Search Results (80)

Background: Emerging evidence suggests that biological sex shapes glioma biology and therapeutic response. Methods: We performed a sex-stratified analysis of CGGA (Chinese Glioma Genome Atlas) RNA sequencing data comparing low-grade glioma (LGG) with high-grade glioma (HGG) and glioblastoma (GBM). Using the 3PodR framework, we integrated differential expression analysis with Gene Set Enrichment Analysis (GSEA), EnrichR, leading-edge analysis, and iLINCS drug repurposing. Results: These comparisons provide a proxy for biological processes underlying malignant transformation. In LGG vs. HGG, 973 significantly differentially expressed genes (DEGs) were identified in females and 1236 in males, with 15.5% and 33.5% unique to each sex, respectively. In LGG vs. GBM, 2011 DEGs were identified in females and 2537 in males, with 12.6% and 30.7% being unique. Gene-level contrasts included GLI1 upregulation in males and downregulation in females, GCGR upregulation in males, MYOD1 upregulation in females, and HIST1H2BH downregulation in males. Additional top DEGs included PRLHR, DGKK, DNMBP-AS1, HOXA9, CTB-1I21.1, RP11-47I22.1, HPSE2, SAA1, DLK1, H19, PLA2G2A, and PI3. In both sexes, LGG–HGG and LGG–GBM grade comparisons converged on neuronal and synaptic programs, with enrichment of glutamatergic receptor genes and postsynaptic modules, including GRIN2B, GRIN2A, GRIN2C, GRIN1, and CHRNA7. In contrast, collateral pathways diverged by sex: females showed downregulation of mitotic and chromosome-segregation programs, whereas males showed reduction of extracellular matrix and immune-interaction pathways. Perturbagen analysis nominated signature-reversing compounds across sexes, including histone deacetylase inhibitors, Aurora kinase inhibitors, microtubule-targeting agents such as vindesine, and multi-kinase inhibitors targeting VEGFR, PDGFR, FLT3, PI3K, and MTOR. Conclusions: Glioma grade comparisons reveal a shared neuronal–synaptic program accompanied by sex-specific transcriptional remodeling. These findings support sex-aware therapeutic strategies that pair modulation of neuron–glioma coupling with chromatin- or receptor tyrosine kinase/angiogenic-targeted agents, and they nominate biomarkers such as GLI1, MYOD1, GCGR, PRLHR, and HIST1H2BH for near-term validation. Full article

Fibroblast growth factor 21 (FGF21) is a key hormone for metabolic homeostasis under conditions such as obesity, aging and diabetes. While extensively studied in males, its role in female physiology remains poorly defined. This study evaluated the effects of hepatic FGF21 deletion in 12-month-old female mice using a liver-specific FGF21 knockout (FKO) model. FKO females exhibited reduced body weight and improved glucose tolerance, with no changes in circulating FGF21 levels. In the liver, RT-qPCR analysis showed that the expression of genes involved in de novo lipogenesis, including Srebp1c, Fasn, and Scd1, was downregulated, whereas markers of fatty acid uptake (Cd36) and β-oxidation (Cpt1a) were upregulated without alterations in hepatic triglyceride content and lower levels of serum adiponectin. Remarkably, telomere length in both liver and adipose tissue was preserved, indicating improved cellular aging. Hepatic transcriptomic analysis revealed a global downregulation of genes linked to cytoskeletal organization, immune processes and fibrosis. Among these, Chrna4, a hepatocyte-specific nicotinic acetylcholine receptor subunit implicated in protection against metabolic-associated steatohepatitis (MASH), was significantly reduced. These findings suggest that hepatic FGF21 deficiency in aged female mice promotes metabolic health by limiting pro-inflammatory and fibrotic pathways and preserving telomere integrity, with Chrna4 emerging as a potential mediator. Full article

Background: Chronic obstructive pulmonary disease (COPD) is a complex condition influenced by both environmental and genetic factors. Among the genetic determinants, polymorphisms in the CHRNA3/5 and EPHX1 genes have been implicated in nicotine dependence and susceptibility to COPD in several populations. However, evidence remains limited in admixed populations such as Brazilians. Methods: This cross-sectional study investigated the association between CHRNA3 (rs1051730, rs8034191) and EPHX1 (rs2234922) polymorphisms with tobacco nicotine dependence and COPD in a Brazilian cohort. Genotyping was performed using TaqMan^® SNP assays, and pulmonary function was assessed via spirometry according to ATS/ERS standards. Associations between genetic variants, tobacco intake, and COPD status were evaluated using χ² and Fisher’s exact tests, with odds ratios (ORs) and 95% confidence intervals (CIs). Post hoc power analyses were conducted to estimate detectable effect sizes. Results: A total of 123 active or former smokers were analyzed. The CHRNA3 variants (rs1051730 and rs8034191) showed a trend toward higher prevalence among individuals with heavy tobacco intake (>40 pack-years), though no significant allelic or genotypic differences were found between COPD and control groups (p > 0.05). The EPHX1 rs2234922 A allele was significantly more frequent in COPD patients, suggesting increased disease risk (p < 0.05), while the GG genotype appeared protective. Post hoc power analyses indicated moderate power (≈0.56–0.63) for the observed associations. Conclusions: In this Brazilian population, the CHRNA3/5 polymorphisms may influence nicotine dependence, while EPHX1 rs2234922 appears to be associated with COPD susceptibility. These findings support a potential genetic contribution to disease risk and tobacco nicotine dependence, warranting further large-scale studies to confirm these associations and explore their therapeutic implications. Full article

Autosomal-dominant sleep-related hypermotor epilepsy (ADSHE) was the first distinct genetic epilepsy proven to be caused by mutation of the CHRNA4 gene, originally reported in 1994. In the past three decades, pathomechanisms of ADSHE associated with mutant nicotinic acetylcholine receptors (nAChRs) have been explored via various studies, including in vitro experiments and genetic rodent models. However, findings emphasize that functional abnormalities of ADSHE-mutant nAChRs alone cannot generate ictogenesis; rather, development of abnormalities in various other transmission systems induced by ADSHE-mutant nAChRs during the neurodevelopmental process before the ADSHE onset is involved in development of epileptogenesis/ictogenesis. Intra-thalamic GABAergic disinhibition induced by loss-of-function of S284L-mutant nAChRs (S286L-mutant nAChRs in rat ADSHE models) contributes to enhancing propagation of physiological ripple-burst high-frequency oscillation (HFO) and Erk signaling during sleep, leading to enhancement of the trafficking of pannexin1, connexin43, and P2X7 purinergic receptor to the astroglial plasma membrane. The combination of activation of physiological ripple-HFO and upregulation of astroglial hemichannels under the GABAergic disinhibition plays an important role in generation of epileptogenic fast-ripple-HFO during sleep. Therefore, loss-of-function of the S284L-mutation alone cannot drive ictogenesis but contributes to the development of epileptogenesis as an initial abnormality. Based on these recent findings using genetic rat ADSHE models, harboring the rat S286L-mutant Chrna4 corresponding to the human S284L-mutant CHRNA4, this report proposes hypothetical pathomechanisms of ADSHE. Full article

Background/Objectives: Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease characterized by irreversible airway obstruction. This study aims to investigate the associations between COPD and its phenotypes with polymorphic variants of the IREB2 and CHRNA5 genes in the Kazakhstan population. Methods: A case–control study was conducted involving 265 COPD patients and 267 controls. Genotyping of the IREB2 polymorphisms rs13180 and rs2568494, as well as CHRNA5 rs16969968 polymorphism, was performed using real-time polymerase chain reactions (Real-Time PCRs). Results: A higher frequency of the AA genotype of the IREB2 rs2568494 polymorphism was identified in COPD patients with moderate to very severe airflow obstruction (Chronic Obstructive Lung Disease (GOLD) stages II, III, and IV), with an odds ratio of 0.69 (95% CI = 0.23–2.10; Padj = 0.03). The IREB2 rs13180 polymorphism was significantly more frequent or prevalent in smokers and showed a correlation with FEV₁ (forced expiratory volume in one second) (β = 7.79, SE = 2.98, p = 0.01) and FEV₁/ FVC (forced vital capacity) (β = 9.51, SE = 2.95, p = 0.002). Additionally, the CC genotype of this polymorphism was associated with clinical manifestations of COVID-19 in COPD patients (χ²= 3,95, df = 2, p = 0.05). Conclusions: Our study identified a significant association between the IREB2 rs2568494 polymorphism and an increased risk of severe COPD. The IREB2 rs13180 polymorphism was linked to smoking behavior, as well as key lung function indicators, suggesting its potential role in disease progression and lung damage. Furthermore, the CC genotype of the IREB2 rs13180 polymorphism was associated with clinical manifestations of COVID-19 in COPD patients, indicating a potential impact of this genetic variant on susceptibility to viral infections in this population. Full article

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition often associated with genetic syndromes. Structural variants on the long arm of chromosome 15 (15q) are recurrently implicated in syndromic ASD, yet their phenotypic spectrum remains insufficiently characterized in diverse populations. We retrospectively analyzed clinical and molecular data from three patients with ASD treated at a Brazilian public reference center who also presented neurological and systemic comorbidities. Genetic investigations included G-banded karyotyping, chromosomal microarray analysis (CMA), methylation assays, and multiplex ligation-dependent probe amplification (MLPA) when indicated. Variants were classified according to ACMG guidelines and correlated with individual phenotypes. Case 1 showed an 8.4 Mb triplication at 15q11.2–q13.1 encompassing SNRPN, UBE3A, and GABRB3, which are associated with epilepsy, delayed neuropsychomotor development, and dysmorphic traits. Case 2 presented a 418 kb duplication at 15q13.3 involving CHRNA7 and OTUD7A, a variant of uncertain significance correlated with intellectual disability, speech apraxia, and self-injurious behavior. Case 3 demonstrated extensive loss of heterozygosity at 15q11.2–q13.1 and 15q21.3–q26.2, which is compatible with maternal uniparental disomy and Prader–Willi syndrome, manifesting hypotonia, seizures, and global delay. These findings underscore the potential involvement of the 15q region in syndromic ASD and related neurological comorbidities, highlighting the diverse pathogenic mechanisms and the importance of comprehensive genomic profiling for diagnosis, counseling, and individualized care. Full article

Delta-9-tetrahydrocannabinol (THC) is a psychoactive element of Cannabis sativa and affects the human cannabinoid system through its receptors, CB1R and CB2R. CB1R was found in several brain areas, including the hippocampal formation (HF), and it is responsible for most THC side effects. We investigated THC’s effects in the HF of female Wistar rats to assess changes in its neurotransmission. Female Wister rats (n = 20) were gonadectomized under anesthesia at 8 weeks old. Afterwards, they received estradiol benzoate (EB) and/or THC. Immunohistochemistry was performed to assess the expression of the cholinergic receptor alpha 7 subunit (CHRNA7), the vesicular acetylcholine transporter (VAChT), the vesicular glutamate transporter (VGLUT), the gamma-aminobutyric acid type A receptor (GABRA), the CB1 receptor, and estradiol receptor alpha (EBα). In the HF, the expression of CHRNA7 was increased by EB and by THC in the Oil groups but decreased by THC in the EB groups. The same is true for VGLUT expression in the DG and hilum and for GABRA expression in the hilum. The expression of VAChT and CB1 is reduced by EB, while the concomitant administration of THC increases it. GAD expression is reduced by EB administration in CA1, CA3, and DG. Our results may help with decision-making regarding the prescription of low doses of THC as a therapeutical approach. Full article

A part of autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is caused by mutant CHRNA4. The pathomechanisms underlying motor seizures followingly brief/sudden awakening (paroxysmal arousal) in ADSHE seizures remain to be clarified. This study determined extracellular levels of ACh and L-glutamate in the pedunculopontine nucleus (PPN) and its projection regions, including the thalamus and basal ganglia, during wakefulness, slow-wave sleep (SWS) and paroxysmal arousal of transgenic rats bearing rat S286L-mutant Chrna4 (S286L-TG), corresponding to human S284L-mutant CHRNA4, using microdialysis. The expression of connexin43 and pannexin1 in the plasma membrane of the PPN was determined using capillary immunoblotting. The expressions of connexin43 and pannexin1 in the PPN plasma membrane of S286L-TG were larger than the wild type. The extracellular L-glutamate levels in the PPN and projection regions of S286L-TG consistently increased during both wakefulness and SWS compared to the wild type. The extracellular levels of ACh and L-glutamate in the PPN and projection regions decreased accompaning SWS in the wild type. In S286L-TG, this decreasing extracellular ACh level was observed, whereas decreasing L-glutamate level was impaired. Both extracellular levels of ACh and L-glutamate in the PPN and projection regions drastically increased during paroxysmal arousal. Hemichannel inhibitors suppressed the increasing releases of ACh and L-glutamate induced by paroxysmal arousal but decreased and did not affect extracellular levels of L-glutamate and ACh during wakefulness and SWS, respectively. In particular, under hemichannels inhibition, decreasing L-glutamate release accompanying SWS was observed in S286L-TG. This study elucidated that enhanced hemichannels are predominantly involved in the dysfunction of glutamatergic transmission compared to AChergic transmission during the interictal stage in S286L-TG, whereas the hyperactivation of hemichannels contributes to the generation of paroxysmal arousal. Therefore, the hyperactivated excitatory tripartite synaptic transmission associated with hemichannels in the PPN and projection regions plays important roles in epileptogenesis/ictogenesis in S286L-TG. Full article

Breast cancer is a major global health burden with the highest incidence in women, and triple-negative breast cancer (TNBC) stands out as the most malignant subtype. Effective therapeutic targets are urgently needed to develop new therapies for TNBC. Nicotinic acetylcholine receptor is a ligand-gated ion channel receptor that is associated with the advancement of multiple cancers. Notably, α9 nicotinic acetylcholine receptor (α9 nAChR) is less investigated towards its role in cancer. This study sought to clarify the significance of α9 nAChR in TNBC. Firstly, our results uncovered that the expression of CHRNA9 was notably elevated in TNBC tissues and was associated with poor prognosis of TNBC patients. Further, our data indicated that overexpression of α9 nAChR facilitated the growth of TNBC cells, via mechanisms of simultaneously activating AKT-, ERK- and STAT3-mediated proliferation and negatively regulating ferroptosis through promoting SLC7A11/GSH/GPX4 and Keap1/Nrf2/HO1 signaling. Conversely, CHRNA9 knockdown would completely reverse all this signaling, ultimately inhibiting TNBC tumor growth both in vitro and in vivo. Finally, we reported a specific polypeptide antagonist of α9 nAChR, GeXIVA[1,2] and exerted good anti-tumor effects in tumor-bearing mice of TNBC, which indicated a great potential of GeXIVA[1,2] to be further studied as a novel targeted therapy for TNBC. This study provides a scientific basis for establishing α9 nAChR as a novel therapeutic target for TNBC, which is worthy of further development in the future. Full article

Cervical cancer is the second leading cause of cancer-related death in Mexico, primarily due to persistent infection with high-risk Alpha-papillomavirus genotypes, such as HPV16 and 18. Next-generation sequencing (NGS) has revealed a high prevalence of Beta- and Gamma-HPVs, mainly Beta-2 types 38b, 80, 107, and 122, in cervical cancer samples from Mexico. Our group previously reported that HPVs 38b, 107, and 122 possess transforming properties in primary fibroblasts; however, the oncogenic potential of E6/E7-HPV80 has not yet been elucidated. For this purpose, primary human fibroblasts were transduced with E6/E7-HPV80 (FB-E6/E7-HPV80), and functional assays were conducted to evaluate changes in proliferation, metabolic activity, and cell migration. RNA-seq analysis identified differentially expressed genes (DEGs) and enriched pathways. Fibroblasts transduced with E6/E7-HPV16 (FB-E6/E7-HPV16) or empty vector (FB-pLVX) served as controls. FB-E6/E7-HPV80 extended their lifespan and exhibited increased proliferation, metabolic activity, and migration capacity. RNA-seq analysis identified 196 upregulated DEGs (such as GPAT2, MST1R, ACAN, SLCO4A1, and CHRNA3) and 887 downregulated DEGs (such as KLHDC7B, TRIM58, CST1, FBLL1, INHBE, and TMEM132D) shared between FB-E6/E7-HPV80 and FB-E6/E7-HPV16. Enriched pathways included p53, TNF, IL-17, apoptosis, cell cycle, etc. These findings suggest that E6/E7-HPV80 exhibits transforming capabilities that could play an important role in cervical carcinogenesis. Full article

Approximately 70% of people will experience a traumatic event in their lifetime, but post-traumatic stress disorder (PTSD) will only develop in 3.9% and complex post-traumatic stress disorder (CPTSD) in 1–8% of the population worldwide, although in some countries (e.g., Poland and Northern Ireland) it will develop in a much higher percentage. Stress-related disorders have a complex pathogenesis involving neurophysiological, genetic, epigenetic, neuroendocrine and environmental factors. This article reviews the current state of knowledge on the molecular aspects of selected PTSD symptoms: hypervigilance, re-experiencing, emotion dysregulation and dissociation, i.e., the symptoms with strong neurobiological components. Among analysed susceptibility factors are specific gene polymorphisms (e.g., FKBP5, COMT, CHRNA5, CRHR1, 5-HTTLPR, ADCY8 and DRD2) and their interactions with the environment, changes in the HPA axis, adrenergic hyperactivity and disturbances in the activity of selected anatomical structures (including the amygdala, prefrontal cortex, corpus callosum, anterior cingulate gyrus and hippocampus). It is worth noting that therapeutic methods with proven effectiveness in PTSD (TF-CBT and EMDR) have a substantial neurobiological rationale. Molecular aspects seem crucial when searching for effective screening/diagnostic methods and new potential therapeutic options. Full article

Background/Objectives: Several genetic factors are related to the risk of Alzheimer’s disease (AD) and the response to cholinesterase inhibitors (ChEIs) (donepezil, galantamine, and rivastigmine) or memantine. However, findings have been controversial, and, to the best of our knowledge, admixed populations have not been previously evaluated. We aimed to determine the impact of genetic and non-genetic factors on the risk of AD and the short-term response to ChEIs and memantine in patients with AD from Mexico. Methods: This study included 117 patients from two specialty hospitals in Mexico City, Mexico. We evaluated cognitive performance via clinical evaluations and neuropsychological tests. Nineteen variants in ABCB1, ACHE, APOE, BCHE, CHAT, CYP2D6, CYP3A5, CHRNA7, NR1I2, and POR were assessed through TaqMan assays or PCR. Results: Minor alleles of the ABCB1 rs1045642, ACHE rs17884589, and CHAT rs2177370 and rs3793790 variants were associated with the risk of AD; meanwhile, CHRNA7 rs6494223 and CYP3A5 rs776746 were identified as low-risk variants in AD. BCHE rs1803274 was associated with worse cognitive functioning. None of the genetic and non-genetic factors studied were associated with the response to pharmacological treatment. Conclusions: We identified potential genetic variants related to the risk of AD; meanwhile, no factor was observed to impact the response to pharmacological therapy in patients with AD from Mexico. Full article

Ageing is a major risk factor for cognitive and physical decline, but its mechanisms remain poorly understood. This study aimed to detect early cognitive and physical changes, and to analyze the pathway involved by monitoring two groups of mice: a young and an adult group. The study has identified the types of molecules involved in the hippocampus. Adult mice (47 weeks) showed significantly reduced exploratory behavior compared to young mice (11 weeks), although spatial working memory showed no difference. In terms of physical function, grip strength was significantly reduced in adult mice. The Frailty Index (FI) further highlighted age-related changes in adult mice. To investigate the causes of cognitive decline, adult mice were categorized based on their declining cognitive function. Microarray analysis of their hippocampi revealed that the cholinergic receptor nicotinic α3 subunit (Chrna3) was significantly reduced in mice with cognitive decline compared to controls. Subsequent in vitro experiments showed that oxidative stress and cholinesterase inhibitors decreased Chrna3 expression, whereas nicotine and cytisine increased it. These results suggest that Chrna3 is a key factor in age-related cognitive decline. The development of therapeutic strategies targeting Chrna3 expression may offer promising avenues for preclinical and clinical research to mitigate cognitive ageing. Full article

Birds are inherently social creatures that rely on pairing to enhance their well-being. Since many bird species lack obvious physical differences between females and males, sex identification is essential for ensuring their welfare. Additionally, early determination of the sexes of birds is crucial for their breeders, especially considering that most companion birds do not display clear sexual characteristics. Molecular genetic sexing has been demonstrated to be the most reliable method for determining the sexes of monomorphic birds. The objective of the present study was to demonstrate rapid, effective, and precise identification of sex in birds through quantitative real-time PCR (qPCR) using samples obtained via a minimally invasive technique (oral swabs). This qPCR method assesses variations in gene copy numbers within conserved Z-specific genes such as CHRNA6, DDX4, VPS13A, LPAR1, and TMEM161B, which are absent from the W chromosome. A total of 34 samples were included in this study from the following 17 bird species: domestic pigeon (Columba livia domestica), domestic chicken (Gallus gallus domesticus), domestic goose (Anser anser f domesticus), domestic duck (Anas platyrhynchos domesticus), Mute swan (Cygnus olor), Budgerigar (Melopsittacus undulatus), Lovebird (Agapornis roseicollis), Cockatiel (Nymphicus hollandicus), Red-rumped parrot (Psephotus haematonotus), Rose-ringed parakeet (Psittacula krameri), African grey parrot (Psittacus erithacus), domestic Canary (Serinus canaria forma domestica), Goldfinch (Carduelis carduelis major), Gouldian Finch (Chloebia gouldiae), Red Siskin (Carduelis cucullata), Australian Zebra Finch (Taeniopygia castanotis), and Common buzzard (Buteo buteo). The results proved that the CHRNA6, DDX4, VPS13A, LPAR1, and TMEM161B genes can reveal the sexes in the Neognath birds tested. Full article

The increased prevalence of electronic cigarettes, particularly among adolescents, has escalated concerns about nicotine addiction. Nicotine, a potent psychostimulant found in tobacco products, exerts its effects by interacting with nicotinic acetylcholine receptors (nAChRs) in the brain. Recent findings in both pre-clinical and clinical studies have enhanced our understanding of nAChRs, overcoming the limitations of pharmacological tools that previously hindered their investigation. Of particular interest is the α6 subunit, whose expression peaks during adolescence, a critical period of brain development often marked by the initiation of substance use. Pre-clinical studies have linked α6-containing nAChRs (α6*nAChRs) to nicotine-induced locomotion, dopamine release, and self-administration behavior. Furthermore, clinical studies suggest an association between the α6 subunit and increased smoking behavior in humans. Specifically, a single nucleotide polymorphism in the 3′ untranslated region of the CHRNA6 gene that encodes for this subunit is linked to smoking behavior and other substance use. A comprehensive understanding of this subunit’s role in addiction is of high importance. This review aims to consolidate current knowledge regarding the α6 subunit’s functions and implications in addiction and other disorders, with the hope of paving the way for future research and the development of targeted therapies to address this pressing public health concern. Full article