RESUMEN
Pruritus, also known as itching, is a complex sensation that involves the activation of specific physiological and cellular receptors. The skin is innervated with sensory nerves as well as some receptors for various sensations, and its immune system has prominent neurological connections. Sensory neurons have a considerable impact on the sensation of itching. However, immune cells also play a role in this process, as they release pruritogens. Disruption of the dermal barrier activates an immune response, initiating a series of chemical, physical, and cellular reactions. These reactions involve various cell types, including keratinocytes, as well as immune cells involved in innate and adaptive immunity. Collective activation of these immune responses confers protection against potential pathogens. Thus, understanding the molecular and cellular mechanisms that contribute to pruritus in host skin is crucial for the advancement of effective treatment approaches. This review provides a comprehensive analysis of the present knowledge concerning the molecular and cellular mechanisms underlying itching signaling in the skin. Additionally, this review explored the integration of these mechanisms with the broader context of itch mediators and the expression of their receptors in the skin.
Asunto(s)
Prurito , Piel , Humanos , Prurito/genética , Prurito/metabolismo , Queratinocitos , Células Receptoras Sensoriales/metabolismo , Transducción de SeñalRESUMEN
In the precedent research conducted by the same team, it concluded that the activities in C-type natriuretic peptide (CNP)/cyclic guanosine monophosphate (cGMP)/cyclic adenosine monophosphate (cAMP)/ß-type phospholipase C (PLCß) pathways of rat antral smooth muscle were changed due to diabetes, which was the key pathogenetic mechanism for diabetic gastric dysmotility. As the follow-on step, this study was designed to probe into the downstream signaling pathway of CNP/PLCß. The results showed that level of α-type protein kinase C (PKCα),cell membrane to cytoplasm ratio of PKCα, cell membrane to cytoplasmic ratio of ßI-type protein kinase C (PKCßI) and level of Phosphor-PKCα (P-PKCα) were significantly reduced in diabetes rat antral smooth muscle samples. The content of tetraphosphate inositol (IP4) in gastric antral smooth muscle of diabetic rats reduced, and the content of diacyl-glycerol (DG) was unchanged. CNP significantly decreased the content of IP4 and DG, this effect was more obvious in diabetic rats. Subsequent to the addition of protein kinase A (PKA) blocker N-[2- (p-Bromocin-namylamino)ethyl]-5 -isoquinolinesulfonamide dihydrochloride (H-89) before CNP treatment, the inhibitory effect of CNP was reduced; subsequent to the addition of protein kinase G (PKG) blocker KT5823 before CNP treatment, the inhibitory effect of CNP was also reduced. With the addition of the combination of H-89 and KT5823 before CNP treatment, the inhibition by CNP could be offset. These results were concluded that CNP inhibited the activity of PKC family in rat smooth muscle and reduced the levels of IP4 and DG through the PKG/PKA-PLCß pathways, causing inhibited muscular contractions, which may be a key pathogenetic factor for diabetic gastroparesis.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Diglicéridos/metabolismo , Gastroparesia/metabolismo , Fosfatos de Inositol/metabolismo , Péptido Natriurético Tipo-C/farmacología , Proteína Quinasa C/metabolismo , Animales , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Motilidad Gastrointestinal/efectos de los fármacos , Gastroparesia/etiología , Gastroparesia/patología , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/patología , Músculo Liso/fisiología , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacosRESUMEN
Our previous work demonstrated that the C-type natriuretic peptide (CNP)/cyclic guanosine monophosphate (cGMP)/cyclic adenosine monophosphate (cAMP) pathway in gastric antrum smooth muscle of rats with diabetes was upregulated and played an important role in the development of diabetic gastric dysmotility. Our goal for this study was to explore the downstream signaling pathways of CNP. We found that the expressions of protein kinase G (PKG) and protein kinase A (PKA) in gastric smooth muscle tissue of rats with diabetes were significantly upregulated. The expressions of ß-type phospholipase C 3(PLCß3) and ß-type phospholipase C 1(PLCß1) protein were reduced, whereas Phosphor-PLCß3Ser1105 (P-PLCß3Ser1105) was increased. The inhibitory effect of CNP on gastric antral smooth muscle in diabetic rats was significantly greater than in the normal group. The content of trisphosphate inositol (IP3) in the gastric antral smooth muscle of rats with diabetes was significantly lower than that of the normal group. After blocking PKA with N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H-89, a blockage PKA), the effect of CNP on the production of IP3 was decreased, while blocking PKG with KT5823 (a blockage PKG) simultaneously, and CNP can no longer reduce the IP3 production. CNP promoted the phosphorylation of PLCß3Ser1105, thereby inhibiting the activity of PLCß3 in gastric smooth muscle tissue of rats with diabetes; this effect can be abolished by blocking PKA and PKG. These results suggested that CNP can decrease IP3 level in gastric smooth muscle cells and thus inhibit gastric smooth muscle contraction through PKG/PKA-PLCß pathway, which may play an important role in the development of diabetic gastroparesis.
Asunto(s)
Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Diabetes Mellitus Experimental/complicaciones , Enfermedades Gastrointestinales/etiología , Enfermedades Gastrointestinales/metabolismo , Motilidad Gastrointestinal/fisiología , Péptido Natriurético Tipo-C/metabolismo , Fosfolipasa C beta/metabolismo , Animales , Ensayo de Inmunoadsorción Enzimática , Femenino , Inmunohistoquímica , Masculino , RatasRESUMEN
The aim of the present study was to investigate the significance of cell apoptosis, the phosphoinositide-3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway, and the 5' adenosine monophosphate-activated protein kinase (AMPK)mTOR pathways in the process of diabetic gastroparesis. Changes in gastric smooth muscle cells of diabetic rats with induced gastroparesis were examined. The diabetic rat model was established by dividing animals into a normal control group and diabetic model groups examined at 2, 4 and 6 weeks. Diabetic gastroparesis was evaluated by examining the rates of gastric residual pigment, whereas flow cytometry was used to detect the apoptosis of gastric smooth muscle cells. The expression levels of PI3K and phosphorylated (p) AKT, AMPK, mTOR, tuberous sclerosis complex 2, p70 ribosomal S6 kinase, and eukaryotic translation initiation factor 4binding protein 1 were determined in gastric muscles using western blot analysis. Diabetic gastroparesis was confirmed in models at 6 weeks. The apoptosis of gastric smooth muscle cells gradually increased in all diabetic groups, and significant changes were observed in key proteins involved in PI3KAKTmTOR and AMPKmTOR signaling. The results indicated that apoptosis was important in the occurrence of diabetic gastroparesis, and the PI3KAKTmTOR and AMPKmTOR pathways were activated during the apoptotic processes, but were incapable of regulating apoptosis.
Asunto(s)
Apoptosis , Diabetes Mellitus Experimental/patología , Gastroparesia/patología , Miocitos del Músculo Liso/patología , Transducción de Señal , Estómago/patología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Proteínas Portadoras/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Modelos Animales de Enfermedad , Gastroparesia/complicaciones , Gastroparesia/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Masculino , Miocitos del Músculo Liso/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfoproteínas/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Our previous studies have shown that CNP-NPR-B/pGC-cGMP is upregulated in the diabetic rats. The present study was designed to determine whether the upregulation of CNP-NPR-B/pGC-cGMP signal pathway affects cGMP-PDE3-cAMP signal pathway in diabetic gastric smooth muscle. The gastric smooth muscle motility was observed by using isometric measurement. PDEs expressions in diabetic gastric smooth muscle tissue were observed by using immunohistochemistry, Western blotting, and RT-PCR methods. The results demonstrated that the inhibitory effect of CNP on the spontaneous contraction of gastric antral circular smooth muscle was potentiated in STZ-induced diabetic rat. CNP-induced increase of cGMP and cAMP was much higher in diabetic gastric smooth muscle tissue than in controls. The expression of PDE3 is downregulated while the levels of gene expression of PDE1, PDE2, PDE4, and PDE5 were not altered in the diabetic gastric smooth muscle tissue. The results suggest that the sensitivity of gastric smooth muscle to CNP is potentiated via activation of CNP-pGC-cGMP-PDE3-cAMP signal pathway in STZ-induced diabetic rats, which may be associated with diabetes-induced gastric motility disorder.
RESUMEN
The aim of the present study was to investigate the effects of cyclic adenosine monophosphate (cAMP) on rat gastric antral circular smooth muscle function. Forskolin, a direct activator of adenylyl cyclase (AC), was used to observe the influences of cAMP. Multi-channel physiological recorder was used to record spontaneous contraction activity of gastric antral circular muscle from Wistar rats. And ELISA method was used to detect the change of cAMP production in perfusate. The results showed that forskolin concentration-dependently suppressed the amplitude and frequency of the spontaneous contraction of the gastric antral muscle, and lowered the baseline of contraction movement significantly. Forskolin concentration-dependently increased the production of cAMP in the perfusate, which showed a significant negative correlation with the contraction amplitude of gastric antral ring muscle. The inhibitory effect of forskolin on spontaneous contraction activity of rat gastric antral circular muscle could be blocked by cAMP-dependent protein kinase (PKA) inhibitor H-89. These results suggest forskolin increases cAMP production and then activates PKA pathway, resulting in the inhibition of the spontaneous contraction activity of rat gastric antral circular smooth muscle.
Asunto(s)
Colforsina/farmacología , AMP Cíclico/farmacología , Músculo Liso/efectos de los fármacos , Antro Pilórico/efectos de los fármacos , Adenilil Ciclasas/metabolismo , Animales , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Isoquinolinas/farmacología , Ratas , Ratas Wistar , Sulfonamidas/farmacologíaRESUMEN
In the present study, we investigated the mechanism of C-type natriuretic peptide (CNP)-induced inhibitory effect on spontaneous contraction of gastric antral smooth muscle to clarify CNP-NPR-B/pGC-cGMP downstream signal transduction pathway using organ bath and ELISA methods in rat. CNP significantly reduced the amplitude of the spontaneous contraction and increased the contents of cGMP and cAMP in the gastric antral smooth muscle tissue. In the presence of IBMX, a non-selective phosphodiesterase (PDE) inhibitor, the inhibitory effect of CNP on spontaneous contraction was significantly suppressed; however, the production of cGMP but not cAMP was still increased by CNP. EHNA, a PDE2 inhibitor, did not affect both CNP-induced inhibition of the contraction and CNP-induced increase of cGMP and cAMP generations in gastric smooth muscle tissue, while milrinone, a PDE3 inhibitor, similar to IBMX, attenuated the CNP-induced inhibitory effect on spontaneous contraction and increased the content of cGMP but not cAMP. The results suggest that cGMP-PDE3-cAMP signal pathway is also involved in the CNP-induced inhibition of gastric motility in rat.