Search Results (12)

Hepatic ischemia–reperfusion injury (IRI) is a critical clinical condition associated with liver transplantation and acute liver injury. This study investigated the role of sulfide quinone oxidoreductase (SQOR) and its downstream product, supersulfides, in hepatic IRI. C57BL/6NJ mice were subjected to 45 min of partial hepatic ischemia, followed by reperfusion lasting 4 h. Control of shRNA mediated knockdown of SQOR expressing adeno-associated viral vectors were administered 3 weeks prior to liver ischemia. In the shRNA-mediated knockdown of SQOR group, the hydro-trisulfide donor sodium trisulfide was administered daily for 1 week prior to the induction of liver ischemia. SQOR played a crucial protective role during hepatic IRI by facilitating electron transport to the mitochondrial respiratory chain and maintaining the oxidized and reduced nicotinamide adenine dinucleotide ratio. Administration of sodium trisulfide, exhibited protective effects against hepatic IRI. Sodium trisulfide restored the oxidized and reduced nicotinamide adenine dinucleotide ratio, reduced oxidative stress, and preserved the expression of key enzymes involved in the sulfide oxidation pathway. SQOR and supersulfides contribute to hepatic protection against IRI, likely through their potent antioxidative and redox-regulating functions, and highlight sodium trisulfide as a potential therapeutic agent. Full article

Background: The aim of this study was to characterise the performance, perceptual, and wellness responses to a barbell back squat overreaching training protocol. Methods: Eight trained male participants (age = 24.6 ± 2.8 years; relative to body mass back squat one repetition maximum (1-RM) = 1.9 ± 0.4; training experience = 7.0 ± 3.2 years) participated in a 5-day squat OR protocol (SqOR), followed by a 14-day taper. SqOR consisted of five sets of barbell back squats using 80% of daily adjusted 1-RM. A 40% velocity loss threshold was used to determine the set end point. For performance, isometric mid-thigh pull (IMTP) peak force (PF), and countermovement jump (CMJ) PF and jump height; for perceptual, perceived recovery scale (PRS); and for wellness, Hooper Wellness Index (HWI), were recorded at baseline, each day of SqOR, and at select intervals during the taper (POST 1 d, 2 d, 7 d, and 14 d). Follow-up back squat 1-RM testing was conducted at POST 7 d and POST 14 d to determine strength-performance changes relative to baseline. Results: Back squat 1-RM increased by 4.8% at POST 7 d and 5.2% at POST 14 d. IMTP PF increased by 10.3% at POST 7 d and 11.4% at POST 14 d relative to the baseline. CMJ PF and jump height decreased during SqOR but returned to baseline by POST 7 d. PRS and HWI worsened during SqOR, with the greatest impairment occurring on day 3 (PRS = −41.5%; HWI = 34.4%), and did not return to baseline until POST 14 d and POST 2 d, respectively. Conclusions: These findings demonstrate that a short-term period of planned OR improves muscular strength performance, but the duration of the taper influences when peak strength improvements are observed. Full article

Background/Objectives: Visceral adipose tissue (VAT) may play a direct role in the development of metabolic dysfunction-associated steatotic liver disease (MASLD) and its progression to metabolic dysfunction-associated steatohepatitis (MASH). In this study, we employed untargeted proteomics analyses on paired biopsies from VAT and liver tissues of patients with obesity, MASLD, and MASH. Our objective was to investigate tissue-specific protein expression patterns in search of a potential proteomic signature associated with MASH in both VAT and liver tissue. Methods: VAT and liver tissue were collected from 70 subjects with severe obesity (SWOs) and nine control study subjects without obesity (CON). SWOs were stratified on the basis of liver histology into LS− (no liver steatosis), LS+ (liver steatosis), and MASH. Peptides were extracted from frozen tissue and were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Raw files were analyzed with Spectronaut, proteins were searched against the human FASTA Uniprot database, and the significantly expressed proteins in the two tissues were analyzed. The p-values were false discovery rate (FDR) corrected. Results: A total of 59 VAT and 42 liver proteins were significantly differentially expressed between the four groups: LS−, LS+, MASH, and CON. The majority were upregulated, and many were related to lipid metabolism. In VAT, only one protein, the mitochondrial sulfide:quinone oxidoreductase (SQOR), was significantly downregulated in the MASH group only. In liver tissue from patients with MASH, six proteins were significantly altered compared with the three other groups. Correlation analyses between the top 10 positive VAT and liver proteins were dominated by inflammatory and detoxification proteins. Conclusions: The presence of MASH was not reflected in the VAT proteome, and both the VAT and the liver proteome were generally affected more by the presence of obesity than by MASLD severity. Several immunomodulating proteins correlated significantly between VAT and liver tissue and could reflect common pathophysiological characteristics. Full article

Medulloblastoma (MB) is the most common malignant brain tumor in children, typically arising during infancy and childhood. Despite multimodal therapies achieving a response rate of 70% in children older than 3 years, treatment remains challenging. Ferroptosis, a form of regulated cell death, can be induced in medulloblastoma cells in vitro using erastin or RSL3. Using two independent medulloblastoma RNA-sequencing cohorts (MB-PBTA and MTAB-10767), we investigated the expression of ferroptosis-related molecules through multiple approaches, including Weighted Gene Co-Expression Network Analysis (WGCNA), molecular subtype stratification, protein–protein interaction (PPI) networks, and univariable and multivariable overall survival analyses. A prognostic expression score was computed based on a cross-validated ferroptosis signature. In training and validation cohorts, the regulation of the ferroptosis transcriptional program distinguished the four molecular subtypes of medulloblastoma. WGCNA identified nine gene modules in the MB tumor transcriptome; five correlated with molecular subtypes, implicating pathways related to oxidative stress, hypoxia, and trans-synaptic signaling. One module, associated with disease recurrence, included epigenetic regulators and nucleosome organizers. Univariable survival analyses identified a 45-gene ferroptosis prognostic signature associated with nutrient sensing, cysteine and methionine metabolism, and trans-sulfuration within a one-carbon metabolism. The top ten unfavorable ferroptosis genes included CCT3, SNX5, SQOR, G3BP1, CARS1, SLC39A14, FAM98A, FXR1, TFAP2C, and ATF4. Patients with a high ferroptosis score showed a worse prognosis, particularly in the G3 and SHH subtypes. The PPI network highlighted IL6 and CBS as unfavorable hub genes. In a multivariable overall survival model, which included gender, age, and the molecular subtype classification, the ferroptosis expression score was validated as an independent adverse prognostic marker (hazard ratio: 5.8; p-value = 1.04 × 10⁻⁹). This study demonstrates that the regulation of the ferroptosis transcriptional program is linked to medulloblastoma molecular subtypes and patient prognosis. A cross-validated ferroptosis signature was identified in two independent RNA-sequencing cohorts, and the ferroptosis score was confirmed as an independent and adverse prognostic factor in medulloblastoma. Full article

Zhaotong pig (ZTP) is a Chinese indigenous pig breed in Yunnan Province, known for its unique body shape and appearance, good meat quality, strong foraging ability, and adaptability. However, there is still a lack of research on its genome. In order to investigate the genetic diversity, population structure, and selection signatures of the breed, we conducted a comprehensive analysis by resequencing on 30 ZTPs and comparing them with genomic data from 10 Asian wild boars (AWBs). A total of 45,514,452 autosomal SNPs were detected in the 40 pigs, and 23,649,650 SNPs were retained for further analysis after filtering. The H_E, H_O, P_N, MAF, π, and Fis values were calculated to evaluate the genetic diversity, and the results showed that ZTPs had higher genetic diversity and lower inbreeding coefficient compared with AWBs. Population structure was analyzed using NJ tree, PCA, ADMIXTURE, and LD methods. It was found that ZTPs were population independent of AWBs and had a lower LD decay compared to AWBs. Moreover, the results of the IBS genetic distance and G matrix showed that most of the individuals had large genetic distances and distant genetic relationships in ZTPs. Selection signatures were detected between ZTPs and AWBs by using two methods, F_ST and π ratio. Totals of 1104 selected regions and 275 candidate genes were identified. Finally, functional enrichment analysis identified some annotated genes that might affect fat deposition (NPY1R, NPY5R, and NMU), reproduction (COL3A1, COL5A2, GLRB, TAC3, and MAP3K12), growth (STAT6 and SQOR), tooth development (AMBN, ENAM, and ODAM), and immune response (MBL2, IL1A, and DNAJA3). Our results will provide a valuable basis for the future effective protection, breeding, and utilization of ZTPs. Full article

This study investigates the immunomodulatory potential of Galium aparine L. (GAE) in immunodeficient animals. In this study, animals were categorized into five groups: the normal group, CYP group (cyclophosphamide intraperitoneal injection), GA5 group (cyclophosphamide + 5 μg GAE), GA50 group (cyclophosphamide + 50 μg GAE), and GA500 group (cyclophosphamide + 500 μg GAE). The CYP group exhibited significantly reduced spleen weights compared to the normal group, while the groups obtaining GAE displayed a dose-dependent increase in spleen weight. Furthermore, the GAE demonstrated dose-dependent enhancement of splenocyte proliferating activity, with significant increases observed in both LPS and ConA-induced assays. NK cell activity significantly increased in the GA50 and GA500 groups compared to the CYP group. Cytokine analysis revealed a significant increase in IL-6, TNF-α, and IFN-γ levels in ConA-induced splenocytes treated with GAE. Gene expression analysis identified 2434 DEG genes in the extract groups. Notable genes, such as Entpd1, Pgf, Thdb, Syt7, Sqor, and Rsc1al, displayed substantial differences in individual gene expression levels, suggesting their potential as target genes for immune enhancement. In conclusion, Galium aparine L. extract exhibits immunomodulatory properties. The observed gene expression changes further support the potential of Galium aparine L. extract as a natural agent for immune augmentation. Full article

Amyotrophic lateral sclerosis (ALS) is a fatal rare disease of progressive degeneration of motor neurons. The most common genetic mutation in ALS is the hexanucleotide repeat expansion (HRE) located in the first intron of the C9orf72 gene (C9-ALS). HRE can produce dipeptide repeat proteins (DPRs) such as poly glycine-alanine (GA) in a repeat-associated non-ATG (RAN) translation. GA-DPR has been shown to be toxic to motor neurons in various biological models. However, its effects on microglia involved in C9-ALS have not been reported. Here, we show that GA-DPR (GA₅₀) activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome in a human HMC3 microglia model. MCC950 (specific inhibitor of the NLRP3) treatment can abrogate this activity. Next, using yeast two-hybrid screening, we identified sulfide quinone oxidoreductase (SQOR) as a GA₅₀ interacting protein. SQOR knockdown in HMC3 cells can significantly induce the activity of the NLRP3 inflammasome by upregulating the level of intracellular reactive oxygen species and the cytoplasmic escape of mitochondrial DNA. Furthermore, we obtained irisflorentin as an effective blocker of the interaction between SQOR and GA₅₀, thus inhibiting NLRP3 inflammasome activity in GA₅₀-expressing HMC3 cells. These results imply the association of GA-DPR, SQOR, and NLRP3 inflammasomes in microglia and establish a treatment strategy for C9-ALS with irisflorentin. Full article

Body size is one of the most economically important traits of dairy cattle, as it is significantly associated with cow longevity, production, health, fertility, and environmental adaptation. The identification and application of genetic variants using a novel genetic approach, such as genome-wide association studies (GWASs), may give more insights into the genetic architecture of complex traits. The identification of genes, single nucleotide polymorphisms (SNPs), and pathways associated with the body size traits may offer a contribution to genomic selection and long-term planning for selection in dairy cows. In this study, we performed GWAS analysis to identify the genetic markers and genes associated with four body size traits (body height, body depth, chest width, and angularity) in 1000 Chinese Holstein cows. We performed SNPs genotyping in 1000 individuals, based on the GeneSeek Genomic Profiler Bovine 100 K. In total, we identified 11 significant SNPs in association with body size traits at the threshold of Bonferroni correction (5.90 × 10⁻⁷) using the fixed and random model circulating probability unification (FarmCPU) model. Several genes within 200 kb distances (upstream or downstream) of the significant SNPs were identified as candidate genes, including MYH15, KHDRBS3, AIP, DCC, SQOR, and UBAP1L. Moreover, genes within 200 kb of the identified SNPs were significantly enriched (p ≤ 0.05) in 25 Gene Ontology terms and five Kyoto Encyclopedia of Genes and Genomes pathways. We anticipate that these results provide a foundation for understanding the genetic architecture of body size traits. They will also contribute to breeding programs and genomic selection work on Chinese Holstein cattle. Full article

The protective effects of hydrogen sulphide (H₂S) to limit oxidative injury and preserve mitochondrial function during sepsis, ischemia/reperfusion, and neurodegenerative diseases have prompted the development of soluble H₂S-releasing compounds such as GYY4137. Yet, the effects of GYY4137 on the mitochondrial function of endothelial cells remain unclear, while this cell type comprises the first target cell after parenteral administration. Here, we specifically assessed whether human endothelial cells possess a functional sulfide:quinone oxidoreductase (SQOR), to oxidise GYY4137-released H₂S within the mitochondria for electron donation to the electron transport chain. We demonstrate that H₂S administration increases oxygen consumption by human umbilical vein endothelial cells (HUVECs), which does not occur in the SQOR-deficient cell line SH-SY5Y. GYY4137 releases H₂S in HUVECs in a dose- and time-dependent fashion as quantified by oxygen consumption and confirmed by lead acetate assay, as well as AzMC fluorescence. Scavenging of intracellular H₂S using zinc confirmed intracellular and intramitochondrial sulfur, which resulted in mitotoxic zinc sulfide (ZnS) precipitates. Together, GYY4137 increases intramitochondrial H₂S and boosts oxygen consumption of endothelial cells, which is likely governed via the oxidation of H₂S by SQOR. This mechanism in endothelial cells may be instrumental in regulating H₂S levels in blood and organs but can also be exploited to quantify H₂S release by soluble donors such as GYY4137 in living systems. Full article

Hydrogen sulfide (H₂S) is a toxic gas that has important regulatory functions. In the colon, H₂S can be produced and detoxified endogenously. Both too little and too much H₂S exposure are associated with inflammatory bowel disease (IBD), a chronic intestinal disease mainly classified as Crohn’s disease (CD) and ulcerative colitis (UC). As the pathogenesis of IBD remains elusive, this study’s aim was to investigate potential differences in the expression of H₂S-metabolizing enzymes in normal aging and IBD. Intestinal mucosal biopsies of 25 adults and 22 children with IBD along with those of 26 healthy controls were stained immunohistochemically for cystathionine-γ-lyase (CSE), 3-mercapto-sulfurtransferase (3-MST), ethylmalonic encephalopathy 1 protein (ETHE1), sulfide:quinone oxidoreductase (SQOR) and thiosulfate sulfurtransferase (TST). Expression levels were calculated by multiplication of the staining intensity and percentage of positively stained cells. Healthy adults showed an overall trend towards lower expression of H₂S-metabolizing enzymes than healthy children. Adults with IBD also tended to have lower expression compared to controls. A similar trend was seen in the enzyme expression of children with IBD compared to controls. These results indicate an age-related decrease in the expression of H₂S-metabolizing enzymes and a dysfunctional H₂S metabolism in IBD, which was less pronounced in children. Full article

Hydrogen sulfide (H₂S) has been proposed to promote tumor growth. Elevated H₂S levels have been detected in human colorectal cancer (CRC) biopsies, resulting from the selective upregulation of cystathionine β-synthase (CBS). In contrast, the recently identified novel H₂S-generating enzyme, selenium-binding protein 1 (SELENBP1), is largely suppressed in tumors. Here, we provide the first comparative analysis of the four human H₂S-producing enzymes and the key H₂S-catabolizing enzyme, sulfide:quinone oxidoreductase (SQOR), in Caco-2 human colorectal adenocarcinoma cells. The gene expression pattern of proliferating Caco-2 cells parallels that of CRC, while confluent cells undergo spontaneous differentiation to a colonocyte-like phenotype. SELENBP1 and SQOR were strongly upregulated during spontaneous differentiation, whereas CBS was downregulated. Cystathionine γ-lyase and 3-mercaptopyruvate sulfurtransferase remained unaffected. Terminally differentiated cells showed an enhanced capacity to produce H₂S from methanethiol and homocysteine. Differentiation induced by exposure to butyrate also resulted in the upregulation of SELENBP1, accompanied by increased SELENBP1 promoter activity. In contrast to spontaneous differentiation, however, butyrate did not cause downregulation of CBS. In summary, SELENBP1 and CBS are reciprocally regulated during the spontaneous differentiation of Caco-2 cells, thus paralleling their opposing regulation in CRC. Butyrate exposure, while imitating some aspects of spontaneous differentiation, does not elicit the same expression patterns of genes encoding H₂S-modulating enzymes. Full article

Improving the genetic process of growth traits is one of the major goals in the beef cattle industry, as it can increase meat production and reduce the cost of raising animals. Although several quantitative trait loci affecting growth traits in beef cattle have been identified, the genetic architecture of these economically important traits remains elusive. This study aims to map single nucleotide polymorphisms (SNPs) and genes associated with birth weight (BW), yearling weight (YW), average daily gain from birth to yearling (BYADG), and body weight at the age of 18 months (18MW) in a Chinese Simmental beef cattle population using a weighted, single-step, genome-wide association study (wssGWAS). Phenotypic and pedigree data from 6022 animals and genotypes from 744 animals (596,297 SNPs) were used for an association analysis. The results showed that 66 genomic windows explained 1.01–20.15% of the genetic variance for the four examined traits, together with the genes near the top SNP within each window. Furthermore, the identified genomic windows (>1%) explained 50.56%, 57.71%, 61.78%, and 37.82% of the genetic variances for BW, YW, BYADG, and 18MW, respectively. Genes with potential functions in muscle development and regulation of cell growth were highlighted as candidates for growth traits in Simmental cattle (SQOR and TBCB for BW, MYH10 for YW, RLF for BYADG, and ARHGAP31 for 18MW). Moreover, we found 40 SNPs that had not previously been identified as being associated with growth traits in cattle. These findings will further advance our understanding of the genetic basis for growth traits and will be useful for the molecular breeding of BW, YW, BYADG, and 18MW in the context of genomic selection in beef cattle. Full article