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Dairy cattle, particularly in Australia where dairy farming is predominantly pasture based, are experiencing an increased incidence of heat stress through rising global temperatures, causing a detrimental impact on productivity and welfare. Improving the thermotolerance of dairy cows through genetic selection is a potential proactive solution for mitigating the impact of heat stress for the dairy industry. Although heat tolerance breeding values for milk yield traits have been available to Australian dairy producers since 2017, considerable potential remains to develop genetic evaluation for heat tolerance of fertility and understanding of the underlying genetic architecture for heat tolerance. The objective of this study was to investigate the effect of heat stress measured as temperature and humidity index (THI) on fertility traits and to identify genomic regions associated with heat tolerance in 2 specific fertility traits: first service non-return rate (FNRR) and successful calving rate to first service (SCRFS). In this study, we assembled more than 892k phenotypic records of Holstein cows with THI and fertility traits and identified specific periods with respect to service day. The effect of heat stress on fertility was assessed using random regression (RR) sire model for estimating the change in genetic variance of fertility across various THI and obtaining heat tolerance solution (slope) for sires. Also, whole genome sequence genome-wide association studies (GWAS) were undertaken based on heat tolerance phenotypes of 5k Holstein bulls with at least 10 daughters with fertility data. The assessment of the different THI definitions based on different numbers of days before and after artificial service days on the fertility traits showed that the most prominent effect of THI on fertility outcomes was observed for THI 7 d preceding service (including the service day) and 6 d after service day. Heat tolerance (HT) traits with respect to FNRR and SCRFS are lowly heritable and ranged from 0.01 to 0.04 under moderate THI conditions ranging between 60 and 70. However, as the THI exceeded 70, the heritability increased to up to 0.08, indicating increased genetic variance as THI increased. Genetic correlations between extreme THI ranges were as low as 0.13, while correlations between consecutive THI ranges reached up to 0.98. This finding suggests the presence of genotype by environment interactions due to heat stress. Notable variation in heat stress sensitivity among sires was also observed for HT fertility. In total, 553 sequence variants were significantly associated HT fertility, and 52 of them were identified as independent QTL. Some of QTL regions were located near or within the genes that are involved in oxidative stress, inflammation, and fertility (e.g., TRPC5, CDK5RAP2, MGAT1, COMMD10, PRR7, GRK6, CUGBP1, MAFG, HERC2, NAPRT, HSD17B12, THRB, and EEF1D). The findings in this study will further aid in understanding genetic architecture and provide valuable information for improving the accuracy of genomic prediction of heat tolerance in dairy cattle. Show less

Psoralea corylifolia(PF) is widely utilized for the treatment of conditions such as kidney yang deficiency, frequent urination, and cold pain in the waist and knees. However, both basic research and clinical reports indicate that it induce hepatotoxicity. Our preliminary research has confirmed that PF has hepatotoxicity and in vitro research indicated that psoralidin is hepatotoxic. but it remains unclear whether psoralidin is the hepatotoxic component of PF and the mechanism of psoralidin induces hepatotoxicity. This study aimed to investigate the hepatotoxicity induced by psoralidin and its toxic mechanisms. Kunming mice were used to conduct long-term toxicity experiments. Liver function indices, organ coefficients, and histopathological observations were employed to assess the hepatotoxicity of psoralidin. Non-targeted metabolomics and proteomics analyses were conducted to elucidate the potential pathways and targets associated with psoralidin-induced hepatotoxicity. Furthermore, immunofluorescence staining, molecular docking and Western blotting analyses were utilized to validate the mechanisms underlying psoralidin hepatotoxicity. The elevation of ALT and AST, accompanied by hepatic steatosis and lipid droplet aggregation were observed after psoralidin treatement. Psoralidin affected biosynthesis of unsaturated fatty acid, fatty acid metabolism, arachidonic acid metabolism, phospholipid metabolism, and oxidative phosphorylation. Further validation research found that psoralidin induced the expressions of Acot4 and Plin5, which in turn caused up-regulations of TGs and FFA in mice, and increased the HSD17B12 level, thereby promoting the synthesis of long-chain fatty acids and facilitating lipid synthesis. And psoralidin catalyzed the conversion of phosphatidylcholine into LPC by enhancing Pla2g6 and Pla2g12b levels, which promoted the synthesis and accumulation of TGs, ultimately inducing disorders in glycerophospholipid metabolism. Furthermore, psoralidin caused upregulation of ROS and mitochondrial damage, leading to a decrease in FA oxidation. Psoralidin is one of the hepatotoxic components of PF, which induced hepatotoxicity via promoting lipid synthesis and inhibiting lipid oxidative degradation. Show less

Steroid hormones, particularly estrogens, modulate neuronal survival in the central nervous system and the retina; however, their specific cell-type-specific roles in the human retina remain incompletely characterized. We analyzed the single-cell RNA sequencing dataset E-MTAB-7316 to profile genes from the KEGG steroid hormone biosynthesis and oestrogen signalling pathways. Functional relevance of local oestrogen synthesis was tested in mouse retinal explants treated with the aromatase inhibitor letrozole (20 μM). Over 50% of steroid hormone metabolism genes were expressed in retinal cells, with cell-type specificity. COMT, HSD17B12, and HSD11B1L were broadly distributed, while LRTOMT, HSD17B7, and SRD5A1 were enriched in rod photoreceptors. Among oestrogen signalling genes, 114/139 were detected, with HSP90AA1 as the most abundant. When oestrogen synthesis was blocked with letrozole, retinal explants showed increased cell death, particularly in the outer nuclear layer, without inducing macrogliosis but with significant microglial activation (IBA1+). Our data indicate that the human retina expresses multiple components of steroid hormone metabolism and oestrogen signalling. The results are consistent with a potential role of locally synthesized oestrogens in photoreceptor maintenance and immune regulation, which may warrant further investigation as a possible avenue for retinal protection. Show less

The yellow oil crab is a highly valuable aquatic species, with the accumulation of nutritional and flavor compounds closely linked to the degree of gonadal degeneration. However, the molecular mechanisms of gonadal degeneration remain unclear. In this study, we analyzed the differences in gene expression and metabolite accumulation across three gonadal degeneration stages (QX, GX, and TSX) in yellow oil crab using transcriptome and non-targeted metabolomics approaches, and identified key genes and metabolites involved. A total of 240 differential accumulated metabolites (DAMs) were identified, most of which were significantly more highly accumulated in GX and TSX than in QX. K-means clustering analysis of DAMs and gene expression data revealed distinct stage-specific expression patterns from QX to TSX stage. Moreover, the “steroid hormone biosynthesis” pathway was significantly enriched, with 15 highly expressed steroid hormones and their derivatives in GX and TSX. 7 types of key genes involved in steroid hormone biosynthesis (such as Therefore, the identified differential steroid hormones and seven key genes were positively associated with gonadal degeneration in yellow oil crab. These results offer a theoretical basis for understanding the formation and aquaculture of the yellow oil crab. The online version contains supplementary material available at 10.1186/s12864-026-12597-y. Show less

The high prevalence of cancer immunotherapy resistance, coupled with substantial tumor heterogeneity, underscores the urgent need for innovative therapeutic targets. A deeper understanding of immunoregulatory mechanisms would provide new targets and combination therapeutic strategies for tumor therapy. In this study, we demonstrate that HSD17B12 enhances anti-tumor immunity and represents a promising therapeutic target. Mechanistically, HSD17B12 promotes lysosome-dependent degradation of PD-L1 via the VAC14 and ESCRT complexes across various malignancies, regardless of its 3-ketoacyl-CoA reductase activity. HSD17B12-deficient cells displayed PD-L1 accumulation in both tumor cells and exosomes, reducing T cell-mediated cytotoxicity. Notably, we found a significant negative correlation between HSD17B12 and PD-L1 expression in colorectal cancer tissues. Furthermore, high HSD17B12 expression in CRC correlated with increased infiltration of cytotoxic T cells. Based on these findings, we designed a peptide, HSD-CC1-NPGY, which effectively reduces PD-L1 expression in cells and suppresses tumor growth in a mouse model. Overall, our results establish HSD17B12 as an important regulator of anti-tumor immunity and a promising therapeutic target for cancer treatment. Show less

17β-Hydroxysteroid dehydrogenase 3 (17β-HSD3) deficiency is a rare 46XY disorder of sex development (DSD) of androgen biosynthesis. We aimed to describe the complexities in diagnosis, gender assignment, and the timing of irreversible surgical interventions in 17β-HSD3 deficiency. We described three genetically confirmed cases of 46XY DSD due to 17β-HSD3 deficiency. All of them had female-appearing external genitalia, and the third case had well-developed breasts with clitoromegaly. The biochemical evaluation showed hCG-stimulated T/A ratios of 0.4 and 0.35 in Cases 1 and 2, respectively, and an unstimulated T/A ratio of 0.25 in Case 3. Molecular analysis revealed three different 17β-HSD3 deficiency remains a challenging 46 XY DSD due to its clinical heterogeneity and diverse molecular spectrum. This report adds to current molecular knowledge by reporting two novel variants in the Show less

Intramuscular fat (IMF) critically governs beef sensory attributes (juiciness, tenderness, flavor). Previous studies have predominantly focused on genomics and transcriptomics, with limited proteomic data available. To gain a more comprehensive understanding of the mechanisms regulating IMF deposition, we integrated proteomic and metabolomic profiling of the Longissimus dorsi across three genetically distinct cattle breeds. A comprehensive analysis of 633 differentially abundant proteins (DAPs) and 1456 differential metabolites (DAMs) identified 20 potential protein regulators (e.g., ACAA1, ACACA, ADIPOQ, and HSD17B12) and 19 candidate metabolites (e.g., hexadecanoic acid, icosadienoic acid, oleic acid, and oxaloacetate) as key molecular markers. Furthermore, HSD17B12 was found to inhibit IMF cell proliferation while promoting differentiation and lipid accumulation. This integrated approach highlights HSD17B12 as a critical regulator in enhancing IMF content, providing a theoretical foundation for improving beef quality. Show less

This study aimed to collaboratively investigate the mechanism of variations in intramuscular fat (IMF) content in Wandong cattle using transcriptomics and metabolomics techniques. Longissimus dorsi (LD) muscle samples were collected from thirteen free-range Wandong cattle in Fengyang County, Anhui Province, China. From this initial cohort, eight animals closely matched in age and body weight were selected. Based on IMF content measured by Soxhlet extraction, these eight cattle were divided into two groups: the high-IMF (HF, n = 4) and low-IMF (LF, n = 4) groups. Subsequent analyses were performed on integrated datasets comprising the transcriptome, metabolome, and fatty acid profile. The results revealed a significant increase in IMF in the HF group compared to the LF group ( Show less

Dominant follicular development and atresia are governed by the proliferation of granulosa cells (GCs), a process influenced by the delicate balance between apoptosis and autophagy. Oxidative stress, a pivotal catalyst of GCs apoptosis, modulates gene expression through epigenetic mechanisms, including chromatin remodeling. Nevertheless, the regulatory mechanisms underpinning GCs functionality in relation to prolificacy remain inadequately elucidated. In this study, we discovered that the chromatin accessibility of nuclear receptor subfamily 1 group D member 1 (NR1D1) was markedly enhanced in dominant follicular GCs from low-prolificacy sheep, as evidenced by Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq), which correlated with elevated NR1D1 transcript levels. Remarkably, NR1D1 emerged as a novel regulator of follicular development, exhibiting heightened expression in dominant follicles. The overexpression of NR1D1 induced cell cycle arrest, autophagy activation, and mitochondrial dysfunction via the AMPK pathway, while its knockdown fostered GCs survival and functionality. Furthermore, NR1D1 inhibits the transcription of HSD17B12, thereby contributing to oxidative stress (ROS)-induced apoptosis, as demonstrated by CUT&Tag-qPCR and dual luciferase assays. The downregulation of HSD17B12 partially alleviated the effects of NR1D1 knockdown on GCs functionality. These findings indicate that NR1D1 orchestrates GCs proliferation and apoptosis through the suppression of HSD17B12 and the activation of the AMPK pathway, establishing NR1D1 as a novel transcription factor implicated in follicular development and ovarian function, with significant implications for prolificacy. Show less

Historically, 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) was thought to be the key enzyme responsible for testicular testosterone production. In humans, loss-of-function mutations in HSD17B3 impair testosterone production during prenatal life leading to impaired development of androgen-dependent tissues in 46,XY individuals. However, male mice with HSD17B3 deficiency exhibit normal testicular testosterone concentrations, normal development of reproductive organs and are fertile, suggesting that mice express other hydroxysteroid dehydrogenase enzymes capable of testicular testosterone synthesis. This study aimed to investigate whether 17β-hydroxysteroid dehydrogenase type 12 (HSD17B12), which can convert androstenedione to testosterone in mice but not in humans, compensates for the lack of HSD17B3 in Hsd17b3 knockout (KO) mice. We used CRISPR/Cas9 to substitute the amino acid in mouse HSD17B12 that is responsible for its ability to convert androstenedione to testosterone with the amino acid of the human enzyme that prevents androstenedione being used as a substrate. When this Hsd17b12 mutation was introduced into Hsd17b3 KO mice, males exhibited normal reproductive tracts but reduced testicular testosterone production with a consequential reduction in seminal vesicle weight. This suggests HSD17B12 contributes toward testosterone production in the absence of HSD17B3, but other enzymes must also contribute. We therefore quantified other testicular hydroxysteroid dehydrogenases, finding that HSD17B7 mRNA and protein was markedly upregulated in Hsd17b3 KO testes. We confirmed that mouse, but not human, HSD17B7 can produce testosterone in vitro. We conclude that compared to humans, mice exhibit increased plasticity in testosterone production via hydroxysteroid dehydrogenase enzymes to support androgen action and male fertility. Show less

17-beta hydroxysteroid dehydrogenase-3 enzyme is an enzyme expressed almost exclusively in the testes; it plays a crucial role in gonadal differentiation by catalysing the conversion of androstenedione (Δ4) to testosterone (T). The enzyme is encoded by the 17-B-hydroxysteroid dehydrogenase-3 ( Show less

Various studies have highlighted significant differences in developmental kinetics and sensitivity to developmental conditions between male and female bovine embryos. These differences are thought to be caused in part by the sexually dimorphic expression of genes located on the sex or autosomal chromosomes. However, little is known about the dimorphic gene expression patterns of bovine embryos at the initiation of elongation, which is one of the critical stages of development. Furthermore, to the best of our knowledge, there is little or no data available on the sexually dimorphic gene expression patterns in bovine embryos in relation to maternal environmental conditions during the initiation of elongation. Therefore, the main objective of this study was to investigate the sexually dimorphic gene expression responses of embryos to the maternal environment at the initiation of elongation in embryos developed in lactating dairy cows and nonlactating nulliparous heifers. Gene expression analysis showed that 159 genes including those involved in steroid biosynthesis and gastrulation were differentially expressed exclusively between male and female embryos developed in cows. Among these, 61 genes including CYP39 A1, CYP2R1 and CYP27B1 were upregulated and 98 genes including HSD17B1, HSD17B10 and aromatase (CYP19 A1) were downregulated in male embryos. Chromosomal analysis showed that 31.2% of the differentially expressed genes (DEGs) including glucose-6-phosphate dehydrogenase (G6PD) were located on the X chromosome, and 96% of those were upregulated in female embryos. Similarly, 254 genes including those involved in female sex differentiation, placenta development, transmembrane transport, and cell adhesion were differentially expressed exclusively between the male and female embryos developed in heifers. Of these, 108 genes including HSD17B11, HSD17B12, and HSD3B1 were upregulated, and 146 genes including SLC16 A9, SLC10 A1, SLC10 A3, SLC16 A5, SLC22 A23, SLC25 A43, SLC35 A2, SLC35 C1, and SLC4 were downregulated in male compared to female embryos. In addition, 17.3% of the DEGs were located on the X chromosome and 75% of the DEGs located on the X chromosome were upregulated in female embryos. On the other hand, 38 genes including SLC30 A10, SLC10 A4, ATP6 AP1, and KDM5 C showed sexually dimorphic expression patterns in day 13 bovine embryos irrespective of the maternal environment. These genes accounted for only 19% and 13% of the genes that showed sexually dimorphic expression in embryos developed in cows and heifers, respectively and the expression difference of these genes in male and female embryos was then likely influenced by the sex of the embryo. This study revealed that embryos developed in lactating cows showed sexually dimorphic expression of genes involved in various functions including steroid biosynthesis and gastrulation. In contrast, embryos developed in heifers displayed sexually dimorphic expression of genes related to placental development, female sex differentiation, and transmembrane transport. This suggests that the reproductive tract environments of cows and heifers differently affect the sex specific expression of genes in bovine embryos. A higher proportion of genes that showed sexually dimorphic expression in cow embryos were located on the X chromosome, and the majority of these genes were upregulated in female embryos. Overall, this study provides insight into genes that exhibit sexually dimorphic expression patterns in day 13 bovine embryos due to the maternal reproductive tract microenvironment or solely due to the sex of the embryo. Show less

Single nucleotide polymorphisms (SNPs) located in the genes participating in the steroid hormone metabolism pathway may influence the outcomes of androgen deprivation therapy (ADT) in prostate cancer (PCa) patients, but findings on the Chinese population remain limited. A multicentric cohort of 301 Chinese PCa patients receiving first-line ADT was enrolled. Germline SNPs located in 62 steroid hormone metabolism-related genes were analyzed for associations with time to ADT failure using multivariate Cox regression. Important expression quantitative trait loci (eQTLs) were discovered. Four SNPs were significantly associated with time to ADT failure: rs36119043 in AKR1D1 (hazard ratio, HR = 2.02, 95% confidence interval, 95% CI: 1.44-2.85, p = 5.72 × 10 SNPs in the steroid hormone metabolism pathway can predict time to ADT failure in Chinese PCa patients, supporting their potential role for drug response and pharmacogenomic stratification. Show less

A Genome-wide association study (GWAS) on a European-American cohort identified chr11p11.2 as a neuroblastoma predisposition locus. Combining in-house and public genomic data from neuroblastoma cell lines, this work implicates rs2863002 as the candidate causal variant at the 11p11.2 locus, confirming its cis-regulatory activity through a luciferase reporter assay. The genetic association of rs2863002 with neuroblastoma risk is validated in an Italian case-control cohort. Using ChIP-qPCR, Hi-C, and CRISPR genome editing, this work deciphers the regulatory mechanisms at the risk locus, demonstrating that the rs2863002-C risk allele regulates HSD17B12 expression and reduces GATA3 binding affinity. In vitro functional assays and targeted lipidomic analyses reveal the involvement of the rs2863002-C risk allele in tumorigenicity and modulation of lipid metabolism in neuroblastoma cells through HSD17B12 regulation. This study provides new insights into the genetic basis of neuroblastoma and underscores the importance of post-GWAS functional characterization of risk loci in uncovering relevant biological findings for understanding complex diseases. Show less

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia and insulin resistance, Migraine is a common chronic neurological disease caused by increased excitability of the central nervous system, both exerting substantial health burdens. However, the shared genetic basis and underlying molecular mechanisms remain largely unexplored. This study integrates single-cell data and Mendelian randomization (MR) analysis to identify comorbidity-associated genes and elucidate potential mechanistic links between these two conditions. Single-cell datasets from T2DM and migraine were analyzed to identify differentially expressed genes (DEGs). MR analysis was employed to prioritize key causal genes, followed by network-based functional characterization, disease-drug association analysis, cell annotation, and pseudo-time trajectory modeling. Analysis of single-cell data identified 2,128 migraine-associated and 3,833 T2DM-associated genes, with 714 genes shared between the two diseases. MR analysis highlighted AP4E1 and HSD17B12 as key regulators implicated in both conditions. Network analysis further linked these genes to lipid metabolism and vesicle transport pathways. Computational predictions revealed common comorbidities, including metabolic dysregulation and chemical-induced liver injury, as well as potential therapeutic agents such as valproic acid and bisphenol A. Single-cell annotation identified six major immune cell types in T2DM (T cells, NK cells, B cells, CD14 monocytes, CD16 monocytes, and dendritic cells), with T cells emerging as central players. In migraine, five immune cell types were identified (CD4 T cells, CD8 T cells, B cells, NK cells, and monocytes), with monocytes being the predominant cell type. Pseudo-time analysis delineated seven subpopulations of T cells and four subpopulations of monocytes, suggesting distinct functional trajectories in disease pathogenesis. However, due to the use of peripheral blood-derived single-cell data, genes primarily expressed in the central nervous system, such as CALCA and RAMP1, could not be detected, limiting the identification of certain migraine-specific pathways. This single-cell data and MR analysis investigation identifies AP4E1 and HSD17B12 as pivotal genetic determinants in T2DM-migraine comorbidity, shedding light on their molecular interplay and potential therapeutic relevance. Show less

17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) deficiency is a rare autosomal recessive disorder that impairs testosterone synthesis, leading to undervirilisation in 46,XY individuals. An individual in their early 20s, raised as female, developed male secondary sexual characteristics at puberty. Evaluation revealed a 46,XY karyotype. Hormonal and genetic analyses confirmed the diagnosis of 17β-HSD3 deficiency, showing the homozygous Show less

Ischemic stroke (IS) is a major cause of disability and mortality, but its genetic basis remains poorly understood. This study integrates data from three large-scale genome-wide association studies (GWASs), the GWAS Catalog, MEGASTROKE, and Open GWAS, to identify novel genetic loci linked to IS. Our meta-analysis revealed 124 new IS-associated loci, with enrichment in genes involved in cerebrovascular function, inflammation, and metabolism. Candidate genes like Show less

Ischemic stroke (IS) treatment remains a significant challenge. This study aimed to identify potential druggable genes for IS using a systematic druggable genome-wide Mendelian Randomization (MR) analysis. Two-sample MR analysis was conducted to identify the causal association between potential druggable genes and IS. This involved integrating data from the druggable genome, expression quantitative trait loci (eQTL), protein quantitative trait loci (pQTL), and genome-wide association study summary data of IS. Sensitivity and Bayesian colocalization analyses were used to validate the causal relationships. In addition, phenome-wide MR analysis was used to evaluate the side effects or other indications of the identified druggable genes, and their functions were explored using the Metascape database. Our MR analysis identified 16 potential druggable genes significantly associated with IS, three of which were significant in the two QTL datasets. Colocalization analysis revealed six druggable genes (two in the blood eQTL [CALCRL, KCNJ11], two in the brain eQTL [NEK3, THSD1], one in the blood pQTL [MMP12], and one in the brain pQTL [HSD17B12]) had a PP.H4 greater than 0.75. Phenome-wide MR analysis indicated that CALCRL is correlated with benign breast neoplasms, and HSD17B12 is associated with essential hypertension and hypertension. This study identified six potential druggable genes (CALCRL, KCNJ11, NEK3, THSD1, MMP12, and HSD17B12) associated with IS risk. Further research is required to explore the specific roles of these druggable genes in the onset and progression of IS. Show less

BACKGROUND Defects in androgen synthesis, such as 17-beta-hydroxysteroid dehydrogenase type 3 (17-ß-HSD3) deficiency, can lead to ambiguous genitalia in people with karyotype 46,XY due to impaired testosterone and dihydrotestosterone production. This condition may be initially diagnosed as androgen insensitivity syndrome (AIS), an X-linked disorder characterized by female external genitalia, absence of Mullerian structures, inguinal testes, and primary amenorrhea in adolescence. This report describes the case of a 13-year-old phenotypic female with 46,XY karyotype and a history of virilization due to 17-ß-HSD3 deficiency, previously diagnosed with AIS. CASE REPORT We report the case of a 13-year-old phenotypic female who was initially diagnosed with AIS during early childhood at a rural hospital. Several years later, she presented to a pediatric endocrinology clinic with progressive signs of virilization, including hirsutism, deepening of the voice, and severe facial acne. Laboratory evaluation, including a human chorionic gonadotropin (hCG) stimulation test, revealed a markedly low testosterone-to-androstenedione (T/AND) ratio of 0.1, strongly suggestive of 17ß-HSD3 deficiency. Whole-exome sequencing identified a homozygous missense variant of uncertain significance in exon 4 of the HSD17B3 gene. As the patient had been raised as a female, the parents chose to maintain her female gender assignment. Subsequently, the patient underwent bilateral orchiectomy along with clitoroplasty and labioplasty at another medical center. CONCLUSIONS Genetic and hormonal testing play a crucial role in differentiating among various types of disorders of sex development, thereby reducing the risk of diagnostic uncertainty. Early referral to a pediatric endocrinologist is essential to ensure accurate diagnosis and appropriate management of affected individuals. Show less

Sepsis-associated acute lung injury (SA-ALI), a critical complication of sepsis, is characterized by immune dysregulation-induced pulmonary dysfunction. Shenmai Injection (SMI) is a standardized herbal preparation consisting of Panax ginseng C.A.Mey (Hongshen) and Ophiopogon japonicus (Thunb.) Ker Gawl (Maidong), traditionally used for qi-replenishing, collapse-stabilizing, and lung-moistening therapy. Although clinically utilized in the management of SA-ALI, the specific mechanisms by which it acts against SA-ALI necessitate further investigation. The present study endeavors to comprehensively determine the therapeutic efficacy of SMI against SA-ALI through an integrated approach combining network pharmacology, metabolomics, metagenomic sequencing, and experimental validation. In this study, murine SA-ALI was established using lipopolysaccharide (LPS) and Poly(I:C). Results indicated that SMI administration significantly attenuated pulmonary inflammation, restored blood-gas barrier integrity, reduced serum pro-inflammatory cytokines and suppressed NF-κB pathway activation in SA-ALI mice. Network pharmacology elucidated the multi-targeted mechanism of SMI in modulating steroid hormone biosynthesis. Integrated metabolomics and target analysis revealed that ophiopogonin A/B and luteolin in SMI alleviates metabolic dysregulation by targeting key enzymes, including AKR1C3, HSD17B1/2, and SULT1E1. Metagenomic profiling demonstrated SMI-mediated gut microbiota remodeling, marked by suppression of pathogenic Chlamydiaceae (particularly Chlamydia abortus) and enrichment of commensal Lactobacillaceae. Correlation analysis showed that intestinal androstenedione and androsterone levels during SMI treatment recovery were negatively correlated with Chlamydia abortus abundance. In conclusion, SMI enhances the recovery from sepsis-associated SA-ALI by dual modulation of gut microbial ecology and host metabolic homeostasis, thereby establishing its potential as a multi-mechanistic therapeutic candidate for sepsis-related organ injury. Show less

Over the last 20 years, tributyltin (TBT) has been reported to cause metabolic disruption in both invertebrates and vertebrates, highlighting the need for further detailed analysis of its physiological effects. This study aimed to investigate the metabolic-disrupting effects of TBT from the behavioral to the molecular level. Adult specimens of the great pond snail (Lymnaea stagnalis) were exposed to an environmentally relevant concentration (100 ng L Show less

Gonadotropin dysregulation seems to play a potential role in the carcinogenesis of testicular germ cell tumor (TGCT). The aim of this study was to explore the expression of specific genes related to sex hormone regulation, synthesis, and metabolism in TGCT and to define specific hormonal clusters. Two publicly available databases were used for this analysis (TCGA and GSE99420). By means of hard-threshold regularized KMEANS clustering, we assigned TGCT samples into four clusters defined in respect to different expression of the sex hormone-related genes. We analysed clinical data, protein and gene expression, signaling regarding hormonal clusters. Based on whole-transcriptome gene expression, prediction of anti-cancer drug response was made by RIDGE models. Cluster #1 (12-16%) consisted primarily of non-seminomatous germ cell tumor (NSGCT), characterized by high expression of PRL, GNRH1, HSD17B2 and SRD5A1. Cluster #2 (42-50%) included predominantly seminomas with high expression of SRD5A3, being highly infiltrated by T and B cells. Cluster #3 (8.3-18%) comprised of NSGCT with high expression of CGA, CYP19A1, HSD17B12, HSD17B1, SHBG. Cluster #4 (23-30%), which consisted primarily of NSGCT with a small fraction of seminomas, was outlined by increased expression of STAR, POMC, CYP11A1, CYP17A1, HSD3B2 and HSD17B3. Elevated fibroblast levels and increased extracellular matrix- and growth factor signaling-related gene signature scores were described in cluster #1 and #3. In the combined model of progression-free survival, S2/S3 tumor marker status, hormonal cluster #1 or #3 and teratoma histology, were independently associated with 25-30% increase of progression risk. Based on the increased receptor tyrosine kinase and growth factor signaling, cluster #1, #3 and #4 were predicted to be sensitive to tyrosine kinase inhibitors, FGFR inhibitors or EGFR/ERBB inhibitors. Cluster #2 and #4 were responsive to compounds interfering with DNA synthesis, cytoskeleton, cell cycle and epigenetics. Response to apoptosis modulators was predicted only for cluster #2. Hormonal cluster #1 or #3 is an independent prognostic factor regarding poor progression-free survival. Hormonal cluster assignment also affects the predicted drug response with cluster-dependent susceptibility to specific novel therapeutic compounds. Show less

Mammalian scent glands mediate species-specific chemical communication, yet the mechanistic basis for convergent musk production remain incompletely understood. Forest musk deer and muskrat have independently evolved specialized musk-secreting glands, representing a striking case of convergent evolution. Through an integrated multi-omics approach, this study identified cyclopentadecanone as a shared key metabolic precursor in musk from both forest musk deer and muskrat, although downstream metabolite profiles diverged between the two lineages. Single-cell RNA sequencing revealed that these specialized apocrine glands possessed unique secretory architecture and exhibited transcriptional profiles associated with periodic musk production, distinct from those in conventional apocrine glands. Convergent features were evident at the cellular level, where acinar, ductal, and basal epithelial subtypes showed parallel molecular signatures across both taxa. Notably, acinar cells in both species expressed common genes involved in fatty acid and glycerolipid metabolism (e.g., Show less

Hypothalamic gonadotropin-releasing hormone (GnRH) regulates the production of gonadotropins, which control reproduction. In elasmobranchs, unlike other gnathostomes, GnRH is released into the systemic circulation to stimulate gonadotrope cells located in the ventral lobe of the pituitary. The aim of this study was to investigate the potential role of systemic GnRH in the regulation of the testis in Scyliorhinus canicula. Phylogeny and synteny analyses identified three GnRHs and four GnRH receptor (ScGnRHR-I1, -IIa1, -IIa2 and -IIb2). In vitro functional hormone-receptor interactions using synthetic ScGnRHs showed that all ScGnRHs were effective at receptors, except ScGnRHRIIa2, at femtomolar to nanomolar concentrations, with lower efficiency for ScGnRH1/ScGnRHRIIb2. Real-time PCR analyses in a wide range of tissues, including male and female reproductive tracts, showed that all three gnrh were expressed mainly in the brain and all four gnrhr were expressed in the testis, particularly during spermiogenesis. Testicular explants containing cysts with spermatids were treated with ScGnRHs and their protein content analyzed by NanoLC-ESI-MS/MS, highlighting 1677 significantly differentially expressed proteins. Among them, the growth hormone receptor (GHR) and proteins involved in cholesterol and steroid metabolism, including several HSD17bs, were upregulated. In situ hybridization showed that ghr, hsd17b3 and hsd17b12 transcripts were localized in Sertoli cells, which are the main testicular steroidogenic cells in S. canicula. Fifteen steroids were assayed in the culture media, using LC-ESI-HRMS/MS, and an increase in 17β-estradiol concentrations was observed, consistent with hsd17b expressions. Furthermore, proteins involved in transcription and DNA structure were downregulated in response to GnRHs. In conclusion, this study showed that ScGnRHs may play a direct role in the regulation of elasmobranch testes by promoting spermiogenesis and modulating steroidogenesis. Show less

Adipose tissue metabolism plays a crucial role in sheep meat quality and the optimization of adipose tissue utilization. To reveal the molecular mechanisms of adipose tissue metabolism during growth in naturally grazing sheep, we investigated the mRNA and miRNA profiles in subcutaneous adipose tissue (SAT) from naturally grazing Sunit sheep at 6, 18, and 30 months of age (Mth-6, Mth-18, and Mth-30). We identified 927 differentially expressed (DE) genes and 134 DE miRNAs in the SAT of sheep at different growth stages. Specifically, the expressions of Show less

Dengue virus (DENV) is a global health threat, with approximately 390 million infections annually, ranging from mild dengue fever to severe dengue hemorrhagic fever and shock syndrome. MicroRNA (miRNA) are crucial post-transcriptional regulators which may regulate host resistance to DENV infection. This study aimed to identify miRNAs involved in natural resistance to DENV infection. Individuals from a dengue-endemic area were classified as susceptible (SD) or resistant (RD) according to their anti-DENV antibody status. RD individuals were seronegative despite high local DENV infection prevalence. Monocytes susceptibility to DENV infection was assessed in vitro. The miRNome profiles of the monocytes from 7 individuals per group were assessed upon mock or DENV-2 infection. The antiviral effect of differentially expressed miRNAs was analyzed using miRNA mimics in HeLa cells followed by infection with DENV-1, DENV-2, DENV-3, and DENV-4 serotypes. We performed RNA-seq on miRNA mimic-transfected cells to identify miRNA-targeted genes interacting with DENV proteins. Monocytes from RD individuals exhibit lower DENV-2 production in vitro. The miRNAs miR-155, miR-132-3p, miR-576-5p were overexpressed in monocytes from RD group upon DENV-2 infection. The transfection of miR-155-5p mimic reduced DENV infection and viral production in HeLa cells, regulating 18 genes interacting with DENV proteins and downregulating target genes involved in interferon response, TP53 regulation, apoptosis, and vesicle trafficking (e.g. HSD17B12, ANXA2). Therefore, we show that monocytes from RD individuals show a distinct miRNA expression profile and reduced viral production. In vitro miR-155-5p upregulation induces an antiviral state, revealing potential therapeutic targets to treat dengue. Show less

Neuroblastoma is the most common extracranial solid tumor in children and has complex genetic underpinnings. Previous genome-wide association studies (GWASs) have identified many loci associated with neuroblastoma susceptibility; however, their application in risk prediction for Chinese children has not been systematically explored. This study seeks to enhance neuroblastoma risk prediction by validating these loci and evaluating their performance in polygenic risk models. We validated 35 GWAS-identified neuroblastoma susceptibility loci in a cohort of Chinese children, consisting of 402 neuroblastoma patients and 473 healthy controls. Genotyping these polymorphisms was conducted via the TaqMan method. Univariable and multivariable logistic regression analyses revealed the genetic loci significantly associated with neuroblastoma risk. We constructed polygenic risk models by combining these loci and assessed their predictive performance via area under the curve (AUC) analysis. We also established a polygenic risk scoring (PRS) model for risk prediction by adopting the PLINK method. Fourteen loci, including ten protective polymorphisms from Our findings validate multiple loci as neuroblastoma risk factors in Chinese children and demonstrate the utility of polygenic risk models, particularly the PRS, in improving risk prediction. These results suggest that integrating multiple genetic variants into a PRS can enhance neuroblastoma risk stratification and potentially improve early diagnosis by guiding targeted screening programs for high-risk children. Show less

17β-hydroxysteroid dehydrogenase type 3 deficiency is a 46,XY difference of sex development (DSD) that may present in childhood with inguinal testes or at puberty following virilization. We present four individuals, assigned female at birth, to highlight complexities and considerations surrounding orchiectomy. We reviewed the literature and created a "FACT sheet" to guide shared decision-making for patients, parents, and providers. "Ruth" presented at 16 months with inguinal herniae and underwent orchiectomy, based on parental preference. "Erica" presented at 13 years with voice deepening; she and her parents chose pubertal suppression and eventual orchiectomy. "Riley" presented at 18 months with inguinal herniae; after pubertal suppression and estrogen replacement, orchiectomy at age 13 years revealed germ cell neoplasia Show less

Recent introduction of new steatotic liver disease categorizations has necessitated updated epidemiologic studies. Specifically, recognition of (1) "MetALD" defined as where metabolic dysfunction-associated steatotic liver disease (MASLD) overlaps with alcohol use and (2) alcohol-related liver disease (ALD) without cardiometabolic risk factors (CMRFs) creates new clinical phenotypes with undefined prevalence. We conducted a cross-sectional multicenter analysis of liver disease associated with alcohol use (ALD and MetALD). We included adults with an International Classification of Diseases (ICD) diagnosis of ALD or both metabolic dysfunction associated liver disease and alcohol use disorder assigned from 1/1/2000-1/1/2024. Among 4057 patients, only 118 (2.9%) did not have any CMRF ("pure ALD"). Compared to patients with CMRF, patients with pure ALD were more commonly female (56% [0 CRMF] vs. 48%, 45%, 38%, and 42% [1, 2, 3, and 4 CMRFs, respectively]; ALD without diagnosed metabolic disease is uncommon and associated with higher rates of cirrhosis, HCC, and all-cause mortality than ALD with concurrent CMRF. Having a BMI measuring 25-30 kg/m Show less