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Breast cancer (BC) is a global health concern with a growing prevalence. Since BC is a heterogeneous cancer, transcriptome analyzes were carried out on breast tumor tissues relative to their corresponding normal tissues in order to identify gene expression signatures and perform meta-analysis. Five expression profiling by array data sets from breast tumor tissues and non-tumor neighboring tissues were retrieved following a search in the GEO database (GSE70947, GSE70905, GSE10780, GSE29044, and GSE42568). Meta-analysis of gene expression using the Network Analyst tool identified common differentially expressed genes and biological pathways in all data sets. Then, the DEGs were analyzed through PPI network construction, gene ontology, and pathway analysis. The detected hub genes underwent Kaplan-Meier (KM) plotter and UALCAN validation. Finally, Real-time PCR analysis was used on BC patients' samples to determine mRNA levels of cAMP signaling pathway members ATP1A2, FXYD1, and ADCY3. Breast tumor tissues showed 710 differentially expressed genes (DEGs), with 392 overexpressed and 318 underexpressed, compared to normal marginal tissues. On the EnrichR library, GO, and KEGG pathway analyses were performed on the DEGs list. Progesterone-mediated oocyte maturation and the NF-kappa B signaling system were upregulated DEGs' top deregulated signaling pathways. In contrast, pathways related to cancer and the cAMP signaling pathway were the most enriched terms for down-regulated genes. Next, Real-time PCR quantification of cAMP signaling cascade members ATP1A2, FXYD1, and ADCY3 was performed on 50 BC tumoral and non-tumoral tissues for validation. Results of meta-analyzed array data sets revealed DEGs representing BC gene signatures, and cAMP signaling pathway members as effective factors in BC. The results of our real-time PCR expression level determination for ATP1A2, FXYD1, and ADCY3 in breast tumor tissues relative to the normal margins contradicted our bioinformatics investigations, which found increased levels for these genes. Of these, only ATP1A2's expression levels were statistically significant. This study focused on identifying gene expression signatures that provide an invaluable source of evidence for BC-related underlying mechanisms to provide new therapeutic targets and biomarkers. Show less

Primary cilia are hair-like structures found on nearly all mammalian cell types, including cells in the developing and adult brain. A diverse set of receptors and signaling proteins localize within cilia to regulate many physiological and developmental pathways, including the Hedgehog (Hh) pathway. Defects in cilia structure, protein localization, and function lead to genetic disorders called ciliopathies, which present with various clinical features that include several neurodevelopmental phenotypes and hyperphagia-associated obesity. Despite their dysfunction being implicated in several disease states, understanding their roles in central nervous system (CNS) development and signaling has proven challenging. We hypothesize that dynamic changes to ciliary protein composition contribute to this challenge and may reflect unrecognized diversity of CNS cilia. The proteins ARL13B and ADCY3 are established markers of cilia in the brain. ARL13B is a regulatory GTPase important for regulating cilia structure, protein trafficking, and Hh signaling, and ADCY3 is a ciliary adenylyl cyclase. Here, we examine the ciliary localization of ARL13B and ADCY3 in the perinatal and adult mouse brain. We define changes in the proportion of cilia enriched for ARL13B and ADCY3 depending on brain region and age. Furthermore, we identify distinct lengths of cilia within specific brain regions of male and female mice. ARL13B+ cilia become relatively rare with age in many brain regions, including the hypothalamic feeding centers, while ADCY3 becomes a prominent cilia marker in the mature adult brain. It is important to understand the endogenous localization patterns of these proteins throughout development and under different physiological conditions as these common cilia markers may be more dynamic than initially expected. Understanding regional- and developmental-associated cilia protein composition signatures and physiological condition cilia dynamic changes in the CNS may reveal the molecular mechanisms associated with the features commonly observed in ciliopathy models and ciliopathies, like obesity and diabetes. Show less

Anorectal malformations (ARMs) are congenital diseases that lead to postoperative fecal incontinence, constipation, and soiling, despite improvements in surgery; however, their pathological mechanisms remain unclear. Here, we report the role of microRNA-141-3p in maintaining homeostasis between apoptosis and autophagy in the lumbosacral defecation center of fetal rats with ARMs. Elevated microRNA-141-3p expression inhibited YIN-YANG-1 expression by binding its 3' UTR, and repressed autophagy and triggered apoptosis simultaneously. Then, adenylate cyclase 3 was screened to be the downstream target gene of YIN-YANG-1 by chromatin immunoprecipitation sequencing experiments, and Yin Yang 1 could positively activate the transcription of adenylate cyclase 3 by directly interacting with the motif GAGATGG and ATGG in its promoter. Intraamniotic microinjection of adeno-rno-microRNA-141-3p-sponge-GFP in fetal rats with ARMs on embryonic day 15 restored apoptosis-autophagy homeostasis. These findings reveal that microRNA-141-3p upregulation impaired homeostasis between apoptosis and autophagy by inhibiting the YIN-YANG-1/adenylate cyclase 3 axis, and that intraamniotic injection of anti-microRNA-141-3p helped maintain homeostasis in the lumbosacral defecation center of ARMs during embryogenesis. Show less

Disordered eating contributes to weight gain, obesity, and type 2 diabetes (T2D), but the precise mechanisms underlying the development of different eating patterns and connecting them to specific metabolic phenotypes remain unclear. We aimed to identify genetic variants linked to eating behaviour and investigate its causal relationships with metabolic traits using Mendelian randomization (MR). We tested associations between 30 genetic variants and eating patterns in individuals with T2D from the Volga-Ural region and investigated causal relationships between variants associated with eating patterns and various metabolic and anthropometric traits using data from the Volga-Ural population and large international consortia. We detected associations between Show less

Obesity is a global health issue influenced primarily by genetic variants and environmental factors. This study aimed to examine the relationship between genetic and lifestyle factors and their interaction with obesity risk among university students. A total of 658 students from the same university participated in this study, including 531 females (mean age (SD): 21.6 (3.9) years) and 127 males (21.9 (4.6) years). Among them, 550 were classified as normal weight or underweight (456 females and 94 males), while 108 were identified as overweight or obese (75 females and 33 males). All the participants underwent anthropometric and genetic screening and completed lifestyle and sleep quality questionnaires. The polygenic risk score, based on seven genetic variants ( This study revealed that individuals with a higher genetic predisposition, as defined by the seven polymorphic loci, are more susceptible to becoming overweight or obese under certain lifestyle conditions. Show less

The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts. Integrating childhood obesity GWAS summary statistics with our existing 3D genomic datasets for 57 human cell types, consisting of high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, and RNA-seq, we applied stratified LD score regression and calculated the proportion of genome-wide SNP heritability attributable to cell type-specific features, revealing pancreatic alpha cell enrichment as the most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out for genome-wide significant childhood obesity loci and their linkage disequilibrium proxies to implicate effector genes, yielded the most abundant number of candidate variants and target genes at the Show less

Olfactory dysfunction (OD) is not uncommon following viral infection. Herein, we explore the interplay of host genetics with viral correlates in coronavirus disease 2019 (COVID-19)- and long COVID-related OD, and its diagnosis and treatment that remain challenging. Two genes associated with olfaction, UGT2A1 and UGT2A2, appear to be involved in COVID-19-related anosmia, a hallmark symptom of acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), particularly in the early stages of the pandemic. SARS-CoV-2 infects olfactory support cells, sustentacular and Bowman gland cells, that surround olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) where the initial step of odor detection takes place. Anosmia primarily arises from the infection of support cells of the OE, followed by the deciliation and disruption of OE integrity, typically without OSN infection. Through the projected axons of OSNs, the virus could theoretically reach the olfactory bulb and brain, but current evidence points against this route. Intriguingly, SARS-CoV-2 infection of support cells leads to profound alterations in the nuclear architecture of OSNs, leading to the downregulation of odorant receptor-related genes, e.g., of Adcy3. Viral factors associated with the development of OD include spike protein aminoacidic changes, e.g., D614G, the first substitution that was selected early during SARS-CoV-2 evolution. More recent variants of the Omicron family are less likely to cause OD compared to Delta or Alpha, although OD has been associated with a milder disease course. OD is one of the most prevalent post-acute neurologic symptoms of SARS-CoV-2 infection. The tens of millions of people worldwide who have lingering problems with OD wait eagerly for effective new treatments that will restore their sense of smell which adds value to their quality of life. Show less

Epilepsy is a common neurological disorder characterized by recurrent epilepsy episodes. As a non-pharmacological treatment, the ketogenic diet has been widely applied in treating epilepsy. However, the exact therapeutic mechanism of the ketogenic diet for epilepsy remains unclear. This study investigates the molecular mechanisms of the ketogenic diet in regulating fatty acid metabolism and activating the ADCY3-initiated cAMP signaling pathway to enhance neuronal inhibition and thereby treat epilepsy. Meta-analysis reveals that the ketogenic diet is superior to the conventional diet in treating epilepsy. Animal experiments demonstrate that the ketogenic diet is more effective than the conventional diet in treating epilepsy, with the best results achieved using the classic ketogenic diet. Transcriptome sequencing analysis identifies six essential genes, among which ADCY3 shows increased expression in the ketogenic diet. In vivo experiments confirm that the activation of the cAMP-PKA signaling pathway by ADCY3 enhances neuronal inhibition and improves epilepsy control. Clinical observations indicate that the ketogenic diet improves patient epilepsy episodes by regulating the ADCY3-initiated cAMP signaling pathway. Show less

Obesity is a serious health problem that progressively affects individuals’ lives with comorbidities, such as heart disease, stroke, and diabetes mellitus. Since its prevalence has increased, particularly in children less than five years old, its genetic and environmental causes should be determined for prevention and control of the disease. The aim of this study was to detect underlying genetic risk factors in a family with an exclusively breastfed obese infant. A three-generation family was recruited to be evaluated for obesity. Detailed examinations along with body mass index (BMI) calculations were performed on available family members. Whole exome sequencing (WES) was performed on a 7-month-old obese infant. Bioinformatic analyses were performed on the Genomize SEQ platform with variant filtering at minor allele frequencies <1% for all normal populations. Sanger sequencing was applied in variant confirmation and family segregation. Neuro-motor developmental features were normal and genetic syndromes were excluded from the index. Early-onset severe obesity (+4.25 standard deviation score weight-for-height) was evident in index case; his father and grandmother were also obese (BMIs 38.1 kg/m This study confirmed the paternal inheritance of all potentially deleterious obesity-related variants. The cumulative effect of individual variants might explain the obesity phenotype in this family. The infant is recommended to be followed up periodically due to increased risk for later childhood obesity. Show less

Patients with monogenic obesity display numerous medical features on top of hyperphagic obesity, but no study to date has provided an exhaustive description of their semiology. Two reviewers independently conducted a systematic review of MEDLINE, Embase, and Web of Science Core Collection databases from inception to January 2022 to identify studies that described symptoms of patients carrying pathogenic mutations in at least one of eight monogenic obesity genes (ADCY3, LEP, LEPR, MC3R, MC4R, MRAP2, PCSK1, and POMC). Of 5207 identified references, 269 were deemed eligible after title and abstract screening, full-text reading, and risk of bias and quality assessment. Data extraction included mutation spectrum and mode of inheritance, clinical presentation (e.g., anthropometry, energy intake and eating behaviors, digestive function, puberty and fertility, cognitive features, infectious diseases, morphological characteristics, chronic respiratory disease, and cardiovascular disease), biological characteristics (metabolic profile, endocrinology, hematology), radiological features, and treatments. The review provides an exhaustive description of mandatory, non-mandatory, and unique symptoms in heterozygous and homozygous carriers of mutation in eight monogenic obesity genes. This information is critical to help clinicians to orient genetic testing in subsets of patients with suspected monogenic obesity and provide actionable treatments (e.g., recombinant leptin and MC4R agonist). Show less

We recently reported that growth/differentiation factor 15 (GDF15) and its receptor GDNF family receptor alpha-like (GFRAL) are expressed in the periventricular germinal epithelium thereby regulating apical progenitor proliferation. However, the mechanisms are unknown. We now found GFRAL in primary cilia and altered cilia morphology upon GDF15 ablation. Mutant progenitors also displayed increased histone deacetylase 6 (Hdac6) and ciliary adenylate cyclase 3 (Adcy3) transcript levels. Consistently, microtubule acetylation, endogenous sonic hedgehog (SHH) activation and ciliary ADCY3 were all affected in this group. Application of exogenous GDF15 or pharmacological antagonists of either HDAC6 or ADCY3 similarly normalized ciliary morphology, proliferation and SHH signalling. Notably, Show less

The present study, as one part of a larger project that aimed to investigate the effects of dietary berberine (BBR) on fish growth and glucose regulation, mainly focused on whether miRNAs involve in BBR's modulation of glucose metabolism in fish. Blunt snout bream Megalobrama amblycephala (average weight of 20.36 ± 1.44 g) were exposed to the control diet (NCD, 30% carbohydrate), the high-carbohydrate diet (HCD, 43% carbohydrate) and the berberine diet (HCB, HCD supplemented with 50 mg/kg BBR). After 10 weeks' feeding trial, intraperitoneal injection of glucose was conducted, and then, the plasma and liver were sampled at 0 h, 1 h, 2 h, 6 h, and 12 h. The results showed the plasma glucose levels in all groups rose sharply and peaked at 1 h after glucose injection. Unlike the NCD and HCB groups, the plasma glucose in the HCD group did not decrease after 1 h, while remained high level until at 2 h. The NCD group significantly increased liver glycogen content at times 0-2 h compared to the other two groups and then liver glycogen decreased sharply until at times 6-12 h. To investigate the role of BBR that may cause the changes in plasma glucose and liver glycogen, miRNA high-throughput sequencing was performed on three groups of liver tissues at 2 h time point. Eventually, 20 and 12 differentially expressed miRNAs (DEMs) were obtained in HCD vs NCD and HCB vs HCD, respectively. Through function analyzing, we found that HCD may affect liver metabolism under glucose loading through the NF-κB pathway; and miRNAs regulated by BBR mainly play roles in adipocyte lipolysis, niacin and nicotinamide metabolism, and amino acid transmembrane transport. In the functional exploration of newly discovered novel:Chr12₁₈₈₉₂, we found its target gene, adenylate cyclase 3 (adcy3), was widely involved in lipid decomposition, amino acid metabolism, and other pathways. Furthermore, a targeting relationship of novel:Chr12₁₈₈₉₂ and adcy3 was confirmed by double luciferase assay. Thus, BBR may promote novel:Chr12₁₈₈₉₂ to regulate the expression of adcy3 and participate in glucose metabolism. Show less

Promoting brown adipose tissue (BAT) activity innovatively targets obesity and metabolic disease. While thermogenic activation of BAT is well understood, the rheostatic regulation of BAT to avoid excessive energy dissipation remains ill-defined. Here, we demonstrate that adenylyl cyclase 3 (AC3) is key for BAT function. We identified a cold-inducible promoter that generates a 5' truncated AC3 mRNA isoform (Adcy3-at), whose expression is driven by a cold-induced, truncated isoform of PPARGC1A (PPARGC1A-AT). Male mice lacking Adcy3-at display increased energy expenditure and are resistant to obesity and ensuing metabolic imbalances. Mouse and human AC3-AT are retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and lack enzymatic activity. AC3-AT interacts with AC3 and sequesters it in the endoplasmic reticulum, reducing the pool of adenylyl cyclases available for G-protein-mediated cAMP synthesis. Thus, AC3-AT acts as a cold-induced rheostat in BAT, limiting adverse consequences of cAMP activity during chronic BAT activation. Show less

Premature ovarian failure (POF) is a complex and heterogeneous disease that causes infertility and subfertility. However, the molecular mechanism of POF has not been fully elucidated. Here, we show that the loss of adenylyl cyclase III (Adcy3) in female mice leads to POF and a shortened reproductive lifespan. We found that Adcy3 is abundantly expressed in mouse oocytes. Adcy3 knockout mice exhibited the excessive activation of primordial follicles, progressive follicle loss, follicular atresia, and ultimately POF. Mechanistically, we found that mitochondrial oxidative stress in oocytes significantly increased with age in Adcy3-deficient mice and was accompanied by oocyte apoptosis and defective folliculogenesis. In contrast, compared with wild-type female mice, humanized ADCY3 knock-in female mice exhibited improved fertility with age. Collectively, these results reveal that the previously unrecognized Adcy3 signaling pathway is tightly linked to female ovarian aging, providing potential pharmaceutical targets for preventing and treating POF. Show less

Gestational diabetes mellitus (GDM) is associated with DNA methylation and lifestyle. The effects of DNA methylation on GDM, and the interaction between DNA methylation and lifestyle factors are not well elucidated. The objective of this study was to explore the association between GDM, DNA methylation and lifestyle factors. A nest case-control design was performed. Sociodemographic data, dietary intake and daily physical activity information of pregnant women were collected. Bisulfate pyrosequencing was used to detect the DNA methylation level of PPARGC1A, HLA-DQA1, and ADCY3 genes. The differences of DNA methylation levels between the GDM group and the control group were compared. The correlation between clinical characteristics, dietary, physical activity and DNA methylation level was analyzed. A total of 253 pregnant women were enrolled, of which, 60 participants (GDM: 30; control: 30) were included in the final analysis. There were no significant differences in DNA methylation levels of six methylated sites between the two groups in this study (P > 0.05). Daily intake of potato and poultry were associated with DNA methylation level of the CpG 1 site of the ADCY3 gene in all participants and the control group (P < 0.05). Duration of folic acid intake before pregnancy was correlated with the methylation level of the CpG 1 site of the ADCY3 gene in all participants (r = 0.341, P = 0.04) and the control group (r = 0.431, P = 0.025). Daily oil intake was correlated with the methylation level of CpG 2 (r = 0.627, P = 0.016) and CpG 3 (r = 0.563, P = 0.036) of PPARGC1A in the GDM group. The association between the DNA methylation levels and GDM wasn't validated. There were associations between dietary and DNA methylation in pregnant women. A large-sample-sized and longitudinal study is warranted to further investigate the impacts of lifestyle on DNA methylation. Show less

Variants of the G protein-coupled receptor 75 (GPR75) are associated with a lower BMI in large-scale human exome-sequencing studies. However, how GPR75 regulates body weight remains poorly understood. Using random germline mutagenesis in mice, we identified a missense allele (Thinner) of Gpr75 that resulted in a lean phenotype and verified the decreased body weight and fat weight in Gpr75-knockout (Gpr75-/-) mice. Gpr75-/- mice displayed reduced food intake under high-fat diet (HFD) feeding, and pair-feeding normalized their body weight. The endogenous GPR75 protein was exclusively expressed in the brains of 3xFlag-tagged Gpr75-knockin (3xFlag-Gpr75) mice, with consistent expression across different brain regions. GPR75 interacted with Gαq to activate various signaling pathways after HFD feeding. Additionally, GPR75 was localized in the primary cilia of hypothalamic cells, whereas the Thinner mutation (L144P) and human GPR75 variants in individuals with a lower BMI failed to localize in the cilia. Loss of GPR75 selectively inhibited weight gain in HFD-fed mice but failed to suppress the development of obesity in leptin ob-mutant (Lepob-mutant) mice and adenylate cyclase 3-mutant (Adcy3-mutant) mice on a chow diet. Our data reveal that GPR75 is a ciliary protein expressed in the brain and plays an important role in regulating food intake. Show less

Obesity is a growing public health concern that affects the longevity and lifestyle of all human populations including children and older individuals. Diverse factors drive obesity, making it challenging to understand and treat. While recent studies highlight the importance of GPCR signaling for metabolism and fat accumulation, we lack a molecular description of how obesogenic signals accumulate and propagate in cells, tissues, and organs. In this issue of the JCI, Jiang et al. utilized germline mutagenesis to generate a missense variant of GRP75, encoded by the Thinner allele, which resulted in mice with a lean phenotype. GPR75 accumulated in the cilia of hypothalamic neurons. However, mice with the Thinner allele showed defective ciliary localization with resistance to fat accumulation. Additionally, GPR75 regulation of fat accumulation appeared independent of leptin and ADCY3 signaling. These findings shed light on the role of GPR75 in fat accumulation and highlight the need to identify relevant ligands. Show less

The diagnosis of monogenic obesity is burdened by frequent variants of uncertain significance (VUS). We describe our real-life approach of variant reassessment over time and we assess whether inconclusive variants are decreasing in monogenic obesity. We tested for monogenic obesity (genes: LEPR, POMC, ADCY3, PCSK1, CARTPT, SIM1, MRAP2, LEP, NTRK2, BDNF, KSR2, MAGEL2, SH2B1, MC4R, MC3R) in 101 children/adolescents (11.7 [7.3-13.7] years, 3.6 [3.3-4.0] z-BMI) in Verona and 183 (11.3 [8.4-12.2] years, 3.2 [2.7-3.9] z-BMI) in Naples from January 2020 to February 2023. In March-July 2024 we reassessed the baseline variants by updated software interpretation and literature renavigation. We initially found 20 VUS, 4 Likely Pathogenic (LP), 5 Likely Benign (LB) and 1 benign variant in 33 individuals. At follow-up, 6 VUS were reclassified as benign/LB, one LP as pathogenic and 3 LB as benign. Overall, 10/30 variants (6/18 in Verona, 3/11 in Naples and a variant found in both centres) were reclassified, leading to a less uncertain report for 13 of 33 variant-carrying patients. Monogenic obesity was diagnosed in 3 probands in Verona and 4 in Naples, carrying variants at MC4R or NTRK2. Our variant reassessment was effective to improve classification certainty for the 39% of patients and suggested that the molecular diagnosis of monogenic obesity is becoming more accurate over time. Show less

Ulcerative colitis (UC) is an increasing incidence of inflammatory disorder in the colon mucosa. One of the current research focuses is the alteration of metabolic networks in UC. One of the important aspects of this metabolic shift is the expression of purine metabolism genes (PMGs) vital for nucleic acid synthesis. Nevertheless, the precise function of PMGs in the pathophysiology of UC is not yet fully known. To this end, this study used state-of-the-art bioinformatics tools and approaches to discover and confirm the PMGs involved in UC. All the 114 candidate PMGs were compared for their expression levels. GSEA and GSVA were applied to define the functional and pathway implications of these PMGs. Lasso regression and SVM-RFE approaches were used for the identification of hub genes and to assess the diagnostic potential of eight PMGs in UC classification. The relationship between these critical PMGs and clinical features was also systematically evaluated as well. The expression levels of these eight PMGs were validated using datasets GSE206285 and GSE179285. Using bioinformatics and machine learning, this work seeks to establish the involvement of PMGs in UC. From the LASSO and SVM models, 114 DE PMGs were selected and investigated to build a stable predictive model. Based on these studies, the following genes: IMPDH1, GUK1, POLE3, ADCY3, ADCY4, PDE6B, PNPT1 and PDE4D were suggested as potential biomarkers of UC. Gene ontology enrichment analysis revealed that these genes are implicated in the biological processes of particular relevance to immune and inflammatory responses. The study also provided a lot of information on the interaction between immune cells and PMGs indicating that these genes may control some immune-related pathways in UC. Moreover, drug-gene interaction analysis presents potential therapeutic opportunities for potential drug targets which were further confirmed through molecular docking. Mendelian randomization analysis revealed that ADCY4 and PDAZN are involved in PMG-related processes, thus opening new possibilities for treatment. This work reveals eight PMGs closely related to UC and provides new perspectives on possible markers of this inflammatory disease. These findings not only increase the understanding of the pathogenesis of UC but also offer potential for improving the surveillance of disease and its progression. Show less

Brown adipose tissue (BAT) is the main site of nonshivering thermogenesis which plays an important role in thermogenesis and energy metabolism. However, the regulatory factors that inhibit BAT activity remain largely unknown. Here, cardiotrophin-like cytokine factor 1 (CLCF1) is identified as a negative regulator of thermogenesis in BAT. Adenovirus-mediated overexpression of CLCF1 in BAT greatly impairs the thermogenic capacity of BAT and reduces the metabolic rate. Consistently, BAT-specific ablation of CLCF1 enhances the BAT function and energy expenditure under both thermoneutral and cold conditions. Mechanistically, adenylate cyclase 3 (ADCY3) is identified as a downstream target of CLCF1 to mediate its role in regulating thermogenesis. Furthermore, CLCF1 is identified to negatively regulate the PERK-ATF4 signaling axis to modulate the transcriptional activity of ADCY3, which activates the PKA substrate phosphorylation. Moreover, CLCF1 deletion in BAT protects the mice against diet-induced obesity by promoting BAT activation and further attenuating impaired glucose and lipid metabolism. Therefore, our results reveal the essential role of CLCF1 in regulating BAT thermogenesis and suggest that inhibiting CLCF1 signaling might be a potential therapeutic strategy for improving obesity-related metabolic disorders. Show less

The specific molecular mechanistic link between atherosclerotic plaques and ischemic stroke (IS) is not clear. The aim of this study is to explore the potential molecular relationship between atherosclerotic plaques and IS. All data were downloaded from the Gene Expression Omnibus (GEO) database. Key hub differentially expressed mRNAs (DEmRNAs) related to atherosclerotic plaques and IS were identified by differential expression analysis and least absolute shrinkage and selection operator (LASSO) analysis. Subsequently, a diagnostic model was established based on the expression of key hub DEmRNAs and logistic regression. In order to understand the molecular mechanism of key hub DEmRNAs, the transcription factor (TF) regulatory network and mRNA-miRNA-lncRNA regulatory network were also constructed. In addition, functional enrichment analysis and single-sample Gene Set Enrichment Analysis (ssGSEA) analysis were also performed. Four key hub DEmRNAs (ADCY3, CLDN7, PPM1B and RRAS2) were identified by differential expression analysis and LASSO analysis. Moreover, the diagnostic model based on four key hub DEmRNAs has excellent diagnostic accuracy. We also found that Type 1 T helper cell may be associated with IS caused by atherosclerosis based on ssGSEA analysis. In the mRNA-miRNA-lncRNA regulatory network, we found that multiple signaling axes such as RRAS2-hsa-miR-3150b-3p-ILF3-AS1, PPM1B-hsa-miR-541-5p-LINC00294, CLDN7-hsa-miR-184-LINC00467 and ADCY3-hsa-miR-488-3p-URB1-AS1 may play an important role in the progression of IS. In addition, some signaling pathways, including chemokine signaling pathway, MAPK signaling pathway and cAMP signaling pathway, may be involved in regulating IS. The identified key molecules, signaling pathways and immune cells may help to provide a theoretical basis for exploring the relationship between atherosclerotic plaque and the progression of IS. Show less

Adult T-cell leukemia/lymphoma (ATLL) is a poor prognosis malignancy of peripheral T-cells caused by human T-cell leukemia virus type 1 (HTLV-1). The low survival rates observed in the patients are the result of the lack of sufficient knowledge about the disease pathogenesis. In the present study, we first identified differentially expressed genes in ATLL patients and the cellular signaling pathways affected by them. Then, genes of these pathways were subjected to more comprehensive evaluations, including WGCNA and module validation studies on five external datasets. Finally, potential biomarkers were selected for qRT-PCR validation. Thirteen signaling pathways, including Apoptosis, Human T-cell leukemia virus 1 infection, IL-17 signaling pathway, pathways in cancer, T cell receptor signaling pathway, Th1 and Th2 cell differentiation, and seven others were selected for deeper investigations. Results of our in-depth bioinformatics evaluations, highlighted pathways related to regulation of immune responses, T-cell receptor and activation, regulation of cell signaling receptors and messengers, Wnt signaling pathway, and apoptosis as key players in ATLL pathogenesis. MAPK3, PIK3CD, KRAS, NFKB1, TNF, PLCB3, PLCB2, PLCB1, MAPK11, JUN, ITPR1, ADCY1, GNAQ, ADCY3, ADCY4, CHEK1, CCND1, SOS2, BAX, FOS and GNA12 were identified as possible biomarkers. Upregulation of ADCY1 and ADCY3 genes was confirmed via qRT-PCR. In this study, we performed a deep bioinformatic examination on a limited set of genes with high probabilities of involvement in the pathogenesis of ATLL. Our results highlighted signaling pathways and genes with potential key roles in disease formation and resistance against current treatment strategies. Further studies are required to test the possible benefits of highlighted genes as biomarkers and targets of treatment. Show less

Obesity has become a severe public health challenge globally. The present study aimed to identify separate and interactive dietary, genetic, and other factors that increase the risk of obesity as measured by body fat (BF) mass. We utilized a genome-wide association study to identify genetic variants associated with high fat mass (obesity; Show less

Obesity and overweight are common conditions in dogs, but individual susceptibility varies with numerous risk factors, including diet, age, sterilization, and gender. In addition to environmental and biological factors, genetic and epigenetic risk factors can influence predisposition to canine obesity, however, they remain unknown. Labrador Retrievers are one of the breeds that are prone to obesity. The purpose of this study was to analyse 41 canine orthologues of human genes linked to monogenic obesity in humans to identify genes associated with body weight in Labrador Retriever dogs. We analysed 11,520 variants from 50 dogs using a linear mixed model with sex, age, and sterilization as covariates and population structure as a random effect. Estimates obtained from the model were subjected to a maxT permutation procedure to adjust Show less

Intermittent hypoxia (IH) results in low-grade inflammation, sympathetic overactivity, and oxidative stress. However, the specific effects of IH on olfaction have not yet been directly assessed and remain unclear. Therefore, the purpose of this study was to investigate the cytotoxic effects of IH exposure on the mouse olfactory epithelium and the relationship between the concentration of hypoxia and the degree of destruction of the olfactory system. Thirty mice were randomly divided into six groups: control (room air for 4 weeks), recovery control (room air for 5 weeks), IH 5% oxygen concentration, IH 7% oxygen concentration, recovery 5% hypoxia, and recovery 7% hypoxia groups. Mice in the two hypoxia groups were exposed to 5% and 7% oxygen for 4 weeks. Mice in the two recovery groups were exposed to room air for 1 week after 4 weeks of hypoxia period. Based on, the olfactory marker protein ( Our findings suggest that IH damages the olfactory neuroepithelium and brain tissue in mouse model. The activity of olfactory marker genes and neurogenesis in the olfactory neuroepithelium were decreased. The levels of oxygen may be affect changes in the olfactory neuroepithelium. The olfactory ensheathing cell may be a major factor in the recovery of the olfactory neuroepithelium. Show less