STING-dependent trained immunity contributes to host defense against Clostridium perfringens infection via mTOR signaling.

Clostridium perfringens (C. perfringens) infection is recognized as one of the most challenging issues threatening food safety and perplexing agricultural development. To date, the molecular mechanisms of the interactions between C. perfringens and the host remain poorly understood. Here, we show that stimulator of interferon genes (STING)-dependent trained immunity protected against C. perfringens infection through mTOR signaling. Heat-killed Candida albicans (HKCA) training elicited elevated TNF-α and IL-6 production after LPS restimulation in mouse peritoneal macrophages (PM). Although HKCA-trained PM produced decreased levels of TNF-α and IL-6, the importance of trained immunity was demonstrated by the fact that HKCA training resulted in enhanced bacterial phagocytic ability and clearance in vivo and in vitro during C. perfringens infection. Interestingly, HKCA training resulted in the activation of STING signaling. We further demonstrate that STING agonist DMXAA is a strong inducer of trained immunity and conferred host resistance to C. perfringens infection in PM. Importantly, corresponding to higher bacterial burden, reduction in cytokine secretion, phagocytosis, and bacterial killing were shown in the absence of STING after HKCA training. Meanwhile, the high expression levels of AKT/mTOR/HIF1α were indeed accompanied by an activated STING signaling under HKCA or DMXAA training. Moreover, inhibiting mTOR signaling with rapamycin dampened the trained response to LPS and C. perfringens challenge in wild-type (WT) PM after HKCA training. Furthermore, STING­deficient PM presented decreased levels of mTOR signaling-related proteins. Altogether, these results support STING involvement in trained immunity which protects against C. perfringens infection via mTOR signaling.

Dihydroartemisinin is an inhibitor of trained immunity through Akt/mTOR/HIF1α signaling pathway.

Trained immunity is mechanistically defined as the metabolically and epigenetically mediated long-term functional adaptation of the innate immune system, characterized by a heightened response to a secondary stimulation. Given appropriate activation, trained immunity represents an attractive anti-infective therapeutic target. Nevertheless, excessive immune response and subsequent inflammatory cascades may contribute to pathological tissue damage, indicating that the negative impacts of trained immunity appear to be significant. In this study, we show that innate immune responses such as the production of extracellular traps, pro-inflammatory cytokines, and autophagy-related proteins were markedly augmented in trained BMDMs. Furthermore, heat-killed C. albicans priming promotes the activation of the AIM2 inflammasome, and AIM2-/- mice exhibit impaired memory response induced by heat-killed C. albicans. Therefore, we establish that the AIM2 inflammasome is involved in trained immunity and emerges as a promising therapeutic target for potentially deleterious effects. Dihydroartemisinin can inhibit the memory response induced by heat-killed C. albicans through modulation of mTOR signaling and the AIM2 inflammasome. The findings suggest that dihydroartemisinin can reduce the induction of trained immunity by heat-killed C. albicans in C57BL/6 mice. Dihydroartemisinin is one such therapeutic intervention that has the potential to treat of diseases characterized by excessive trained immunity.

Identification and biological characteristics of Enterococcus casseliflavus TN-47 isolated from Monochamus alternatus.

With the widespread use of antibiotics, the incidence of antibiotic resistance in microorganisms has increased. Monochamus alternatus is a trunk borer of pine trees. This study aimed to investigate the in vitro antimicrobial and biological characteristics of Enterococcus casseliflavus TN-47 (PP411196), isolated from the gastrointestinal tract of M. alternatus in Jilin Province, PR China. Among 13 isolates obtained from the insects, five were preliminarily screened for antimicrobial activity. E. casseliflavus TN-47, which exhibited the strongest antimicrobial activity, was identified. E. casseliflavus TN-47 possessed antimicrobial activity against Staphylococcus aureus USA300 and Salmonella enterica serovar Pullorum ATCC 19945. Furthermore, E. casseliflavus TN-47 was sensitive to tetracyclines, penicillins (ampicillin, carbenicillin, and piperacillin), quinolones and nitrofuran antibiotics, and resistant to certain beta-lactam antibiotics (oxacillin, cefradine and cephalexin), macrolide antibiotics, sulfonamides and aminoglycosides. E. casseliflavus TN-47 could tolerate low pH and pepsin-rich conditions in the stomach and grow in the presence of bile acids. E. casseliflavus TN-47 retained its strong auto-aggregating ability and hydrophobicity. This strain did not exhibit any haemolytic activity. These results indicate that E. casseliflavus TN-47 has potential as a probiotic. This study provides a theoretical foundation for the future applications of E. casseliflavus TN-47 and its secondary metabolites in animal nutrition and feed.

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.

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.

CGA alleviates LPS-induced inflammation and milk fat reduction in BMECs through the NF-κB signaling pathway.

Mastitis is an easy clinical disease in dairy cows, which seriously affects the milk yield and quality of dairy cows. Chlorogenic acid (CGA), a polyphenolic substance, is abundant in Eucommia ulmoides leaves and has anti-inflammatory and anti-oxidative stress effects. Here, we explore whether CGA attenuated lipopolysaccharide (LPS)-induced inflammation and decreased milk fat in bovine mammary epithelial cells (BMECs). 10 µg/mL LPS was used to induce mastitis in BMECs. QRT-PCR, Western blotting, oil red O staining, and triglyceride (TG) assay were used to examine the effects of CGA on BMECs, including inflammatory response, oxidative stress response, and milk fat synthesis. The results showed that CGA repaired LPS-induced inflammation in BMECs. The expression of IL-6, IL-8, TNF-α, IL-1ß, and iNOS was decreased, and the expression levels of CHOP, XCT, NRF2, and HO-1 were increased, which reduced the oxidative stress level of cells and alleviated the reduction of milk fat synthesis. In addition, the regulation of P65 phosphorylation by CGA suggests that CGA may exert its anti-inflammatory and anti-oxidative effects through the NF-κB signaling pathway. Our study showed that CGA attenuated LPS-induced inflammation and oxidative stress, and restored the decrease in milk fat content in BMECs by regulating the NF-κB signaling pathway.

EGF-driven EGFR/miR-27b-3p/FOXO1 promotes rat FSH synthesis and secretion.

The adenopituitary secretes follicle-stimulating hormone (FSH), which plays a crucial role in regulating the growth, development, and reproductive functions of organisms. Investigating the process of FSH synthesis and secretion can offer valuable insights into potential areas of focus for reproductive research. Epidermal growth factor (EGF) is a significant paracrine/autocrine factor within the body, and studies have demonstrated its ability to stimulate FSH secretion in animals. However, the precise mechanisms that regulate this action are still poorly understood. In this research, in vivo and in vitro experiments showed that the activation of epidermal growth factor receptor (EGFR) by EGF induces the upregulation of miR-27b-3p and that miR-27b-3p targets and inhibits Foxo1 mRNA expression, resulting in increased FSH synthesis and secretion. In summary, this study elucidates the precise molecular mechanism through which EGF governs the synthesis and secretion of FSH via the EGFR/miR-27b-3p/FOXO1 pathway.

MSI2 Modulates Unsaturated Fatty Acid Metabolism by Binding FASN in Bovine Mammary Epithelial Cells.

The regulation of fatty acid metabolism is crucial for milk flavor and quality. Therefore, it is important to explore the genes that play a role in fatty acid metabolism and their mechanisms of action. The RNA-binding protein Musashi2 (MSI2) is involved in the regulation of numerous biological processes and plays a regulatory role in post-transcriptional translation. However, its role in the mammary glands of dairy cows has not been reported. The present study examined MSI2 expression in mammary glands from lactating and dry milk cows. Experimental results in bovine mammary epithelial cells (BMECs) showed that MSI2 was negatively correlated with the ability to synthesize milk fat and that MSI2 decreased the content of unsaturated fatty acids (UFAs) in BMECs. Silencing of Msi2 increased triglyceride accumulation in BMECs and increased the proportion of UFAs. MSI2 affects TAG synthesis and milk fat synthesis by regulating fatty acid synthase (FASN). In addition, RNA immunoprecipitation experiments in BMECs demonstrated for the first time that MSI2 can bind to the 3'-UTR of FASN mRNA to exert a regulatory effect. In conclusion, MSI2 affects milk fat synthesis and fatty acid metabolism by regulating the triglyceride synthesis and UFA content through binding FASN.

Ferulic acid ameliorates the quality of in vitro-aged bovine oocytes by suppressing oxidative stress and apoptosis.

Ferulic acid (FA) is a well-known natural antioxidant that scavenges oxygen free radicals and alleviates oxidative stress. This study investigated the chemopreventive potential of FA against bovine oocyte quality decline during in vitro aging. The results showed that 5 µM FA supplementation decreased the abnormality rate of in vitro-aged bovine oocytes. In addition, FA supplementation effectively improved antioxidant capacity by removing excessive ROS and maintaining intracellular GSH levels and antioxidant enzyme activity. The mitochondrial activity, mitochondrial membrane potential and intracellular ATP levels in aged bovine oocytes were obviously enhanced by FA supplementation. Furthermore, FA supplementation reduced in vitro aging-induced DNA damage and maintained DNA stability in bovine oocytes. Moreover, sperm binding assay showed the number of sperm that bound to the zona pellucida on aged bovine oocytes was significantly higher in the FA supplemented group than in the Aged group. Therefore, FA is beneficial for maintaining in vitro-aged bovine oocyte quality and could become a potential antioxidant for preventing bovine oocyte in vitro aging during in vitro maturation.

Ferulic Acid Enhances Oocyte Maturation and the Subsequent Development of Bovine Oocytes.

Improving the quality of oocytes matured in vitro is integral to enhancing the efficacy of in vitro embryo production. Oxidative stress is one of the primary causes of quality decline in oocytes matured in vitro. In this study, ferulic acid (FA), a natural antioxidant found in plant cell walls, was investigated to evaluate its impact on bovine oocyte maturation and subsequent embryonic development. Bovine cumulus-oocyte complexes (COCs) were treated with different concentrations of FA (0, 2.5, 5, 10, 20 µM) during in vitro maturation (IVM). Compared to the control group, supplementation with 5 µM FA significantly enhanced the maturation rates of bovine oocytes and the expansion of the cumulus cells area, as well as the subsequent cleavage and blastocyst formation rates after in vitro fertilization (IVF) and somatic cell nuclear transfer (SCNT). Furthermore, FA supplementation was observed to effectively decrease the levels of ROS in bovine oocytes and improve their mitochondrial function. Our experiments demonstrate that FA can maintain the levels of antioxidants (GSH, SOD, CAT) in oocytes, thereby alleviating the oxidative stress induced by H2O2. RT-qPCR results revealed that, after FA treatment, the relative mRNA expression levels of genes related to oocyte maturation (GDF-9 and BMP-15), cumulus cell expansion (HAS2, PTX3, CX37, and CX43), and embryo pluripotency (OCT4, SOX2, and CDX2) were significantly increased. In conclusion, these findings demonstrate that FA supplementation during bovine oocyte IVM can enhance oocyte quality and the developmental potential of subsequent embryos.

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.

ID3 regulates progesterone synthesis in bovine cumulus cells through modulation of mitochondrial function.

DNA binding inhibitory factor 3 (ID3) has been shown to have a key role in maintaining proliferation and differentiation. It has been suggested that ID3 may also affect mammalian ovarian function. However, the specific roles and mechanisms are unclear. In this study, the expression level of ID3 in cumulus cells (CCs) was inhibited by siRNA, and the downstream regulatory network of ID3 was uncovered by high-throughput sequencing. The effects of ID3 inhibition on mitochondrial function, progesterone synthesis, and oocyte maturation were further explored. The GO and KEGG analysis results showed that after ID3 inhibition, differentially expressed genes, including StAR, CYP11A1, and HSD3B1, were involved in cholesterol-related processes and progesterone-mediated oocyte maturation. Apoptosis in CC was increased, while the phosphorylation level of ERK1/2 was inhibited. During this process, mitochondrial dynamics and function were disrupted. In addition, the first polar body extrusion rate, ATP production and antioxidation capacity were reduced, which suggested that ID3 inhibition led to poor oocyte maturation and quality. The results will provide a new basis for understanding the biological roles of ID3 as well as cumulus cells.

WITHDRAWN: RNA binding protein Musashi2 regulates dairy cows' mastitis by activating the TGFß signaling pathway.

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Maslinic Acid Supplementation during the In Vitro Culture Period Ameliorates Early Embryonic Development of Porcine Embryos by Regulating Oxidative Stress.

As a pentacyclic triterpene, MA exhibits effective free radical scavenging capabilities. The purpose of this study was to explore the effects of MA on porcine early-stage embryonic development, oxidation resistance and mitochondrial function. Our results showed that 1 µM was the optimal concentration of MA, which resulted in dramatically increased blastocyst formation rates and improvement of blastocyst quality of in vitro-derived embryos from parthenogenetic activation (PA) and somatic cell nuclear transfer (SCNT). Further analysis indicated that MA supplementation not only significantly decreased the abundance of intracellular reactive oxygen species (ROS) and dramatically increased the abundance of intracellular reductive glutathione (GSH) in porcine early-stage embryos, but also clearly attenuated mitochondrial dysfunction and inhibited apoptosis. Moreover, Western blotting showed that MA supplementation upregulated OCT4 (p < 0.01), SOD1 (p < 0.0001) and CAT (p < 0.05) protein expression in porcine early-stage embryos. Collectively, our data reveal that MA supplementation exerts helpful effects on porcine early embryo development competence via regulation of oxidative stress (OS) and amelioration of mitochondrial function and that MA may be useful for increasing the in vitro production (IVP) efficiency of porcine early-stage embryos.

Allicin Alleviated LPS-Induced Mastitis via the TLR4/NF-κB Signaling Pathway in Bovine Mammary Epithelial Cells.

Dairy farming is the most important economic activity in animal husbandry. Mastitis is the most common disease in dairy cattle and has a significant impact on milk quality and yield. The natural extract allicin, which is the main active ingredient of the sulfur-containing organic compounds in garlic, has anti-inflammatory, anticancer, antioxidant, and antibacterial properties; however, the specific mechanism underlying its effect on mastitis in dairy cows needs to be determined. Therefore, in this study, whether allicin can reduce lipopolysaccharide (LPS)-induced inflammation in the mammary epithelium of dairy cows was investigated. A cellular model of mammary inflammation was established by pretreating bovine mammary epithelial cells (MAC-T) with 10 µg/mL LPS, and the cultures were then treated with varying concentrations of allicin (0, 1, 2.5, 5, and 7.5 µM) added to the culture medium. MAC-T cells were examined using RT-qPCR and Western blotting to determine the effect of allicin. Subsequently, the level of phosphorylated nuclear factor kappa-B (NF-κB) was measured to further explore the mechanism underlying the effect of allicin on bovine mammary epithelial cell inflammation. Treatment with 2.5 µM allicin considerably decreased the LPS-induced increase in the levels of the inflammatory cytokines interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) and inhibited activation of the NOD-like receptor protein 3 (NLRP3) inflammasome in cow mammary epithelial cells. Further research revealed that allicin also inhibited the phosphorylation of inhibitors of nuclear factor kappa-B-α (IκB-α) and NF-κB p65. In mice, LPS-induced mastitis was also ameliorated by allicin. Therefore, we hypothesize that allicin alleviated LPS-induced inflammation in the mammary epithelial cells of cows probably by affecting the TLR4/NF-κB signaling pathway. Allicin will likely become an alternative to antibiotics for the treatment of mastitis in cows.

DNA Double-Strand Break-Related Competitive Endogenous RNA Network of Noncoding RNA in Bovine Cumulus Cells.

(1) Background: DNA double strand breaks (DSBs) are the most serious form of DNA damage that affects oocyte maturation and the physiological state of follicles and ovaries. Non-coding RNAs (ncRNAs) play a crucial role in DNA damage and repair. This study aims to analyze and establish the network of ncRNAs when DSB occurs and provide new ideas for next research on the mechanism of cumulus DSB. (2) Methods: Bovine cumulus cells (CCs) were treated with bleomycin (BLM) to construct a DSB model. We detected the changes of the cell cycle, cell viability, and apoptosis to determine the effect of DSBs on cell biology, and further evaluated the relationship between the transcriptome and competitive endogenous RNA (ceRNA) network and DSBs. (3) Results: BLM increased γH2AX positivity in CCs, disrupted the G1/S phase, and decreased cell viability. Totals of 848 mRNAs, 75 long noncoding RNAs (lncRNAs), 68 circular RNAs (circRNAs), and 71 microRNAs (miRNAs) in 78 groups of lncRNA-miRNA-mRNA regulatory networks, 275 groups of circRNA-miRNA-mRNA regulatory networks, and five groups of lncRNA/circRNA-miRNA-mRNA co-expression regulatory networks were related to DSBs. Most differentially expressed ncRNAs were annotated to cell cycle, p53, PI3K-AKT, and WNT signaling pathways. (4) Conclusions: The ceRNA network helps to understand the effects of DNA DSBs activation and remission on the biological function of CCs.

Culturing the Chicken Intestinal Microbiota and Potential Application as Probiotics Development.

Pure cultures of chicken intestinal microbial species may still be crucial and imperative to expound on the function of gut microbiota, and also contribute to the development of potential probiotics and novel bioactive metabolites from gut microbiota. In this study, we isolated and identified 507 chicken intestinal bacterial isolates, including 89 previously uncultured isolates. Among these, a total of 63 Lactobacillus strains, belonging to L. vaginalis, L. crispatus, L. gallinarum, L. reuteri, L. salivarius, and L. saerimneri, exhibited antibacterial activity against S. Pullorum. Acid tolerance tests showed Limosilactobacillus reuteri strain YPG14 (L. reuteri strain YPG14) has a particularly strong tolerance to acid. We further characterized other probiotic properties of L. reuteri strain YPG14. In simulated intestinal fluid, the growth of L. reuteri strain YPG14 remained stable after incubation for 4 h. The auto-aggregation test showed the auto-aggregation percentage of L. reuteri strain YPG14 was recorded as 15.0 ± 0.38%, 48.3 ± 2.51%, and 75.1 ± 4.44% at 3, 12, and 24 h, respectively. In addition, the mucin binding assay showed L. reuteri strain YPG14 exhibited 12.07 ± 0.02% adhesion to mucin. Antibiotic sensitivity testing showed that L. reuteri strain YPG14 was sensitive to the majority of the tested antibiotics. The anti-Salmonella Pullorum (S. Pullorum) infection effect in vivo revealed that the consumption of L. reuteri strain YPG14 could significantly improve body weight loss and survival rate of chicks infected by S. Pullorum; reduce the loads of S. Pullorum in the jejunum, liver, spleen, and feces; and alleviate the jejunum villi morphological structure damage, crypt loss, and inflammatory cell infiltration caused by S. Pullorum. Overall, this study may help us to understand the diversity of chicken intestinal microflora and provide some insights for potential probiotic development from gut microbiota and may find application in the poultry industry.

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.

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.

miR-375 upregulates lipid metabolism and inhibits cell proliferation involved in chicken fatty liver formation and inheritance via targeting recombination signal binding protein for immunoglobulin kappa J region (RBPJ).

Poultry is susceptible to fatty liver which lead to decrease egg production and increase mortality. But the potential molecular mechanisms remain largely unclear. In the current study, in combination with transcriptome sequencing and miRNA sequencing data analysis from F1 generation of the normal liver and fatty liver tissues, the differentially expressed miR-375 and its target gene RBPJ were screened and verified. The expression levels of miR-375 and RBPJ gene in the liver between control and fatty liver groups of F0-F3 generation for Jingxing-Huang (JXH) chicken are different significantly (P < 0.05 or P < 0.01). And downregulated RBPJ expression can promote TG content and lipid droplets in primary hepatocytes cultured in vitro (P < 0.01). Cell proliferation-related genes, including PMP22, IGF-1, IGF-2, and IGFBP-5, increased or decreased significantly after overexpression or knock-down RBPJ (P < 0.05 or P < 0.01), respectively. This study uniquely revealed that miR-375 induced lipid synthesis and inhibited cell proliferation may partly due to regulation of RBPJ expression, thereby involving in fatty liver formation and inheritance in chicken. The results could be useful in identifying candidate genes and revealing the pathogenesis of fatty liver that may be used for disease-resistance selective breeding in chicken.