Oral histone deacetylase inhibitor synergises with T cell targeted immunotherapy to preserve beta cell metabolic function and induce stable remission of new-onset autoimmune diabetes in NOD mice

Besançon, Alix; Goncalves, Tania; Valette, Fabrice; Dahllöf, Mattias Salling; Mandrup‐Poulsen, Thomas; Chatenoud, Lucienne; You, Sylvaine

doi:10.1007/s00125-017-4459-0

Cited by 16 publications

(11 citation statements)

References 47 publications

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“…Givinostat (formerly ITF2357), an orally active HDAC inhibitor, has been shown to prevent the development of diabetes. 84 , 85 Similarly, activation of sirtuin1, which is involved in inflammation, metabolism, and aging, has been shown to have anti-inflammatory properties in diabetes. 86 …”

Section: Mechanisms Of Vascular Complications In Diabetes and The Impmentioning

confidence: 99%

Diabetes, Hypertension, and Cardiovascular Disease: Clinical Insights and Vascular Mechanisms

Petrie

Guzik

Touyz

2018

Canadian Journal of Cardiology

1,306

779

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Hypertension and type 2 diabetes are common comorbidities. Hypertension is twice as frequent in patients with diabetes compared with those who do not have diabetes. Moreover, patients with hypertension often exhibit insulin resistance and are at greater risk of diabetes developing than are normotensive individuals. The major cause of morbidity and mortality in diabetes is cardiovascular disease, which is exacerbated by hypertension. Accordingly, diabetes and hypertension are closely interlinked because of similar risk factors, such as endothelial dysfunction, vascular inflammation, arterial remodelling, atherosclerosis, dyslipidemia, and obesity. There is also substantial overlap in the cardiovascular complications of diabetes and hypertension related primarily to microvascular and macrovascular disease. Common mechanisms, such as upregulation of the renin-angiotensin-aldosterone system, oxidative stress, inflammation, and activation of the immune system likely contribute to the close relationship between diabetes and hypertension. In this article we discuss diabetes and hypertension as comorbidities and discuss the pathophysiological features of vascular complications associated with these conditions. We also highlight some vascular mechanisms that predispose to both conditions, focusing on advanced glycation end products, oxidative stress, inflammation, the immune system, and microRNAs. Finally, we provide some insights into current therapies targeting diabetes and cardiovascular complications and introduce some new agents that may have vasoprotective therapeutic potential in diabetes.

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Section: Mechanisms Of Vascular Complications In Diabetes and The Impmentioning

confidence: 99%

Diabetes, Hypertension, and Cardiovascular Disease: Clinical Insights and Vascular Mechanisms

Petrie

Guzik

Touyz

2018

Canadian Journal of Cardiology

1,306

779

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“…HFSR manifests mainly as excessive keratinization around the erythema, while HFS shows symmetrical sensory abnormalities, erythema, and edema. These syndromes also show histologically distinct features . Although the mechanisms are unclear, both may be associated with the simultaneous inhibition of the PDGFR and VEGFR pathways and a decline in the capacity of the skin to repair.…”

Section: Discussionmentioning

confidence: 99%

Adverse reactions of sorafenib, sunitinib, and imatinib in treating digestive system tumors

Xing

et al. 2018

Thoracic Cancer

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BackgroundThis study was conducted to assess the adverse reactions caused by multi‐target tyrosine kinase inhibitor treatment of gastrointestinal tumors.MethodsWe carried out a retrospective study of drug‐related adverse reactions in 115 patients who were treated with sorafenib, sunitinib, and imatinib for primary hepatocellular carcinoma or gastrointestinal stromal tumors from October 2003 to March 2012 at the Peking University International Hospital.ResultsThe total incidence of adverse reactions of sorafenib, sunitinib, and imatinib in patients with hepatocellular carcinoma and gastrointestinal stromal tumors was > 80%. The main adverse reactions of sorafenib were hypertension in 38 patients (33.3%) and diarrhea in 28 patients (24.4%). Sunitinib was associated with higher incidence and greater grade 3–4 toxicity. The common toxicities were skin color changes in 105 patients (90.9%), hand‐foot skin reactions in 65 patients (54.6%), and leukopenia (63.6%), hypertension (22.7%), proteinuria (22.7%), liver function impairment (22.7%), and hypomagnesemia (27.3%). While imatinib was well tolerated, it was associated with the highest number of adverse reactions, including skin color change (55.6%) and edema (38.9%). Hypophosphatemia (4.4%) and hoarseness (2.2%) only occurred in the sorafenib treatment group.ConclusionsThe adverse reactions of multi‐target tyrosine kinase inhibitor treatments are generally mild to moderate, and most patients can tolerate these without the need for further intervention. Some serious adverse reactions may be alleviated by discontinuing the drugs or by administering symptomatic treatment.

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“…Histone deacetylase inhibitors are expected to be potentially therapeutic against autoimmune diseases such as type I diabetes, MS, pancreatitis, and IBD. [34][35][36][37] For instance, HDAC isoforms such as HDAC2, HDAC3, and HDAC6 are involved in chronic intestinal inflammation, and pan-HDAC inhibitors (HDACis) suppress pro-inflammatory cytokine production such as IL-6, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ). 37) In K Ca 3.1-expressing breast and prostate cancer cells, pharmacological and small interfering RNA (siRNA)- mediated inhibition of HDAC2 and HDAC3 resulted in the down-regulation of K Ca 3.1.…”

Section: Post-transcriptional and Proteasomal Regulation Of K Ca 31mentioning

confidence: 99%

Ca2+-Activated K+ Channel KCa3.1 as a Therapeutic Target for Immune Disorders

Ohya

Kurihara

2018

Biological & Pharmaceutical Bulletin

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In lymphoid and myeloid cells, membrane hyperpolarization by the opening of K channels increases the activity of Ca release-activated Ca (CRAC) channels and transient receptor potential (TRP) Ca channels. The intermediate-conductance Ca-activated K channel K3.1 plays an important role in cell proliferation, differentiation, migration, and cytokine production in innate and adaptive immune systems. K3.1 is therefore an attractive therapeutic target for allergic, inflammatory, and autoimmune disorders. In the past several years, studies have provided new insights into 1) K3.1 pharmacology and its auxiliary regulators; 2) post-transcriptional and proteasomal regulation of K3.1; 3) K3.1 as a regulator of immune cell migration, cytokine production, and phenotypic polarization; 4) the role of K3.1 in the phosphorylation and nuclear translocation of Smad2/3; and 5) K3.1 as a therapeutic target for cancer immunotherapy. In this review, we have assembled a comprehensive overview of current research on the physiological and pathophysiological significance of K3.1 in the immune system.

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Oral histone deacetylase inhibitor synergises with T cell targeted immunotherapy to preserve beta cell metabolic function and induce stable remission of new-onset autoimmune diabetes in NOD mice

Cited by 16 publications

References 47 publications

Diabetes, Hypertension, and Cardiovascular Disease: Clinical Insights and Vascular Mechanisms

Diabetes, Hypertension, and Cardiovascular Disease: Clinical Insights and Vascular Mechanisms

Adverse reactions of sorafenib, sunitinib, and imatinib in treating digestive system tumors

Ca<sup>2+</sup>-Activated K<sup>+</sup> Channel K<sub>Ca</sub>3.1 as a Therapeutic Target for Immune Disorders

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