Search Results (4,428)

Endometriosis affects an estimated one in ten women of reproductive age and remains defined clinically by the presence of endometrial-like tissue outside the uterine cavity, yet its persistence depends on biological processes that extend well beyond estrogen exposure. This review argues that endometriosis is best understood as a set of molecularly heterogeneous, interconnected disease processes, hormonal, immune, vascular, epigenetic, and metabolic, that converge on a compact set of intracellular signaling nodes rather than as a single hormonal disorder. These convergence points are mapped onto candidate therapeutic targets spanning established, investigational, and preclinical stages of development, and onto biomarker strategies organized here by clinical application, diagnosis, disease stratification, prognosis, and treatment monitoring, rather than by sample source alone. Translational obstacles, including the limited predictive value of current animal models, the recurring disconnect between preclinical and clinical results, and the distinction between symptom control and disease modification, are addressed throughout rather than confined to a single closing section. Endometriosis management continues to rely on symptomatic hormonal suppression; treatment strategies grounded in the disease’s molecular heterogeneity, rather than a uniform hormonal model, appear to offer the most realistic path toward durable, individualized management. Full article

Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are the most common subtype of NETs, and their incidence continues to increase worldwide. Many NETs express somatostatin receptors (SSTRs), enabling molecular imaging and treatment with radiolabeled somatostatin analogs (SSTAs). [¹⁷⁷Lu]Lu-DOTATATE is an established treatment for advanced SSTR-positive NETs, but complete and durable responses remain uncommon. This review summarizes current clinical experience with [¹⁷⁷Lu]Lu-DOTATATE and emerging SSTR-targeting radiopharmaceuticals and examines strategies to improve PRRT efficacy. Treatment may be enhanced at several interconnected steps, including increasing receptor availability and tumor targeting, improving radiopharmaceutical uptake and absorbed dose, preventing repair of radiation-induced damage, suppressing cellular stress adaptation and survival, and promoting tumor cell elimination. These approaches include radiation priming and fractionation, somatostatin analog pretreatment, epigenetic modifiers, inhibitors of DNA repair and cellular survival pathways, immunotherapy, and chemotherapy-based combinations. PARP, DNA-PK, and HSP90 inhibitors and chemotherapy-based combinations have shown particularly strong preclinical or clinical evidence, whereas mTOR inhibitors, tyrosine kinase inhibitors, Hedgehog inhibitors, immunotherapy, NAMPT inhibitors, p53 stabilization, and epigenetic modifiers remain under investigation. Ongoing development of novel radiopharmaceuticals, personalized dosimetry, retreatment strategies, and rational combinations is expected to refine PRRT and improve outcomes for patients with NETs. Full article

Melatonin is a hormone primarily secreted by the pineal gland, best known for regulating circadian rhythms. It also plays a critical role in ovarian physiology by modulating granulosa cell (GC) function during follicular development, although the underlying molecular mechanisms remain incompletely understood. Recent advances in ribosome sequencing (Ribo-seq) have revealed that many small open reading frames (sORFs), previously overlooked in conventional annotations, actually encode functional micropeptides. However, whether melatonin exerts its ovarian effects through such micropeptides has remained unexplored. In the present study, we identified a previously unannotated sORF within the 5′untranslated region (UTR) of sheep IGF1R mRNA and demonstrated that this sORF encodes a 32-amino-acid micropeptide, which we named IGF1Raa. Knockdown and overexpression of IGF1Raa in sheep GCs, assessed by CCK-8, Edu, flow cytometry, and ELISA, revealed that IGF1Raa negatively regulates GC proliferation and E2 secretion and promotes apoptosis. Co-ip assays and RNA-seq show that IGF1Raa physically associates with PPP2R2B, a regulatory subunit of protein phosphatase 2A (PP2A), and modulates PP2A protein expression. Consequently, IGF1Raa regulates the phosphorylation of AMPK (Thr172) and its downstream effector Raptor (Ser792), thereby controlling the AMPK/mTOR signaling cascade. Importantly, melatonin suppresses IGF1Raa expression, and overexpression of IGF1Raa partially abrogates melatonin’s stimulatory effects on GC proliferation and steroidogenesis. Collectively, our findings identify IGF1Raa as a melatonin-responsive micropeptide that governs GC function through the PP2A/AMPK/mTOR axis, providing new insights into the regulatory network of ovarian physiology and offering potential therapeutic targets for reproductive disorders. Full article

Background/Objectives: Breast cancer remains a leading cause of cancer-related mortality among women, highlighting the need for further investigation of bioactive compounds with selective effects on cancer cells. This study evaluated the biological effects of the natural coumarin derivative umbelliferone in MCF-7 breast cancer cells using integrated in silico and in vitro approaches. Methods: Molecular docking predicted interactions with AKT1, mTOR, PI3Kα, and Caspase-7, while molecular dynamics simulations and MM/PBSA calculations provided further information on interactions with AKT1 and mTOR. Results: Umbelliferone reduced MCF-7 cell viability in a concentration-dependent manner, with an IC₅₀ of 492 µM after 24 h, whereas 50% viability was not reached in BJ normal fibroblasts up to 1400 µM, corresponding to an IC₅₀ > 1400 µM and a selectivity index > 2.85. Annexin V-FITC/PI analysis showed increased apoptotic populations, with total apoptosis significantly increased at 800 µM. Colony formation analysis further indicated reduced clonogenic capacity. At 400 µM, umbelliferone significantly increased relative Caspase-3/7 and Caspase-9 activities to 1.873 ± 0.635 and 2.483 ± 0.092, respectively, whereas neither activity was significantly increased at 800 µM. In silico ADME analysis predicted properties compatible with commonly used drug-likeness criteria. Conclusions: Collectively, the findings demonstrate effects of umbelliferone on cell viability, apoptosis, clonogenic capacity, and caspase activity in MCF-7 cells, with comparatively lower cytotoxicity toward normal fibroblasts. Computational findings remain hypothesis-generating and do not establish direct target engagement or pathway inhibition. Further mechanistic and in vivo studies are required to determine the biological and pharmacological relevance of these findings. Full article

Treatment for locally advanced and recurrent cervical cancer has advanced substantially with immune checkpoint inhibitors, induction chemotherapy, bevacizumab, and antibody-drug conjugates. However, subgroup analyses of major phase III trials suggest that cervical adenocarcinoma (AC) may respond differently from squamous cell carcinoma (SCC). Therefore, novel treatment strategies based on the distinct biological characteristics of AC are needed. This review aimed to evaluate the efficacy of current treatments for AC by examining histology-specific subgroup analyses from major clinical trials and to identify potential therapeutic strategies for AC. We also reviewed ongoing AC-focused clinical trials of novel molecularly targeted agents and combination therapies for advanced or recurrent disease. A structured search of PubMed and ClinicalTrials.gov through 1 June 2026, identified studies of advanced or recurrent cervical adenocarcinoma. Randomized trials, prospective studies, and histology-specific subgroup analyses were included, while case reports, preclinical studies, and SCC-only studies were excluded. Survival and response outcomes were extracted, with histology-specific findings considered exploratory. AC exhibits distinct molecular and immunological features compared with SCC, including frequent alterations in ERBB2/3, KRAS, PIK3CA, PTEN, ARID1A, and STK11 and a relatively immune-cold tumor microenvironment. HPV-independent AC, particularly gastric-type adenocarcinoma, shows aggressive clinical behavior and resistance to conventional therapies. Although bevacizumab, immune checkpoint inhibitors, and tisotumab vedotin have improved outcomes in cervical cancer, evidence specific to AC remains limited because most pivotal trials predominantly enrolled SCC or reported combined AC/adenosquamous subgroups. Emerging strategies targeting HER2, CLDN18.2, TROP2, Nectin-4, FAK, PI3K/AKT/mTOR, and ROS1 may provide new therapeutic opportunities for AC. AC represents a biologically heterogeneous disease distinct from SCC, supporting treatment strategies based on histology and molecular characteristics. Future AC-specific clinical trials and molecular stratification according to HPV association, histological subtype, and actionable alterations are needed to establish biomarker-driven personalized therapy, particularly for treatment-resistant HPV-independent AC. Full article

Breast cancer is the most frequently diagnosed malignancy in women, and hormone receptor-positive disease represents its predominant subtype. Aromatase inhibitors (AIs) are a cornerstone of endocrine therapy, particularly in postmenopausal patients, but their long-term efficacy is frequently limited by intrinsic or acquired resistance. Increasing evidence indicates that epigenetic dysregulation, especially aberrant histone deacetylase (HDAC) activity, contributes to altered estrogen receptor signaling, transcriptional plasticity, activation of compensatory survival pathways, and endocrine treatment failure. This narrative review examines the biological and therapeutic interplay between aromatase and HDACs in breast cancer, integrating evidence from mechanistic studies, in vitro models, preclinical experiments, and clinical trials. HDAC inhibition may restore endocrine sensitivity by modifying chromatin accessibility, reactivating estrogen-responsive and tumor-suppressor genes, suppressing adaptive pathways such as HER2, NF-κB, and PI3K/AKT/mTOR signaling, and promoting cell-cycle arrest and apoptosis. Preclinical studies support synergistic or sensitizing effects of combined AI–HDAC inhibition, while clinical trials with entinostat, tucidinostat, panobinostat, and exemestane- or letrozole-based regimens have produced heterogeneous results. These findings suggest that endocrine–epigenetic combinations may benefit selected patients rather than represent an universally effective strategy. Future clinical translation will require improved HDAC selectivity, optimized dosing, toxicity management, and validation of predictive biomarkers enabling biomarker-guided patient selection. Full article

Schizophrenia is a highly heritable neuropsychiatric disorder whose pathophysiology remains poorly understood. While neurotransmitter, neurodevelopmental, synaptic, and dysconnectivity hypotheses explain important aspects of the disorder, growing evidence suggests that metabolic dysfunction also plays a central role. This narrative review synthesises evidence from genetics, cell signalling, molecular neuroscience, and metabolism to propose a theoretical framework linking insulin resistance and mitochondrial dysfunction to schizophrenia. We argue that genetic susceptibility and environmental risk factors converge to produce insulin resistance, impaired insulin signalling, and chronic metabolic stress. Reduced insulin signalling suppresses PI3K/AKT activity, while nutrient overload initially hyperactivates mTORC1 independently of PI3K/AKT. Together, these abnormalities shift cellular metabolism away from oxidative metabolism, promote neuroinflammation, impair mitophagy, disrupt mitochondrial dynamics, and increase oxidative stress. Progressive mitochondrial dysfunction subsequently reduces ATP production and downregulates mTORC1, resulting in persistent bioenergetic impairment. We propose that these metabolic abnormalities provide mechanistic links to hallmark features of schizophrenia, including GABAergic and dopaminergic dysfunction, abnormal neurodevelopment, synaptic pathology, cortical structural changes, and disrupted brain connectivity. Finally, we suggest that schizophrenia differs from mood disorders through greater prenatal neurodevelopmental disruption and reduced mitochondrial repair capacity, producing more severe and persistent metabolic dysfunction. Full article

Asthma is a chronic inflammatory airway disease characterized by considerable clinical and molecular heterogeneity, involving complex interactions between genetic susceptibility, environmental factors, and immune dysregulation. Increasing evidence indicates that non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and other regulatory RNA species, play essential roles in the development and progression of asthma—modulate inflammatory responses, immune cell differentiation, airway remodeling, and epithelial barrier function by interacting with key molecular and signaling pathways, notably the NF-κB, JAK/STAT, PI3K/AKT/mTOR, and TGF-β/Smad cascades. For example, miR-125b-5p and miR-223-3p demonstrate consistent dysregulation across varying biological compartments and independent cohorts, while miR-21, miR-146a, miR-155, and lncRNAs like NEAT1 and MALAT1 are frequently confirmed as central regulators of airway pathology. Aberrant expression of these ncRNAs has been associated with distinct asthma phenotypes, disease severity, and therapeutic responses, highlighting their potential as diagnostic and prognostic biomarkers. This review summarizes current knowledge on the biological functions of ncRNAs in asthma, their involvement in critical pathogenic mechanisms, and discusses their emerging clinical applications and the challenges of translating RNA-based therapeutics into clinical practice. Full article

Limb regeneration is one of the most fascinating phenomena in life sciences. Although Procambarus clarkii exhibits remarkable regenerative capabilities, the molecular mechanisms underlying its limb regeneration remain poorly understood. To address this, we investigated the transcriptome data and DNA methylation levels during the limb regeneration process in Procambarus clarkii. We employed fluorescence in situ hybridization (FISH), RNA interference (RNAi), and mTOR inhibitors to validate the impact of key genes and pathways. Our findings from the weighted gene co-expression network analysis (WGCNA) suggest that Innexin2 may be associated with limb regeneration. Whole-genome bisulfite sequencing (WGBS) analysis revealed changes in methylation levels between the 0 dpa and 15 dpa stages of limb regeneration, while KEGG enrichment analysis highlighted the mTOR signaling pathway. Furthermore, both Torin1 and Rapamycin, as mTOR inhibitors, demonstrated that this pathway is required for limb regeneration. Overall, our study provides insights into the molecular regulatory mechanisms underlying limb regeneration in the Procambarus clarkii, offering valuable data support for future research in regeneration biology. Full article

The gut microbiota is recognized as important to maternal and child health through associations with immune maturation, metabolic programming, barrier integrity, and early-life disease susceptibility. Indigenous food systems, fermented foods, probiotics, and postbiotics may influence gut microbial communities and functions, suggesting potential avenues for investigation into nutritional resilience, particularly in low-resource settings. This review synthesizes evidence on microbiome-informed maternal and child nutrition, focusing on indigenous foods, fermented foods, probiotics, postbiotics, and microbiome-mediated mechanisms. Literature was searched in PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar for studies, systematic reviews, and meta-analyses published between 2015 and 2025. Evidence indicates that microbiome-directed nutritional interventions may influence microbial metabolites, particularly short-chain fatty acids, and pathways associated with barrier integrity, immune regulation, and cellular signaling, including adenosine monophosphate-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), toll-like receptor (TLR), and peroxisome proliferator-activated receptor (PPAR). Artificial intelligence, multi-omics, and precision nutrition may support the investigation and future development of more targeted approaches. However, gaps remain regarding population-specific microbiome profiles, standardized probiotic and postbiotic formulations, longitudinal maternal–infant relationships, and evidence from African and other low-resource settings. The Microbiome-Informed Nutrition Framework (MINF) is proposed as a hypothesis-generating model integrating indigenous food systems, microbiome-directed interventions, precision nutrition, and community-based primary healthcare as potential areas for future research, rather than established clinical or public health interventions. Full article

Alzheimer’s disease (AD) is characterised by progressive accumulation of misfolded proteins and failure of cellular clearance pathways, particularly the autophagy–lysosomal system. Given the limited disease-modifying efficacy of current pharmacological strategies, intermittent fasting (IF) has emerged as a potentially relevant non-pharmacological intervention capable of modulating energy metabolism, proteostasis and cellular stress responses. This review analyses the mechanisms through which IF and fasting-like metabolic states may stimulate macroautophagy and chaperone-mediated autophagy, and evaluates their potential neuroprotective relevance in AD. Evidence from in vitro models and animal studies suggests that fasting-induced metabolic switching, particularly β-hydroxybutyrate production, can modulate AMPK–mTOR signalling, autophagic flux, oxidative stress, synaptic plasticity and Aβ/Tau-related proteostasis. However, the translation of these findings to humans remains incomplete. Current clinical studies suggest potential benefits in selected cognitive, sleep, and metabolic outcomes but rely mainly on indirect readouts such as neuropsychological testing, peripheral biomarkers, neuroimaging, metabolomics and microbiota-derived signatures. Larger, longer and biomarker-integrated randomised controlled trials using nutritionally supervised protocols are required to determine whether IF can safely produce clinically meaningful neuroprotection in AD without increasing frailty, sarcopenia or hypoglycaemic risk in older adults. Full article

Background: Sophocarpine (SC), a tetracyclic quinolizidine alkaloid, has shown antitumor potential, yet its activity and underlying mechanisms in breast cancer remain unexplored. This study aimed to investigate the anticancer effects of SC and the molecular mechanism, focusing on the involvement of microRNA-21 (miR-21) and AKT/mTOR and ERK1/2 signaling networks. Methods: In MDA-MB-231 and T-47D breast cancer cells, SC cytotoxicity and growth-inhibitory effects were evaluated using MTT viability, colony formation, migration assays, and flow cytometry for cell cycle and apoptosis analysis. RT-qPCR analysis, Western blotting, and immunofluorescence staining were performed to measure RNA and protein expression, respectively. Molecular docking analysis was performed to explore SC’s interaction with the miR-21 precursor. Results: SC treatment effectively inhibited the proliferation, survival, and migration of breast cancer cells. It also induced cell cycle arrest and triggered apoptosis in both cell lines. Mechanistically, SC downregulated oncogenic miR-21 transcription, thereby enhancing tumor suppressors PTEN and PDCD4 and suppressing AKT/mTOR and ERK1/2 signaling. Interestingly, restoration of miR-21 reversed SC’s effects on PTEN and PDCD4, confirming SC’s miR-21 dependency. Docking analysis suggested that SC may bind the miR-21 precursor and interfere with its maturation. SC also increased long noncoding RNA GAS5 while reducing miR-196a-5p and HIF-1α transcripts. It shifted the Bcl2/Bax/Bad/caspases balance toward apoptosis. Conclusions: These findings identify SC as a potential structural scaffold exhibiting preliminary anti-tumor activity against breast cancer cells, at least in part, through modulating miR-21 and inhibition of the AKT/mTOR/ERK1/2 survival network. Full article

Skeletal muscle development is a key determinant of meat production and meat-quality traits in sheep, but the coordinated long non-coding RNA (lncRNA) and messenger RNA (mRNA) co-expression landscape underlying postnatal muscle development in Hanper sheep remains unclear. In this study, RNA sequencing was performed on Longissimus Dorsi muscle samples from Hanper sheep at 1 month (M1), 7 months (M7), and 13 months (M13) of age to characterize lncRNA and mRNA expression profiles during postnatal growth. A total of 13,940 candidate lncRNAs were identified, and these lncRNAs exhibited typical structural features, including shorter transcript lengths, fewer exons, and shorter open reading frames than mRNAs. Differential expression analysis identified 39, 11, and 174 differentially expressed lncRNAs in M7_vs_M1, M13_vs_M7, and M13_vs_M1, respectively, while 357, 160, and 446 differentially expressed mRNAs were detected in the corresponding comparisons. Functional enrichment analyses showed that differentially expressed mRNAs and co-expressed mRNAs associated with differentially expressed lncRNAs were mainly involved in RNA metabolism, translation, ribosome biogenesis, amino acid biosynthesis, energy and lipid metabolism, extracellular matrix remodeling, and cell adhesion. Several muscle-development-related signaling pathways, including AMPK, insulin, PI3K-Akt, PPAR, mTOR, FoxO, ECM–receptor interaction, and focal adhesion pathways, were also enriched. Integrated lncRNA–mRNA analysis further identified candidate lncRNA-associated differentially expressed genes, including IGF2, FOS, ACTC1, ADIPOQ, SPP1, PECAM1, and SLC16A7. These findings provide a comprehensive lncRNA and mRNA transcriptomic resource and reveal candidate regulatory molecules potentially involved in postnatal Longissimus Dorsi muscle development in Hanper sheep. Full article

Background and Objectives: This study evaluated eight targets related to proliferation (miR-21, miR-210, PTEN, and mTOR), ferroptosis regulation (SLC7A11, GPX4, and miR-214), and immune regulation (STAT3) in bulk (unfractionated) peripheral blood mononuclear cells (PBMCs) from patients with breast cancer. Their exploratory discriminative performance and associations with clinicopathological characteristics, including immunohistochemical parameters, were also examined. Materials and Methods: Target expression was quantified by qRT-PCR in PBMCs from 41 patients with histopathologically confirmed breast cancer and 30 healthy controls. Immunohistochemistry-defined surrogate subtypes (hereafter, IHC-defined subtypes) were assigned according to ER, PR, HER2 and Ki-67 status. Between-group comparisons were performed using the independent-samples t-test or the Mann–Whitney U test; multiple comparisons were corrected using the Benjamini–Hochberg false discovery rate (BH-FDR) method. Exploratory discriminative performance was determined by ROC analysis with 2000-iteration bootstrap confidence intervals. Directional consistency was examined in two independent PBMC GEO datasets (GSE27562, GSE47862); this was a directional comparison rather than formal external validation. Results: Seven of the eight targets differed significantly after BH-FDR correction: STAT3, mTOR, SLC7A11, miR-21, and miR-210 were upregulated, whereas PTEN and miR-214 were downregulated. In this exploratory, single-cohort case-control study, the largest exploratory single-marker AUCs were observed for STAT3, PTEN, miR-210 and SLC7A11. No association with clinicopathological parameters survived multiple-testing correction. In a post hoc exploratory comparison, PBMC PTEN levels were lower in TNBC (n = 13) than in non-TNBC cases (n = 28), but this difference did not remain significant after BH-FDR correction (Mann–Whitney U, p = 0.024; BH-FDR p = 0.193). Conclusions: Breast cancer was associated with distinct expression patterns in bulk PBMCs, including increased miR-21 and mTOR expression with decreased PTEN expression, increased SLC7A11 with decreased miR-214 expression, and increased STAT3 expression. Five significant pairwise correlations were identified among the measured targets. Because these findings were derived from transcript-level measurements in unfractionated PBMCs, they do not establish functional pathway activation or ferroptosis resistance. Lower PBMC PTEN expression in TNBC reached nominal but not FDR-corrected significance, so no clinicopathological association is claimed. Full article

Background/Objectives: To describe the clinical and genetic features of hemimegalencephaly in pediatric patients, and to highlight treatment outcomes in this population. Methods: This is a systematic literature review following PRISMA guidelines. We used PubMed, Google Scholar, and Scopus for this systematic literature review as databases. Clinical data, imaging findings, EEG patterns, genetic variants, associated syndromes and treatment modalities and outcomes were reviewed, analyzed and summarized in tables. A total of 161 pediatric patients with hemimegalencephaly are described. A risk of bias and sensitivity analysis was conducted. Results: Hemimegalencephaly is more frequently reported in males. The most common subtype was isolated hemimegalencephaly followed by the syndromic subtype, in particular the association with Ito’s hypomelanosis. The most common seizure type was focal onset with impaired awareness. Genetic analysis showed variants in TSC1, TSC2, NPRL3, and PIK3CA, supporting mTOR pathway involvement. Drug-resistant epilepsy was present in approximately 73.2% (118/161) of the sample size. Hemispherectomy, especially functional, in our sample was more frequently reported and the current limited available literature suggests potentially comparable seizure outcomes compared to anatomical hemispherectomy in terms of seizure reduction. Our biggest limitation is the lack of long-term neurological follow-up in the existing literature. Conclusions: Hemimegalencephaly presents with a wide clinical and genetic spectrum and frequently results in drug-resistant epilepsy and developmental impairment. Although surgery may offer seizure relief, outcomes vary and the optimal approach remains individualized. Early diagnosis is essential to enable timely intervention and coordinated care. A multidisciplinary team including neurology, genetics, radiology and neurosurgery is key to optimizing outcomes. Broader studies including milder cases and long follow-up are needed to fully understand disease progression and guide management. Full article