Search Results (1,297)

MicroRNAs (miRNAs) are small non-coding RNAs that play pivotal roles in post-transcriptional gene regulation, influencing development, differentiation, and disease pathogenesis. Since their discovery in 1993, miRNAs have been recognized for their evolutionary conservation and pleiotropic effects, with the 2024 Nobel Prize underscoring their significance in post-transcriptional regulation via the RNA interference (RNAi) pathway. This review synthesizes the complete life cycle of miRNAs—from transcription and processing to function and decay—emphasizing regulatory mechanisms and their implications in human diseases, particularly cancer. We discuss how epitranscriptomic modifications influence miRNA biogenesis and activity, explore their nuclear and mitochondrial functions, and address emerging challenges in miRNA-based therapeutics, including the expanding small RNA landscape such as tRNA-derived small RNAs (tsRNAs), and Argonaute (AGO)-independent activities. Despite hurdles such as modest multi-target effects, off-target interactions, and delivery challenges, miRNAs remain promising as both biomarkers and therapeutic agents, underscoring the need for sustained research to bridge preclinical insights with clinical applications. Full article

Seed dormancy and germination is regulated by internal hormones and exogenous environment cues. Ethylene is one of the hormones that break seed dormancy and induce seed germination. Our previous study showed that N-degron pathway gene, proteolysis6 (PRT6) was involved in dormancy release by ethylene, the defection of which exhibiting ethylene-insensitivity in Arabidopsis thaliana. In the present study, through screening an ethyl methyl sulfonate-mutagenized (EMS) population of prt6−1, we isolated a recessive mutant that acted as a suppressor of prt6 that rescued its insensitivity to ethylene as well as a phenotype of shorter silique length. Further bulk segregant analysis on F2 population identified a premature termination located in the third exon of LONGIFOLIA1 (LNG1), previously reported in the regulation of longitudinal cell elongation. Mutation of LNG1 in prt6−1 background by CRISPR-Cas9 confirmed that LNG1 was epistatic to PRT6 in seed responsiveness to ethylene. Our finding proposed the pleiotropic effect of LNG1 in seed dormancy breakage by ethylene via PRT6, providing novel functional component at the downstream of the coordinated PRT6 and ethylene signaling pathway. Full article

Understanding trait relationships is fundamental in soybean breeding because the goal is to maximize simultaneous gains. Standard multi-trait genome-wide association studies (MT-GWAS) identify variants linked to multiple traits but fail to capture phenotypic structures or interrelations. Structural Equation Models (SEM) account for covariances and recursion, enabling the decomposition of single nucleotide polymorphism (SNP) effects into direct or indirect components and identifying pleiotropic regions. We applied SEM to analyze morphology (pod thickness, PT) and yield traits (number of pods, NP; number of grains, NG; hundred-grain weight, HGW). The dataset comprised 96 soybean individuals genotyped with 4070 SNP markers. The phenotypic network was constructed using the hill-climbing algorithm, a class of score-based methods commonly applied to learn the structure of Bayesian networks, and structural coefficients were estimated with SEM. According to coefficient signs, we identified negative interrelationships between NG and HGW, and positive ones between NP and NG, and HGW and PT. NG, HGW, and PT showed indirect SNP effects. We also found loci jointly controlling traits. In total, 46 candidate genes were identified: 7 associated exclusively with NP and 4 associated with NG. An additional 15 genes were common to NP and NG, 3 were common to NP and HGW, 6 were common to NG and HGW, and 11 were common to NP, NG, and HGW. In summary, SEM-GWAS revealed novel relationships among soybean traits, including PT, supporting breeding programs. Full article

Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive memory loss and cognitive decline. Its key pathological hallmarks include extracellular amyloid plaques composed of amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein. Although numerous studies have investigated the complex pathology of AD, its underlying mechanisms remain incompletely understood. The amyloid cascade hypothesis continues to be the leading model of AD pathogenesis. It suggests that Aβ aggregation is the initial trigger of neurotoxicity, setting off a cascade of pathological events including inflammation, oxidative stress, tau hyperphosphorylation, synaptic dysfunction, and, ultimately, dementia. Molecular dynamics (MD) is a powerful tool in structure-based drug design (SBDD). By simulating biomolecular motions at the atomic level, MD provides unique insights into molecular properties, functions, and inhibition mechanisms—insights often inaccessible through other experimental or computational techniques. When integrated with experimental data, MD further deepens our understanding of molecular interactions and biological processes. Natural compounds, known for their pleiotropic pharmacological activities, favorable safety profiles, and general tolerability (despite occasional side effects), are increasingly explored for their potential in both the treatment and prevention of various diseases, including AD. In this review, we summarize current findings from MD simulations of natural compounds with anti-amyloidogenic potential. This work builds upon our previous publication, which focused on endogenous compounds and repurposed drugs. The review is structured as follows: an overview of the amyloid cascade hypothesis; a discussion of Aβ oligomeric structures and their stabilizing interactions; a section on molecular dynamics, including its challenges and future directions; and a comprehensive analysis of the inhibitory mechanisms of natural compounds, categorized by their shared structural features. Full article

Potato (Solanum tuberosum L.) is a globally important food crop, but its tetrasomic inheritance and diploid self-incompatibility have limited the discovery of potato genes and progress in breeding. Here, we developed an F₂ segregating population consisting of 174 lines by crossing a self-compatible genome-homozygous diploid line (Y8, female parent) with a heterozygous diploid line (IVP101, male parent), followed by selfing. Using whole-genome resequencing, we constructed a high-density genetic map containing 4464 recombinant bin markers with an average physical distance of 165.51 Kb. Phenotypic evaluation of 8 traits related to yield, tuber shape, and tuber eye number across three environments revealed significant parental differences and wide phenotypic variation within the F₂ population. QTL (Quantitative trait loci) mapping using this genetic map and multi-environment phenotypic data identified 89 QTLs, including 7 previously reported QTLs/genes. In addition, 10 QTLs were stably detected across multiple seasons (stable QTLs). Further genetic effect analysis showed that favorable alleles of these stable QTLs significantly enhanced phenotypic values. Notably, two pleiotropic QTLs were identified on chromosomes 5 and 12; the major-effect QTL on chromosome 12 (qTY-12-6, qTS-12-3, and qTE-12-4) exhibited high phenotypic variance explained (PVE). Its favorable allele from Y8 significantly increased mean tuber weight, tuber number per plant, and promoted rounder tuber shape while reducing eye number, simultaneously improving yield and quality. Collectively, this study provides a reference for genetic mapping using homozygous and heterozygous diploid parents, and the identified QTLs offer valuable genetic resources for potato breeding and molecular mechanism research, enhancing our understanding of the genetic regulation of yield, tuber shape, and eye number in potato. Full article

The healing issue is a central, not completely understood, problem in pharmacology, approached by many concepts. One of the most well-known is Robert’s and Szabo’s concept of cytoprotection, which holds innate cell (epithelial (Robert), endothelial (Szabo)) integrity, protection/maintenance/reestablishing in the stomach to be translated to other organ therapy (cytoprotection→organoprotection) via cytoprotection agent’s effect. Thereby, we defend stable gastric pentadecapeptide BPC 157 therapy, efficacy, pleiotropic beneficial effects along with high safety (LD1 not achieved) against Józwiak and collaborators’ review speculating its negative impact, speculation of angiogenesis toward tumorogenesis, increased NO and eNOS, toward damaging free radicals formation, and neurodegenerative diseases (Parkinson’s disease and Alzheimer’s disease). Contrarily, in wound healing and general healing capabilities as reviewed, as a cytoprotective agent, and native cytoprotection mediator, BPC 157 controls angiogenesis and the NO-system healing functions, and counteracts the pathological presentation of neurodegenerative diseases in acknowledged animal models (i.e., Parkinson’s disease and Alzheimer’s disease), and presents prominent anti-tumor potential, in vivo and in vitro. BPC 157 resolved cornea transparency maintenance, cornea healing “angiogenic privilege” (vs. angiogenesis/neovascularization/tumorogenesis), does not produce corneal neovascularization, but rather opposes it, and per Folkman’s concept, it demonstrates anti-tumor effect in vivo and in vitro. BPC 157 exhibits a distinctive effect on NO-level (increase vs. decrease), always combined with counteraction of free radicals formation, and in mice and rats, BPC 157 therapy counteracts Parkinson’s disease-like and Alzheimer’s disease-like disturbances. Thus, BPC 157 therapy means targeting angiogenesis and NO’s cytotoxic and damaging actions, but maintaining, promoting, or recovering their essential protective functions. Full article

Preeclampsia affects 2–8% of pregnancies globally and remains a leading cause of maternal and perinatal morbidity, with limited preventive options beyond low-dose aspirin. Low-molecular-weight heparin (LMWH) has emerged as a promising therapeutic candidate due to its pleiotropic effects extending beyond anticoagulation, including anti-inflammatory, pro-angiogenic, and placental-protective properties. This comprehensive narrative review examines LMWH’s effects on preeclampsia-associated biomarkers and evaluates clinical evidence for its preventive efficacy. LMWH exerts multifaceted effects on disease pathophysiology, including restoration of angiogenic balance through sFlt-1 reduction and PlGF preservation, attenuation of inflammatory responses via decreased TNF-α and IL-6 production, normalization of coagulation parameters, and enhancement of trophoblast invasion and placental vascularization. Clinical trials reveal heterogeneous results, with meta-analyses suggesting significant benefit primarily in high-risk subgroups. Women with previous severe placenta-mediated complications demonstrate relative risk reductions of 40–60% for recurrent preeclampsia with LMWH prophylaxis, particularly when initiated before 16 weeks’ gestation. Combination therapy with low-dose aspirin appears to enhance protective effects. However, larger trials in unselected populations have failed to demonstrate significant benefit, highlighting the importance of appropriate patient selection. Current international guidelines reflect this evidence heterogeneity, with most recommending against routine LMWH use while acknowledging potential benefit in selected high-risk populations, particularly those with antiphospholipid syndrome or previous severe early-onset disease. Future research should focus on biomarker-guided patient selection, optimal dosing regimens, and integration with multimodal preventive strategies to maximize therapeutic benefit while minimizing unnecessary interventions. Full article

Nitrogen is an essential macronutrient for crop growth. Although sorghum can tolerate poor soils, its low-nitrogen (LN) tolerance mechanisms remain underexplored. We conducted a genome-wide association study (GWAS) and RNA sequencing (RNA-seq) to dissect LN tolerance mechanisms in a diverse panel of 232 sorghum accessions. Phenotypic analyses revealed extensive variation in nitrogen-use efficiency traits, with shoot dry weight and shoot nitrogen accumulation in (SNAcc) showing the highest diversity. GWAS identified 10 quantitative trait loci harboring pleiotropic single-nucleotide polymorphisms (SNPs), including q1 (Chr3: 8.59–8.68 Mb), which is associated with biomass and nitrogen accumulation. Transcriptome profiling under LN stress revealed 6208 differentially expressed genes, with nitrate transporters showing genotype-specific regulation. Integration prioritized SORBI_3004G286700, where Hap2 accessions (14.66%) showed superior agronomic performance under LN conditions. We also identified pivotal transcription factors (TFs) that govern LN tolerance in sorghum, notably bHLH35 (SORBI_3007G051800) and three WRKY TFs, demonstrating constitutive upregulation in tolerant genotypes, whereas three previously uncharacterized TFs (MYB, bZIP, and B3) exhibited > 5-fold genotype-specific induction under LN. The integration of GWAS and transcriptome analyses offers an effective strategy for exploring candidate genes and elucidating nitrogen adaptation mechanisms in sorghum, while providing actionable molecular targets for precise breeding of nitrogen-efficient cultivars. Full article

Alkali burns to the cornea cause severe damage characterized by an intense inflammatory response driven by inflammatory cytokines, which orchestrate pathological processes, including neovascularization, fibrosis, apoptosis, abnormal cell proliferation, and disorganization of the extracellular matrix (ECM), often resulting in permanent vision impairment or loss. Rapamycin (RAPA), a well-known mTOR inhibitor with potent immunosuppressive activity and pleiotropic therapeutic effects, was investigated as a novel restorative modality for promoting corneal wound healing in a mouse model of alkali burn injury. Topical RAPA treatment significantly reduced clinical signs of inflammation and decreased the infiltration of F4/80⁺ macrophages and CD45⁺ leukocytes, along with suppressed expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-17A). RAPA also markedly downregulated angiogenic mediators, such as VEGF, and endothelial markers, like CD31, resulting in significant inhibition of neovascularization. Furthermore, it prevented fibrotic tissue formation and myofibroblast activation, as evidenced by reduced α-SMA levels, and attenuated pathological matrix remodeling through decreased MMP-9 expression. Notably, RAPA preserved epithelial barrier function by maintaining the tight junction protein ZO-1 and reduced both apoptotic cell death (TUNEL) and dysregulated proliferation (Ki67⁺), thereby preserving the functional and structural integrity of the cornea. In conclusion, RAPA represents a promising therapeutic candidate for managing severe corneal alkali burn injuries, with the potential to enhance corneal wound healing, minimize long-term complications, and protect visual function. Full article

Background: Understanding the genetic mechanisms and identifying potential therapeutic targets are essential for clarifying Autism Spectrum Disorder (ASD) etiology and improving treatments. This study aims to bridge the gap between basic transcriptomic discoveries and clinical applications in ASD research. Methods: Differentially expressed genes (DEGs) of GSE18123 datase were identified. A protein–protein interaction (PPI) network was constructed. Functional enrichment analysis was performed to link genetic loci to relevant biological pathways. Connectivity Map (CMap) analysis was used to predict potential drugs. Furthermore, immune infiltration correlation analysis explored associations between key genes and immune cell subpopulations. Diagnostic performance of top genes was evaluated by receiver operating characteristic (ROC) analysis. Results: The functional enrichment analysis successfully revealed relevant biological processes associated with ASD, while the CMap analysis predicted potential drugs that were consistent with some clinical trial results. Random forest analysis selected ten key feature genes (SHANK3, NLRP3, SERAC1, TUBB2A, MGAT4C, TFAP2A, EVC, GABRE, TRAK1, and GPR161) with the highest importance scores for autism prediction. Immune infiltration analysis showed significant correlations in genes and multiple immune cell types, demonstrating complex pleiotropic associations within the immune microenvironment. ROC curve analysis indicated that most top genes had strong discriminatory power in differentiating ASD from controls, particularly MGAT4C (AUC = 0.730), highlighting its potential as a robust biomarker. Conclusions: This study effectively bridges the basic transcriptomic discoveries and clinical applications in ASD research. The findings contribute to a better understanding of the etiology of ASD and provide potential therapeutic leads. Future research could focus on validating these potential drugs in clinical studies, as well as further exploring the biological functions of the identified genes to develop more targeted and effective treatments for ASD. Full article

Atopic dermatitis (AD) and autoimmune diseases exhibit epidemiological comorbidity, yet the shared genetic architecture remains incompletely understood. We investigated the genetic overlap between AD and three autoimmune disorders including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and vitiligo, leveraging genome-wide association data. Despite modest evidence for global genetic correlations, we found 113 independent pleiotropic loci shared among AD and autoimmune diseases, with 11 displaying a concordant effect across all 3 pairwise comparisons. Gene-set and tissue enrichment analyses evidenced the inflammatory background of pleiotropic associations. Multi-trait colocalization analysis prioritized 22 loci, linking the tissue-specific expression of DOK2, GPR132, RERE, RERE-AS1, SUOX, TNFRSF11A, and TRAF1 pleiotropic genes with AD risk. Mendelian randomization revealed no causal effect of genetic liability to AD on autoimmune diseases. Nevertheless, genetic liability to IBD increased AD risk, while vitiligo exhibited a protective effect post outlier correction. Our findings provide mechanistic insights into the multimorbidity of atopic dermatitis (AD) and autoimmune diseases, offering additional evidence for the pleiotropic genetic architecture of AD that contributes to systemic immune dysregulation across multiple organ systems. Full article

Atherosclerosis as a multifactorial disease remains the first cause of death worldwide. Current oral lipid-lowering drugs (especially statins) reduce low-density lipoprotein cholesterol (LDLC) levels in the blood, but their clinical efficacy seems to be partially attributed to pleiotropic effects on different pathophysiologic factors of atherosclerosis extending beyond lipid-lowering properties such as anti-inflammatory, antithrombotic and antioxidative features. Novel drugs that interfere with proprotein convertase subtilisin/kexin type 9 (PCSK9) axis of LDL-C receptors (LDLRs) degradation, from the group of monoclonal antibodies (e.g., alirocumab, evolocumab) or small interfering RNA (siRNA), e.g., inclisiran, are effective in reducing LDLC as well. However, data depicting their antithrombotic and antiplatelet activity are scarce, whereas prothrombotic properties of PCSK9 are widely described. Thus, we performed a study to assess the effects of inclisiran on subclinical prothrombotic [fibrinogen, coagulation factor VIII (FVIII), plasminogen activator inhibitor-1 (PAI-1)] and platelet activation markers (platelet factor-4 (PF-4), soluble p-selectin (sCD62P)). Ten patients at high cardiovascular risk with concomitant heterozygous familial hypercholesterolemia (HeFH)—study group 1, and fourteen patients at very high cardiovascular risk without concomitant HeFH—study group 2, were recruited for the study. Lipid profile, subclinical prothrombotic and platelet activation markers were assessed at the beginning and after 3 months of therapy with inclisiran. During therapy, statistically significant reductions in both study groups were seen in total cholesterol levels (study group 1: from 287.6 ± 94.2 to 215.2 ± 89.1 (mg/dL), p = 0.022; study group 2: from 211.7 ± 52.7 to 147.6 ± 55.4 (mg/dL), p < 0.001) and LDL-c (study group 1: from 180.8 ± 73.3 to 114.7 ± 71.5 (mg/dL), p = 0.031; study group 2: from 129.6 ± 46.8 to 63.4 ± 43.6 (mg/dL), p < 0.001). Lipid profile changes were associated with significant decrease in the concentration of FVIII in both groups (study group 1: from 33.3 ± 22 to 22 ± 14.5 (ng/mL), p = 0.006; study group 2: from 37 ±16.9 to 29.3 ±16.4 (ng/mL), p = 0.002) and fibrinogen, but only in study group 2 (from 51.4 (33.2–72.7) to 42.6 (31.3–57.2) (µg/mL), p = 0.035). Among platelet activation markers, a significant decrease in PF-4 in study group 2 was noted (from 286 (272–295.5) to 272 (268–281.5) (ng/mL), p = 0.047). However, there were no statistically significant changes in PAI-1 and sCD62P throughout the study. In our study, inclisiran appeared to be an effective lipid-lowering drug in patients at high cardiovascular risk. Moreover, it was shown that beyond lipid-lowering properties, the drug may also partially affect thrombogenesis and platelet activation. Full article

Plasminogen activator inhibitor-1 (PAI-1), a key regulator of fibrinolysis, has emerged as a critical stromal factor that contributes to tumor progression in various malignancies, including skin cancers. Beyond its classical role in inhibiting plasminogen activators, PAI-1 exerts pleiotropic effects within the tumor microenvironment, promoting immunosuppression, angiogenesis, and extracellular matrix remodeling. This review highlights the tumor-promoting functions of PAI-1 in melanoma, cutaneous squamous cell carcinoma, cutaneous angiosarcoma and cutaneous T-cell lymphoma, with a particular focus on its modulation of tumor-associated macrophages, cancer-associated fibroblasts, and endothelial cells. We also discuss recent preclinical and clinical studies targeting PAI-1, including TM5614, a novel oral PAI-1 inhibitor currently under investigation in phase II /III trials. By summarizing the multifaceted roles of PAI-1 and its impact on the immune and stromal landscape of skin malignancies, this review provides a rationale for PAI-1 as a promising therapeutic target and calls for further clinical validation of PAI-1–directed therapies. Full article

Erythropoietin (EPO) is a glycoprotein hormone essential for red blood cell production and a cornerstone therapy for anemia, particularly in chronic kidney disease. Beyond hematopoiesis, EPO exerts pleiotropic effects on metabolism, neuroprotection, and tissue regeneration. This review summarizes current insights into the molecular mechanisms, pharmacokinetics, and clinical applications of recombinant human EPO (rHuEPO) and its analogs, with emphasis on personalized therapeutic strategies. Emerging evidence highlights both therapeutic opportunities and risks, including resistance, cardiovascular complications, and misuse in sports doping. Advances in detection methods, pharmacogenomics, and the development of novel agents such as HIF-prolyl hydroxylase inhibitors are discussed, underscoring the expanding role of EPO in precision medicine. Full article

Dyslipidemia is a major modifiable risk factor in patients with acute coronary syndrome (ACS), and effective management is essential to reduce the risk of recurrent cardiovascular events. Recent guidelines emphasize early, intensive lipid-lowering therapy (LLT) and increasingly recommend combination regimens to achieve ambitious low-density lipoprotein cholesterol (LDL-C) targets. This review evaluates current evidence and recommendations for dyslipidemia treatment in ACS, with a focus on the rationale, timing, and selection of combination therapy. We conducted a comprehensive review of recent clinical guidelines, randomized controlled trials, and observational studies addressing lipid management in ACS. The analysis included data on LDL-C targets, efficacy and safety of high-intensity statins, adjunctive non-statin therapies (ezetimibe, PCSK9 inhibitors), and the impact of dietary interventions. Early and intensive LLT, initiated within 24–48 h of ACS, is associated with significant reductions in recurrent events and mortality. High-intensity statins (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) are first-line, with combination therapy (statin plus ezetimibe and/or PCSK9 inhibitor) recommended for patients not achieving LDL-C < 1.4 mmol/L (<55 mg/dL) or >50% reduction from baseline. Evidence supports further LDL-C lowering (<1.0 mmol/L) in very high-risk patients. The Mediterranean and DASH diets provide additional benefit in lipid profile optimization and risk reduction. Statins also confer pleiotropic effects, including anti-inflammatory and plaque-stabilizing actions. Recent studies and real-world data confirm the efficacy and safety of combination approaches but highlight the need for individualized therapy based on residual risk, comorbidities, and tolerability. Achieving guideline-recommended LDL-C targets in ACS patients often requires early initiation of combination lipid-lowering therapy. Optimal management should be individualized considering both LDL-C levels and broader risk profiles. Ongoing research is needed to refine patient selection for combination therapy and to integrate novel agents into clinical practice. Full article