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Ischemic stroke is the result of a permanent or transient occlusion of a brain artery, leading to irreversible tissue injury and long-term sequelae. Despite ongoing advancements in revascularization techniques, stroke remains the second leading cause of death worldwide. A comprehensive understanding of the complex and interconnected mechanisms, along with the endogenous mediators that modulate stroke responses is essential for the development of effective interventions. Our study investigates cortistatin, a neuropeptide extensively distributed in the immune and central nervous systems, known for its immunomodulatory properties. With neuroinflammation and peripheral immune deregulation as key pathological features of brain ischemia, cortistatin emerges as a promising therapeutic candidate. To this aim, we evaluated its potential effect in a well-established middle cerebral artery occlusion (MCAO) preclinical stroke model. Our findings indicated that the peripheral administration of cortistatin at 24 h post-stroke significantly reduced neurological damage and enhanced recovery. Importantly, cortistatin-induced neuroprotection was multitargeted, as it modulated the glial reactivity and astrocytic scar formation, facilitated blood-brain barrier recovery, and regulated local and systemic immune dysfunction. Surprisingly, administration of cortistatin at immediate and early post-stroke time points proved to be not beneficial and even detrimental. These results emphasize the importance of understanding the spatio-temporal dynamics of stroke pathology to develop innovative therapeutic strategies with appropriate time windows. Premature interruption of certain neuroinflammatory processes might inadvertently compromise neuroprotective mechanisms. In summary, our study highlights cortistatin as a novel pleiotropic therapeutic approach against ischemic stroke, offering new treatment options for patients who undergo early revascularization intervention but unsuccessful recovery.

Abstract Background Brain activity governing cognition and behaviour depends on the fine-tuned microenvironment provided by a tightly controlled blood–brain barrier (BBB). Brain endothelium dysfunction is a hallmark of BBB breakdown in most neurodegenerative/neuroinflammatory disorders. Therefore, the identification of new endogenous molecules involved in endothelial cell disruption is essential to better understand BBB dynamics. Cortistatin is a neuroimmune mediator with anti-inflammatory and neuroprotective properties that exerts beneficial effects on the peripheral endothelium. However, its role in the healthy and injured brain endothelium remains to be evaluated. Herein, this study aimed to investigate the potential function of endogenous and therapeutic cortistatin in regulating brain endothelium dysfunction in a neuroinflammatory/neurodegenerative environment. Methods Wild-type and cortistatin-deficient murine brain endothelium and human cells were used for an in vitro barrier model, where a simulated ischemia-like environment was mimicked. Endothelial permeability, junction integrity, and immune response in the presence and absence of cortistatin were evaluated using different size tracers, immunofluorescence labelling, qPCR, and ELISA. Cortistatin molecular mechanisms underlying brain endothelium dynamics were assessed by RNA-sequencing analysis. Cortistatin role in BBB leakage was evaluated in adult mice injected with LPS. Results The endogenous lack of cortistatin predisposes endothelium weakening with increased permeability, tight-junctions breakdown, and dysregulated immune activity. We demonstrated that both damaged and uninjured brain endothelial cells isolated from cortistatin-deficient mice, present a dysregulated and/or deactivated genetic programming. These pathways, related to basic physiology but also crucial for the repair after damage (e.g., extracellular matrix remodelling, angiogenesis, response to oxygen, signalling, and metabolites transport), are dysfunctional and make brain endothelial barrier lacking cortistatin non-responsive to any further injury. Treatment with cortistatin reversed in vitro hyperpermeability, tight-junctions disruption, inflammatory response, and reduced in vivo BBB leakage. Conclusions The neuropeptide cortistatin has a key role in the physiology of the cerebral microvasculature and its presence is crucial to develop a canonical balanced response to damage. The reparative effects of cortistatin in the brain endothelium were accompanied by the modulation of the immune function and the rescue of barrier integrity. Cortistatin-based therapies could emerge as a novel pleiotropic strategy to ameliorate neuroinflammatory/neurodegenerative disorders with disrupted BBB.

Glioma is a common tumor originating in the brain that has a high mortality rate. Temozolomide (TMZ) is the first-line treatment for high-grade gliomas. However, a large proportion of gliomas are resistant to TMZ, posing a great challenge to their treatment. In the study, the specific functions and mechanism(s) by which cortistatin (CORT) regulates TMZ resistance and glioma progression were evaluated. The decreased expression of CORT was detected in glioma tissues, and highly expressed CORT was associated with a better survival rate in patients with glioma. CORT overexpression notably decreased the capacity of glioma cells to proliferate and migrate in vitro and to form tumors in vivo. CORT overexpression also markedly suppressed the viability and enhanced the apoptosis of TMZ-resistant U251 cells by regulating MGMT, p21, and Puma expression. Importantly, CORT overexpression reduced the resistance of gliomas to TMZ in vivo. CORT expression was negatively correlated with MGMT expression in both glioma tissues and cells, and it was found that CORT inhibited NF-κB pathway activation in glioma cells, thereby inhibiting MGMT expression. In conclusion, CORT regulates glioma cell growth, migration, apoptosis, and TMZ resistance by weakening the activity of NF-κB/p65 and thereby regulating MGMT expression. The CORT/NF-κB/MGMT axis might be regarded as a molecular mechanism contributing to the resistance of glioma to TMZ. Our data also suggest that CORT regulates the viability and metastatic potential of glioma cells, independent of its effects on TMZ resistance, providing evidence of novel therapeutic targets for glioma that should be evaluated in further studies.

Parkinson's disease (PD) is a complex disorder characterized by the impairment of the dopaminergic nigrostriatal system. PD has duplicated its global burden in the last few years, becoming the leading neurological disability worldwide. Therefore, there is an urgent need to develop innovative approaches that target multifactorial underlying causes to potentially prevent or limit disease progression. Accumulating evidence suggests that neuroinflammatory responses may play a pivotal role in the neurodegenerative processes that occur during the development of PD. Cortistatin is a neuropeptide that has shown potent anti-inflammatory and immunoregulatory effects in preclinical models of autoimmune and neuroinflammatory disorders. The goal of this study was to explore the therapeutic potential of cortistatin in a well-established preclinical mouse model of PD induced by acute exposure to the neurotoxin 1-methil-4-phenyl1-1,2,3,6-tetrahydropyridine (MPTP). We observed that treatment with cortistatin mitigated the MPTP-induced loss of dopaminergic neurons in the substantia nigra and their connections to the striatum. Consequently, cortistatin administration improved the locomotor activity of animals intoxicated with MPTP. In addition, cortistatin diminished the presence and activation of glial cells in the affected brain regions of MPTP-treated mice, reduced the production of immune mediators, and promoted the expression of neurotrophic factors in the striatum. In an in vitro model of PD, treatment with cortistatin also demonstrated a reduction in the cell death of dopaminergic neurons that were exposed to the neurotoxin. Taken together, these findings suggest that cortistatin could emerge as a promising new therapeutic agent that combines anti-inflammatory and neuroprotective properties to regulate the progression of PD at multiple levels. [ABSTRACT FROM AUTHOR]

Background: Brain activity governing cognition and behaviour depends on the fine-tuned microenvironment provided by a tightly controlled blood–brain barrier (BBB). Brain endothelium dysfunction is a hallmark of BBB breakdown in most neurodegenerative/neuroinflammatory disorders. Therefore, the identification of new endogenous molecules involved in endothelial cell disruption is essential to better understand BBB dynamics. Cortistatin is a neuroimmune mediator with anti-inflammatory and neuroprotective properties that exerts beneficial effects on the peripheral endothelium. However, its role in the healthy and injured brain endothelium remains to be evaluated. Herein, this study aimed to investigate the potential function of endogenous and therapeutic cortistatin in regulating brain endothelium dysfunction in a neuroinflammatory/neurodegenerative environment. Methods: Wild-type and cortistatin-deficient murine brain endothelium and human cells were used for an in vitro barrier model, where a simulated ischemia-like environment was mimicked. Endothelial permeability, junction integrity, and immune response in the presence and absence of cortistatin were evaluated using different size tracers, immunofluorescence labelling, qPCR, and ELISA. Cortistatin molecular mechanisms underlying brain endothelium dynamics were assessed by RNA-sequencing analysis. Cortistatin role in BBB leakage was evaluated in adult mice injected with LPS. Results: The endogenous lack of cortistatin predisposes endothelium weakening with increased permeability, tight-junctions breakdown, and dysregulated immune activity. We demonstrated that both damaged and uninjured brain endothelial cells isolated from cortistatin-deficient mice, present a dysregulated and/or deactivated genetic programming. These pathways, related to basic physiology but also crucial for the repair after damage (e.g., extracellular matrix remodelling, angiogenesis, response to oxygen, signalling, and metabolites transport), are dysfunctional and make brain endothelial barrier lacking cortistatin non-responsive to any further injury. Treatment with cortistatin reversed in vitro hyperpermeability, tight-junctions disruption, inflammatory response, and reduced in vivo BBB leakage. Conclusions: The neuropeptide cortistatin has a key role in the physiology of the cerebral microvasculature and its presence is crucial to develop a canonical balanced response to damage. The reparative effects of cortistatin in the brain endothelium were accompanied by the modulation of the immune function and the rescue of barrier integrity. Cortistatin-based therapies could emerge as a novel pleiotropic strategy to ameliorate neuroinflammatory/neurodegenerative disorders with disrupted BBB. [ABSTRACT FROM AUTHOR]

Tiantian Sun,1,&ast; Chang Wang,1,2,&ast; Lijing Huo,3 Yichao Wang,1 Ke Liu,1 Changmei Wei,3 Hang Zhao,1 Shuchun Chen,1 Luping Ren1 1Department of Endocrinology, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 2North China University of Science and Technology, Tangshan, People’s Republic of China; 3Department of Clinical Laboratory, Hebei General Hospital, Shijiazhuang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Luping Ren, No. 348 Heping West Road, Shijiazhuang, Hebei Province, People’s Republic of China, Tel +86 0311-85988975, Email renluping1122@163.comPurpose: To evaluate serum cortistatin (CST) levels in type 2 diabetes mellitus (T2DM) patients with or without non-alcoholic fatty liver disease (NAFLD) and to examine the relationship between CST and NAFLD.Methods: A total of 90 T2DM patients, which included 56 NAFLD patients (referred to as DM+NAFLD group) and 34 patients without NAFLD (DM-only group), and 83 non-diabetes individuals that included 39 NAFLD patients (NAFLD-only group) and 44 without NAFLD that acted as the normal-control group (NC group). The differences in the serum CST levels between the groups were compared, and the correlations between CST and other variables were calculated by applying both correlational analysis and multiple linear regression analysis.Results: The mean serum CST levels were significantly lower in the DM+NAFLD and DM groups than in the NC group (P < 0.05). In addition, the CST levels were lower in the DM group relative to that in the NAFLD group (P < 0.05). However, no statistical difference was noted in the serum CST between diabetic patients with and without NAFLD (P > 0.05). Similarly, in the non-diabetic group, the serum CST level was not significantly different between individuals with and without NAFLD (P > 0.05). Furthermore, the serum CST levels were negatively associated with the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), homeostasis model assessment-insulin resistance (HOMA-IR), and insulin cell function index (HOMA-β). Conversely, the serum CST levels were positively associated with high-density lipoprotein cholesterol (HDL-C). The data obtained through multiple linear regression implied that LDL-C and HOMA-β, but not HOMA-IR, were closely related to serum CST levels.Conclusion: T2DM was related to decreased serum CST. However, serum CST was correlated with HOMA-β in T2DM patients, while HOMA-IR was not. There was no correlation between CST and NAFLD.Keywords: type 2 diabetes mellitus, cortistatin, nonalcoholic fatty liver disease

Cortistatin is a cyclic neuropeptide that recently emerged as an attractive therapeutic factor for treating inflammatory, autoimmune, fibrotic, and pain disorders. Despite of its efficiency and apparent safety in experimental preclinical models, its short half-life in body fluids and its potential pleiotropic effects, due to its promiscuity for several receptors expressed in various cells and tissues, represent two major drawbacks for the clinical translation of cortistatin-based therapies. Therefore, the design of new strategies focused on increasing the stability, bioavailability, and target specificity of cortistatin are lately demanded by the industry. Here, we generated by molecular engineering a new cortistatin-based prodrug formulation that includes, beside the bioactive cortistatin, a molecular-shield provided by the latency-associated protein of the transforming growth factor-β1 and a cleavage site specifically recognized by metalloproteinases, which are abundant in inflammatory/fibrotic foci. Using different models of sepsis, inflammatory bowel disease, scleroderma, and pulmonary fibrosis, we demonstrated that this latent form of cortistatin was a highly effective protection against these severe disorders. Noteworthy, from a therapeutic point of view, is that latent cortistatin seems to require significantly lower doses and fewer administrations than naive cortistatin to reach the same efficacy. Finally, the metalloproteinase-cleavage site was essential for the latent molecule to exert its therapeutic action. In summary, latent cortistatin emerges as a promising innovative therapeutic tool for treating chronic diseases of different etiologies with difficult clinical solutions and as a starting point for a rational development of prodrugs based on the use of bioactive peptides. [ABSTRACT FROM AUTHOR]

Somatostatin (SST), cortistatin (CORT), and their receptors (SSTR1-5/sst5TMD4-TMD5) comprise a multifactorial hormonal system involved in the regulation of numerous pathophysiological processes. Certain components of this system are dysregulated and play critical roles in the development/progression of different endocrine-related cancers. However, the presence and therapeutic role of this regulatory system in prostate cancer (PCa) remain poorly explored. Accordingly, we performed functional (proliferation/migration/colonies-formation) and mechanistic (Western-blot/qPCR/microfluidic-based qPCR-array) assays in response to SST and CORT treatments and CORT-silencing (using specific siRNA) in different PCa cell models [androgen-dependent (AD): LNCaP; androgen-independent (AI)/castration-resistant PCa (CRPC): 22Rv1 and PC-3], and/or in the normal-like prostate cell-line RWPE-1. Moreover, the expression of SST/CORT system components was analyzed in PCa samples from two different patient cohorts [internal (n = 69); external (Grasso, n = 88)]. SST and CORT treatment inhibited key functional/aggressiveness parameters only in AI-PCa cells. Mechanistically, antitumor capacity of SST/CORT was associated with the modulation of oncogenic signaling pathways (AKT/JNK), and with the significant down-regulation of critical genes involved in proliferation/migration and PCa-aggressiveness (e.g., MKI67/MMP9/EGF). Interestingly, CORT was highly expressed, while SST was not detected, in all prostate cell-lines analyzed. Consistently, endogenous CORT was overexpressed in PCa samples (compared with benign-prostatic-hyperplasia) and correlated with key clinical (i.e., metastasis) and molecular (i.e., SSTR2/SSTR5 expression) parameters. Remarkably, CORT-silencing drastically enhanced proliferation rate and blunted the antitumor activity of SST-analogues (octreotide/pasireotide) in AI-PCa cells. Altogether, we provide evidence that SST/CORT system and SST-analogues could represent a potential therapeutic option for PCa, especially for CRPC, and that endogenous CORT could act as an autocrine/paracrine regulator of PCa progression. [ABSTRACT FROM AUTHOR]

Background: Recently, the expression of the mast cell (MC) receptor Mas-related G protein-coupled receptor X2 (MRGPRX2) has been detected in lesional skin of adult patients with cutaneous mastocytosis. As of yet, little is known about the clinical relevance of MRGPRX2 and its agonists in patients with mastocytosis, including indolent systemic mastocytosis (ISM). Methods: MRGPRX2 and MRGPRX2 agonists, cortistatin (CST), and major basic protein (MBP) were analyzed in lesional and non-lesional skin of patients with ISM and skin of healthy controls by immunohistochemistry. Co-localization of MRGPRX2 and MRGPRX2-mRNA with the MC marker tryptase was assessed by immunofluorescence microscopy and in situ hybridization, respectively. We assessed clinical, demographic, and laboratory data, including mastocytosis activity score (MAS), serum tryptase, and KIT D816V allele burden. Results: The number of MRGPRX2-expressing (MRGPRX2+) cells, MRGPRX2-mRNA+ MCs, and CST-expressing (CST+) and MBP-expressing (MBP+) cells was significantly higher in lesional skin as compared to non-lesional skin and/or skin of healthy controls (all p < 0.05). Increased numbers of MRGPRX2+ cells, MRGPRX2-mRNA+ MCs, and CST+ and MBP+ cells were not associated with clinical and laboratory features of ISM, including disease burden, symptom severity, evidence of anaphylaxis, and tryptase levels. Conclusions: Skin lesions of patients with ISM showed high numbers of MRGPRX2+ cells, although they were not linked to symptom severity. Clinical relevance of the MRGPRX2-mediated pathway of MC activation in ISM remains unclear and should be investigated in further studies. [ABSTRACT FROM AUTHOR]

Aseptic loosening is a major complication of prosthetic joint surgery and is associated with impaired osteoblast homeostasis. Cortistatin (CST) is a neuropeptide that protects against inflammatory conditions. In this study, we found that expression of CST was diminished in patients with prosthetic joint loosening and in titanium (Ti) particle–induced animal models. A Ti particle–induced calvarial osteolysis model was established in wild‐type and CST gene knockout mice; CST deficiency enhanced, while exogenously added CST attenuated, the severity of Ti particle–mediated osteolysis. CST protected against inflammation as well as apoptosis and maintained the osteogenic function of MC3T3‐E1 osteoblasts upon stimulation with Ti particles. Furthermore, CST antagonized reactive oxygen species production and suppressed caspase‐3–associated apoptosis mediated by Ti particles in osteoblasts. Additionally, CST protects against Ti particle–induced osteolysis through tumor necrosis factor receptor 1. Taken together, CST might provide a therapeutic strategy for wear debris–induced inflammatory osteolysis. [ABSTRACT FROM AUTHOR]

Simple Summary: Growth trait is one of the most important economic traits for meat animals. Somatostatin DNA vaccine has been proven to enhance the growth rate of animals. However, the growth-promoting effect is not ideal. This study aimed to evaluate the immune effects of a novel eukaryotic dual expression vaccine known as pIRES-S/CST14-S/2SS in mice. Firstly, we demonstrated pIRES-S/CST14-S/2SS could functionally express in GH3 pituitary cells by regulating the growth hormone (GH) and prolactin (PRL) productions. Secondly, we observed that all concentrations of pIRES-S/CST14-S/2SS vaccine could evoke anti-somatostatin (SS) antibodies, leading to a higher level of GH concentration. Notably, pIRES-S/CST14-S/2SS (10 μg/100 μL) immunized mice obtained maximum body weight gain in a booster vaccination period. Our results are helpful for better understanding of the relationship between SS and CST, and pIRES-S/CST14-S/2SS vaccine may be used as a promising alternative for developing growth-promoting vaccine. Animal growth traits are directly linked with the economics of livestock species. A somatostatin DNA vaccine has been developed to improve the growth of animals. However, the growth-promoting effect is still unsatisfying. The current study aimed to evaluate the effect of a novel eukaryotic dual expression vaccine known as pIRES-S/CST14-S/2SS, which encodes the genes obtained by fusing somatostatin (SS) and cortistatin (CST) into hepatitis B surface antigen (HBsAg). After transfection into GH3 cells with pIRES-S/CST14-S/2SS, green fluorescence signals were observed by fluorescence microscopy, suggesting the effective expression of CST and SS in GH3 cells using the IRES elements. Subsequently, both GH and PRL levels were found to be significantly lower in pIRES-S/CST14-S/2SS-treated cells as compared to the control group (p < 0.05). Furthermore, the antibody level, hormone secretion, and weight gain in the mice injected with novel recombinant plasmids were also evaluated. The anti-SS antibodies were detectable in all vaccine treated groups, resulting in significantly higher levels of GH secretion (p < 0.05). It is worth mentioning that pIRES-S/CST14-S/2SS (10 μg/100 μL) vaccinated mice exhibited a higher body weight gain in the second immunization period. This study increases the understanding of the relationship between somatostatin and cortistatin, and may help to develop an effective growth-promoting DNA vaccine in animals. [ABSTRACT FROM AUTHOR]

BackgroundRecently, the expression of the mast cell (MC) receptor Mas-related G protein–coupled receptor X2 (MRGPRX2) has been detected in lesional skin of adult patients with cutaneous mastocytosis. As of yet, little is known about the clinical relevance of MRGPRX2 and its agonists in patients with mastocytosis, including indolent systemic mastocytosis (ISM).MethodsMRGPRX2 and MRGPRX2 agonists, cortistatin (CST), and major basic protein (MBP) were analyzed in lesional and non-lesional skin of patients with ISM and skin of healthy controls by immunohistochemistry. Co-localization of MRGPRX2 and MRGPRX2-mRNA with the MC marker tryptase was assessed by immunofluorescence microscopy and in situ hybridization, respectively. We assessed clinical, demographic, and laboratory data, including mastocytosis activity score (MAS), serum tryptase, and KIT D816V allele burden.ResultsThe number of MRGPRX2-expressing (MRGPRX2+) cells, MRGPRX2-mRNA+ MCs, and CST-expressing (CST+) and MBP-expressing (MBP+) cells was significantly higher in lesional skin as compared to non-lesional skin and/or skin of healthy controls (all p < 0.05). Increased numbers of MRGPRX2+ cells, MRGPRX2-mRNA+ MCs, and CST+ and MBP+ cells were not associated with clinical and laboratory features of ISM, including disease burden, symptom severity, evidence of anaphylaxis, and tryptase levels.ConclusionsSkin lesions of patients with ISM showed high numbers of MRGPRX2+ cells, although they were not linked to symptom severity. Clinical relevance of the MRGPRX2-mediated pathway of MC activation in ISM remains unclear and should be investigated in further studies.

Steroidal alkaloid cortistatin is a promising marine natural compound isolated from marine sponges Corticium simplex. Experimental studies and clinical evidence have shown that cortistatin and its derivatives have a curative effect in patients with autoimmune disorders, HIV infection and several types of cancer. The objective of our study was to examine the potential cancer-related therapeutic objectives of Cortistatin using a network pharmacology method, which is a computational approach, including inverse pharmacophore research, enrichment analysis, molecular docking and dynamics study. Systematic protocol also involves the assessment of ADMET parameters to define the pharmacokinetic profile of cortistatin. Inverse pharmacophore search method was used for computational target fishing and target proteins were ranked based on the graph theory approach. Cancer target proteins, namely HSP90, EGFR, CDK2, MMP13, MAPK13, AR, ESR1, PTPN11 and SRC, were classified as top-ranking proteins according to graph theory parameters, namely MCC, DMNC, MNC, Degree(Local-based methods), EPC, Bottleneck, Eccentricity, Closeness, Radiality, Betweenness, Stress(Global-based methods) and Clustering Coefficient. Enrichment assessment established on Gene Ontology and pathway analysis of these proteins that play a vital role in cancer pathways, FaxO Signalling pathways, Ras Signalling pathways and tyrosine metabolism. Molecular docking and dynamic simulation studies of cortistatin with proposed target proteins were found to be stable and conformers generated after 3ns were consistent with stable inter-molecular interactions. The current study summarized here would provide a broad perspective on the therapeutic potential of cortistatin and provide new insights into the future development of cancer therapy strategies. [ABSTRACT FROM AUTHOR]

Cortistatin (CST), an endogenous bioactive polypeptide, has been acknowledged for its protective effect against several cardiovascular diseases, but its relationship with hypertension remains unclear. Therefore, we aimed to investigate changes in plasma CST in hypertensive patients and further analyze correlations with blood pressure, metabolic parameters and left ventricular structure and function. In this hospital-based study, basic information and plasma samples for evaluating clinically relevant indicators such as total cholesterol (TC), triglycerides (TGs), fasting blood glucose (FGB), serum creatinine (Scr) and CST were collected from 81 essential hypertension patients and 75 normotensive subjects. Plasma CST levels were examined by enzyme-linked immunosorbent assay (ELISA). Compared with normotensive subjects, plasma CST was significantly lower in hypertensive patients. Plasma CST levels in hypertensive patients without blood pressure control was significantly lower than those of hypertensive patients with blood pressure control. Plasma CST levels were significantly negatively correlated with SBP and serum creatinine (Scr) in the overall population. Furthermore, multivariate logistic regression analysis showed that the OR of CST for hypertension was 0.64 using the unadjusted model, and there was still statistical significance using the four-adjusted model. The circulating concentration of CST was significantly lower in hypertensive patients and was higher after blood pressure control, suggesting that CST may be a new endogenous protective target for hypertension. • The circulating CST was significantly decreased in hypertensive patients and increased after blood pressure controlled. • CST may be a new endogenous protective target for hypertension. • CST is an indicator for hypertension risk stratification, diagnosis and treatment monitoring. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the anti-inflammatory effect of cortistatin (CST) in endotoxin-induced uveitis (EIU) model and to compare the results with corticosteroid treatment. Methods: A total of 35 healthy Wistar albino rats were randomly divided into five groups. EIU was induced by a single subcutaneous injection of lipopolysaccharide (LPS). Group I received intraperitoneal (ip) normal saline (NS), Group II received ip 150 μg LPS plus NS, Group III received ip 150 μg LPS plus 250 μg/kg CST, Group IV received ip 150 μg LPS plus 1mg/kg dexamethasone, and Group V received ip 250 μg/kg CST only. The aqueous humor was collected 24 h after injection and the infiltrating cells were determined. Moreover, histopathological and immunohistochemical examinations were also performed. Results: The clinical score and infiltrated cell count were reduced in Groups III and IV compared with Group II (P < 0.001). The pathological findings of Groups III and IV were significantly reduced compared with Group II (P < 0.001). These findings were similar between Groups III and IV (P = 1.000). Tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β) immunoreactivity in the ciliary body of Group III and Group IV were significantly reduced compared with Group II (P < 0.001). TNF-α and IL-1β immunoreactivity in the ciliary body of Group III and Group IV were similar compared with Group I and Group V (range of P values was 0.539–0.958). Conclusion: CST administration as a therapeutic agent might ameliorate the severity of intraocular inflammation in uveitis patients. In conclusion, effect of CST and dexamethasone in EIU model was comparable.

Objective: To investigate the relationship between serum cortistatin(CST), humanin and vascular adhesion protein-1(VAP-1), glucose and lipid metabolism and insulin resistance in pregnant women with gestational diabetes mellitus(GDM). Methods: 79 patients with GDM(GDM group) admitted to the department of Obstetrics and gynecology of our hospital from January 2017 to October2019 were selected. In addition, 52 normal pregnant women(NGT group) who came to our hospital for antenatal examination in the same period were selected. Serum level of CST, humanin, and VAP-1 were detected and compared, and the correlation between CST,humanin, and VAP-1 and glucose and lipid metabolism and insulin resistance in PATIENTS with GDM were analyzed. Binary Logistic regression analysis was conducted to explore the risk factors for GDM. Results: The serum CST, humanin, fasting C peptide(FC-P), C-P peak/FC-P, insulin β cell function index [HOMA-β(C-P)] levels in GDM group were lower than those in NGT group(P<0.05), VAP-1,fasting plasma glucose(FPG), insulin resistance index [HOMA-IR(C-P)], triglycerides(TG), low-density lipoprotein cholesterol(LDL-C) levels were higher than those in NGT group(P<0.05). Pearson correlation analysis showed that serum CST level were negatively correlated with FPG and HOMA-IR(C-P)(P<0.05), and positively correlated with FC-P, C-P peak/FC-P, and HOMA-β(C-P)(P<0.05). humanin level were negatively correlated with TG, FPG, HOMA-IR(C-P), and positively correlated with FC-P, C-P peak/FC-P, and HOMA-β(C-P)(P<0.05). VAP-1 were positively correlated with TG, FPG, HOMA-IR(C-P)(P<0.05), and negatively correlated with FC-P, C-P peak/FC-P and HOMA-β(C-P)(P<0.05). Binary Logistic regression analysis showed that CST, humanin,HOMA-β(C-P) decreased, and age, BMI, LDL-C, VAP-1, HOMA-IR(C-P) increased were risk factors of GMD(P<0.05). Conclusion:Serum CST and humanin levels of GDM patients are decreased, and serum VAP-1 level is increased. All of them are involved in the incidence of GDM and insulin resistance. CST is related to glucose and lipid metabolism disorder, and humanin and VAP-1 are related to glucose and lipid metabolism abnormality. [ABSTRACT FROM AUTHOR]

Somatostatin is an important modulator of neurotransmission in the central nervous system and acts as a potent inhibitor of hormone and exocrine secretion and regulator of cell proliferation in the periphery. These pleiotropic actions occur through interaction with five G protein-coupled somatostatin receptor subtypes (sst(1) (-) (5)) that are widely expressed in the brain and peripheral organs. The characterization of somatostatin's effects can be investigated by pharmacological or genetic approaches using newly developed selective sst agonists and antagonists and mice lacking specific sst subtypes. Recent evidence points toward a divergent action of somatostatin in the brain and in the periphery to regulate circulating levels of ghrelin, an orexigenic hormone produced by the endocrine X/A-like cells in the rat gastric mucosa. Somatostatin interacts with the sst(2) in the brain to induce an increase in basal ghrelin plasma levels and counteracts the visceral stress-related decrease in circulating ghrelin. By contrast, stimulation of peripheral somatostatin-sst(2) signaling results in the inhibition of basal ghrelin release and mediates the postoperative decrease in circulating ghrelin. The peripheral sst(2)-mediated reduction of plasma ghrelin is likely to involve a paracrine action of D cell-derived somatostatin acting on sst(2) bearing X/A-like ghrelin cells in the gastric mucosa. The other member of the somatostatin family, named cortistatin, in addition to binding to sst(1) (-) (5) also directly interacts with the ghrelin receptor and therefore may simultaneously modulate ghrelin release and actions at target sites bearing ghrelin receptors representing a link between the ghrelin and somatostatin systems.

Asthma is a chronic inflammatory disease affecting millions of people around the world, yet much remains unknown about its underlying mechanisms. Cortistatin (CST) is a neuropeptide which is reported to be a potential endogenous anti-inflammatory factor in several conditions. To testify the potential involvement of CST in airway inflammatory reaction, an ovalbumin (OVA)-induced mice model was established in wild-type (WT) as well as CST-knockout (Cort -/-) mice. Thereafter, lung tissue or cell samples were gathered in each group, and histological analysis as well as cell counting assay indicated that Cort -/- mice exhibited exaggeration of asthma compared with WT control group. Moreover, mRNA sequencing assay revealed that CCL2 was a potential target of CST in asthma, and administration of CCL2 inhibitor alleviated airway inflammation of asthma in Cort -/- mice. Moreover, NF-κB signaling pathway might be closely associated with the protective function of CST in asthma, as enhanced activation of NF-κB signaling pathway was observed in OVA-induced asthma model of Cort -/- mice, and SN50, an inhibitor of NF-κB signaling pathway, antagonized asthma development in Cort -/- mice. In summary, CST might represent as a promising target for the treatment of asthma through interacting with CCL2 and NF-κB signaling pathway. • Cort −/− mice exhibit exaggerated ovalbumin-induced airway inflammation compared to WT mice. • Exogenous addition of CST effectively meliorates the severity of airway inflammation. • CST protects against inflammatory airway diseases via curbing CCL2 and NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the anti-inflammatory effect of cortistatin (CST) in endotoxin-induced uveitis (EIU) model and to compare the results with corticosteroid treatment.Methods: A total of 35 healthy Wistar albino rats were randomly divided into five groups. EIU was induced by a single subcutaneous injection of lipopolysaccharide (LPS). Group I received intraperitoneal (ip) normal saline (NS), Group II received ip 150 μg LPS plus NS, Group III received ip 150 μg LPS plus 250 μg/kg CST, Group IV received ip 150 μg LPS plus 1mg/kg dexamethasone, and Group V received ip 250 μg/kg CST only. The aqueous humor was collected 24 h after injection and the infiltrating cells were determined. Moreover, histopathological and immunohistochemical examinations were also performed.Results: The clinical score and infiltrated cell count were reduced in Groups III and IV compared with Group II (P < 0.001). The pathological findings of Groups III and IV were significantly reduced compared with Group II (P < 0.001). These findings were similar between Groups III and IV (P = 1.000). Tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β) immunoreactivity in the ciliary body of Group III and Group IV were significantly reduced compared with Group II (P < 0.001). TNF-α and IL-1β immunoreactivity in the ciliary body of Group III and Group IV were similar compared with Group I and Group V (range of P values was 0.539-0.958).Conclusion: CST administration as a therapeutic agent might ameliorate the severity of intraocular inflammation in uveitis patients. In conclusion, effect of CST and dexamethasone in EIU model was comparable. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate serum cortistatin (CST) levels in patients with ocular active and ocular inactive Behçet disease (BD) and its relationship with disease activity.Methods: 24 BD patients with ocular active, 24 BD patients with ocular inactive patients and 24 healthy control subjects were included in the study.Results: In ocular active and ocular inactive BD patients and healthy control subjects, the mean serum CST levels were 4.38 ± 1.63ng/ml, 5.46 ± 1.81ng/ml and 7.56 ± 1.73ng/ml, respectively. ESR, serum CRP, CST levels and NLR were significantly different between the groups (p < 0.001 for all). The CST levels were similar between ocular active and inactive BD patient groups (p = 0.197). ESR, CRP and NLR were significantly higher in ocular active BD patients compared to ocular inactive BD patients and healthy control subjects (p < 0.05 for all).Conclusion: Serum CST level was significantly lower in BD patients. CST may be a neuropeptide that plays a role in the pathogenesis of BD. [ABSTRACT FROM AUTHOR]

Objective: To investigate serum cortistatin levels in women with gestational diabetes mellitus (GDM) and women with uncomplicated pregnancies.Material and methods: This case-control study consisted of 40 pregnancies with GDM and 41 healthy singleton pregnancies matched for maternal and gestational age. The maternal serum levels of cortistatin were measured with enzyme-linked immunosorbent assay and compared between groups.Results: Cortistatin levels were significantly lower in GDM group (48.85 ± 20.18 versus 65.84 ± 33.98 ng/ml, p = .008). There was a statistically significant difference in cortistatin levels between different treatment modalities and control group (χ2(2) = 8.828, p = .012). Pairwise comparisons showed that diet group had significantly lower CST levels than control group (p = .012). Serum cortistatin levels were negatively correlated with serum insulin and glucose levels and HOMA-IR (r = -0.358, p = .001; r = -0.303, p = .006; r = -0.444, p < .001, respectively).Conclusion: Cortistatin levels were significantly lower in GDM pregnancies and related to serum insulin and glucose levels and HOMA-IR in pregnancy. This may help to better clarify the mechanism of GDM pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract Although there is growing evidence that cortistatin regulates several functions in different tissues, its role in the endocrine pancreas is not totally known. Here, we aim to study the effect of cortistatin on pancreatic beta-cells and glucose-stimulated insulin secretion (GSIS). Exposure of isolated mouse islets to cortistatin inhibited GSIS. This effect was prevented using a somatostatin receptor antagonist. Additionally, cortistatin hyperpolarized the membrane potential and reduced glucose-induced action potentials in isolated pancreatic beta-cells. Cortistatin did not modify ATP-dependent K+ (K ATP) channel activity. In contrast, cortistatin increased the activity of a small conductance channel with characteristics of G protein-coupled inwardly rectifying K+ (GIRK) channels. The cortistatin effects on membrane potential and GSIS were largely reduced in the presence of a GIRK channel antagonist and by down-regulation of GIRK2 with small interfering RNA. Thus, cortistatin acts as an inhibitory signal for glucose-induced electrical activity and insulin secretion in the mouse pancreatic beta-cell. Graphical abstract Image 1 Highlights • Cortistatin inhibited glucose-stimulated insulin secretion from mouse islets. • Cortistatin induced plasma membrane hyperpolarization in pancreatic beta-cells. • This peptide did not affect the activity of K ATP channels. • Cortistatin activated channels with characteristics of GIRK channels. • Down-regulation and antagonism of GIRK channels prevented the cortistatin effects. [ABSTRACT FROM AUTHOR]

Signaling of brain-derived neurotrophic factor (BDNF) via tropomyosin receptor kinase B (TrkB) plays a critical role in the maturation of cortical inhibition and controls expression of inhibitory interneuron markers, including the neuropeptide cortistatin (CST). CST is expressed exclusively in a subset of cortical and hippocampal GABAergic interneurons, where it has anticonvulsant effects and controls sleep slow-wave activity (SWA). We hypothesized that CST-expressing interneurons play a critical role in regulating excitatory/inhibitory balance, and that BDNF, signaling through TrkB receptors on CST-expressing interneurons, is required for this function. Ablation of CST-expressing cells caused generalized seizures and premature death during early postnatal development, demonstrating a critical role for these cells in providing inhibition. Mice in which TrkB was selectively deleted from CST-expressing interneurons were hyperactive, slept less and developed spontaneous seizures. Frequencies of spontaneous excitatory post-synaptic currents (sEPSCs) on CST-expressing interneurons were attenuated in these mice. These data suggest that BDNF, signaling through TrkB receptors on CST-expressing cells, promotes excitatory drive onto these cells. Loss of excitatory drive onto CST-expressing cells that lack TrkB receptors may contribute to observed hyperexcitability and epileptogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Aim: Cortistatin (CST) is a newly discovered endogenous active peptide that exerts protective effects on the cardiovascular system. However, the relationship between CST and aortic calcification and the underlying mechanism remain obscure. Therefore, we investigated effects of CST on aortic calcification and its signalling pathways. Methods: Calcium content and alkaline phosphatase (ALP) activity were measured using the o‐cresolphthalein colorimetric method and ALP assay kit respectively. Protein expression of smooth muscle (SM)‐ɑ‐actin, osteocalcin (OCN), β‐catenin, glycogen synthase kinase 3β (GSK3β), p‐GSK3β, protein kinase C (PKC), p‐PKC, c‐Jun N‐terminal kinase (JNK) and p‐JNK was determined using Western blotting. Results: In aorta from a rat vitamin D3 calcification model, CST abrogated calcium deposition and pathological damage, decreased the protein expression of OCN and β‐catenin and increased SM‐ɑ‐actin expression. In a rat cultured vascular smooth muscular cell (VSMC) calcification model induced by β‐glycerophosphate (β‐GP), CST inhibited the increase in ALP activity, calcium content and OCN protein and the decrease in SM‐α‐actin expression. CST also inhibited the β‐GP‐induced increase in p‐GSK3β and β‐catenin protein (both P < .05). The inhibitory effects of CST on ALP activity, calcium deposition and β‐catenin protein were abolished by pretreatment with lithium chloride, a GSK3β inhibitor. CST promoted the protein expression of p‐PKC by 68.5% (P < .01), but not p‐JNK. The ability of CST to attenuate β‐GP‐induced increase in ALP activity, calcium content and OCN expression in the VSMC model was abolished by pretreatment with the PKC inhibitor Go6976. Conclusion: These results indicate that CST inhibits aortic calcification and osteogenic differentiation of VSMCs likely via the GSK3β/β‐catenin and PKC signalling pathways, but not JNK signalling pathway. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the role of cortistatin (CST) on cyclosporine A (CsA)-induced myocardial apoptosis in rats and determine its effect on the expressions of myocardial apoptosis genes. MATERIALS AND METHODS: H9C2 cells were treated with different concentrations of CsA solution (0.04, 0.2, 1 and 5 μM) for 24, 48 and 72 h, respectively. The cell viability was detected via methyl thiazolyl tetrazolium (MTT) assay, and the appropriate dose and time were compared and determined. At the same time, CST in different concentrations (0.08, 0.04, 0.2, 1, 5 and 25 μM) was added into cell culture, and the appropriate dose was identified using MTT assay. The cellular morphology in each group was observed, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was performed for the detection of cell apoptosis. Moreover, in molecular mechanism research, the apoptosis-associated factors, factor associated suicide (Fas), Fas ligand (FasL) and B-cell lymphoma-2-associated X protein (Bax), were detected via quantitive Real-time polymerase chain reaction (qPCR). Finally, the levels of a protein related to myocardial apoptosis in rats were investigated via Western blotting. RESULTS: The treatment with 1 μM CsA for 48 h caused significant apoptosis. The results of TUNEL staining showed the inhibitory role of CST on the myocardial apoptosis in rats induced by CsA. The detection of apoptosis factors via Real-time PCR revealed that after the induction of CsA, the expressions of Fas, FasL and Bax mRNA in cells were significantly higher than those in control group, but were significantly decreased after administration of CST. Western blotting showed that the protein expressions of Caspase 3 and Caspase 9 were remarkably elevated in cells after the use of CsA, but were significantly reduced after administration of CST (p < 0.01). CONCLUSIONS: CST contributes to antagonistic function against the CsA-induced apoptosis of rat myocardial cells, and its effect is related to the down-regulation of expressions of apoptotic factors, Fas, FasL, Bax, Caspase 3, and Caspase 9. [ABSTRACT FROM AUTHOR]

Long‑term exposure to ultraviolet (UV) radiation is associated with pathological alterations of the retinal pigment epithelium (RPE). It has been indicated that Cortistatin (CST) and somatostatin (SST) are able to inhibit the neurodegeneration of the RPE associated with diabetic retinopathy and retinal ischemia via activation of SST receptors (SSTRs). To the best of our knowledge, the present study indicated for the first time that treatment with UV‑A (30 and 60 min) causes an increase of CST expression, rather than SST, which was linked with the upregulation of STTR3,4,5 subtype receptor gene expression levels. The study revealed that: i) SST and CST mRNA expression were both detected under basal conditions in a human retinal pigment epithelial cell line (Arpe‑19); ii) SST expression remained constant from baseline to 1 h of UV‑A treatment; iii) CST mRNA expression levels were 80 times increased compared with time 0 and after 30 min of exposition to ultraviolet irradiation; iv) SSTR1, SSTR2 mRNA and low levels of SSTR4 were expressed in basal conditions, whereas SSTR3 and SSTR5 mRNA were not detected under the same conditions; and v) only SSTR3, SSTR4 and SSTR5 were overexpressed after UV‑A treatment, although in a different way. In conclusion, the findings provide reasonable evidence to support the pathophysiological role of the CST/SST/SSTRs system in the adaptive response of the RPE exposed to UV‑A radiation. [ABSTRACT FROM AUTHOR]

Abdominal aortic aneurysm (AAA) is a fatal disease that is associated with chronic inflammation in the vessel wall. Cortistatin is implicated in inflammation, vascular smooth muscle cell migration and other cardiovascular pathologies. But, the hypothetical effect of cortistatin on AAA remains uncertain. We investigated the effect of cortistatin administration to angiotensin (Ang) II-induced AAA formation in apolipoprotein E deficient (Apoe −/− ) mice. We showed that cortistatin administration significantly suppresses incidence and severity of AAA in Apoe −/− mice. A significant increase in macrophage infiltration, excretion of inflammatory cytokines, activities and expression levels of MMP2 and MMP9, reactive oxygen species levels and cell apoptosis in aneurysmal aortic wall of Apoe −/− mice infused with Ang-II, and these events were significantly alleviated by co-treatment with cortistatin. Mechanistic studies showed that the protective effects of cortistatin were related to the blocking of ERK1/2 signaling pathways, while does not was not actually affect JNK, P38 phosphorylation. In conclusion, cortistatin appears to play an essential role in the formation of AAA and indicate cortistatin may as novel therapeutic option for AAA. [ABSTRACT FROM AUTHOR]

Berberine, an isoquinoline alkaloid, has been reported to ameliorate various autoimmune diseases including rheumatoid arthritis by oral administration. However, its mechanism remains mysterious due to an extremely low bioavailability. The fact that berberine readily accumulates in the gut, the largest endocrine organ in the body, attracted us to explore its antiarthritic mechanism in view of the induction of intestinal immunosuppressive neuropeptides. In this study, berberine (200 mg kg-1, i.g.) was shown to ameliorate collagen-induced arthritis in rats, which was manifested by the reduction of clinical signs and joint destruction, as well as marked down-regulation of Th17 cell frequency and interleukin-17 level in blood. In contrast, an intravenous injection of berberine failed to affect arthritis in rats, implying that its anti-arthritic effect was gut-dependent. Further studies revealed that oral berberine selectively elevated the levels of cortistatin, of five gut-derived neuropeptides tested, in the intestines and sera of arthrititic rats. Antagonists of ghrelin/growth hormone secretagogue receptor 1 (a subtype of cortistatin receptor) almost completely abolished the ameliorative effect of berberine on arthritis and Th17 cell responses in rats. In vitro, berberine showed a moderate ability to promote the expression of cortistatin in nerve cells, which was strengthened when the nerve cells were cocultured with enteroendocrine cells to induce an autocrine/paracrine environment. In summary, oral berberine exerted anti-arthritic effect through inhibiting the Th17 cell response, which was closely associated with the induction of cortistatin generation from gut through augmenting autocrine/paracrine action between enteric nerve cells and endocrine cells. [ABSTRACT FROM AUTHOR]

Cortistatin (CST) is a recently discovered cyclic neuropeptide with multiple bioactive effects. The aim of this study was to investigate the relationship between plasma CST and various metabolic markers in patients with newly diagnosed type 2 diabetes mellitus (T2DM). For this study, 60 patients with newly diagnosed T2DM and 38 age- and gender-matched healthy controls were recruited. Fasting plasma glucose (FPG), serum insulin and hemoglobin A 1c (HbA 1c ) levels and a blood lipid profile were obtained with commercially available diagnostic reagents. CST plasma levels were determined using an enzyme immunoassay kit. The results showed that the plasma levels of CST were substantially lower in patients with newly diagnosed T2DM compared with the healthy controls. Plasma CST levels were positively correlated with high-density lipoprotein and negatively related to FPG, serum insulin, the homeostasis model assessment of insulin resistance (HOMA-IR) and HbA 1c in all subjects. Further analysis showed that CST levels were positively correlated with systolic blood pressure and negatively correlated with FPG, serum insulin, HOMA-IR and HbA 1c in patients with newly diagnosed T2DM. Moreover, logistic regression analyses indicated that plasma CST was correlated with newly diagnosed T2DM. In conclusion, patients with newly diagnosed T2DM had significantly lower plasma levels of CST than healthy controls, and plasma CST was associated with glucose metabolism and insulin resistance, indicating a potential role of CST in the development of T2DM. [ABSTRACT FROM AUTHOR]

The chemical synthesis of secosterols is an arena for the application of C-H functionalization methods as well as C-C manipulations. Studies on the innate reactivity of synthetic intermediates to undergo C-C scissions and rearrangements can shed light on biosynthetic pathways, or, provide proof for biosynthetic proposals. Examples of the authors work (synthesis of the 14,15-secosterol strophasterol A), as well as examples from current literature (Tian's synthetic work on 13,14:14,15-disecosterols glaucogenins C and D, and Baran's synthesis of 9,10-secosterol cortistatin A) are discussed. 1 Introduction 2 The Synthesis of Strophasterol A Employing the Concept of Innate Reactivity 3 Synthetic Work in the Glaucogenin Family of Natural Products 4 The Synthesis of Cortistatin A Using a Radical Ring Expansion 5 Conclusion. [ABSTRACT FROM AUTHOR]

Cortistatin is a neuropeptide originally identified in cortical brain regions, which displays a high structural and functional homology with somatostatin. However, cortistatin possesses distinct, unique functions, in the immune and central nervous systems, and it also shows specific endocrine effects, particularly on pituitary growth hormone, prolactin and adrenocorticotropin axes. Somatostatin and cortistatin bind similarly to the five native somatostatin receptors, sst1-sst5, whereas both compounds bind differentially to the recently discovered truncated variants of the sst subtype 5 (sst5TMD4, sst5TMD5); moreover, only cortistatin is able to bind other non-sst receptors (GHS-R and MrgX2). The non-overlapping tissue-specific distribution of each neuropeptide, together with the differential receptor binding profile, may be the cause of the singular effects of cortistatin. In this review we have provided and overview of the role of cortistatin on pituitary function by summarizing: 1) Its direct effect on pituitary cells using in vitro primary cultures derived from different species (from chicken to human); 2) Its putative physiological role revealed by in vivo assays, enabling to explore cortistatin effects on growth hormone, prolactin and adrenocorticotropin axes; and 3) The information provided by studying cortistatin knock-out mice. Altogether, these studies provide compelling evidence that cortistatin is a singular regulator of endocrine function, distinct from somatostatin. [ABSTRACT FROM AUTHOR]

RA attenuates MRGPRX2-PLCγ1-PKC-NF-κB and PLC-IP3R-Ca2+signaling pathway. [Display omitted] • Rosmarinic acid ameliorates skin inflammation and pruritus in ACD. • RA regulated MRGPRX2-PLCγ1-PKC-NF-κB signaling pathway. • RA directly act on MRGPRX2 receptor expression to ameliorate ACD. Allergic contact dermatitis (ACD) is one of the most common dermatoses, which has high disease burden and quality of life impairment. Anti-histamine is not effective in a part of the ACD patients. Thus, the discovery of novel antipruritic therapy is of highly demand. In this study, we investigated the anti-pruritic effects of rosmarinic acid (RA) and explored the underlying mechanism. SPF Balb/c mice were randomly divided into control group, ACD model group, RA group (1.0 mg/kg) and loratadine (LORA) group (1.5 mg/kg). Back epidermal thickness was recorded. H&E staining was used for pathological observation. Mast cell degranulation was assessed by toluidine blue staining. ELISA assay was employed to detect cytokines levels. Cortistatin-14 (CST-14) and Mas-related G protein-coupled receptor X2 (MRGPRX2) expression was detetcted by RT-PCR and western blot. Molecular docking assay was used to predict the affinity of RA and MRGPRX2. Surface plasmon resonance (SPR) assay was used to verify structure affinity of RA and MRGPRX2. RA treatment significantly decreased epidermal keratinization and inflammatory cell infiltration in ACD mouse model. Administration of RA significantly reduced secretion of histamine, IL-13, and mRNA expression of CST-14. Furthermore, RA treatment increased mRNA expression of MRGPRX2. In addition, Molecular docking results predict that RA has a good affinity with MRGPRX2. RA displayed a structure affinity (K D = 8.89 × 10-4) with MRGPRX2 by SPR. RA inhibited CST-14 and Compound 48/80 (C48/80)-induced mast cell activation via MRGPRX2-PLCγ1-PKC-NF-κB signaling pathway. RA exhibits anti-pruritic and anti-inflammatory effects in ACD mice by inhibiting MRGPRX2-PLCγ1-PKC-NF-κB signaling pathway. RA might emerge as a potential drug for the treatment of pruritus and skin inflammation in the setting of ACD. [ABSTRACT FROM AUTHOR]

Estuarine tapertail anchovy (Coilia nasus) is a rare and endangered species and also an important resource with high economic value. Somatostatin (SS) is a neuropeptide family which effects growth, development and metabolism. In this study, full-length of one type of SS cDNA from C. nasus was synthesized, cloned and sequenced. This SS cDNA encodes a protein with 114 amino acids that contains the SS14 sequence at its C-terminus. This putative peptide is identical to that generated by the SS1 gene in other vertebrates. Tissue distribution of C. nasus SS1 mRNA was analyzed by real-time polymerase chain reaction (PCR), which demonstrated high expression level in the brain. During embryogenesis, SS1 mRNA was detected during early-stage embryonic development, decreased during subsequent developmental stages then increased gradually from the stage of midgastrula onward. This study provides some basic evidence that SS1 may play a role in growth, development and metabolism in C. nasus, and provides a basis for further study of SS neuropeptide family in C. nasus. [ABSTRACT FROM AUTHOR]

Objectives:: The endoplasmic reticulum (ER) stress-induced apoptotic pathway is associated with the development of acute myocardial infarction (AMI). Cortistatin (CST) is a novel bioactive peptide that inhibits apoptosis-related injury. Therefore, we investigated the cardioprotective effects and potential mechanisms of CST in a rat model of AMI.Methods:: Male Wistar rats were randomly divided into sham, AMI, and AMI + CST groups. Cardiac function and the degree of infarction were evaluated by echocardiography, cardiac troponin I activity, and 2,3,5-triphenyl-2H-tetrazolium chloride staining after 7 days. The expression of CST, ER stress markers, and apoptotic markers was examined using immunohistochemistry and Western blotting.Results:: Compared to the AMI group, the AMI + CST group exhibited markedly better cardiac function and a lower degree of infarction. Electron microscopy and terminal deoxynucleotidyl transferase dUTP nick end labeling confirmed that myocardial apoptosis occurred after AMI. Cortistatin treatment reduced the expression of caspase 3, cleaved caspase 3, and Bax (proapoptotic proteins) and promoted the expression of Bcl-2 (antiapoptotic protein). In addition, the reduced expression of glucose-regulated protein 94 (GRP94), glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding proteins homologous protein, and caspase 12 indicated that ER stress and the apoptotic pathway associated with ER stress were suppressed.Conclusions:: Exogenous CST has a notable cardioprotective effect after AMI in a rat model in that it improves cardiac function by suppressing ER stress and myocardial apoptosis. [ABSTRACT FROM AUTHOR]

Objectives CST has been recently identified as a mediator of various beneficial effects in animal models of sepsis. At present, no data are available concerning the levels of CST in sepsis patients. In sepsis the plasma amino acid pattern is characterized by decreased branced chain amino acids (BCAAs). We investigated the levels of plasma CST or branched-chain α-ketoacid dehydrogenase kinase (BCKDK) and their relationship to component traits in patients with sepsis. Design and methods We studied 228 patients and divided them into two groups based on severity of infection. Blood samples were taken at study entry, and CST, BCKDK were measured. Results CST and BCKDK levels were significantly higher in patients with sepsis than in controls: the median plasma CST concentration was 103.1 ng/ml (range, <83.13–189.7 ng/ml) in patients with sepsis and 49.69 ng/ml (range, <19.38–100.8 ng/ml) in controls ( p = 0.0022); the median plasma BCKDK concentration was 801.7 ng/ml in sepsis group and 745 ng/ml in controls ( p = 0.0292). Additionally, there was correlation between the plasma concentrations of CST and BCKDK in sepsis patients (r 2 = 0.6357, p < 0.01). Conclusions We conclude that the plasma levels of CST in sepsis patients were higher than in controls, and there is a relationship between CST and BCKDK in sepsis patients. Future experimental and clinical studies are needed to evaluate CST as a novel prognostic tool in sepsis patients and its potential therapeutic use in sepsis. [ABSTRACT FROM AUTHOR]

Accumulating evidence has indicated that vascular smooth muscular cells (VSMCs) play an important role in the development of vascular calcification (VC). Cortistatin (CST), a novel bio-active peptide, has been shown to exert multiple protective effects on the cardiovascular system. However, the role and possible mechanism of CST in VC remain unclear. Therefore, we used β-glycerophosphoric acid (β-GP) to induce calcification in rat and human VSMCs to determine the effects of CST on osteoblastic differentiation and VSMC mineralization in vitro. Compared with the control, β-GP significantly increased alkaline phosphatase (ALP) activity and calcium content in cultured rat and human VSMCs, as well as multicellular node formation and calcium deposition, as confirmed by von Kossa and Alizarin Red S staining assays. After incubating rat and human VSMCs with β-GP in the presence of different doses of CST (10 or 10 mol/L), CST clearly reversed the β-GP-induced increases in ALP activity and calcium content and formation of pathological calcified nodes of VSMCs in a dose-independent manner. Moreover, 10 and 10 mol/L CST inhibited the phenotypic transformation of VSMCs into osteoblastic cells by decreasing the osteocalcin protein levels, increasing the SM-α-actin protein levels, and reducing endoplasmic reticulum stress by decreasing the protein expression of glucose-regulated protein 94 and CCAAT/enhancer-binding protein homologous protein. In conclusion, CST directly inhibited β-GP-induced calcification of VSMCs in vitro, probably by suppressing ERS and phenotypic transformation of VSMCs into osteoblastic cells. These results indicate that CST represents a potential target for the prevention and treatment of VC. [ABSTRACT FROM AUTHOR]

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are essential factors in mammary-gland (MG) development and are altered during fasting. However, no studies have investigated the alterations in the expression of GH/IGF-I and its regulatory systems (somatostatin/cortistatin and ghrelin) in MG during fasting. Therefore, this study was aimed at characterizing the regulation of GH/IGF-I/somatostatin/cortistatin/ghrelin-systems expression in MG of fasted female-mice (compared to fed-controls) and the influence of endogenous-cortistatin (using cortistatin-knockouts). Fasting decreased IGF-I while increased IGF-I/Insulin-receptors expression in MGs. Fasting provoked an increase in GH expression that might be associated to enhanced ghrelin-variants/ghrelin-O-acyl-transferase enzyme expression, while an upregulation of somatostatin-receptors was observed. However, cortistatin-knockouts mice showed a decrease in GH and somatostatin receptor-subtypes expression. Altogether, we demonstrate that GH/IGF-I, somatostatin/cortistatin and ghrelin systems expression is altered in MG during fasting, suggesting a relevant role in coordinating its response to metabolic stress, wherein endogenous cortistatin might be essential for an appropriate response. [ABSTRACT FROM AUTHOR]

Background: Somatostatin (SST) and cortistatin (CORT), two structurally and functionally related peptides, share a family of widespread receptors (sst1-5) to exert apparently similar biological actions, including endocrine/metabolic regulation and suppression of tumor cell proliferation. However, despite their therapeutic potential, attempts to apply SST-analogs to treat breast cancer have yielded unsatisfactory results. Actually, the specific roles of SST and CORT in mammary gland tumorigenesis (MGT), particularly in relation to metabolic dysregulation (i.e. obesity), remain unknown.Methods: The role of endogenous SST and CORT in carcinogen-induced MGT was investigated under normal (lean) and obesity conditions. To that end, SST- and CORT-knockout (KO) mice and their respective littermate-controls, fed low-fat (LF) or high-fat (HF) diets, were treated with 7,12-dimethyl-benza-anthracene (DMBA) once a week (wk) for 3 wk, and MGT was monitored for 25 wk. Additionally, we examined the effect of SST or CORT removal in the development of the mammary gland.Results: Lack of SST did not alter DMBA-induced MGT incidence under lean conditions; conversely, lack of endogenous CORT severely aggravated DMBA-induced MGT in LF-fed mice. These differences were not attributable to altered mammary gland development. HF-diet modestly increased the sensitivity to DMBA-induced carcinogenesis in control mice, whereas, as observed in LF-fed CORT-KO, HF-fed CORT-KO mice exhibited aggravated tumor incidence, discarding a major influence of obesity on these CORT actions. In marked contrast, HF-fed SST-KO mice exhibited much higher tumor incidence than LF-fed SST-KO mice, which could be associated with higher mammary complexity.Conclusions: Endogenous SST and CORT distinctly impact on DMBA-induced MGT, in a manner that is strongly dependent on the metabolic/endocrine milieu (lean vs. obese status). Importantly, CORT, rather than SST, could represent a major inhibitor of MGT under normal/lean-conditions, whereas both neuropeptides would similarly influence MGT under obesity conditions. The mechanisms mediating these different effects likely involve mammary development and hormones, but the precise underlying factors are still to be fully elucidated. However, our findings comprise suggestive evidence that CORT-like molecules, rather than classic SST-analogs, may help to identify novel tools for the medical treatment of breast cancer. [ABSTRACT FROM AUTHOR]