Search

Chronic kidney disease (CKD) is characterized by a steady decline in kidney function and affects roughly 10% of the world's population. This review focuses on the critical function of cyclic adenosine monophosphate (cAMP) signaling in CKD, specifically how it influences both protective and pathogenic processes in the kidney. cAMP, a critical secondary messenger, controls a variety of cellular functions, including transcription, metabolism, mitochondrial homeostasis, cell proliferation, and apoptosis. Its compartmentalization inside cellular microdomains ensures accurate signaling. In kidney physiology, cAMP is required for hormone-regulated activities, particularly in the collecting duct, where it promotes water reabsorption through vasopressin signaling. Several illnesses, including Fabry disease, renal cell carcinoma, nephrogenic diabetes insipidus, Bartter syndrome, Liddle syndrome, diabetic nephropathy, autosomal dominant polycystic kidney disease, and renal tubular acidosis, have been linked to dysfunction in the cAMP system. Both cAMP analogs and phosphodiesterase inhibitors have the potential to improve kidney function and reduce kidney damage. Future research should focus on developing targeted PDE inhibitors for the treatment of CKD. [ABSTRACT FROM AUTHOR]

Two new binuclear tetranitrosyl iron complexes of the composition [Fe2L2(NO)4] (1, L = 4-methoxybenzenemethanethiolyl; 2, L = 4-chlorobenzenemethanethiolyl) were synthesized. Their crystals were characterized by X-ray diffraction, by IR, ESR, UV, and Mössbauer spectroscopies, and by elemental analysis. The NO-donating properties and transformations of the complexes in physiological solutions, including reactions in the presence of bovine serum albumin, were studied. The cytotoxicity of compounds 1 and 2 was studied on normal Vero cells. The effect of the complexes on enzymes was investigated taking guanylate cyclase and adenylate cyclase as examples. The results obtained allow one to recommend compound 2 for further investigations as a potential drug with vaso- and bronchodilator properties. [ABSTRACT FROM AUTHOR]

Key message: cAMP modulates the phosphorylation status of highly conserved phosphosites in RNA-binding proteins crucial for mRNA metabolism and reprogramming in response to heat stress. In plants, 3′,5′-cyclic adenosine monophosphate (3′,5′-cAMP) is a second messenger that modulates multiple cellular targets, thereby participating in plant developmental and adaptive processes. Although its role in ameliorating heat-related damage has been demonstrated, mechanisms that govern cAMP-dependent responses to heat have remained elusive. Here we analyze the role cAMP–dependent phosphorylation during prolonged heat stress (HS) with a view to gain insight into processes that govern plant responses to HS. To do so, we performed quantitative phosphoproteomic analyses in Nicotiana tabacum Bright Yellow-2 cells grown at 27 °C or 35 °C for 3 days overexpressing a molecular “sponge” that reduces free intracellular cAMP levels. Our phosphorylation data and analyses reveal that the presence of cAMP is an essential factor that governs specific protein phosphorylation events that occur during prolonged HS in BY-2 cells. Notably, cAMP modulates HS-dependent phosphorylation of proteins that functions in mRNA processing, transcriptional control, vesicular trafficking, and cell cycle regulation and this is indicative for a systemic role of the messenger. In particular, changes of cAMP levels affect the phosphorylation status of highly conserved phosphosites in 19 RNA-binding proteins that are crucial during the reprogramming of the mRNA metabolism in response to HS. Furthermore, phosphorylation site motifs and molecular docking suggest that some proteins, including kinases and phosphatases, are conceivably able to directly interact with cAMP thus further supporting a regulatory role of cAMP in plant HS responses. [ABSTRACT FROM AUTHOR]

Recent studies using different experimental approaches demonstrate that silent synapses may exist in the adult cortex including the sensory cortex and anterior cingulate cortex (ACC). The postsynaptic form of long-term potentiation (LTP) in the ACC recruits some of these silent synapses and the activity of calcium-stimulated adenylyl cyclases (ACs) is required for such recruitment. It is unknown if the chemical activation of ACs may recruit silent synapses. In this study, we found that activation of ACs contributed to synaptic potentiation in the ACC of adult mice. Forskolin, a selective activator of ACs, recruited silent responses in the ACC of adult mice. The recruitment was long-lasting. Interestingly, the effect of forskolin was not universal, some silent synapses did not undergo potentiation or recruitment. These findings suggest that these adult cortical synapses are not homogenous. The application of a selective calcium-permeable AMPA receptor inhibitor 1-naphthyl acetyl spermine (NASPM) reversed the potentiation and the recruitment of silent responses, indicating that the AMPA receptor is required. Our results strongly suggest that the AC-dependent postsynaptic AMPA receptor contributes to the recruitment of silent responses at cortical LTP. [ABSTRACT FROM AUTHOR]

Objective To investigate the expression, distribution, and activity of thyroid-stimulating hormone receptor (TSHR) in human microglia (HMC3). Methods In this study, we used human microglial cells (HMC3) as the experimental group and human thyroid cells and hepatocytes as the controls. Reverse transcription polymerase chain reaction was used to detect the expression of TSHR mRNA to identify the transcript of TSHR mRNA. Western blotting and immunofluorescence staining analysis was used to detect TSHR protein level and the distribution in HMC3 cells. HMC3 cells were divided into the 0, 20, 50, 100, 200 ng/mL thyroid-stimulating hormone receptor-stimulating antibody (TSAb) groups and negative control group. Each group was preincubated with 100 µmol/L phosphodiesterase inhibitor (IBMX) for 60 minutes. The corresponding concentrations of TSAb were added to cells of the TSAb groups and then they were incubated for 24 h. We measured cyclic adenosine monophosphate (cAMP) levels by immu noassay kits to verify the functional activity of TSHR in HMC3 cells. Results TSHR mRNA was detected in HMC3 cells with the same sequence as mRNAs derived from human thyroid cells and hepatocytes. TSHR protein was expressed in the cell membrane of HMC3 cells. Compared with the 0 ng/mL TSAb group, there was no significant statistical difference in cAMP levels in the 20 ng/mL TSAb group. However, cAMP levels increased in the 50, 100, and 200 ng/mL TSAb groups, and the high-concentration group had higher cAMP levels than the low-concentration group (P<0.05 or P<0.01). Conclusion TSHR is expressed in the cell membrane of human microglia and has a signaling function. [ABSTRACT FROM AUTHOR]

Phosphodiesterases (PDEs), a superfamily of enzymes that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), are recognized as a therapeutic target for various diseases. However, the current screening methods for PDE inhibitors usually experience problems due to complex operations and/or high costs, which are not conducive to drug development in respect of this target. In this study, a new method for screening PDE inhibitors based on GloSensor technology was successfully established and applied, resulting in the discovery of several novel compounds of different structural types with PDE inhibitory activity. Compared with traditional screening methods, this method is low-cost, capable of dynamically detecting changes in substrate concentration in live cells, and can be used to preliminarily determine the type of PDEs affected by the detected active compounds, making it more suitable for high-throughput screening for PDE inhibitors. [ABSTRACT FROM AUTHOR]

Cyclic adenosine monophosphate (cAMP) is an important second messenger in cells, mediating various stimulation signals such as the growth and development of organisms and stress and participating in regulating various biological processes of cells. This article explores the quantitative determination of cAMP in plants using High-Performance Liquid Chromatography (HPLC) and applies this method to analyzing the changes in cAMP content during the process of plant response to the bacterial quorum sensing signal N-acyl homoserine lactone (AHL). Research has shown that the optimal detection conditions for HPLC are as follows: the chromatographic column is Venusil MP C18 (2), the mobile phase is methanol–water (0.1% trifluoroacetic acid) (v:v, 10:90), the detection wavelength is 259 nm, the column temperature is 35 °C, and the flow rate is 0.8 mL/min. The precision of the standard sample of this method is 98.21%, the precision of the sample is 98.87%, and the recovery rate is 101.067%. The optimal extraction conditions for cAMP in Arabidopsis are to use 15% methanol ultrasonic extraction for 10 min, followed by a 40 °C water bath for 4 h. Bacterial AHL signal processing can significantly stimulate an increase in cAMP levels in Arabidopsis leaves and roots. The establishment of HPLC detection methods for the cAMP content in plants is of great significance for in-depth research on the signal transduction mechanisms of plant–bacterial interactions. [ABSTRACT FROM AUTHOR]

Copyright of Modern Food Science & Technology is the property of Editorial Office of Modern Food Science & Technology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Chronic kidney disease (CKD) is characterized by a steady decline in kidney function and affects roughly 10% of the world’s population. This review focuses on the critical function of cyclic adenosine monophosphate (cAMP) signaling in CKD, specifically how it influences both protective and pathogenic processes in the kidney. cAMP, a critical secondary messenger, controls a variety of cellular functions, including transcription, metabolism, mitochondrial homeostasis, cell proliferation, and apoptosis. Its compartmentalization inside cellular microdomains ensures accurate signaling. In kidney physiology, cAMP is required for hormone-regulated activities, particularly in the collecting duct, where it promotes water reabsorption through vasopressin signaling. Several illnesses, including Fabry disease, renal cell carcinoma, nephrogenic diabetes insipidus, Bartter syndrome, Liddle syndrome, diabetic nephropathy, autosomal dominant polycystic kidney disease, and renal tubular acidosis, have been linked to dysfunction in the cAMP system. Both cAMP analogs and phosphodiesterase inhibitors have the potential to improve kidney function and reduce kidney damage. Future research should focus on developing targeted PDE inhibitors for the treatment of CKD.

Copyright of Food & Fermentation Industries is the property of Food & Fermentation Industries and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Although 17β-estradiol (E2) and its receptors (ERs) are reported to play important roles in regulating oocyte maturation, the specific mechanism remains unclear. First, we performed immunohistochemistry analyses to determine the expression of the ERα and ERβ proteins in ovine ovarian tissue. Second, E2 (0.5 ng/mL and 1 μg/mL) were added to pre-IVM medium for 0 h, 1 h and 2 h. The effects of E2 (0.5 ng/mL and 1 μg/mL) on cyclic adenosine monophosphate (cAMP) level in cumulus-oocyte complexes (COCs) and on oocyte meiotic progression were evaluated by ELISA and DAPI staining respectively. Third, the effects of E2 on the gene and protein expression of ERα and ERβ in COCs were investigated by Western blotting and real-time PCR. Afterward, ERβ and cAMP regulators were added to the 2-h pretreatment medium with or without E2 (0.5 ng/mL) to explore the possible interactions among E2, cAMP and ERβ. The results showed that both ERα and ERβ proteins were expressed in ovine cumulus layers and oocytes. E2 significantly increased intra-COC cAMP levels, maintained oocyte meiotic arrest, and promoted ERβ transcript and protein expression. E2 treatment increased the cAMP concentration, which was enhanced by ERβ agonist treatment and remarkably attenuated by ERβ inhibitor treatment. Forskolin plus IBMX treatment increased ERβ protein expression in COCs (P < 0.05), and this was attenuated by Rp-cAMP treatment. In conclusion, E2 (0.5 ng/mL) increased intra-COC cAMP levels by promoting ERβ expression, thereby maintaining oocyte meiotic arrest. cAMP in COCs has a positive feedback effect on ERβ expression, which provides a novel explanation for the positive role of E2 in regulating ovine follicle development and oocyte maturation. [Display omitted] • 0.5 ng/mL E2 promote ovine ERβ expression. • 0.5 ng/mL E2 increase intra-COC cAMP concentration and maintain oocyte meiotic arrest. • The cAMP in COCs have a positive feedback effect on the production of ERβ [ABSTRACT FROM AUTHOR]

AIM: To observe the effect of acupuncture on adenosine A1 receptor （A1R） in the caudate putamen （CPu） of complete Freund's adjuvant （CFA） rats, and to explore the potential mechanism of acupuncture in treatment of inflammatory pain. METHODS: Sixty-four 6~8-week-old male Wistar rats were randomly divided into saline group, model group （CFA group）, CFA+manual acupuncture （MA） group, CFA+solvent dimethyl sulfoxide （DMSO） group, CFA+A1R agonist 2-chloro-N6-cyclopentyladenosine （CCPA） group, CFA+A1R antagonist 8-cyclopentyl-1, 3-dipropylxanthine（ DPCPX） group, CFA+MA+DMSO group and CFA+MA+DPCPX group. In MA groups, on the 2nd day after modeling, the rats were needled at Zusanli points on both sides, 30 min at a time, once per day, for 7 d. Pain threshold of plantar thermal radiation was used to observe the pain response of the rats. The content of cyclic adenosine monophosphate （cAMP） in the CPu was detected by ELISA. The protein expression and phosphorylation levels of protein kinase A （PKA） and cAMP response element-binding protein （CREB） were detected by Western blot. The expression of A1R in the CPu was detected by immunofluorescence staining. RESULTS: Compared with saline group, CFA modeling significantly lowered the thermal pain threshold of the rats （P<0. 01）. Compared with CFA group, the thermal pain threshold of the rats in CFA+MA group and CFA+CCPA group was significantly increased （P<0. 05 or P<0. 01）. Compared with CFA+ MA+DMSO group, the thermal pain threshold of the rats in CFA+MA+DPCPX group was decreased （P<0. 05）. Compared with CFA group, A1R protein relative expression level and positive cells in the CPu of the rats in CFA+MA group were increased （P<0. 05 or P<0. 01）. Compared with saline group, cAMP content and p-CREB protein level in the CPu of the rats in CFA+MA group were decreased （P<0. 05）. Compared with CFA+DMSO group, cAMP content and p-CREB protein level in CFA+MA+DMSO and CFA+CCPA groups were significantly decreased （P<0. 01）. Compared with CFA+MA+ DMSO group, the levels of cAMP, p-PKA and p-CREB in CFA+MA+DPCPX group were significantly increased （P<0. 05 or P<0. 01）. CONCLUSION: Acupuncture on bilateral Zusanli can relieve inflammatory pain in CFA rats, and its mechanism may be related to A1R/cAMP/p-CREB signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Myocardial necrosis is one of the most common cardiac and pathological diseases. Unfortunately, using the available medical treatment is not sufficient to rescue the myocardium. So that, we aimed in our model to study the possible cardioprotective effect of roflumilast (ROF) in an experimental model of induced myocardial injury using a toxic dose of isoprenaline (ISO) and detecting the role of vascular endothelial growth factor/endothelial nitric oxide synthase (VEGF/eNOS) and cyclic guanosine monophosphate/cyclic adenosine monophosphate/sirtuin1 (cGMP/cAMP/SIRT1) signaling cascade. Materials and Methods: Animals were divided into five groups; control, ISO given group (150 mg/kg) i.p. on the 4th and 5th day, 3 ROF co-administered groups in different doses (0.25, 0.5, 1 mg/kg/day) for 5 days. Results: Our data revealed that ISO could induce cardiac toxicity as manifested by significant increases in troponin I, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), malondialdehyde (MDA), tumor necrosis factor alpha (TNFa), and cleaved caspase-3 with toxic histopathological changes. Meanwhile, there were significant decreases in reduced glutathione (GSH), total antioxidant capacity (TAC), VEGF, eNOS, cGMP, cAMP and SIRT1. However, co-administration of ROF showed significant improvement and normalization of ISO induced cardiac damage. Conclusion: We concluded that ROF successfully reduced ISO induced myocardial injury and this could be attributed to modulation of PDE4, VEGF/eNOS and cGMP/cAMP/SIRT1 signaling pathways with antioxidant, anti-inflammatory, and anti-apoptotic properties. [ABSTRACT FROM AUTHOR]

Introduction: The cyclic nucleotide cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger, which is known to play an important anti-inflammatory role. Astrocytes in the central nervous system (CNS) can modulate inflammation but little is known about the significance of cAMP in their function. Methods: We investigated cAMP dynamics in mouse olfactory bulb astrocytes in brain slices prepared from healthy and experimental autoimmune encephalomyelitis (EAE) mice. Results: The purinergic receptor ligands adenosine and adenosine triphosphate (ATP) both induced transient increases in cAMP in astrocytes expressing the genetically encoded cAMP sensor Flamindo2. The A2A receptor antagonist ZM241385 inhibited the responses. Similar transient increases in astrocytic cAMP occurred when olfactory receptor neurons were stimulated electrically, resulting in ATP release from the stimulated axons that increased cAMP, again via A2A receptors. Notably, A2A-mediated responses to ATP and adenosine were not different in EAE mice as compared to healthy mice. Discussion: Our results indicate that ATP, synaptically released by afferent axons in the olfactory bulb, is degraded to adenosine that acts on A2A receptors in astrocytes, thereby increasing the cytosolic cAMP concentration. However, this pathway is not altered in the olfactory bulb of EAE mice. [ABSTRACT FROM AUTHOR]

Caveolae are tiny invaginations in the sarcolemma that buffer extra membrane and contribute to mechanical regulation of cellular function. While the role of caveolae in membrane mechanosensation has been studied predominantly in non-cardiomyocyte cells, caveolae contribution to cardiac mechanotransduction remains elusive. Here, we studied the role of caveolae in the regulation of Ca2+ signaling in atrial cardiomyocytes. In Langendorff-perfused mouse hearts, atrial pressure/volume overload stretched atrial myocytes and decreased caveolae density. In isolated cells, caveolae were disrupted through hypotonic challenge that induced a temporal (<10 min) augmentation of Ca2+ transients and caused a rise in Ca2+ spark activity. Similar changes in Ca2+ signaling were observed after chemical (methyl-β-cyclodextrin) and genetic ablation of caveolae in cardiac-specific conditional caveolin-3 knock-out mice. Acute disruption of caveolae, both mechanical and chemical, led to the elevation of cAMP level in the cell interior, and cAMP-mediated augmentation of protein kinase A (PKA)-phosphorylated ryanodine receptors (at Ser2030 and Ser2808). Caveolae-mediated stimulatory effects on Ca2+ signaling were abolished via inhibition of cAMP production by adenyl cyclase antagonists MDL12330 and SQ22536, or reduction of PKA activity by H-89. A compartmentalized mathematical model of mouse atrial myocytes linked the observed changes to a microdomain-specific decrease in phosphodiesterase activity, which disrupted cAMP signaling and augmented PKA activity. Our findings add a new dimension to cardiac mechanobiology and highlight caveolae-associated cAMP/PKA-mediated phosphorylation of Ca2+ handling proteins as a novel component of mechano-chemical feedback in atrial myocytes. [Display omitted] • Caveolae are an important but poorly understood component of membrane mechanosensing complex in cardiomyocytes. • Stretching of atrial myocytes flattens caveolae and increases membrane tension. • Caveolae disruption results in augmented Ca2+ signaling via cAMP-mediated increase in PKA-phosphorylated ryanodine receptors. • Computational modeling linked observed changes in Ca2+ signaling to a loss of caveolae-confined control of phosphodiesterases. • Caveolae-associated changes in Ca2+ signaling is a novel part of mechano-chemical feedback in atrial myocytes. [ABSTRACT FROM AUTHOR]

Gap junction channels in cumulus–oocyte complexes (COCs) enable the transmission and communication of small molecular signals between adjacent cells, such as cAMP. However, the regulation of gap junction function (GJF) by cAMP and the underlying mechanisms involved are not fully clarified. This study investigated the effect of cAMP on connexin 43 (CX43) expression and GJF in ovine COCs using immunofluorescence , quantitative real-time PCR (qRT-PCR), western blotting, and GJF detection. The CX 43 was only found in the cumulus cells (CCs) side of ovine COC. The intra-oocyte cAMP sh owed a significant increase at 30 min, while the intra-CC cAMP exhibited two peaks at 10 min and 1 h during in vitro maturation (IVM). Phosphorylated CX43 protein exhibited an immediate increase at 10 min, and CX43 protein displayed two peaks at 10 min and 1 h during IVM. The duration of pre- IVM exposure to forskolin and IBMX significantly enhanced phosphorylated and total CX43, as well as Gja1 and Creb genes, for 10 min; these effects were counteracted by Rp-cAMP. Both pre-IVM with forskolin and IBMX for 1 h and the GJF and CX43/p-CX43 ratio were elevated. The closure of gap junction channels caused by phosphorylated CX43 to prevent cAMP outflow from oocytes in early IVM of COC. Cyclic AMP upregulated phosphorylated and total CX43 via genomic and non-genomic pathways, but its functional regulation was dependent on the balance of the two proteins. This study provides a new insight into the regulatory mechanism between cAMP and GJF, which would improve IVM in animal and clinical research.

Phosphodiesterases (PDEs), a superfamily of enzymes that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), are recognized as a therapeutic target for various diseases. However, the current screening methods for PDE inhibitors usually experience problems due to complex operations and/or high costs, which are not conducive to drug development in respect of this target. In this study, a new method for screening PDE inhibitors based on GloSensor technology was successfully established and applied, resulting in the discovery of several novel compounds of different structural types with PDE inhibitory activity. Compared with traditional screening methods, this method is low-cost, capable of dynamically detecting changes in substrate concentration in live cells, and can be used to preliminarily determine the type of PDEs affected by the detected active compounds, making it more suitable for high-throughput screening for PDE inhibitors.

Jujube contains abundant cyclic adenosine monophosphate (cAMP) and the ultrasonic-assisted pectinase extraction (UAPE) conditions for obtaining the maximum cAMP yield from jujube were optimized. Orthogonal array design was applied to evaluate the effects of 4 variables by UAPE on cAMP yield. The results showed that the optimal cAMP yield (783.0 μg/g) was derived at ratio of liquid to solid 5 mL/g, ratio of pectinase to raw material 1.5 %, time 60 min and temperature 40 °C. Moreover, the effect of cAMP on the anti-allergic function of action induced by immunoglobulin E (IgE) and its meschanism was investigated through establishing the sensitized cell model in rat basophilic leukemia (RBL-2H3) cells using dinitrophenylated (DNP)-bovine serum albumin (BSA)-IgE. The results showed that cAMP interfered with sensitized cells, effectively inhibited the occurrence of basophil degranulation in dose dependence, and significantly reduced the activity of β-hexosamindase (β-hex), at the optimal concentration of 50 μg/mL. The level of anti-inflammatory factor interleukin-10 (IL-10) was promoted and the content of pro-inflammatory factor tumor necrosis factor-α (TNF-α) was suppressed by cAMP. In addition, influx of intracellular Ca2+ was repressed effectively. Our results demonstrate that jujube cAMP regulated the cytokine balance in the allergy pathway through blocking the influx of extracellular Ca2+, with the prevention of allergy symptoms.

IntroductionThe cyclic nucleotide cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger, which is known to play an important anti-inflammatory role. Astrocytes in the central nervous system (CNS) can modulate inflammation but little is known about the significance of cAMP in their function.MethodsWe investigated cAMP dynamics in mouse olfactory bulb astrocytes in brain slices prepared from healthy and experimental autoimmune encephalomyelitis (EAE) mice.ResultsThe purinergic receptor ligands adenosine and adenosine triphosphate (ATP) both induced transient increases in cAMP in astrocytes expressing the genetically encoded cAMP sensor Flamindo2. The A2A receptor antagonist ZM241385 inhibited the responses. Similar transient increases in astrocytic cAMP occurred when olfactory receptor neurons were stimulated electrically, resulting in ATP release from the stimulated axons that increased cAMP, again via A2A receptors. Notably, A2A-mediated responses to ATP and adenosine were not different in EAE mice as compared to healthy mice.DiscussionOur results indicate that ATP, synaptically released by afferent axons in the olfactory bulb, is degraded to adenosine that acts on A2A receptors in astrocytes, thereby increasing the cytosolic cAMP concentration. However, this pathway is not altered in the olfactory bulb of EAE mice.

Abstract The vitamin D receptor (VDR) gene serves as a good candidate gene for susceptibility to essential hypertension. The gene regulates the renin angiotensin system by influencing blood pressure regulation. Around 3% of the human genome is regulated by the vitamin D endocrine system. Several studies have reported mixed results with respect to relationship of VDR gene and hypertension. Observational evidence supports the concept that vitamin D plays a role in the pathogenesis of cardiovascular disease and arterial hypertension which is further supported by meta-analysis and case control studies reporting how VDR polymorphism leads to the onset and development of hypertension. In this review, we summarize the existing literature on the link between VDR and hypertension, including mechanistic studies, observational data, and clinical trials showing relationship of vitamin D level and hypertension with a focus on recent findings related to genetic studies that showed the relationship of VDR gene polymorphism with vitamin D level in hypertensive and normotensive groups. As a result, determining the association of VDR polymorphisms with essential hypertension is expected to aid in the risk assessment for the condition.

Cyclic adenosine monophosphate (cAMP) is an important second messenger in cells, mediating various stimulation signals such as the growth and development of organisms and stress and participating in regulating various biological processes of cells. This article explores the quantitative determination of cAMP in plants using High-Performance Liquid Chromatography (HPLC) and applies this method to analyzing the changes in cAMP content during the process of plant response to the bacterial quorum sensing signal N-acyl homoserine lactone (AHL). Research has shown that the optimal detection conditions for HPLC are as follows: the chromatographic column is Venusil MP C18 (2), the mobile phase is methanol–water (0.1% trifluoroacetic acid) (v:v, 10:90), the detection wavelength is 259 nm, the column temperature is 35 °C, and the flow rate is 0.8 mL/min. The precision of the standard sample of this method is 98.21%, the precision of the sample is 98.87%, and the recovery rate is 101.067%. The optimal extraction conditions for cAMP in Arabidopsis are to use 15% methanol ultrasonic extraction for 10 min, followed by a 40 °C water bath for 4 h. Bacterial AHL signal processing can significantly stimulate an increase in cAMP levels in Arabidopsis leaves and roots. The establishment of HPLC detection methods for the cAMP content in plants is of great significance for in-depth research on the signal transduction mechanisms of plant–bacterial interactions.

Jujube, commonly known as the Chinese date, is a nutritious fruit with medicinal importance. Fresh jujube fruits have a shelf life of about ten days in ambient conditions that can be extended by drying. However, nutrition preservation varies with the drying method and parameters selected. We studied total phenolic content (TPC), proanthocyanidins (PA), vitamin C, cyclic adenosine monophosphate (cAMP), and antioxidant activities in jujube fruits dried with freeze-drying (FD), convective oven drying (OD) at 50 °C, 60 °C, and 75 °C, and sun drying (SD) with FD as a control. The cultivars used for this study were 'Capri' and 'Xiang' from Las Cruces in 2019, and 'Sugarcane', 'Lang', and 'Sherwood' from Las Cruces and Los Lunas, New Mexico, in 2020. Freeze-drying had the highest of all nutrient components tested, the best estimates of mature jujube fruits' nutrient contents. Compared with FD, the majority of PA (96–99%) and vitamin C (90–93%) was lost during SD or OD processes. The retention rates of antioxidant activities: DPPH and FRAP were higher in OD at 50/60 °C than SD. SD retained a higher cAMP level than OD at 50/60 °C in both years. The increase in oven drying temperature from 60 °C to 75 °C significantly decreased TPC, PA, antioxidant activities, and cAMP. [ABSTRACT FROM AUTHOR]

Jujube (Ziziphus jujuba Mill.) is also called Chinese date. There are ∼100 jujube cultivars with limited commercial availability, and the majority of them have scant details in the United States. In this study, nutrient dynamics during fruit maturation of different jujube cultivars grown at Las Cruces, Los Lunas, and Alcalde, NM, were examined in 2018 and 2019. Cultivars varied by location and year, and included ‘Li’, ‘Lang’, ‘Sugarcane’, ‘September Late’, and ‘Sherwood’. Parameters tested were total phenolic content (TPC), proanthocyanidins (PAs), vitamin C, cyclic adenosine monophosphate (cAMP), and antioxidant capacity: 2,2-diphenylpicrylhydrazyl radical scavenging capacity and ferric reducing antioxidant potential (FRAP). Moisture, TPC, PAs, FRAP, and vitamin C content decreased with fruit maturity; however, the latter stage of fruit maturity showed an increase in cAMP. Compared with fruit at full-red maturity, creamy fruit had TPC, PA, FRAP, and vitamin C concentrations that were 1.0 to 1.8, 4.4 to 12.4, 1.9 to 2.6, and 0.1 to 1.3 times higher, respectively, depending on location (P < 0.05). From creamy to full-red maturity, cAMP increased by 0.9 to 4.5 times. At full-red maturity, estimated TPC in jujube fruit ranged from 10.6 to 16.8 mg gallic acid equivalent per gram dry weight (DW), whereas estimated PAs ranged from 1.8 to 5.3 mg PA B2/g DW. Jujube fruit at full-red maturity had a vitamin C content that ranged from 649.0 to 1153.3 mg/100 g DW. At full-red maturity, the concentration of cAMP ranged from 148.1 to 277.6 μg/g DW in Las Cruces samples.

The relationship between psoriasis severity and psychological stress has been described in several studies. However, the mechanism by which chronic stress exacerbates psoriasis is not completely understood. This study aimed at investigating whether chronic psychological stress can aggravate psoriasis‐like skin inflammation. Mice were subjected to a restraint stress model and topically treated with imiquimod (IMQ). Differentiated human keratinocytes were treated with high epinephrine levels and IMQ in vitro. Stress aggravated macroscopic features and the increase in epidermal thickness induced by IMQ in mouse skin. The increase in NF‐κB and IL‐17A expression induced by IMQ was potentiated by chronic stress in mouse skin. The skin of stressed mice treated with IMQ showed higher levels of β2‐adrenergic receptors (β2‐AR). In human keratinocytes, high epinephrine levels exacerbated the increase in the levels of β2‐AR and IL‐17A induced by IMQ. β‐AR antagonist reversed the effects of chronic stress in IMQ‐induced inflammation both in vivo and in vitro. In conclusion, stress‐stimulated overactivation of the β2‐AR and NF‐κB pathways potentiates a Th1/Th17 profile leading to an exacerbation of psoriasis. [ABSTRACT FROM AUTHOR]

Jujube (Ziziphus jujuba Mill.) is also called Chinese date. There are ~100 jujube cultivars with limited commercial availability, and the majority of them have scant details in the United States. In this study, nutrient dynamics during fruit maturation of different jujube cultivars grown at Las Cruces, Los Lunas, and Alcalde, NM, were examined in 2018 and 2019. Cultivars varied by location and year, and included 'Li', 'Lang', 'Sugarcane', 'September Late', and 'Sherwood'. Parameters tested were total phenolic content (TPC), proanthocyanidins (PAs), vitamin C, cyclic adenosine monophosphate (cAMP), and antioxidant capacity: 2,2-diphenylpicrylhydrazyl radical scavenging capacity and ferric reducing antioxidant potential (FRAP). Moisture, TPC, PAs, FRAP, and vitamin C content decreased with fruit maturity; however, the latter stage of fruit maturity showed an increase in cAMP. Compared with fruit at full-red maturity, creamy fruit had TPC, PA, FRAP, and vitamin C concentrations that were 1.0 to 1.8, 4.4 to 12.4, 1.9 to 2.6, and 0.1 to 1.3 times higher, respectively, depending on location (P < 0.05). From creamy to full-red maturity, cAMP increased by 0.9 to 4.5 times. At full-red maturity, estimated TPC in jujube fruit ranged from 10.6 to 16.8 mg gallic acid equivalent per gram dry weight (DW), whereas estimated PAs ranged from 1.8 to 5.3 mg PA B2/g DW. Jujube fruit at full-red maturity had a vitamin C content that ranged from 649.0 to 1153.3 mg/100 g DW. At full-red maturity, the concentration of cAMP ranged from 148.1 to 277.6 µg/g DW in Las Cruces samples. [ABSTRACT FROM AUTHOR]

Using green and highly efficient deep eutectic solvent (DES) as the extraction agent, this study extracted the functional ingredient—cyclic adenosine 3',5'-monophosphate (cAMP) from Xinjiang jujube through ultrasound-assisted technology. The relationships between the molar ratio of deep eutectic solvent, water content of deep eutectic solvent, solid-liquid ratio, ultrasonic time, ultrasonic temperature and extraction amount of cAMP were studied. Through single factor experimentas and response surface optimization experiment, the optimal conditions for cAMP extraction from Xinjiang jujube were as follows: The molar ratio of choline chloride to glycerol was 1:3, the water content of DES system was 44%, the solid-liquid ratio of jujube powder to DES was 1:35 g/mL, the ultrasonic time was 45 min, and the ultrasonic temperature was 45 ℃. At this time, compared with water extraction and alcohol extraction under the same ultrasonic conditions, the highest content of cAMP extracted by deep eutectic solvent was (284.15±0.06) μg/g. Therefore, ultrasonic-assisted deep eutectic solvent extraction of cAMP in Xinjiang jujube was a new, efficient and safe method to obtain a higher extraction amount.

The design of enantiopure stereoisomers of N-2-phenylcyclopropylmethyl-substituted ortho-c oxide-bridged phenylmorphans, the E and Z isomers of an N-cinnamyl moiety, and N-propyl enantiomers were based on combining the most potent oxide-bridged phenylmorphan (the ortho-c isomer) with the most potent N-substituent that we previously found with a 5-(3-hydroxy)phenylmorphan (i.e., N-2-phenylcyclopropyl methyl moieties, N-cinnamyl, and N-propyl substituents). The synthesis of the eight enantiopure N-2-phenylcyclopropylmethyl ortho-c oxide-bridged phenylmorphans and six additional enantiomers of the N-substituted ortho-c oxide-bridged phenylmorphans (N-E and Z-cinnamyl compounds, and N-propyl compounds) was accomplished. The synthesis started from common intermediates (3R,6aS,11aS)-10-methoxy-1,3,4,5,6,11a-hexahydro-2H-3,6a-methano-benzofuro[2,3-c]azocine (+)-6 and its enantiomer, (3S, 6aR, 11aR)-(-)-6, respectively. The enantiomers of ±-6 were obtained through salt formation with (S)-(+)- and (R)-(-)-p-methylmandelic acid, and the absolute configuration of the (R)-(-)-p-methylmandelate salt of (3S, 6aR, 11aR)-(-)-6 was determined by single-crystal X-ray analysis. The enantiomeric secondary amines were reacted with N-(2-phenylcyclopropyl)methyl derivatives, 2-(E)-cinnamyl bromide, and (Z)-3-phenylacrylic acid. These products led to all of the desired N-derivatives of the ortho-c oxide-bridged phenylmorphans. Their opioid receptor binding affinity was measured. The compounds with MOR affinity < 50 nM were examined for their functional activity in the forskolin-induced cAMP accumulation assay. Only the enantiomer of the N-phenethyl ortho-c oxide-bridged phenylmorphan ((-)-1), and only the (3S,6aR,11aR)-2-(((1S,2S)-2-phenylcyclopropyl)methyl)-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol isomer ((+)-17), and the N-phenylpropyl derivative ((-)-25) had opioid binding affinity < 50 nM. Both (-)-1 and (-)-25 were partial agonists in the cAMP assay, with the former showing high potency and low efficacy, and the latter with lower potency and less efficacy. Most interesting was the N-2-phenylcyclopropylmethyl (3S,6aR,11aR)-2-(1S,2S)-enantiomer ((+)-17). That compound had good MOR binding affinity (Ki = 11.9 nM) and was found to have naltrexone-like potency as a MOR antagonist (IC50 = 6.92 nM). [ABSTRACT FROM AUTHOR]

Parasympathetic nerve-mediated contractions of detrusor smooth muscle are generated by ATP and acetylcholine (ACh) release from efferent nerve terminals. In humans, ACh is responsible for detrusor contractions in normal human bladders, whereas ATP has an additional role in overactive bladder pathologies. The ATP metabolite, adenosine, relaxes nerve-mediated contractions, with a potential action via presynaptic adenosine A1 receptor activation and subsequent suppression of neuronal ATP release. We investigated the effect of A1 receptor activation and downstream cAMP-dependent pathways on nervemediated ATP and ACh release, and detrusor contraction in mouse detrusor. Bladders from male C57BL/6 mice (12 wk) were used for in vitro experiments. Upon electrical field stimulation of intact preparations (detrusor and mucosal layers), ATP or ACh release was measured simultaneously with tension recordings. Activation of A1 receptors by adenosine or exogenous agonists reduced the lower frequency component of nerve-mediated contractions and neuronal ATP release. The A1 receptor antagonist abolished these effects. A1 receptor activation inhibits adenylyl cyclase (AC) activity and cAMP generation. The effect of A1 receptor activation was mimicked by a PKA antagonist but not by modulators of exchange proteins activated by cAMP, demonstrating that modulation of nerve-mediated ATP release is via PKA. Adenosine had no effect on ACh release or the higher frequency component of nerve-mediated contractions. Differential regulation of neurotransmitter release is possible at the detrusor nerve-muscle junction, as demonstrated by A1 receptor activation, and downstream inhibition of AC, cAMP generation, and PKA. The ability to specifically attenuate ATP release offers a potential to target purinergic motor pathways enhanced in overactive bladder pathologies. [ABSTRACT FROM AUTHOR]

Neurodegenerative illness develops as a result of genetic defects that cause changes at numerous levels, including genomic products and biological processes. It entails the degradation of cyclic nucleotides, cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP). PDE7 modulates intracellular cAMP signalling, which is involved in numerous essential physiological and pathological processes. For the therapy of neurodegenerative illnesses, the normalization of cyclic nucleotide signalling through PDE inhibition remains intriguing. In this article, we shall examine the role of PDEs in neurodegenerative diseases. Alzheimer's disease, Multiple sclerosis, Huntington's disease, Parkinson's disease, Stroke, and Epilepsy are related to alterations in PDE7 expression in the brain. Earlier, animal models of neurological illnesses including Alzheimer's disease, Parkinson's disease, and multiple sclerosis have had significant results to PDE7 inhibitors, i.e., VP3.15; VP1.14. In addition, modulation of CAMP/CREB/GSK/PKA signalling pathways involving PDE7 in neurodegenerative diseases has been addressed. To understand the etiology, treatment options of these disorders mediated by PDE7 and its subtypes can be the focus of future research. [ABSTRACT FROM AUTHOR]

Human infertility, of both male and female origin, is often caused by the deficient response of the testis and the ovary to hormonal stimuli that govern sperm and oocyte development and fertilization. The effects of hormones and other extracellular ligands involved in these events are often mediated by G-protein-coupled receptors that employ cyclic adenosine monophosphate (cAMP) as the principal second messenger transducing the receptor-generated signal to downstream elements. This opinion article summarizes the actions of cAMP in sperm and oocyte development and fertilization, leading to therapeutic actions targeting cAMP metabolism to alleviate human male and female infertility. [ABSTRACT FROM AUTHOR]

Axons in the peripheral nervous system have the ability to repair themselves after damage, whereas axons in the central nervous system are unable to do so. A common and important characteristic of damage to the spinal cord, brain, and peripheral nerves is the disruption of axonal regrowth. Interestingly, intrinsic growth factors play a significant role in the axonal regeneration of injured nerves. Various factors such as proteomic profile, microtubule stability, ribosomal location, and signalling pathways mark a line between the central and peripheral axons' capacity for self-renewal. Unfortunately, glial scar development, myelin-associated inhibitor molecules, lack of neurotrophic factors, and inflammatory reactions are among the factors that restrict axonal regeneration. Molecular pathways such as cAMP, MAPK, JAK/STAT, ATF3/CREB, BMP/SMAD, AKT/mTORC1/p70S6K, PI3K/AKT, GSK-3β/CLASP, BDNF/Trk, Ras/ERK, integrin/FAK, RhoA/ROCK/LIMK, and POSTN/integrin are activated after nerve injury and are considered significant players in axonal regeneration. In addition to the aforementioned pathways, growth factors, microRNAs, and astrocytes are also commendable participants in regeneration. In this review, we discuss the detailed mechanism of each pathway along with key players that can be potentially valuable targets to help achieve quick axonal healing. We also identify the prospective targets that could help close knowledge gaps in the molecular pathways underlying regeneration and shed light on the creation of more powerful strategies to encourage axonal regeneration after nervous system injury. [ABSTRACT FROM AUTHOR]

Cyclic AMP (cAMP) is an important second messenger in virtually all animal cell types, including astrocytes. In the brain, it modulates energy metabolism, development and synaptic plasticity. Dopamine receptors are G protein-coupled receptors that affect cAMP production by adenylyl cyclases. They are divided into two subgroups, D1-like receptors linked to G s proteins stimulating cAMP production and D2-like receptors linked to G i/o proteins inhibiting cAMP production. In the present study, we investigated the effect of dopamine receptor activation on cAMP dynamics in astrocytes of the mouse olfactory bulb, the brain region with the largest population of dopaminergic neurons. Using the genetically encoded cAMP sensor Flamindo2 we visualized changes in the cytosolic cAMP concentration and showed that dopamine application results in a transient increase in cAMP. This cAMP increase could be mimicked by the D1-like receptor agonist A 68930 and was inhibited by the D1-like receptor antagonist SCH 23390, whereas D2-like receptor ligands had no effect on the astrocytic cAMP concentration. Thus, olfactory bulb astrocytes express D1-like receptors that are linked to cAMP production. • Chages in the cAMP concentration in mouse astrocytes were visualized by the genetically encoced cAMP sensor Flamindo2. • Dopamine evoked increases in cAMP in olfactory bulb astrocytes. • Dopamine-evoked cAMP signals were mimicked by agonists of D1-like receptors, but not D2-like receptors. [ABSTRACT FROM AUTHOR]

Protein kinase A, plays a crucial role in cAMP signaling and its further downstream regulation of received stimuli. A kinase anchoring protein (AKAP); a binding protein provides a platform to the substrates to perform signaling events. AKAP serve its role in cAMP signaling by interacting with GPCR, PKA, ACs, Epac or PDE. More than 70 AKAP have been identified from which role of some AKAPs have been identified. AKAPs are found in heart, brain, testis, skeletal muscle, pancreas, placenta, oocytes, thyroid, kidney, liver, lungs. Amongst which the regulatory role of some AKAPs like AKAP149, AKAP5, AKAP4 and AKAP18 has been reported in mitochondrial function, recycling of β1-adrenoceptors, sperm motility, and insulin secretion respectively; whereas AKAP149 interaction is involved in reverse transcriptase activity of HIV; mutation in AKAP9 isoform causes prolonged QT interval, AKAP10 causes arrhythmia, risk of colorectal cancer and familial breast cancer. Although its dominating role is majorly reported in heart and brain, few reports are available regarding its role in respiratory system. The probable action of AKAP is via IL-8 release; IL-10, IL-6 and iNOS synthesis; mitochondrial function mediation, ROS generation and apoptosis. In the current review, attempt has been made to explore the general role of AKAPs with special emphasis in respiratory system. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Chinese Institute of Food Science & Technology is the property of Journal of Chinese Institute of Food Science & Technology Periodical Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Tau is a protein that normally participates in the assembly and stability of microtubules. However, it can form intraneuronal hyperphosphorylated aggregates that are hallmarks of Alzheimer's disease and other neurodegenerative disorders known as tauopathies. Tau can be phosphorylated by multiple kinases at several sites. Among such kinases, the cAMP‐dependent protein kinase A (PKA) phosphorylates tau at Ser214 (pTAU‐S214), an event that was shown to reduce the pathological assembly of the protein. Given that the neuronal cAMP/PKA‐activated cascade is involved in synaptic plasticity and memory, and that cAMP‐enhancing strategies demonstrated promising therapeutic potential for the treatment of cognitive deficits, we investigated the impact of cAMP on pTAU‐S214 in N2a cells and rat hippocampal slices. Our results confirm that the activation of adenylyl cyclase increases pTAU‐S214 in both model systems and, more interestingly, this effect is mimicked by GEBR‐7b, a phosphodiesterase 4D inhibitor with proven pro‐cognitive efficacy in rodents. [ABSTRACT FROM AUTHOR]

Objectives: Antipsychotics (APs) are medications used for different psychological disorders. They can introduce diabetogenic effects through different mechanisms, including cyclic adenosine monophosphate (cAMP) and calcium (Ca2+) signaling pathways. However, this effect is poorly understood. Therefore, this study aimed to evaluate the effect of three widely used APs (chlorpromazine, haloperidol, and clozapine) on cAMP and Ca2+ signaling. Methods: The local bioethics committee of Northern Border University approved the study. Pancreatic β-cells were isolated from male CD1 mice, and three drug stock solutions were made in different concentrations (0.1, 1, 10, and 100 µM). The levels of glucose-stimulated insulin secretion (GSIS) and cAMP as well as the activities of adenylyl cyclase (AC), cAMP-dependent protein kinase (PKA), guanine-nucleotide exchange protein activated by cAMP (Epac 1 and 2), Ca2+ mobilization, and Ca2+/ calmodulin kinase II (CaMKII) were then determined using different methods. Results: APs were found to be cytotoxic to pancreatic β cells and caused a parallel and significant decrease in GSIS. APs significantly reduced the levels of cAMP in the treated cells, with an associated reduction in ATP production, CaMKII, PKA, and transmembrane AC activities as well as Ca2+ mobilization to variable extents. In addition, the gene expression results showed that APs significantly decreased the expression of both the active subunits AC1 and AC8, the PKA α and β subunits, Epac1 and Epac2 as well as the four main subunits of CaMKII to variable extents. Conclusion: AP-induced alterations in the cAMP and Ca2+ signaling pathways can play a significant role in their diabetogenic potential. [ABSTRACT FROM AUTHOR]

The GTP-binding protein-coupled receptors (GPCRs) play important roles in physiology and neuronal signaling. More than a thousand genes, excluding the olfactory receptors, have been identified that encode these integral membrane proteins. Their pharmacological and functional properties make them fascinating targets for drug development, since various disease states can be treated and overcome by pharmacologically addressing these receptors and/or their downstream interacting partners. The activation of the GPCRs typically causes transient changes in the intracellular second messenger concentrations as well as in membrane conductance. In contrast to ion channel-mediated electrical signaling which results in spontaneous cellular responses, the GPCR-mediated metabotropic signals operate at a different time scale. Here we have studied the kinetics of two common GPCR-induced signaling pathways: (a) Ca2+ release from intracellular stores and (b) cyclic adenosine monophosphate (cAMP) production. The latter was monitored via the activation of cyclic nucleotide-gated (CNG) ion channels causing Ca2+ influx into the cell. Genetically modified and stably transfected cell lines were established and used in stopped-flow experiments to uncover the individual steps of the reaction cascades. Using two homologous biogenic amine receptors, either coupling to Go/q or Gs proteins, allowed us to determine the time between receptor activation and signal output. With ~350 ms, the release of Ca2+ from intracellular stores was much faster than cAMP-mediated Ca2+ entry through CNG channels (~6 s). The measurements with caged compounds suggest that this difference is due to turnover numbers of the GPCR downstream effectors rather than the different reaction cascades, per se. [ABSTRACT FROM AUTHOR]

Background: The cyclic adenosine monophosphate/phosphodiesterase 4 (cAMP/PDE4) pathway is involved in inflammation and immune regulation; however, the effect of cAMP/PDE4 on immune infiltration and immune evasion in lung adenocarcinoma (LUAD) remains unclear. Methods: CBioPortal, which is the The Cancer Genome Atlas (TCGA) online database, and the Kaplan Meier plotter were used to analyze the association between genes and the prognosis of TCGA-LUAD. Tumor Immune Estimation Resource (TIMER) was used to analyze the association between gene expression and immune infiltration. The Genecards database was used to identify the transcription factors of related genes. The lung adenocarcinoma cell line H1299 and A549 were treated with cAMP pathway drugs. Flow cytometry and qRT-PCR were used to detect the PD-L1 protein and gene expression, respectively. A one-way analysis of variance with Tukey's post-hoc test or a Student's t-test were used. Results: It was found that PDE4B and CREB1, which are downstream genes of the cAMP/PDE4 axis, were differentially expressed in LUAD and adjacent tissues and are correlated with the prognosis and immune infiltration of LUAD. In the CBioPortal database, cAMP pathway genes are closely related to programmed cell death-ligand 1 (PD-L1) expression in TCGA-LUAD. The protein-protein interaction revealed that there was a direct interaction between CREB1/CREBBP, which are the downstream molecules of the cAMP/PDE4 axis, and MYC; additionally, MYC was predicted to bind to the PD-L1 transcription site and regulate PD-L1 expression. CREB1 was also predicted to transcriptionally bind to both MYC and PD-L1. These results predicted the interaction network of cAMP/PDE4/CREB1/CREBP/MYC/PD-L1, and the core factor may be related to MYC. In the cell experiment, forskolin (an adenylate cyclase activator) and zardaverine (a PDE4 inhibitor) enhance the cAMP pathway and decrease PD-L1 expression, while SQ2253 (an adenylate cyclase inhibitor) inhibits the cAMP pathway and increases PD-L1 expression of the LUAD cell lines H1299 and A549, and MYC regulation by these drugs was positively correlated with PD-L1 regulation, which verified the regulation of the cAMP/PDE4 pathway on MYC and PD-L1. Conclusions: This study showed that the cAMP/PDE4 pathway may play an important role in PD-L1 regulation and immune infiltration in LUAD. [ABSTRACT FROM AUTHOR]

Background: Phosphodiesterases (PDEs) are enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate AMP (cAMP) and/or cyclic guanosine monophosphate (cGMP). PDE inhibitors can mitigate chronic pain and depression when these disorders occur individually; however, there is limited understanding of their role in concurrent chronic pain and depression. We aimed to evaluate the mechanisms of action of PDE using 2 mouse models of concurrent chronic pain and depression., Methods: C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) to induce chronic neuropathic pain or injected with complete Freund's adjuvant (CFA) to induce inflammatory pain, and both animals showed depression-like behavior. First, we determined the change in PDE expression in both animal models. Next, we determined the effect of PDE7 inhibitor BRL50481 or hippocampal PDE7A knockdown on PSNL- or CFA-induced chronic pain and depression-like behavior. We also investigated the role of cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling and neuroinflammation in the effect of PDE7A inhibition on PSNL- or CFA-induced chronic pain and depression-like behavior., Results: This induction of chronic pain and depression in the 2 animal models upregulated hippocampal PDE7A. Oral administration of PDE7 inhibitor, BRL50481, or hippocampal PDE7A knockdown significantly reduced mechanical hypersensitivity and depression-like behavior. Hippocampal PDE7 inhibition reversed PSNL- or CFA-induced downregulation of cAMP and BDNF and the phosphorylation of PKA, CREB, and p65. cAMP agonist forskolin reversed these changes and caused milder behavioral symptoms of pain and depression. BRL50481 reversed neuroinflammation in the hippocampus in PSNL mice., Conclusions: Hippocampal PDE7A mediated concurrent chronic pain and depression in both mouse models by inhibiting cAMP-PKA-CREB-BDNF signaling. Inhibiting PDE7A or activating cAMP-PKA-CREB-BDNF signaling are potential strategies to treat concurrent chronic pain and depression., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

Mycobacterium tuberculosis adenylyl cyclase (AC) Rv1625c/Cya is an evolutionary ancestor of the mammalian membrane ACs and a model system for studies of their structure and function. Although the vital role of ACs in cellular signalling is well established, the function of their transmembrane (TM) regions remains unknown. Here, we describe the cryo-EM structure of Cya bound to a stabilizing nanobody at 3.6 Å resolution. The TM helices 1–5 form a structurally conserved domain that facilitates the assembly of the helical and catalytic domains. The TM region contains discrete pockets accessible from the extracellular and cytosolic side of the membrane. Neutralization of the negatively charged extracellular pocket Ex1 destabilizes the cytosolic helical domain and reduces the catalytic activity of the enzyme. The TM domain acts as a functional component of Cya, guiding the assembly of the catalytic domain and providing the means for direct regulation of catalytic activity in response to extracellular ligands.

BACKGROUND: Schwann cells are the most ideal seed cells for peripheral nerve tissue engineering, but Schwann cells have many defects, so the research of cell therapy to repair peripheral nerve injury mainly focuses on other cells with Schwann cells characteristics, and Schwann cells-like cells have become the main source of choice for peripheral nerve injury repair. OBJECTIVE: To investigate the method of differentiation of muscle derived stem cells into Schwann cells phenotypes induced by ciliary neurotrophic factor combined with forskolin and 3-isobutyl-1-methylxanthine and the correlation between the induction and the cyclic adenosine monophosphate signaling pathway, so as to lay the foundation for further application of muscle derived stem cells in peripheral nerve injury repair. METHODS: Muscle derived stem cells were extracted from one-week old SD rats with mixed digestive enzymes. Dedifferentiation of muscle derived stem cells was induced by ciliary neurotrophic factor, and then the dedifferentiated muscle derived stem cells were induced by 3-isobutyl-1-methylxanthine. Cell morphology, immunofluorescence, CCK-8 assay, western blot assay, RT-qPCR and other techniques were used to identify and analyze muscle derived stem cells, dedifferentiated cells and Schwann cells-like cells. The expression of proteins related to cyclic adenosine monophosphate signaling pathway during dedifferentiation and Schwann cells-like differentiation was detected. RESULTS AND CONCLUSION: (1) Cell immunofluorescence staining showed that primary cells taken from SD rats could be labeled with Desmin, a specific marker of muscle derived stem cells. CCK-8 assay results showed that the proliferation activity of P1-3 muscle derived stem cells gradually increased, and the proliferation activity of P3-8 muscle derived stem cells tended to stabilize. (3) Western blot assay showed that the expression of myogenic differentiationrelated proteins p21 and MyoG decreased after ciliary neurotrophic factor induction, and the expression of cyclic adenosine monophosphate-related protein p-CREB increased. After 3-isobutyl-1-methylxanthine induction, the expression levels of Schwann cells markers S100β, GFAP, p75 and p-CREB increased, while cyclic adenosine monophosphate inhibitor SQ22536 could inhibit the effects of ciliary neurotrophic factor and 3-isobutyl-1-methylxanthine. (4) The RT-qPCR results were consistent with the western blot results; that was, the expression levels of S100β, GFAP and p75 mRNA increased after 3-isobutyl-1- methylxanthine induction, and SQ22536 could inhibit this effect. The results of CCK-8 assay showed that the cell activity was reduced after 3-isobutyl-1- methylxanthine induction. (5) Results concluded that ciliary neurotrophic factor combined with 3-isobutyl-1-methylxanthine can induce muscle derived stem cells to differentiate into Schwann cells phenotype, and the induction process activates the cyclic adenosine monophosphate signaling pathway. [ABSTRACT FROM AUTHOR]

A homogeneous polysaccharide (GAP), with a molecular weight of 51.8 kDa, was isolated from edible red seaweed Gelidium amansii. Composition analysis suggested GAP contained 5.31% sulfate and 17.33% 3,6-anhydro-galactose and was mainly composed of galactose. Furthermore, GAP, as a biopolymer matrix, was used to form the composite films with the small biological molecules cytidine-5′-monophosphate (CMP), adenosine-5′-monophosphate (AMP), and cyclic adenosine monophosphate (cAMP). Scanning electron microscope (SEM), Fourier transform infrared (FTIR) spectrum, and X-ray diffraction (XRD) results showed that CMP, AMP, and cAMP interacted with the film substrates and might made films more complex. Notably, the addition of CMP, AMP, and cAMP promoted the light, water vapor, and oxygen barrier ability, surface wettability, mechanical strength, and antimicrobial activity against Gram-negative and –positive bacteria. Finally, GAP-based films composited with cAMP (cAMPF) exhibited the best characteristics were applied to fish packaging and preservation at 4 °C and extended the fish shelf life. All these data suggested the potential value of cAMPF as a functional edible polysaccharide film applied in food industries. [ABSTRACT FROM AUTHOR]

NO synthase activity (mtNOS) in uterine smooth muscle mitochondria under the action of the cAMP/protein kinase A signaling system modulators was studied. The experiments were performed on isolated mitochondria from rat myometrium using the NO-sensitive fluorescent probe DAF-FM-DA. NO synthesis in mitochondria was increased by adenylate cyclase activators NaHCO3 (30 mM) and forskolin (10 µM), as well as phosphodiesterase inhibitor caffeine (1 mM). The addition of ATP (0.5-5 mM) caused a slight increase in nitric oxide synthesis. The effect of ATP was enhanced in the presence of NaHCO3 and caffeine. The intensity of NO formation in mitochondria decreased by approximately 50 % in the case of inhibition of adenylate cyclase activity by the compound KH7 (25 µM). In the presence of the protein kinase A inhibitor PKI (10 nM) NO synthesis in mitochondria was also significantly reduced. When the constitutive NO-synthase inhibitor L-NAME (100 µM) was introduced into the incubation medium, the stimulating effect of the studied compounds on NO synthesis in mitochondria was not observed. These data suggests a possible dependence of mtNOS function on the activity of the cAMP/protein kinase A signaling system in smooth muscle mitochondria. [ABSTRACT FROM AUTHOR]

Heterotrimeric G-proteins play crucial roles in growth, asexual development, and pathogenicity of fungi. The regulator of G-protein signaling (RGS) proteins function as negative regulators of the G proteins to control the activities of GTPase in Ga subunits. In this study, we functionally characterized the six RGS proteins (i.e., RgsA, RgsB, RgsC, RgsD, RgsE, and FlbA) in the pathogenic fungus Aspergillus flavus. All the aforementioned RGS proteins were also found to be functionally different in conidiation, aflatoxin (AF) biosynthesis, and pathogenicity in A. flavus. Apart from FlbA, all other RGS proteins play a negative role in regulating both the synthesis of cyclic AMP (cAMP) and the activation of protein kinase A (PKA). Additionally, we also found that although RgsA and RgsE play a negative role in regulating the FadAcAMP/PKA pathway, they function distinctly in aflatoxin biosynthesis. Similarly, RgsC is important for aflatoxin biosynthesis by negatively regulating the GanA-cAMP/PKA pathway. PkaA, which is the cAMP-dependent protein kinase catalytic subunit, also showed crucial influences on A. flavus phenotypes. Overall, our results demonstrated that RGS proteins play multiple roles in the development, pathogenicity, and AF biosynthesis in A. flavus through the regulation of Gaα subunits and cAMP-PKA signals. [ABSTRACT FROM AUTHOR]

This study investigated the release and proteomic profile of tissue factor microparticles (TFMPs) prospectively (up to 6 months) following a myocardial infarction (MI) in a chronic porcine model to establish their utility in tracking cellular level activities that predict physiologic outcomes. Our animal groups (n = 6 to 8 each) consisted of control, noninfarcted (negative control); infarcted only (positive control); and infarcted animals treated with cardiac resynchronization therapy (CRT) and a β-blocker (BB) (metoprolol succinate). The authors found different protein profiles in TFMPs between the control, infarcted only group, and the CRT + BB treated group with predictive impact on the outward phenotype of pathological remodeling after an MI within and between groups. This novel approach of monitoring cellular level activities by profiling the content of TFMPs has the potential of addressing a shortfall of the current crop of cardiac biomarkers, which is the inability to capture composite molecular changes associated with chronic maladaptive signaling in a spatial and temporal manner.