cAMP Signaling Research Articles

Diesel exhaust particles alter mitochondrial bioenergetics and cAMP producing capacity in human bronchial epithelial cells.

Introduction: Air pollution from diesel combustion is linked in part to the generation of diesel exhaust particles (DEP). DEP exposure induces various processes, including inflammation and oxidative stress, which ultimately contribute to a decline in lung function. Cyclic AMP (cAMP) signaling is critical for lung homeostasis. The impact of DEP on cAMP signaling is largely unknown. Methods: We exposed human bronchial epithelial (BEAS-2B) cells to DEP for 24-72h and evaluated mitochondrial bioenergetics, markers of oxidative stress and inflammation and the components of cAMP signaling. Mitochondrial bioenergetics was measured at 72h to capture the potential and accumulative effects of prolonged DEP exposure on mitochondrial function. Results: DEP profoundly altered mitochondrial morphology and network integrity, reduced both basal and ATP-linked respiration as well as the glycolytic capacity of mitochondria. DEP exposure increased gene expression of oxidative stress and inflammation markers such as interleukin-8 and interleukin-6. DEP significantly affected mRNA levels of exchange protein directly activated by cAMP-1 and -2 (Epac1, Epac2), appeared to increase Epac1 protein, but left phospho-PKA levels unhanged. DEP exposure increased A-kinase anchoring protein 1, β2-adrenoceptor and prostanoid E receptor subtype 4 mRNA levels. Interestingly, DEP decreased mRNA levels of adenylyl cyclase 9 and reduced cAMP levels stimulated by forskolin (AC activator), fenoterol (β2-AR agonist) or PGE2 (EPR agonist). Discussion: Our findings suggest that DEP induces mitochondrial dysfunction, a process accompanied by oxidative stress and inflammation, and broadly dampens cAMP signaling. These epithelial responses may contribute to lung dysfunction induced by air pollution exposure.

Cyclic AMP signaling promotes regeneration of cochlear synapses after excitotoxic or noise trauma.

Cochlear afferent synapses connecting inner hair cells to spiral ganglion neurons are susceptible to excitotoxic trauma on exposure to loud sound, resulting in a noise-induced cochlear synaptopathy (NICS). Here we assessed the ability of cyclic AMP-dependent protein kinase (PKA) signaling to promote cochlear synapse regeneration, inferred from its ability to promote axon regeneration in axotomized CNS neurons, another system refractory to regeneration. We mimicked NICS in vitro by applying a glutamate receptor agonist, kainic acid (KA) to organotypic cochlear explant cultures and experimentally manipulated cAMP signaling to determine whether PKA could promote synapse regeneration. We then delivered the cAMP phosphodiesterase inhibitor rolipram via implanted subcutaneous minipumps in noise-exposed CBA/CaJ mice to test the hypothesis that cAMP signaling could promote cochlear synapse regeneration in vivo. We showed that the application of the cell membrane-permeable cAMP agonist 8-cpt-cAMP or the cAMP phosphodiesterase inhibitor rolipram promotes significant regeneration of synapses in vitro within twelve hours after their destruction by KA. This is independent of neurotrophin-3, which also promotes synapse regeneration. Moreover, of the two independent signaling effectors activated by cAMP - the cAMP Exchange Protein Activated by cAMP and the cAMP-dependent protein kinase - it is the latter that mediates synapse regeneration. Finally, we showed that systemic delivery of rolipram promotes synapse regeneration in vivo following NICS. In vitro experiments show that cAMP signaling promotes synapse regeneration after excitotoxic destruction of cochlear synapses and does so via PKA signaling. The cAMP phosphodiesterase inhibitor rolipram promotes synapse regeneration in vivo in noise-exposed mice. Systemic administration of rolipram or similar compounds appears to provide a minimally invasive therapeutic approach to reversing synaptopathy post-noise.

Role of Ca2+/cAMP signalling in cancer with concurrent hypertension

Role of Ca2+/cAMP signalling in cancer with concurrent hypertension

MicroRNAs as markers of congenital aniridia

Subjects with congenital aniridia often develop aniridia‐associated keratopathy (AAK), which is related to limbal stem cell insufficiency. Loss of limbal epithelial stem cell function results in corneal inflammation and neovascularization, and several subjective symptoms. MicroRNAs (miRNAs) are approximately 22 nt long non‐coding RNA molecules capable of regulating gene expression at the post‐transcriptional level.It is of interest to investigate the expression of microRNAs and their possible effect on AAK development, as deeper understanding of their function in limbal epithelial cells could help in designing new therapeutic approaches of AAK.Previous studies verified deregulated miRNAs in conjunctival cells of aniridia subjects, among others miR‐204‐5p and miR‐7150, which are more deregulated in mild cases of AAK. In addition, numerous studies suggest that miRNAs regulate genes involved either directly or indirectly in inhibition or promotion of pathological angiogenesis of the cornea. Several pathways, including JAK–STAT, focal adhesion, Hippo, WNT and PI3K‐AKT signalling pathways, could potentially play a role. In limbal epithelial cells of aniridia subjects, deregulation of miR‐138‐5p may play a role, which is involved in the regulation of cell differentiation and migration and in Hippo, Wnt, Focal adhesion cAMP and p53 signalling pathways.

Virus‐Triggered Autoimmunity Was Associated With Hirschsprung’s Disease Through Activation of Innate Immunity

Background: Hirschsprung’s disease (HSCR) is a congenital enteric nervous system (ENS) disorder. Genetics cannot explain most sporadic cases. To explore the relationship between pathogen infection, autoantibodies, innate immune, and HSCR.Methods: Pathogen microarray was conducted in the serum of the prospective neonatal abdominal distension (NAD) cohort, consisting of 56 children followed for at least 6 months until the final diagnosis of HSCR was determined or excluded. We conducted an autoantibody microarray in an HSCR cohort, which is comprised of diagnosed HSCR patients (HSCR) and healthy control subjects (HC). RNA‐seq of colon tissues from aganglionic and ganglionic segments of HSCR patients was performed.Results: Experimental results show that the serum lgM and lgG of enterovirus 71 (EV71) were significantly higher in HSCR than in the gastrointestinal dysfunction (GI) group, with a prediagnose value reaching area under the curve (AUC) over 0.76. We discovered that a group of autoantibodies were significantly higher in HSCR including neuronal pentraxin 1 (NPTX1), amyloid, neuron lysate, and myelin‐associated oligodendrocytic basic protein (MOBP) than that in the HC group. These four autoantibodies could distinguish HSCR from the HC group, with a combined AUC of over 0.90 using both serum IgG and IgM. Further analysis showed that wide activation of innate immune pathways, including toll‐like receptor (TLR) signaling pathway, neutrophil‐to‐lymphocyte ratio (NLR) signaling pathway, red cell distribution width to lymphocyte ratio (RLR) signaling pathway, and cyclic adenosine monophosphate (cAMP) signaling pathway in aganglionic compared to ganglionic segments of HSCR.Conclusion: This study suggested that virus‐triggered autoimmunity may contribute to HSCR through activation of innate immunity, which facilitates the diagnosis and prevention of HSCR.

LncRNA GTL2 regulates myoblast proliferation and differentiation via the PKA-CREB pathway in Duolang sheep.

Long non-coding RNAs (lncRNAs), which are RNA molecules longer than 200 nucleotides that do not encode proteins, are implicated in a variety of biological processes, including growth and development. Despite research into the role of lncRNAs in skeletal muscle development, the regulatory mechanisms governing ovine skeletal muscle development remain unclear. In this study, we analyzed the expression profiles of lncRNAs in skeletal muscle from 90-day-old embryos (F90), 1-month-old lambs (L30), and 3-year-old adult sheep (A3Y) using RNA sequencing. In total, 4 738 lncRNAs were identified, including 997 that were differentially expressed. Short-time series expression miner analysis identified eight significant expression profiles and a subset of lncRNAs potentially involved in muscle development. Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that the predicted target genes of these lncRNAs were primarily enriched in pathways associated with muscle development, such as the cAMP and Wnt signaling pathways. Notably, the expression of lncRNA GTL2 was found to decrease during muscle development. Moreover, GTL2 was highly expressed during the differentiation of skeletal muscle satellite cells (SCs) and was shown to modulate ovine myogenesis by affecting the phosphorylation levels of PKA and CREB. Additionally, GTL2 was found to regulate both the proliferation and differentiation of SCs via the PKA-CREB signaling pathway. Overall, this study provides a valuable resource and offers novel insights into the functional roles and regulatory mechanisms of lncRNAs in ovine skeletal muscle growth and development.

Causal relationship between hypothyroidism and coronary atherosclerotic cardiovascular disease: a bidirectional two-sample Mendelian randomization.

Epidemiological and observational studies demonstrate a comorbid relationship between hypothyroidism and atherosclerotic cardiovascular disease (ASCVD). The nature and direction of this causal relationship, however, remain unclear. This study aims to elucidate the causal relationship between hypothyroidism and ASCVD using a bidirectional Mendelian randomization approach. Single nucleotide polymorphisms (SNPs) associated with hypothyroidism were identified and selected as genetic instrumental variables from aggregated data of genome-wide association studies (GWAS). The outcome of interest, ASCVD, included seven conditions: coronary artery disease (CAD), angina pectoris (AP), myocardial infarction (MI), ischemic stroke (IS), and subtypes IS-large artery atherosclerosis (IS-LAA), IS-small vessels (IS-SV), and peripheral artery disease (PAD). MR analysis employed multiple methods-chiefly inverse variance weighting (IVW), along with MR Egger, weighted median, and weighted mode-to assess causality. Cochrane's Q test was utilized to evaluate heterogeneity in the MR findings. Causal association reliability was assessed using the MR-Egger intercept, MR-PRESSO tests, and leave-one-out analysis. Reverse MR analysis ensued if forward MR identified a positive exposure-outcome association. Moreover, the DAVID database facilitated GO functional and KEGG pathway enrichment analyses of neighboring genes to instrumental variables, exploring potential disease mechanisms. GWAS pooled data yielded 122 SNPs as potential instrumental variables for hypothyroidism. Forward MR analysis, using the IVW method, indicated hypothyroidism as a risk factor for CAD (OR = 2.34, 95% CI = 1.39-3.94, P = 0.001), AP (OR = 2.01, 95% CI = 1.28-3.16, P = 0.002), MI (OR = 1.02, 95% CI = 1.01-1.04, P = 0.004), and IS-SV (OR = 6.92, 95% CI = 2.45-19.55, P < 0.001). However, no significant link was found between hypothyroidism and the remaining three diseases, with sensitivity analysis reinforcing result robustness. In contrast, reverse MR analysis did not corroborate a causal link from ASCVD to hypothyroidism. The R package identified 83 neighboring genes as instrumental variables. GO enrichment analysis via the DAVID database yielded 53 entries, predominantly involving cAMP catabolic processes, protein binding, and signal transduction. KEGG analysis identified 31 pathways, notably those related to Th1/Th2 and Th17 cell differentiation, and Herpes simplex virus 1 infection. The marked association between hypothyroidism and CAD, AP, MI, and IS suggests that thyroid function assessment could be integral to preventing and diagnosing specific ASCVD types. This underscores the need for individuals with hypothyroidism to be proactive regarding ASCVD risk factors. A balanced Th1/Th2 and Th17/Treg ratio may offer a novel strategy in preventing CAD and enhancing the prognosis for hypothyroid patients.

Identification of the Gene Network in the Progress and Development of Pterygium

The prevalence of pterygium was 12%. Pterygium have been a common ophthalmic disease in the whole world, but its mechanism is still unclear. To comprehensively understand the reasons for the formation and progress of pterygium, here we analyzed the difference in transcriptomes between pterygium and healthy conjunctiva. Using the database of GSE51995 and GSE183153.We queried all data sets involving pterygium studies in GEO. GO annotation, KEGG pathway, and PPI enrichment analysis were used in the exploration of the mechanism. Then we validated the transcription level of the key network node genes with qRT-PCR. We identified 143 down-regulated genes and 221 up-regulated genes, and the bioinformatic analysis and qPCR validation confirmed 10 up-regulated and 7 down-regulated genes, what related AGER, ECM, estrogen and cAMP. We comprehensively analyzed two pterygium transcriptome data sets, GSE51995 and GSE183153. The PPI analysis result and the further qPCR result suggested that the AGER-RAGE pathway, ECM-receptor interaction, estrogen receptor pathway, and cAMP signal pathway might be involved in pterygium progression and development.

Deep insights into the mechanism of isorhamnetin's anti-motion sickness effect based on photoshoproteomics.

Isorhamnetin has recently been found to exhibit a remarkable anti-motion sickness effect, yet the underlying mechanism is still unclear. Herein, network pharmacology was employed to conduct a preliminary analysis on the possible biological processes involved. Results showed that common targets were localized in membranes, mitochondria, and glutamatergic synapses. In particular, protein phosphorylation, protein serine/threonine/tyrosinase activity and signal transduction might play a role in isorhamnetin's anti-motion sickness effect. Thus, mice phosphoproteomics analysis was further performed to explore the phosphorylated protein changes in the motion sickness process. Results showed that differentially phosphorylated proteins have an effect on postsynaptic density, glutamatergic synapses and other sites and are involved in various neurodegenerative disease pathways, endocytic pathways, cAMP signaling pathways and MAPK signaling pathways. Two key differentially phosphorylated proteins in glutamatergic synapses, namely, DLGAP and EPS8, might play key roles in isorhamnetin's anti-motion sickness process. The final molecular experimental verification results from qRT-PCR and western blot analyses indicated that isorhamnetin firstly regulates glutamatergic synapses and then reduces the excitability of the vestibular nucleus through inhibiting the NMDAR1/CaMKII/CREB signaling pathway, ultimately alleviating a series of symptoms of motion sickness in mice. The findings of this study provide valuable insights and a useful theoretical basis for the application of isorhamnetin as a new anti-motion sickness food ingredient.

Phosphodiesterase 7 inhibitor reduces stress-induced behavioral and cytoarchitectural changes in C57BL/6J mice by activating the BDNF/TrkB pathway.

Phosphodiesterase 7 (PDE7) plays a role in neurological function. Increased expression and activity of PDE7 has been detected in several central nervous system diseases. However, the role of PDE7 in regulating stress levels remains unclear. Thus, this study aimed to determine whether and how PDE7 involved in the stress-induced behavioral and neuron morphological changes. The single prolonged stress (SPS) was used to build a stress exposure model in C57BL/6J mice and detected PDE7 activity in hippocampus, amygdala, prefrontal cortex and striatum. Next, three doses (0.2, 1, and 5mg/kg) of the PDE7 inhibitor BRL-50481 were intraperitoneally administered for 10 days, then behavioral, biochemical, and morphological tests were conducted. PDE7 activity in hippocampus of mice significantly increased at all times after SPS. BRL-50481 significantly attenuated SPS induced anxiety-like behavior and fear response in both context and cue. In addition, BRL-50481 increased the levels of key molecules in the cAMP signaling pathway which were impaired by SPS. Immunofluorescent staining and Sholl analysis demonstrated that BRL-50481 also restored the nucleus/cytoplasm ratio of hippocampal neurons and improved neuronal plasticity. These effects of BRL-50481 were partially blocked by the TrkB inhibitor ANA-12. PDE7 inhibitors attenuate stress-induced behavioral changes by protecting the neuron cytoarchitecture and the neuronal plasticity in hippocampus, which is mediated at least partly through the activation of BDNF/TrkB signaling pathway. These results proved that PDE7 is a potential target for treating stress-induced behavioral and physiological abnormalities.

CNKSR2 expression is correlated with immune infiltrates in Cervical Cancer as a favorable prognostic factor.

Connector enhancer of kinase suppressor of Ras 2 (CNKSR2) is a scaffold protein that mediates mitogen-activated protein kinase pathways. However, the molecular function of CNKSR2 in cervical squamous cell carcinoma (CESC) remains unknown. This study aimed to characterize the role of CNKSR2 in patients with CESC. Immunohistochemistry revealed that the expression of CNKSR2 in CESCs is relatively low compared with that in normal cells. We also explored the gene expression profile of high- and low-CNKSR2 expression in patients with cervical cancer. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the expression of CNKSR2 was upregulated in synapse assembly, which was coordinately regulated using the cAMP signaling pathway and calcium signaling pathway. The correlation between CNKSR2 and cancer immune cell infiltration was investigated via single-sample gene set enrichment analysis (ssGSEA). High CNKSR2 expression was associated with better overall survival (OS) and disease-free survival (DFS). Interestingly, high CNKSR2 expression was a good predictor of the survival outcome in cervical cancer patients. Additionally, CNKSR2 expression was strongly correlated with diverse immune cells in CESCs, including NK cells and T cells. These findings suggest that CNKSR2 is correlated with prognosis and immune infiltration, laying the foundation for future studies on the functional role of CNKSR2 in CESC.

Cancer Cell-Type-Dependent Modifications of Metastatic Parameters by SLIT2-ROBO1 and RHOA cAMP Signaling in Response to TGFβ1 and FGF2.

The epithelial to mesenchymal transition (EMT) is a multistep process involving structural and functional alterations that are required for cancer metastasis, as well as loss of epithelial markers (e.g., E-cadherin/CDH1) and gain of mesenchymal markers (e.g., N-cadherin/CDH2, vimentin/VIM). Pathological events modify cell-cell interactions, cell-matrix adhesion and extra cellular matrix integrity leading to cell migration, evasion from the primary tumor and augmented invasiveness in the metastatic niche. This transformation is modulated by multiple paracrine factors (e.g., chemokines, growth factor), as well as SLIT2-ROBO1 signaling that collectively regulate expression of RHO GTPases (e.g., RHOA) and EMT marker genes. Yet, the roles of SLIT proteins in cancer remain enigmatic. In some cancer types, SLIT2 is anti-tumorigenic, while in other cancers it contributes towards the metastatic phenotype. Here we investigated the ambivalent metastatic activity of SLIT2 by analyzing how cAMP/RHOA signal transduction modulates SLIT-ROBO controlled metastatic parameters in response to the phosphodiesterase inhibitor IBMX (3-isobutyl-1-methylxanthine) and paracrine factors (TGF-β/TGFβ1 and FGF2). Upon SLIT2 administration cell migration and proliferation increases in colon cancer cells and decreases in cervical cancer cells, while altering cell morphology and proliferation in both cancer types. These effects are reinforced by TGF-β/TGFβ1 and FGF2, but attenuated by elevation of cAMP with IBMX, depending on the cancer cell type. Our data indicate that SLIT2 represents a potential biomarker for cancer diagnosis, prognosis, and therapy.

Peanut oil odor enhances the immunomodulatory effect on immunosuppressed mice by regulating the cAMP signaling pathway via the brain-spleen axis.

The role of sniffing relative to immune function has attracted considerable attention. The present study investigated the immunomodulatory effects of peanut oil odor on cyclophosphamide (CTX)-induced immunosuppressed mice. The subset of mice subjected to prolonged (8 h) sniffing peanut oil odor (PL) demonstrated significantly elevated levels of agouti-related peptide, neuropeptide Y, and glutamate (p < 0.05), whereas it significantly down-regulated the level of γ-aminobutyric acid in the brain (p < 0.05). Furthermore, immunohistochemistry results indicated significantly increased expression of mGluR1/5 and decreased expression of GABABR in the hippocampus and hypothalamus (p < 0.05) of the PL group. Additionally, the PL group had significantly up-regulated expression levels of cAMP, Epac, Rap1, ERK1/2 and PKA (p < 0.05) and remarkably increased phosphorylation of CREB in the cAMP signaling pathway (p < 0.05), which influenced the central nervous system. Moreover, compared with CTX-induced mice, the percentages of peripheral blood T lymphocytes (CD3+CD4+ and CD3+CD8+) and the levels of splenic cytokines (IL-2, IL-4, and TNF-α) were significantly increased following PL treatment (p < 0.05). The PL group also showed significantly up-regulated expression levels of cAMP, p-p65, and p-IκBα in the spleen (p < 0.05) by western blot analysis. In summary, PL intervention significantly up-regulated the expression levels of cAMP in the brain (p < 0.05), with subsequent transfer of cAMP to the spleen which promoted phosphorylation of p65 and IκBα. This series of events enhanced the immunity of mice, which confirmed the regulatory effect of PL on the cAMP signaling pathway, thereby enhancing immune function via the brain-spleen axis.

Relevance Analysis of TPM2 and Clinicopathological Characteristics in Breast Cancer.

The function of tropomyosin 2 (TPM2) in breast cancer is still far understudied. In this study, we aim to explore the roles of TPM2 in breast cancer progression. This research included 155 breast cancer tissues. The expression of TPM2 was analyzed by immunohistochemical staining and grading. The mRNA expression of TPM2 in pan-cancer was analyzed with The Cancer Genome Atlas (TCGA) data plate form. The differential expression of TPM2 protein and the differential promoter methylation level of TPM2 between breast cancer tissues and normal breast tissues were analyzed by the UALCAN online database. The relationship between TPM2 and signaling pathways was interpreted by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) pathway enrichment analyses. The survival curve of TPM2 was analyzed across the Kaplan-Meier plotter online database. Furthermore, the relationship between TPM2 expression and infiltrating macrophages was validated through in vitro co-culture experiments. TPM2 expression was significantly down-regulated in breast cancer samples. In addition, TPM2 expression was correlated with lymph node metastasis and high-grade histopathological morphology. The receiver operating characteristic (ROC) curve indicated that TPM2 expression could well distinguish between normal breast tissue and breast cancer tissue. TPM2 may have potential value in breast cancer diagnosis. Bioinformatics analysis illustrated that TPM2 was mainly involved in extracellular matrix organization, collagen fibril organization, cell junction assembly, focal adhesion, cAMP signaling pathway, estrogen signaling pathway, Wnt signaling pathway, and adaptive immune system. TPM2 expression was correlated with immune infiltrating cells and immune checkpoint molecules. Our in vitro co-culture experiments showed that the M2 macrophages could upregulate the expression of TPM2. TPM2 may play key roles in breast cancer occurrence and development, especially in cancer metastasis. TPM2 may be a potential biomarker for breast cancer diagnosis.

Signalling of Adrenoceptors: Canonical Pathways and New Paradigms.

The concept of G protein-coupled receptors initially arose from studies of the β-adrenoceptor, adenylyl cyclase, and cAMP signalling pathway. Since then both canonical G protein-coupled receptor signalling pathways and emerging paradigms in receptor signalling have been defined by experiments focused on adrenoceptors. Here, we discuss the evidence for G protein coupling specificity of the nine adrenoceptor subtypes. We summarise the ability of each of the adrenoceptors to activate proximal signalling mediators including cAMP, calcium, mitogen-activated protein kinases, and protein kinase C pathways. Finally, we highlight the importance of precise spatial and temporal control of adrenoceptor signalling that is controlled by the localisation of receptors at intracellular membranes and in larger protein complexes.

A106: Aerobic Exercise Modulates GPCR/cAMP/PKA Signaling Pathway and Complement-Microglia Axis to Prevent Synaptic Loss in APP/PS1 Mice

Purpose: Synaptic failure serves as a primary contributor to memory dysfunction in Alzheimer's disease (AD). Physical exercise has demonstrated the potential to thwart and delay degenerative alterations in memory functions linked to AD. Investigating the underlying mechanisms may unveil crucial insights into early pathological changes, offering breakthroughs for both understanding and treating AD. Methods: We utilized 3-month-old APP/PS1 mice and subjected them to a 12-week aerobic exercise intervention. The spatial learning and memory functions of the mice were assessed using the Morris water maze test, while Golgi staining was employed to determine dendritic spine density in each mouse group. To analyze the potential mechanisms mediating the effects of exercise intervention in the AD brain, we conducted RNA sequencing. Subsequently, pathway enrichment analysis, immunofluorescence, real-time quantitative PCR, and western blotting were employed to elucidate the impact of regular aerobic exercise on the GPCR/cAMP/PKA signaling pathway and complement-microglia axis. Results: Our findings reveal that a 12-week aerobic exercise intervention significantly enhanced spatial learning and memory function in APP/PS1 mice. Moreover, it led to a substantial increase in dendritic spine density and elevated expression of postsynaptic density protein 95 (PSD-95) in the cortex and hippocampus. Aerobic exercise demonstrated the ability to improve the expression of certain genes and enhance synaptic pathways in the brains of APP/PS1 mice. This suggests that aerobic exercise facilitates synaptic growth in APP/PS1 mice by modulating G protein-coupled receptors (GPCRs) and activating the cAMP signaling pathway, with significant alterations observed in the expressions of Hcar1 and Vipr2 genes. Furthermore, exercise intervention resulted in the significant down-regulation (P &lt; 0.05 or P &lt; 0.01) of cAMP, p-PKA/PKA, GluA1, and CaMKII protein expressions in the brain tissue of APP/PS1 mice, which were subsequently up-regulated after exercise (P &lt; 0.01). Notably, regular aerobic exercise effectively suppressed the activation of IBA-1+ microglia cells (P &lt; 0.01), reversed changes in M1 phenotype markers (Cd86 and iNOS) and M2 phenotype markers (Arg-1) of microglia cells (P &lt; 0.05), reduced the production of promoters C1q and central factor C3 in the macrosomatic cascade (P &lt; 0.05), and prevented the colocalization of microglia and PSD-95 (P &lt; 0.01). Conclusion: In conclusion, our results indicate that physical exercise plays a pivotal role in fostering early synaptic growth and averting synaptic loss in Alzheimer's disease (AD). This effect may be attributed to the regulation of the G protein-coupled receptors (GPCRs)/cAMP/PKA signaling pathway and the suppression of complement-mediated microglial phagocytosis of synapses. This mechanistic insight underscores the inherent contribution of exercise to health promotion, offering potential avenues for synaptic-focused interventions in the early stages of AD treatment.

Prognostic Value and Clinical Significance of Vesicular Transport-Related Genes in Clear Cell Renal Cell Carcinoma

Introduction: Vesicular transport (VT) has a complex relationship with tumor progression and immunity. But prognostic significance of VT in clear cell renal cell carcinoma (ccRCC) is unclear. Thus, we aimed to establish a prognostic model according to VT to predict overall survival of ccRCC patients. Methods: We used patient data from TCGA database and built a prognostic model with 13 VT-related genes (VTRGs) by differential expression analysis, LASSO regression, and univariate/multivariate Cox analysis. The model was validated internally and externally, and survival analysis and ROC curves depicted excellent predictive ability. Furthermore, higher modeled riskscores corresponded to more advanced tumor progression. To further understand the potential reasons for different prognoses in patients, we did enrichment analysis on differentially expressed genes identified by the model in risk groups. The expression levels and roles of SAA1 and KIF18B in ccRCC were verified by qRT-PCR and cell function experiments. Results: Humoral immune response and cAMP signaling pathway may be the biological processes and pathways leading to poor prognosis. Further analysis of immune microenvironment presented that ccRCC patients with poor prognoses had highly immune-infiltrated characteristics. We compared the drug response data of samples from different prognostic patients in the GDSC database and identified drug sensitivity differences associated with prognosis. Finally, we demonstrated that SAA1 and KIF18B could increase the proliferation, migration, and invasion ability of ccRCC cells using cellular experiments. Conclusion: In summary, we further revealed the importance of VTRGs in ccRCC prognosis.

Metabolomic insight into regulatory mechanism of heterotrophic bacteria nitrification-aerobic denitrification bacteria to high-strength ammonium wastewater treatment

This work aimed to elucidate the metabolic mechanism of heterotrophic nitrification-aerobic denitrification (HN-AD) bacteria influenced by varying concentrations of ammonium nitrogen (NH4+-N) in high-strength synthetic wastewater treatment. The results showed that the removal rates of NH4+-N and total nitrogen, along with enzymatic activities related to nitrification and denitrification, increased with rising NH4+-N concentrations (N500:500 mg/L, N1000:1000 mg/L and N2000:2000 mg/L). The relative abundances of HN-AD bacteria were 50 %, 62 % and 82 % in the three groups. In the N2000 group, the cAMP signaling pathway, glycerophospholipid metabolites, purines and pyrimidines related to DNA/RNA synthesis, electron donor NAD+-related energy, the tricarboxylic acid (TCA) cycle and glutamate metabolism were upregulated. Therefore, influent NH4+-N at 2000 mg/L promoted glutamate metabolism to accelerate the TCA cycle, and enhanced cellular energy and advanced denitrification activity of bacteria for HN-AD. This mechanism, in turn, enhanced microbial growth and the carbon and nitrogen metabolism of bacteria for HN-AD.

Structural and pharmacological characterization of a medium-chain fatty acid receptor GPR84 in common carp (Cyprinus carpio)

The medium-chain fatty acid receptor GPR84, a member of the G protein-coupled receptor family, is mainly expressed in macrophages and microglia, and is involved in the regulation of inflammatory responses and retinal development in mammals and amphibians. However, structure, tissue distribution, and pharmacology of this receptor have rarely been reported in fish. In this study, we cloned the coding sequence (CDS) of common carp GPR84 (ccGPR84), examined its tissue distribution, and explored its cellular signaling function. The results showed that the CDS of ccGPR84 is 1191 bp and encodes a putative protein with 396 amino acids. Phylogenetic and chromosomal synteny analyses revealed that ccGPR84 was evolutionarily conserved with Cyprinids. Real-time quantitative PCR (qPCR) indicated that ccGPR84 was predominantly expressed in the intestine and spleen. Luciferase reporter assay demonstrated that nonanoic acid, capric acid (decanoic acid), undecanoic acid and lauric acid could inhibit cAMP signaling pathway and activate MAPK/ERK signaling pathway, while the potencies of these four fatty acids on the two signaling pathways were different. Lauric acid has the highest inhibitory potency on cAMP signaling pathway, followed by undecanoic acid, nonanoic acid, and capric acid. While for MAPK/ERK signaling pathway, nonanoic acid has the highest activation potency, followed by undecanoic acid, capric acid, and lauric acid. These findings lay the foundation for revealing the roles of different medium-chain fatty acids in the inflammatory response of common carp.

Identification of the Hub Genes Linked to Lead (IV)-Induced Spleen Toxicity Using the Rat Model.

Exposure to lead (Pb) has harmful effects on the organs of both humans and animals, particularly the spleen. However, the precise mechanisms through which Pb (IV) exposure leads to spleen toxicity remain unclear. Hence, this study aimed to identify the key genes and signaling pathways involved in spleen toxicity caused by Pb (IV) incubation. We obtained the dataset GSE59925 from the Gene Expression Omnibus, which included spleen samples treated with lead tetraacetate (PbAc4) as well as control samples on the 1st and 5th day. Through differential expression analysis, we identified 607 and 704 differentially expressed genes (DEGs) in the spleens on the 1st and 5th day following PbAc4 treatment, respectively, with 245 overlapping DEGs between the two time points. Gene ontology analysis revealed that the commonly shared DEGs were primarily involved in signal transduction, drug response, cell proliferation, adhesion, and migration. Pathway analysis indicated that the common DEGs were primarily associated with MAPK, TNF, cAMP, Hippo, and TGF-β signaling pathways. Furthermore, we identified the hub genes such as CXCL10, PARP1, APOE, and VDR contributing to PbAc4-induced spleen toxicity. This study enhances our understanding of the molecular mechanisms underlying Pb (IV) toxicity in the spleen.