Search Results (283)

Cyclic adenosine monophosphate and cyclic guanosine monophosphate are key regulators of cellular physiology and tissue homeostasis. Conventional experimental models have provided fundamental insights into cyclic nucleotide pathways; however, they often fail to fully recapitulate essential features of in vivo systems. Two-dimensional cell cultures lack spatial organization, while animal models incompletely capture cell–cell interactions and the dynamic microenvironment shaping signaling processes. In recent years, advanced three-dimensional and microengineered systems have emerged as tools to bridge this gap. In this review, we discuss how three-dimensional and organ-on-chip systems are transforming the study of cyclic nucleotide signaling by enabling reconstruction of tissue architecture and signaling niches. Spheroids and organoids provide robust models to investigate compartmentalized signaling and intercellular communication. Complementarily, microfluidic organ-on-chip devices introduce controlled mechanical cues, perfusion, and tissue interfaces, enabling real-time monitoring of signaling dynamics. We highlight recent advances in microphysiological systems for investigating the spatial and temporal dynamics of cyclic adenosine monophosphate and cyclic guanosine monophosphate signaling, including biosensors, live-cell imaging, and genome editing. We further discuss applications in physiological and pathological contexts, including metabolic, cardiovascular and cancer diseases, and outline current challenges and future perspectives for integrating three-dimensional and organ-on-chip technologies. Full article

Elderly patients with heart failure (HF) represent a rapidly growing and highly heterogeneous population marked by multimorbidity, frailty, and polypharmacy. These age-related features profoundly influence the course of HF and modify therapeutic response. Vericiguat, a novel oral soluble guanylate cyclase (sGC) stimulator, targets the impaired nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway, a central mechanism in vascular dysfunction and maladaptive remodelling. Clinical evidence, primarily from the VICTORIA trial and subsequent studies, supports vericiguat in selected patients with heart failure with reduced ejection fraction (HFrEF), particularly following recent worsening HF despite guideline-directed medical therapy (GDMT). Most of the available evidence derives from HFrEF populations, whereas studies in heart failure with preserved ejection fraction (HFpEF) have not demonstrated significant clinical benefit. In addition, dedicated evidence in frail older adults and in patients with geriatric syndromes remains limited. This review summarises current knowledge on the pharmacological rationale, pharmacokinetics, and pivotal clinical studies of vericiguat, highlighting quantitative results and their implications for clinical implementation in elderly patients with HFrEF and complex clinical profiles. Full article

Heart failure (HF) remains a major global health burden despite substantial therapeutic advances. Vericiguat, an oral soluble guanylate cyclase (sGC) stimulator, represents a distinct pharmacological strategy targeting impaired nitric oxide–sGC–cyclic guanosine monophosphate (NO–sGC–cGMP) signaling, a pathway closely linked to endothelial dysfunction, vascular stiffness, myocardial fibrosis, and adverse remodeling. This narrative review synthesizes the current evidence on the efficacy, safety, and clinical positioning of vericiguat across the heart failure spectrum, with a particular focus on worsening heart failure with reduced ejection fraction (HFrEF), while integrating recent trial data, updated guideline recommendations, and emerging real-world evidence to define its contemporary role in clinical practice. Randomized trials, subgroup analyses, and contemporary meta-analyses indicate that vericiguat provides a modest but clinically relevant reduction in HF-related outcomes, especially in high-risk patients with recent decompensation. However, its overall effect appears smaller than that of foundational therapies such as angiotensin receptor–neprilysin inhibitors and sodium–glucose cotransporter 2 inhibitors. Recently published data from the VICTOR program further refine the role of vericiguat in compensated outpatients with chronic HFrEF, showing a neutral primary outcome but providing supportive hypothesis-generating signals across a broader risk continuum while confirming a favorable safety profile. Overall, vericiguat should be regarded not as a replacement for cornerstone therapy but as a mechanistically complementary, risk-targeted adjunct for selected patients with persistent residual risk despite guideline-directed medical therapy. Full article

This study aims to elucidate the mechanism by which exogenous guanosine monophosphate (GMP) enhances the stress tolerance of Lactiplantibacillus plantarum Y12. Phenotypic assays demonstrated that GMP supplementation significantly improved biofilm formation, adhesion index, and auto-aggregation ability. The survival ability of Y12 in simulated gastric juice, intestinal juice, and freeze-drying stress was also significantly increased. Transcriptomic results revealed that GMP increased the intracellular content of the second messengers C-di-AMP and C-di-GMP by reducing phosphodiesterase (PDE, RS04640). This, together with the upregulated expression of luxR and rpoN, synergistically promoted biofilm formation. Furthermore, GMP enhanced acid tolerance by increasing glutamate decarboxylase activity (GAD, RS05235). It also significantly elevated the levels of extracellular proteins, exopolysaccharides, membrane polysaccharides, and membrane fatty acids by modulating genes related to proteins (yidC, yajC), polysaccharides (agaB, agaC), and membrane fatty acid synthesis (RS02005, plsY), which was also demonstrated by quantitative determination. Collectively, these regulatory mechanisms substantially improve the stress tolerance of L. plantarum Y12, providing a theoretical basis for its application. Full article

Vericiguat is currently indicated for patients with heart failure with reduced ejection fraction (HFrEF) following recent clinical worsening, based on evidence demonstrating a reduction in cardiovascular death or heart failure hospitalization in a high-risk population. While this positioning is clinically justified, it may underestimate the broader pathophysiological context in which soluble guanylate cyclase (sGC) stimulation may be relevant, particularly in phases of persistent biological activation following apparent clinical stabilization. In routine practice, acute coronary syndromes (ACS), acute heart failure (AHF), and chronic HFrEF are approached as distinct clinical entities. However, these conditions often represent sequential manifestations of a continuous disease trajectory driven by persistent endothelial dysfunction, impaired nitric oxide–sGC–cyclic guanosine monophosphate (NO–sGC–cGMP) signaling, and residual vascular risk. In this perspective, we revisit the mechanistic and clinical rationale for vericiguat and propose a reframing of its therapeutic role. Its greatest utility may lie in patients with recently worsening HFrEF who remain biologically vulnerable after stabilization. Extension of this concept to post-ACS populations remains hypothesis-generating and is not supported by direct clinical evidence. This “post-stabilization vulnerable state” represents a clinically recognizable yet insufficiently targeted phase, characterized by ongoing biological activation despite apparent clinical improvement. Adopting a continuum-based view of cardiovascular disease may improve alignment between pathophysiology and treatment, refine patient selection, and inform future trial design focused on this early post-event window. Importantly, this perspective is hypothesis-generating and reflects an effort to align emerging mechanistic insights with clinical trajectory, rather than to extend current indications beyond the available evidence base. Full article

One potential strategy to mitigate the detrimental effects of heat stress on corals is upwelling, which brings deep, cold, nutrient-rich water to the reef surface, creating transient cooling. However, cold temperatures can also stress corals, and it is, therefore, important to understand the mechanisms of both cold and heat stress responses in corals. Similar to how mammals activate thermogenic and adaptive metabolic pathways, corals may also regulate energy and redox metabolism under fluctuating environmental conditions. Guanosine monophosphate reductase (GMPR), a conserved enzyme in purine metabolism, plays a critical role in maintaining intracellular adenine and guanine nucleotide balance. To study this enzyme in corals, we expressed Pocillopora damicornis (PD) GMPR heterologously in Escherichia coli and purified the recombinant protein using nickel–NTA affinity chromatography. SDS-PAGE analysis showed a single band corresponding to the expected molecular weight, indicating high purity. Sequence alignment revealed ~70% identity with mammalian GMPR2 orthologs, suggesting evolutionary conservation of function. Structural modeling and phylogenetic analysis positioned PD GMPR between the GMPR1 and GMPR2 clades, suggesting it may represent an ancestral or functionally intermediate variant. Kinetic analysis determined Km values of 33.76 ± 6.44 μM for GMP and 17.71 ± 0.99 μM for NADPH under fixed substrate concentrations. This study provides the first biochemical characterization of GMPR, which may open the door to uncovering mechanisms of cold tolerance in corals and inform strategies to enhance coral resilience in the face of climate change. Full article

Osteoporosis in women is strongly influenced by menopause, a major physiological transition that reshapes bone metabolism. Although low bone mineral density (BMD) in premenopausal women and osteoporosis in postmenopausal women share the clinical outcome of skeletal fragility, it remains unclear whether they reflect a shared molecular program or distinct regulatory mechanisms. Here, we compared genetic signals associated with premenopausal and postmenopausal low BMD in Korean women using two independent genotyping platforms with distinct variant coverage. After allele harmonization and heterogeneity testing, variants were classified as reversal signals, showing directionally discordant effects across menopausal status, or stable signals, showing concordant effects. Gene-level association analysis was performed using Multi-marker Analysis of GenoMic Annotation (MAGMA), followed by functional enrichment and network-based analyses. Reversal and stable signals showed distinct biological patterns. Reversal signals consistently converged on cyclic nucleotide-related pathways, including cyclic adenosine monophosphate/cyclic guanosine monophosphate (cAMP/cGMP) signaling and nitric oxide-mediated processes, whereas stable signals were more broadly distributed across pathways related to ion homeostasis, cell–substrate adhesion, and structural maintenance. These pathway-level patterns were reproducible across platforms despite limited SNP-level overlap. These findings suggest that low BMD across the menopausal transition is better resolved at the gene and pathway levels than at the level of individual SNPs. Full article

Glucagon-like peptide (GLP)-1 receptor (GLP1R) agonists exert a multitude of beneficial cardiovascular effects beyond control of blood glucose levels and obesity reduction. GLP-1R is a G protein-coupled receptor (GPCR), coupling to adenylyl cyclase (AC)-stimulatory Gs proteins to raise cyclic 3′-5′-adenosine monophosphate (cAMP) levels in cells. cAMP exerts various effects mainly via protein kinase A (PKA) and Exchange protein directly activated by cAMP (Epac). Cardiac GLP-1R has been reported to induce atrial natriuretic peptide (ANP) secretion via Epac2, while ANP is known to inhibit aldosterone secretion from adrenocortical zona glomerulosa (AZG) cells. Herein, we tested the effects of the GLP-1R agonist liraglutide on ANP secretion in H9c2 cardiomyocytes and on angiotensin II (AngII)-induced aldosterone secretion. We also examined whether phosphodiesterase (PDE)-4 inhibition with roflumilast could potentiate liraglutide’s effects. We found that liraglutide stimulated ANP secretion from H9c2 cardiomyocytes, an effect potentiated by roflumilast but blocked by AC inhibition. Epac inhibition with ESI-09 also significantly reduced liraglutide-dependent ANP secretion in H9c2 cardiomyocytes. Moreover, application of medium from liraglutide-treated H9c2 cardiomyocytes, but not from control cardiomyocytes, led to suppression of AngII-dependent aldosterone secretion from H295R cells. This effect was blocked by cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibition (an effector of ANP) in H295R cells, while direct application of liraglutide to these cells failed to suppress AngII-induced aldosterone secretion. Again, aldosterone suppression was more potent when medium from liraglutide plus roflumilast-treated cardiomyocytes was applied to H295R cells. Taken together, these results suggest that roflumilast enhances the adrenocortical aldosterone suppression induced by GLP-1R agonists via cardiac GLP-1R/cAMP/Epac-dependent ANP secretion. Given the cardio-toxic effects of elevated aldosterone levels in the context of various heart diseases, such as post-myocardial infarction heart failure, combination of a GLP-1R agonist drug with a PDE4 inhibitor drug may be more advantageous than either agent alone in treatment of certain cardiovascular diseases. Full article

Venlafaxine, a serotonin–norepinephrine reuptake inhibitor, shows analgesic effects in rodents, but its efficacy and pharmacological profile in acute stimulus-evoked nociception may depend on the nociceptive test used and the pharmacological context. The aim of this review was to identify the receptors implicated in venlafaxine antinociceptive effects and to examine which molecular processes most consistently explain its acute antinociceptive profile. We reviewed in vivo rodent studies testing venlafaxine in acute nociceptive assays (writhing, tail-flick, hot-plate, and other eligible acute tests) as monotherapy or associated with other pharmacologically active substances. PubMed/MEDLINE and Web of Science were searched from 1993 to 5 January 2026, and reference lists were also screened. Outcomes were synthesized and stratified by type of nociceptive test and interaction class. Fourteen studies were identified as relevant to the scope of this review. Venlafaxine produced dose-dependent antinociception across tests, reducing writhing and increasing thermal withdrawal latency. Central administration generally yielded effects at lower absolute doses than systemic routes. Interaction studies most consistently supported modulation of opioid receptors (e.g., leftward opioid dose–response shifts and attenuation of morphine tolerance in repeated-exposure designs), with convergent evidence implicating opioid and α₂-adrenergic mechanisms and context-dependent serotonergic contributions. Additional pathways were variably implicated, including nitric oxide—cyclic guanosine monophosphate (NO–cGMP) signaling and oxidative/mitochondrial processes in opioid tolerance paradigms. Preclinical evidence supports venlafaxine as a modulator of acute nociceptive control with notable opioid-interaction potential. Standardized pharmacodynamic reporting and translationally oriented studies are needed. Full article

Migraine is a highly prevalent and disabling neurovascular disorder that represents a major global health burden due to its significant impact on quality of life and socioeconomic costs. Increasing evidence suggests that migraine pathophysiology involves complex interactions between neuronal hyperexcitability, vascular dysregulation, oxidative stress, and neuroinflammatory processes. Oxidative and nitrosative stress are increasingly recognized as key contributors to migraine mechanisms, influencing mitochondrial dysfunction, cortical spreading depression, and trigeminovascular activation. Nitric oxide plays a central role in these processes by regulating vascular tone, nociceptive signaling, and neurogenic inflammation through downstream pathways such as the soluble guanylate cyclase–cyclic guanosine monophosphate (NO–sGC–cGMP) signaling cascade. Dysregulation of nitric oxide signaling and increased oxidative stress may contribute to endothelial dysfunction and impaired cerebrovascular regulation observed in migraine patients. In addition, accumulating evidence highlights the role of neuroinflammatory mechanisms, including microglial activation and cytokine-mediated signaling, which may amplify nociceptive transmission within trigeminal pathways. Migraine is increasingly recognized as a systemic disorder associated with several comorbid conditions, including Parkinson’s disease, fibromyalgia, and autoimmune diseases such as Sjögren’s syndrome. This review summarizes recent advances regarding the interactions between oxidative stress, nitric oxide signaling, endothelial dysfunction, and neuroinflammation in migraine and discusses their potential therapeutic implications. Full article

(1) Background: The “Bider” marking refers to the symmetrical black stripes distributed on the shoulder blades of Dun Mongolian horses, representing an ancestral trait of significant genetic value. However, the molecular mechanisms underlying its formation remain unclear. This study aims to elucidate the molecular basis of these markings by comparing transcriptomic differences in skin tissues from variously pigmented areas of Mongolian horses’ “Bider” patterns. (2) Methods: Using three Dun Mongolian horses as subjects, skin tissue samples were collected from their shoulders (dark-marked and light-marked areas), dorsal midline, and croup regions for transcriptome sequencing. Differentially expressed genes were identified based on sequencing data, followed by Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Key findings were validated through quantitative reverse transcription polymerase chain reaction (qRT-PCR). (3) Results: The sequencing yielded approximately 893 million high-quality clean reads, with an overall alignment rate exceeding 96%. A total of 140 to 775 differentially expressed genes were identified. GO enrichment analysis revealed that these genes were significantly enriched in biological processes related to pigment metabolism, skin and hair follicle development, signal transduction (including calcium and cyclic guanosine monophosphate (cGMP) signaling), and immune regulation. KEGG analysis further indicated that multiple pathways closely associated with pigment regulation, including the calcium signaling pathway, tyrosine metabolism, cyclic adenosine monophosphate (cAMP) signaling pathway, and melanoma pathway, were significantly enriched across different tissue comparison groups, suggesting their potential key roles in coat color phenotype formation. The reliability of the sequencing data was corroborated by the results of qRT-PCR validation. (4) Conclusions: This study conducted a transcriptome analysis of skin samples from various pigmented regions of the Dun Mongolian horse’s Bider marking, revealing that the formation of this marking is associated with the differential expression of numerous genes and is co-regulated by multiple pigment-related signaling pathways. Full article

Hypertension remains a major global health challenge, and pharmacological therapy is often constrained by tolerability issues. Adjunctive approaches targeting the nitric oxide synthase and soluble guanylate cyclase–cyclic guanosine monophosphate (sGC–cGMP) pathway may offer additional benefits. This study investigated the efficacy and safety of a nutraceutical formulation combining grape pomace extract (Taurisolo^®) and L-arginine in patients with grade 1 and grade 2 hypertension. The formulation was designed to enhance nitric oxide (NO) bioavailability and support sGC–cGMP signaling. Taurisolo^®, a polyphenol-rich extract, is known for its antioxidant and endothelial-protective properties, while L-arginine serves as the physiological substrate for endothelial NO synthase. Clinical outcomes included blood pressure changes, renal function parameters, and health-related quality of life assessed through the SF-12 questionnaire. Supplementation with Taurisolo^® plus L-arginine resulted in significant and sustained reductions in systolic and diastolic blood pressure, with renal function remaining stable throughout the study. Participants also reported meaningful improvements in perceived health, emotional well-being, vitality, and social functioning. The intervention was well tolerated, with no major adverse effects. These findings support the potential of Taurisolo^® combined with L-arginine as a safe and effective adjunctive strategy to conventional antihypertensive therapy, warranting further mechanistic investigation. Full article

The yak represents a distinct domestic animal species that predominantly inhabits the Qinghai–Tibet Plateau and adjacent areas, possessing considerable value in both scientific and economic contexts. Compared to animals that mainly dwell on plains, such as cattle, the sperm maturation process in yak exhibits a certain degree of species specificity to adapt to their unique reproductive needs in high-altitude environments. Serving as the main storage site for functionally competent sperm, the cauda epididymis plays an integral role in mediating their post-testicular maturation. MiRNAs are vital regulatory molecules in the epididymis, influencing sperm maturation by modulating gene expression after transcription. To investigate the unique regulatory mechanisms of sperm maturation in yak, this study compared the miRNA expression profiles in the cauda epididymis of yak and cattle using high-throughput small RNA (sRNA) sequencing. The comparative analysis identified and characterized sRNA populations in the cauda epididymis of yak and cattle, revealing a similar length distribution that peaked at 22 nt and a predominance of known miRNAs. Notably, eight miRNAs were found to be highly expressed in both species. Furthermore, the first-nucleotide bias differed significantly between known and novel miRNAs within each species. A total of 31 differentially expressed (DE) miRNAs were identified, with 11 upregulated and 20 downregulated in yak compared to cattle. Among these, bta-miR-1298 exhibited the most significant upregulation, while bta-miR-2344 displayed the most pronounced downregulation. Bioinformatic analysis linked the predicted target genes of these miRNAs to numerous critical signaling pathways, including calcium signaling, the mitogen-activated protein kinase (MAPK) signaling pathway, the Ras-associated protein 1 (Rap1) signaling pathway, and the cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signaling pathway. Furthermore, eight significantly DE miRNAs, including bta-miR-2443, bta-miR-503-3p, bta-miR-6517, bta-miR-2440, bta-miR-2431-3p, bta-miR-2436-3p, bta-miR-6523a, and bta-miR-6775, were predicted to target genes involved in various aspects of sperm structural and functional maturation. These aspects include flagellum formation, sperm motility, chromatin remodeling, acrosome reaction, acrosome structure, sperm capacitation, chemotaxis, and nuclear chromatin condensation. Multiple miRNAs and their corresponding predicted target genes were analyzed by quantitative real-time PCR (qPCR), demonstrating an inverse correlation between miRNA expression and target gene levels. These findings reveal a distinct, species-specific miRNA signature in the yak cauda epididymis, which suggests a potential contribution to regulating the epididymal luminal environment and the process of sperm maturation. This study provides preliminary foundational data for elucidating the differences in sperm maturation mechanisms between yak and cattle, and offers potential novel targets for improving reproductive efficiency in plateau livestock. Full article

Cyclic di-GMP (bis-(3′→5′) cyclic dimeric guanosine monophosphate) is a ubiquitous bacterial second messenger that regulates a wide range of cellular processes, including biofilm formation, motility, virulence, and environmental adaptation. Its intracellular levels are dynamically controlled by diguanylate cyclases (DGCs), which synthesize c-di-GMP from GTP, and phosphodiesterases (PDEs), which degrade it into linear pGpG or GMP. The functional effects of cytoplasmic c-di-GMP are mediated through diverse effector proteins, including PilZ domain-containing receptors, transcription factors, and riboswitches. In Leptospira interrogans, a major pathogenic species responsible for leptospirosis, the regulatory roles of c-di-GMP remain poorly understood. Here, we performed a comprehensive bioinformatics and structural analysis of all predicted c-di-GMP related proteins in L. interrogans serovar Copenhageni strain Fiocruz L1-130, a serovar generally associated with severe manifestations of leptospirosis in humans. Our analysis identified seventeen proteins containing GGDEF domain, five proteins containing both GGDEF and EAL domains, four proteins containing EAL domain, five proteins containing HD-GYP domain, twelve proteins containing PilZ domain, and one protein containing an MshEN domain. Comparative analysis with well-characterized bacterial homologs suggests that L. interrogans possess a complex c-di-GMP signaling network, likely involved in modulating biofilm formation, host–pathogen interactions, and environmental survival. These findings provide new insights into the c-di-GMP regulatory network and on signal transduction in Leptospira and lay the foundation for future functional studies aimed at understanding its roles in physiology, virulence, and persistence. Full article

Acute lung injury (ALI) pathogenesis is intricately linked to microvascular permeability. Soluble guanylate cyclase (sGC) is prominently expressed in the vascular system, playing a central role in vascular function. In contrast, its expression and function diminish notably during the progression of ALI, indicating sGC’s potential significance as a pivotal modulator in the pathological processes of ALI. Nonetheless, the precise localization of sGC within lung tissue and its distinct mechanism in maintaining vascular homeostasis remain unclear. Furthermore, there is a necessity for a pharmacological agent capable of consistently activating sGC for the treatment of ALI. A novel sGC stimulator, sGC003, was engineered through structural modification of Riociguat. In a mouse model of ALI, sGC003 exhibited superior sGC activation and more potent anti-inflammatory effects relative to Riociguat. It also exhibited superior efficacy in improving respiratory function and reducing pulmonary edema. Through single-cell RNA sequencing and immunofluorescence co-localization analysis, we confirmed predominant expression of soluble guanylate cyclase in pericytes. The sGC stimulators were found to modulate the LPS-induced pericyte transcriptome reprogramming via the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway. Differential gene expression analysis categorized pericytes into nine distinct subgroups, which were sequentially activated during vascular development, inflammation, and myofibrosis. Pseudotime analysis revealed that sGC003 more effectively suppressed the myofibroblast differentiation of pericytes compared to Riociguat. In conclusion, sGC003 mitigates ALI-induced pulmonary inflammation by modulating pericyte differentiation, particularly in preserving microvascular integrity outstanding performance. Its exceptional efficacy suggests that it could potentially serve as a safer and more efficient option as a novel sGC stimulant in the future. Full article