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In this large international study of patients with adrenal cancer, a rare, treatment-refractory disease, mitotane plus a combination of etoposide, cisplatin, and doxorubicin had greater antitumor activity than mitotane plus streptozotocin. Adrenocortical carcinoma is a rare cancer (estimated incidence, 0.7 to 2.0 cases per 1 million population per year) 1 , 2 with a poor prognosis; the 5-year survival rate is less than 15% among patients with metastatic disease. 3 – 7 Mitotane is the only drug approved for the treatment of adrenocortical carcinoma and is used both as adjuvant therapy and for advanced disease, 8 – 14 although its efficacy has never been shown in a randomized trial. The experience with other antineoplastic drugs for the treatment of this disease is even more limited. Current treatment strategies for advanced disease are based exclusively on retrospective series . . .

Endothelial cells play a key role in the regulation of disease. Defective regulation of endothelial cell homeostasis may cause mesenchymal activation of other endothelial cells or neighboring cell types, and in both cases contributes to organ fibrosis. Regulatory control of endothelial cell homeostasis is not well studied. Diabetes accelerates renal fibrosis in mice lacking the endothelial glucocorticoid receptor (GR), compared to control mice. Hypercholesterolemia further enhances severe renal fibrosis. The fibrogenic phenotype in the kidneys of diabetic mice lacking endothelial GR is associated with aberrant cytokine and chemokine reprogramming, augmented Wnt signaling and suppression of fatty acid oxidation. Both neutralization of IL-6 and Wnt inhibition improve kidney fibrosis by mitigating mesenchymal transition. Conditioned media from endothelial cells from diabetic mice lacking endothelial GR stimulate Wnt signaling-dependent epithelial-to-mesenchymal transition in tubular epithelial cells from diabetic controls. These data demonstrate that endothelial GR is an essential antifibrotic molecule in diabetes. The endothelial glucocorticoid receptor plays a key role in the regulation of many diseases, including diabetes. Loss of this receptor results in accelerated renal fibrosis, a heightened inflammatory milieu, augmented Wnt signaling and suppression of fatty acid oxidation in diabetic kidneys.

Streptozotocin (STZ), a glucosamine-nitrosourea compound derived from soil bacteria and originally developed as an anticancer agent, in 1963 has been found to induce diabetes in experimental animals. Since then, systemic application of STZ became the most frequently studied experimental model of insulin-dependent (type 1) diabetes. The compound is selectively toxic toward insulin-producing pancreatic beta cells, which is explained as the result of its cellular uptake by the low-affinity glucose transporter 2 (GLUT2) protein located in their cell membranes. STZ cytotoxicity is mainly due to DNA alkylation which results in cellular necrosis. Besides pancreatic beta cells, STZ applied systemically damages also other organs expressing GLUT2, such as kidney and liver, whereas brain is not affected directly because blood-brain barrier lacks this transporter protein. However, single or double intracerebroventricular (icv) STZ injection(s) chronically decrease cerebral glucose uptake and produce multiple other effects that resemble molecular, pathological, and behavioral features of Alzheimer’s disease (AD). Taking into consideration that glucose hypometabolism is an early and persistent sign of AD and that Alzheimer’s brains present features of impaired insulin signaling, icv STZ injections are exploited by some investigators as a non-transgenic model of this disease and used for preclinical testing of pharmacological therapies for AD. While it has been assumed that icv STZ produces cerebral glucose hypometabolism and other effects directly through desensitizing brain insulin receptors, the evidence for such mechanism is poor. On the other hand, early data on insulin immunoreactivity showed intense insulin expression in the rodent brain, and the possibility of local production of insulin in the mammalian brain has never been conclusively excluded. Also, there are GLUT2-expressing cells in the brain, in particular in the circumventricular organs and hypothalamus; some of these cells may be involved in glucose sensing. Thus, icv STZ may damage brain glucose insulin producing cells and/or brain glucose sensors. Mechanistic explanation of the mode of action of icv STZ, which is currently lacking, would provide a valuable contribution to the field of animal models of Alzheimer’s disease.

Objective The present study aims at determining the stability of a popular type 2 diabetes rat model induced by a high-fat diet combined with a low-dose streptozotocin injection. Methods Wistar rats were fed with a high-fat diet for 8 weeks followed by a one-time injection of 25 or 35 mg/kg streptozotocin to induce type 2 diabetes. Then the diabetic rats were fed with regular diet/high-fat diet for 4 weeks. Changes in biochemical parameters were monitored during the 4 weeks. Results All the rats developed more severe dyslipidemia and hepatic dysfunction after streptozotocin injection. The features of 35 mg/kg streptozotocin rats more resembled type 1 diabetes with decreased body weight and blood insulin. Rats with 25 mg/kg streptozotocin followed by normal diet feeding showed normalized blood glucose level and pancreatic structure, indicating that normal diet might help recovery from certain symptoms of type 2 diabetes. In comparison, diabetic rats fed with high-fat diet presented decreased but relatively stable blood glucose level, and this was significantly higher than that of the control group ( P >0.05). Conclusions This model easily recovers with normal diet feeding. A high-fat diet is suggested as the background diet in future pharmacological studies using this model.

Alzheimer’s disease (AD) can be divided into sporadic AD (SAD) and familial AD (FAD). Most AD cases are sporadic and result from multiple etiologic factors, including environmental, genetic, and metabolic factors, whereas FAD is caused by mutations in the presenilins or amyloid-β (Aβ) precursor protein (APP) genes. A commonly used animal model for AD is the 3xTg-AD transgenic mouse model, which harbors mutated presenilin 1, APP, and tau genes and thus represents a model of FAD. There is an unmet need in the field to characterize animal models representing different AD mechanisms, so that potential drugs for SAD can be evaluated preclinically in these animal models. A mouse model generated by intracerebroventricular (icv) administration of streptozocin (STZ), the icv-STZ mouse, shows many aspects of SAD. In this study, we compared the non-cognitive and cognitive behaviors as well as biochemical and immunohistochemical alterations between the icv-STZ mouse and the 3xTg-AD mouse. We found that both mouse models showed increased exploratory activity as well as impaired learning and spatial memory. Both models also demonstrated neuroinflammation, altered synaptic proteins and insulin/IGF-1 (insulin-like growth factor-1) signaling, and increased hyperphosphorylated tau in the brain. The most prominent brain abnormality in the icv-STZ mouse was neuroinflammation, and in the 3xTg-AD mouse it was elevation of hyperphosphorylated tau. These observations demonstrate the behavioral and neuropathological similarities and differences between the icv-STZ mouse and the 3xTg-AD mouse models and will help guide future studies using these two mouse models for the development of AD drugs.

Background Proteins of the insulin signaling pathway are needed for cell proliferation and development and glucose homeostasis. It is not known whether insulin signalling markers (Foxo1, Gsk3β) can be correlated with the expression on PI3K-Akt-mTOR pathway, which are needed for cell survival and maintenance of glucose homeostasis. In the present study, we studied the expression of Foxo1, Gsk3β and PI3K-Akt-mTOR in the brain of streptozotocin-induced type 2 diabetes mellitus Wistar rats. Methods The study was performed both in vitro (RIN5F cells) and in vivo (male Wistar rats). Gene expression of Nf-kB, IkB, Bax, Bcl-2 and Pdx1 gene was studied invitro by qRT-PCR in RIN5F cells. In STZ (65 mg/kg i.p.)-induced type 2 DM Wistar rats, blood glucose and insulin levels, iNOS, Foxo1, NF-κB, pGsk3β and PPAR-γ1 levels along with PI3k-Akt-mTOR were measured in brain tissue. Results RIN5F cells treated with STZ showed increase in the expression of NF-kB and Bax and decrease in IkB, Bcl-2 and PDX1. Brain tissue of STZ-induced type 2 DM animals showed a significant reduction in secondary messengers of insulin signalling ( Foxo1) ( P < 0.001) and Gsk3β ( P < 0.01) and a significant alteration in the expression of phosphorylated-Akt ( P < 0.001) mTOR ( P < 0.01) and PI3K. Conclusion These results suggest that STZ induces pancreatic β cell apoptosis by enhancing inflammation. Significant alterations in the expression brain insulin signaling and cell survival pathways seen in brain of STZ-treated animals implies that alterations neuronal apoptosis may have a role in altered glucose homeostasis seen in type 2 DM that may also explain the increased incidence of cognitive dysfunction seen in them.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia, leading to microvascular and macrovascular complications including cardiomyopathy, retinopathy, neuropathy, and nephropathy. This study evaluated the diabetogenic potential and pathological outcomes of two single intraperitoneal doses of streptozotocin (STZ) in male Sprague Dawley rats. Twenty-four rats (200–220 g) were randomly assigned to three groups (n = 8/group): control, STZ 45 mg/kg, and STZ 60 mg/kg. DM was confirmed 72 h post-injection via elevated serum glucose. At the end of the experiment, blood and tissue samples were collected to assess metabolic parameters, lipid profile, liver function, oxidative stress markers, inflammatory cytokines, and histopathological changes. Both doses induced significant hyperglycemia, elevated glycated hemoglobin, and reduced insulin levels. Diabetic rats also showed dyslipidemia, liver dysfunction, increased oxidative stress (↓GSH, ↑MDA), and elevated inflammatory markers (TNF-α, il-6). Histopathological and morphometric analyses confirmed tissue damage and biochemical alterations. Notably, the 60 mg/kg dose produced a more severe and consistent diabetic phenotype, with greater metabolic derangements, oxidative injury, inflammation, and organ pathology compared to the 45 mg/kg dose. These findings suggest that while both doses effectively induce experimental diabetes, 60 mg/kg STZ provides a more robust model for studying DM-associated complications in vital organs.

AbstarctDiabetic complications are among the largely exigent health problems currently. Cardiovascular complications, including diabetic cardiomyopathy (DCM), account for more than 80% of diabetic deaths. Investigators are exploring new therapeutic targets to slow or abate diabetes because of the growing occurrence and augmented risk of deaths due to its complications. Research on rodent models of type 1 and type 2 diabetes mellitus, and the use of genetic engineering techniques in mice and rats have significantly sophisticated for our understanding of the molecular mechanisms in human DCM. DCM is featured by pathophysiological mechanisms that are hyperglycemia, insulin resistance, oxidative stress, left ventricular hypertrophy, damaged left ventricular systolic and diastolic functions, myocardial fibrosis, endothelial dysfunction, myocyte cell death, autophagy, and endoplasmic reticulum stress. A number of molecular and cellular pathways, such as cardiac ubiquitin proteasome system, FoxO transcription factors, hexosamine biosynthetic pathway, polyol pathway, protein kinase C signaling, NF-κB signaling, peroxisome proliferator-activated receptor signaling, Nrf2 pathway, mitogen-activated protein kinase pathway, and micro RNAs, play a major role in DCM. Currently, there are a few drugs for the management of DCM and some of them have considerable adverse effects. So, researchers are focusing on the natural products to ameliorate it. Hence, in this review, we discuss the pathogical, molecular, and cellular mechanisms of DCM; the current diagnostic methods and treatments; adverse effects of conventional treatment; and beneficial effects of natural product-based therapeutics, which may pave the way to new treatment strategies.

Cerebral aging is often associated with the occurrence of neurodegenerative diseases leading to dementia. Animal models are critical to elucidate mechanisms associated to dementia and to evaluate neuroprotective drugs. Rats that received intracerebroventricular injection of streptozotocin (icv-STZ) have been reported as a model of dementia. In these animals, this drug induces oxidative stress and brain glucose metabolism impairments associated to insulin signal transduction failure. These mechanisms are reported to be involved in the pathogenesis of Alzheimer's disease and other dementia. Icv-STZ rats also display memory impairments. However, little is known about the precise location of the lesions induced by STZ administration. In this context, the present study characterized the cerebral lesions induced by two-doses of icv-STZ by using high-field magnetic resonance imaging to easily and longitudinally detect cerebral abnormalities and by using immunohistochemistry to evaluate neuronal loss and neuroinflammation (astrocytosis and microgliosis). We showed that, at high doses, icv-STZ induces severe and acute neurodegenerative lesions in the septum and corpus callosum. The lesions are associated with an inflammation process. They are less severe and more progressive at low doses. The relevance of high and low doses of icv-STZ to mimic dementia and evaluate new drugs is discussed in the final part of this article.

Background: The role of chemotherapy for neuroendocrine tumours remains controversial and there is no standard regimen. Method: We report the outcome for a consecutive series of chemonaive patients with metastatic or locally advanced neuroendocrine tumours treated with a combination of 5-fluorouracil (500 mg m −2 ), cisplatin (70 mg m −2 ) and streptozocin (1000 mg m −2 ) (FCiSt) administered three weekly for up to six cycles. Patients were assessed for radiological response, toxicity and survival. Results: In the 79 patients assessable for response, treatment with FCiSt was associated with an overall response rate of 33% (38% for pancreatic primary sites and 25% for non-pancreatic primary sites). Stable disease occurred in a further 51%, with progression in 16%. The median time to progression was 9.1 months and median overall survival was 31.5 months. The most common grade 3–4 toxicity was neutropaenia (28% patients) but grade 3–4 infection was rare (7%). The most frequent non-haematological grade 3–4 toxicity was nausea and vomiting (17%). Prognostic factors included Ki-67, mitotic index, grade and chromogranin A, whereas response to chemotherapy was predicted by mitotic index, grade and α -fetoprotein. Conclusions: FCiSt is an effective regimen for neuroendocrine tumours with an acceptable toxicity profile. Grade and mitotic index are the best predictors of response.