Search Results (183)

Obesity is one of the most serious public health challenges worldwide and has reached the scale of a global epidemic. Its etiology is multifactorial and includes genetic, environmental, hormonal, and neurobiological factors. In recent years, increasing attention has been paid to the role of the gut microbiota in the regulation of energy metabolism, inflammatory processes, and the functioning of the gut–brain axis. An increasing body of evidence suggests that the gut microbiota may influence the dopaminergic system and eating behaviors through bacterial metabolites, immune pathways, and the vagus nerve. Disturbances in microbiota composition may contribute to the development of chronic low-grade inflammation and compulsive consumption of highly processed foods. This article discusses the concept of food addiction as a phenomenon involving loss of control over eating, excessive reward system reactivity, and dopaminergic dysfunction within the mesolimbic reward system. Particular attention is given to the role of the gut microbiota in modulating these processes, including the potential effects of selected commensal bacteria and the importance of dietary interventions such as the ketogenic diet in regulating the gut–brain axis. The presented data suggest that modulation of the gut microbiota may represent a promising supportive strategy in the treatment of obesity and disorders associated with compulsive eating. At the same time, it is emphasized that the current state of knowledge is largely preclinical and observational, highlighting the need for further translational and clinical studies. Full article

Background: This study was conducted to identify genetic risk variants associated with nicotine addiction in the CHRNA5, HTR2A, DRD4, and CYP2A6 genes among electronic cigarette users who also smoke combustible cigarettes (dual users), and to assess potential genotoxic and cytotoxic damage in the oral mucosal cells of the study population. Methods: We included dual e-cig users (ECIG, n = 70), combustible cigarette smokers (CCU, n = 24), and non-smokers and non-e-cig users (NS, n = 110). Genetic variants in CHRNA5, HTR2A, DRD4, and CYP2A6 were genotyped. Micronucleus analysis was performed on oral mucosal cells to detect cellular abnormalities. Results: The ECIG group demonstrated greater nicotine addiction on the Fagerström Test for Nicotine Dependence (FTND, 5.5 vs. 1, p = 0.023). Salivary cotinine levels were significantly higher in the ECIG group compared to the CCU group (39 vs. 12 ng/mL, p < 0.001). The carriers of the A allele (rs16969968/CHRNA5) had higher FTND scores, carriers of the C allele (rs1800955/DRD4) used electronic cigarettes more frequently each day, and carriers of the T allele (rs4105144/CYP2A6) started using nicotine products at a younger age. The number of micronuclei and cellular abnormalities in the oral mucosa was higher in the ECIG and CCU groups compared to the NS group. Conclusions: Salivary cotinine levels and FTND are higher in dual e-cigarette users than in combustible cigarette users. Dual users exhibit risk alleles in the CHRNA5, DRD4, and CYP2A6 genes, which are associated with traits linked to increased nicotine addiction. Dual e-cigarette use poses comparable genotoxic risks to combustible smoking. Full article

Both genetic and epigenetic factors influence the development and pathology of alcohol use disorder (AUD), which is further associated with changes in learning, memory, and synaptic plasticity. Histone acetylation is an epigenetic mechanism that changes the chromatin architecture, influencing gene transcription, which may further impact neuronal signaling, cognition, and addiction-related behaviors. In this review, we summarize the existing literature on how alcohol exposure impacts histone acetylation and the expression and activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Overall, alcohol appears to dynamically regulate histone acetylation and the expression and activity of HATs and HDACs in a brain region-, alcohol quantity-, exposure paradigm-, and sex-specific manner. While general patterns exist, more work is needed to elucidate the precise mechanisms through which alcohol changes histone marks across a variety of experimental and biological conditions, thus changing downstream gene expression. We suggest here that a more nuanced understanding of the relationship between histone acetylation and alcohol consumption is needed. Going forward, unbiased molecular techniques for profiling histone marks across the genome will allow for greater precision in determining the impact of alcohol on epigenetic regulation of transcription. However, these approaches must be performed with consideration to differences in mode and quantity of alcohol exposure, as well as withdrawal time and sex, in order for this research to uncover therapeutic targets for future treatment options. Overall, comprehensive, unbiased studies may yield novel insights into the regulatory role of alcohol-induced epigenetic modifications in the pathophysiology and neuropsychiatric correlates of AUD. Full article

Clear cell renal cell carcinoma (ccRCC) is increasingly recognized as a lipid-addicted malignancy in which de novo lipogenesis (DNL) supports tumor growth, survival, and treatment resistance. ccRCC-specific genetic alterations, particularly loss of VHL and activation of hypoxia-inducible factor (HIF) signaling, promote SREBP-mediated upregulation of key lipogenic enzymes, including ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and stearoyl-CoA desaturase 1 (SCD1). These pathways support membrane biogenesis and redox balance while also promoting metabolic flexibility, enabling adaptation to therapeutic and microenvironmental stresses. Emerging preclinical studies suggest that pharmacological inhibition of lipogenic enzymes, either alone or in combination with tyrosine kinase inhibitors, mTOR inhibitors, HIF-2α antagonists, or immune checkpoint blockade, may suppress ccRCC progression. However, most therapeutic data remain limited to preclinical models, and clinical validation is still lacking. This review synthesizes recent advances in molecular regulation and therapeutic targeting of DNL in ccRCC and discusses the challenges and future opportunities to improve mechanistic understanding and explore potential therapeutic applications. Full article

Tumor-agnostic therapies represent an evolving approach in oncology, shifting from conventional histology-based treatment models to strategies guided by molecular alterations. Regulatory approvals of therapies targeting tumors harboring genomic alterations such as NTRK and RET fusions, BRAF V600E mutation, and those with deficient mismatch repair (dMMR) and a high tumor mutational burden (TMB-H) have demonstrated clinical activity across multiple cancer types. However, responses to these therapies are not uniform across all tumors. This review examines the variability of clinical outcomes across different cancer histologies and the challenges associated with this tumor-agnostic treatment paradigm. Despite sharing the same molecular alterations, some malignancies, including pancreatic and colorectal cancers, demonstrate lower response rates due to tissue-specific resistance mechanisms such as bypass signaling pathways and co-occurring genomic alterations. We discuss how these biological differences influence treatment response and their implications for future drug development and clinical trial design. Addressing these biological and clinical complexities will be essential to optimize the use of tumor-agnostic therapies across diverse cancer types. Full article

Background/Objectives: Opioid use disorder (OUD) is caused by a complex interplay between genetic and non-genetic factors. DNA methylation is an epigenetic mechanism that modulates gene expression. Data on DNA methylation and opioid addiction and treatment are limited. This association study was designed to assess the difference in genome-wide methylation patterns between individuals with OUD in methadone maintenance treatment (MMT) (n = 114) and those with OUD who achieved long-term abstinence (>10 years) without mu opioid receptor agonist treatment (n = 136). Methods: Differential DNA methylation analysis was performed in whole blood using the Illumina EPIC array. Results: A total of 135 differentially methylated probes (DMPs) reached epigenome-wide significance (p < 1 × 10⁻⁷), controlling for sex, age, estimates of blood cell proportions, and the first two principal components based on genome-wide SNP genotypes. The methylation sites were annotated to 157 genes, including 32% long non-coding RNAs. These genes are related to several systems, including cell adhesion (e.g., SAXO4), immune system and inflammation (e.g., UBTF, USP39, C10orf90, PRKCA), stress response (e.g., CRHR1, GPR19), and spermatogenesis (e.g., SPATA16, COX7B2). DMP cg11641410 is located in lncRNA ENSG00000254687, an antisense to OPRK1. Six of the DMPs were also identified in a related longitudinal study of MMT. Conclusions: At this point, it is not possible to determine whether the minor methylation differences observed in this study cause clinically relevant changes in gene expression. However, these findings have the potential to identify biomarkers and to provide new targets for treatment optimization. Full article

Background: This study aimed to further explore the application of genetic risk assessments in 24 metabolic bariatric surgery (MBS) patients to predict weight loss outcomes three years after the procedure. Methods: Participants were assessed using the Genetic Addiction Risk Severity (GARS) test, which evaluates neurogenic polymorphisms linked to addiction and reward deficiency. Genetic and psychosocial data collected prior to surgery were analyzed in relation to post-operative weight loss measures, including weight change, body mass index (BMI), percentage of total weight loss (%TWL), and percentage of expected weight loss (%EWL). The analysis examined associations between specific genetic risk alleles, weight-related outcomes at three to four years post-surgery, and psychosocial trait scores. Results: Spearman’s correlations revealed that the DRD2 risk allele is negatively correlated with 3-year BMI (r_s = −0.481, p < 0.05, 95% CI: –0.746 to –0.083). One-way ANOVA indicated that there is a significant difference in 3-year BMI (p = 0.018) between 0 and 1 DRD2 risk allele copy. There is also a significant difference in ∆weight (p = 0.022), ∆BMI (p = 0.014), and %EWL (p = 0.032) among the different SNP expression values of the MAOA risk allele. In addition, Spearman’s correlation revealed that FCQ scores are negatively correlated with ∆BMI (r_s = −0.470, p < 0.05, 95% CI: −0.767, −0.005), %TWL (r_s = −0.561, p < 0.05, 95% CI: −0.814, −0.129), and %EWL (r_s = −0.533, p < 0.05, 95% CI: −0.800, −0.090) at 3 years post-surgery and positively correlated with 3-year weight (r_s = 0.576, p < 0.05, 95% CI: 0.151, 0.821) and 3-year BMI (r_s = 0.552, p < 0.05, 95% CI: 0.117, 0.810). Lastly, GARS scores are positively correlated with 3-year ∆weight (r_s = 0.422, p < 0.05, 95% CI: 0.010, 0.712). Full article

Transcription-associated cyclin-dependent kinases (tCDKs) precisely control the gene transcription process (initiation, elongation, and termination) by mediating RNA polymerase II phosphorylation. In several cancers, disrupted transcriptional control is emerging as a hallmark. In this review we summarize research studies of tCDKs’ role in gastrointestinal (GI) tumors, particularly, in the biology of esophageal, gastric, pancreatic, and hepatobiliary cancers. Across these tumor types, tCDKs are implicated as activators of super enhancer (SE) regions and contribute to the “transcriptional addiction” that not only drives cancer cell growth but is also attributed to therapeutic vulnerabilities. Overall, expression of tCDKs is increased in GI tumor tissues, indicating a rational target for therapeutics. We further describe emerging approaches, including genetic manipulation, small-molecule inhibitors or targeted protein degradation that disrupt tCDK functions in GI malignancies. We conclude by describing key challenges in targeting tCDKs and future treatment directions. Full article

The neuropharmacology of psychedelics has traditionally focused on serotonergic mechanisms, particularly 5-HT2A receptor activation. However, this paradigm incompletely explains the diversity of neurobiological and therapeutic effects observed across psychedelic compounds. Non-classical psychedelics such as salvinorin A, the primary active constituent of Salvia divinorum, challenge this framework through direct kappa opioid receptor (KOR) agonism, representing a serotonin-independent pathway to altered consciousness. This review systematically examines the role of the endogenous opioid system in mediating psychedelic effects, with emphasis on salvinorin A’s unique KOR-dependent mechanisms. We synthesized preclinical and clinical evidence from in vitro studies, genetically modified animal models, optogenetic circuit dissection, and human neuroimaging trials. Salvinorin A’s selective KOR activation is characterized by pronounced β-arrestin-biased signaling, distinguishing it from endogenous dynorphins and classical KOR agonists. This produces rapid receptor desensitization, transient functional plasticity, and profound dissociative effects mediated through thalamocortical disruption, mesolimbic dopaminergic suppression, and fragmentation of large-scale brain networks. Classical serotonergic psychedelics indirectly engage opioid systems through downstream 5-HT2A signaling, contributing to analgesic and mood-regulatory effects via secondary MOR/DOR modulation. Despite being a potent opioid agonist, salvinorin A exhibits low abuse potential due to aversive phenomenology, dopaminergic suppression, and absence of positive reinforcement in animal models. Incorporating opioid receptor pharmacology into psychedelic neuroscience expands mechanistic understanding beyond serotonin-centric models, revealing multiple neurochemical pathways capable of inducing therapeutically relevant altered states. This framework enables rational development of biased KOR ligands and establishes salvinorin A as a paradigmatic model for non-serotonergic psychedelia with applications in treatment-resistant depression, addiction, and chronic pain. Full article

Objectives: Addiction disorders remain a major challenge in contemporary psychiatry due to high relapse rates and significant individual and societal burden. Despite advances in addiction neurobiology, current diagnostic frameworks and dominant models offer limited tools for early risk identification and dynamic support of clinical decision-making across the course of treatment. The aim of this narrative review is to introduce the MAC/MAB–RCS model as an integrated conceptual framework for risk stratification and personalized intervention in addiction psychiatry. Methods: The proposed model integrates evidence from four complementary domains: genetic, epigenetic, and stress-axis biomarkers; functional brain network organization; and psychological/psychiatric dimensions relevant to addictive behaviors. These domains are synthesized into a unified conceptual structure designed to capture dynamic regulatory processes underlying addiction vulnerability. Results: At the core of the model lies the Regulatory Control State (RCS), a latent higher-order construct representing an individual’s dynamic regulatory capacity through the integration of cognitive control, emotional regulation, and motivational drive modulation. Disruption of the RCS is conceptualized as a shared transdiagnostic mechanism driving craving escalation, compulsive behavior, and relapse vulnerability, independent of substance class or specific addictive behavior. Conclusions: The MAC/MAB–RCS model aligns with the principles of precision psychiatry by offering a pragmatic, clinically oriented translational framework with potential applicability across clinical settings, bridging neurobiological research and clinical practice. The review discusses its relationship to existing models, potential clinical and systemic applications, key limitations, and priorities for future validation studies. Full article

The search for new therapeutic principles is essential for treating relapsed/refractory (r/r) acute myeloid leukemia (AML). Novel principles include genome-agnostic differentiation induction, controlling AML-triggering inflammation, potentiating the immune response and ‘normalizing’ AML metabolism. This review summarizes data from a phase I study (10 patients, pts) and three case reports reporting 7 pts on the treatment of r/r AML by reprogramming AML hallmarks using APA, low-dose azacitidine, pioglitazone (PPARα/γ agonist) and all-trans retinoic acid. APA reprograms the r/r AML phenotype in patients with clinically and molecularly/genetically unfavorable risk profiles (17 pts, 16 refractory, one relapsed) in a genome-agnostic manner, restoring the plasticity of AML hallmarks, thereby improving immune surveillance, attenuating inflammation-triggered promotion of AML and distant microbial inflammation (healing of fungal pneumonia during induction of complete remission (CR) with APA), while normalizing leukemia metabolism (restoring phagocytosis and ROS production in leukemic neutrophils). APA induces CR in 10 pts (59%), with only modest hematotoxicity following CR induction. This allows treatment to be carried out in an outpatient setting, including for elderly and comorbid patients. Triple transcriptional modulation, facilitated by epigenetic modelling with azacitidine, targets reprogramming of non-oncogene addiction networks in AML, re-establishing functionally active, closely interrelated myeloid hallmarks and AML cell death genome-agnostically. Full article

Background: Tic spectrum disorder (TSD), encompassing Tourette syndrome and chronic tic disorder, is a childhood-onset neurodevelopmental condition with complex genetic and environmental contributions. Heritable components have been implicated in TSD, but no clear genetic mechanisms have been identified. Significant aspects of TSD etiology remain unclear, with key uncertainties concerning the role of environmental influences in its development. In this study, we aimed to identify environmentally induced epigenomic and transcriptomic changes contributing to TSD pathology by investigating genetically similar monozygotic twins discordant for TSD. Methods: To investigate environmentally driven mechanisms, we analyzed peripheral blood from eleven monozygotic twin pairs, either discordant or concordant for TSD, using RNA sequencing and DNA methylation analysis. Results: Differential expression analysis identified a dozen differentially expressed genes between TSD and non-TSD individuals, most of which were long non-coding RNAs or pseudogenes. Expression of the small RNA gene RNY1 was significantly associated with tic severity, suggesting involvement of immune-related processes. DNA methylation (DNAm) analysis revealed ~30,000 probes with a nominal p < 0.05, however none of these were significant after multiple testing correction. Expression quantitative trait methylation (eQTM) analysis identified 236 methylation-associated genes. Gene set enrichment analysis demonstrated broad downregulation in TSD individuals for pathways related to translation, RNA processing, and neurobiological functions, with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways including ribosome, nucleocytoplasmic transport, pluripotency signaling, and nicotine addiction. Conclusions: These results suggest that environmentally influenced gene expression may contribute to TSD pathogenesis through dysregulation of immune and neuronal pathways. Despite a small sample size, the monozygotic twin design provides strong control for genetic background and identifies significant differences that contribute to the understanding of the underlying molecular mechanisms of TSD. Full article

Background/Objectives: The variation in the treatment outcomes of extended-release naltrexone (XR-NTX) including the potential role of genetic factors are poorly understood. This study aimed to explore the potential association between the catechol-O-methyltransferase (COMT) rs4680 and mu-opioid receptor (OPRM₁) rs1799971 genotypes and XR-NTX treatment outcomes in patients with opioid use disorder (OUD) specifically focusing on treatment retention, relapse to opioids, number of days of opioid use, and opioid cravings. Methods: This was a 24-week, open-label clinical prospective, exploratory study involving patients with OUD who chose treatment with monthly injections of intramuscular XR-NTX. Men and women aged 18–65 years with OUD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, were included. The participants were interviewed using the European Addiction Severity Index. Survival analyses and linear mixed models were used to analyze the data. Results: Of the 162 participants included in this study, 138 (21% female) initiated treatment with XR-NTX, with 88 genotyped for COMT rs4680 and 86 for OPRM₁ rs1799971. Heterozygous Met/Val carriers of COMT rs4680 were less likely to relapse to opioids compared with those with the COMT rs4680 Met/Met genotype. No significant association was observed for the OPRM₁ polymorphism. Conclusions: Patients with the COMT rs4680 Met/Val genotype exhibit a reduced risk of relapse to opioids and may therefore derive greater benefit from XR-NTX treatment compared with those with the COMT rs4680 Met/Met genotype. Future studies should be conducted with a larger number of participants and possibly include other genetic variants and treatment outcomes. The trial is registered at ClinicalTrials.gov (#NCT03647774) and the EU Clinical Trial Register (#2017-004706-18). Full article

Cancer reversion therapy represents a paradigm shift in oncology, focusing on reprogramming malignant cells to a non-malignant state rather than destroying them. This narrative review synthesizes current evidence, emerging technologies, and future directions in this promising field. Cancer reversion is founded on key biological observations: somatic cell reprogramming, spontaneous cancer regression, and microenvironmental influences on malignant behavior. Current approaches include epigenetic reprogramming using HDAC inhibitors and DNA methyltransferase inhibitors; microenvironmental modulation through extracellular matrix manipulation and vascular normalization; differentiation therapy exemplified by all-trans retinoic acid in acute promyelocytic leukemia; and targeting oncogene addiction as demonstrated in BCR-ABL-driven leukemias. Emerging technologies accelerating progress include single-cell analyses that reveal cancer heterogeneity and cellular state transitions; CRISPR-based approaches enabling precise genetic and epigenetic manipulation; patient-derived organoids that model tumor complexity; and artificial intelligence applications that identify novel reversion-inducing agents. Critical evaluation reveals that many reported “reversion” phenomena represent stimulus-dependent plasticity or transient growth arrest rather than stable phenotypic normalization. True cancer reversion requires durable, heritable phenotypic changes that persist after treatment withdrawal, with evidence of epigenetic consolidation and functional restoration. Despite promising advances, significant challenges remain: cancer cell plasticity facilitating therapeutic escape, difficulties in establishing stable reversion states, delivery challenges for solid tumors, and the need for combination approaches to address tumor heterogeneity. Future directions include integrated multi-omics analyses to comprehensively map cellular state transitions, studies of natural regression phenomena to identify reversion mechanisms, advanced nanodelivery systems for targeted therapy, and synthetic biology approaches creating intelligent therapeutic systems. By redirecting rather than destroying cancer cells, reversion therapy offers the potential for reduced toxicity and resistance, potentially transforming cancer from a deadly disease to a manageable condition. Full article

Despite valuable insights into the individual roles of genetic factors and personality traits, their combined contribution to addiction susceptibility remains insufficiently characterized. Within this framework, the potential influence of epigenetic mechanisms, particularly those mediated by the gut microbiome, also remains underexplored. This comprehensive review aims to address these gaps in an integrative manner by examining: (i) the association of gene regulation with personality traits; (ii) the genetics of substance use disorders; (iii) the roles of genes and personality in addiction; and (iv) epigenetic influences on addiction, with a particular focus on the role of the gut microbiome. Genetic influences on personality act primarily via regulatory variants that modulate gene expression during neurodevelopment, shaping cognitive, emotional, and behavioral traits that contribute to individual differences. Substance use disorders share partially overlapping genetic foundations, with specific loci, heritability estimates, and causal pathways differing across substances, reflecting both shared vulnerability and substance-specific genetic influences on addiction susceptibility. Impulsivity, novelty-seeking, and stress responsiveness are heritable personality traits that interact to shape susceptibility to substance use disorders, with genetic factors modulating risk across different forms of addiction. Environmental factors, early-life stress, and social influences interact with the gut microbiome to shape neurobiological and behavioral pathways that modulate addiction risk. These interactions highlight the multifactorial nature of substance use disorders, in which epigenetic, microbial, and psychosocial mechanisms converge to influence susceptibility, progression, and maintenance of addictive behaviors. Full article