFOS caused NASH in mice, and lipid accumulation and inflammatory response in the L-02 cells. PFOS induced hepatic ferroptosis in vivo and in vitro, as evidenced by the decrease in glutathione peroxidase 4 (GPX4), and the increases in cytosolic iron, acyl-CoA synthetase long-chain family member 4 (ACSL4) and lipid peroxidation. In the PFOS-treated cells, the increases in the inflammatory factors and lipid contents were reversed by ferroptosis inhibitor. PFOS-induced ferroptosis was relieved by autophagy inhibitor. The expression of mitochondrial calcium uniporter (MCU) was accelerated by PFOS, leading to subsequent mitochondrial calcium accumulation, and inhibiting autophagy reversed the increase in MCU. Inhibiting mitochondrial calcium reversed the variations in GPX4 and cytosolic iron, without influencing the change in ACSL4, induced by PFOS. MCU interacted with ACSL4 and the siRNA against MCU reversed the changes in ACSL4，GPX4 and cytosolic iron systemically. This study put forward the involvement of hepatic ferroptosis in PFOS-induced NASH and identified MCU as the mediator of the autophagy-dependent ferroptosis.

Unraveling Quercetin's Potential: A Comprehensive Review of Its Properties and Mechanisms of Action, in Diabetes and Obesity Complications.

The prevalence of diabetes is escalating alarmingly, placing a significant economic burden on the global healthcare system. The use of chemical substances extracted from plants has been demonstrated to be an effective method for the treatment and control of insulin resistance and Type 2 diabetes mellitus (T2DM). New research indicates that natural phytochemicals present in fruits and vegetables are expected to become drugs for the treatment of diabetes and the prevention of related complications. Quercetin, a widely distributed flavonoid, is well-known for its antioxidant, anti-inflammatory, anticancer, and antidiabetic properties. This article provides a comprehensive account of the mechanism of action of quercetin on diabetes and obesity complications in vivo and in vitro. It elucidates the impact of quercetin on various cells. These include hepatocytes, renal cells, skeletal muscle cells, and adipocytes. Furthermore, this article discusses the mechanism of quercetin on organ damage in diabetic mice induced by STZ, alloxan, diet, and spontaneous Type 2 diabetic mice caused by genetic defects. Additionally, it addresses the pharmacokinetics of quercetin and its potential for synergistic effects with existing diabetic drugs.

AS3MT facilitates NLRP3 inflammasome activation by m6A modification during arsenic-induced hepatic insulin resistance.

N6-methyladenosine (m6A) messenger RNA methylation is the most widespread gene regulatory mechanism affecting liver functions and disorders. However, the relationship between m6A methylation and arsenic-induced hepatic insulin resistance (IR), which is a critical initiating event in arsenic-induced metabolic syndromes such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), remains unclear. Here, we showed that arsenic treatment facilitated methyltransferase-like 14 (METTL14)-mediated m6A methylation, and that METTL14 interference reversed arsenic-impaired hepatic insulin sensitivity. We previously showed that arsenic-induced NOD-like receptor protein 3 (NLRP3) inflammasome activation contributed to hepatic IR. However, the regulatory mechanisms underlying the role of arsenic toward the post-transcriptional modification of NLRP3 remain unclear. Here, we showed that NLRP3 mRNA stability was enhanced by METTL14-mediated m6A methylation during arsenic-induced hepatic IR. Furthermore, we demonstrated that arsenite methyltransferase (AS3MT), an essential enzyme in arsenic metabolic processes, interacted with NLRP3 to activate the inflammasome, thereby contributing to arsenic-induced hepatic IR. Also, AS3MT strengthened the m6A methylase association with NLRP3 to stabilize m6A-modified NLRP3. In summary, we showed that AS3MT-induced m6A modification critically regulated NLRP3 inflammasome activation during arsenic-induced hepatic IR, and we identified a novel post-transcriptional function of AS3MT in promoting arsenicosis.

Novel Insights of Anti-EGFR Therapy in HNSCC: Combined with Immunotherapy or Not?

PURPOSE OF REVIEW: The efficacy of anti-EGFR therapy is still unfavorable in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) patients. Disorder of antitumor immunity and aberrantly expressed checkpoint biomarkers had been validated to involve anti-EGFR therapy tolerance and efficacy. Here we review the immunomodulation of anti-EGFR therapy in the tumor immune microenvironment (TIME) of HNSCC and assist clinicians in finding the potential strategies to rescue anti-EGFR tolerance therapy in the era of immunotherapy for HNSCC. RECENT FINDINGS: Anti-EGFR therapy, especially cetuximab, was validated to induce the innate and adaptive immune responses of HNSCC patients. It is mainly through inducing natural killer (NK) cells mediating antibody-dependent cell-mediated cytotoxicity (ADCC), recruiting multiple tumor-infiltrating immune cells, and finally remodeling the TIME. Moreover, mountains of preclinical models and clinical trials revealed that combining anti-EGFR agents with immunotherapy could enhance the antitumor effectiveness in HNSCC. Anti-EGFR therapy may usher in another dawn in the treatment of patients with HNSCC through combination with immunotherapy. We offer an overview of the ongoing efforts to make out the immunomodulation of the EGFR pathway in both innate and adaptive immune responses; update the constant preclinical models and clinical trials for the combination of anti-EGFR and immunotherapy in HNSCC; and finally evaluate the efficacy and advantages of the combination therapeutic strategies in clinical use.

Mitochondrial iron overload mediated by cooperative transfer of plasma membrane ATP5B and TFR2 to mitochondria triggers hepatic insulin resistance under PFOS exposure.

In general populations, insulin resistance (IR) is related to perfluorooctane sulfonate (PFOS), a persistent organic pollutant. However, the underlying mechanism remains unclear. In this study, PFOS induced mitochondrial iron accumulation in the liver of mice and human hepatocytes L-O2. In the PFOS-treated L-O2 cells, mitochondrial iron overload preceded the occurrence of IR, and pharmacological inhibition of mitochondrial iron relieved PFOS-caused IR. Both transferrin receptor 2 (TFR2) and ATP synthase ß subunit (ATP5B) were redistributed from the plasma membrane to mitochondria with PFOS treatment. Inhibiting the translocation of TFR2 to mitochondria reversed PFOS-induced mitochondrial iron overload and IR. In the PFOS-treated cells, ATP5B interacted with TFR2. Stabilizing ATP5B on the plasma membrane or knockdown of ATP5B disturbed the translocation of TFR2. PFOS inhibited the activity of plasma-membrane ATP synthase (ectopic ATP synthase, e-ATPS), and activating e-ATPS prevented the translocation of ATP5B and TFR2. Consistently, PFOS induced ATP5B/TFR2 interaction and redistribution of ATP5B and TFR2 to mitochondria in the liver of mice. Thus, our results indicated that mitochondrial iron overload induced by collaborative translocation of ATP5B and TFR2 was an up-stream and initiating event for PFOS-related hepatic IR, providing novel understandings of the biological function of e-ATPS, the regulatory mechanism for mitochondrial iron and the mechanism underlying PFOS toxicity.

Mitochondrial dysfunction and endoplasmic reticulum stress induced by activation of PPARα leaded testicular to apoptosis in SD rats explored to di-(2-ethylhexyl) phthalate (DEHP).

Di-2-ethylhexyl phthalate (DEHP), as a common endocrine disrupting chemicals, can induce toxicity to reproductive system. However, the mechanism remains to be explored. In our study, DEHP exposure induced testicular injury in rats. The high throughput transcriptional sequencing was performed to identify differentially expressed genes (DEGs) between the treatment and control groups. KEGG analysis revealed that DEGs were enriched in apoptosis, PPARα, and ER stress pathway. DEHP up-regulated the expression of PPARα, Bax, Bim, caspase-4. GRP78, PERK, p-PERK, eIF2α, p-eIF2α, ATF4 and CHOP. This view has also been confirmed in TM3 and TM4 cells. In vitro, after pre-treatment with GW6471 (an inhibitor of PPARα) or GSK (an inhibitor of PERK), the apoptosis was inhibited and mitochondrial dysfunction was improved. Moreover, the improvement of mitochondrial dysfunction decreased the expression of PERK pathway by using SS-31(a protective agent for mitochondrial function). Interestingly, ER stress promoted the accumulation of ROS by ERO1L (the downstream of CHOP during ER stress), and the ROS further aggravated the ER stress, thus forming a feedback loop during the apoptosis. In this process, a vicious cycle consisting of PERK, eIF2α, ATF4, CHOP, ERO1L, ROS was involved. Taken together, our results suggested that mitochondrial dysfunction and ER stress-ROS feedback loop caused by PPARα activation played a crucial role in DEHP-induced apoptosis. This work provides insight into the mechanism of DEHP-induced reproductive toxicity.

Preliminary experience of permanent left bundle branch area pacing using stylet-directed pacing lead without delivery sheath.

BACKGROUND: Left bundle branch area pacing (LBBAP) aims to capture the cardiac conduction system in area of the left bundle branch. Currently, LBBAP is mainly performed using lumen-less pacing leads (LLLs) with preshaped sheath. However, the data on LBBAP with stylet-driven leads (SDLs) without sheath is limited. OBJECTIVE: This study presents the feasibility, safety, and pacing characteristics of LBBAP using SDLs without the support of sheath. METHODS: A total of 25 patients with bradycardia indications who received LBBAP implantation with an attempt of SDL (FINELINE II 4471 lead, Boston Scientific, MA, US) between August 2020 and April 2021 at Sir Run Run Shaw Hospital were included in this retrospective cohort study. Twenty of them finally were paced with SDL in priority (SDL-LBBAP group). Twenty propensity score matching patients who underwent LBBAP with LLL (Select Secure 3830 lead, Medtronic, MN, US) and 20 right ventricular septal pacing (RVSP) with regular active fixation lead respectively in the same period (the LLL-LBBAP group and RVSP group) were compared using ECG characteristics, pacing parameters and complications during 6-month follow-up. RESULTS: LBBAP was successful with SDL in 23 of 25 patients (92%) and 20 of them were paced with SDL first. In the SDL-LBBAP group, the average age was 70.4 ± 8.2 years, and 55% of patients were male. Paced QRS duration and the stimulus to peak left ventricular activation time (Sti-LVAT) in SDL-LBBAP group were similar with those in LLL-LBBAP group and significantly shorter than those in RVSP group (126.1±14.1 ms vs. 124.8±10.9 ms, p = 1.00; 77.7 ± 11.2 ms vs. 73.5 ± 9.3 ms, P = .75; 126.1 ± 14.1 ms vs. 147.7 ± 22.5 ms, P<.001; 77.7 ± 11.2 ms vs. 97.0 ± 13.2 ms, P<.001). The pacing threshold and R-wave amplitude of SDL-LBBAP group were 0.53 ± 0.18V and 11.53 ± 3.63 mV at baseline respectively, which were comparable with the other two groups. During the 6-month follow-up, the pacing parameters remained stable and no lead-related complications were recorded. CONCLUSION: It is feasible and safe to use stylet-directed pacing lead for permanent LBBAP without a delivery sheath. Similar to LLL, LBBAP using SDL showed stable parameters and narrower paced QRS duration compared with RVSP, which could be an alternative to LLL in LBBAP.

2-undecanone protects against fine particles-induced heart inflammation via modulating Nrf2/HO-1 and NF-κB pathways.

Exposure to air pollution has been closely associated with some cardiovascular disease. One of the mechanisms of PM2.5 -mediated heart injury may be to promote inflammation. We aim to investigate whether the main extract of Houttuynia cordata, 2-undecanone, can prevent the inflammation caused by PM2.5 , and to reveal the underlying mechanisms. The results showed that PM2.5 increased the expression of certain inflammatory cytokines, and caused oxidative damage in BALB/c mice and H9C2 cells. Supplementation with 2-undecanone attenuated this PM2.5 -induced inflammatory injury and oxidative damage. Further, we elucidated that the protective effect of 2-undecanone may be associated with NF-κB and Nrf2/HO-1 pathways. The NF-κB pathway was distinctly activated after treated by PM2.5 , which can be blocked by 2-undecanone, accompanied by increasing Nrf2 and HO-1 levels. To figure out the relationship between NF-κB and Nrf2/HO-1 pathways, we knocked down Nrf2 gene. NF-κB pathway proteins and downstream inflammatory cytokines were significantly increased after treatment with PM2.5 , while 2-undecanone could decrease expression of these proteins. In conclusion, it is possible that 2-undecanone can induce the expression of the antioxidant enzyme HO-1 by activating Nrf2, thereby reducing NF-κB pathway and inflammatory damage of mouse myocardium caused by PM2.5 exposure.

Oncologic feasibility for negative pressure wound therapy application in surgical wounds: A meta-analysis.

Negative pressure wound therapy (NPWT) decreases postoperative complications of various surgeries. However, the use of NPWT for oncological surgical wounds remains controversial. To evaluate the association of NPWT with oncologic recurrence in surgical wounds without residual malignancy, we analysed studies that compared NPWT with conventional non-pressure dressings for cancer surgical wounds without residual tumour by August 12, 2020. We compared tumour recurrence rates and postoperative complications between the two procedures. The six studies included 118 patients who received NPWT, and 149 patients who received conventional non-pressure wound care. The overall quality of the included studies was high based on the Newcastle-Ottawa scale score of 7.5. Tumour recurrence after NPWT was not significantly different compared with conventional non-negative pressure wound care (9.3% versus 11.4%, P = 0.40). There was no significant heterogeneity between the studies (I2  = 3%). Although NTWT was associated with a lower complication rate compared with the control group, the result was non-significant (P = 0.15). Application of NPWT in oncologic resection wounds without residual malignancy revealed no difference in local recurrence and may reduce the risk of postoperative complications compared with conventional non-negative pressure dressings. NPWT can be considered an alternative method for reconstruction in challenging cases.

IRE1α/NOX4 signaling pathway mediates ROS-dependent activation of hepatic stellate cells in NaAsO2 -induced liver fibrosis.

Liver fibrosis is a severe health problem worldwide, and it is characterized by the activation of hepatic stellate cells (HSCs) and excessive deposition of collagen. Prolonged arsenic exposure can induce HSCs activation and liver fibrosis. In the present study, the results showed that chronic NaAsO2 ingestion could result in liver fibrosis and oxidative stress in Sprague-Dawley rats, along with representative collagen deposition and HSCs activation. In addition, the inositol-requiring enzyme 1α (IRE1α)-endoplasmic reticulum (ER)-stress pathway was activated, and the activity of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) was upregulated in rat livers. Simultaneously, the excessive production of reactive oxygen species (ROS) could induce HSCs activation, and NOX4 played an important role in generating ROS in vitro. Moreover, ER stress occurred with HSCs activation at the same time under NaAsO2 exposure, and during ER stress, the IRE1α pathway was responsible for NOX4 activation. Therefore, inhibition of IRE1α activation could attenuate the HSCs activation induced by NaAsO2 . In conclusion, the present study manifested that inorganic arsenic exposure could activate HSCs through IRE1α/NOX4-mediated ROS generation.

Plaque-Type Variant of Acquired Rhabdomyomatous Mesenchymal Hamartoma on the Chin: A Case Series.

ABSTRACT: Rhabdomyomatous mesenchymal hamartoma (RMH) is a rare benign tumor composed of skeletal muscle fibers and other mesenchymal-derived cells. The lesions are generally solitary sessile papules or skin tag lesions that occur during childhood. We retrospectively reviewed patients diagnosed with RMH pathologically between January 2001 and June 2020 at a tertiary medical center. A literature review was conducted. Seven plaque-type RMHs on the chin were found, including 6 in adults and one in a 14-year-old boy. The average age was 45.7 years. The onset of the RMH appearance was between several months and years. Pathologically, all patients showed a scattered haphazard arrangement of skeletal muscle bundles in the dermis and/or subcutis. Subcutis replaced by fibrous tissue and skeletal muscle bundles was present in 2 cases. Some skeletal muscles had a periadnexal distribution. This case series demonstrated a distinct clinical presentation of acquired RMH specifically located on the chin.

NLRP3 inflammasome blocked the glycolytic pathway via targeting to PKLR in arsenic-induced hepatic insulin resistance.

Arsenic exposure is related to insulin resistance (IR). However, the underlying mechanism is still uncertain. NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasome is a key driving factor of IR. We found that NaAsO2 caused hepatic IR, activated NLRP3 inflammasome, and inhibited glycolysis pathway in vivo. We also found that tricarboxylic acid cycle (TCA cycle) was inhibited, and the content of hepatic lactate was upregulated with the treatment of arsenic. Consistent with these findings, we found that NLRP3 inflammasome and glycolysis were involved in the development of IR in L-02 cells. Besides, inhibiting NLRP3 inflammasome upregulated aerobic glycolysis and inhibited anaerobic glycolysis. Moreover, we demonstrated that NLRP3 inflammasome could bind to pyruvate kinase, liver and RBC (PKLR). Simultaneously, insulin signaling rather than NLRP3 inflammasome activation was altered by overexpressing PKLR. In summary, after treatment with NaAsO2, NLRP3 inflammasome blocked the glycolytic pathway via binding to PKLR, which in turn caused hepatic IR. This study shed new light on the molecular mechanism underlying arsenic-induced IR.

Ferroptosis mediated by the interaction between Mfn2 and IREα promotes arsenic-induced nonalcoholic steatohepatitis.

Exposure to arsenic is a risk factor for nonalcoholic steatohepatitis (NASH). Ferroptosis is a form of regulated cell death defined by the accumulation of lipid peroxidation. In the current study, we observed the occurrence of ferroptosis in arsenic-induced NASH by assessing ferroptosis related hallmarks. In vitro, we found that ferrostatin-1 effectively attenuated the executing of ferroptosis and NASH. Simultaneously, the expression of ACSL4 (acyl-CoA synthetase long-chain family member 4) was upregulated in rat's liver and L-02 cells exposed to arsenic. While, suppression of ACSL4 with rosiglitazone or ACSL4 siRNA remarkably alleviated arsenic-induced NASH and ferroptosis through diminishing 5-hydroxyeicosatetraenoic acid (5-HETE) content. Additionally, Mitofusin 2 (Mfn2), a physical tether between endoplasmic reticulum and mitochondria, has rarely been explored in the ferroptosis. Using Mfn2 siRNA or inositol-requiring enzyme 1 alpha (IRE1α) inhibitor, we found NASH and ferroptosis were obviously mitigated through reducing 5-HETE content. Importantly, Co-IP assay indicated that Mfn2 could interact with IRE1α and promoted the production of 5-HETE, ultimately led to ferroptosis and NASH. Collectively, our data showed that ferroptosis is involved in arsenic-induced NASH. These data provide insightful viewpoints into the mechanism of arsenic-induced NASH.

Taurine improves low-level inorganic arsenic-induced insulin resistance by activating PPARγ-mTORC2 signalling and inhibiting hepatic autophagy.

Inorganic arsenic (iAs) is reportedly associated with the increased incidence of type 2 diabetes in the population. Here, we found that iAs exposure significantly decreased the expression of glycolytic genes and glycogen content and increased gluconeogenesis gene levels in C57/BL6J mice. The expression of peroxisome proliferator-activated receptor γ (PPARγ), and mechanistic target of rapamycin complex 2 (mTORC2) were decreased in the livers of iAs-treated mice. Furthermore, in iAs-treated HepG2 cells, we found that PPARγ agonist rosiglitazone (RGS) increased the expression of mTORC2, inhibited autophagy, and improved glucose metabolism. mTORC2 agonist palmitic acid inhibited autophagy and improved glucose metabolism as well as the autophagosome formation inhibitor 3-methyladenine. Taurine, a natural compound, reversed impaired glucose metabolism and decreased expression of PPARγ and mTORC2 induced by iAs in mice liver and HepG2 cells. These data indicated that taurine administration could ameliorate iAs-induced insulin resistance through activating PPARγ-mTORC2 signalling and subsequently inhibiting hepatic autophagy.