Search Results (2,063)

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic ciliopathy resulting from loss-of-function mutations in the PKD1 and PKD2 genes, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC1 and PC2 regulate mechanosensation, calcium signaling, and key pathways controlling tubular epithelial structure and function. Loss of PC1/PC2 disrupts calcium homeostasis, elevates cAMP, and activates proliferative cascades such as PKA–B-Raf–MEK–ERK, mTOR, and Wnt, driving cystogenesis via epithelial proliferation, impaired apoptosis, fluid secretion, and fibrosis. Recent evidence also implicates novel signaling axes in ADPKD progression including, the Hippo pathway, where dysregulated YAP/TAZ activity enhances c-Myc-mediated proliferation; the stimulator of interferon genes (STING) pathway, which is activated by mitochondrial DNA release and linked to NF-κB-driven inflammation and fibrosis; and the TWEAK/Fn14 pathway, which mediates pro-inflammatory and pro-apoptotic responses via ERK and NF-κB activation in tubular cells. Mitochondrial dysfunction, oxidative stress, and maladaptive extracellular matrix remodeling further exacerbate disease progression. A refined understanding of ADPKD’s complex signaling networks provides a foundation for precision medicine and next-generation therapeutics. This review gathers recent molecular insights and highlights both established and emerging targets to guide targeted treatment strategies in ADPKD. Full article

The Anti-Müllerian hormone (AMH) is widely recognized for promoting Müllerian duct regression in higher vertebrates and regulating key reproductive functions like steroidogenesis, folliculogenesis, and Leydig cell development. In teleost fish, which lack Müllerian ducts, Amh primarily influences male reproductive functions, including sex determination, testis differentiation, and germ cell proliferation. In adult fish, Amh supports gonad development and spermatogenesis, but its role in teleost gonadal physiology remains largely underexplored. This study reveals a novel steroidogenic function in the European sea bass (Dicentrarchus labrax) using in vitro testis culture, in vivo plasmid injection, and cell-based transactivation assays. The Amh-induced significant increase in androgen levels was also confirmed in Japanese medaka (Oryzias latipes) treated with recombinant sea bass Amh. Beyond activating the canonical Smad pathway, Amh also triggered the cAMP/PKA signalling pathway via its cognate type II receptor, Amhr2. Inhibitors of these pathways independently and synergistically counteracted Amh-induced CRE-Luc activity, indicating pathway crosstalk. Moreover, inhibition of the cAMP pathway suppressed Amh-induced androgen production in testis cultures, emphasizing the crucial role of protein kinase A in mediating Amh steroidogenic action. These findings uncover a novel steroidogenic function of Amh in teleosts and highlight its broader role in male reproductive physiology. Full article

This article investigates the paradox of disappearance as both an aesthetic and a political phenomenon. Taking inspiration from Radiohead’s song “How to Disappear Completely,” it argues that aesthetic representations of disappearance never achieve total erasure; instead, they give rise to new forms of visibility. A true aesthetics of disappearance does not exist. Through case studies such as H.G. Wells’s The Invisible Man and Guy Debord’s Society of the Spectacle, the article demonstrates that disappearance is always mediated: the invisible man becomes hyper-visible through his clothing, bandages, and mask, while the spectacle conceals marginalized lives only to expose them through mechanisms of institutional control (e.g., prisons, medical facilities, schools—as analyzed in Michel Foucault’s work). An investigation of the “novel of the institution” (Campe), especially as it appears in the works of Franz Kafka and Robert Walser, eventually explores the nexus between aesthetic representation and institutionalized forms of coerced visibility. Ultimately, the essay argues that disappearance, as an aesthetic and political event, destabilizes regimes of visibility—not by erasure alone, but by exposing the fragility of appearance itself. The tension between opacity and exposure suggests that resistance lies not in pure absence but in subverting the very mechanisms of representation. Full article

Background: Signaling pathways like those depending on cAMP/PKA, calcium/calmodulin/CaMK, MEK-1/MAPK or PI3K/Akt have been described to modulate suprachiasmatic nucleus (SCN) neuronal signaling via influencing transcription factors like CREB. Here, we analyzed the effect of cyclic nucleotide phosphodiesterase inhibitors and structurally similar substances commonly used as autophagy modulators on a cell line stably expressing a cyclic nucleotide element-driven luciferase reporter. Methods: We used an SCN cell line stably transfected with a CRE-luciferase reporter (SCNCRE) to evaluate signaling and vitality responses to various isoform-selective PDE inhibitors and autophagy modulators to evaluate the mechanism of action of the latter. Results: In this study the different impacts of common PDE inhibitors and autophagy modulators on CRE-luciferase activity applied alone and in combination with known CRE-luciferase activating agents showed that (1) PDE3, 4 and 5 are present in SCNCRE cells, with (2) PDE3 being the most active and (3) the autophagy inhibitor 3-Methyladenin (3-MA) displaying PDE inhibitor-like behavior. Conclusions: Experiments provide evidence that, in addition to the extracellular signaling pathways components shown before to be involved in CRE-luciferase activity regulation like cAMP analogs, adenylate cyclase activators and beta-adrenoceptor agonists, cyclic nucleotide metabolism as realized by phosphodiesterase activity, or molecule/agents influencing processes like autophagy or inflammation, modulate transcriptional CRE-dependent activity in these cells. Specifically, we provide evidence that the autophagy inhibitor 3-MA, given that PDEs are expressed, may also act as a PDE inhibitor and inducer of CRE-mediated transcriptional activity. Full article

Cyclic nucleotide signaling pathways play essential roles in the physiology of the nematode Caenorhabditis elegans, influencing processes such as reproduction, environmental sensing, and cellular homeostasis. The intracellular levels of cAMP and cGMP are tightly regulated by their synthesis by adenylyl and guanylyl cyclases and their degradation catalyzed by 3′,5′-cyclic nucleotide phosphodiesterases (PDEs). Mammals possess eleven PDE families (PDE1 through PDE11), whereas nematode genomes contain six PDE genes orthologous to six of the mammalian PDE families. Despite their evolutionary conservation, the signaling pathways, regulatory mechanisms, and enzymatic properties of nematode PDEs remain incompletely understood. This review synthesizes current knowledge on the regulation of cyclic nucleotide levels in C. elegans, highlighting how dysregulation of nematode PDEs affects a wide range of physiological and behavioral processes, including sensory transduction, development, and locomotion. Full article

Spurred by the enormous therapeutic success of glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP1-RAs) against diabetes and obesity, glucagon family receptor pharmacology has garnered a tremendous amount of interest. Glucagon family receptors, e.g., the glucagon receptor itself (GCGR), the GLP-1R, and the glucose-dependent insulinotropic peptide receptor (GIPR), belong to the incretin receptor superfamily, i.e., receptors that increase blood glucose-dependent insulin secretion. All incretin receptors are class B1 G protein-coupled receptors (GPCRs), coupling to the G_s type of heterotrimeric G proteins which activates adenylyl cyclase (AC) to produce cyclic adenosine monophosphate (cAMP). Most GPCRs undergo desensitization, i.e., uncouple from G proteins and internalize, thanks to interactions with the βarrestins (arrestin-2 and -3). Since the βarrestins can also mediate their own G protein-independent signaling, any given GPCR can theoretically signal (predominantly) either via G proteins or βarrestins, i.e., be a G protein- or βarrestin-“biased” receptor, depending on the bound ligand. A plethora of experimental evidence suggests that the GLP-1R does not undergo desensitization in physiologically relevant tissues in vivo, but rather, it produces robust and prolonged cAMP signals. A particular property of constant cycling between the cell membrane and caveolae/lipid rafts of the GLP-1R may underlie its lack of desensitization. In contrast, GIPR signaling is extensively mediated by βarrestins and the GIPR undergoes significant desensitization, internalization, and downregulation, which may explain why both agonists and antagonists of the GIPR exert the same physiological effects. Here, we discuss this evidence and make a case for the GLP-1R being a phenotypically or functionally G_s-selective receptor. We also discuss the implications of this for the development of GLP-1R poly-ligands, which are increasingly pursued for the treatment of obesity and other diseases. Full article

Aberrant DNA methylation has been shown to be a fingerprint characteristic in human colorectal tumors. In this study, we hypothesize that investigating global DNA methylation could offer potential candidates for clinical application in CRC. The epigenome-wide association analysis was conducted in both the tumor area (N = 27) and the adjacent tumor-free (NAT) area (N = 15). We found 78,935 differentially methylated CpG sites (DMCs) (FDR < 0.05), 42,888 hypomethylated and 36,047 hypermethylation showing overall hypomethylation. Gene ontology and KEGG analysis of differentially methylated genes showed significant enrichment in developmental genes, as well as in genes involved in metabolic processes and the cell cycle, such as the TFGβ and cAMP signaling pathways. Through filtered analysis, we identified TNXB as the most epigenetically dysregulated gene, hypomethylated and downregulated in CRC (both with p < 0.001) and associated with poor overall survival. In the functional analysis, TNXB was epigenetically regulated in a dose-dependent manner, suggesting a potential role in CRC. The epigenetic dysregulation and functional role of TNXB in CRC could have clinical implications, serving as indicators of malignant potential, with adverse effects associated with disease origin and progression in CRC. Full article

Heat stress (HS) is a major environmental factor negatively impacting the reproductive performance of livestock. This study investigates the molecular mechanisms of heat stress on the hypothalamic–pituitary–ovarian (HPO) axis in Hu sheep. A heat-stressed animal model was established, and high-throughput RNA sequencing (RNA-seq) was employed to analyze gene expression in the hypothalamus, pituitary, and ovarian tissues of both control and heat-stressed groups. The results revealed significant changes in estrus behavior, hormone secretion, and reproductive health in heat-stressed sheep, with a shortened estrus duration, prolonged estrous cycles, and decreased levels of FSH, LH, E₂, and P4. A total of 520, 649, and 482 differentially expressed genes (DEGs) were identified in the hypothalamus, pituitary, and ovary, respectively. The DEGs were enriched in pathways related to hormone secretion, neurotransmission, cell proliferation, and immune response, with significant involvement of the p53 and cAMP signaling pathways. Tissue-specific responses to heat stress were observed, with distinct regulatory roles in each organ, including GPCR activity and cytokine signaling in the hypothalamus, calcium-regulated exocytosis in the pituitary, and cilium assembly and ATP binding in the ovary. Key genes such as SYN3, RPH3A, and IGFBP2 were identified as central to the coordinated regulation of the HPO axis. These findings provide new insights into the molecular basis of heat stress-induced impairments in reproductive function—manifested by altered estrous behavior, reduced hormone secretion (FSH, LH, E₂, and P4), and disrupted gene expression in the hypothalamic–pituitary–ovarian (HPO) axis—and offer potential targets for improving heat tolerance and reproductive regulation in sheep. Full article

Equine lutropin hormone/choriogonadotropin receptor (LH/CGR) is a G protein-coupled receptor that binds to both luteinizing hormone and choriogonadotropin, with multiple potential N-linked glycosylation sites in the long extracellular domain region. The roles of these glycosylation sites in hormone binding have been widely studied; however, their relationships with cyclic adenosine monophosphate (cAMP) activation, loss of cell surface receptors, and phosphorylated extracellular signal-regulated kinases1/2 (pERK1/2) expression are unknown. We used site-directed mutagenesis with the substitution of Asn for Gln to alter the consensus sequences for N-linked glycosylation, and cAMP signaling was analyzed in the mutants. Specifically, the N174Q and N195Q mutants exhibited markedly reduced expression levels, reaching approximately 15.3% and 2.5%, respectively, of that observed for wild-type equine LH/CGR. Correspondingly, the cAMP EC₅₀ values were decreased by 7.6-fold and 5.6-fold, respectively. Notably, the N195Q mutant displayed an almost complete loss of cAMP activity, even at high concentrations of recombinant eCG, suggesting a critical role for this glycosylation site in receptor function. Despite these alterations, Western blot analysis revealed that pERK1/2 phosphorylation peaked at 5 min following agonist stimulation across all mutants, indicating that the ERK1/2 signaling pathway remains functionally intact. This study demonstrates that the specific N-linked glycosylation site, N195, in equine LH/CGR is indispensable for cAMP activity but is normally processed in pERK1/2 signaling. Thus, we suggest that in equine LH/CGR, agonist treatment induces biased signaling, differentially activating cAMP signaling and the pERK1/2 pathway. Full article

FP is a detrimental behavior for chickens, ducks, and geese associated with numerous physiological and neurobiological characteristics, which have been identified in many species as regulated by the gut microbiota. However, it is unknown whether and how gut microbiota influences FP by regulating neurotransmitter systems in geese. This study aimed to investigate the phenotypic correlation between feather pecking and changes in physiological, neurobiological, and gut microbiota profiles in gosling. Three behavioral phenotypes were observed in goslings, including severe feather peckers (SFPs), victims of SFPs, and non-peckers (NFPs). The significantly lower feather scores and body weights were observed in victims compared to both SFPs and NFPs (p < 0.05). Regarding the physiological phenotype, victims had higher dopamine (DA) levels than NFPs, and SFPs had lower 5-hydroxytryptamine (5-HT) in the serum than NFPs (p < 0.001), with intermediate 5-HT levels in victims. Victims had lower glutathione peroxidase (GSH-Px) compared to SFPs and NFPs (p < 0.05). Moreover, higher mRNA expression levels of HTR1A, SLC6A4, and TPH2 in the 5-HT metabolic pathway were detected in NFPs than those in SFPs and victims (p < 0.05). In addition, regarding gut microbiota measured by 16S rRNA sequencing, SFPs had lower diversity and comparable cecal microbiota compared to victims and NFPs. Proteobacteria, Verrucomicrobia, Ruminococcus spp., and Bilophila spp. were enriched in SFPs, while Bacteroides and Parabacteroides were enriched in NFPs. From the predicted bacterial functional genes, the cAMP signaling pathway, cGMP–PKG signaling pathway, and pyruvate metabolism were activated in SFPs. The correlation analysis revealed that the genera Bacteroides spp. were associated with differences in 5-HT metabolism between the SFPs and NFPs. In summary, differences in the cecal microbiota profile and 5-HT metabolism drive FP phenotypes, which could be associated with the reduced gut abundance of the genera Bacteroides spp. Full article

Bibenzyls are now recognized as compounds for use in cancer therapy, and many molecules from the bibenzyl group have shown promising anticancer activity; therefore, the characterization of new bibenzyls with strong biological activity is important for developing new anticancer drugs. In this study, we compared the effects of three bibenzyls (3,3′-dihydroxy-4,5-dimethoxybibenzyl, 3,5-dihydroxy-4-methoxybibenzyl and 3,5,3′-trihydroxy-4-methoxybibenzyl) isolated from Empetrum nigrum and erianin on platelets and the MOLT-3 T-lymphoblast cell line. Among the studied bibenzyls, 3,3′-dihydroxy-4,5-dimethoxybibenzyl significantly reduced the viability of MOLT-3 cells and platelets and induced strong phosphatidylserine (PS) surface exposure. We showed that 3,3′-dihydroxy-4,5-dimethoxybibenzyl induced the death of MOLT-3 cells and platelets, which was not mediated by apoptosis, pyroptosis, necroptosis, autophagy, or calpain-dependent pathways, and that the p38 MAP kinase pathways are at least partly involved in the activity of 3,3′-dihydroxy-4,5-dimethoxybibenzyl. In conclusion, our data show that 3,3′-dihydroxy-4,5-dimethoxybibenzyl could be a promising candidate for future analysis as an anticancer drug. Full article

Cancer remains a leading cause of mortality worldwide, necessitating innovative therapeutic strategies. Drug repurposing offers a cost-effective approach to cancer treatment by identifying new anticancer applications for existing drugs. Terbutaline, a β2-adrenergic receptor agonist, and Milrinone, a phosphodiesterase-3 inhibitor, are traditionally used as positive inotropic agents but have shown potential anticancer effects. This review explores their mechanisms of action in cancer, focusing on their roles in modulating cyclic adenosine monophosphate (cAMP) levels, oxidative stress, and the tumor microenvironment. Terbutaline influences β2-adrenergic signaling, impacting cell proliferation, angiogenesis, and immune evasion. Milrinone, through PDE3 inhibition, elevates cAMP, promoting apoptosis and reducing tumor growth. Both agents exhibit anti-inflammatory and anti-angiogenic properties, suggesting their potential as adjuvant therapies in oncology. Despite promising preclinical data, clinical validation is required to confirm their efficacy and safety in cancer patients. This review highlights the therapeutic promise of repurposing Terbutaline and Milrinone, emphasizing the need for further research to optimize their application in cancer therapy. Full article

Refugee settlements are often positioned around natural borders, which often have a heightened danger of environmental hazards. Here, we aim to better understand why settlements are in environmentally vulnerable land and what social and physical factors contribute to this phenomenon. To do this, we present a holistic narrative that maps climate threats among displaced populations in Cox’s Bazar district, Bangladesh, while contextualizing environmental vulnerability by incorporating historical and social constraints. Using ArcGIS, an online mapping program, we illustrate the overlap between different climatic events and how these vulnerabilities compound and intensify one another. We also discuss the history of natural migration and settlement pertaining to the physical landscape and the sociopolitical reasons refugees remain in environmentally vulnerable areas. Overall, we find an emerging trend that may be broadly applicable to instances of forced displacement; physical settlement locations near international borders demarcated by landforms may be more vulnerable to the effects of climate change and extreme climate events. However, physical, social, and political reasons often cement these locations. Recommendations include enhancing the resilience of refugee camps through infrastructure improvements, sustainable land management, and reforestation efforts, which would benefit both the environment and local and refugee communities. Full article

Background/Objectives: Urolithin A (UA), a gut-derived metabolite of ellagitannins or ellagic acid, has recently gained attention for its potential benefits to brain health. The present research aimed to assess the antidepressant-like properties of UA in both in vitro and in vivo models and explored the molecular mechanisms underlying these effects. Methods: We investigated the antidepressant effects and mechanisms of UA in a model of corticosterone-induced damage to PC12 cells and in a model of chronic socially frustrating stress. Results: Our results demonstrate that UA treatment (5 and 10 μM) significantly alleviated cellular damage and inflammation in corticosterone (CORT)-treated PC12 cells. Furthermore, UA administration (50 and 100 mg/kg) significantly reduced immobility time in the mouse tail suspension test (TST) and forced swim test (FST), indicating its antidepressant-like activity. Additionally, treatment with UA led to the activation of the cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling cascade and triggered the activation of adenosine monophosphate-activated protein kinase (AMPK) during these processes. Importantly, pretreatment with AMPK-specific inhibitor Compound C abolished UA’s cytoprotective effects in PC12 cells, as well as its behavioral efficacy in the FST and TST, and its neurotrophic effects, highlighting the critical role of AMPK activation in mediating these effects. Furthermore, in the chronic social defeat stress (CSDS) mouse model, UA treatment (50 and 100 mg/kg) significantly alleviated depression-like behaviors, including reduced sucrose preference in the sucrose preference test, increased social avoidance behavior in the social interaction test, and anxiety-like behaviors, including diminished exploration, in the elevated plus maze test, suggesting the antidepressant-like and anxiolytic-like activities of UA. Moreover, UA treatment reversed elevated serum stress hormone levels, hippocampal inflammation, and the decreased AMPK/CREB/BDNF signaling pathway in the hippocampus of CSDS mice. Conclusions: Together, these results provide compelling evidence for UA as a viable dietary supplement or therapeutic option for managing depression. Full article

Forskolin (FSK) induces the browning of white adipose tissue (WAT) through the activation of adenylate cyclase (AC) and cyclic adenosine monophosphate (cAMP) generation. When administered intravenously or orally, FSK undergoes significant metabolism and accumulation in the liver and other tissues, resulting in high side effects and low anti-obesity effects due to trivial amounts reaching WAT. This study examines the potential anti-obesity and metabolic effects of the inguinal WAT (IWAT) delivery of FSK in high-fat diet-induced C57BL/6J obese mice. Mice received one of the following treatments twice weekly for 4 weeks: 1. Control into both IWAT depots (Con^both); 2. FSK 15 mg/kg body weight (BW)/injection into both inguinal WAT (IWAT) depots (FSK15^both); 3. FSK 7.5 mg/kg BW/injection into both IWAT depots (FSK7.5^both); and 4. FSK 7.5 mg/kg BW/injection into the left IWAT depot (FSK7.5^left). Both the FSK15^both and FSK7.5^both treatments improved metabolic parameters by lowering blood glucose, enhancing glucose tolerance, and reducing serum insulin and cholesterol. The FSK15^both treatment had a greater impact on IWAT, resulting in smaller adipocytes and increased expression of Ucp1 and Tmem26 mRNA levels. All FSK treatments also reduced inflammatory and lipogenic markers in the liver, indicating improved hepatic metabolism. These findings suggest that local delivery of FSK into subcutaneous WAT is a potential strategy for combating obesity and improving metabolic health. However, further studies are needed to confirm the statistical and biological significance of these effects. Full article