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Ferroptosis, a newform of programmed cell death, driven by peroxidative damages of polyunsaturated-fatty-acid-containing phospholipids in cellular membranes and is extremely dependent on iron ions, which is differs characteristics from traditional cell death has attracted greater attention. Based on the curiosity of this new form of regulated cell death, there has a tremendous progress in the field of mechanistic understanding of ferroptosis recent years. Ferroptosis is closely associated with the development of many diseases and involved in many diseases related signaling pathways. Not only a variety of oncoproteins and tumor suppressors can regulate ferroptosis, but multiple oncogenic signaling pathways can also have a regulatory effect on ferroptosis. Ferroptosis results in the accumulation of large amounts of lipid peroxides thus involving the onset of oxidative stress and energy stress responses. The MAPK pathway plays a critical role in oxidative stress and AMPK acts as a sensor of cellular energy and is involved in the regulation of the energy stress response. Moreover, activation of AMPK can induce the occurrence of autophagy-dependent ferroptosis and p53-activated ferroptosis. In recent years, there have been new advances in the study of molecular mechanisms related to the regulation of ferroptosis by both pathways. In this review, we will summarize the molecular mechanisms by which the MAPK-AMPK signaling pathway regulates ferroptosis. Meanwhile, we sorted out the mysterious relationship between MAPK and AMPK, described the crosstalk among ferroptosis and MAPK-AMPK signaling pathways, and summarized the relevant ferroptosis inducers targeting this regulatory network. This will provide a new field for future research on ferroptosis mechanisms and provide a new vision for cancer treatment strategies. CQk632wjDSDpD5-dCjDzAa Video Abstract

Variation in the TGF-β signaling pathway is emerging as an important mechanism by which gonadal sex determination is controlled in teleosts. Here we show that amhy, a Y-specific duplicate of the anti-Müllerian hormone (amh) gene, induces male sex determination in Nile tilapia. amhy is a tandem duplicate located immediately downstream of amhΔ-y on the Y chromosome. The coding sequence of amhy was identical to the X-linked amh (amh) except a missense SNP (C/T) which changes an amino acid (Ser/Leu92) in the N-terminal region. amhy lacks 5608 bp of promoter sequence that is found in the X-linked amh homolog. The amhΔ-y contains several insertions and deletions in the promoter region, and even a 5 bp insertion in exonVI that results in a premature stop codon and thus a truncated protein product lacking the TGF-β binding domain. Both amhy and amhΔ-y expression is restricted to XY gonads from 5 days after hatching (dah) onwards. CRISPR/Cas9 knockout of amhy in XY fish resulted in male to female sex reversal, while mutation of amhΔ-y alone could not. In contrast, overexpression of Amhy in XX fish, using a fosmid transgene that carries the amhy/amhΔ-y haplotype or a vector containing amhy ORF under the control of CMV promoter, resulted in female to male sex reversal, while overexpression of AmhΔ-y alone in XX fish could not. Knockout of the anti-Müllerian hormone receptor type II (amhrII) in XY fish also resulted in 100% complete male to female sex reversal. Taken together, these results strongly suggest that the duplicated amhy with a missense SNP is the candidate sex determining gene and amhy/amhrII signal is essential for male sex determination in Nile tilapia. These findings highlight the conserved roles of TGF-β signaling pathway in fish sex determination.

Studies of gene function in non-model animals have been limited by the approaches available for eliminating gene function. The CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR associated) system has recently become a powerful tool for targeted genome editing. Here, we report the use of the CRISPR/Cas9 system to disrupt selected genes, including nanos2, nanos3, dmrt1, and foxl2, with efficiencies as high as 95%. In addition, mutations in dmrt1 and foxl2 induced by CRISPR/Cas9 were efficiently transmitted through the germline to F1. Obvious phenotypes were observed in the G0 generation after mutation of germ cell or somatic cell-specific genes. For example, loss of Nanos2 and Nanos3 in XY and XX fish resulted in germ cell-deficient gonads as demonstrated by GFP labeling and Vasa staining, respectively, while masculinization of somatic cells in both XY and XX gonads was demonstrated by Dmrt1 and Cyp11b2 immunohistochemistry and by up-regulation of serum androgen levels. Our data demonstrate that targeted, heritable gene editing can be achieved in tilapia, providing a convenient and effective approach for generating loss-of-function mutants. Furthermore, our study shows the utility of the CRISPR/Cas9 system for genetic engineering in non-model species like tilapia and potentially in many other teleost species.

ObjectiveThis study aimed to estimate the prevalence of hyperuricaemia (HUA) and investigate its risk factors in the general adult population of Ningxia Hui Autonomous Region (NHAR), China.DesignCross-sectional study.SettingSurvey of cardiovascular disorders and their related risk factors in NHAR, China.Participants10 803 permanent residents aged 18 and older.Main outcome measuresHUA was defined as serum uric acid levels >420 µmol/L for men and >360 µmol/L for women.ResultsThe overall prevalence of HUA in NHAR adults was 19.81% (95% CI 19.06 to 20.57), with prevalence values of 24.91% (95% CI 23.70 to 26.14) in men and 15.58% (95% CI 14.66 to 16.53, p<0.001) in women. The prevalence of HUA was higher in urban residents than in rural residents (23.26% vs 17.02%, p<0.001). HUA prevalence was relatively high in individuals younger than 30 years for both men and women, then decreased with age, and began to increase at the age of 40 for women and 60 for men. Higher level of education, being overweight or obese, alcohol consumption, hypertension, diabetes, higher triglycerides, higher total cholesterol and poorer renal function were associated with an increased risk of HUA.ConclusionsHUA prevalence is high among adults in NHAR. Young adults under 30 years and women over 50 years were identified as populations at high risk for HUA. Further attention ought to be placed to promoting healthy diets and implementing early interventions to manage dyslipidaemia, obesity and blood glucose level, as well as advocating for moderation of alcohol consumption.

Background Spotted scat, a marine aquaculture fish, has variable body color development stages during their ontogenesis. However, the regulatory mechanism of body color patterns formation was poorly understood. Thyroid hormones (TH) function as an important endocrine factor in regulating metamorphosis. In this study, exogenous thyroid hormones 3,5,3′-L-triiodothyronine (T3) and its inhibitor thiourea (TU) were used to treat spotted scat juveniles during the metamorphosis stage (from 60 to 90 dpf). The function and molecular mechanism of thyroid hormone signaling in regulating body color patterns formation was revealed, using the micro-observation of pigments cells distribution, colorimetric evaluation and carotenoids concentration measurement by spectrophotometry, and comparative transcriptome analysis. Results Spotted scat body color patterns consisted of whole body black color, black bar, black and red spots, and its final pattern was formed through the metamorphosis. When spotted scat were treated with the inhibitor TU to disrupt thyroid hormone signaling, the levels of T3 and T4 were significantly decreased, the melanophores numbers were significantly increased, as well as the expression of genes involved in melanin synthesis and melanophore differentiation ( tyr , tyrp1 , dct , mitf, pmel , oca2 , slc24a5 , and erbb3 ) was significantly increased. Besides, the expression of genes associated with carotenoids and pteridine metabolism ( apod , pnpla2 , rdh12 , stard10 , xdh , abca1 , retsat , scarb1 , rgs2 , and gch1 ) and carotenoids accumulation were stimulated, when thyroid hormone signaling was disrupted by TU. On the contrary, the levels of T3 and T4 were significantly elevated in spotted scat treated with T3, which could weaken the skin redness and reduce the number of black spots and melanophores, as well as the number and diameter of larval erythrophores. Notably, unlike melanophores and erythrophores, the differentiation of iridophore was promoted by thyroid hormones, gene related to iridophore differentiation ( fhl2-l , fhl2 , ltk , id2a , alx4 ) and guanine metabolism ( gmps , hprt1 , ppat , impdh1b ) were up-regulated after T3 treatment, but they were down-regulated after TU treatment. Conclusions Above results showed that thyroid hormone signaling might play critical roles in regulation pigments synthesis and deposition, thereby affecting pigment cells (melanophores, iridophores and erythrophores) formation and body color patterns. The mechanisms of hyperthyroid and hypothyroid on different pigment cells development were different. Excess thyroid hormone might impact the rearrangement of melanophore by regulating cell cycle, resulting in the abnormalities of black spots in spotted scat. Meanwhile, the excessed thyroid hormone could reduce the number and diameter of larval erythrophores, as well as weaken the skin redness of juvenile erythrophores, but they were enhanced by the disruption of thyroid hormone. However, the formation of iridophore differentiation and guanine synthesis genes expression were stimulated by thyroid hormones. These findings provide new insights for exploring the formation of body color patterns in fish, and help to elucidate the molecular mechanism of thyroid hormone in regulating pigment cell development and body coloration, and may also contribute to selective breeding of ornamental fish.

Meiosis is a process unique to the differentiation of germ cells. Retinoic acid (RA) is the key factor controlling the sex-specific timing of meiotic initiation in tetrapods; however, the role of RA in meiotic initiation in teleosts has remained unclear. In this study, the genes encoding RA synthase aldh1a2 and catabolic enzyme cyp26a1 were isolated from Nile tilapia ( Oreochromis niloticus ), a species without stra8 . The expression of aldh1a2 was up-regulated and expression of cyp26a1 was down-regulated before the meiotic initiation in ovaries and in testes. Treatment with RA synthase inhibitor or disruption of Aldh1a2 by CRISPR/Cas9 resulted in delayed meiotic initiation, with simultaneous down-regulation of cyp26a1 and up-regulation of sycp3 . By contrast, treatment with an inhibitor of RA catabolic enzyme and disruption of cyp26a1 resulted in earlier meiotic initiation, with increased expression of aldh1a2 and sycp3 . Additionally, treatment of XY fish with estrogen (E2) and XX fish with fadrozole led to sex reversal and reversion of meiotic initiation. These results indicate that RA is indispensable for meiotic initiation in teleosts via a stra8 independent signaling pathway where both aldh1a2 and cyp26a1 are critical. In contrast to mammals, E2 is a major regulator of sex determination and meiotic initiation in teleosts.

Objective This study was designed to examine the correlation between serum uric acid (SUA) and fasting plasma glucose (FPG) levels across non‐diabetic, pre‐diabetic, and diabetic adults from Northwest China. Materials and Methods This study utilized data from a cross‐sectional survey conducted in Ningxia Hui Autonomous Region, which investigated the prevalence and risk factors of cardiovascular disease. All subjects underwent tests for SUA and FPG levels. Generalized additive models and two‐piecewise linear regression models were applied to explore the relationships between SUA and FPG level. The triglyceride–glucose (TyG) index was examined as a measure of insulin resistance, with an analysis of its mediating effects on the association between SUA and FPG level. Results A total of 10,217 individuals aged 18 and over were included. Generalized additive models verified the inverted U‐shaped association between SUA and FPG levels, and the inflection points of FPG levels in the curves were 6.5 mmol/L in males and 8.8 mmol/L in females. The TyG index is an intermediate variable in the relationship between SUA levels and elevated FPG levels, with mediating effects of 12.82% (P < 0.001) for males and 34.02% (P < 0.001) for females. Conclusions An inverted U‐shaped association between FPG and SUA levels was observed in both genders. The threshold of FPG level was lower in males than in females. The relationship between these variables seems to be partially mediated by serum insulin levels. The current findings support the hypothesis that SUA levels might be involved in the early, rather than advanced, stages of glucose metabolism disorder. Patients with pre‐diabetes and newly diagnosed diabetes might be at a higher risk of hyperuricemia. The findings are of great significance for the management of diabetes.

Circular RNAs (circRNAs) are novel single-stranded noncoding RNAs that can decoy other RNAs to inhibit their functions. Kaposi’s sarcoma (KS), caused by oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV), is a highly angiogenic and invasive vascular tumor of endothelial origin commonly found in AIDS patients. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) induces cell invasion, angiogenesis and cellular transformation; however, the role of circRNAs is largely unknown in the context of KSHV vIRF1. Herein, transcriptome analysis identified 22 differentially expressed cellular circRNAs regulated by vIRF1 in an endothelial cell line. Among them, circARFGEF1 was the highest upregulated circRNA. Mechanistically, vIRF1 induced circARFGEF1 transcription by binding to transcription factor lymphoid enhancer binding factor 1 (Lef1). Importantly, upregulation of circARFGEF1 was required for vIRF1-induced cell motility, proliferation and in vivo angiogenesis. circARFGEF1 functioned as a competing endogenous RNAs (ceRNAs) by binding to and inducing degradation of miR-125a-3p. Mass spectrometry analysis demonstrated that glutaredoxin 3 (GLRX3) was a direct target of miR-125a-3p. Knockdown of GLRX3 impaired cell motility, proliferation and angiogenesis induced by vIRF1. Taken together, vIRF1 transcriptionally activates circARFGEF1, potentially by binding to Lef1, to promote cell oncogenic phenotypes via inhibiting miR-125a-3p and inducing GLRX3. These findings define a novel mechanism responsible for vIRF1-induced oncogenesis and establish the scientific basis for targeting these molecules for treating KSHV-associated cancers.

Sex determination and differentiation in teleosts are governed by complex genetic regulatory networks that include evolutionarily conserved mechanisms. In this study, we investigated Boleophthalmus pectinirostris, a Gobiidae species lacking heterogametic sex chromosomes, using comparative gonadal transcriptome analysis to identify sex differentially expressed genes (DEGs). RNA sequencing of ovarian and testicular tissues identified 17,214 DEGs, including 14,302 upregulated in males and 2912 upregulated in females. These DEGs were primarily associated with male (e.g., dmrt1, amh, amhr2) or female (e.g., bmp15, gdf9, rspo1) sex determination and differentiation, steroidogenesis (e.g., hsd17b1, hsd3b1, cyp17a1), and meiosis (e.g., cyp26b1, aldh1a2, piwil2). Functional enrichment analysis revealed that male upregulated DEGs were involved in spermatogenesis pathways such as calcium signaling, while female upregulated DEGs were associated with oogenesis pathways including oocyte meiosis and progesterone-mediated oocyte maturation. Conserved regulators, notably dmrt1 and amh, were predicted to act as key hubs in protein–protein interaction networks, being primarily associated with reproductive processes and sex differentiation in B. pectinirostris. The amh gene produces two alternatively spliced isoforms that differ by a partial deletion in the second exon, both expressed in ovaries and testes. Collectively, this study provides the first comprehensive molecular framework of sex determination and differentiation in Gobiidae species, offering critical insights into the regulatory mechanisms of B. pectinirostris reproductive development.

The fish brain plays a crucial role in regulating growth, reproduction, development, and adaptation to environmental stress. However, there are few studies that have examined the entire fish brain transcriptome and its responses to long‐term hypo‐ and hyper‐salinity stress. Greater amberjack ( Seriola dumerili ) has a high commercial value in mariculture worldwide due to its high growth rate and excellent flesh quality. Consequently, high‐throughput RNA‐Seq was employed to elucidate the molecular regulatory mechanisms underlying salinity adaptation by identifying gene expression changes in the brain of greater amberjack exposed to elevated and/or reduced salinity environments. We subjected individuals to salinity levels of 20, 30, and 40 ppt (parts per thousand) for 30 days. A total of 272 (198 up‐regulated and 74 down‐regulated) differentially expressed genes (DEGs) were identified in the B30 vs. B20 group, 21 (10 up‐regulated and 11 down‐regulated) DEGs in the B30 vs. B40 group, and 343 (119 up‐regulated and 224 down‐regulated) DEGs in the B20 vs. B40 group. Transcriptomic analysis revealed that salinity stress influenced the expression of genes associated with amino acid metabolism and transport ( gpt , arg2 , LOC111237759 , slc3a2 , and slc7a5 ), carbohydrate metabolism ( aldob , ldhba , and gapdh ), and signal transduction ( map3k8 , map3k2 , map2k7 , and lepr ). Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that the DEGs were significantly enriched in metabolism pathways, especially in amino acid and carbohydrate metabolism, transcription, translation, et cetera. Furthermore, gene set enrichment analysis (GSEA) demonstrated that the metabolism, signal transduction, translation, immune system, and transport and catabolism pathways were more active in the brain. These findings provide a foundation for further studies to clarify the molecular mechanisms of salinity adaptation and transcriptional regulation in the brain of marine fish.