The role and mechanism of VDAC1 in type 2 diabetes: An underestimated target of environmental pollutants.

Type 2 diabetes (T2D) is a chronic metabolic disease that accounts for more than 90% of diabetic patients. Its main feature is hyperglycemia due to insulin resistance or insulin deficiency. With changes in diet and lifestyle habits, the incidence of T2D in adolescents has burst in recent decades. The deterioration in the exposure to the environmental pollutants further aggravates the prevalence of T2D, and consequently, it imposes a significant economic burden. Therefore, early prevention and symptomatic treatment are essential to prevent diabetic complications. Mitochondrial number and electron transport chain activity are decreased in the patients with T2D. Voltage-Dependent Anion Channel 1 (VDAC1), as a crucial channel protein on the outer membrane of mitochondria, regulates signal transduction between mitochondria and other cellular components, participating in various biological processes. When VDAC1 exists in oligomeric form, it additionally facilitates the entry and exit of macromolecules into and from mitochondria, modulating insulin secretion. We summarize and highlight the interplay between VDAC1 and T2D, especially in the environmental pollutants-related T2D, shed light on the potential therapeutic implications of targeting VDAC1 monomers and oligomers, providing a new possible target for the treatment of T2D.

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.

Curcumin inhibits PAT-induced renal ferroptosis via the p62/Keap1/Nrf2 signalling pathway.

Patulin (PAT), the most common mycotoxin, is widespread in foods and beverages which poses a serious food safety issue to human health. Our previous research confirmed that exposure to PAT can lead to acute kidney injury (AKI). Curcumin is the most abundant active ingredient in turmeric rhizome with various biological activities. The aim of this study is to investigate whether curcumin can prevent the renal injury caused by PAT, and to explore potential mechanisms. In vivo, supplementation with curcumin attenuated PAT-induced ferroptosis. Mechanically, curcumin inhibited autophagy, led to the accumulation of p62 and its interaction with Keap1, promoted the nuclear translocation of nuclear factor E2 related factor 2 (Nrf2), and increased the expression of antioxidant stress factors in the process of ferroptosis. These results have also been confirmed in HKC cell experiments. Furthermore, knockdown of Nrf2 in HKC cells abrogated the protective effect of curcumin on ferroptosis. In conclusion, we confirmed that curcumin mitigated PAT-induced AKI by inhibiting ferroptosis via activation of the p62/Keap1/Nrf2 pathway. This study provides new potential targets and ideas for the prevention and treatment of PAT.

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.

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.

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.

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.

Systematic review and metanalysis of neutrophil to lymphocyte ratio and prognosis in patients with nasopharyngeal carcinoma.

Background: Hematological parameters have been associated with prognosis in patients with nasopharyngeal carcinoma (NPC). The present meta-analysis investigated the utility of neutrophil-lymphocyte ratio (NLR) in the prognosis of patients with NPC. Methods: Multiple electronic databases, including PubMed, Embase, the Cochrane Library, and the Web of Science, were systematically searched for studies assessing the association between NLR and NPC from 2011 to 2021. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were utilized to estimate effect size. Use of a fixed effect or random effect model was based on heterogeneity stability was tested by sensitivity analysis, and the risk of bias was assessed by funnel plots. Random effects models were used based on the actual results. Because the NLR grouping criteria for the included studies differed, subgroup analyses were performed. Results: A search of the electronic databases identified 14 studies, encompassing 6693 patients, that met the selection criteria. NLR higher than the cutoff value was significantly associated with poorer OS [HR 1.760, 95% CI 1.470-2.120, p <0.00001] and PFS [HR 1.850, 95% CI 1.430-2.390, p = .006]. Sensitivity analysis showed that the results of the meta-analysis were relatively stable, and funnel plots were used to exclude the risk of bias. Conclusions: Elevated pretreatment NLR in peripheral blood is predictive of poorer OS and PFS in patients with NPC. NLR is an easily measured and important prognostic factor in patients with NPC.

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.

m6A methylation-mediated PGC-1α contributes to ferroptosis via regulating GSTK1 in arsenic-induced hepatic insulin resistance.

Arsenic exposure has been closely linked to hepatic insulin resistance (IR) and ferroptosis with the mechanism elusive. Peroxisome proliferator γ-activated receptor coactivator 1-α (PGC-1α) is essential for glucose metabolism as well as for the production of reactive oxygen species (ROS). However, it was unclear whether there is a regulatory connection between PGC-1α and ferroptosis. Besides, the definitive mechanism of arsenic-induced hepatic IR progression remains to be determined. Here, we found that hepatic insulin sensitivity impaired by sodium arsenite (NaAsO2) could be reversed by inhibiting ferroptosis. Mechanistically, we found that PGC-1α suppression inhibited the protein expression of glutathione s-transferase kappa 1 (GSTK1) via nuclear respiratory factor 1 (NRF1), thereby increasing ROS accumulation and promoting ferroptosis. Furthermore, we showed that NaAsO2 induced hepatic IR and ferroptosis via methyltransferase-like 14 (METTL14) and YTH domain-containing family protein 2 (YTHDF2)-mediated N6-methyladenosine (m6A) of PGC-1α mRNA. In conclusion, NaAsO2-mediated PGC-1α suppression was m6A methylation-dependent and induced ferroptosis via the PGC-1α/NRF1/GSTK1 pathway in hepatic IR. The data might provide insight into potential targets for diabetes prevention and treatment.

Filamin A facilitates NLRP3 inflammasome activation during arsenic-induced nonalcoholic steatohepatitis.

Prolonged exposure to arsenic can cause nonalcoholic steatohepatitis (NASH). The NOD-like receptor protein 3 (NLRP3) inflammasome plays an essential role in the process of NASH. However, the mechanism by which arsenic promotes NLRP3 expression remains unclear. Three-month NaAsO2 gavage led to the nuclear factor-κB (NF-κB) signaling pathway activation and NASH. Additionally, NaAsO2 upregulated the level of Filamin A (FLNA) and pyroptosis, thereby activating the NLRP3 inflammasome in SD rat liver. Using FLNA siRNA, NASH-associated inflammation and pyroptosis were clearly mitigated by reducing activation of the NLRP3 inflammasome. Furthermore, arsenic treatment facilitated activation of the NF-κB signaling pathway and promoted p-p65 translocation into the nucleus. Chromatin immunoprecipitation (Ch-IP) assay indicated that FLNA promoted p65 binding to the NLRP3 gene and upregulated the transcription of NLRP3, ultimately leading to pyroptosis and NASH. Our findings indicate that FLNA and pyroptosis are strongly associated with NASH induced by NaAsO2. Collectively, the findings of this study indicated that FLNA mediates NF-κB signaling pathway-induced activation of the NLRP3 inflammasome and ultimately activates pyroptosis and NASH upon NaAsO2 exposure. This information may be useful for improving therapeutic strategies against arsenic-induced NASH.

Insights into the role of N6-methyladenosine in ferroptosis.

N6-methyladenosine (m6A) methylation modification is one of the most prevalent epigenetic modifications of eukaryotic RNA. m6A methylation is widely associated with many biological processes through the modification of RNA metabolism and is associated with multiple disease states. As a newly discovered regulatory cell death in recent years, ferroptosis is an iron-dependent cell death characterized by excessive lipid peroxidation. Emerging evidence supports that ferroptosis has a significant role in the progression of diverse diseases. Besides, the key regulators of ferroptosis exhibit aberrant m6A levels under different pathological conditions. However, the correlation between m6A-modified ferroptosis and multiple diseases has not been well elucidated. In this review, we summarized the functions of m6A in ferroptosis, which are associated with the initiation and progression of multiple diseases. Investigating the role of m6A in ferroptosis might both facilitate a better understanding of the pathogenesis of these diseases and provide new opportunities for targeted treatment.

Ferritinophagy activation and sideroflexin1-dependent mitochondrial iron overload contribute to patulin-induced cardiac inflammation and fibrosis.

Patulin (PAT) is a mycotoxin that is commonly present throughout the ecosystem where fungi grow and mainly contaminates food, soil, and water. PAT was found to be cardiotoxic in previous studies. However, the detailed mechanism has not been fully elucidated. The present study aimed to explore the role and underlying mechanism of ferroptosis in PAT-induced cardiac injury. Here, we confirmed in vivo and in vitro that ferroptosis is involved in PAT-induced myocardial inflammation and fibrosis. Mice exposed to PAT (1 and 2 mg/kg body weight/day for 14 days) exhibited myocardial inflammation and fibrosis along with disrupted iron homeostasis, elevated lipid peroxidation, depletion of glutathione peroxidase 4, and abnormal mitochondrial morphology. When primary neonatal rat cardiomyocytes (NRCMs) and H9c2 cells were exposed to PAT, ferroptosis was initiated in a dose-dependent manner, and this process could be significantly attenuated by ferrostatin-1. Mechanistically, we found that nuclear receptor coactivator (NCOA) 4, a master regulator of ferritinophagy, bound to and degraded ferritin in response to PAT treatment, thereby releasing large amounts of ferrous iron and further leading to sideroflexin (SFXN) 1-dependent mitochondrial iron overload. Conversely, knockdown of NCOA4 or SFXN1 with small interfering RNAs could effectively ameliorate ferroptotic cell death, cellular or mitochondrial iron overload and lipid peroxides accumulation. Furthermore, myocardial inflammation and fibrosis in PAT-exposed mice was alleviated by the mitochondrial iron chelator deferiprone. Overall, our findings underscore that ferritinophagy activation and SFXN1-dependent mitochondrial iron overload play critical roles in PAT-induced myocardial ferroptosis and consequent cardiotoxicity.

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.

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.

The role of iron metabolism in chronic diseases related to obesity.

Obesity is one of the major public health problems threatening the world, as well as a potential risk factor for chronic metabolic diseases. There is growing evidence that iron metabolism is altered in obese people, however, the highly refined regulation of iron metabolism in obesity and obesity-related complications is still being investigated. Iron accumulation can affect the body's sensitivity to insulin, Type 2 diabetes, liver disease and cardiovascular disease. This review summarized the changes and potential mechanisms of iron metabolism in several chronic diseases related to obesity, providing new clues for future research.

Predisposed obesity and long-term metabolic diseases from maternal exposure to fine particulate matter (PM2.5) - A review of its effect and potential mechanisms.

Ambient air pollution is one of the most serious public health problems over the last decade. It causes about 4.2 million deaths worldwide each year, and fine particulate matter (PM2.5) is one of the major components of air pollution. Many chronic non-communicable diseases may originate from the early-life environment that alters the development of offspring. Pregnancy and lactation are plastic "window periods" for offspring metabolism, during which PM2.5 exposure is associated with long-term metabolic dysfunction in offspring. In this review, we summarized the scientific evidence from both epidemiological and toxicological studies, which suggest that perinatal exposure to PM2.5 causes obesity and metabolic diseases in progeny, including hypertension, cardiometabolic dysfunction, diabetes, and non-alcoholic fatty liver disease (NAFLD). Therefore, prevention strategies are needed to inform government policies and clinical counseling to reduce maternal exposure and its associated health hazards, and ultimately improve the quality of the newborn population.

Annexin A1 inhibition facilitates NLRP3 inflammasome activation in arsenic-induced insulin resistance in rat liver.

Hepatic insulin resistance (IR) is the primary pathology of type 2 diabetes (T2D). The role of the NOD-like receptor protein 3 (NLRP3) inflammasome in arsenic-induced hepatic IR has been previously demonstrated. However, the mechanism of the arsenic-induced activation of the NLRP3 inflammasome is still unclear. Here, we demonstrate that NaAsO2 downregulated the mRNA and protein level of Annexin A1 (AnxA1), an anti-inflammatory factor, in rat livers and L-02 cells. Moreover, AnxA1 overexpression significantly alleviated arsenic-induced NLRP3 inflammasome activation and IR in L-02 cells. Importantly, Co-immunoprecipitation (Co-IP) results showed that AnxA1 1-190 peptide could bind to the domain encompassing amino acids 1-210 and 211-550 of NLRP3. In conclusion, our experiments demonstrated that arsenic exposure could activate the NLRP3 inflammasome and IR by inhibiting the AnxA1 activity. These findings suggest that AnxA1 may be a promising therapeutic target of arsenicosis.

Hsp47 acts as a bridge between NLRP3 inflammasome and hepatic stellate cells activation in arsenic-induced liver fibrosis.

The activation of hepatic stellate cells (HSCs) is a key event during the progression of liver fibrosis (LF). We have previously indicated that NLRP3 inflammasome plays a crucial role in arsenic-induced HSCs activation. However, the mechanism of cascade responses between NLRP3 inflammasome and HSCs activation is unclear. Here, we showed that the transcription and protein level of Hsp47 was upregulated after 4 µM arsenic treatment, both in vivo and in vitro. Additionally, arsenic-induced HSCs activation was remarkably alleviated by the interference of Hsp47. Furthermore, blockage of NLRP3 significantly mitigated the activation of the NLRP3 inflammasome and decreased the expression of Hsp47, thereby attenuating the arsenic-induced HSCs activation. However, the ablation of Hsp47 did not affect the activation of the NLRP3 inflammasome. Notably, the protein-protein interaction between NLRP3 and Hsp47 was observed both in vivo and in vitro, and the target amino acid sequences were further identified. In summary, the present study indicated that NaAsO2 induced HSCs activation via the NLRP3 inflammasome-Hsp47 pathway. These findings provide direct evidence that Hsp47 may be a potential therapeutic target for arsenic-induced LF.

Patulin Induces Acute Kidney Injury in Mice through Autophagy-Ferroptosis Pathway.

Patulin (PAT) is a common mycotoxin, widely found in cereals, seafood, nuts, and especially in fruits and their products. Exposure to this mycotoxin has been reported to induce kidney injury. However, the possible mechanism remains unclear. In our study, short-term high-dose intake of PAT caused acute kidney injury (AKI) in mice. We performed high-throughput transcriptional sequencing to identify differentially expressed genes (DEGs) between the treatment and control groups. The ferroptosis signaling pathway had the highest enrichment, suggesting ferroptosis is involved in PAT-induced AKI. Further, the existence of ferroptosis and autophagy was confirmed by observing the changes of mitochondria morphology and the formation of autophagosomes by electron microscopy. And the expression of solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), p62, nuclear receptor coactivator 4 (NCOA4), and ferritin heavy chain 1 (FTH1) were downregulated, whereas acyl-CoA synthase long-chain family member 4 (ACSL4), transferrin (TF), LC3, and ferritin light chain (FTL) expression were upregulated in PAT-exposed mice. These results suggested autophagy-dependent ferroptosis occurred in the animal model. This view has also been confirmed in the human renal tubular epithelial cell (HKC) experiments. Autophagy inhibitor 3-methyladenine (3MA) attenuated PAT-induced ferroptosis and the iron contents in HKC cells. Simultaneous autophagy-dependent ferroptosis can be inhibited by ferroptosis inhibitors ferrostatin-1 (Fer-1) and desferrioxamine (DFO). In general, this study provides a new perspective for exploring the new mechanism of acute kidney injury caused by PAT.