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Juliana Bender Hoppe Rudimar Luiz Frozza Ana Paula Horn Ricardo Argenta Comiran Andressa Bernardi Maria Martha Campos Ana Maria Oliveira Battastini Christianne Salbego 《Journal of pineal research》2010,48(3):230-238
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by accumulation of extracellular deposits of amyloid‐β (Aβ) peptide in brain regions that are important for memory and cognition. The buildup of Aβ aggregates in the AD is followed by the formation of intracellular neurofibrillary tangles and activation of neuroinflammatory reactions. The present study investigated whether melatonin possesses a neuroprotective effect against Aβ‐induced toxicity. For this purpose, organotypic hippocampal slices were cultured and exposed to 25 μm of Aβ25–35 in the absence or in the presence of melatonin (25, 50, or 100 μm ). In addition, the authors have investigated the involvement of GSK‐3β, tau protein, astroglial, and microglial activation, and cytokine levels in the melatonin protection against Aβ‐induced neurotoxicity. Melatonin prevented the cell damage in hippocampus induced by the exposure to Aβ25–35. In addition, melatonin significantly reduced the activation of GSK‐3β, the phosphorylation of tau protein, the glial activation and the Aβ‐induced increase of TNF‐α and IL‐6 levels. On the basis of these findings, we speculate that melatonin may provide an effective therapeutic strategy for AD, by attenuating Aβ‐induced phosphorylation of tau protein, and preventing GSK‐3β activation and neuroinflammation. 相似文献
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Impact of serum Wisteria floribunda agglutinin positive Mac‐2‐binding protein and serum interferon‐γ‐inducible protein‐10 in primary biliary cirrhosis 下载免费PDF全文
Hiroki Nishikawa Hirayuki Enomoto Yoshinori Iwata Kunihiro Hasegawa Chikage Nakano Ryo Takata Takashi Nishimura Kazunori Yoh Nobuhiro Aizawa Yoshiyuki Sakai Naoto Ikeda Tomoyuki Takashima Akio Ishii Hiroko Iijima Shuhei Nishiguchi 《Hepatology research》2016,46(6):575-583
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Melatonin regulates the transcription of βAPP‐cleaving secretases mediated through melatonin receptors in human neuroblastoma SH‐SY5Y cells 下载免费PDF全文
Napapit Chavanich Mayuri Shukla Sujira Mukda Weihong Song Bruno Vincent Piyarat Govitrapong 《Journal of pineal research》2015,59(3):308-320
Melatonin is involved in the control of various physiological functions, such as sleep, cell growth and free radical scavenging. The ability of melatonin to behave as an antioxidant, together with the fact that the Alzheimer‐related amyloid β‐peptide (Aβ) triggers oxidative stress through hydroxyl radical‐induced cell death, suggests that melatonin could reduce Alzheimer's pathology. Although the exact etiology of Alzheimer's disease (AD) remains to be established, excess Aβ is believed to be the primary contributor to the dysfunction and degeneration of neurons that occurs in AD. Aβ peptides are produced via the sequential cleavage of β‐secretase β‐site APP‐cleaving enzyme 1 (BACE1) and γ‐secretase (PS1/PS2), while α‐secretase (ADAM10) prevents the production of Aβ peptides. We hypothesized that melatonin could inhibit BACE1 and PS1/PS2 and enhance ADAM10 expression. Using the human neuronal SH‐SY5Y cell line, we found that melatonin inhibited BACE1 and PS1 and activated ADAM10 mRNA level and protein expression in a concentration‐dependent manner and mediated via melatonin G protein‐coupled receptors. Melatonin inhibits BACE1 and PS1 protein expressions through the attenuation of nuclear factor‐κB phosphorylation (pNF‐κB). Moreover, melatonin reduced BACE1 promoter transactivation and consequently downregulated β‐secretase catalytic activity. The present data show that melatonin is not only a potential regulator of β/γ‐secretase but also an activator of α‐secretase expression through the activation of protein kinase C, thereby favoring the nonamyloidogenic pathway over the amyloidogenic pathway. Altogether, our findings suggest that melatonin may be a potential therapeutic agent for reducing the risk of AD in humans. 相似文献
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Eric Snoeck Stephanos J. Hadziyannis Claudio Puoti Mark G. Swain Thomas Berg Patrick Marcellin Jean‐Pierre Zarski Karin Jorga Stefan Zeuzem 《Liver international》2008,28(1):61-71
Background: Currently, the approved dosage of ribavirin has not been studied in patients with ‘normal’ alanine aminotransferase (ALT) levels. Methods: Modelling and simulations were performed using generalised additive models (GAMs) to predict the incidence of anaemia and rate of sustained virological response (SVR) in patients with hepatitis C virus (HCV) genotype 1 and persistently ‘normal’ ALT levels treated with peginterferon α‐2a (40KD) 180 μg/week plus ribavirin 1000/1200 mg/day for 48 weeks. Results: Model‐based simulations predicted that SVR rates would increase from 39 to 48% if patients with genotype 1 and persistently ‘normal’ ALT levels had received the standard weight‐adjusted dose of ribavirin. This was similar to the predicted 49% SVR rate for genotype 1 patients with elevated ALT levels. The incidence of anaemia was predicted to increase from 13% to 23% in patients with persistently ‘normal’ ALT activity and was higher than that predicted for patients with elevated ALT levels; however, the difference appeared to be largely explained by the higher proportion of women in the former group. Conclusions: Simulations based on GAM suggest that regimens for patients with HCV genotype 1 should include the standard weight‐adjusted dose of ribavirin, as similar SVR rates are predicted to be achieved, regardless of patients' ALT status at baseline. 相似文献
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β‐blockers interfere with cell homing receptors and regulatory proteins in a model of spontaneously hypertensive rats 下载免费PDF全文
Bruna Eibel Melissa Kristochek Thiago R. Peres Lucinara D. Dias Daniela R. Dartora Karina R. Casali Renato A. K. Kalil Alexandre M. Lehnen Maria Claudia Irigoyen Melissa M. Markoski 《Cardiovascular therapeutics》2018,36(4)
Aim
To examine the interference of β‐blockers with the chemokine stromal cell‐derived factor‐1 (SDF‐1) found in cell homing receptors, C‐X‐C chemokine receptor type 4 (CXCR‐4) and CXCR‐7, and regulatory proteins of homing pathways, we administered atenolol, carvedilol, metoprolol, and propranolol for 30 days using an orogastric tube to hypertensive rats.Method
We collected blood samples before and after treatment and quantified the levels of SDF‐1 with enzyme‐linked immunosorbent assay (ELISA). On day 30 of treatment, the spontaneously hypertensive rats (SHR) were euthanized, and heart, liver, lung, and kidney tissues were biopsied. Proteins were isolated for determining the expression of CXCR‐4, CXCR‐7, GRK‐2 (G protein‐coupled receptors kinase 2), β‐arrestins (β1‐AR and β2‐AR), and nuclear factor kappa B (NFκB).Results
We found that the study drugs modulated these proteins, and metoprolol and propranolol strongly affected the expression of β1‐AR (P = .0102) and β2‐AR (P = .0034).Conclusion
β‐blockers modulated tissue expression of the proteins and their interactions following 30 days of treatment. It evidences that this class of drugs can interfere with proteins of cell homing pathways.11.
Expression of microRNA‐155 correlates positively with the expression of Toll‐like receptor 7 and modulates hepatitis B virus via C/EBP‐β in hepatocytes 下载免费PDF全文
N. Sarkar R. Panigrahi A. Pal A. Biswas S. P. Singh S. K. Kar M. Bandopadhyay D. Das D. Saha T. Kanda M. Sugiyama S. Chakrabarti A. Banerjee R. Chakravarty 《Journal of viral hepatitis》2015,22(10):817-827
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Mikio Zeniya Masanori Nakano Chisato Saeki Keitaro Yokoyama Toru Ishikawa Koichi Takaguchi Hiroki Takahashi 《Hepatology research》2014,44(10):E257-E260
Hepatitis C virus (HCV) infection is common among hemodialysis (HD) patients and has been recognized as an important prognostic factor. Therefore, the aggressive antiviral therapy is necessary for HCV infection in HD patients. However, various treatment limitations exist in HD patients such as the inability to use ribavirin. We have previously reported that HCV RNA can be eradicated by administration of interferon (IFN)‐β during HD in patients with HCV infection caused by genotypes known to be sensitive to IFN therapy and low serum HCV RNA levels. In this case report, we tried to clarify the efficacy of combined application of double‐filtration plasmapheresis (DFPP) and IFN‐β in HD patients with HCV genotype 1b infection and high serum HCV RNA levels. We report two HD patients with HCV genotype 1b infection and high viral loads who were successfully treated by five sessions of DFPP undertaken prior to treatment with IFN‐β (twice‐daily injections for 2 weeks). HCV was eradicated by this combination therapy in both patients. We revealed the efficacy of combined application of DFPP and IFN‐β in HD patients with HCV genotype 1b infection and high serum HCV RNA levels. This combined therapy may be useful for the HD patients who are resistant to conventional IFN monotherapy. 相似文献
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Dong‐Jie Li Jie Tong Yong‐Hua Li Hong‐Bo Meng Qing‐Xin Ji Guo‐Yan Zhang Jia‐Hui Zhu Wen‐Jing Zhang Fei‐Yan Zeng Gang Huang Xia Hua Fu‐Ming Shen Pei Wang 《Journal of pineal research》2019,67(4)
Melatonin has been previously shown to prevent nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms are poorly understood. Here, we identified a previously unknown regulatory action of melatonin on apoptosis signal‐regulating kinase 1 (ASK1) signaling pathway in the pathogenesis and development of NAFLD. Although melatonin administration did not alter food intake, it significantly alleviated fatty liver phenotypes, including the body weight gain, insulin resistance, hepatic lipid accumulation, steatohepatitis, and fibrosis in a high‐fat diet (HFD)‐induced NAFLD mouse model (in vivo). The protection of melatonin against NAFLD was not affected by inactivation of Kupffer cell in this model. In NAFLD mice liver, ASK1 signal cascade was substantially activated, evidence by the enhancement of total ASK1, phospho‐ASK1, phospho‐MKK3/6, phospho‐p38, phospho‐MKK4/7, and phospho‐JNK. Melatonin treatment significantly suppressed the ASK1 upregulation and the phosphorylation of ASK1, MKK3/6, MKK4/7, p38, and JNK. Mechanistically, we found that lipid stress triggered the interaction between ASK1 and TNF receptor‐associated factors (TRAFs), including TRAF1, TRAF2, and TRAF6, which resulted in ASK1 deubiquitination and thereby increased ASK1 protein stability. Melatonin did not alter ASK1 mRNA level; however, it activated a scaffold protein β‐arrestin‐1 and enabled it to bind to ASK1, which antagonized the TRAFs‐mediated ASK1 deubiquitination, and thus reduced ASK1 protein stability. Consistent with these findings, knockout of β‐arrestin‐1 in mice partly abolished the protection of melatonin against NAFLD. Taken together, our results for the first time demonstrate that melatonin safeguards against NAFLD by eliminating ASK1 activation via inhibiting TRAFs‐mediated ASK1 deubiquitination and stabilization in a β‐arrestin‐1 dependent manner. 相似文献
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P. H. Thang N. Ruffin D. Brodin B. Rethi P. D. Cam N. T. Hien L. Lopalco N. Vivar F. Chiodi 《Journal of internal medicine》2010,268(2):181-193
Abstract. Thang PH, Ruffin N, Brodin D, Rethi B, Cam PD, Hien NT, Lopalco L, Vivar N, Chiodi F (Karolinska Institutet, Stockholm, Sweden; National Institute of Hygiene and Epidemiology, Hanoi, Vietnam; San Raffaele Scientific Institute, Milan, Italy). The role of IL‐1β in reduced IL‐7 production by stromal and epithelial cells: a model for impaired T‐cell numbers in the gut during HIV‐1 infection. J Intern Med 2010; 268 : 181–193. Objectives. Interleukin (IL)‐7 is a key cytokine in T‐cell homeostasis. Stromal cells, intestinal epithelial cells and keratinocytes are known to produce this cytokine. The mechanisms and cellular factors regulating IL‐7 production are still unclear. We assessed whether IL‐1β and interferon (IFN)‐γ, cytokines produced during inflammatory conditions, may impact on IL‐7 production. Design. We used human intestinal epithelial cells (DLD‐1 cell line) and bone marrow stromal cells (HS27 cell line), known to produce IL‐7; IL‐7 production was evaluated at the mRNA and protein levels. To assess whether treatment of HS27 cells with IL‐1β and/or IFN‐γ leads to changes in the gene expression of cytokines, Toll‐like receptors (TLRs) and chemokines, we analysed gene expression profiles using the whole‐genome microarray Human Gene 1.0 ST. Results. We found that IFN‐γ enhanced the expression of IL‐7 mRNA (P < 0.001) in both cell lines. IL‐1β treatment led to a significant down‐regulation (P < 0.001) of IL‐7 mRNA expression in both cell lines. The IL‐7 concentration in supernatants collected from treated DLD‐1 and HS27 cell cultures reflected the trend of IL‐7 mRNA levels. The gene profiles revealed dramatic changes in expression of cytokines and their receptors (IL‐7/IL‐7Rα; IL‐1α,IL‐1β/IL‐1R1; IFN‐γ/IFN‐γR1), of IFN regulatory factors (IRF‐1 and 2), of TLRs and of important chemo‐attractants for T cells. The microarray results were verified by additional methods. Conclusions. Our results are discussed in the setting of inflammation and T‐cell survival in the gut compartment during HIV‐1 infection where stromal and epithelial cells may produce factors that contribute to impaired IL‐7 homeostasis and homing of T cells. 相似文献
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Longer warm ischemia can accelerate tumor growth through the induction of HIF‐1α and the IL‐6–JAK–STAT3 signaling pathway in a rat hepatocellular carcinoma model 下载免费PDF全文
Yuhei Hamaguchi Akira Mori Yasuhiro Fujimoto Takashi Ito Taku Iida Shintaro Yagi Hideaki Okajima Toshimi Kaido Shinji Uemoto 《Journal of hepato-biliary-pancreatic sciences》2016,23(12):771-779
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A comprehensive diagnostic approach using galactomannan,targeted β‐d‐glucan,baseline computerized tomography and biopsy yields a significant burden of invasive fungal disease in at risk haematology patients 下载免费PDF全文
M. Mansour Ceesay Sujal R. Desai Lisa Berry Joanne Cleverley Christopher C. Kibbler Sabine Pomplun Andrew G. Nicholson Abdel Douiri Jim Wade Melvyn Smith Ghulam J. Mufti Antonio Pagliuca 《British journal of haematology》2015,168(2):219-229
Invasive fungal disease (IFD) is difficult to diagnose. We investigated the incidence of IFD and risk factors using the revised European Organization for Research and Treatment of Cancer (EORTC) and the Mycoses Study Group (MSG) definitions. Patients (N = 203) undergoing intensive therapy with expected neutropenia ≥10 d were recruited prospectively and followed for a median (range) of 556 (12–730) d. Baseline chest computerized tomography (CT) was performed pre‐therapy. Twice‐weekly surveillance with galactomannan (GM) was combined with targeted β‐d ‐glucan (BDG) testing on patients with possible IFD or who were GM‐positive. Tissue diagnosis was obtained whenever possible. The cumulative incidence of proven/probable IFD among the 202 evaluable cases after 2 years follow‐up was 21%, including 14 proven and 30 probable IFDs. Using either GM or BDG as the sole biomarker (plus host and clinical evidence) the apparent overall incidence of proven/probable IFD was 11% and 16%, respectively. Combined GM/BDG detected all biopsy‐proven mould IFD. Baseline CT abnormalities were found in 76/202 (38%) patients. Baseline CT abnormalities and Karnofsky score <90, monocytopenia >10 d and bacteraemia were independent risk factors associated with greater than twofold increased IFD risk. This combined diagnostic approach identified a high incidence of IFD and important risk factors in this cohort. 相似文献
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