Search Results (142)

Nitric oxide and reactive nitrogen species are key signalling molecules with pleiotropic effects in plants. They are crucial elements of the redox regulation of plant stress responses to abiotic and biotic stresses. Nitric oxide is known to enhance photosynthetic efficiency under abiotic stress, and reactive nitrogen species-mediated alterations in photosynthetic metabolism have been shown to confer resistance to abiotic stresses. However, knowledge about the role of reactive nitrogen species in plant immune responses remains limited. In this review, we highlight recent advancements in understanding the role of NO in regulating stomatal movement, which contributes to resistance against pathogens. We will examine the involvement of NO in the regulation of photosynthesis, which provides energy, reducing equivalents and carbon skeletons for defence, as well as the significance of protein S-nitrosylation in relation to immune responses. The role of NO synthesis induced in pathogenic organisms during plant–pathogen interactions, along with S-nitrosylation of pathogen effectors to counteract their pathogenesis-promoting activity, is also reported. We will discuss the progress in understanding the interactions between reactive nitrogen species and photosynthetic metabolism, focusing on enhancing crop plants’ productivity and resistance in challenging environmental conditions. Full article

Wheat stripe rust (Puccinia striiformis f. sp. tritici, Pst) resistance and agronomic traits are crucial determinants of wheat yield. Elucidating the quantitative trait loci (QTLs) associated with these essential traits can furnish valuable genetic resources for improving both the yield potential and disease resistance in wheat. Lantian 31 is an excellent Chinese winter wheat cultivar; multi-environment phenotyping across three ecological regions (2022–2024) confirmed stable adult-plant resistance (IT 1–2; DS < 30%) against predominant Chinese Pst races (CYR31–CYR34), alongside superior thousand-kernel weight (TKW) and kernel morphology. Here, we dissected the genetic architecture of these traits using a total of 234 recombinant inbred lines (RILs) derived from a cross between Lantian 31 and the susceptible cultivar Avocet S (AvS). Genotyping with a 15K SNP array, complemented by 660K SNP-derived KASP and SSR markers, identified four stable QTLs for stripe rust resistance (QYrlt.swust-1B, -1D, -2D, -6B) and eight QTLs governing plant height (PH), spike length (SL), and kernel traits. Notably, QYrlt.swust-1B (1BL; 29.9% phenotypic variance) likely represents the pleiotropic Yr29/Lr46 locus, while QYrlt.swust-1D (1DL; 22.9% variance) is the first reported APR locus on chromosome 1DL. A pleiotropic cluster on 1B (670.4–689.9 Mb) concurrently enhanced the TKW and the kernel width and area, demonstrating Lantian 31’s dual utility as a resistance and yield donor. The integrated genotyping pipeline—combining 15K SNP discovery, 660K SNP fine-mapping, and KASP validation—precisely delimited QYrlt.swust-1B to a 1.5 Mb interval, offering a cost-effective model for QTL resolution in common wheat. This work provides breeder-friendly markers and a genetic roadmap for pyramiding durable resistance and yield traits in wheat breeding programs. Full article

Oleocanthal (OC), a secoiridoid phenolic compound exclusive to extra virgin olive oil (EVOO), has emerged as a promising nutraceutical with multifaceted anti-cancer properties. Despite its well-characterized anti-inflammatory and antioxidant effects, the mechanistic breadth and translational potential of OC in oncology remain underexplored and fragmented across the literature. This comprehensive review synthesizes and critically analyzes recent advances in the molecular, pharmacological, and translational landscape of OC’s anti-cancer activities, providing an integrative framework to bridge preclinical evidence with future clinical application. We delineate the pleiotropic mechanisms by which OC modulates cancer hallmarks, including lysosomal membrane permeabilization (LMP)-mediated apoptosis, the inhibition of key oncogenic signaling pathways (c-MET/STAT3, PAR-2/TNF-α, COX-2/mPGES-1), the suppression of epithelial-to-mesenchymal transition (EMT), angiogenesis, and metabolic reprogramming. Furthermore, this review uniquely highlights the emerging role of OC in modulating drug resistance mechanisms by downregulating efflux transporters and sensitizing tumors to chemotherapy, targeted therapies, and immunotherapies. We also examine OC’s bidirectional interaction with gut microbiota, underscoring its systemic immunometabolic effects. A major unmet need addressed by this review is the lack of consolidated knowledge regarding OC’s pharmacokinetic limitations and drug–drug interaction potential in the context of polypharmacy in oncology. We provide an in-depth analysis of OC’s poor bioavailability, extensive first-pass metabolism, and pharmacogenomic interactions, and systematically compile preclinical evidence on advanced delivery platforms—including nanocarriers, microneedle systems, and peptide–drug conjugates—designed to overcome these barriers. By critically evaluating the mechanistic, pharmacological, and translational dimensions of OC, this review advances the field beyond isolated mechanistic studies and offers a strategic blueprint for its integration into precision oncology. It also identifies key research gaps and outlines the future directions necessary to transition OC from a nutraceutical of dietary interest to a viable adjunctive therapeutic agent in cancer treatment. Full article

Leaf rust (LR) is a devastating foliar disease that impacts common wheat (Triticum aestivum L.) globally. For optimal disease protection, wheat cultivars should possess adult plant resistance (APR) to leaf rust. In the current study, the objective was to map quantitative trait loci (QTL) related to leaf rust resistance. This was achieved by using 193 recombinant inbred line (RIL) populations which were developed from the cross between N. Strampelli and Huixianhong. Four trials were conducted in China (three in Baoding, Hebei province, and one in Zhoukou, Henan province) to assesses the leaf rust response of the RILs and parental lines. The wheat 660K SNP array and additional SSR markers were used to genotype the RIL populations. Through inclusive composite interval mapping (ICIM), three QTL related to leaf rust (LR) resistance were detected. ICIM was also employed to reevaluate previously published data in order to identify QTL with pleiotropic effects. To determine the physical positions, the flanking sequences of all SNP probes were compared against the Chinese Spring wheat reference sequence through BLAST searches. Three leaf rust resistance loci, two on chromosome 2A and 5B, were contributed by N. Strampelli. QLr.hbau-2AL.1 was detected in three leaf rust environments with phenotypic variance explained (PVE of 12.2–17%); QLr.hbau-2AL.2 was detected in two environments with 12.5–13.2% of the PVE; and QLr.hbau-5BL was detected in all leaf rust environments with phenotypic variance explained (PVE) of 17.8–19.1%. QLr.hbau-5BL exhibited potentially pleiotropic responses to multiple diseases. The QTL and the associated flanking markers discovered in this study could prove valuable for purposes such as fine mapping, the exploration of candidate genes, and marker-assisted selection (MAS). Full article

Type 2 diabetes mellitus represents a major global health burden and is often preceded by a prediabetic state characterized by insulin resistance and metabolic dysfunction. Mitochondrial alterations, oxidative stress, and disturbances in lipid metabolism are central to the prediabetes pathophysiology. Melatonin, a pleiotropic indolamine, is known to regulate metabolic and mitochondrial processes; however, its therapeutic potential in prediabetes remains poorly understood. This study investigated the effects of melatonin on energy metabolism, oxidative stress, and mitochondrial function in a rat model of prediabetes induced by chronic sucrose intake and low-dose streptozotocin administration. Following prediabetes induction, animals were treated with melatonin (20 mg/kg) for four weeks. Biochemical analyses were conducted to evaluate glucose and lipid metabolism, and mitochondrial function was assessed via gene expression, enzymatic activity, and oxidative stress markers. Additionally, hepatic mitochondrial dynamics were examined by quantifying key regulators genes associated with biogenesis, fusion, and fission. Prediabetic animals exhibited dyslipidemia, hepatic lipid accumulation, increased fat depots, and impaired glucose metabolism. Melatonin significantly reduced serum glucose, triglycerides, and total cholesterol levels, while enhancing the hepatic high-density lipoprotein content. It also stimulated β-oxidation by upregulating hydroxyacyl-CoA dehydrogenase and citrate synthase activity. Mitochondrial dysfunction in prediabetic animals was evidenced by the reduced expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha and mitochondrial transcription factor A, both of which were markedly upregulated by melatonin. The indolamine also modulated mithocondrial dynamics by regulating fusion and fission markers, including mitosuin 1 and 2, optic atrophy protein, and dynamin-related protein. Additionally, melatonin mitigated oxidative stress by enhancing the activity of superoxide dismutase and catalase while reducing lipid peroxidation. These findings highlight melatonin’s protective role in prediabetes by improving lipid and energy metabolism, alleviating oxidative stress, and restoring mitochondrial homeostasis. This study provides novel insights into the therapeutic potential of melatonin in addressing metabolic disorders, particularly in mitigating mitochondrial dysfunction associated with prediabetes. Full article

Cardiovascular diseases and cancer are the two primary causes of mortality worldwide. Although traditionally regarded as distinct pathologies, they share numerous pathophysiological mechanisms and risk factors, including chronic inflammation, insulin resistance, obesity, and metabolic dysregulation. Notably, several cancers have been identified as closely linked to cardiovascular diseases, including lung, breast, prostate, and colorectal cancers, as well as hematological malignancies, such as leukemia and lymphoma. Additionally, renal and pancreatic cancers exhibit a significant association with cardiovascular complications, partly due to shared risk factors and the cardiotoxic effects of cancer therapies. Addressing the overlapping risk factors through lifestyle modifications—such as regular physical activity, a balanced diet, and cessation of smoking and alcohol—has proven effective in reducing both CV and oncological morbidity and mortality. Furthermore, even in patients with established cancer, structured interventions targeting physical activity, nutritional optimization, and smoking cessation have been associated with improved outcomes. Beyond lifestyle modifications, pharmacological strategies play a crucial role in the prevention of both diseases. Several cardiovascular medications, including statins, aspirin, beta-blockers, and metformin, exhibit pleiotropic effects that extend beyond their primary indications, demonstrating potential anti-neoplastic properties in preclinical and observational studies. Recently, novel therapeutic agents have garnered attention for their possible cardioprotective and metabolic benefits. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is), initially developed for managing type 2 diabetes, have shown CV and renal protective effects, alongside emerging evidence of their role in modulating cancer-related metabolic pathways. Inclisiran, a small interfering RNA targeting PCSK9, effectively lowers LDL cholesterol and may contribute to reducing CV risk, with potential implications for tumor biology. Additionally, sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor, has revolutionized heart failure management by improving hemodynamic parameters and exerting anti-inflammatory effects that may have broader implications for chronic disease prevention. Given the intricate interplay between CVD and cancer, further research is essential to clarify the exact mechanisms linking these conditions and assessing the potential of CV therapies in cancer prevention. This review aims to examine shared risk factors, consider the role of pharmacological and lifestyle interventions, and emphasize crucial epidemiological and mechanistic insights into the intersection of CV and oncological health. Full article

Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness in older adults. Its pathogenesis involves multiple factors, including aging, environmental influences, genetic predisposition, oxidative stress, metabolic dysfunction, and immune dysregulation. Currently, AMD treatment focuses primarily on wet AMD, managed through repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) therapies. While anti-VEGF agents represent a major breakthrough in wet AMD care, repeated injections may lead to incomplete responses or resistance in some patients, and carry a risk of progressive fibrosis. Artemisinin (ART) and its derivatives, originally developed as antimalarial drugs, exhibit a broad spectrum of pleiotropic activities beyond their established use, including anti-inflammatory, anti-angiogenic, antioxidant, anti-fibrotic, mitochondrial regulatory, lipid metabolic, and immunosuppressive effects. These properties position ART as a promising therapeutic candidate for AMD. A growing interest in ART-based therapies for AMD has emerged in recent years, with numerous studies demonstrating their potential benefits. However, no comprehensive review has systematically summarized the specific roles of ART and its derivatives in AMD pathogenesis and treatment. This paper aims to fill the knowledge gap by synthesizing the therapeutic efficacy and molecular mechanisms of ART and its derivatives in AMD, thereby providing a foundation for future investigations. Full article

FKBP5 has been of special scientific interest in the behavioral sciences since it has been involved in the pathophysiology of several mental disorders. It is a gene with pleiotropic effects which encodes the protein FKBP5, a cochaperone that decreases glucocorticoid receptor (GR) affinity for glucocorticoids by competing with FKBP4, altering the GR chaperone complex, and impairing GR activation. As a key modulator of the stress response, FKBP5 plays a critical role in regulating cortisol levels in the organism. The FKBP5 gene is regulated through a combination of transcriptional, epigenetic, post-transcriptional, and environmental mechanisms, as well as genetic polymorphisms that influence its transcription and stress responsiveness. Notably, the rs1360780 T-allele in FKBP5 significantly affects FKBP5 regulation and has been linked to stress-related disorders by influencing transcription and stress responsiveness. In this narrative review, we aim to provide an overview of the role played by the single-nucleotide polymorphism rs1360780 in the FKBP5 locus in gene expression, its epigenetic regulation, and the impact of early stress in its functioning. We discuss some brain regions with differential expression of FKBP5 and some behavioral phenotypes linked to the locus. The T-allele of rs1360780 is considered a risk variant, as it leads to high FKBP5 induction, which delays negative feedback and increases GR resistance. This results in states of relative hypercortisolemia and brain morphofunctional alterations, particularly in regions sensitive to glucocorticoid activity during critical periods of neurodevelopment. Additionally, exposure to childhood maltreatment is associated with demethylation of the glucocorticoid response elements of FKBP5, further increasing its expression levels. Among the psychological dimensions analyzed in which FKBP5 is involved are neurocognition, aggression, suicidality, and social cognition. At the level of mental disorders, the gene may play a role in the pathogenesis of post-traumatic stress disorder, depression, and bipolar disorder. In psychotic disorders, its role is less clear. This knowledge enhances the understanding of disease mechanisms that operate through psychopathological dimensions, and highlights the need to design specific, person-centered psychopharmacological and environmental therapeutic interventions. Full article

Background/Objectives: The treatment of diabetic foot ulcers (DFU) is a challenging medical problem of extreme clinical and social importance, as a consequence of the emerging antibiotic resistance and decreased quality of life of diabetic patients due to impaired wound healing. One of the current trends in world science is the search for biologically active substances derived from living organisms. Biologically active peptides from snail mucus attract considerable scientific interest because of their pleiotropic pharmacological properties. The aim of our study was to evaluate the activity of a combination between a snail mucus protein fraction (MW > 20 kDa) obtained from the garden snail Cornu aspersum and the clinically applied antibacterial chemotherapeutic ciprofloxacin on pathogenic bacterial strains isolated from DFU. Results: The test bacterial strains were characterized as multidrug resistant. The combination between ciprofloxacin and the snail mucus fraction of interest led to additive or synergistic effects depending on the test strain. The mucus fraction exerted a well-pronounced wound-healing effect and no cytotoxicity on normal human fibroblasts and keratinocytes. Methods: The snail mucus was obtained by a patented technology (BG Utility model 2097/2015) and its electrophoretic profile was presented by SDS-PAGE. The bacterial strains were identified and tested for antimicrobial susceptibility (BD Phoenix M50 and Kirby–Bauer assay). The in vitro cytotoxicity of the mucus was evaluated by ISO 10995-5. The antimicrobial activity and combination effects were tested through ISO 20776/1 and the Checkerboard assay. Conclusions: The obtained results are promising and open new horizons for the development of novel combination treatment schemas for healing of infected DFU. Full article

Cohort studies consistently show that a high intake of cereal fiber and whole-grain products is associated with a decreased risk of type 2 diabetes (T2DM), cancer, and cardiovascular diseases. Similar findings are also reported for infectious and chronic inflammatory disorders. All these disorders are at least partially caused by inflammaging, a chronic state of inflammation associated with aging and Metabolic Syndrome. Surprisingly, insoluble (cereal) fiber intake consistently shows stronger protective associations with most long-term health outcomes than soluble fiber. Most humans consume soluble fiber mainly from sweet fruits, which usually come with high levels of sugar, counteracting the potentially beneficial effects of fiber. In both observational and interventional studies, high-fiber diets show a beneficial impact on inflammation, which can be attributed to a variety of nutrients apart from dietary fiber. These confounders need to be considered when evaluating the effects of fiber as part of complex dietary patterns. When assessing specific types of fiber, inulin and resistant starch clearly elicit anti-inflammatory short-term effects, while results for pectins, beta-glucans, or psyllium turn out to be less convincing. For insoluble fiber, promising but sparse data have been published so far. Hypotheses on putative mechanisms of anti-inflammatory fiber effects include a direct impact on immune cells (e.g., for pectin), fermentation to pleiotropic short-chain fatty acids (for fermentable fiber only), modulation of the gut microbiome towards higher levels of diversity, changes in bile acid metabolism, a differential release of gut hormones (such as the glucose-dependent insulinotropic peptide (GIP)), and an improvement of insulin resistance via the mTOR/S6K1 signaling cascade. Moreover, the contribution of phytate-mediated antioxidative and immune-modulatory means of action needs to be considered. In this review, we summarize the present knowledge on the impact of fiber-rich diets and dietary fiber on the human inflammatory system. However, given the huge heterogeneity of study designs, cohorts, interventions, and outcomes, definite conclusions on which fiber to recommend to whom cannot yet be drawn. Full article

Most cultivated potato (Solanum tuberosum) varieties are highly susceptible to common scab (Streptomyces scabei). The disease is widespread in all major potato production areas and leads to high economic losses and food waste. Varietal resistance is seen as the most viable and sustainable long-term management strategy. However, resistant potato varieties are scarce, and their genetic architecture and resistance mechanisms are poorly understood. Moreover, diploid potato relatives to commercial potatoes remain to be fully explored. In the current study, a panel of 384 ethyl methane sulfonate (EMS)-mutagenized diploid potato clones were evaluated for common scab coverage, severity, and incidence traits under field conditions, and genome-wide association studies (GWASs) were conducted to dissect the genetic architecture of their traits. Using the GAPIT-MLM and RTM-GWAS statistical models, and Mann–Whitney non-parametric U-tests, we show that 58 QTNs/QTLs distributed on all 12 potato chromosomes were associated with common scab resistance, 52 of which had significant allelic effects on the three traits. In total, 38 of the 52 favorable QTNs/QTLs were found to be pleiotropic on at least two of the traits, while 14 were unique to a single trait and were found distributed over 3 chromosomes. The identified QTNs/QTLs showed low to high effects, highlighting the quantitative and multigenic inheritance of common scab resistance. The QTLs/QTNs associated with the three common scab traits were found to be co-located in genomic regions carrying 79 candidate genes playing roles in plant defense, cell wall component biosynthesis and modification, plant–pathogen interactions, and hormone signaling. A total of 61 potato clones were found to be tolerant or resistant to common scab. Taken together, the data show that the studied germplasm panel, the identified QTNs/QTLs, and the candidate genes are prime genetic resources for breeders and biologists in breeding and targeted gene editing. Full article

Background: Glucagon-like peptide-1 (GLP-1) agonists are an existing treatment option for patients with insulin-resistant states, which elicit further pleiotropic effects related to immune cell recruitment and vascular inflammation. GLP-1 agonists downregulate the cluster of differentiation 147 (CD147) receptor, one of several receptors for the SARS-CoV-2 spike protein that mediate viral infection of host cells. Methods: We conducted an open-label prospective safety and tolerability study including biomarker responses of the GLP-1 agonist Liraglutide, administered for 5 days as an add-on therapy to the standard of care within 48 h of presentation in a cohort of 13 patients hospitalized with COVID-19 pneumonia. Biomarker responses were compared in patients admitted to critical care and those not requiring critical care admission (non-critical group). Results: Liraglutide (0.6 mg, subcutaneously) was well tolerated by all patients and all patients were alive 30 days after diagnosis. Plasma soluble CD147 levels were reduced in the non-critical patient group at day 5 in contrast to critical care-treated patients, who demonstrated an increase in soluble CD147 levels between day 0 and day 5. Patients with milder COVID-19 pneumonia severity also demonstrated improvement in echocardiographic parameters of right and left ventricular function, reduction in plasma Troponin levels, increased CD147 expression on T lymphocytes, and reduction in plasma IL-8. Conclusions: This first-in-disease use of the GLP-1 agonist Liraglutide demonstrates its safety and tolerability in an unselected cohort of patients hospitalized with COVID-19 pneumonia across a range of clinical severities. Full article

The MCF-7R breast cancer cell line, developed by treating the parental MCF-7 cells with increasing doses of doxorubicin, serves as a model for studying acquired multidrug resistance (MDR). MDR is a major challenge in cancer therapy, often driven by overexpression of the efflux pump P-glycoprotein (P-gp) and epigenetic modifications. While many P-gp inhibitors show promise in vitro, their nonspecific effects on the efflux pump limit in vivo application. Curcumin, a natural compound with pleiotropic action, is a nontoxic P-gp inhibitor capable of modulating multiple pathways. To explore curcumin’s molecular effects on MCF-7R cells, we analyzed the expression of genes involved in DNA methylation and transcription regulation, including ABCB1/MDR1. Reduced representation bisulfite sequencing further unveiled key epigenetic changes induced by curcumin. Our findings indicate that curcumin treatment not only modulates critical cellular processes, such as ribosome biogenesis and cytoskeletal dynamics, but also reverses the resistant phenotype, toward that of sensitive cells. This study highlights curcumin’s potential as an adjuvant therapy to overcome chemoresistance, offering new avenues for pharmacological strategies targeting epigenetic regulation to re-sensitize resistant cancer cells. Full article

Antibiotics, widely used medications that have significantly increased life expectancy, possess a broad range of effects beyond their primary antibacterial activity. While some are recognized as adverse events, others have demonstrated unexpected benefits. These adjunctive effects, which have been defined as “pleiotropic” in the case of other pharmacological classes, include immunomodulatory properties and the modulation of the microbiota. Specifically, macrolides, tetracyclines, and fluoroquinolones have been shown to modulate the immune system in both acute and chronic conditions, including autoimmune disorders (e.g., rheumatoid arthritis, spondyloarthritis) and chronic inflammatory pulmonary diseases (e.g., asthma, chronic obstructive pulmonary disease). Azithromycin, in particular, is recommended for the long-term treatment of chronic inflammatory pulmonary diseases due to its well-established immunomodulatory effects. Furthermore, antibiotics influence the human microbiota. Rifaximin, for example, exerts a eubiotic effect that enhances the balance between the gut microbiota and the host immune cells and epithelial cells. These pleiotropic effects offer new therapeutic opportunities by interacting with human cells, signaling molecules, and bacteria involved in non-infectious diseases like spondyloarthritis and inflammatory bowel diseases. The aim of this review is to explore the pleiotropic potential of antibiotics, from molecular and cellular evidence to their clinical application, in order to optimize their use. Understanding these effects is essential to ensure careful use, particularly in consideration of the threat of antimicrobial resistance. Full article

Barley (Hordeum vulgare L.), a major cereal crop grown in arid and semi-arid regions, faces significant yield variability due to drought and heat stresses. In this study, the HvABF2 gene, encoding an ABA-dependent transcription factor, was cloned using specific primers from water deficit-stressed barley seedlings. Gene expression analysis revealed high HvABF2 expression in developing caryopses and inflorescences, with significant induction under stress conditions. The HvABF2 coding sequence was utilized to generate transgenic barley plants with both stress-inducible and constitutive expression, driven by the rice SNAC1 and maize Ubiquitin promoters, respectively. Selected transgenic barley lines, along with control lines, were subjected to water deficit-stress experiments at seedling and flag leaf stages under controlled and greenhouse conditions. The transgenic lines exhibited higher relative water content and stomatal resistance under stress compared to control plants. However, constitutive overexpression of HvABF2 led to growth retardation under well-watered conditions, resulting in reduced plant height, grain weight, and grain number. In contrast, stress-inducible expression mitigated these effects, demonstrating improved drought tolerance without adverse growth impacts. This study highlights that the stress-inducible expression of HvABF2, using the SNAC1 promoter, effectively improves drought tolerance while avoiding the negative pleiotropic effects observed with constitutive expression. Full article