Search Results (787)

Activation of cGAS, a receptor recognizing cytosolic DNA, in macrophages might be associated with rabies (an RNA virus) through mitochondrial damage. A similar mortality rate was observed between cGAS-deficient (cGAS-/-) and wild-type (WT) mice post-CVS-11 strain injection. However, 2 out of 12 cGAS-/- mice (but not WT) survived for 15 days post-injection. At 7 days post-infection, less severe brain inflammation in cGAS-/- mice was demonstrated by the viral abundance in the hippocampus, the expression of proinflammatory genes (TNF-α and IL-1β), and the Evans blue dye assay (blood–brain barrier defect) with the presence of higher anti-inflammatory genes (TGF-β and arginase-1). Fecal Proteobacteria was more prominent in the infected WT mice, while serum cytokines (TNF-α and IL-1β) were similar in both mouse strains. There were less prominent responses against the rabies virus in cGAS-/- macrophages than in WT cells, as indicated by supernatant IL-6 and the gene expression of TLR-3, RIG-1, MDA-5, and iNOS. On the other hand, mitochondrial injury and cGAS activation were more prominent in WT macrophages over cGAS-/- cells, as indicated by cGAS expression, supernatant cGAMP (a secondary messenger of cGAS), and mitochondrial oxidative stress (MitoSox) together with a decrease in mitochondrial DNA and maximal respiration (extracellular flux analysis). In conclusion, (i) rabies-damaged mitochondria led to cGAS activation that was less severe in cGAS-/- than in WT, (ii) rabies-induced dysbiosis was demonstrated, and (iii) cGAS manipulation and gut–brain axis-associated inflammation warrants further investigation. Full article

In chronic obstructive pulmonary disease (COPD), dysregulated calcium homeostasis, oxidative stress, and mucus hypersecretion converge to suppress ciliary beat frequency (CBF), thereby compromising mucociliary clearance (MCC). These mechanisms are subject to pharmacological modulation. Long-acting muscarinic antagonists (LAMAs) exert direct cilia-stimulatory effects and may counteract pathogen-induced mucin overproduction without impairing clearance. Long-acting β₂-agonists (LABAs) enhance ciliary activity through the cAMP–PKA–dynein (cyclic adenosine monophosphate–protein kinase A–dynein) signalling pathway. Inhaled corticosteroids (ICSs), although largely neutral on CBF, provide indirect protection by suppressing IL-13–driven inflammation. Phosphodiesterase (PDE)-4 inhibitors sustain intracellular cAMP and promote ciliary motility, though their clinical use remains limited by adverse effects. Emerging evidence suggests that dual and triple therapies may provide additive or synergistic benefits for preserving mucociliary function. Clinically, ex vivo CBF interpretation may be influenced by ongoing pharmacotherapy and tissue sampling site. Nasal brush samples may predominantly reflect systemic rather than inhaled therapy. Moreover, differences in PDE isoform expression between nasal and bronchial epithelium further complicate direct extrapolation of results. Rigorous patient stratification by treatment regimen is therefore essential to reconcile inconsistencies reported across studies. Ultimately, preservation of MCC in COPD depends on a delicate balance between oxidative stress and pharmacological modulation of ciliary function. Full article

Phenolic compounds such as resorcinol (RS) have negative impacts on aquatic life, the environment, and human health. Thus, it is necessary to develop sensing devices for the monitoring of RS. The electrochemical method is one of the most significant approaches for the determination of toxic substances. In electrochemical methods, electrode modifiers play a vital role and affect the sensing performance of the electrochemical sensors. Thus, the selection of efficient electrode material is of great importance. In recent years, various electrode modifiers such as graphene, metal–organic frameworks (MOFs), MXenes, metal oxides, polymers, and composite materials have been extensively used for the fabrication of RS sensors. In this review, we have summarized the reported electrode modifiers for the fabrication of RS electrochemical sensors. Various electrochemical sensing techniques, including differential pulse voltammetry (DPV), square wave voltammetry (SWV), amperometry (Amp), cyclic voltammetry (CV), and linear sweep voltammetry (LSV) have been discussed. This review provides an overview of a large number of electrode modifiers for the determination of RS. The limitations, challenges, and future perspectives for RS sensors are discussed. We believe that the present review article is beneficial for the scientific community and electrochemists working on the construction of RS sensors. Full article

Yersinia enterocolitica is a foodborne pathogen capable of biofilm formation and virulence modulation in response to environmental signals. Among these, glucose—present at physiologically relevant concentrations in the human body—may serve as a regulatory cue affecting infection-associated pathways, including those governed by the pYV virulence plasmid. Although the role of glucose has been investigated under host-mimicking conditions, its impact in non-host environments remains poorly understood. This study was designed to evaluate the glucose-dependent physiological responses of two isogenic Y. enterocolitica strains, KT0001 (pYV-negative) and KT0003 (pYV-positive), under non-host conditions (26 °C). Both strains were cultured in TYE medium containing 0–3% glucose. Comparative analyses were conducted under identical in vitro conditions to elucidate plasmid-associated phenotypic differences. Glucose elicited markedly divergent responses. In KT0001, growth remained unaffected; however, biofilm formation declined by 77.7%, accompanied by a 90% reduction in surface hydrophobicity, a 40% decrease in motility, and a 59% drop in intracellular cyclic AMP—suggesting classical carbon catabolite repression. Conversely, KT0003 exhibited 86% growth inhibition but maintained biofilm levels. This was associated with substantial extracellular polymeric substance induction (~20-fold increase in polysaccharides and ~4.7-fold in extracellular DNA) and nearly fivefold elevation in cyclic AMP levels, despite concurrent decreases in motility (64%) and hydrophobicity (40%). These findings indicate that glucose functions as a strain-specific modulator in Y. enterocolitica. In particular, KT0003’s response suggests that the pYV plasmid enables the bacterium to interpret glucose as a host-associated cue, even under non-host conditions, potentially initiating virulence-related adaptations prior to host contact. Full article

Neuroinflammation via the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway and reduced hippocampal brain-derived neurotrophic factor (BDNF) expression are key mechanisms underlying stress-induced depression. Vitamin D3, acting through the vitamin D receptor (VDR), is known to possess immunomodulatory and neurotrophic properties, but its role under chronic stress remains unclear. This study investigated the effects of vitamin D3 on chronic unpredictable mild stress (CUMS)-induced neuroinflammation and neurotrophic deficits in male Wistar rats. Thirty-two rats were divided into four groups: control, CUMS only, CUMS + vitamin D3 (1000 IU/kg), and CUMS + vitamin D3 (10,000 IU/kg). Vitamin D3 was injected intramuscularly three times weekly for 28 days. Hippocampal mRNA expression of cGAS–STING pathway markers, BDNF, microglial activation marker Iba1, and pro-inflammatory cytokines was quantified by RT-qPCR, and relative expression was calculated using the 2^−ΔΔCt method. Serum vitamin D3 and corticosterone concentrations were measured by ELISA. CUMS significantly reduced serum vitamin D3, increased corticosterone, activated hippocampal cGAS–STING signaling, upregulated inflammatory mediators and Iba1, and suppressed VDR and BDNF mRNA expression (all p < 0.05). Vitamin D3 administration effectively restored serum vitamin D3, normalized corticosterone levels, attenuated cGAS–STING activation and inflammatory gene expression, reduced microglial activation, and enhanced hippocampal VDR and BDNF mRNA expression (all p < 0.05). These findings demonstrate that vitamin D3 alleviates CUMS-induced hippocampal inflammation and neurotrophic deficits through coordinated modulation of immune signaling and BDNF, highlighting its potential as a therapeutic approach for stress-related brain disorders. Full article

The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway, a central innate immune sensor of cytosolic DNA, plays a dual role in immunoregulation within pulmonary diseases. Recent studies demonstrate its critical role in sensing microbial infections and tissue injury in the lung, allowing it to drive the production of type I interferons (IFN-I) and pro-inflammatory cytokines. While this pathway is essential for anti-viral defense and anti-tumor immunity, its dysregulation can exacerbate pathologies such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, and lung cancer, mainly through sustained inflammation and fibroblast proliferation. Nowadays, many cGAS-STING agonists and inhibitors are available to treat different diseases. This review comprehensively summarizes the basic mechanism of the cGAS-STING pathway, its diverse roles across various pulmonary diseases, and the current landscape of potential therapeutic strategies targeting this pathway. Notably, the critical role of the cGAS-STING signaling pathway in various lung diseases offers new avenues for therapeutic research. Full article

Pulmonary arterial hypertension (PAH) is a fatal disease with no cure. Until recently, most specific therapies for PAH had aimed at enhancing cyclic nucleotide (cAMP and cGMP) pathways, taking advantage of the vasorelaxant and antiproliferative properties of these key intracellular messengers. This process can be achieved by inhibiting phosphodiesterases (PDEs), which are intracellular enzymes responsible for cyclic nucleotide degradation. To date, only inhibitors of PDE type 5 (PDE5) have been approved for the treatment of PAH. Because the PDE superfamily comprises 11 families that encompass many variants, substantial experimental investigation has been conducted to assess the relevance of inhibiting other PDE families, aiming to offer therapeutic alternatives. This review synthesizes the main research work conducted on in vivo or ex vivo models, as well as on biological resources from patients. It helps provide evidence for the expression of PDE isoforms in the lung vasculature, as well as the efficacy and limitations of various pharmacological compounds tested for inhibiting pathological processes ongoing in the disease. Perspectives and suggestions for future research orientation are proposed. Full article

Mycobacterium avium is an opportunistic pathogen and a leading contributor to nontuberculous mycobacterial infections in immunocompromised individuals. However, treatment duration, antibiotic toxicity, and resistance present challenges in the management of mycobacterium infections, prompting the need for novel treatment. N-acetylcysteine (NAC) has demonstrated potent antimycobacterial activity, while antimicrobial peptides such as the cyclic [R₄W₄] have shown additive effects when combined with first-line antibiotics. This study aimed to investigate the mechanism and efficacy of NAC and [R₄W₄] combination therapy against M. avium. A membrane depolarization assay was used to evaluate the effects of NAC and [R₄W₄] on M. avium cell membrane integrity. Antimycobacterial activity was assessed by treating cultures with varying concentrations of NAC, [R₄W₄], a combination, or a sham treatment. The same regimens were applied to M. avium-infected THP-1-derived macrophages to assess intracellular efficacy. NAC and [R₄W₄] each disrupted the M. avium membrane potential, with enhanced effects in combination. The combination treatment significantly reduced M. avium survival in both the culture and infected macrophages compared with NAC alone and untreated controls. [R₄W₄] and NAC also demonstrated potent antibacterial activity, while the lowest MIC and the combination of [R₄W₄] and NAC displayed additive effects, indicating an improved bacterial inhibition compared to individual treatments. These findings demonstrate the additive activity of NAC and [R₄W₄] against M. avium in vitro and suggest that combining antioxidant compounds with antimicrobial peptides may represent a promising strategy for treating mycobacterial infections. Full article

Background/Objectives: Cardiovascular diseases (CVD) remain the leading cause of diet-related mortality, with hepatic overproduction of very-low-density lipoprotein (VLDL) being a central driver of dyslipidemia. The microsomal triglyceride transfer protein (MTP) is essential for this process, and its activity is negatively regulated by cyclic adenosine monophosphate (cAMP). Theophylline, a methylxanthine found in tea, increases intracellular cAMP. This study aimed to evaluate whether physiologically relevant concentrations of theophylline could beneficially modulate lipoprotein secretion in an ex vivo model of diet-induced MTP activation. Methods: Primary hepatocytes were isolated from rats fed a high-fat, high-carbohydrate diet (HFCD). Cells were treated with 100 µM theophylline, and the secretion of triglyceride (TG), total cholesterol (TC), VLDL-cholesterol (VLDL-C), and HDL-cholesterol (HDL-C) was quantified. Hepatocellular MTP activity and atherogenic indices were also assessed. Results: Compared to untreated control cells, theophylline treatment significantly reduced the secretion of TG by 6% and TC by 24%. Specifically, VLDL-C secretion decreased by 6%, while HDL-C secretion increased substantially by 93%. These lipid-modulating effects were correlated with a 6.9% reduction in MTP activity. Consequently, significant improvements were observed in the atherogenic indices TG/HDL-C, TC/HDL-C, and the atherogenic index (AI) (p < 0.01). Conclusions: Our findings demonstrate that physiologically attainable concentrations of theophylline rebalance lipoprotein secretion by suppressing hepatic MTP activity, shifting the lipid profile toward an anti-atherogenic state. These results highlight the potential of theophylline as a functional dietary component for mitigating diet-induced dyslipidemia and reducing cardiovascular risk. Full article

Background: β-casomorphin-10 (CM-10), a peptide fragment derived from milk casein with the sequence YPFPGPIPNS, has demonstrated notable anxiolytic activity in BALB/c mice. Yet, its cellular responses and mechanistic pathways remain largely uncharacterized. Methods: We performed RNA-seq analysis to profile gene expression changes in δ-opioid receptor-expressing HEK293 cells (DOR-HEK), comparing CM-10-treated and untreated conditions. Results: CM-10 exposure led to differential expression of 1714 genes in DOR-HEK cells, with 34 upregulated (>1.4-fold) (1.9%) and 1680 downregulated (<0.71-fold) (98.1%), based on a predicted p-value threshold of <0.05. Notably, we identified 10 clusters that were associated with reduced cyclic AMP (cAMP) in DOR-HEK cells following CM-10 treatment. These clusters particularly involved genes related to regulatory subunits of cAMP-dependent protein kinases, such as PRKAR2A, cAMP-responsive element-binding pathway, circadian rhythms, such as CLOCK, ARNT1, CRY2, PER1, and PER2, and anxiety and depression, such as NOTCH1, NOTCH2 and ANK2. A network with these selected genes was confirmed by STRING analysis. Conclusions: These findings indicate that CM-10 may activate DOR-mediated signaling by suppressing cAMP levels, implicating a distinct molecular cascade in HEK293 cells. Full article

The stimulator of interferon genes (STING) serves as a pivotal signaling hub in innate immunity, orchestrating type I interferon (IFN-I) and pro-inflammatory responses upon detection of cytosolic DNA. While the canonical cyclic GMP-AMP synthase (cGAS)-STING axis has been extensively studied in host defense and sterile inflammation, increasing evidence indicates that STING can also be activated through a variety of both pattern recognition receptors (PRRs)-dependent and PRRs-independent mechanisms. In this review, we comprehensively summarize the molecular pathways through which PRRs—including cGAS, interferon gamma inducible protein 16 (IFI16), DEAD-box helicase 41 (DDX41), and DNA-dependent protein kinase (DNA-PK)—engage and regulate STING activation. Beyond PRRs-triggered pathways, we explore emerging evidence of PRRs-independent STING activation, driven by genetic mutations, endoplasmic reticulum (ER) stress, dysregulated intracellular trafficking, and impaired protein degradation. These mechanisms contribute to the pathogenesis of a broad spectrum of inflammatory and autoimmune disorders affecting multiple organ systems, including the digestive, cardiovascular, renal, pulmonary, and nervous systems. We also highlight the current landscape of pharmacological inhibitors targeting cGAS and STING, categorized according to their mechanisms of action and therapeutic potential. The redundancy and complexity of components within the STING signaling network present challenges in effectively suppressing inflammatory overactivation by targeting a single molecule. Nevertheless, the central role of STING offers multiple opportunities for therapeutic intervention, whether by modulating upstream or downstream signaling elements. This review not only provides a systematic framework for understanding the intricacies of STING signaling, but offers insights into the development of next-generation therapeutics aimed at selectively modulating STING activity in disease contexts. Full article

Highly selective inhibitors of the members of the cAMP-selective cyclic nucleotide phosphodiesterases, or PDE4 family, have shown clinically meaningful activity in two different classes of lung disease: roflumilast in obstructive lung disease, specifically chronic obstructive pulmonary disease (COPD), and nerandomilast in restrictive lung diseases characterized by inflammation/fibrosis of the alveolar interstitium, including idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). The beneficial therapeutic benefit of these agents in both of these disorders suggests that they share a common mechanism that underlies their effects on different pulmonary cells and tissues. This review outlines the biochemical, pharmacologic and cellular effects of PDE4-selective inhibitors, emphasizing their role in signal transduction pathways common to many pulmonary cell types. It then compares and contrasts the myriad cellular effects of these agents and their effects in pre-clinical animal models of these disorders. The emerging data are compatible with PDE4-selective inhibitors having targets of action in a large number of pulmonary cell types, only a subset of which is dysregulated in either COPD or IPF. This suggests that differences between the benefits observed with these individual agents in their various clinical indications reflect differences in disease pathogenesis, rather than proven differences in the enzyme-inhibitory effects of the various PDE4 inhibitors that have been studied to date. Full article

Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are neurodevelopmental disorders marked by deficits in communication and social interaction, often accompanied by anxiety, seizures, and intellectual disability. FXS, the most common monogenic cause of ASD, results from silencing of the FMR1 gene and consequent loss of FMRP, a regulator of synaptic protein synthesis. Disruptions in cyclic nucleotide (cAMP and cGMP) signaling underlie both ASD and FXS contributing to impaired neurodevelopment, synaptic plasticity, learning, and memory. Notably, reduced cAMP levels have been observed in platelets, lymphoblastoid cell lines and neural cells from FXS patients as well as Fmr1 KO and dfmr1 Drosophila models, linking FMRP deficiency to impaired cAMP regulation. Phosphodiesterase (PDE) inhibitors, which prevent the breakdown of cAMP and cGMP, have emerged as promising therapeutic candidates due to their ability to modulate neuronal signaling. Several PDE isoforms—including PDE2A, PDE4D, and PDE10A—have been implicated in ASD, and FXS, as they regulate pathways involved in synaptic plasticity, cognition, and social behavior. Preclinical and clinical studies show that PDE inhibition modulates neuroplasticity, neurogenesis, and neuroinflammation, thereby ameliorating autism-related behaviors. BPN14770 (a PDE4 inhibitor) has shown promising efficacy in FXS patients while cilostazol, pentoxifylline, resveratrol, and luteolin have showed improvements in children with ASD. However, challenges such as isoform-specific targeting, optimal therapeutic window, and timing of intervention remain. Collectively, these findings highlight PDE inhibition as a novel therapeutic avenue with the potential to restore cognitive and socio-behavioral functions in ASD and FXS, for which effective targeted treatments remain unavailable. Full article

Adrenomedullin (AM), a biologically active peptide, induces complete remission with mucosal healing in patients with refractory ulcerative colitis. We have developed 40 kDa PEGylated AM (PEG-AM), a long-acting AM derivative, as a potential therapeutic agent for inflammatory bowel disease (IBD). Both PEG-AM and native AM stimulated cyclic adenosine monophosphate (cAMP) production in HEK-293 cells stably expressing the AM1 receptor (CLR/RAMP2 complex), in a dose-dependent manner. The pEC₅₀ values for PEG-AM and AM were 7.23 ± 0.05 and 8.42 ± 0.10, respectively. PEG-AM exhibited significantly greater stability in plasma and serum than native AM. We evaluated the in vivo anti-colitis effects of intravenously administered PEG-AM in a dextran sodium sulfate (DSS)-induced murine colitis model. A single intravenous dose of PEG-AM, as low as 25 nmol/kg, demonstrated therapeutic efficacy. Notably, AM receptor expression was not downregulated, despite sustained high plasma concentrations of PEG-AM. Additionally, PEG-AM exerted both therapeutic and preventive effects in a DSS colitis model. These findings suggest that PEG-AM is a promising therapeutic candidate for the treatment of patients with IBD. Full article

Since the first paper published by Susan Cole in 1990 detailing multidrug resistance mediated by ABCC1/MRP1, research into the C-subfamily of ATP-binding cassette transporters has continued to uncover a wide range of functionally divergent proteins. However, several orphan transporters remain in the C-subfamily, and the physiological function and substrates of ABCC5, ABCC11, and ABCC12 remain elusive. This review explores the emerging understanding of human ABCC5. Unlike other ABC transporters with well-defined drug export functions, ABCC5’s physiological roles remain only partially understood. While it is known for its involvement in multidrug resistance in cancers, recent studies suggest broader implications in development, metabolism, neurobiology, and male fertility. ABCC5 exports various endogenous substrates, including cyclic nucleotides (cAMP and cGMP), glutamate conjugates like NAAG, and possibly haem. Knockout models in mice, zebrafish, and sea urchins reveal ABCC5’s role in gut formation, brain function, eye development, and iron metabolism. In mice, its deletion results in lower adipose tissue mass, enhanced insulin sensitivity, and neurobehavioral changes resembling schizophrenia, highlighting its role in glutamatergic signalling and circadian regulation. Functionally, ABCC5 appears to impact adipocyte differentiation and GLP-1 release, implicating it in type 2 diabetes susceptibility in humans. Structural studies using human ABCC5 revealed a novel autoinhibitory mechanism involving a peptide segment (C46–S64) that blocks substrate binding, offering new potential for selective inhibitor development. However, this review emphasises caution in targeting ABCC5 for cancer therapy due to its underappreciated physiological function(s), particularly in the brain and male reproductive system. Understanding ABCC5’s substrate specificity, regulatory mechanisms, and functional redundancy with its paralog ABCC12 remains critical for successful therapeutic strategies in humans. Full article