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1.
BMC Cancer ; 19(1): 970, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31638925

RESUMO

BACKGROUND: Neuroblastoma (NB) is a paediatric tumour of the sympathetic nervous system. Half of all cases are defined high-risk with an overall survival less than 40% at 5 years from diagnosis. The lack of in vitro models able to recapitulate the intrinsic heterogeneity of primary NB tumours has hindered progress in understanding disease pathogenesis and therapy response. METHODS: Here we describe the establishment of 6 patient-derived organoids (PDOs) from cells of NB tumour biopsies capable of self-organising in a structure resembling the tissue of origin. RESULTS: PDOs recapitulate the histological architecture typical of the NB tumour. Moreover, PDOs expressed NB specific markers such as neural cell adhesion molecules, NB84 antigen, synaptophysin (SYP), chromogranin A (CHGA) and neural cell adhesion molecule NCAM (CD56). Analyses of whole genome genotyping array revealed that PDOs maintained patient-specific chromosomal aberrations such as MYCN amplification, deletion of 1p and gain of chromosome 17q. Furthermore, the PDOs showed stemness features and retained cellular heterogeneity reflecting the high heterogeneity of NB tumours. CONCLUSIONS: We were able to create a novel preclinical model for NB exhibiting self-renewal property and allowing to obtain a reservoir of NB patients' biological material useful for the study of NB molecular pathogenesis and to test drugs for personalised treatments.


Assuntos
Doenças do Sistema Nervoso Autônomo/genética , Doenças do Sistema Nervoso Autônomo/patologia , Modelos Biológicos , Neuroblastoma/genética , Neuroblastoma/patologia , Organoides/patologia , Doenças do Sistema Nervoso Autônomo/metabolismo , Biomarcadores Tumorais/metabolismo , Biópsia , Criança , Pré-Escolar , Cromogranina A/metabolismo , Aberrações Cromossômicas , Amplificação de Genes/genética , Humanos , Lactente , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/metabolismo , Organoides/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Sinaptofisina/metabolismo
2.
Nutrients ; 11(8)2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31405122

RESUMO

Short-term administration of Lactobacillus gasseri CP2305 improves stress-associated symptoms and clinical symptoms in healthy young adults and in patients with irritable bowel syndrome, respectively. We evaluated the efficacy and health benefits of the long-term use of a tablet containing heat-inactivated, washed Lactobacillus gasseri CP2305 (CP2305) in healthy young adults. Sixty Japanese medical students (41 men and 19 women) preparing for the national examination for medical practitioners ingested CP2305-containing or placebo tablets once daily for 24 weeks. Intake of the CP2305 tablet significantly reduced anxiety and sleep disturbance relative to placebo, as quantitated by the Spielberger State-Trait Anxiety Inventory and the Pittsburgh Sleep Quality Index. Single-channel sleep electroencephalograms show that CP2305 significantly shortened sleep latency and wake time after sleep onset and increased the delta power ratio in the first sleep cycle. CP2305 also significantly lowered salivary chromogranin A levels compared with placebo. Furthermore, 16S rRNA gene sequencing of participant feces demonstrated that CP2305 administration attenuated the stress-induced decline of Bifidobacterium spp. and the stress-induced elevation of Streptococcus spp. We conclude that the long-term use of CP2305-containing tablets may improve the mental state, sleep quality, and gut microbiota of healthy adults under stressful conditions.


Assuntos
Lactobacillus gasseri , Probióticos/administração & dosagem , Estresse Psicológico/microbiologia , Estresse Psicológico/terapia , Adulto , Bifidobacterium/metabolismo , Cromogranina A/metabolismo , Doença Crônica , Método Duplo-Cego , Feminino , Microbioma Gastrointestinal , Voluntários Saudáveis , Humanos , Masculino , RNA Ribossômico 16S/análise , Saliva/química , Transtornos do Sono-Vigília/microbiologia , Transtornos do Sono-Vigília/psicologia , Transtornos do Sono-Vigília/terapia , Streptococcus/metabolismo , Estresse Psicológico/psicologia , Estudantes de Medicina/psicologia , Comprimidos , Resultado do Tratamento , Adulto Jovem
3.
Int J Mol Sci ; 20(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31207989

RESUMO

Colon cancer is one of the major causes of cancer death worldwide. The five-year survival rate for the early-stage patients is more than 90%, and only around 10% for the later stages. Moreover, half of the colon cancer patients have been clinically diagnosed at the later stages. It is; therefore, of importance to enhance the ability for the early diagnosis of colon cancer. Taking advantages from our previous studies, there are several potential biomarkers which have been associated with the early diagnosis of the colon cancer. In order to investigate these early diagnostic biomarkers for colon cancer, human chromogranin-A (CHGA) was further analyzed among the most powerful diagnostic biomarkers. In this study, we used a logistic regression-based meta-analysis to clarify associations of CHGA expression with colon cancer diagnosis. Both healthy populations and the normal mucosa from the colon cancer patients were selected as the double normal controls. The results showed decreased expression of CHGA in the early stages of colon cancer as compared to the normal controls. The decline of CHGA expression in the early stages of colon cancer is probably a new diagnostic biomarker for colon cancer diagnosis with high predicting possibility and verification performance. We have also compared the diagnostic powers of CHGA expression with the typical oncogene KRAS, classic tumor suppressor TP53, and well-known cellular proliferation index MKI67, and the CHGA showed stronger ability to predict early diagnosis for colon cancer than these other cancer biomarkers. In the protein-protein interaction (PPI) network, CHGA was revealed to share some common pathways with KRAS and TP53. CHGA might be considered as a novel, promising, and powerful biomarker for early diagnosis of colon cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Cromogranina A/metabolismo , Neoplasias do Colo/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/normas , Cromogranina A/genética , Cromogranina A/normas , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Redes Reguladoras de Genes , Humanos , Metanálise como Assunto , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Sensibilidade e Especificidade , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
4.
Biomed Pharmacother ; 116: 108959, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31108350

RESUMO

AIMS: To investigate the role of pancreastatin inhibitor (PSTi8) in lipid homeostasis and insulin sensitivity in dexamethasone induced fatty liver disease associated type 2 diabetes. MAIN METHODS: Glucose releases assay, lipid O staining and ATP/AMP ratio were performed in HepG2 cells. Twenty four mice were randomly divided into 4 groups: Control group (saline), DEX (1 mg/kg, im) for 17 days, DEX+PSTi8 (acute 5 mg/kg and chronic 2 mg/kg, ip) for 10 days. The glucose, insulin and pyruvate tolerance tests (GTT, ITT and PTT), biochemical parameters and Oxymax-CLAMS were performed. Further to elucidate the action mechanisms of PSTi8, we performed genes expression and western blotting of biological samples. KEY FINDINGS: We found that PSTi8 suppresses hepatic glucose release, lipid deposition, oxidative stress induced by DEX, stimulates the cellular energy level in hepatocytes and enhances GRP78 activity. It reduces lipogensis and enhances fatty acid oxidation to improve insulin sensitivity and glucose tolerance in DEX induced diabetic mice. The above cellular effects are the result of activated AMPK signalling pathway in liver, which increases Srebp1c and ACC phosphorylation. The increased ACC phosphorylation suppresses protein kinase C activity and enhances insulin sensitivity. The increased expression of UCP3 in liver elicits fatty acid oxidation and energy expenditure, which suppress oxidative stress. SIGNIFICANCE: Thus the activation of AMPK signalling through GRP78, improves lipid homeostasis, enhances insulin sensitivity via inhibition of PKC activity. PSTi8 suppresses inflammation associated with incomplete fatty acid oxidation. Hence, PSTi8 may be a potential therapeutic agent to treat glucocorticoid-induced fatty liver associated type 2 diabetes.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Cromogranina A/antagonistas & inibidores , Fígado Gorduroso/enzimologia , Fígado Gorduroso/patologia , Proteínas de Choque Térmico/metabolismo , Transdução de Sinais , Trifosfato de Adenosina/metabolismo , Adipocinas/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Cromogranina A/metabolismo , Dexametasona , Metabolismo Energético , Fígado Gorduroso/sangue , Glucose/metabolismo , Células Hep G2 , Homeostase/efeitos dos fármacos , Humanos , Insulina/sangue , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Distribuição Tecidual/efeitos dos fármacos
5.
In Vitro Cell Dev Biol Anim ; 55(7): 559-566, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31144267

RESUMO

A novel cell line of canine medullary thyroid carcinoma (MTC) was established from the neck mass, diagnosed histopathologically and immunohistochemically as ectopic MTC. The neoplastic cells arranging trabecular structures were characterized as pleomorphic cells with eosinophilic cytoplasm and nucleus, containing often clear nucleolus. These tumor cells were immuno-positive for calcitonin gene-related protein (CGRP), somatostatin, and chromogranin A. In addition, 8th passaged cultured cells were also immuno-positive for CGRP, somatostatin, and chromogranin A. The cloned tumor cells showed logarithmic cell growth with a doubling time of 33.3 h. From the results of DNA sequencing of rearranged during transfection (RET) proto-oncogene, the cloned tumor cells had four single base substitution, including exon 5 codon 82, exon 16 codon 750, exon 17 codon 777, and exon 24 codon 1085, all of which were single nucleotide polymorphism reported in RET gene of dogs. After the xenotransplantation into severe combined immunodeficiency (SCID) mice, the cloned cells showed tumorigenicity potentials. The morphological and immunohistochemical features of the xenotransplanted tumor were almost in conformity with those of the original tumor, including positive immunoreactivity for calcitonin, CGRP, and chromogranin A. To our knowledge, this is the first report of canine MTC cell line, which provides useful in vitro tool for understanding oncogenic mechanism and pathophysiological state of MTC in dogs.


Assuntos
Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Animais , Sequência de Bases , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Proliferação de Células , Cromogranina A/metabolismo , Cães , Feminino , Camundongos , Camundongos SCID , Transplante de Neoplasias , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA , Somatostatina/metabolismo , Transplante Heterólogo
6.
Ann Diagn Pathol ; 40: 53-58, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31031215

RESUMO

Merkel cell carcinoma (MCC) is an uncommon primary neuroendocrine carcinoma of the skin. Nowadays, pathologists are required to perform immunohistochemistry to demonstrate neuroendocrine and epithelial differentiation for diagnosis of MCC. Insulinoma-associated protein 1 (INSM1) is a zinc-finger transcription factor expressed in tissues undergoing terminal neuroendocrine differentiation, and INSM1 immunohistochemistry is a well-validated nuclear marker of neuroendocrine differentiation. We evaluated 24 cases of MCC for the expression of INSM1 and compared it with frequently used neuroendocrine markers, Chromogranin A, Synaptophysin, and CD56. INSM1 was positive in all cases, and its expression was stronger, more extensive, clean and homogeneous compared to other markers. As a consequence, INSM1 can be used to serve as a solitary marker for neuroendocrine differentiation due to high sensitivity and specificity in MCC cases.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Célula de Merkel/metabolismo , Carcinoma Neuroendócrino/metabolismo , Insulinoma/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Cutâneas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno CD56/metabolismo , Carcinoma de Célula de Merkel/patologia , Carcinoma Neuroendócrino/patologia , Cromogranina A/metabolismo , Feminino , Humanos , Insulinoma/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Proteínas Repressoras/metabolismo , Sensibilidade e Especificidade , Neoplasias Cutâneas/patologia , Sinaptofisina/metabolismo , Fatores de Transcrição/metabolismo
7.
Pancreas ; 48(4): 514-518, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30946234

RESUMO

OBJECTIVE: Neuroendocrine tumors (NETs) comprise 41.8% of small intestine malignancies. The NET nomogram is a 15-item prognostic tool that includes relevant factors for guiding management decisions. This is the first external validation of this tool among American patients at a tertiary treatment center. METHODS: Patients who underwent surgical intervention from 2005 to 2017 were screened by retrospective chart review. Nomogram scores were calculated following the methods outlined by Modlin et al (Neuroendocrinology. 2010;92:143-157). Validation assessed the association between nomogram scores and survival using Wilcoxon test and Cox regression. RESULTS: Among the 121 patients selected, the NET nomogram significantly predicted survival as a continuous variable (P < 0.01) and when dichotomized using 83 points to distinguish low-risk versus high-risk groups (P < 0.01). However, the nomogram was not universally applicable as even at our specialty center, variables such as chromogranin A and urinary 5-hydroxyindoleacetic acid are not routinely collected, whereas others, like tumor grade, do not reflect the most recently updated classifications. CONCLUSION: The NET nomogram accurately identified patients at low and high risk of death. However, revision to update prognosticators could improve its usefulness for predicting survival of small intestine NETs.


Assuntos
Neoplasias Intestinais/patologia , Intestino Delgado/patologia , Tumores Neuroendócrinos/patologia , Nomogramas , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromogranina A/metabolismo , Feminino , Humanos , Neoplasias Intestinais/cirurgia , Intestino Delgado/metabolismo , Intestino Delgado/cirurgia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/cirurgia , Prognóstico , Encaminhamento e Consulta , Estudos Retrospectivos , Adulto Jovem
8.
Cancer Res ; 79(8): 1925-1937, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30796053

RESUMO

The unbalanced production of pro- and antiangiogenic factors in tumors can lead to aberrant vasculature morphology, angiogenesis, and disease progression. In this study, we report that disease progression in various murine models of solid tumors is associated with increased cleavage of full-length chromogranin A (CgA), a circulating vasoregulatory neurosecretory protein. Cleavage of CgA led to the exposure of the highly conserved PGPQLR site, which corresponds to residues 368-373 of human CgA1-373, a fragment that has proangiogenic activity. Antibodies against this site, unable to bind full-length CgA, inhibited angiogenesis and reduced tumor perfusion and growth. The PGPQLR sequence of the fragment, but not of the precursor, bound the VEGF-binding site of neuropilin-1; the C-terminal arginine (R373) of the sequence was crucial for binding. The proangiogenic activity of the CgA1-373 was blocked by anti-neuropilin-1 antibodies as well as by nicotinic acetylcholine receptor antagonists, suggesting that these receptors, in addition to neuropilin-1, play a role in the proangiogenic activity of CgA1-373. The R373 residue was enzymatically removed in plasma, causing loss of neuropilin-1 binding and gain of antiangiogenic activity. These results suggest that cleavage of the R373R374 site of circulating human CgA in tumors and the subsequent removal of R373 in the blood represent an important "on/off" switch for the spatiotemporal regulation of tumor angiogenesis and may serve as a novel therapeutic target. SIGNIFICANCE: This work reveals that the interaction between fragmented chromogranin A and neuropilin-1 is required for tumor growth and represents a novel potential therapeutic target.


Assuntos
Neoplasias da Mama/prevenção & controle , Carcinoma Pulmonar de Lewis/prevenção & controle , Cromogranina A/metabolismo , Melanoma/prevenção & controle , Neovascularização Patológica/prevenção & controle , Neuropilina-1/metabolismo , Animais , Apoptose , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Proliferação de Células , Feminino , Humanos , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Análise Espaço-Temporal , Células Tumorais Cultivadas
9.
Res Vet Sci ; 123: 178-183, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30682579

RESUMO

In this study, the changes of salivary stress biomarkers were contrasted with skin lesions during weaning in piglets. The stress biomarkers evaluated were cortisol (as the reflection of hypothalamic-pituitary-adrenal (HPA) axis), chromogranin A (CgA) and alpha amylase (sAA) (both as the reflection of sympathoadrenal-medullary (SAM) axis). In addition, the accumulation of skin lesions were assessed as proxy measures of aggression. One hundred and two Danbred piglets (51 female and 51 male) from primiparous and multiparous sows were studied from birth to two days post-weaning. Saliva sampling and lesion scoring were performed one day pre-weaning (-1), and one (+1) and two days post-weaning (+2). Our results show that on +1, there was a significant (P < .0001) increase in salivary cortisol, CgA and skin lesions; whereas on +2, there was a significant increase (P < .0001) in salivary CgA and skin lesions. CgA was correlated with the skin lesion score (r = 0.4; P < .0001). sAA did not significantly change at any sampling time. It can be concluded that stress associated to weaning, is associated with changes in salivary CgA and cortisol stress biomarkers and an increase in skin lesions. However, CgA shows higher correlation with skin lesions which indicates that stress due to fighting activates the SAM stress pathway. Therefore, a combination of physiological biomarkers (CgA and cortisol) and proxy of aggression (skin lesions) is preferable than the use of a single biomarker or behavioural indicator when monitoring the social stress response associated to weaning in piglets.


Assuntos
Agressão , Hidrocortisona/química , Monitorização Fisiológica/veterinária , Saliva/química , Estresse Psicológico/fisiopatologia , Suínos , Animais , Biomarcadores/química , Biomarcadores/metabolismo , Cromogranina A/metabolismo , Feminino , Hidrocortisona/metabolismo , Masculino , Saliva/metabolismo , alfa-Amilases
10.
Hum Pathol ; 85: 309-312, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30171991

RESUMO

Neuroendocrine tumors of the ovary are rare and of uncertain histogenesis. They may be primary or metastatic. Pathogenesis of ovarian carcinomas remains unknown. We report the case of an ovarian large cell carcinoma expressing all neuroendocrine markers (CD56, chromogranin A, synaptophysin) that presented as a primary tumor and coexisted with a typical endometrial serous carcinoma also expressing one neuroendocrine marker (CD56). The 2 tumors had identical molecular mutational profiles as examined by next-generation sequencing. We propose that the ovarian neuroendocrine tumor was metastatic from an endometrial serous carcinoma with limited neuroendocrine differentiation.


Assuntos
Carcinoma Neuroendócrino/secundário , Neoplasias Ovarianas/secundário , Ovário/patologia , Neoplasias Uterinas/patologia , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Carcinoma Neuroendócrino/metabolismo , Cromogranina A/metabolismo , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , Ovário/metabolismo , Sinaptofisina/metabolismo , Neoplasias Uterinas/metabolismo
11.
Pancreatology ; 19(1): 57-63, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30470614

RESUMO

BACKGROUND: A reliable and accessible biomarker for nonfunctioning pancreatic neuroendocrine tumors (NF-PanNET) is currently unavailable. Chromogranin A (CgA) represents the best-described neuroendocrine biomarker, but its accuracy is low. Vasostatin-1 (VS-1), a fragment derived from the cleavage of CgA, was recently investigated and found to be more accurate as tumor biomarker in a cohort of patients affected by mainly metastatic small intestinal NET. METHODS: Patients submitted to surgery for sporadic localized NF-PanNET at San Raffaele Hospital were included. Preoperative plasma samples were prospectively collected. Circulating levels of total-CgA and VS-1 were retrospectively investigated by sandwich Enzyme-Linked ImmunoSorbent Assays. RESULTS: Overall, 50 patients were included. VS-1 value (P=0.0001) was the only preoperatively retrievable factor independently associated with NF-PanNET size. No significant correlation between CgA and tumor diameter was found (P = 0.057). A VS-1 value of 0.39 nM was identified as the optimal VS-1 cut-off accurately associated with NF-PanNET larger than 4 cm. Patients with VS-1 > 0.39 nM had a significantly higher frequency of microvascular invasion (P = 0.005) and nodal metastasis (P = 0.027). Median VS-1 plasma level was significantly higher in the presence of microvascular invasion (P = 0.001) and nodal metastasis (P = 0.012). PPI assumption significantly increased total-CgA levels, but not those of VS-1 (P = 0.111). CONCLUSIONS: In localized, non-metastatic NF-PanNET, VS-1 is strongly associated to tumor dimension and its plasma levels are significantly higher in the presence of microvascular invasion and nodal metastases; moreover, VS-1 value is not affected by the PPI use.


Assuntos
Cromogranina A/metabolismo , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Fragmentos de Peptídeos/metabolismo , Biomarcadores Tumorais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/metabolismo , Estudos Retrospectivos , Sensibilidade e Especificidade
12.
Zhonghua Bing Li Xue Za Zhi ; 47(11): 851-856, 2018 Nov 08.
Artigo em Chinês | MEDLINE | ID: mdl-30423609

RESUMO

Objective: To investigate the clinicopathologic characteristics, diagnostic features and prognosis of primary renal neuroendocrine carcinoma (NEC). Methods: The clinicopathologic data of eight cases of renal NEC was collected from January 2008 to December 2017 from Affiliated Hospital of Qingdao University. Immunohistochemical staining was performed, and follow-up information was analyzed, and the relevant literature reviewed. Results: The patients' mean age at diagnosis was 45 years (range, 27-66 years); five were women, and three were men. The tumors located on the left side in five patients, and on the right side in three. Five cases were detected incidentally, and three patients presented with loin pain. Microscopically, these cases included five well-differentiated NECs (three carcinoids, two atypical carcinoids), two small cell NECs, and one large cell NEC according to the World Health Organization classification of 2016. The tumors infiltrated the renal capsule in six cases. Necrosis was found in five cases. Vascular invasion with tumor emboli was seen in three cases. Lymph node metastasis was identified in one case. Immunohistochemically, the expression rates of neuroendocrine markers CD56, chromogranin A (CgA) and synaptophysin (Syn) were 6/8, 4/8, and 8/8 respectively. Some of the NECs were positive for epithelial markers CKpan (6/8, with three cases showing focal positivity) and CAM5.2 (4/8) of variable degrees. The Ki-67 proliferation index was≤3% in the carcinoids; ≥50% in the small cell carcinoma and large cell carcinoma; and 5% and 8% for the two cases of atypical carcinoid, respectively. All cases were negative for EMA, CK7, CA9, CD10, CD117, PAX2, PAX8, WT1, p63, S-100 and TTF1. Three patients (two with small cell carcinoma and one with large cell carcinoma) died of extensive metastases at 3 months, 4 months and 9 months after operation, while five patients were well, without recurrence or distant metastasis for follow-up period of one to nine years. Conclusions: Primary renal NEC is rare. Carcinoid is the most common histological type. The pathomorphological features and neuroendocrine markers (CD56, CgA, Syn), epithelial markers (CKpan, CAM5.2) and nephrogenic markers (PAX2, PAX8) are important for the diagnosis. Renal carcinoid tumors are indolent and prone to early metastasis, but are associated with prolonged survival. The small cell renal cell carcinoma and large cell carcinoma are highly malignant renal tumors with poor prognosis and short survival.


Assuntos
Carcinoma Neuroendócrino/patologia , Neoplasias Renais/patologia , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Tumor Carcinoide/metabolismo , Tumor Carcinoide/patologia , Carcinoma de Células Grandes/metabolismo , Carcinoma de Células Grandes/mortalidade , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/mortalidade , Carcinoma de Células Pequenas/metabolismo , Carcinoma de Células Pequenas/mortalidade , Carcinoma de Células Pequenas/patologia , Cromogranina A/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neprilisina/metabolismo , Prognóstico , Sinaptofisina/metabolismo
13.
Clin Sci (Lond) ; 132(23): 2493-2507, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30401690

RESUMO

Vasostatin-1, a chromogranin A (CgA)-derived peptide (76 amino acids), is known to suppress vasoconstriction and angiogenesis. A recent study has shown that vasostatin-1 suppresses the adhesion of human U937 monocytes to human endothelial cells (HECs) via adhesion molecule down-regulation. The present study evaluated the expression of vasostatin-1 in human atherosclerotic lesions and its effects on inflammatory responses in HECs and human THP-1 monocyte-derived macrophages, macrophage foam cell formation, migration and proliferation of human aortic smooth muscle cells (HASMCs) and extracellular matrix (ECM) production by HASMCs, and atherogenesis in apolipoprotein E-deficient (ApoE-/-) mice. Vasostatin-1 was expressed around Monckeberg's medial calcific sclerosis in human radial arteries. Vasostatin-1 suppressed lipopolysaccharide (LPS)-induced up-regulation of monocyte chemotactic protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in HECs. Vasostatin-1 suppressed inflammatory M1 phenotype and LPS-induced interleukin-6 (IL-6) secretion via nuclear factor-κB (NF-κB) down-regulation in macrophages. Vasostatin-1 suppressed oxidized low-density lipoprotein (oxLDL)-induced foam cell formation associated with acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) and CD36 down-regulation and ATP-binding cassette transporter A1 (ABCA1) up-regulation in macrophages. In HASMCs, vasostatin-1 suppressed angiotensin II (AngII)-induced migration and collagen-3 and fibronectin expression via decreasing ERK1/2 and p38 phosphorylation, but increased elastin expression and matrix metalloproteinase (MMP)-2 and MMP-9 activities via increasing Akt and JNK phosphorylation. Vasostatin-1 did not affect the proliferation and apoptosis in HASMCs. Four-week infusion of vasostatin-1 suppressed the development of aortic atherosclerotic lesions with reductions in intra-plaque inflammation, macrophage infiltration, and SMC content, and plasma glucose level in ApoE-/- mice. These results indicate the inhibitory effects of vasostatin-1 against atherogenesis. The present study provided the first evidence that vasostatin-1 may serve as a novel therapeutic target for atherosclerosis.


Assuntos
Aterosclerose/prevenção & controle , Cromogranina A/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fragmentos de Peptídeos/metabolismo , Placa Aterosclerótica , Animais , Apoptose , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Proteínas da Matriz Extracelular/metabolismo , Células Espumosas/metabolismo , Células Espumosas/patologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Knockout para ApoE , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Transdução de Sinais , Células THP-1
14.
Endokrynol Pol ; 69(5): 598-610, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30074235

RESUMO

Chromogranin A is a member of the granin glycoprotein family that is expressed by the endocrine and neuroendocrine cells of different organs. Intracellularly, chromogranin A contributes to the regulation of secretion and gives several cleavage products after secretion. Some of its cleavage products modify the hormone functions in autocrine and paracrine ways, while the functions of others have not been fully understood yet. Serum chromogranin A level is most prominently used in neuroendocrine tumour diagnostics. In addition, recent studies have suggested that chromogranin A and some of its cleavage products (pancreastatin and WE-14) also play important roles in the pathogenesis of the various forms of diabetes mellitus, but their exact mechanisms still need to be clarified. Higher chromogranin A, pancreastatin, and WE-14 levels have been reported in type 1, type 2, and gestational diabetic patients compared to healthy controls. A notable connection has been inferred through the observation that type 1 diabetes mellitus is not at all or rarely developed in chromogranin A gene-knockout, non-obese diabetic model mice compared to non-knockout, non-obese diabetic mice. Pancreastatin inhibits insulin release in various cell and animal models, and WE-14 serves as an autoantigen for both CD4+ and CD8+ beta cell-destructive diabetogenic T-cell clones in type 1 diabetes. Chromogranin A contributes to the pathogenesis of diabetes mellitus according to the available literature. The current findings facilitate further investigation to unravel the deeper relationships between this glycoprotein and diabetes.


Assuntos
Cromogranina A/metabolismo , Diabetes Mellitus/metabolismo , Animais , Diabetes Mellitus/etiologia , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Gestacional/etiologia , Diabetes Gestacional/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Gravidez
15.
Sci Rep ; 8(1): 11896, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30093637

RESUMO

Hypoparathyroidism is a deficiency of the parathyroid hormone (PTH) in the body. We previously reported the possibility of treating it using tonsil-derived mesenchymal stem cells (TMSCs) differentiated into PTH-releasing cells. The purpose of this study was to evaluate the feasibility of using autologous plasma gel as scaffold material in treatment of hypoparathyroidism with TMSC. We obtained plasma by venous sampling of autologous blood and centrifuged and fabricated the plasma gel using a sinusoidal pattern heating machine. After we created the hypoparathyroidism animal model, we administered undifferentiated TMSCs and TMSCs differentiated into parathyroid cells at each rat dorsum by intramuscular injection with and without the plasma gel. In the plasma gel groups, intact PTH was detected from on day 21 after TMSC injection; we did not detect intact PTH in the groups that were only transplanted with TMSCs during the entire experimental period. Serum calcium was higher and phosphorous was lower in the TMSC with plasma gel groups than in the groups with TMSCs alone. We detected PTH and chromogranin A in the TMSC-plasma gel-transplanted areas on immunohistochemistry and immunofluorescence stain. Plasma gel can be considered as a cell-delivery scaffold for treating hypoparathyroidism with tonsil-derived mesenchymal stem cells.


Assuntos
Hipoparatireoidismo/terapia , Células-Tronco Mesenquimais/metabolismo , Plasma Rico em Plaquetas , Transplante de Células-Tronco/métodos , Animais , Diferenciação Celular , Células Cultivadas , Pré-Escolar , Cromogranina A/metabolismo , Estudos de Viabilidade , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Tonsila Palatina/citologia , Hormônio Paratireóideo/metabolismo , Ratos Sprague-Dawley , Transplante Autólogo
16.
Brain Res Bull ; 142: 138-146, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30016729

RESUMO

Neuropathic pain is defined as a type of chronic pathological pain that often results from nerve damage or disease. The purinergic receptor P2X4 is mainly expressed on the cell surface of spinal dorsal horn microglia and is known to be involved in neuropathic pain. Catestatin (CST) is an endogenous peptide derived from chromogranin A. Here, we attempted to identify how CST function in neuropathic pain. Rat model of chronic constriction injury (CCI) was used and experimental results indicated that mechanical and thermal pain sensitivities were significantly increased in CCI rats. The group of CCI rats that received intrathecal CST injection (CCI + CST) exhibited higher P2X4 mRNA and protein levels compared with the CCI group. Moreover, the phosphorylation level of extracellular signal-regulated kinase 1/2 (ERK1/2) in the CCI + CST group was higher than in the CCI group. This suggested that CST might aggravate neuropathic pain by enhancing P2X4 receptor expression in spinal microglia, and that the ERK1/2 pathway might be key in the development of neuropathic pain.


Assuntos
Cromogranina A/metabolismo , Microglia/metabolismo , Neuralgia/metabolismo , Fragmentos de Peptídeos/metabolismo , Receptores Purinérgicos P2X4/metabolismo , Medula Espinal/metabolismo , Animais , Cromogranina A/administração & dosagem , Constrição Patológica , Modelos Animais de Doenças , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Masculino , Microglia/patologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neuralgia/patologia , Fragmentos de Peptídeos/administração & dosagem , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Nervo Isquiático/lesões , Medula Espinal/patologia , Regulação para Cima
17.
Diabetes ; 67(9): 1836-1846, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29976617

RESUMO

We recently established that hybrid insulin peptides (HIPs), formed in islet ß-cells by fusion of insulin C-peptide fragments to peptides of chromogranin A or islet amyloid polypeptide, are ligands for diabetogenic CD4 T-cell clones. The goal of this study was to investigate whether HIP-reactive T cells were indicative of ongoing autoimmunity. MHC class II tetramers were used to investigate the presence, phenotype, and function of HIP-reactive and insulin-reactive T cells in NOD mice. Insulin-reactive T cells encounter their antigen early in disease, but they express FoxP3 and therefore may contribute to immune regulation. In contrast, HIP-reactive T cells are proinflammatory and highly diabetogenic in an adoptive transfer model. Because the frequency of antigen-experienced HIP-reactive T cells increases over progression of disease, they may serve as biomarkers of autoimmune diabetes.


Assuntos
Autoantígenos/metabolismo , Peptídeo C/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Cromogranina A/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Recombinação Genética , Animais , Autoantígenos/química , Autoantígenos/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Doenças Autoimunes/fisiopatologia , Autoimunidade , Biomarcadores/sangue , Peptídeo C/química , Peptídeo C/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Células Cultivadas , Cromogranina A/química , Cromogranina A/genética , Células Clonais , Cruzamentos Genéticos , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/fisiopatologia , Progressão da Doença , Feminino , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética , Ativação Linfocitária , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Organismos Livres de Patógenos Específicos
18.
Sci Rep ; 8(1): 8715, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29880906

RESUMO

Pancreastatin (PST) is an endogenous peptide which regulates glucose and lipid metabolism in liver and adipose tissues. In type 2 diabetic patients, PST level is high and plays a crucial role in the negative regulation of insulin sensitivity. Novel therapeutic agents are needed to treat the diabetes and insulin resistance (IR) against the PST action. In this regard, we have investigated the PST inhibitor peptide-8 (PSTi8) action against diabetogenic PST. PSTi8 rescued PST-induced IR in HepG2 and 3T3L1 cells. PSTi8 increases the GLUT4 translocation to cell surface to promote glucose uptake in L6-GLUT4myc cells. PSTi8 treatment showed an increase in insulin sensitivity in db/db, high fat and fructose fed streptozotocin (STZ) induced IR mice. PSTi8 improved the glucose homeostasis which is comparable to metformin in diabetic mice, characterized by elevated glucose clearance, enhanced glycogenesis, enhanced glycolysis and reduced gluconeogenesis. PST and PSTi8 both were docked to the GRP78 inhibitor binding site in protein-protein docking, GRP78 expression and its ATPase activity studies. The mechanism of action of PSTi8 may be mediated by activating IRS1/2-phosphatidylinositol-3-kinase-AKT (FoxO1, Srebp-1c) signaling pathway. The discovery of PSTi8 provides a promising therapeutic agent for the treatment of metabolic diseases mainly diabetes.


Assuntos
Cromogranina A/antagonistas & inibidores , Diabetes Mellitus Experimental/tratamento farmacológico , Resistência à Insulina , Peptídeos , Células 3T3-L1 , Animais , Cromogranina A/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Gluconeogênese/efeitos dos fármacos , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/metabolismo , Células Hep G2 , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Peptídeos/química , Peptídeos/farmacologia , Domínios Proteicos , Transdução de Sinais/efeitos dos fármacos
19.
Dig Liver Dis ; 50(11): 1205-1213, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29803758

RESUMO

BACKGROUND: Inflammatory bowel disease (IBD) is associated with neuroendocrine cell hyperplasia. AIMS: We investigated neuroendocrine cells in J-pouches of patients with ulcerative colitis undergoing restorative proctocolectomy and ileal pouch-anal anastomosis. METHODS: Sections from pouch biopsies of 17 patients and ileal biopsies of 17 active IBD patients and 16 controls were processed by immunohistochemistry for chromogranin A (CgA) and serotonin. Mucosal tryptophan hydroxylase (TpH)-1 and serotonin-selective reuptake transporter (SERT) transcripts were measured by quantitative RT-PCR. TpH-1 and SERT transcripts were detected in pouch biopsies cultured with infliximab or its isotype control, while interleukin (IL)-6 and IL-8 were measured in biopsy supernatants. RESULTS: A significant increase in CgA-positive cells and serotonin-positive cells was observed in both pouch and IBD ileum compared to control ileum. Significantly raised transcripts of TpH-1, but not SERT, were found in IBD ileum in comparison to control ileum, with no significant difference between pouch and IBD ileum. Infliximab had no influence on ex vivo pouch expression of TpH-1 and SERT, nor on the production of IL-6 and IL-8. CONCLUSION: We here demonstrated neuroendocrine cell hyperplasia in pouch mucosa. Further studies are needed to clarify the pathophysiological implication of this finding.


Assuntos
Cromogranina A/metabolismo , Colite Ulcerativa/cirurgia , Mucosa Intestinal/patologia , Pouchite/metabolismo , Serotonina/metabolismo , Adulto , Biópsia , Colite Ulcerativa/patologia , Bolsas Cólicas/efeitos adversos , Feminino , Humanos , Íleo/patologia , Imuno-Histoquímica , Infliximab/uso terapêutico , Itália , Masculino , Pessoa de Meia-Idade , Pouchite/etiologia , Proctocolectomia Restauradora
20.
Ann Diagn Pathol ; 34: 122-130, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29661717

RESUMO

Primary breast carcinoma with neuroendocrine features (NEBC) is an uncommon tumor. In the classification of WHO 2012, these tumors were categorized as: 1- neuroendocrine tumor, well-differentiated; 2- neuroendocrine carcinoma, poorly differentiated/small cell carcinoma; and 3- invasive breast carcinoma with neuroendocrine differentiation. In this study, we reviewed NEBC except poorly differentiated/small cell carcinoma variant in order to define the morphological growth patterns and cytonuclear details of these tumors. All breast surgical excision materials between 2007 and 2016 were re-evaluated in terms of neuroendocrine differentiation. Thirty-six cases showing positive staining for synaptophysin and/or chromogranin A in ≥50% of tumor cells were included in the study. All cases were female with a mean age of 67.4. Mean tumor diameter was 26 mm. Multifocality was noted in 5 cases. Grossly, they were mostly infiltrative mass lesions. T stages, identified in 34 cases, were as follows: 13 cases with pT1; 19 pT2 and 2 pT3. We described schematically 4 types of patterns depending on predominant growth pattern, except one case: 1) Large-sized solid cohesive groups (6 cases), 2) Small- to medium-sized solid cohesive groups with trabeculae/ribbons and glandular structures (6 cases), 3) Mixed growth patterns (20 cases), 4) Invasive tumor with prominent extracellular and/or intracellular mucin (3 cases). The tumor cells were mostly polygonal-oval with eosinophilic/eosinophilic-granular cytoplasm. The nuclei of tumor cells were mostly round to oval with evenly distributed chromatin. Only 5 cases showed high grade nuclear and histological features. Molecular subtypes of the cases were as follows: 33 luminal A, 2 luminal B, and 1 triple negative. NEBC should come to mind when a tumor display one of the morphological patterns described above, composed of monotonous cells with mild to moderate nuclear pleomorphism and abundant eosinophilic/eosinophilic granular or clear cytoplasm, especially in elderly patients.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Neuroendócrino/patologia , Tumores Neuroendócrinos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/patologia , Núcleo Celular/patologia , Cromogranina A/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Sinaptofisina/metabolismo
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