Correction: Tumor Immunotherapy-Related Information on Internet-Based Videos Commonly Used by the Chinese Population: Content Quality Analysis.

[This corrects the article DOI: 10.2196/50561.].

Targeting EFHD2 Inhibits Interferon-γ Signaling and Ameliorates Non-Alcoholic Steatohepatitis.

BACKGROUND & AIMS: The precise pathomechanisms underlying the development of nonalcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis [MASH]) remain incompletely understood. This study investigates the potential role of EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, in NASH pathogenesis. METHODS: Hepatic EFHD2 expression was characterized in NASH patients and two diet-induced NASH mouse models. Single-cell RNA-sequencing (scRNA-seq) and double-immunohistochemistry were employed to explore EFHD2 expression patterns in NASH livers. The effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma (HCC) were assessed. Molecular mechanisms underlying EFHD2 function were investigated, along with its potential as a therapeutic target by chemical and genetic means. RESULTS: EFHD2 expression was significantly elevated in liver tissue macrophages/monocytes in both NASH patients and mice. Deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis in NASH. Additionally, it hindered the development of NASH-related HCC. Specifically, deletion of myeloid EFHD2 prevented the replacement of TIM4+ resident Kupffer cells by infiltrated monocytes and reversed the decreases in patrolling monocytes and CD4+/CD8+ T cell ratio in NASH. Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of interferon-γ receptor-2 (IFNγR2) onto the plasma membrane. This interaction mediates IFNγ signaling, which triggers immune and inflammatory responses in macrophages during NASH. Finally, a developed stapled α-helical peptide targeting EFHD2 demonstrated its efficacy in protecting against NASH pathology in mice. CONCLUSION: Our study reveals a pivotal immunomodulatory and inflammatory role of EFHD2 in NASH, underscoring EFHD2 as a promising druggable target for NASH treatment. IMPACT AND IMPLICATIONS: Nonalcoholic steatohepatitis (NASH) represents an advanced stage of non-alcoholic fatty liver disease (NAFLD); however, not all NAFLD patients progress to NASH. A key challenge is identifying the factors triggering inflammation, which propels the transition from simple fatty liver to NASH. Our research pinpointed EFHD2 as a pivotal driver of NASH, orchestrating the over-activation of IFNγ signaling within the liver during NASH progression. A stapled peptide designed to target EFHD2 exhibited therapeutic promise in NASH mice. These findings suggest EFHD2 as a promising target for drug development aimed at NASH treatment.

A Mobile Applet for Assessing Medication Adherence and Managing Adverse Drug Reactions Among Patients With Cancer: Usability and Utility Study.

BACKGROUND: Medication adherence and the management of adverse drug reactions (ADRs) are crucial to the efficacy of antitumor drugs. A WeChat applet, also known as a "Mini Program," is similar to the app but has marked advantages. The development and use of a WeChat applet makes follow-up convenient for patients with cancer. OBJECTIVE: This study aimed to assess the usability and utility of a newly developed WeChat applet, "DolphinCare," among patients with cancer in Shanghai. METHODS: A qualitative methodology was used to obtain an in-depth understanding of the experiences of patients with cancer when using DolphinCare from the usability and utility aspects. The development phase consisted of 2 parts: alpha and beta testing. Alpha testing combined the theory of the Fogg Behavior Model and the usability model. Alpha testing also involved testing the design of DolphinCare using a conceptual framework, which included factors that could affect medication adherence and ADRs. Beta testing was conducted using in-depth interviews. In-depth interviews allowed us to assist the patients in using DolphinCare and understand whether they liked or disliked DolphinCare and found it useful. RESULTS: We included participants who had an eHealth Literacy Scale (eHEALS) score of ≥50%, and a total of 20 participants were interviewed consecutively. The key positive motivators described by interviewers were to be reminded to take their medications and to alleviate their ADRs. The majority of the patients were able to activate and use DolphinCare by themselves. Most patients indicated that their trigger to follow-up DolphinCare was the recommendation of their known and trusted health care professionals. All participants found that labels containing the generic names of their medication and the medication reminders were useful, including timed pop-up push notifications and text alerts. The applet presented the corresponding information collection forms of ADRs to the patient to fill out. The web-based consultation system enables patients to consult pharmacists or physicians in time when they have doubts about medications or have ADRs. The applet had usabilities and utilities that could improve medication adherence and the management of ADRs among patients with cancer. CONCLUSIONS: This study provides preliminary evidence regarding the usability and utility of this type of WeChat applet among patients with cancer, which is expected to be promoted for managing follow-up among other patients with other chronic disease.

Gasdermin-E-Dependent Non-Canonical Pyroptosis Promotes Drug-Induced Liver Failure by Promoting CPS1 deISGylation and Degradation.

Drug-induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen (APAP) overdose. GSDME is an effector protein that induces non-canonical pyroptosis. In this study, the activation of GSDME, but not GSDMD, in the liver tissue of mice and patients with APAP-DILI is reported. Knockout of GSDME, rather than GSDMD, in mice protected them from APAP-DILI. Mice with hepatocyte-specific rescue of GSDME reproduced APAP-induced liver injury. Furthermore, alterations in the immune cell pools observed in APAP-induced DILI, such as the replacement of TIM4+ resident Kupffer cells (KCs) by monocyte-derived KCs, Ly6C+ monocyte infiltration, MerTk+ macrophages depletion, and neutrophil increase, reappeared in mice with hepatocyte-specific rescue of GSDME. Mechanistically, APAP exposure led to a substantial loss of interferon-stimulated gene 15 (ISG15), resulting in deISGylation of carbamoyl phosphate synthetase-1 (CPS1), promoted its degradation via K48-linked ubiquitination, causing ammonia clearance dysfunction. GSDME deletion prevented these effects. Delayed administration of dimethyl-fumarate inhibited GSDME cleavage and alleviated ammonia accumulation, mitigating liver injury. This findings demonstrated a previously uncharacterized role of GSDME in APAP-DILI by promoting pyroptosis and CPS1 deISGylation, suggesting that inhibiting GSDME can be a promising therapeutic option for APAP-DILI.

Tumor Immunotherapy-Related Information on Internet-Based Videos Commonly Used by the Chinese Population: Content Quality Analysis.

BACKGROUND: Tumor immunotherapy is an innovative treatment today, but there are limited data on the quality of immunotherapy information on social networks. Dissemination of misinformation through the internet is a major social issue. OBJECTIVE: Our objective was to characterize the quality of information and presence of misinformation about tumor immunotherapy on internet-based videos commonly used by the Chinese population. METHODS: Using the keyword "tumor immunotherapy" in Chinese, we searched TikTok, Tencent, iQIYI, and BiliBili on March 5, 2022. We reviewed the 118 screened videos using the Patient Education Materials Assessment Tool-a validated instrument to collect consumer health information. DISCERN quality criteria and the JAMA (Journal of the American Medical Association) Benchmark Criteria were used for assessing the quality and reliability of the health information. The videos' content was also evaluated. RESULTS: The 118 videos about tumor immunotherapy were mostly uploaded by channels dedicated to lectures, health-related animations, and interviews; their median length was 5 minutes, and 79% of them were published in and after 2018. The median understandability and actionability of the videos were 71% and 71%, respectively. However, the quality of information was moderate to poor on the validated DISCERN and JAMA assessments. Only 12 videos contained misinformation (score of >1 out of 5). Videos with a doctor (lectures and interviews) not only were significantly less likely to contain misinformation but also had better quality and a greater forwarding number. Moreover, the results showed that more than half of the videos contain little or no content on the risk factors and management of tumor immunotherapy. Overall, over half of the videos had some or more information on the definition, symptoms, evaluation, and outcomes of tumor immunotherapy. CONCLUSIONS: Although the quality of immunotherapy information on internet-based videos commonly used by Chinese people is moderate, these videos have less misinformation and better content. Caution must be exercised when using these videos as a source of tumor immunotherapy-related information.

Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence.

Senescence of vascular smooth muscle cells (VSMCs) contributes to aging-related cardiovascular diseases by promoting arterial remodelling and stiffness. Ferroptosis is a novel type of regulated cell death associated with lipid oxidation. Here, we show that pro-ferroptosis signaling drives VSMCs senescence to accelerate vascular NAD+ loss, remodelling and aging. Pro-ferroptotic signaling is triggered in senescent VSMCs and arteries of aged mice. Furthermore, the activation of pro-ferroptotic signaling in VSMCs not only induces NAD+ loss and senescence but also promotes the release of a pro-senescent secretome. Pharmacological or genetic inhibition of pro-ferroptosis signaling, ameliorates VSMCs senescence, reduces vascular stiffness and retards the progression of abdominal aortic aneurysm in mice. Mechanistically, we revealed that inhibition of pro-ferroptotic signaling facilitates the nuclear-cytoplasmic shuttling of proliferator-activated receptor-γ and, thereby impeding nuclear receptor coactivator 4-ferrtin complex-centric ferritinophagy. Finally, the activated pro-ferroptotic signaling correlates with arterial stiffness in a human proof-of-concept study. These findings have significant implications for future therapeutic strategies aiming to eliminate vascular ferroptosis in senescence- or aging-associated cardiovascular diseases.

Sting mutation attenuates acetaminophen-induced acute liver injury by limiting NLRP3 activation.

Acetaminophen (N-acetyl-p-aminophenol; APAP), a widely used effective nonsteroidal anti-inflammatory drug, leads to acute liver injury at overdose worldwide. Evidence showed that the severity of liver injury associated with the subsequent involvement of inflammatory mediators and immune cells. The innate immune stimulator of interferon genes protein (STING) pathway was critical in modulating inflammation. Here, we show that STING was activated and inflammation was enhanced in the liver in APAP-overdosed C57BL/6J mice, and Sting mutation (Stinggt/gt) mice exhibited less liver damage. Multiplexing flow cytometry displayed that Sting mutation changed hepatic recruitment and replacement of macrophages/monocytes in APAP-overdosed mice, which was inclined to anti-inflammation. In addition, Sting mutation limited NLRP3 activation in the liver in APAP-overdosed mice, and inhibited the expression of inflammatory cytokines. Finally, MCC950, a potent and selective NLRP3 inhibitor, significantly ameliorated APAP-induced liver injury and inflammation. Besides, pretreatment of MCC950 in C57 mice resulted in changes of immune cells infiltration in the liver similar to Stinggt/gt mice. Our study revealed that STING played a crucial role in APAP-induced acute liver injury, possibly by maintaining liver immune cells homeostasis and inhibiting NLRP3 inflammasome activation, suggesting that inhibiting STING-NLRP3 pathway might be a potential therapeutic strategy for acute liver injury.

SIRT1, a target of miR-708-3p, alleviates fluoride-induced neuronal damage via remodeling mitochondrial network dynamics.

INTRODUCTION: Neurological dysfunction induced by fluoride contamination is still one of major concern worldwide. Recently, neuroprotective roles of silent information regulator 1 (SIRT1) focusing on mitochondrial function have been highlighted. However, what roles SIRT1 exerts and the underlying regulative mechanisms, remain largely uncharacterized in such neurotoxic process of fluoride. OBJECTIVES: We aimed at evaluating the regulatory roles of SIRT1 in human neuroblastoma SH-SY5Y cells and Sprague-Dawley rats with fluoride treatment, and to further identify potential miRNA directly targeting SIRT1. METHODS: Pharmacological suppression of SIRT1 by nicotinamide (NIC) and promotion of SIRT1 by adenovirus (Ad-SIRT1) or resveratrol (RSV) were employed to assess the effects of SIRT1 in mitochondrial dysfunction induced by fluoride. Also, miRNAs profiling and bioinformatic prediction were used to screen the miRNAs which can regulate SIRT1 directly. Further, chemical mimic or inhibitor of chosen miRNA was applied to validate the modulation of chosen miRNA. RESULTS: NIC exacerbated defects in mitochondrial network dynamics and cytochrome c (Cyto C) release-driven apoptosis, contributing to fluoride-induced neuronal death. In contrast, the ameliorative effects were observed when overexpressing SIRT1 by Ad-SIRT1 in vitro or RSV in vivo. More importantly, miR-708-3p targeting SIRT1 directly was identified. And interestingly, moreover, treatment with chemically modified miR-708-3p mimic aggravated, while miR-708-3p inhibitor suppressed fluoride-caused neuronal death. Further confirmedly, overexpressing SIRT1 effectively neutralized miR-708-3p mimic-worsened fluoride neuronal death via correcting mitochondrial network dynamics. On contrary, inhibiting SIRT1 counteracted the promotive effects of miR-708-3p inhibitor against neurotoxic response by fluoride through aggravating abnormal mitochondrial network dynamics. CONCLUSION: These data underscore the functional importance of SIRT1 to mitochondrial network dynamics in neurotoxic process of fluoride and further screen a novel unreported neuronal function of miR-708-3p as an upstream regulator of targeting SIRT1, which has important theoretical implications for a potential therapeutic and preventative target for treatment of neurotoxic progression by fluoride.

Colchicine protects against the development of experimental abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is characterized by at least 1.5-fold enlargement of the infrarenal aorta, a ruptured AAA is life-threatening. Colchicine is a medicine used to treat gout and familial Mediterranean fever, and recently, it was approved to reduce the risk of cardiovascular events in adult patients with established atherosclerotic disease. With an AAA mice model created by treatment with porcine pancreatic elastase (PPE) and ß-aminopropionitrile (BAPN), this work was designed to explore whether colchicine could protect against the development of AAA. Here, we showed that colchicine could limit AAA formation, as evidenced by the decreased total aortic weight per body weight, AAA incidence, maximal abdominal aortic diameter and collagen deposition. We also found that colchicine could prevent the phenotypic switching of vascular smooth muscle cells from a contractile to synthetic state during AAA. In addition, it was demonstrated that colchicine was able to reduce vascular inflammation, oxidative stress, cell pyroptosis and immune cells infiltration to the aortic wall in the AAA mice model. Finally, it was proved that the protective action of colchicine against AAA formation was mainly mediated by preventing immune cells infiltration to the aortic wall. In summary, our findings demonstrated that colchicine could protect against the development of experimental AAA, providing a potential therapeutic strategy for AAA intervention in the clinic.

Base-Mediated α-gem-Difluoroalkenylations of Aldehydes and Ketones.

Herein, we present a base-mediated nucleophilic substitution reaction of α-trifluoromethylstyrenes with simple silyl enol ethers, enabling the efficient synthesis of carbonyl-substituted gem-difluoroalkenes. The merit of this protocol is exhibited by its mild reaction conditions, broad substrate scope, and scalable preparation. Notably, this method demonstrates its applicability for late-stage functionalization of structurally complex molecules. Moreover, we illustrate that the resulting products can serve as valuable precursors for the synthesis of diverse medicinally relevant compounds.

Ferroptosis-Regulated Cell Death as a Therapeutic Strategy for Neurodegenerative Diseases: Current Status and Future Prospects.

Ferroptosis is increasingly being recognized as a key element in the pathogenesis of diverse diseases. Recent studies have highlighted the intricate links between iron metabolism and neurodegenerative disorders. Emerging evidence suggests that iron homeostasis, oxidative stress, and neuroinflammation all contribute to the regulation of both ferroptosis and neuronal health. However, the precise molecular mechanisms underlying the involvement of ferroptosis in the pathological processes of neurodegeneration and its impact on neuronal dysfunction remain incompletely understood. In our Review, we provide a comprehensive analysis and summary of the potential molecular mechanisms underlying ferroptosis in neurodegenerative diseases, aiming to elucidate the disease progression of neurodegeneration. Additionally, we discuss potential therapeutic agents that modulate ferroptosis with the goal of identifying novel drug molecules for the treatment of neurodegenerative disorders.

Advanced Messaging Intervention for Medication Adherence and Clinical Outcomes Among Patients With Cancer: Randomized Controlled Trial.

BACKGROUND: Medication adherence is crucial for improving clinical outcomes in the treatment of patients with cancer. The lack of adherence and adverse drug reactions can reduce the effectiveness of cancer therapy including the quality of life. The commonly used intervention methods for medication adherence continue to evolve, and the age of fifth-generation (5G) messaging has arrived. OBJECTIVE: In this study, we conducted a prospective, pilot randomized controlled trial to evaluate the effect of 5G messaging on medication adherence and clinical outcomes among patients with cancer in China. METHODS: The research population was patients with nonsmall cell lung cancer undergoing pemetrexed chemotherapy who require regular folic acid (FA) and vitamin B12 supplements. The intervention and control groups were assigned to 5G messaging and second-generation (2G) messaging, respectively. The patients' medication adherence and quality of life were assessed at baseline and 1-month and 3-month time points. Moreover, the chemotherapy-related hematologic or nonhematologic toxicities, as well as the serum levels of FA and vitamin B12, were measured. RESULTS: Of the 567 patients assessed for eligibility between January and May 2021, a total of 154 (27.2%) patients were included. Overall, 80 were randomized to the control group and 74 to the intervention group. The odds of adherence in the 5G messaging intervention group were significantly higher than the control group at the 1-month (62/69, 90% vs 56/74, 76%; adjusted odds ratio 2.67, 95% CI 1.02-7.71) and 3-month (50/60, 83% vs 48/64, 75%; adjusted odds ratio 2.36, 95% CI 1.00-5.23) time points. Correspondingly, the FA and vitamin B12 serum levels of patients in the 5G messaging group were higher than those of the control group. Regarding hematologic toxicities, only the incidence of leukopenia in the intervention group was lower than that in the control group (25/80, 31% in the control group vs 12/74, 16% in the intervention group; P=.04). There were no differences in nonhematologic toxicities and quality of life between the 2 groups. CONCLUSIONS: In summary, we conclude that compared with conventional 2G text-based messaging, a 5G messaging intervention can better improve medication adherence and clinical outcome among patients with cancer. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200058188; https://www.chictr.org.cn/showproj.html?proj=164489.

Influence of continuous renal replacement therapy on the plasma concentration of tigecycline in patients with septic shock: A prospective observational study.

Objective: The influence of continuous renal replacement therapy (CRRT) on the steady-state plasma concentration of high-dose tigecycline was investigated in septic shock patients to provide references for drug dosing. Methods: In this prospective observational study, 17 septic shock patients presenting with severe infections needing a broad-spectrum antibiotic therapy with high-dose tigecycline (100 mg per 12 h) in the intensive care unit were included and divided into CRRT group (n = 6) or non-CRRT group (n = 11). The blood samples were collected and plasma drug concentration was determined by SHIMADZU LC-20A and SHIMADZU LCMS 8040. The steady-state plasma concentration was compared between groups using unpaired t-test. Furthermore, between-groups comparisons adjusted for baseline value was also done using multivariate linear regression model. Results: Peak concentration (Cmax) of tigecycline was increased in CRRT group compared to non-CRRT group, but there were no statistical differences (505.11 ± 143.84 vs. 406.29 ± 108.00 ng/mL, p-value: 0.129). Trough concentration (Cmin) of tigecycline was significantly higher in CRRT group than in non-CRRT group, with statistical differences (287.92 ± 41.91 vs. 174.79 ± 33.15 ng/mL, p-value: 0.000, adjusted p-value: 0.000). In safety, Cmin was reported to be a useful predictor of hepatotoxicity with a cut-off of 474.8 ng/mL. In our studies, Cmin of all patients in CRRT group was lower than 474.8 ng/mL. Conclusion: The plasma concentration of tigecycline was increased in septic shock patients with CRRT treatment and only Cmin shown statistical differences. No dose adjustment seems needed in the view of hepatotoxicity. Clinical Trial Registration: https://www.chictr.org.cn/, identifier ChiCTR2000037475.

Long survival in a pancreatic carcinoma patient with multi-organ toxicities after sintilimab treatment: A case report.

Pancreatic carcinoma is the leading cause of death among digestive malignancies in China. In particular, there is no breakthrough in prolonging the survival of pancreatic cancer patients with chemical and targeted therapies. Tumor immunotherapy brings opportunities and progress for the treatment of pancreatic cancer. Sintilimab is an innovative PD-1 inhibitor which was reported certain clinical benefits in multi-line treatments of advanced pancreatic cancer with gemcitabine. The combination therapy of PD-1 with gemcitabine plus high-intensity focused ultrasound (HIFU) in pancreatic cancer has not been reported. Here we report a case of a Chinese old patient diagnosed with metastatic pancreatic cancer. Two months after sintilimab treatment, the patient occurred severe immune colitis. The patient was diagnosed with immune ureteritis after 8 months of treatment. The immue-related adverse events (irAEs) refined after timely recognition and correct intervention by the clinician and clinical pharmacist. After first-line treatment of sintilimab plus gemcitabine combined with pancreatic HIFU, the patient achieved a remarkable benefit of 11-month progression-free survival (PFS) and 20-month overall survival (OS). The first-line treatment of sintilimab plus gemcitabine combined with HIFU demonstrates a potential therapeutic effect on metastatic pancreatic carcinoma with tolerable adverse reactions.

Pyroptosis, Metabolism, and Oxidation in Tumorigenesis: Mechanisms and Therapeutic Implications.

Significance: Pyroptosis is a discovered programmed cell death that is mainly executed by the gasdermin protein family. Cell swelling and membrane perforation are observed when pyroptosis occurs, and is accompanied by the liberation of cell contents. Recent Advances: As the study of pyroptosis continues to progress, there is increasing evidence that pyroptosis influences the development of tumors. In addition, the relationship between pyroptosis and tumor is diverse for different tissues and cells. Critical Issues: In this review, we first introduce the research history and molecular mechanisms of pyroptosis. Then we specifically discuss the link between pyroptosis and metabolic and oxidation in tumorigenesis. In the subsequent sections, we focus on the induction of pyroptosis in cancer and its potential role as a promising target for cancer therapy, and discuss the implications of pyroptosis in tumor treatment. In addition, we further summarize the therapeutic value of pyroptosis in tumor treatment. Future Directions: A detailed understanding of the role played by pyroptosis in tumors will help us to further explore tumor formation and progression and provide ideas for the development of new pyroptosis-based therapeutic approaches for patients. Antioxid. Redox Signal. 39, 512-530.

Chromium-Catalyzed Defluorinative Reductive Coupling of Aldehydes with gem-Difluoroalkenes.

Herein, a mild and convenient defluorinative reductive cross coupling of gem-difluoroalkenes with aliphatic aldehydes has been developed to afford diverse silyl-protected ß-fluorinated allylic alcohols. The reaction is operationally simple and shows good functional group tolerance with moderate to excellent yields. The utility of this method is demonstrated by converting the products into various bioactive fluorinated compounds, showing its potential applications in drug discovery and biochemistry.

Targeting ferroptosis in cardio-metabolic-diseases: Mechanisms and therapeutic prospects.

Cardio-metabolic-diseases (cardio-metabolic-diseases) are leading causes of death and disability worldwide and impose a tremendous burden on whole society as well as individuals. As a new type of regulated cell death (RCD), ferroptosis is distinct from several classical types of RCDs such as apoptosis and necroptosis in cell morphology, biochemistry, and genetics. The main molecular mechanisms of ferroptosis involve iron metabolism dysregulation, mitochondrial malfunction, impaired antioxidant capacity, accumulation of lipid-related peroxides and membrane disruption. Within the past few years, mounting evidence has shown that ferroptosis contributes to the pathophysiological process in cardio-metabolic-diseases. However, the exact roles and underlying molecular mechanisms have not been fully elucidated. This review comprehensively summarizes the mechanism of ferroptosis in the development and progression of cardio-metabolic-diseases, so as to provide new insights for cardio-metabolic-diseases pathophysiology. Moreover, we highlight potential druggable molecules in ferroptosis signaling pathway, and discuss recent advances in management strategies by targeting ferroptosis for prevention and treatment of cardio-metabolic-diseases.

Ferroptosis inhibitor liproxstatin-1 alleviates metabolic dysfunction-associated fatty liver disease in mice: potential involvement of PANoptosis.

Ferroptosis is a new form of regulated cell death characterized by excessive iron accumulation and uncontrollable lipid peroxidation. The role of ferroptosis in metabolic dysfunction-associated fatty liver disease (MAFLD) is not fully elucidated. In this study we compared the therapeutic effects of ferroptosis inhibitor liproxstatin-1 (LPT1) and iron chelator deferiprone (DFP) in MAFLD mouse models. This model was established in mice by feeding a high-fat diet with 30% fructose in water (HFHF) for 16 weeks. The mice then received LPT1 (10 mg·kg-1·d-1, ip) or DFP (100 mg·kg-1·d-1, ig) for another 2 weeks. We showed that both LPT1 and DFP treatment blocked the ferroptosis markers ACSL4 and ALOX15 in MAFLD mice. Furthermore, LPT1 treatment significantly reduced the liver levels of triglycerides and cholesterol, lipid peroxidation markers 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), and ameliorated the expression of lipid synthesis/oxidation genes (Pparα, Scd1, Fasn, Hmgcr and Cpt1a), insulin resistance, mitochondrial ROS content and liver fibrosis. Importantly, LPT1 treatment potently inhibited hepatic apoptosis (Bax/Bcl-xL ratio and TUNEL+ cell number), pyroptosis (cleavages of Caspase-1 and GSDMD) and necroptosis (phosphorylation of MLKL). Moreover, LPT1 treatment markedly inhibited cleavages of PANoptosis-related caspase-8 and caspase-6 in MAFLD mouse liver. In an in vitro MAFLD model, treatment with LPT1 (100 nM) prevented cultured hepatocyte against cell death induced by pro-PANoptosis molecules (TNF-α, LPS and nigericin) upon lipid stress. On the contrary, DFP treatment only mildly attenuated hepatic inflammation but failed to alleviate lipid deposition, insulin resistance, apoptosis, pyroptosis and necroptosis in MAFLD mice. We conclude that ferroptosis inhibitor LPT1 protects against steatosis and steatohepatitis in MAFLD mice, which may involve regulation of PANoptosis, a coordinated cell death pathway that involves apoptosis, pyroptosis and necroptosis. These results suggest a potential link between ferroptosis and PANoptosis.

Ferroptotic stress facilitates smooth muscle cell dedifferentiation in arterial remodelling by disrupting mitochondrial homeostasis.

Smooth muscle cell (SMC) phenotypic switch from a quiescent 'contractile' phenotype to a dedifferentiated and proliferative state underlies the development of cardiovascular diseases (CVDs); however, our understanding of the mechanism is still incomplete. In the present study, we explored the potential role of ferroptosis, a novel nonapoptotic form of cell death, in SMC phenotypic switch and related neointimal formation. We found that ferroptotic stress was triggered in cultured dedifferentiated SMCs and arterial neointimal tissue of wire-injured mice. Moreover, pro-ferroptosis stress was activated in arterial neointimal tissue of clinical patients who underwent carotid endarterectomy. Blockade of ferroptotic stress via administration of a pharmacological inhibitor or by global genetic overexpression of glutathione peroxidase-4 (GPX4), a well-established anti-ferroptosis molecule, delayed SMC phenotype switch and arterial remodelling. Conditional SMC-specific gene delivery of GPX4 using adreno-associated virus in the carotid artery inhibited ferroptosis and prevented neointimal formation. Conversely, ferroptosis stress directly triggered dedifferentiation of SMCs. Transcriptomics analysis demonstrated that inhibition of ferroptotic stress mainly targets the mitochondrial respiratory chain and oxidative phosphorylation. Mechanistically, ferroptosis inhibition corrected the disrupted mitochondrial homeostasis in dedifferentiated SMCs, including enhanced mitochondrial ROS production, dysregulated mitochondrial dynamics, and mitochondrial hyperpolarization, and ultimately inhibited SMC phenotypic switch and growth. Copper-diacetyl-bisN4-methylthiosemicarbazone (CuATSM), an agent used for clinical molecular imaging and that potently inhibits ferroptosis, prevented SMC phenotypic switch, neointimal formation and arterial inflammation in mice. These results indicate that pro-ferroptosis stress is likely to promote SMC phenotypic switch during neointimal formation and imply that inhibition of ferroptotic stress may be a promising translational approach to treat CVDs with SMC phenotype switch.

Zinc supplementation ameliorates sorafenib-induced cognitive impairment through ROS/JNK signaling pathway.

Sorafenib, a multiple kinase inhibitor, is widely used in cancer patients. Recently, clinical studies highlighted the relationship between cognitive deficits and sorafenib exposure. Zinc abundant in the body has been reported to exert neuroprotective activities. However, the effects of zinc supplementation on sorafenib-induced cognitive impairment are still unknown. In the current study, we verified that mice challenged with sorafenib displayed characteristic features of cognitive impairment. However, zinc treatment effectively improved these changes. Histopathological staining also showed that zinc significantly alleviated hippocampal microstructural and ultrastructural damages induced by sorafenib. Meanwhile, zinc significantly reduced sorafenib-induced ROS production and neuronal cells apoptosis in vivo and vitro. Additionally, we also investigated whether zinc protected against sorafenib-induced neuronal cells apoptosis via ROS/JNK pathway through treating SH-SY5Y cells with the NAC or the specific JNK activator anisomycin. The results indicated that NAC performed the same protective effects as zinc in sorafenib-challenged SH-SY5Y cells and activation of JNK by anisomycin partly abolished the protective effects of zinc. Collectively, the present study suggested that inhibition of oxidative stress and the JNK pathway might contribute to the protective effects of zinc against sorafenib-caused cognitive impairment in vivo and vitro.