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PubMed2000

5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase.

Insulin regulates the rate of expression of many hepatic genes, including PEPCK, glucose-6-phosphatase (G6Pase), and glucose-6-phosphate dehydrogenase (G6PDHase). The expression of these genes is also abnormally regulated in type 2 diabetes. We demonstrate here that treatment of hepatoma cells with 5-aminoimidazole-4-carboxamide riboside (AICAR), an agent that activates AMP-activated protein kinase (AMPK), mimics the ability of insulin to repress PEPCK gene transcription. It also partially represses G6Pase gene transcription and yet has no effect on the expression of G6PDHase or the constitutively expressed genes cyclophilin or beta-actin. Several lines of evidence suggest that the insulin-mimetic effects of AICAR are mediated by activation of AMPK. Also, insulin does not activate AMPK in H4IIE cells, suggesting that this protein kinase does not link the insulin receptor to the PEPCK and G6Pase gene promoters. Instead, AMPK and insulin may lie on distinct pathways that converge at a point upstream of these 2 gene promoters. Investigation of the pathway by which AMPK acts may therefore give insight into the mechanism of action of insulin. Our results also suggest that activation of AMPK would inhibit hepatic gluconeogenesis in an insulin-independent manner and thus help to reverse the hyperglycemia associated with type 2 diabetes.

AMP-Activated Protein Kinases↗
PubMed2026

Transcriptomic Profiling of Canine Testicular Leydig Cell Tumors Uncovers Key Upregulated Gene Pathways.

Total RNA was isolated from sections of healthy testes and Leydig cell tumors of mixed-breed dogs using TMA Master II device. The RNA-seq libraries were sequenced on the Illumina platform. Following differential expression analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were applied with quality control obtained using FastQC and Trimmomatic. This analysis revealed 1500 transcripts, including 928 upregulated and 168 downregulated genes. The results demonstrated that a significant proportion of these differentially expressed genes are directly involved in the control of sex steroid production (CYP11A1, STAR, and 3β-HSD3B1) or tube formation, angiogenesis, and extracellular matrix remodeling in interstitial cells (ESM1, FGG, and VEGFA). Moreover, we identified the upregulation of transcripts responsible for neurotransmitter or neuroendocrine signaling (SLC6A4, GRIN2C, GABRB3) and cholesterol metabolism and its regulation (GPX3, MSMO1, DHCR24). These genes were strongly associated with the phosphatidylinositol-3-kinase (PI3K)-Protein Kinase B (Akt) cascade and extracellular matrix interactions, features shared with various malignancies. Alterations in estrogen and relaxin signaling appear to be distinctive, understudied mechanisms specific to canine Leydig cell tumors. Concurrently, downregulated genes (e.g., DMRTC2, SEMA3C, ALOX12) were linked with cell differentiation, signaling and immunoregulatory pathway suppression involved in tumorigenesis. A complex transcriptomic profile of canine Leydig cell tumors was developed, revealing a conserved oncogenic core shared in some aspects with human malignancies alongside unique species-specific alterations. Findings seem to be useful for identifying novel diagnostic biomarkers and targeted therapies in veterinary oncology, establishing canine reproductive tissues as a valuable comparative biomedical model for research in human.

Leydig cell tumor↗
PubMed2026

Enhanced identification of key bacterial motility genes via a cross-species genomic hybrid feature machine learning approach.

Efficient and accurate identification of functional genes is critical to biological research, yet traditional single-species approaches are often limited by low efficiency. Previously, we established a novel method for identifying key genes using cross-species protein domain features and machine learning. However, the high multiplicity of gene members associated with specific domains creates a substantial workload for subsequent experimental validation. To address this, this study proposes an enhanced approach that integrates EggNOG-based protein sequence annotation with domain analysis. Unannotated sequences are subsequently analyzed for protein domains, generating a comprehensive "direct gene annotation plus domain" hybrid feature matrix. While the hybrid matrix model yielded comparable predictive accuracy, it significantly enhanced feature resolution: the top 50 predicted features were all known motility-related genes or domains. Furthermore, among the top 100 ranked features, 58 are confirmed to be directly related to motility based on experimental evidence. Although strict genus-level control still yielded 51 confirmed features, excessive taxonomic restriction drastically reduces the number of training genomes, which may paradoxically impair identification efficiency. These results demonstrate that the new method effectively reduces the subsequent experimental workload and enables high-throughput identification of functional genes in a single analysis. With accuracy and efficiency far exceeding those of existing single-species identification methods, it provides a highly efficient solution for mining key genes underlying other complex bacterial phenotypes.

Machine Learning↗
PubMed2002

Discovery of molecular mechanisms of neuroprotection using cell-based bioassays and oligonucleotide arrays.

Oxidative injury and the resulting death of neurons is a major pathological factor involved in numerous neurodegenerative diseases. However, the development of drugs that target this mechanism remains limited. The goal of this study was to test a compound library of approved Food and Drug Administration drugs against a hydrogen peroxide-induced oxidant injury model in neuroblastoma cells. We identified 26 neuroprotective compounds, of which megestrol, meclizine, verapamil, methazolamide, sulindac, and retinol were examined in greater detail. Using large-scale oligonucleotide microarray analysis, we identified genes modulated by these drugs that might underlie the cytoprotection. Five key genes were either uniformly upregulated or downregulated by all six drug treatments, namely, tissue inhibitor of matrix metalloproteinase (TIMP1), ret-proto-oncogene, clusterin, galanin, and growth associated protein (GAP43). Exogenous addition of the neuropeptide galanin alone conferred survival to oxidant-stressed cells, comparable to that seen with the drugs. Our approach, which we term "interventional profiling," represents a general and powerful strategy for identifying new bioactive agents for any biological process, as well as identifying key downstream genes and pathways that are involved.

Biological Assay↗
PubMed2026

Effects of domestication on the body morphology and genetic diversity of the yellowfin seabream (Acanthopagrus latus).

The yellowfin seabream (Acanthopagrus latus) is a significant economic fish along the southeast coast of China. Recently, the drastic decline in the wild populations, exacerbated by overfishing and climate change, has heightened our reliance on aquaculture. However, the current lack of research on its domestication hinders effective conservation of wild populations and balanced management alongside the aquaculture industry. Studies on body characteristics have shown that wild yellowfin seabream possess a higher body, while cultured ones exhibit a wider body. Whole-genome SNP analysis revealed moderate genetic differentiation between cultured and wild populations. Further analyses of linkage disequilibrium, heterozygosity, and genetic diversity revealed that the degree of SNP linkage was lower in the wild population compared to the cultured population. In contrast, heterozygosity and nucleotide polymorphisms were significantly higher in the wild population (P&#xa0;<&#xa0;0.001 and P&#xa0;<&#xa0;0.05, respectively). Additionally, over 300 candidate genes were identified in each cultured population through genomic selection signature analysis, with 67 key genes shared among all three, which were linked to growth and development (ghrb, ghsra, and cfl1), immune response (aire, cd36, and igbp1), and salinity adaptation (abcc3, clic4, and kcnk15). Enrichment analysis indicated that the key candidate genes were significantly enriched in pathways related to protein kinase activity, ion binding and growth hormone synthesis, secretion and action (FDR&#xa0;<&#xa0;0.05). The findings provide valuable insights into the variation in body size of yellowfin seabream under domestication selection and offer an important theoretical basis for the genetic improvement of yellowfin seabream.

Animals↗
PubMed2004

Comparative transcriptional profiling of two human embryonic stem cell lines.

Human embryonic stem cells (ESCs) have generated enormous interest due to their ability to self-renew and produce many different cell types. In conjunction with microarray technology, human ESCs provide a powerful tool for employing a systems-based approach to deciphering the molecular mechanisms that control pluripotency and early development. Recent work has focused on defining "stemness" and pluripotency based on different experimental and analytical approaches in both mouse and human ESCs. Using a mixed linear model statistical approach, we report a stringent direct comparison between data sets obtained from two human ESCs (BG01 and H1) in order to obtain a list of genes that are enriched in ESCs. In addition, we used another pluripotent population derived from BG01 ESCs to obtain a list of genes that we consider important to the maintenance of pluripotency. A total of 133 genes overlapped between the three pluripotent populations. A majority of the 133 genes were classified under the key functional categories of cell-cycle regulation, signaling, and regulation of transcription. Key genes expressed were Oct4, Sox2, LeftyA, and Fgf2. Also found to be enriched in all three populations is FLJ10713, a gene encoding a hypothetical protein of unknown function that has been shown in earlier studies to possess a homolog in mouse ESCs and also to cluster tightly with Oct4 in human ESCs. Although there were many genes unique to each pluripotent population, they shared similarities based on functional ontologies that define pluripotency. The significance of our studies underscores the need for direct comparison of stem cell populations that share biological similarities using uniform stringent analytical approaches, in order to better define pluripotency. Our findings have important implications for the maintenance of pluripotency and in developing directed differentiation strategies for various regenerative applications.

Algorithms↗
PubMed2004

Analysis of vitamin D-regulated gene expression in LNCaP human prostate cancer cells using cDNA microarrays.

BACKGROUND: 1,25-dihydroxyvitamin D(3) [1,25(OH)2D3] exerts growth inhibitory, pro-differentiating, and pro-apoptotic effects on prostate cells. To better understand the molecular mechanisms underlying these actions, we employed cDNA microarrays to study 1,25(OH)2D3-regulated gene expression in the LNCaP human prostate cancer cells. METHODS: mRNA isolated from LNCaP cells treated with vehicle or 50 nM 1,25(OH)2D3 for various lengths of time were hybridized to microarrays carrying approximately 23,000 genes. Some of the putative target genes revealed by the microarray analysis were verified by real-time PCR assays. RESULTS: 1,25(OH)2D3 most substantially increased the expression of the insulin-like growth factor binding protein-3 (IGFBP-3) gene. Our analysis also revealed several novel 1,25(OH)2D3-responsive genes. Interestingly, some of the key genes regulated by 1,25(OH)2D3 are also androgen-responsive genes. 1,25(OH)2D3 also down-regulated genes that mediate androgen catabolism. CONCLUSIONS: The putative 1,25(OH)2D3 target genes appear to be involved in a variety of cellular functions including growth regulation, differentiation, membrane transport, cell-cell and cell-matrix interactions, DNA repair, and inhibition of metastasis. The up-regulation of IGFBP-3 gene has been shown to be crucial in 1,25(OH)2D3-mediated inhibition of LNCaP cell growth. 1,25(OH)2D3 regulation of androgen-responsive genes as well as genes involved in androgen catabolism suggests that there are interactions between 1,25(OH)2D3 and androgen signaling pathways in LNCaP cells. Further studies on the role of these genes and others in mediating the anti-cancer effects of 1,25(OH)2D3 may lead to better approaches to the prevention and treatment of prostate cancer.

Biological Transport↗
PubMed1999

Novel polymorphism of the 5-lipoxygenase activating protein (FLAP) promoter gene associated with asthma.

The human 5-lipoxygenase activating protein (FLAP) gene is one of the key genes involved in the production of the cysteinyl-leukotrienes. We studied novel polymorphism of the FLAP promoter gene and attempted to clarify the relationship between this polymorphism and asthma. We sequenced the FLAP promoter region, containing the -170 to +46-bp sequence from the translational start codon, and found two homozygotes of novel alleles in the polyadenyl region which showed 21 A repeats and 18 A repeats, respectively. The frequency of the 21 A repeats was 52/71 (73.2%) in asthmatics and 39/71 (54.9%) in control subjects. The difference between these frequencies was statistically significant (P = 0.035). This is the first report of FLAP promoter gene polymorphism associated with asthma. Our data suggest that FLAP promoter gene polymorphism might play a crucial role in the pathogenesis of asthma.

5-Lipoxygenase-Activating Proteins↗
PubMed2000

An answer to a complex problem: cloning the mouse t-complex responder.

The t-complex is maintained in wild mouse populations by its high transmission (up to 99%) from heterozygous males and provides an example of "meiotic drive". Its molecular basis has remained obscure despite long and intensive study. In a major advance, the t-complex responder gene, thought to be the key gene on which several distorters act, has now been cloned.

Animals↗
PubMed2026

Long-term PFOA and cadmium Co-contamination alters soil carbon, nitrogen, and phosphorus cycling: Insights from metagenomics and metabolomics.

The co-existence of perfluorooctanoic acid (PFOA) and cadmium (Cd) in soil poses a combined threat to microbial communities. However, the ecological effects and underlying mechanisms of their long-term combined exposure remain poorly understood. This study conducted a 90-day soil microcosm experiment to systematically investigate the effects of individual and combined effects of PFOA and Cd on microbial communities. Our results demonstrated that combined pollution of PFOA and Cd significantly affected four soil enzyme activities associated with carbon, nitrogen, and phosphorus cycling. It also influenced microbial thermal activity with an IC50 of PFOA at 0.94&#x202f;mg/kg. The toxic interaction between PFOA and Cd varied with both toxicity indicators and exposure time. At the community level, PFOA and Cd synergistically reduced bacterial diversity and richness, while exerting more complex interactive effects on fungal communities. Metagenomic analysis revealed that PFOA and Cd significantly affected carbon, nitrogen, and phosphorus cycling by inhibiting inorganic phosphorus solubilization genes (gcd, pqqC) and altering key genes in carbon fixation and nitrogen transformation. Metabolomic profiling further demonstrated that PFOA disrupted membrane lipid homeostasis and amino acid metabolism. Meanwhile, the co-existence of Cd exacerbated disturbances in sugar and carbon metabolism. Our findings provide genetic-level insights into microbial responses to long-term PFOA and Cd co-contamination. These results are essential for risk assessment at such co-contamination sites.

Cadmium↗
PubMed2002

Underexpression of mRNA in human hepatocellular carcinoma focusing on eight loci.

Genetic alterations associated with human hepatocellular carcinoma (HCC) have been reported previously, but are not sufficient to specify differences of HCCs from precancerous diseases of the liver, such as hepatitis, hepatic fibrosis, and cirrhosis. In the present study, we performed differential gene display analysis (DGDA) to clarify the specific genetic alterations associated with gene expression changes in the course of development of HCC from chronic viral hepatitis. Four pairs of surgically resected HCCs and hepatitis tissues were investigated. We found 1,028 expression sequence tags (ESTs) that were decreased or increased in HCC tissues compared with hepatitis tissues in the same patient. Nucleotide sequencing showed that they included 55 EST clones in the GenBank database, which were considered candidates for specific messenger RNA (mRNA) expression alterations in HCCs. After excluding 9 ESTs that code mitochondrial DNA, we performed quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) for the 46 remaining EST clones. We found 8 mRNAs underexpressed in primary HCC tissues in 20 patients in higher percentages than found in previous studies, including 18 cases (90%) for aldolase B (ALDOB), 15 cases (75%) for carbamyl phosphate synthetase 1 (CPS1), albumin (ALB), plasminogen (PLG), and EST 51549, 13 cases (65%) for cytochrome P450 subfamily 2E1 (CYP2E1), 12 cases (60%) for human retinol-binding protein 4 (RBP4), and 11 cases (55%) for human organic anion transporter C (OATP-C) gene. In conclusion, underexpression of key gene products may be important in the development and/or progression of HCC.

Albumins↗
PubMed2002

Molecular cytogenetic characterization of drug-resistant leukemia cell lines by comparative genomic hybridization and fluorescence in situ hybridization.

Resistance to chemotherapeutic drugs is one of the major difficulties encountered during cancer chemotherapy. To detect genomic aberrations underlying the acquired drug resistance, we examined three cultured human myelomonocytic leukemia cell sublines each resistant to adriamycin (ADR), 1-beta-1-D-arabinofuranosylcytosine (ara-C), or vincristine (VCR), using comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), RT-PCR, and western blot techniques. Chromosomes 7, 10 and 16 most conspicuously showed frequent aberrations among the resistant sublines as compared to the parental KY-821 cell line. In ADR-resistant cells, gains at 7q21, 16p12, 16p13.1-13.3, 16q11.1-q12.1, and losses at 7p22-pter, 7q36-qter, 10p12, 10p11.2-pter, 10q21-q25, 10q26-qter were notable. In ara-C-resistant cells, no remarkable gain or loss on chromosome 7, but losses at 10p14-pter, 10q26-qter and 16p11.2-p11.3 were observed. In VCR-resistant cells, gain at 7q21 and losses at 10p11-p13, 10p15 and 16p11.2-p13.3 were found. FISH identified amplified signals for the MDR-1 gene located at 7q21.1 in ADR- and VCR- but not ara-C-resistant cells, and for the MRP-1 gene located at 16p13.1 in ADR-resistant cells. These findings were validated at the mRNA and protein levels. Overlapping of the amplified MRP-1 gene with MDR-1 gene may play a critical part in the acquisition of resistance to ADR. Resistance to ara-C excluded MDR-1 gene involvement and highlighted other key genes such as MXR gene. Several other genes putatively involved in the development of drug resistance might lie in other aberrated chromosomal regions.

Antimetabolites, Antineoplastic↗
PubMed2025

Transcriptome sequencing reveals regulatory genes associated with neurogenic hearing loss.

Hearing loss is a prevalent condition with a significant impact on individuals' quality of life. However, comprehensive studies investigating the differential gene expression and regulatory mechanisms associated with hearing loss are lacking, particularly in the context of diverse patient samples. In this study, we integrated data from 10 patients across different regions, age groups, and genders, with their data retrieved from a public transcriptome database, to explore the molecular basis of hearing loss. These samples are mainly from fibroblasts and keratinocytes. Through differential gene expression analysis, we identified key genes, including ICAM1, SLC1A1, and CD24, which have already been shown to play important roles in neurogenic hearing loss. Furthermore, we predicted potential transcriptional regulatory factors that may modulate the expression of these genes. Enrichment analysis revealed biological processes and pathways associated with hearing loss, highlighting the involvement of circadian rhythm disruption and other neuro-related disorders. Although our study is limited by the sample size and the absence of larger-scale investigations, the identified genes and regulatory factors provide valuable insights into the molecular mechanisms underlying hearing loss. Further molecular and cellular experiments are necessary to validate these findings and elucidate the precise regulatory mechanisms involved. In conclusion, our study contributes to the understanding of hearing loss pathogenesis and offers potential targets for molecular diagnostics and gene-based therapies. This provides a foundation for further research into personalized approaches to diagnosing and treating hearing loss.

Humans↗
PubMed1996

Ontogenic changes in the expression of cytochrome c oxidase subunit I gene in the cerebellar cortex of the perinatal hypothyroid rat.

The thyroid hormone plays a critical role in normal development of the mammalian central nervous system. This study was designed to examine the effect of perinatal hypothyroidism on ontogenic change in cytochrome c oxidase subunit I (COX I) gene expression in the rat cerebellum by using quantitative in situ hybridization histochemistry (ISH). Newborn rats were rendered hypothyroid by continuous administration of methimazole in the mothers' drinking water. The pups were then killed by decapitation on 1, 5, 10, 15, 20, and 30 days after birth (P1, P5, P10, P15, P20, and P30). Their cerebella were removed, and frozen sections were cut and processed for ISH with 35S-labeled RNA probe for COX I messenger RNA. After hybridization, emulsion autoradiography was performed. The numbers of grains within the external granule cell layer, molecular layer, and internal granule cell layer were then counted. A significant decrease in grain density was detected in the hypothyroid animal in all these areas on P5, P10, and P15. On P15, in the molecular layer, a greater hybridization signal was detected in the inner portion than in the outer portion in the euthyroid animal. No such difference was seen in the hypothyroid animal. Daily T4 treatment for 15 days restored the effect of methimazole treatment. The significant effect of perinatal hypothyroidism on COX I gene expression was not detected after P20. These results indicate that altered thyroid states affect the COX I gene expression in the cerebellar cortex during development, suggesting that the COX I gene is one of the key genes regulated by the thyroid hormone and plays an important role in the morphogenetic changes observed in the perinatal hypothyroid cerebellum.

Aging↗
PubMed2005

Expression of many immunologically important genes in Mycobacterium tuberculosis-infected macrophages is independent of both TLR2 and TLR4 but dependent on IFN-alphabeta receptor and STAT1.

Macrophages respond to several subcellular products of Mycobacterium tuberculosis (Mtb) through TLR2 or TLR4. However, primary mouse macrophages respond to viable, virulent Mtb by pathways largely independent of MyD88, the common adaptor molecule for TLRs. Using microarrays, quantitative PCR, and ELISA with gene-disrupted macrophages and mice, we now show that viable Mtb elicits the expression of inducible NO synthase, RANTES, IFN-inducible protein 10, immune-responsive gene 1, and many other key genes in macrophages substantially independently of TLR2, TLR4, their combination, or the TLR adaptors Toll-IL-1R domain-containing adapter protein and Toll-IL-1R domain-containing adapter inducing IFN-beta. Mice deficient in both TLR2 and TLR4 handle aerosol infection with viable Mtb as well as congenic controls. Viable Mtb also up-regulates inducible NO synthase, RANTES, IFN-inducible protein 10, and IRG1 in macrophages that lack mannose receptor, complement receptors 3 and 4, type A scavenger receptor, or CD40. These MyD88, TLR2/4-independent transcriptional responses require IFN-alphabetaR and STAT1, but not IFN-gamma. Conversely, those genes whose expression is MyD88 dependent do not depend on IFN-alphabetaR or STAT1. Transcriptional induction of TNF is TLR2/4, MyD88, STAT1, and IFN-alphabetaR independent, but TNF protein release requires the TLR2/4-MyD88 pathway. Thus, macrophages respond transcriptionally to viable Mtb through at least three pathways. TLR2 mediates the responses of a numerically minor set of genes that collectively do not appear to affect the course of infection in mice; regulation of TNF requires TLR2/4 for post-transcriptional control, but not for transcriptional induction; and many responding genes are regulated through an unknown, TLR2/4-independent pathway that may involve IFN-alphabetaR and STAT1.

Adaptor Proteins, Signal Transducing↗
PubMed2001

[De La Chapelle syndrome].

OBJECTIVE: The De La Chapelle syndrome (XX male) is a peripheral hypogonadism concerning males with 46,XX karyotype. We conducted a retrospective study of 18 cases and report the main clinical biological and hormonal characteristics. PATIENTS AND METHODS: Clinical features (weight, height, aspect of the external genital organs, body hair, gynecomastia), hormone levels (testosterone, gonadotrophin, baseline and stimulated prolactin estradiol), and results of a Barr test and karyotype were recorded in all patients in addition to search for the SRY gene (in 8 of the 18 patients). Findings were compared with a matched male population and a Klinefelter syndrome population. RESULTS: Microrchidia was found in almost all the patients while the penis had a normal size. Signs of hypoandrogenism were frequent and gynecomastia was present in half the cases. De La Chapelle patients differed from Klinefelter patients by the absence of dysmorphism. DISCUSSION: Patients with De La Chapelle syndrome diagnosed around the age of 20 years do not have borderline disorders associating genitalia anomalies or sexual ambiguity. The majority of the patients bear the testis determining SRY gene on one of the X chromosomes, providing the rational explanation of the male phenotype, but 20% of the XX males doe not have this gene. The role of certain key genes that could be implicated in abnormal sexual differentiation is known, but the complexity and heterogeneous nature of this syndrome leaves many questions unanswered. Therapy is based on androgen replacement therapy given at an early stage.

Administration, Oral↗