Background—Forearm endothelial dysfunction, characterized by an impaired vasodilating response to acetylcholine (ACh), may be associated with several cardiovascular risk factors, including essential hypertension. Although the prognostic value of coronary endothelial dysfunction has been demonstrated, that of forearm endothelial dysfunction is still unknown. Methods and Results—Endothelium-dependent and -independent vasodilation was investigated in 225 never-treated hypertensive patients (age, 35 to 54 years) by intra-arterial infusion of increasing doses of ACh and sodium nitroprusside. Patients were divided into tertiles on the basis of their increase in ACh-stimulated forearm blood flow (FBF) from basal: group 1, from 30% to 184%; group 2, from 185% to 333%; and group 3, from 339% to 760% increase from basal. During a mean follow-up of 31.5 of months (range, 4 to 84 months), there were 29 major adverse events at the cardiac (n=19), cerebrovascular (n=9), or peripheral vascular (n=1) level. Events included myocardial infarction, angina, coronary revascularization procedures, stroke, transient cerebral ischemic attack, and aortoiliac occlusive disease. Event rate per 100 patient-years was 8.17, 4.34, and 2.02 in the first, second, and third tertiles of peak percent increase in FBF during ACh infusion. The excess risk associated with an FBF increase in the first tertile was significant (relative risk, 2.084; 95% CI, 1.25 to 3.48;P =0.0049) after controlling for individual risk markers, including 24-hour ambulatory blood pressure. Conclusions—Our data suggest that forearm endothelial dysfunction is a marker of future cardiovascular events in patients with essential hypertension.

Preventive cardiology abstractPrognostic significance of endothelial dysfunction in hypertensive patients

Natural product libraries contain specialized metabolites derived from plants, animals, and microorganisms that play a pivotal role in drug discovery due to their immense structural diversity and wide variety of biological activities. The strategies to greatly extend natural product scaffolds through available biological and chemical approaches offer unique opportunities to access a new series of natural product analogues, enabling the construction of diverse natural product-like libraries. The affordability of these structurally diverse molecules has been a crucial step in accelerating drug discovery. This review provides an overview of various approaches to exploit the diversity of compounds for natural product-based drug development, drawing upon a series of examples to illustrate each strategy.

Strategies to diversify natural products for drug discovery.

Zinc binding groups (ZBGs) play a crucial role in targeting histone deacetylase inhibitors (HDACIs) to the active site of histone deacetylases (HDACs), thus determining the potency of HDACIs. Due to the high affinity to the zinc ion, hydroxamic acid is the most commonly used ZBG in the structure of HDACs. An alternative ZBG is benzamide group, which features excellent inhibitory selectivity for class I HDACs. Various ZBGs have been designed and tested to improve the activity and selectivity of HDACIs, and to overcome the pharmacokinetic limitations of current HDACIs. Herein, different kinds of ZBGs are reviewed and their features have been discussed for further design of HDACIs.

Zinc binding groups for histone deacetylase inhibitors.

Histone deacetylases (HDACs), encompassing at least 18 members, are promising targets for anticancer drug discovery and development. To date, five histone deacetylase inhibitors (HDACis) have been approved for cancer treatment, and numerous others are undergoing clinical trials. It has been well validated that an agent that can simultaneously and effectively inhibit two or more targets may offer greater therapeutic benefits over single-acting agents in preventing resistance to treatment and in potentiating synergistic effects. A prime example of a bifunctional agent is the hybrid HDAC inhibitor. In this perspective, the authors review the majority of reported kinase/HDAC hybrid inhibitors.

Kinase and Histone Deacetylase Hybrid Inhibitors for Cancer Therapy

Histone deacetylases (HDACs) are clinically validated epigenetic drug targets for cancer treatment. HDACs inhibitors (HDACis) have been successfully applied against a series of cancers. First-generation inhibitors are mainly pan-HDACis that target multiple isoforms which might lead to serious side effects. At present, the next-generation HDACis are mainly focused on being class- or isoform-selective which can provide improved risk–benefit profiles compared to non-selective inhibitors. Because of the rapid development in next-generation HDACis, it is necessary to have an updated and state-of-the-art overview. Here, we summarize the strategies and achievements of the selective HDACis.

/pdf/next-generation-of-selective-histone-deacetylase-inhibitors-5b98m7bcsd.pdf

Next-generation of selective histone deacetylase inhibitors

Pharmacological inhibition of histone deacetylases (HDACs) has been successfully applied in the treatment of a wide range of disorders, including Parkinson's disease, infection, cardiac diseases, inflammation, and especially cancer. HDAC inhibitors (HDACIs) have been proved to be effective antitumor agents by various stages of investigation. At present, there are two opposite focuses of HDACI design in the cancer therapy, highly selective inhibitor strategy and dual- or multitargeted inhibitors. The former method, which is supposed to elucidate the function of individual HDAC and provide candidate inhibitors with fewer side effects, has been widely accepted by the inhibitor developer. The latter approach, though less practiced, has promising potential for the antitumor therapy based on HDACIs. Effective HDACIs, some of which are in clinic anticancer research, have been developed by both methods. In order to gain insight into HDACI design, the strategies and achievements of the two diverse methods are reviewed.

Trend of histone deacetylase inhibitors in cancer therapy: isoform selectivity or multitargeted strategy.

The aim of this study is to assess the potential protective effect of oleanolic acid (OA) against ox-LDL induced damage in human umbilical vascular endothelial cells (HUVECs) and investigate potential mechanism of action including antioxidative effects and inhibition of mitochondria apoptosis pathway. Cell counting kit 8 was used to evaluate the viability of HUVECs. 2', 7'-DCFH-DA staining and flow cytometry was used to assess the levels of intracellular reactive oxygen species in HUVECs. The protein expression levels of uncoupling protein 2, cytochrome C, and apoptosis induction factors were measured by western blotting. The results indicated that OA treatment alleviated ox-LDL induced cytotoxicity in HUVECs and ameliorated the reactive oxygen species levels. Western blotting results demonstrated that OA treatment increased the expression level of uncoupling protein 2 and decreased the release of cytochrome C and apoptosis induction factors from mitochondria to cytoplasm, suggesting inhibition of mitochondria apoptosis pathway. In conclusion, OA could protect HUVECs from ox-LDL-induced cytotoxicity; its antioxidant property and inhibition of mitochondria apoptosis are likely crucial contributors.

Cytoprotective Effects of Oleanolic Acid in Human Umbilical Vascular Endothelial Cells is Mediated Via UCP2/ROS/Cytochrome C/AIF Pathway.

The present invention relates to a marine drug for adjuvant treatment of Lewis lung carcinoma, the marine drug includes cisplatin and a dunaliella salina beta-carotene extract, the weight ratio of cisplatin and dunaliella salina beta-carotene extract is 3: 25-100, the content by weight of a cis-isomer in the dunaliella salina beta-carotene extract is greater than 50%, and the dunaliella salina beta-carotene extract uses a dunaliella salina beta-carotene extract dropping pill. The content by weight of the cis-isomer in the dunaliella salina beta-carotene extract used in the marine drug for adjuvant treatment of Lewis lung carcinoma is greater than 50%, the dunaliella salina beta-carotene anti-tumor effect can be effectively improved, and the toxicity is reduced. The marine drug uses the cisplatin and the dunaliella salina beta-carotene extract together for synergically resisting Lewis lung carcinoma, can effectively improve the anti-tumor effect, and reduces the toxicity of platinum drugs.

Marine drug for adjuvant treatment of Lewis lung carcinoma

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Trend of histone deacetylase inhibitors in cancer therapy: isoform selectivity or multitargeted strategy.

Cytoprotective Effects of Oleanolic Acid in Human Umbilical Vascular Endothelial Cells is Mediated Via UCP2/ROS/Cytochrome C/AIF Pathway.

Marine drug for adjuvant treatment of Lewis lung carcinoma