C-Terminal Binding Protein: Regulator between Viral Infection and Tumorigenesis.

C-terminal binding protein (CtBP), a transcriptional co-repressor, significantly influences cellular signaling, impacting various biological processes including cell proliferation, differentiation, apoptosis, and immune responses. The CtBP family comprises two highly conserved proteins, CtBP1 and CtBP2, which have been shown to play critical roles in both tumorigenesis and the regulation of viral infections. Elevated CtBP expression is noted in various tumor tissues, promoting tumorigenesis, invasiveness, and metastasis through multiple pathways. Additionally, CtBP's role in viral infections varies, exhibiting differing or even opposing effects depending on the virus. This review synthesizes the advances in CtBP's function research in viral infections and virus-associated tumorigenesis, offering new insights into potential antiviral and anticancer strategies.

FERREG: ferroptosis-based regulation of disease occurrence, progression and therapeutic response.

Ferroptosis is a non-apoptotic, iron-dependent regulatory form of cell death characterized by the accumulation of intracellular reactive oxygen species. In recent years, a large and growing body of literature has investigated ferroptosis. Since ferroptosis is associated with various physiological activities and regulated by a variety of cellular metabolism and mitochondrial activity, ferroptosis has been closely related to the occurrence and development of many diseases, including cancer, aging, neurodegenerative diseases, ischemia-reperfusion injury and other pathological cell death. The regulation of ferroptosis mainly focuses on three pathways: system Xc-/GPX4 axis, lipid peroxidation and iron metabolism. The genes involved in these processes were divided into driver, suppressor and marker. Importantly, small molecules or drugs that mediate the expression of these genes are often good treatments in the clinic. Herein, a newly developed database, named 'FERREG', is documented to (i) providing the data of ferroptosis-related regulation of diseases occurrence, progression and drug response; (ii) explicitly describing the molecular mechanisms underlying each regulation; and (iii) fully referencing the collected data by cross-linking them to available databases. Collectively, FERREG contains 51 targets, 718 regulators, 445 ferroptosis-related drugs and 158 ferroptosis-related disease responses. FERREG can be accessed at https://idrblab.org/ferreg/.

No-observed adverse effect levels of deoxynivalenol and aflatoxin B1 in combination induced immune inhibition and apoptosis in vivo and in vitro.

Mycotoxins are toxic metabolites produced by fungal species, commonly exist in animal feeds, and pose a serious risk to human as well as animal health. But limited studies have focused on combined effects of no-observed adverse effect levels. In vivo study, 6 weeks old twenty-four mice were individually exposed to Deoxynivalenol (DON) at 0.1 mg/kg BW, Aflatoxin B1 (AFB1) at 0.01 mg/kg BW, and mixture of DON and AFB1 (0.1 mg/kg BW and 0.01 mg/kg BW, respectively) for 28 days. Then, DON at 0.5 µg/mL, AFB1 at 0.04 µg/mL, and mixtures of DON and AFB1 (0.5 µg/mL, 0.04 µg/mL, respectively) were applied to porcine alveolar macrophages (PAMs) in vitro study. Our in vivo results revealed that the combined no-observed adverse effect levels of DON and AFB1 administration decreased IgA and IgG levels in the serum, the splenic TNF-α, IFN-γ, IL-2 and IL-6 mRNA expression and T-lymphocyte subset levels (CD4+ and CD8+) in the spleen. Additionally, the combined administration increased caspase-3, caspase-9, Bax, Cyt-c, and decreased Bcl-2 protein expression. Taken together, the combined no-observed adverse effect levels of DON and AFB1 could induce immunosuppression, which may be related to apoptosis. This study provides new insights into the combined immune toxicity (DON and AFB1).

The roles and mechanisms of SREBP1 in cancer development and drug response.

Cancer occurrence and development are closely related to increased lipid production and glucose consumption. Lipids are the basic component of the cell membrane and play a significant role in cancer cell processes such as cell-to-cell recognition, signal transduction, and energy supply, which are vital for cancer cell rapid proliferation, invasion, and metastasis. Sterol regulatory element-binding transcription factor 1 (SREBP1) is a key transcription factor regulating the expression of genes related to cholesterol biosynthesis, lipid homeostasis, and fatty acid synthesis. In addition, SREBP1 and its upstream or downstream target genes are implicated in various metabolic diseases, particularly cancer. However, no review of SREBP1 in cancer biology has yet been published. Herein, we summarized the roles and mechanisms of SREBP1 biological processes in cancer cells, including SREBP1 modification, lipid metabolism and reprogramming, glucose and mitochondrial metabolism, immunity, and tumor microenvironment, epithelial-mesenchymal transition, cell cycle, apoptosis, and ferroptosis. Additionally, we discussed the potential role of SREBP1 in cancer prognosis, drug response such as drug sensitivity to chemotherapy and radiotherapy, and the potential drugs targeting SREBP1 and its corresponding pathway, elucidating the potential clinical application based on SREBP1 and its corresponding signal pathway.

Arrhythmia onsets triggered by acute myocardial ischemia are not mediated by lysophosphoglycerides accumulation in ventricular myocardium.

Lysophosphoglycerides (LPLs) have been reported to accumulate in myocardium and serve as a cause of arrhythmias in acute myocardial ischemia. However, in this study we found that LPLs level in the ventricular myocardium was decreased by the onset of acute myocardial ischemia in vivo in rats. Decreasing of LPLs level in left ventricular myocardium, but not right, was observed within 26 min of left myocardial ischemia, regardless of whether arrhythmias were triggered. Lower LPLs level in the ventricular myocardium was also observed in aconitine-simulated ventricular fibrillation (P < 0.0001) and ouabain-simulated III° atrioventricular block (P < 0.0001). Shot-lasting electric shock, e.g., ≤ 40 s, decreased LPLs level, while long-lasting, e.g., 5 min, increased it (fold change = 2.27, P = 0.0008). LPLs accumulation was observed in long-lasting myocardial ischemia, e.g., 4 h (fold change = 1.20, P = 0.0012), when caspase3 activity was elevated (P = 0.0012), indicating increased cell death, but not coincided with higher frequent arrhythmias. In postmortem human ventricular myocardium, differences of LPLs level in left ventricular myocardium was not observed among coronary artery disease- and other heart diseases-caused sudden death and non-heart disease caused death. LPLs level manifested a remarkable increasing from postmortem 12 h on in rats, thus abolishing the potential for serving as biomarkers of sudden cardiac death. Token together, in this study we found that LPLs in ventricular myocardium were initially decreased by the onset of ischemia, LPLs accumulation do not confer arrhythmogenesis during acute myocardial ischemia. It is necessary to reassess the roles of LPLs in myocardial infarction.

Chitosan-based hybrid nanospheres for vessel normalization towards enhancing tumor chemotherapy.

Vessel normalization has proved imperative in tumor growth inhibition. In this work, biopolymer-based hybrid nanospheres capable of normalizing blood vessels were designed to improve the therapeutic effect of chemotherapeutic drugs. Zn0.4Fe2.6O4 nanoparticles (ZFO NPs) were synthesized, and were encapsulated in cross-inked chitosan (CS) along with a nitric oxide (NO) precursor, DETA NONOate, forming hybrid ZFO/NO@CS nanospheres highly stable in physiological environment. The structure, morphology and size of the nanospheres were characterized. The ZFO/NO@CS nanospheres could release NO under acidic conditions typical of intratumoral and intracellular environment. The results of related factors expression, wound healing and tube formation assays demonstrated that both the encapsulated ZFO NPs and the released NO were able to inhibit angiogenesis in tumors. The ZFO/NO@CS nanospheres enhanced the antitumor efficacy of the chemotherapeutic drug DOX by normalizing tumor vessels, as evidenced by in vivo experiments for CT26 tumor-bearing mice. By analyzing the contents of Fe in the tumor and different organs, the nanospheres were found to accumulate primarily at the tumor site. The blood analysis showed little side effect of the nanospheres. The ZFO/NO@CS nanospheres have great potential in improving tumor therapeutic effect when used in combination with chemotherapeutic drugs.

E3 ubiquitin ligase RNF148 functions as an oncogene in colorectal cancer by ubiquitination-mediated degradation of CHAC2.

We previously reported that RNF148 was involved in the ubiquitination-mediated degradation of CHAC2. However, its molecular mechanism was not determined. In this study, we investigated the role and mechanism of RNF148 in the progression of colorectal cancer (CRC), especially in the process of ubiquitination-mediated degradation of CHAC2. Our results revealed that RNF148 was upregulated in most CRC tissues, and its expression significantly correlated with the 3-year overall survival rate and most clinicopathological parameters of CRC patients. Furthermore, RNF148 served as an independent prognostic biomarker of CRC and promoted CRC cell proliferation and migration while inhibiting cell apoptosis and sensitivity to 5-FU. Mechanistically, RNF148 used its protease-associated domain to bind to the CHAC domain of CHAC2 and target it for degradation. In addition, we identified two phosphorylation and three ubiquitination residues of CHAC2 and identified Y118 and K102 as the critical phosphorylation and ubiquitination residues, respectively. We also identified CHAC2's and RNF148's interacting proteins and discovered their potential interaction network. In conclusion, our current study unveiled the role of RNF148 in CRC and the mechanism of RNF148 in the ubiquitination-mediated degradation of CHAC2, which shed light on providing potential prognostic biomarkers and molecular targets for CRC patients.

Construction of asymmetric dual-layer polysaccharide-based porous structure on multiple sources for potential application in biomedicine.

Biomedical materials can produce high efficiency and special behavior with an integrated internal structure. It is possible that changing the structure of biomedical materials could extend and promote the application of eco-friendly and multifunctional biomaterials. However, the instantaneous formation of complex structures between tannic acid (TA) and polysaccharides is disrupted, and the reconstruction of the new porous structure becomes a key issue. Here, we present an innovative one-step forming method for an asymmetric dual-layer porous structure of carboxymethyl chitosan (CC)/sodium alginate (SA)/TA, which can be utilized in various biomedical applications. Even after 6 months of storage, it still demonstrates a range of desirable properties including tailorable performance, efficient antibacterial activity, ultrarapid antioxidant activity, low differential blood clotting index and cytotoxicity. This suggests its potential for regulating and controlling wound bleeding, providing flexible possibilities for potential applications in biomedicine.

Phenethyl isothiocyanate induces cytotoxicity and apoptosis of porcine kidney cells through Mitochondrial ROS-associated ERS pathway.

Glucosinolates (GLS) in cruciferous vegetables are anti-nutritional factors. Excessive or long-term intake of GLS-containing feed is harmful to animal health and may cause kidney damage. Phenethyl isothiocyanate (PEITC) is a GLS. In this study, we investigated the inhibitory effect of PEITC on a porcine kidney (PK-15) cell line and explored the mechanism of PEITC-induced apoptosis. We found that PEITC could affect cell viability and induce cell apoptosis after incubating cells for 24 h. High concentrations of PEITC can induce intracellular ROS accumulation, resulting in impaired mitochondrial function (decreased MMP, decreased ATP) and DNA damage (increased 8-OHdG), cytochrome c in mitochondria is released into the cytoplasm and activates mitochondrial pathway apoptosis-related proteins (Bcl-2 family and caspase-9, -3). Meanwhile, PEITC could induce intracellular Ca2+ accumulation, disrupt ER homeostasis, and activate the expression levels of three ER-resident transmembrane proteins orchestrating the UPR (PERK, IRE-1α and ATF6) and ER-related proteins (GRP78 and CHOP), thereby activating ERS-pathway apoptosis-related proteins (caspase-12, -7). Our results showed that low concentration (2.5 µM) of PEITC had no damaging effect on cells. In comparison, a high concentration (10 µM) of PEITC could induce cell damage in porcine kidney cells and induce apoptosis in PK-15 cells via the Mitochondrial ROS-associated ERS pathway.

Arsenic Exposure-Induced Acute Kidney Injury by Regulating SIRT1/PINK1/Mitophagy Axis in Mice and in HK-2 Cells.

Groundwater resources are often contaminated by arsenic, which poses a serious threat to human and animal's health. Some studies have demonstrated that acute arsenic exposure could induce kidney injury because the kidney is a key target organ for toxicity, but the exact mechanism remains unclear. Hence, we investigated the effect of SIRT1-/PINK1-mediated mitophagy on NaAsO2-induced kidney injury in vivo and in vitro. In our study, NaAsO2 exposure obviously induced renal tubule injury and mitochondrial dysfunction. Meanwhile, NaAsO2 exposure could inhibit the mRNA/protein level of SIRT1 and activate the mitophagy-related mRNA/protein levels in the kidney of mice. In HK-2 cells, we also confirmed that NaAsO2-induced nephrotoxicity depended on the activation of mitophagy. Moreover, the activation of SIRT1 by resveratrol alleviated NaAsO2-induced acute kidney injury via the activation of mitophagy in vivo and in vitro. Interestingly, the inhibition of mitophagy by cyclosporin A (CsA) further exacerbated NaAsO2-induced nephrotoxicity and inflammation in HK-2 cells. Taken together, our study found that SIRT1-regulated PINK1-/Parkin-dependent mitophagy was implicated in NaAsO2-induced acute kidney injury. In addition, we confirmed that PINK1-/Parkin-dependent mitophagy played a protective role against NaAsO2-induced acute kidney injury. Therefore, activation of SIRT1 and mitophagy may represent a novel therapeutic target for the prevention and treatment of NaAsO2-induced acute renal injury.

Chitosan-Based Hydrogel-Incorporated Trp-CDs with Antibacterial Properties and pH-Mediated Fluorescence Response as a Smart Food Preservation Material.

The great problem of food spoilage is causing food waste worldwide. However, prolonging the shelf life of food and responding to spoilage are good strategies for dealing with this problem. Herein, we present the design of multifunctional chitosan-based hydrogel-incorporated tryptophan carbon quantum dots (Trp-CDs) with antibacterial properties and pH-mediated fluorescence response (pH = 1-13). This chitosan (CS)/tannic acid (TA)/Trp-CDs hydrogel (CTTC hydrogel) was rapidly formed by a high density of hydrogen bonds and has the advantages of good mechanical properties (1628.55 kPa, 280%), washability (5-10 min), antioxidant activity (95.83%), and antibacterial properties. In practical application with fruits, the hydrogel significantly prolonged the shelf life of strawberries by at least 5 days and oranges by 20 days under ambient conditions. In particular, the hydrogel has good pH-mediated fluorescence responsiveness and reversibility due to doping with Trp-CDs, laying a foundation for its application in response to food spoilage.

PainVision-based evaluation of brain potentials: a novel approach for quantitative pain assessment.

Introduction: The complex and multidimensional nature of pain poses a major challenge in clinical pain assessments. In this study, we aimed to evaluate a novel approach combining quantitative sensory testing (QST) with event-related potential measurements for assessment of experimental pain in healthy individuals. Methods: QST was performed with a commercial device (PainVision, PS-2100), and numeric rating scale (NRS) scores after exposure to different sensory stimuli were reported by the participants. Resting-state electroencephalography (EEG) was simultaneously performed to capture the cortical responses to peripheral stimulation. Results: Pain scores increased with the intensity of stimuli, with mean NRS scores of 2.7 ± 1.0 after mild stimuli and 5.6 ± 1.0 after moderate stimuli. A reproducible, significant P2-N2 complex was evoked by both mild and moderately painful stimuli, but not by non-painful stimuli. The latency of pain-related potentials was not significantly different between stimuli. The amplitudes of both P2 and N2 components significantly increased when intense nociception was applied, and the increments mainly originated from theta oscillations. Conclusion: The combination of QST with EEG was feasible for subjective and objective pain assessment. Distinct patterns of brain potentials were associated with the phenotype of the peripheral stimuli (e.g., noxious versus. innoxious, high versus. low pain intensity).

The roles and mechanism of m6A RNA methylation regulators in cancer immunity.

N6-methyladenosine (m6A), the most common internal modification in RNA, can be regulated by three types of regulators, including methyltransferases (writers), demethylases (erasers), and m6A binding proteins (readers). Recently, immunotherapy represented by immune checkpoint blocking has increasingly become an effective cancer treatment, and increasing shreds of evidence show that m6A RNA methylation affects cancer immunity in various cancers. Until now, there have been few reviews about the role and mechanism of m6A modification in cancer immunity. Here, we first summarized the regulation of m6A regulators on the expression of target messenger RNAs (mRNA) and their corresponding roles in inflammation, immunity response, immune process and immunotherapy in various cancer cells. Meanwhile, we described the roles and mechanisms of m6A RNA modification in tumor microenvironment and immune response by affecting the stability of non-coding RNA (ncRNA). Moreover, we also discussed the m6A regulators or its target RNAs which might be used as predictor of cancer diagnosis and prognosis, and shed light on the potentiality of m6A methylation regulators as therapeutic targets in cancer immunity.

Aflatoxin B1 induces liver injury by disturbing gut microbiota-bile acid-FXR axis in mice.

Aflatoxin B1 (AFB1) is one of major pollutant in food and feed worldwide. The purpose of this study is to investigate the mechanism of AFB1-induced liver injury. Our results showed that AFB1 caused hepatic bile duct proliferation, oxidative stress, inflammation and liver injury in mice. AFB1 exposure induced gut microbiota dysbiosis and reduced fecal bile salt hydrolase (BSH) activity. AFB1 exposure promoted hepatic bile acid (BA) synthesis and changed intestinal BA metabolism, especially increased intestinal conjugated bile acids levels. AFB1 exposure inhibited intestinal farnesoid X receptor (FXR)/fibroblast growth factor 15 (FGF-15) signaling. Furthermore, the mice received fecal microbiota transplantation from AFB1-treated mice induced liver injury, reduced intestinal FXR signaling and increased hepatic BA synthesis. Finally, the intestine-restricted FXR agonist treatment decreased hepatic BA synthesis, ROS level, inflammation and liver injury in AFB1-treated mice. This study suggests that modifying the gut microbiota, altering intestinal BA metabolism and/or activating intestinal FXR/FGF-15 signaling may be of value for the treatment of AFB1-induced liver disease.

Systematic Description of the Content Variation of Natural Products (NPs): To Prompt the Yield of High-Value NPs and the Discovery of New Therapeutics.

Natural products (NPs) have long been associated with human production and play a key role in the survival of species. Significant variations in NP content may severely affect the "return on investment" of NP-based industries and render ecological systems vulnerable. Thus, it is crucial to construct a platform that relates variations in NP content to their corresponding mechanisms. In this study, a publicly accessible online platform, NPcVar (http://npcvar.idrblab.net/), was developed, which systematically described the variations of NP contents and their corresponding mechanisms. The platform comprises 2201 NPs and 694 biological resources, including plants, bacteria, and fungi, curated using 126 diverse factors with 26,425 records. Each record contains information about the species, NP, and factors involved, as well as NP content data, parts of the plant that produce NPs, the location of the experiment, and reference information. All factors were manually curated and categorized into 42 classes which belong to four mechanisms (molecular regulation, species factor, environmental condition, and combined factor). Additionally, the cross-links of species and NP to well-established databases and the visualization of NP content under various experimental conditions were provided. In conclusion, NPcVar is a valuable resource for understanding the relationship between species, factors, and NP contents and is anticipated to serve as a promising tool for improving the yield of high-value NPs and facilitating the development of new therapeutics.

Lipopolysaccharide aggravates canine influenza a (H3N2) virus infection and lung damage via mTOR/autophagy in vivo and in vitro.

Influenza A (H3N2) accounts for the majority of influenza worldwide and continues to challenge human health. Disturbance in the gut microbiota caused by many diseases leads to increased production of lipopolysaccharide (LPS), and LPS induces sepsis and conditions associated with local or systemic inflammation. However, to date, little attention has been paid to the potential impact of LPS on influenza A (H3N2) infection and the potential mechanism. Hence, in this study we used canine influenza A (H3N2) virus (CIV) as a model of influenza A virus to investigate the effect of low-dose of LPS on CIV replication and lung damage and explore the underlying mechanism in mice and A549 and HPAEpiC cells. The results showed that LPS (25 µg/kg) increased CIV infection and lung damage in mice, as indicated by pulmonary virus titer, viral NP levels, lung index, and pulmonary histopathology. LPS (1 µg/ml) also increased CIV replication in A549 cells as indicated by the above same parameters. Furthermore, low doses of LPS reduced CIV-induced p-mTOR protein expression and enhanced CIV-induced autophagy-related mRNA/protein expressions in vivo and in vitro. In addition, the use of the mTOR activator, MHY1485, reversed CIV-induced autophagy and CIV replication in A549 and HPAEpiC cells, respectively. siATG5 alleviated CIV replication exacerbated by LPS in the two lines. In conclusion, LPS aggravates CIV infection and lung damage via mTOR/autophagy.

ADAM9: A regulator between HCMV infection and function of smooth muscle cells.

Lots of epidemiological and clinical studies have shown that human cytomegalovirus (HCMV) is related to the pathogenesis of atherosclerosis. Released by inflammatory cells and vascular smooth muscle cell (VSMCs), metalloproteinases are observed in many pathological vessel conditions, including atherosclerosis and restenosis. This study was designed to investigate the effect of HCMV infection on the expression of metalloproteinases and their involvements in the HCMV-induced functional changes of VSMCs. Differential metalloproteinase after HCMV infection was assayed using reverse transcription-polymerase chain reaction (RT-PCR) microarray. The most significant increased a disintegrin and metalloprotease 9 (ADAM9) was chosen to investigate the mechanism of its specific increase after infection using the treatment of UV-irradiated replication-deficient HCMV, HCMV-infected cell lysate filters or Foscarnet. The function of proliferation, migration, production of inflammatoty factors and phenotypic transformation were determined by using cell counting kit-8, transwell, Enzyme-linked immunosorbent assay, RT-quantitative PCR (qPCR) and Western blot, respectively. Moreover, the effect of ADAM9 deficiency on HCMV replication was also determined using RT-qPCR and immunofluorescence. The expression levels of 6 genes were upregulated and 14 genes were downregulated at different time points after HCMV infection. Among these, the expression level of ADAM9 increased most significantly at each time point and the abnormal expression of ADAM9 might be induced by the early gene products of HCMV. Further studies found that ADAM9 promoted the proliferation, the migration, the production of inflammatory factors and the transit from the contractile phenotype (decreased ACTA2 expression) to the synthetic phenotype (increased osteopontin [OPN] expression). Knockdown theADAM9 expression could rescue the decreased ACTA2 expression, but has no effect on OPN expression. ADAM-9 deficiency didn't affect the replication of HCMV. The findings of our study suggest that HCMV infection changed VSMC function through ADAM9 expression, which may contribute to the understanding of the underlying pathological mechanisms of HCMV-induced atherosclerosis.

Aflatoxin B1 Induces Intestinal Barrier Dysfunction by Regulating the FXR-Mediated MLCK Signaling Pathway in Mice and in IPEC-J2 Cells.

Aflatoxin B1 (AFB1) is a widespread mycotoxin in food and feed. Although the liver is the main target organ of AFB1, the intestine is the first exposure organ to AFB1. However, the mechanism by which AFB1 induced intestinal barrier dysfunction via regulating the farnesoid X receptor (FXR)-mediated myosin light chain kinase (MLCK) signaling pathway has rarely been studied. In vivo, AFB1 exposure significantly decreased the small intestine length and increased the intestinal permeability. Meanwhile, AFB1 exposure markedly suppressed the protein expressions of FXR, ZO-1, occludin, and claudin-1 and enhanced the protein expression of MLCK. In vitro, AFB1 exposure induced intestinal barrier dysfunction by the elevation in the FITC-Dextran 4 kDa flux and inhibition in the transepithelial electrical resistance in a dose-dependent manner. In addition, AFB1 exposure downregulated the mRNA and protein expressions of FXR, ZO-1, occludin, and claudin-1, redistributed the ZO-1 protein, and enhanced the protein expressions of MLCK and p-MLC. However, fexaramine (Fex, FXR agonist) pretreatment markedly reversed the AFB1-induced FXR activity reduction, MLCK protein activation, and intestinal barrier impairment in vitro and in vivo. Moreover, pretreatment with the inhibition of MLCK with ML-7 significantly alleviated the AFB1-induced intestinal barrier dysfunction and tight junction disruption in vitro. In conclusion, AFB1 induced intestinal barrier impairment via regulating the FXR-mediated MLCK signaling pathway in vitro and in vivo and provided novel insights to prevent mycotoxin poisoning in the intestine.

Taurine alleviates ochratoxin A-induced pyroptosis in PK-15 cells by inhibiting oxidative stress.

Ochratoxin A (OTA) is one of the most harmful mycotoxins, which can cause multiple toxicological effects, especially nephrotoxicity in animals and humans. Taurine is an essential amino acid with various biological functions such as anti-inflammatory and anti-oxidation. However, the protective effect of taurine on OTA-induced nephrotoxicity and pyroptosis had not been reported. Our results showed that OTA exposure induced cytotoxicity and oxidative stress in PK-15 cells, including reactive oxygen species (ROS) accumulation, increased mRNA levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2), and decreased mRNA levels of catalase (CAT), glutathione peroxidase 1 (GPx1), and glutathione peroxidase 4 (GPx4). In addition, OTA treatment induced pyroptosis by increasing the expressions of pyroptosis-related proteins NLRP3, GSDMD, Caspase-1 P20, ASC, Pro-caspase-1, and IL-1ß. Meanwhile, taurine could alleviate OTA-induced pyroptosis and cytotoxicity, as well as reduce ROS level, COX-2, and iNOS mRNA levels, and increase the mRNA levels of the antioxidant enzyme in PK-15 cells. Taken together, taurine alleviated OTA-induced pyroptosis in PK-15 cells by inhibiting ROS generation and altering the activity of antioxidant enzymes, thereby attenuating its nephrotoxicity.

The combined effect of deoxynivalenol and Fumonisin B1 on small intestinal inflammation mediated by pyroptosis in vivo and in vitro.

Currently, due to the actual contamination levels of multiple mycotoxins, the limits for a single mycotoxin may be no longer applicable. Deoxynivalenol (DON) and Fumonisin B1 (FB1) had high positive rate in grain and feed worldwide. The intestine is the first target of mycotoxins. NLRP3 plays a crucial role in the gut's defense against external stimuli, which contributes vitally to pyroptosis activation. However, whether pyroptosis is engaged in the regulation of intestinal toxicity induced by DON and FB1 remains unclear. In this study, we explored the combined toxicity of DON and FB1 on the intestine and its underlying mechanisms in vivo and in vitro. Our data demonstrated gavage with DON and FB1 led to intestinal damage and promoted the secretion of pro-inflammatory cytokines (IL-1ß, IL-18, IL-6) in mice, especially in the group exposed to both mycotoxins. Meanwhile, the expressions of pyroptosis related genes (NLRP3, ASC, caspase-1, GSDMD) were significantly increased after mycotoxins exposure. Same as in vivo, DON and FB1 promoted pyroptosis and cellular inflammatory response in IPEC-J2 cells, especially in the group exposed to both mycotoxins. In addition, the pretreatment with MCC950 and VX765, inhibitors for NLRP3 and caspase-1, abolished the expression of GSDMD and the release of pro-inflammatory factors (IL-1ß, IL-18) induced by DON and FB1 exposure in IPEC-J2 cells. Our data demonstrated that the combination of DON and FB1 exhibited a synergistic or additive effect in facilitating intestinal inflammation via pyroptosis. Our finding may contribute to improve mycotoxin limit standards in feed.