AIM: To investigate the influence of experimental obstructive jaundice and exogenous bombesin (BBS) and neurotensin (NT) administration on the expression of the tight junction (TJ)-protein claudin-4 in intestin...AIM: To investigate the influence of experimental obstructive jaundice and exogenous bombesin (BBS) and neurotensin (NT) administration on the expression of the tight junction (TJ)-protein claudin-4 in intestinal epithelium of rats. METHODS: Forty male Wistar rats were randomly divided into five groups: Ⅰ = controls, Ⅱ = sham operated,Ⅲ = bile duct ligation (BDL),Ⅳ = BDL+BBS (30μg/kg per d), V = BDL+NT (300μg/kg per d). At the end of the experiment on d 10, endotoxin was measured in portal and aortic blood. Tissue sections of the terminal ileum were examined histologically and immunohistochemically for evaluation of claudin-4 expression in intestinal epithelium. RESULTS: Obstructive jaundice led to intestinal barrier failure demonstrated by significant portal and aortic endotoxemia. Claudin-4 expression was significantly increased in the upper third of the villi in jaundiced rats and an upregulation of its lateral distribution was noted. Administration of BBS or NT restored claudin-4 expression to the control state and significantly reduced portal and aortic endotoxemia. CONCLUSION: Experimental obstructive jaundice increases claudin-4 expression in intestinal epithelium,which may be a key factor contributing to the disruption of the mucosal barrier. Gut regulatory peptides BBS and NT can prevent this alteration and reduce portal and systemic endotoxemia.展开更多
AIM:To investigate the effects of bombesin (BBS) and neurotensin (NTS) on apoptosis and colitis in an ulcerative colitis model. METHODS:In this study, a total of 50 rats were divided equally into 5 groups. In the cont...AIM:To investigate the effects of bombesin (BBS) and neurotensin (NTS) on apoptosis and colitis in an ulcerative colitis model. METHODS:In this study, a total of 50 rats were divided equally into 5 groups. In the control group, no colitis induction or drug administration was performed. Colitis was induced in all other groups. Following the induction of colitis, BBS, NTS or both were applied to three groups of rats. The remaining group (colitis group) received no treatment. On the 11th d after induction of colitis and drug treatment, blood samples were collected for TNF-α and IL-6 level studies. Malondialdehyde (MDA), carbonyl, myeloperoxidase (MPO) and caspase-3 activities, as well as histopathological findings, evaluated in colonic tissues. RESULTS:According to the macroscopic and microscopic findings, the study groups treated with BBS, NTS and BBS + NTS showed significantly lower damage and inflammation compared with the colitis group (macroscopic score, 2.1 ± 0.87, 3.7 ± 0.94 and 2.1 ± 0.87 vs 7.3 ± 0.94;microscopic score, 2.0 ± 0.66, 3.3 ± 0.82 and 1.8 ± 0.63 vs 5.2 ± 0.78, P < 0.01). TNF-α and IL-6 levels were increased significantly in all groups compared with the control group. These increases were significantly smaller in the BBS, NTS and BBS + NTS groups compared with the colitis group (TNF-α levels, 169.69 ± 53.56, 245.86 ± 64.85 and 175.54 ± 42.19 vs 556.44 ± 49.82;IL-6 levels, 443.30 ± 53.99, 612.80 ± 70.39 and 396.80 ± 78.43 vs 1505.90 ± 222.23, P < 0.05). The colonic MPO and MDA levels were significantly lower in control, BBS, NTS and BBS + NTS groups than in the colitis group (MPO levels, 24.36 ± 8.10, 40.51 ± 8.67 and 25.83 ± 6.43 vs 161.47 ± 38.24;MDA levels, 4.70 ± 1.41, 6.55 ± 1.12 and 4.51 ± 0.54 vs 15.60 ± 1.88, P < 0.05). Carbonyl content and caspase-3 levels were higher in the colitis and NTS groups than in control, BBS and BBS + NTS groups (carbonyl levels, 553.99 ± 59.58 and 336.26 ± 35.72 vs 209.76 ± 30.92, 219.76 ± 25.77 and 220.34 ± 36.95;caspase-3 levels, 451.70 ± 68.27 and 216.20 ± 28.17 vs 28.60 ± 6.46, 170.50 ± 32.37 and 166.50 ± 30.95, P < 0.05). CONCLUSION:The results of this study suggest BBS and NTS, through their anti-inflammatory actions, support the maintenance of colonic integrity and merit consideration as potential agents for ameliorating colonic inflammation.展开更多
AIM: To explore the association of neurotensin receptor 1 (NTSR1) with inflammatory bowel diseases (IBD) and colitis-associated neoplasia. METHODS: NTSR1 was detected by immunohistochemistry in clinical samples of col...AIM: To explore the association of neurotensin receptor 1 (NTSR1) with inflammatory bowel diseases (IBD) and colitis-associated neoplasia. METHODS: NTSR1 was detected by immunohistochemistry in clinical samples of colonic mucosa with IBD colitis, colitis-associated raised low-grade dysplasia (LGD) including dysplasia-associated lesions or masses (DALMs, n = 18) and adenoma-like dysplastic polyps (ALDPs, n = 4), colitis-associated high-grade dysplasia (HGD, n = 11) and colitis-associated colorectal carcinoma (CACRC, n = 13), sporadic colorectal adenomatous polyp (SAP, n = 17), and sporadic colorectal carcinoma (SCRC, n = 12). The immunoreactivity of NTSR1 was semiquantitated (as negative, 1+, 2+, and 3+) and compared among different conditions.RESULTS: NTSR1 was not detected in normal mucosa but was expressed similarly in both active and inactive colitis. LGD showed a significantly stronger expression as compared with non-dysplastic colitic mucosa, with significantly more cases showing > 2+ intensity (68.75% in LGD vs 32.26% in nondysplastic mucosa, P = 0.001). However, no significant difference existed between DALMs and ALDPs. CACRC and HGD showed a further stronger expression, with significantly more cases showing 3+ intensity than that in LGD (61.54% vs 12.50% for CACRC vs LGD, P = 0.022; 58.33% vs 12.50% for CACRC/HGD vs LGD, P = 0.015). No significant difference existed between colitis-associated and non-colitic sporadic neoplasia. CONCLUSION: NTSR1 in colonic epithelial cells is overexpressed in IBD, in a stepwise fashion with sequential progress from inflammation to dysplasia and carcinoma.展开更多
AIM: To investigate the effect of regulatory peptides bombesin (BBS) and neurotensin (NT) on intestinal barrier function in partially hepatectomized rats. METHODS: Ninety male Wistar rats were randomly divided i...AIM: To investigate the effect of regulatory peptides bombesin (BBS) and neurotensin (NT) on intestinal barrier function in partially hepatectomized rats. METHODS: Ninety male Wistar rats were randomly divided into five groups: Ⅰ (n = 10): controls, Ⅱ (n = 20): sham operated, Ⅲ (n = 20): partial hepatectomy 70% (PHx), Ⅳ (n = 20): PHx+BBS (30 μg/kg/d), Ⅴ (n = 20): PHx+NT (300 μg/kg/d). Groups IV and V were treated for 8 days before PHx and 48 h post surgery. At the end of the experiment, on day 10, intestinal barrier function was assessed by measuring endotoxin concentrations in portal and aortic blood. Tissue sections of the terminal ileum were examined histologically and villus density, mucosal thickness, mitotic activity and apoptosis in crypts were assessed. In addition, ileal mucosa was analyzed for DNA and protein content and microbiological analysis was performed in cecal contents. To estimate intestinal oxidative stress, lipid peroxidation was determined on tissue homogenates from terminal ileum. RESULTS: BBS or NT administration significantly reduced portal and systemic endotoxemia observed 48 h after partial hepatectomy. In hepatectomized rats (group Ⅲ), a trend towards induction of mucosal atrophy was observed, demonstrated by the reduction of villus density, mucosal thickness, protein content and significant reduction of DNA, while these alterations were reversed by regulatory peptides administration. This trophic effect of BBS and NT was accompanied by induction of mitoses above control levels and a significant reduction of apoptosis in intestinal crypts. Intestinal lipid peroxidation was found significantly lower in PHx group and regulatory peptides exerted an antioxidant action, further decreasing this parameter of oxidative stress. The :bacterial population of E. coli and aerobic Gram (+) cocci was increased in cecal content of hepatectomized rats, while this parameter was not affected by the administration of BBS or NT. CONCLUSION: Gut regulatory peptides BBS and NT improve intestinal barrier function and reduce endotoxemia in experimental partial hepatectomy. This effect is, at least in part, mediated by their trophic, antiapoptotic, mitogenic, and antioxidant effect on the intestinal epithelium. This observation might be of potential value in patients undergoing liver resection.展开更多
Bombesin and neurotensin are neuropeptides which exert a wide spectrum of biological actions on gastrointestinal tissues influencing intestinal growth and adaptation, intestinal motility, blood flow, secretion, nutrie...Bombesin and neurotensin are neuropeptides which exert a wide spectrum of biological actions on gastrointestinal tissues influencing intestinal growth and adaptation, intestinal motility, blood flow, secretion, nutrient absorption and immune response. Based mainly on their well-established potent enterotrophic effect, numerous experimental studies investigated their potential positive effect on the atrophic or injured intestinal mucosa. These peptides proved to be effective mucosa-healing factors, but the potential molecular and cellular mechanisms for this action remained unresolved. In a recently published study (World J Gastroenterol 2008; 14(8): 1222-1230), it was shown that their protective effect on the intestine in experimentally induced inflammatory bowel disease was related to anti-inflammatory, antioxidant and antiapoptotic actions. These results are in close agreement with our previous studies on jaundiced and hepatectomized rats that showed a regulatory effect of bombesin and neurotensin on critical cellular processes such as enterocyte' proliferation and death, oxidative stress and redox equilibrium, tight junctions' formation and function, and inflammatory response. The pleiotropic effects of bombesin and neurotensin on diverse types of intestinal injury may justify their consideration for clinical trials.展开更多
Multiple sclerosis(MS)is a chronic autoimmune disease of the central nervous system(CNS)characterized by coexisting processes of inflammation,demyelination,axonal neurodegeneration,and gliosis.It is the most commo...Multiple sclerosis(MS)is a chronic autoimmune disease of the central nervous system(CNS)characterized by coexisting processes of inflammation,demyelination,axonal neurodegeneration,and gliosis.It is the most common disabling neurological disease in young adulthood.展开更多
Objective To investigate the change of neuropeptide Y(NPY)and neurotens in(NT)in pqtients with brain glioma.Method The concentration of NPY and NT in an d around brain glioma tissue and plasma were detected with inequ...Objective To investigate the change of neuropeptide Y(NPY)and neurotens in(NT)in pqtients with brain glioma.Method The concentration of NPY and NT in an d around brain glioma tissue and plasma were detected with inequilibrant radio- imunology method.Result NPY concentrqtion in brain glioma tissue was obviously h igher than that in tissue around the tumor(P<0.01).The Concentration of NT in br ain glioma tissue was obviously higher that in tissue around the glioma(P<0.01). Conclusion Detection of NPY and NT in brain gliom aprovides basis for further st udy on brain glioma and explainning clinical and imaginal symjptom of brain glio ma.展开更多
The changes of immunoreactive neurotensin(ir-NT)contents in the brain areas,pituitary gland and plasma in the traumatized rats were observed in the present study.The results of radioimmunoassay exhibited significant c...The changes of immunoreactive neurotensin(ir-NT)contents in the brain areas,pituitary gland and plasma in the traumatized rats were observed in the present study.The results of radioimmunoassay exhibited significant changes of the ir-NT contents inthe hypothalamus,pituitary gland,plasma,injured tissue,hippocampus,central gray andspinal cord in the posttraumatic rats at different intervals.A predominant characteristicsof the changes of ir-NT levels in the brain areas,pituitary gland and plasma was thedramatical decrease at various times except for the hypothalamus,central gray andhippocampus with biphasic alterations.The ir-NT contents in the frontal cortex andpons-medulla also displayed changes to different extent under the acute craniocerebraltrauma condition.These results suggest that NT may play a role in the pathophysiologyof traumatic head injury.展开更多
Neurotensin (NT) is a 13-amino acid peptide with trophic effects on some neoplasms. Its bioactivities are mainly mediated by neurotensin receptor 1 (NTSR1). Both NT and NTSR1 were found to be upregulated in breast can...Neurotensin (NT) is a 13-amino acid peptide with trophic effects on some neoplasms. Its bioactivities are mainly mediated by neurotensin receptor 1 (NTSR1). Both NT and NTSR1 were found to be upregulated in breast cancer. NT/NTSR1 thus becomes a potential therapeutic target. We studied whether any correlation exists between the expression of NTSR1 in breast carcinomas and the expression of ER, PR, and Her2. A total 85 cases of invasive ductal (62) and lobular (23) breast carcinomas were studied. Based on their ER/PR profiles, the ductal carcinomas (DCs) were subcategorized into ER+/PR+ (21), ER+/PR﹣ (20), and ER﹣/PR﹣ (21). All of the lobular carcinomas (LCs) were ER+/PR+. 21.57% of all DCs and 5.56% of LCs were Her2 positive. 77.78% of ER﹣/PR﹣ DCs were also Her2 negative (triple negative). The expression of NTSR1 was detected by immunohistochemistry and was semiquantitated (as negative, 1+, 2+, 3+). Both 2+ and 3+ were collectively defined as overexpression. The expression of NTSR1 was weak and focal in non-neoplastic mammary epithelial cells. It is increased in 74.19% of DCs (80.95% in ER+/PR+, 75% in ER+/PR﹣, and 66.67% in ER﹣/PR﹣ group), and in 95.65% of LCs. The overexpression of NTSR1 is similar between ER+ DCs and ER﹣ DCs (75% vs 66.67%, p > 0.05) as well as between PR+ DCs and PR﹣ DCs (80.95% in ER+/PR+ DCs vs 75% in ER+/PR﹣ DCs, p > 0.05). And it was seen in 77.78% of Her2+ DCs, 78.38% of Her2﹣ DCs, 94.12% of Her2﹣ LCs, and 78.57% of triple negative DCs. Overall, NTSR1 is commonly overexpressed in both ductal and lobular breast carcinomas and is independent of the ER/PR/Her2 profiles of the tumors. The present data supports the potential benefit of developing NTSR1 blockers in the adjuvant therapy of breast carcinomas, particularly for those “triple negative” tumors.展开更多
The parabrachial nucleus(PBN)integrates interoceptive and exteroceptive information to control various behavioral and physiological processes including breathing,emotion,and sleep/wake regulation through the neural ci...The parabrachial nucleus(PBN)integrates interoceptive and exteroceptive information to control various behavioral and physiological processes including breathing,emotion,and sleep/wake regulation through the neural circuits that connect to the forebrain and the brainstem.However,the precise identity and function of distinct PBN subpopulations are still largely unknown.Here,we leveraged molecular characterization,retrograde tracing,optogenetics,chemogenetics,and electrocortical recording approaches to identify a small subpopulation of neurotensin-expressing neurons in the PBN that largely project to the emotional control regions in the forebrain,rather than the medulla.Their activation induces freezing and anxiety-like behaviors,which in turn result in tachypnea.In addition,optogenetic and chemogenetic manipulations of these neurons revealed their function in promoting wakefulness and maintaining sleep architecture.We propose that these neurons comprise a PBN subpopulation with specific gene expression,connectivity,and function,which play essential roles in behavioral and physiological regulation.展开更多
目的构建与海肾荧光素酶(Rluc)融合的人Neurotensin-R1(HumanNeurotensinreceptorl,NTS1 or NTSR1)真核表达载体,用于生物发光共振能量转移法检测人NTS与其它受体间的相互作用以及研究Neurotensin—R介导的细胞内信号转导机制。...目的构建与海肾荧光素酶(Rluc)融合的人Neurotensin-R1(HumanNeurotensinreceptorl,NTS1 or NTSR1)真核表达载体,用于生物发光共振能量转移法检测人NTS与其它受体间的相互作用以及研究Neurotensin—R介导的细胞内信号转导机制。方法以质粒peDNA3.1-hNTS1为模板,PCR方法扩增人NTS。扩增的人NTS以及质粒pRluc—pcDNA3.1用NotI和XbaI双酶切,然后将这2种酶切产物按常规方法连接、转化至大肠杆菌Top10中,该菌在培养箱中孵育12~16h后,挑取菌落培养,提取质粒,进行酶切鉴定,最后进行测序。将测序正确的重组载体用脂质体法转染人胚胎肾(humanembryonickidney293,HEK293)细胞。最后,通过共聚焦显微镜观察经过免疫荧光染色的细胞以及Westernblot鉴定人Neu—rotensinl—R的表达。结果通过PCR扩增出一条1257bp的基因片段,序列与GenBank(NM-002531)相同。Westernblot中大约90kDa处有一蛋白条带,与预期大小相同。人Neurotensin—R表达在细胞膜上。结论成功构建了pRluc—hNeurotensinl—R重组表达载体,建立了该质粒转染HEK293的细胞模型。可被用于检测与其它受体间的相互作用以及研究Neurotensinl—R介导的细胞内信号转导机制,这将有助于探究疾病的发病机制及开发新的药物靶点。展开更多
Objective The globus pallidus plays a critical role in movement regulation. Previous studies have indicated that the globus pallidus receives neurotensinergic innervation from the striatum, and systemic administration...Objective The globus pallidus plays a critical role in movement regulation. Previous studies have indicated that the globus pallidus receives neurotensinergic innervation from the striatum, and systemic administration of a neurotensin analog could produce antiparkinsonian effects. The present study aimed to investigate the effects of pallidal neurotensin on haloperidol-induced parkinsonian symptoms. Methods Behavioral experiments and electrophysiological recordings were performed in the present study. Results Bilateral infusions of neurotensin into the globus pallidus reversed haloperidolinduced parkinsonian catalepsy in rats. Electrophysiological recordings showed that microinjection of neurotensin induced excitation of pallidal neurons in the presence of systemic haloperidol administration. The neurotensin type-1 receptor antagonist SR48692 blocked both the behavioral and the electrophysiological effects induced by neurotensin. Conclusion Activation of pallidal neurotensin receptors may be involved in neurotensin-induced antiparkinsonian effects.展开更多
Diabetic foot ulcers(DFU),which may lead to lower extremity amputation,is one of the severe and chronic complications of diabetic mellitus.This study aims to develop,and use dressings based on Silk fibroin(SF)as the s...Diabetic foot ulcers(DFU),which may lead to lower extremity amputation,is one of the severe and chronic complications of diabetic mellitus.This study aims to develop,and use dressings based on Silk fibroin(SF)as the scaffold material,gelatin microspheres(GMs)as the carrier for the neurotensin(NT),a neuropeptide that acts as an inflammatory modulator in wound healing and NT as accelerate wound healing drug to treat DFU.We evaluated the wound healing processes and neo-tissue formation in rat diabetic model by macroscopic observation,histological observation(H&E staining and Masson's trichrome staining)and immunofluorescence analysis at 3,7,14,21 and 28 post-operation days.Our results show that the NT/GMs/SF group performance the best not only in macroscopic healing and less scars in 28 post-operation days,but also in fibroblast accumulation in tissue granulation,collagen expression and deposition at the wound site.From release profiles,we can know the GMs are a good carrier for control release drugs.The SEM results shows that the NT/GMs/SF dressings have an average pore size are 40–80μm and a porosity of∼85%,this pore size is suit for wound healing regeneration.These results suggest that the NT/GMs/SF dressings may work as an effective support for control release NT to promote DFU wound healing.展开更多
The behavioral responses exerted by spinal administration of the opioid-neurotensin hybrid peptide, PK23, were studied in adult male rats. The antinociceptive effect upon exposure to a thermal stimulus, as well as tol...The behavioral responses exerted by spinal administration of the opioid-neurotensin hybrid peptide, PK23, were studied in adult male rats. The antinociceptive effect upon exposure to a thermal stimulus, as well as tolerance development, was assessed in an acute pain model. The PK23 chimera at a dose of 10 nmol/rat produced a potent pain-relieving effect, especially after its intrathecal administration. Compared with intrathecal morphine, this novel compound was found to possess a favourable side effect profile characterized by a reduced scratch reflex, delayed development of analgesic tolerance or an absence of motor impairments when given in the same manner, though some animals died following barrel rotation as a result of its i.c.v. administration(in particular at doses higher than 10 nmol/rat). Nonetheless, these results suggest the potential use of hybrid compounds encompassing both opioid and neurotensin structural fragments in pain management. This highlights the enormous potential of synthetic neurotensin analogues as promising future analgesics.展开更多
文摘AIM: To investigate the influence of experimental obstructive jaundice and exogenous bombesin (BBS) and neurotensin (NT) administration on the expression of the tight junction (TJ)-protein claudin-4 in intestinal epithelium of rats. METHODS: Forty male Wistar rats were randomly divided into five groups: Ⅰ = controls, Ⅱ = sham operated,Ⅲ = bile duct ligation (BDL),Ⅳ = BDL+BBS (30μg/kg per d), V = BDL+NT (300μg/kg per d). At the end of the experiment on d 10, endotoxin was measured in portal and aortic blood. Tissue sections of the terminal ileum were examined histologically and immunohistochemically for evaluation of claudin-4 expression in intestinal epithelium. RESULTS: Obstructive jaundice led to intestinal barrier failure demonstrated by significant portal and aortic endotoxemia. Claudin-4 expression was significantly increased in the upper third of the villi in jaundiced rats and an upregulation of its lateral distribution was noted. Administration of BBS or NT restored claudin-4 expression to the control state and significantly reduced portal and aortic endotoxemia. CONCLUSION: Experimental obstructive jaundice increases claudin-4 expression in intestinal epithelium,which may be a key factor contributing to the disruption of the mucosal barrier. Gut regulatory peptides BBS and NT can prevent this alteration and reduce portal and systemic endotoxemia.
基金Grant (SBAG-105S338) from the Scientific and Technical Research Council of Turkey (TUBITAK)
文摘AIM:To investigate the effects of bombesin (BBS) and neurotensin (NTS) on apoptosis and colitis in an ulcerative colitis model. METHODS:In this study, a total of 50 rats were divided equally into 5 groups. In the control group, no colitis induction or drug administration was performed. Colitis was induced in all other groups. Following the induction of colitis, BBS, NTS or both were applied to three groups of rats. The remaining group (colitis group) received no treatment. On the 11th d after induction of colitis and drug treatment, blood samples were collected for TNF-α and IL-6 level studies. Malondialdehyde (MDA), carbonyl, myeloperoxidase (MPO) and caspase-3 activities, as well as histopathological findings, evaluated in colonic tissues. RESULTS:According to the macroscopic and microscopic findings, the study groups treated with BBS, NTS and BBS + NTS showed significantly lower damage and inflammation compared with the colitis group (macroscopic score, 2.1 ± 0.87, 3.7 ± 0.94 and 2.1 ± 0.87 vs 7.3 ± 0.94;microscopic score, 2.0 ± 0.66, 3.3 ± 0.82 and 1.8 ± 0.63 vs 5.2 ± 0.78, P < 0.01). TNF-α and IL-6 levels were increased significantly in all groups compared with the control group. These increases were significantly smaller in the BBS, NTS and BBS + NTS groups compared with the colitis group (TNF-α levels, 169.69 ± 53.56, 245.86 ± 64.85 and 175.54 ± 42.19 vs 556.44 ± 49.82;IL-6 levels, 443.30 ± 53.99, 612.80 ± 70.39 and 396.80 ± 78.43 vs 1505.90 ± 222.23, P < 0.05). The colonic MPO and MDA levels were significantly lower in control, BBS, NTS and BBS + NTS groups than in the colitis group (MPO levels, 24.36 ± 8.10, 40.51 ± 8.67 and 25.83 ± 6.43 vs 161.47 ± 38.24;MDA levels, 4.70 ± 1.41, 6.55 ± 1.12 and 4.51 ± 0.54 vs 15.60 ± 1.88, P < 0.05). Carbonyl content and caspase-3 levels were higher in the colitis and NTS groups than in control, BBS and BBS + NTS groups (carbonyl levels, 553.99 ± 59.58 and 336.26 ± 35.72 vs 209.76 ± 30.92, 219.76 ± 25.77 and 220.34 ± 36.95;caspase-3 levels, 451.70 ± 68.27 and 216.20 ± 28.17 vs 28.60 ± 6.46, 170.50 ± 32.37 and 166.50 ± 30.95, P < 0.05). CONCLUSION:The results of this study suggest BBS and NTS, through their anti-inflammatory actions, support the maintenance of colonic integrity and merit consideration as potential agents for ameliorating colonic inflammation.
基金Supported by Calgary Laboratory Services Internally Supported Research, RS09-533
文摘AIM: To explore the association of neurotensin receptor 1 (NTSR1) with inflammatory bowel diseases (IBD) and colitis-associated neoplasia. METHODS: NTSR1 was detected by immunohistochemistry in clinical samples of colonic mucosa with IBD colitis, colitis-associated raised low-grade dysplasia (LGD) including dysplasia-associated lesions or masses (DALMs, n = 18) and adenoma-like dysplastic polyps (ALDPs, n = 4), colitis-associated high-grade dysplasia (HGD, n = 11) and colitis-associated colorectal carcinoma (CACRC, n = 13), sporadic colorectal adenomatous polyp (SAP, n = 17), and sporadic colorectal carcinoma (SCRC, n = 12). The immunoreactivity of NTSR1 was semiquantitated (as negative, 1+, 2+, and 3+) and compared among different conditions.RESULTS: NTSR1 was not detected in normal mucosa but was expressed similarly in both active and inactive colitis. LGD showed a significantly stronger expression as compared with non-dysplastic colitic mucosa, with significantly more cases showing > 2+ intensity (68.75% in LGD vs 32.26% in nondysplastic mucosa, P = 0.001). However, no significant difference existed between DALMs and ALDPs. CACRC and HGD showed a further stronger expression, with significantly more cases showing 3+ intensity than that in LGD (61.54% vs 12.50% for CACRC vs LGD, P = 0.022; 58.33% vs 12.50% for CACRC/HGD vs LGD, P = 0.015). No significant difference existed between colitis-associated and non-colitic sporadic neoplasia. CONCLUSION: NTSR1 in colonic epithelial cells is overexpressed in IBD, in a stepwise fashion with sequential progress from inflammation to dysplasia and carcinoma.
文摘AIM: To investigate the effect of regulatory peptides bombesin (BBS) and neurotensin (NT) on intestinal barrier function in partially hepatectomized rats. METHODS: Ninety male Wistar rats were randomly divided into five groups: Ⅰ (n = 10): controls, Ⅱ (n = 20): sham operated, Ⅲ (n = 20): partial hepatectomy 70% (PHx), Ⅳ (n = 20): PHx+BBS (30 μg/kg/d), Ⅴ (n = 20): PHx+NT (300 μg/kg/d). Groups IV and V were treated for 8 days before PHx and 48 h post surgery. At the end of the experiment, on day 10, intestinal barrier function was assessed by measuring endotoxin concentrations in portal and aortic blood. Tissue sections of the terminal ileum were examined histologically and villus density, mucosal thickness, mitotic activity and apoptosis in crypts were assessed. In addition, ileal mucosa was analyzed for DNA and protein content and microbiological analysis was performed in cecal contents. To estimate intestinal oxidative stress, lipid peroxidation was determined on tissue homogenates from terminal ileum. RESULTS: BBS or NT administration significantly reduced portal and systemic endotoxemia observed 48 h after partial hepatectomy. In hepatectomized rats (group Ⅲ), a trend towards induction of mucosal atrophy was observed, demonstrated by the reduction of villus density, mucosal thickness, protein content and significant reduction of DNA, while these alterations were reversed by regulatory peptides administration. This trophic effect of BBS and NT was accompanied by induction of mitoses above control levels and a significant reduction of apoptosis in intestinal crypts. Intestinal lipid peroxidation was found significantly lower in PHx group and regulatory peptides exerted an antioxidant action, further decreasing this parameter of oxidative stress. The :bacterial population of E. coli and aerobic Gram (+) cocci was increased in cecal content of hepatectomized rats, while this parameter was not affected by the administration of BBS or NT. CONCLUSION: Gut regulatory peptides BBS and NT improve intestinal barrier function and reduce endotoxemia in experimental partial hepatectomy. This effect is, at least in part, mediated by their trophic, antiapoptotic, mitogenic, and antioxidant effect on the intestinal epithelium. This observation might be of potential value in patients undergoing liver resection.
文摘Bombesin and neurotensin are neuropeptides which exert a wide spectrum of biological actions on gastrointestinal tissues influencing intestinal growth and adaptation, intestinal motility, blood flow, secretion, nutrient absorption and immune response. Based mainly on their well-established potent enterotrophic effect, numerous experimental studies investigated their potential positive effect on the atrophic or injured intestinal mucosa. These peptides proved to be effective mucosa-healing factors, but the potential molecular and cellular mechanisms for this action remained unresolved. In a recently published study (World J Gastroenterol 2008; 14(8): 1222-1230), it was shown that their protective effect on the intestine in experimentally induced inflammatory bowel disease was related to anti-inflammatory, antioxidant and antiapoptotic actions. These results are in close agreement with our previous studies on jaundiced and hepatectomized rats that showed a regulatory effect of bombesin and neurotensin on critical cellular processes such as enterocyte' proliferation and death, oxidative stress and redox equilibrium, tight junctions' formation and function, and inflammatory response. The pleiotropic effects of bombesin and neurotensin on diverse types of intestinal injury may justify their consideration for clinical trials.
基金Dr.Mao-Draayer has served as a consultant and/or received grant support from:Acorda,Bayer Pharmaceutical,Biogen Idec,EMD Serono,Genzyme,Novartis,Questor,Teva Neuroscience and Chugai PharmaDr.Mao-Draayeris currently supported by grants from NIH NIAID Autoimmune Center of Excellence:UM1-AI110557+1 种基金NIH NINDS R01-NS080821the University of Michigan Neurology Department
文摘Multiple sclerosis(MS)is a chronic autoimmune disease of the central nervous system(CNS)characterized by coexisting processes of inflammation,demyelination,axonal neurodegeneration,and gliosis.It is the most common disabling neurological disease in young adulthood.
文摘Objective To investigate the change of neuropeptide Y(NPY)and neurotens in(NT)in pqtients with brain glioma.Method The concentration of NPY and NT in an d around brain glioma tissue and plasma were detected with inequilibrant radio- imunology method.Result NPY concentrqtion in brain glioma tissue was obviously h igher than that in tissue around the tumor(P<0.01).The Concentration of NT in br ain glioma tissue was obviously higher that in tissue around the glioma(P<0.01). Conclusion Detection of NPY and NT in brain gliom aprovides basis for further st udy on brain glioma and explainning clinical and imaginal symjptom of brain glio ma.
文摘The changes of immunoreactive neurotensin(ir-NT)contents in the brain areas,pituitary gland and plasma in the traumatized rats were observed in the present study.The results of radioimmunoassay exhibited significant changes of the ir-NT contents inthe hypothalamus,pituitary gland,plasma,injured tissue,hippocampus,central gray andspinal cord in the posttraumatic rats at different intervals.A predominant characteristicsof the changes of ir-NT levels in the brain areas,pituitary gland and plasma was thedramatical decrease at various times except for the hypothalamus,central gray andhippocampus with biphasic alterations.The ir-NT contents in the frontal cortex andpons-medulla also displayed changes to different extent under the acute craniocerebraltrauma condition.These results suggest that NT may play a role in the pathophysiologyof traumatic head injury.
文摘Neurotensin (NT) is a 13-amino acid peptide with trophic effects on some neoplasms. Its bioactivities are mainly mediated by neurotensin receptor 1 (NTSR1). Both NT and NTSR1 were found to be upregulated in breast cancer. NT/NTSR1 thus becomes a potential therapeutic target. We studied whether any correlation exists between the expression of NTSR1 in breast carcinomas and the expression of ER, PR, and Her2. A total 85 cases of invasive ductal (62) and lobular (23) breast carcinomas were studied. Based on their ER/PR profiles, the ductal carcinomas (DCs) were subcategorized into ER+/PR+ (21), ER+/PR﹣ (20), and ER﹣/PR﹣ (21). All of the lobular carcinomas (LCs) were ER+/PR+. 21.57% of all DCs and 5.56% of LCs were Her2 positive. 77.78% of ER﹣/PR﹣ DCs were also Her2 negative (triple negative). The expression of NTSR1 was detected by immunohistochemistry and was semiquantitated (as negative, 1+, 2+, 3+). Both 2+ and 3+ were collectively defined as overexpression. The expression of NTSR1 was weak and focal in non-neoplastic mammary epithelial cells. It is increased in 74.19% of DCs (80.95% in ER+/PR+, 75% in ER+/PR﹣, and 66.67% in ER﹣/PR﹣ group), and in 95.65% of LCs. The overexpression of NTSR1 is similar between ER+ DCs and ER﹣ DCs (75% vs 66.67%, p > 0.05) as well as between PR+ DCs and PR﹣ DCs (80.95% in ER+/PR+ DCs vs 75% in ER+/PR﹣ DCs, p > 0.05). And it was seen in 77.78% of Her2+ DCs, 78.38% of Her2﹣ DCs, 94.12% of Her2﹣ LCs, and 78.57% of triple negative DCs. Overall, NTSR1 is commonly overexpressed in both ductal and lobular breast carcinomas and is independent of the ER/PR/Her2 profiles of the tumors. The present data supports the potential benefit of developing NTSR1 blockers in the adjuvant therapy of breast carcinomas, particularly for those “triple negative” tumors.
基金supported by the University of Michigan startup funds and the NIH Grants R01 AT011652 and R01 HL156989.
文摘The parabrachial nucleus(PBN)integrates interoceptive and exteroceptive information to control various behavioral and physiological processes including breathing,emotion,and sleep/wake regulation through the neural circuits that connect to the forebrain and the brainstem.However,the precise identity and function of distinct PBN subpopulations are still largely unknown.Here,we leveraged molecular characterization,retrograde tracing,optogenetics,chemogenetics,and electrocortical recording approaches to identify a small subpopulation of neurotensin-expressing neurons in the PBN that largely project to the emotional control regions in the forebrain,rather than the medulla.Their activation induces freezing and anxiety-like behaviors,which in turn result in tachypnea.In addition,optogenetic and chemogenetic manipulations of these neurons revealed their function in promoting wakefulness and maintaining sleep architecture.We propose that these neurons comprise a PBN subpopulation with specific gene expression,connectivity,and function,which play essential roles in behavioral and physiological regulation.
文摘目的构建与海肾荧光素酶(Rluc)融合的人Neurotensin-R1(HumanNeurotensinreceptorl,NTS1 or NTSR1)真核表达载体,用于生物发光共振能量转移法检测人NTS与其它受体间的相互作用以及研究Neurotensin—R介导的细胞内信号转导机制。方法以质粒peDNA3.1-hNTS1为模板,PCR方法扩增人NTS。扩增的人NTS以及质粒pRluc—pcDNA3.1用NotI和XbaI双酶切,然后将这2种酶切产物按常规方法连接、转化至大肠杆菌Top10中,该菌在培养箱中孵育12~16h后,挑取菌落培养,提取质粒,进行酶切鉴定,最后进行测序。将测序正确的重组载体用脂质体法转染人胚胎肾(humanembryonickidney293,HEK293)细胞。最后,通过共聚焦显微镜观察经过免疫荧光染色的细胞以及Westernblot鉴定人Neu—rotensinl—R的表达。结果通过PCR扩增出一条1257bp的基因片段,序列与GenBank(NM-002531)相同。Westernblot中大约90kDa处有一蛋白条带,与预期大小相同。人Neurotensin—R表达在细胞膜上。结论成功构建了pRluc—hNeurotensinl—R重组表达载体,建立了该质粒转染HEK293的细胞模型。可被用于检测与其它受体间的相互作用以及研究Neurotensinl—R介导的细胞内信号转导机制,这将有助于探究疾病的发病机制及开发新的药物靶点。
基金supported by the National Natural Science Foundation of China(No.30870800)the Ph.D Program Foundation of Ministry of Education,China(No.200810650002)the Bureau of Science and Technology of Qingdao Municipal,China(No.08-2-1-2-nsh)
文摘Objective The globus pallidus plays a critical role in movement regulation. Previous studies have indicated that the globus pallidus receives neurotensinergic innervation from the striatum, and systemic administration of a neurotensin analog could produce antiparkinsonian effects. The present study aimed to investigate the effects of pallidal neurotensin on haloperidol-induced parkinsonian symptoms. Methods Behavioral experiments and electrophysiological recordings were performed in the present study. Results Bilateral infusions of neurotensin into the globus pallidus reversed haloperidolinduced parkinsonian catalepsy in rats. Electrophysiological recordings showed that microinjection of neurotensin induced excitation of pallidal neurons in the presence of systemic haloperidol administration. The neurotensin type-1 receptor antagonist SR48692 blocked both the behavioral and the electrophysiological effects induced by neurotensin. Conclusion Activation of pallidal neurotensin receptors may be involved in neurotensin-induced antiparkinsonian effects.
基金supported financially by the Natural Science Foundation of China(51303064 and 31271019)the Science and Technology Program of Guangzhou(201601010270,2017010160489,201704030083)+1 种基金the Pearl River S&T Nova Program of Guangzhou(201710010155,201806010072)the Science and Technology Project of Guangdong province(2015A010101313,2017A050506011,2017B090911012,2018A050506040,2018A050506019,2018A050506021).
文摘Diabetic foot ulcers(DFU),which may lead to lower extremity amputation,is one of the severe and chronic complications of diabetic mellitus.This study aims to develop,and use dressings based on Silk fibroin(SF)as the scaffold material,gelatin microspheres(GMs)as the carrier for the neurotensin(NT),a neuropeptide that acts as an inflammatory modulator in wound healing and NT as accelerate wound healing drug to treat DFU.We evaluated the wound healing processes and neo-tissue formation in rat diabetic model by macroscopic observation,histological observation(H&E staining and Masson's trichrome staining)and immunofluorescence analysis at 3,7,14,21 and 28 post-operation days.Our results show that the NT/GMs/SF group performance the best not only in macroscopic healing and less scars in 28 post-operation days,but also in fibroblast accumulation in tissue granulation,collagen expression and deposition at the wound site.From release profiles,we can know the GMs are a good carrier for control release drugs.The SEM results shows that the NT/GMs/SF dressings have an average pore size are 40–80μm and a porosity of∼85%,this pore size is suit for wound healing regeneration.These results suggest that the NT/GMs/SF dressings may work as an effective support for control release NT to promote DFU wound healing.
基金financed by the EU—the European Regional Development Fund within the Operational Program“Innovative economy”for 2007-2013
文摘The behavioral responses exerted by spinal administration of the opioid-neurotensin hybrid peptide, PK23, were studied in adult male rats. The antinociceptive effect upon exposure to a thermal stimulus, as well as tolerance development, was assessed in an acute pain model. The PK23 chimera at a dose of 10 nmol/rat produced a potent pain-relieving effect, especially after its intrathecal administration. Compared with intrathecal morphine, this novel compound was found to possess a favourable side effect profile characterized by a reduced scratch reflex, delayed development of analgesic tolerance or an absence of motor impairments when given in the same manner, though some animals died following barrel rotation as a result of its i.c.v. administration(in particular at doses higher than 10 nmol/rat). Nonetheless, these results suggest the potential use of hybrid compounds encompassing both opioid and neurotensin structural fragments in pain management. This highlights the enormous potential of synthetic neurotensin analogues as promising future analgesics.
文摘目的探讨高血压脑出血(hypertensive intracerebral hemorrhage,HICH)微创术后患者早期高压氧(hyperbaric oxygenation,HBO)治疗对血浆神经肽Y(neuropeptide Y,NPY)、神经降压素(neurotensin,NT)的影响。方法选取2019年1月至2021年12月解放军联勤保障部队第九四〇医院收治的HICH经微创血肿清除术后5d患者172例,采用随机数字表法分为研究组(n=86)和对照组(n=86),另同期选取86例进行体检健康者为正常组。对照组给予常规治疗及康复训练,研究组在对照组的基础上给予HBO治疗。测定治疗前和治疗后10d、22d、34d各组的NPY和NT水平。治疗前和治疗后34d、90d、180d时,采用美国国立卫生研究院卒中量表(National Institutes of Health stroke scale,NIHSS)、简易智能精神状态检查量表(mini-mental state examination,MMSE)、运动功能评估量表(Fugl-Meyer assessment,FMA)、日常生活活动能力表(Barthel index,BI)对研究组和对照组进行评估。结果治疗前,研究组与对照组NPY、NT水平比较,差异无统计学意义(P>0.05)。治疗后10d,22d及34d,研究组NPY、NT水平均显著低于对照组(P<0.05)。研究组治疗前、治疗后10~22d及对照组治疗前、治疗后10~34d NPY和NT水平均显著高于正常值(P<0.05),两组NPY和NT水平逐渐下降,研究组34d基本恢复正常,两组比较差异无统计学意义(P>0.05)。治疗前,研究组与对照组NIHSS、MMSE、Fugl-Meyer、BI评分比较,差异无统计学意义(P>0.05)。治疗后34d,90d及180d,研究组NIHSS评分均显著低于对照组(P<0.05)。治疗后34d,90d及180d,研究组MMSE、Fugl-Meyer、BI评分均显著高于对照组(P<0.05)。结论HICH微创术后早期HBO治疗显著降低血浆NPY及NT水平,有利于患者神经功能、认知功能、躯体运动功能和日常生活能力恢复,值得临床普及应用。