UNASSIGNED: The immunosuppressant tacrolimus is a major cause of new-onset diabetes after transplantation. The aim of this study was to evaluate whether a low dose of the histone-deacetylase inhibitor (vorinostat) might ameliorate tacrolimus-induced new-onset diabetes.
UNASSIGNED: Thirty 8-week-old male Wistar rats were randomly divided into five groups: a control group, tacrolimus group (1.5 mg/kg intraperitoneally for 28 days), vorinostat group (15 mg/kg orally for 28 days), a group receiving tacrolimus with vorinostat for 28 days; and a group receiving coadministration of tacrolimus for 28 days and vorinostat for 14 days. Diabetes development was assessed on the basis of serum glucose, insulin, HOMA-IR and C-peptide. To investigate the mechanism of vorinostat, we assessed inflammatory markers (tumor necrosis factor-α and interleukin-1β), an antioxidant marker (glutathione), an oxidant marker (nicotinamide adenine dinucleotide phosphate hydrogen oxidase) and an apoptosis marker (caspase-3). Kidney functions (creatinine and blood urea nitrogen) were also assessed.
UNASSIGNED: The administration of tacrolimus for 28 days resulted in significantly increased serum glucose and decreased C-peptide and insulin levels than those in the control group. However, coadministration of vorinostat significantly decreased hyperglycemia and increased C-peptide and insulin levels. Moreover, combined treatment with tacrolimus and vorinostat, compared with tacrolimus treatment alone, resulted in significantly reduced inflammatory and oxidant markers, and increased glutathione. Additionally, vorinostat improved the kidney parameters.
UNASSIGNED: Vorinostat at a low dose (15 mg/kg) induces anti-inflammatory and antioxidative effects that protect the pancreas and kidney against the development of new-onset diabetes due to tacrolimus in rats. This experimental study provides insights supporting further clinical trials to improve the post-kidney transplantation protocol through addition of vorinostat to the immunosuppressive regimen.
UNASSIGNED: يعتبر مثبط المناعة (التاكروليموس) أهم مسبب للإصابة بنوع السكري الجديد ما بعد زراعة الكلى. تهدف الدراسة لتقييم فعالية الفورينوستات (مثبط الهستون-دياسيتايلاز) في التحكم بالسكري الناتج عن التاكروليموس.
UNASSIGNED: تم تقسيم ثلاثين ذكر من جرذان ويستر البالغة 8-أسابيع عشوائيا إلى ٥ مجموعات: المجموعة الضابطة، مجموعة التاكروليموس (١.٥ مجم/كجم، داخل الصفاق لمدة ٢٨ يوم)، مجموعة الفورينوستات (١٥ مجم/كجم، عن طريق الفم لمدة ٢٨ يوم). ومجموعتان تم إعطاؤهما الدوائين معا: مجموعة التاكروليموس مع الفورينوستات لمدة ٢٨ يوم، ومجموعة التاكروليموس مع الفورينوستات لمدة ١٤ يوم قبل نهاية التجربة. تم تقييم تطور السكري بقياس نسبة الجلوكوز والأنسولين والببتيد الرابط. وللتحقق من آلية عمل الفورينوستات، تم قياس علامات الالتهاب (عامل نخر الورم-ألفا و انترلوكين١بيتا)، علامات مضادات الأكسدة (الجلوتاثيون) والأكسدة (أكسيد فوسفات ثنائي نيوكلوتيد الأدينين) ومؤشر موت الخلايا المبرمج (كاسباس-٣). أيضاً تم تقييم وظائف الكلى (اليوريا والكرياتينين).
UNASSIGNED: أدى العلاج بالتاكروليموس لمدة 28 يوم إلى زيادة ملحوظة في مستوى السكر وانخفاض في مستويات الببتيد الرابط والأنسولين مقارنة بالمجموعة الضابطة. ومع ذلك، فإن تزامن أخذ الدوائين معا قلل بشكل ملحوظ من ارتفاع السكر وزيادة مستويات الببتيد الرابط والأنسولين. كما قلل جمع الدوائين بشكل ملحوظ مستويات علامات الالتهاب والاكسدة وكاسباس-٣ مع زيادة مستوى الجلوتاثيون مقارنة بالمجموعة المعالجة بالتاكروليموس. أيضا، حافظ الفورينوستات على مستويات عوامل الكلى ضمن المعدل الطبيعي.
UNASSIGNED: استخدام الفورينوستات بجرعة صغيرة (15 مجم/كجم) يستحث التأثير المضاد للالتهاب والمضاد للأكسدة والتي تحمي بنكرياس وكلى الجرذان من الاصابة بالسكري الناتج عن التاكروليموس. تفتح هذه الدراسة الطريق لمزيد من التجارب السريرية لتحسين بروتوكول ما بعد زراعة الكلى عن طريق إضافة الفورينوستات في النظام العلاجي لمثبطات المناعة.

This past decade has seen tremendous advances in understanding the molecular pathogenesis of melanoma and the development of novel effective therapies for melanoma. Targeted therapies and immunotherapies that extend survival of patients with advanced disease have been developed; however, the vast majority of patients experience relapse and therapeutic resistance over time. Moreover, cellular plasticity has been demonstrated to be a driver of therapeutic resistance mechanisms in melanoma and other cancers, largely functioning through epigenetic mechanisms, suggesting that targeting of the cancer epigenetic landscape may prove a worthwhile endeavor to ensure durable treatment responses and cures. Here, we review the epigenetic alterations that characterize melanoma development, progression, and resistance to targeted therapies as well as epigenetic therapies currently in use and under development for melanoma and other cancers. We further assess the landscape of epigenetic therapies in clinical trials for melanoma and provide a framework for future advances in epigenetic therapies to circumvent the development of therapeutic resistance in melanoma.

Liver is the most common metastatic site for colorectal cancer (CRC), there is no satisfied approach to treat CRC liver metastasis (CRCLM). Here, we investigated the role of a polycomb protein BMI-1 in CRCLM. Immunohistochemical analysis showed that BMI-1 expression in liver metastases was upregulated and associated with T4 stage, invasion depth and right-sided primary tumor. Knockdown BMI-1 in high metastatic HCT116 and LOVO cells repressed the migratory/invasive phenotype and reversed epithelial-mesenchymal transition (EMT), while BMI-1 overexpression in low metastatic Ls174T and DLD1 cells enhanced invasiveness and EMT. The effects of BMI-1 in CRC cells were related to upregulating snail via AKT/GSK-3β pathway. Furthermore, knockdown BMI-1 in HCT116 and LOVO cells reduced CRCLM using experimental liver metastasis mice model. Meanwhile, BMI-1 overexpression in Ls174T and DLD1 significantly increased CRCLM. Moreover, sodium butyrate, a histone deacetylase and BMI-1 inhibitor, reduced HCT116 and LOVO liver metastasis in immunodeficient mice. Our results suggest that BMI-1 is a major regulator of CRCLM and provide a potent molecular target for CRCLM treatment.

Growing epidemiological data demonstrate that acute kidney injury (AKI) is associated with long-term cardiovascular morbidity and mortality. Here, the authors present a 1-year study of cardiorenal outcomes following bilateral ischemia-reperfusion injury in male mice. These data suggest that AKI causes long-term dysfunction in the cardiac metabolome, which is associated with diastolic dysfunction and hypertension. Mice treated with the histone deacetylase inhibitor, ITF2357, had preservation of cardiac function and remained normotensive throughout the study. ITF2357 did not protect against the development of kidney fibrosis after AKI.

Evidence of the involvement of epigenetics in pathologies such as cancer, diabetes, and neurodegeneration has increased global interest in epigenetic modifications. For nearly thirty years, it has been known that cancer cells exhibit abnormal DNA methylation patterns. In contrast, the large-scale analysis of histone post-translational modifications (hPTMs) has lagged behind because classically, histone modification analysis has relied on site specific antibody-based techniques. Mass spectrometry (MS) is a technique that holds the promise to picture the histone code comprehensively in a single experiment. Therefore, we developed an MS-based method that is capable of tracking all possible hPTMs in an untargeted approach. In this way, trends in single and combinatorial hPTMs can be reported and enable prediction of the epigenetic toxicity of compounds. Moreover, this method is based on the use of human cells to provide preliminary data, thereby omitting the need to sacrifice laboratory animals. Improving the workflow and the user-friendliness in order to become a high throughput, easily applicable, toxicological screening assay is an ongoing effort. Still, this novel toxicoepigenetic assay and the data it generates holds great potential for, among others, pharmaceutical industry, food science, clinical diagnostics and, environmental toxicity screening. •There is a growing interest in epigenetic modifications, and more specifically in histone post-translational modifications (hPTMs).•We describe an MS-based workflow that is capable of tracking all possible hPTMs in an untargeted approach that makes use of human cells.•Improving the workflow and the user-friendliness in order to become a high throughput, easily applicable, toxicological screening assay is an ongoing effort.

Breast carcinoma is one of the most common malignancies in women. Previous studies have reported that 500 μM valproic acid can sensitize breast tumor cells to the anti-neoplastic agent hydroxyurea. However, the dose requirements for valproic acid is highly variable due to the wide inter-individuals clinical characteristics. High therapeutic dose of valproic acid required to induce anti-tumor activity in solid tumor was associated with increased adverse effects. There are attempts to locate suitably high-efficient low-toxicity valproic acid derivatives. We demonstrated that lower dose of 2-hexyl-4-pentynoic acid (HPTA; 15 μM) has similar effects as 500 μM VPA in inhibiting breast cancer cell growth and sensitizing the tumor cells to hydroxyurea on MCF7 cells, EUFA423 cells, MCF7 cells with defective RPA2-p gene and primary culture cells derived from tissue-transformed breast tumor cells. We discovered HPTA resulted in more DNA double-strand breaks, the homologous recombination was inhibited through the interference of the hyperphosphorylation of replication protein A2 and recombinase Rad51. Our data postulate that HPTA may be a potential novel sensitizer to hydroxyurea in the treatment of breast carcinoma.

Immunotherapy strategies targeting the programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) pathway in clinical treatments have achieved remarkable success in treating multiple types of cancer. However, owing to the heterogeneity of tumors and individual immune systems, PD-L1/PD-1 blockade still shows slow response rates in controlling malignancies in many patients. Accumulating evidence has shown that an effective response to anti-PD-L1/anti-PD-1 therapy requires establishing an integrated immune cycle. Damage in any step of the immune cycle is one of the most important causes of immunotherapy failure. Impairments in the immune cycle can be restored by epigenetic modification, including reprogramming the environment of tumor-associated immunity, eliciting an immune response by increasing the presentation of tumor antigens, and by regulating T cell trafficking and reactivation. Thus, a rational combination of PD-L1/PD-1 blockade and epigenetic agents may offer great potential to retrain the immune system and to improve clinical outcomes of checkpoint blockade therapy.

暂无摘要。

It has become evident that tumor-induced immuno-suppressive factors in the tumor microenvironment play a major role in suppressing normal functions of effector T cells. These factors serve as hurdles that limit the therapeutic potential of cancer immunotherapies. This review focuses on illustrating the molecular mechanisms of immunosuppression in the tumor microenvironment, including evasion of T-cell recognition, interference with T-cell trafficking, metabolism, and functions, induction of resistance to T-cell killing, and apoptosis of T cells. A better understanding of these mechanisms may help in the development of strategies to enhance the effectiveness of cancer immunotherapies.