Current Pharmaceutical Design - Volume 23, Issue 34, 2017

Phytosterols (PS) are plant-based structural analogous of mammalian cholesterol that have been shown to lower blood cholesterol concentrations by ~10%, although inter-individual response to PS supplementation due to subject-specific metabolic and genetic factors is evident. Recent work further suggests that PS may act as effective triglyceride (TG)-lowering agents with maximal TG reductions observed in hypertriglyceridemic subjects. Although PS have been demonstrated to interfere with cholesterol and perhaps TG absorption within the intestine, they also have the capacity to modulate the expression of lipid regulatory genes through liver X receptor (LXR) activation. Identification of single-nucleotide polymorphisms (SNP) in key cholesterol and TG regulating genes, in particular adenosine triphosphate binding cassette G8 (ABCG8) and apolipoprotein E (apoE) have provided insight into the potential of utilizing genomic identifiers as an indicator of PS responsiveness. While PS supplementation is deemed safe, expanding research into the atherogenic potential of oxidized phytosterols (oxyphytosterols) has emerged with their identification in arterial lesions. This review will highlight the lipid-lowering utility and associated mechanisms of PS and discuss novel applications and future research priorities for PS pertaining to in utero PS exposure for long-term cardiovascular disease risk protection and combination therapies with lipidlowering drugs.

Coronary heart disease (CHD) is the leading cause of mortality in the world and atherosclerosis is the main cause of CHD. Traditional Chinese medicines have been applied in the treatment of CHD for centuries. In the recent years, clinical trials have been carried out to evaluate the efficacies of Chinese medicine. Meanwhile, extensive studies have also been carried out to explore the underlying pharmacological mechanisms of Chinese medicine. In this review, we will summarize the commonly prescribed Chinese medicine and patent Chinese drugs in treating patients with atherosclerotic CHD and review published clinical trials of Chinese medicine in treating CHD. The anti-atherosclerosis mechanism of Chinese medicine will also be reviewed. Finally, challenges and opportunities facing application of Chinese medicine in the treatment of CHD will be presented.

Metabolic syndrome (MS) is a very common medical problem worldwide. It includes obesity, hypertension, hyperglycemia, and abnormal levels of triglycerides and high-density lipoprotein cholesterol. It is closely associated with insulin resistance and may lead to diabetes mellitus, liver diseases, or cardiovascular diseases. Corn silk (CS), a traditional Chinese medicine, has been reported to have multiple beneficial effects, including hypotensive, anti-diabetic, and hypolipidemic properties. This suggests that corn silk could be used to treat or prevent metabolic syndrome. In this review, we will discuss the potential role of corn silk in different components of metabolic syndrome.

The genus Digitalis L. containing species, commonly known as the “foxglove”, is the main source of cardenolides, which have various pharmacological properties effective against certain pathological conditions including myocardial infarction, arterial hypertension, cardiac dysfunction, angina, and hypertrophy. Togehter with a prime effect of controlling the heart rhythm, many workers demonstrated that lanatoside C and some other cardiac glycosides are effective in several cancer treatments such as prostate and breast cancers. Due to digoxigenin derivatives of cardenolides, which are mainly used for medicinal purposes, such as digoxigenin, D. lanata as a main source is of great interest for commercial scale production of cardenolides in Europe. Phytochemical studies on cardenolides, naturally occurring plant secondary metabolites, have mainly focused on the species of the genus Digitalis L., as the members of this family have a high level and diverse content of cardenolides. During the last few decades, plant tissue culture techniques have been optimised for many plant species including Digitalis, however, the production capacity of cardenolides somehow failed to reach a commercially desired extent. In this review paper, the genus Digitalis is evaluated in terms of its main botanical and physiological features, traditional uses, molecular genetics and metabolomics, cellular mechanism of action, medicinal uses, clinical pharmacology, drug interactions, therapy in the management of cardiovascular disorders, potential utility of therapy in extracardiac conditions, and toxicity.

Heart failure is one of the major causes of mortality worldwide and it is the end stage of several cardiovascular diseases. Traditional Chinese medicine has been used in the management of heart failure for a long time. Only until recently, well-designed clinical trials have been put into practice to study the efficacies of Chinese herbs. Extensive studies have also been carried out to explore the underlying mechanisms of pharmaceutical actions of Chinese herbs. In this study, we will summarize the frequently used Chinese herbs, formulae and patent Chinese drugs in treating patients with heart failure and review published clinical evaluations of Chinese herbs in treating cardiovascular diseases. The mechanisms by which Chinese herbs exert cardio-protective effects will also be reviewed. In the end, we will point out the limitations of current studies and challenges facing modernization of traditional Chinese medicine.

Danshen (Salvia miltiorrhiza Bunge) is a valued herbal plant in the Traditional Chinese Medicine. The dried root of this plant (Radix Salvia miltiorrhiza), either alone or in combination with other herbal ingredients, has been used for hundreds of years to treat numerous ailments, especially cardiovascular diseases. For the past several decades, many studies have tried to delineate the putative cardioprotective effects of this folk medicine through the lens of modern scientific research. In this review, we have summarized the current knowledge about the pharmacological potentials of danshen. The main focus is laid on the predominant bioactive compounds in danshen, which include phenolic acids and tanshinones. We discussed the absorption and metabolism of these compounds, and examine in detail the cardioprotective mechanisms during atherosclerosis, thrombosis, and myocardial infarction reperfusion.

Nonalcoholic fatty liver disease (NAFLD) has become more prevalent worldwide. It is often associated with some metabolic diseases, such as obesity, type 2 diabetes, and metabolic syndrome. With increasing focus on the treatment of fatty liver, much attention has been paid to numerous medicinal herbs and dietary substances to provide a new strategy for NAFLD treatment. The natural active compounds from the herbs or diet have been studied as promising treatments for NAFLD. This study aimed to summarize the use and mechanism of action of natural active compounds in the treatment of NAFLD in the recent 10 years. An updated search was conducted on the PubMed, Web of Science, and Google Scholar databases from 2006 (for studies on silibinin, resveratrol, curcumin, and berberine compounds since 2010). Fifty-nine active compounds for NAFLD treatment were presented in detail in textual form and tabular form according to their chemical classification.

Irritable bowel syndrome (IBS) is one of the most common functional bowel disorders (FBD), which is characterized by recurrent abdominal pain, abdominal bloating/distention associated with defecation or changed bowel habits. Currently, there is no evidence of obvious anatomic or physiologic abnormalities on the routine diagnostic examinations. There are multiple pathological factors involved in IBS responsible for its heterogeneous nature, although the exact etiology and pathology of IBS are not well known and it is disappointed to develop biomarkers for this disorder. These factors including low-grade inflammation, activation of immune system, changed intestinal microorganism, small intestinal bacterial overgrowth (SIBO), malabsorption of bile acid (BA), increased number of mast cells (MCs). Current pharmacologic treatment for IBS focuses on alleviation of its symptoms, but not on the elimination of its cause. Although there are a lot of conventional chemical medicines for IBS available, due to the limited clinical benefits, high medical expenses and severe side effects, many IBS patients have turned to alternative medicine, particularly Chinese herbal medicine (CHM). Chinese herbal therapies have been used for thousand years in eastern Asia and have been provided that they are effective in relieving symptoms among IBS patients. Generally, traditional Chinese herbal formulae (CHF) consisting of CHM can be easily adjusted in accordance with concrete conditions, which means the treatment is based on syndrome differentiation and varied from individual to individual. Meanwhile, CHF/CHM containing many different ingredients may act on multiple sites/pathways with potential synergistic effects and chemical reactions.

The incidence and prevalence of inflammatory bowel diseases (IBD), which comprise ulcerative colitis and Crohn's disease, are increasing dramatically worldwide. Immunomodulators and biological agents can help but cause severe side effects in long-term use. As such, complementary and alternative medicine, in particular herbal remedy, is becoming more and more popular in the treatment of IBD patients. Many natural compounds have been used in clinical trials and some have been proven promising in IBD treatment. To achieve a better understanding of herbal therapy, researchers focus on understanding the underlying mechanisms by using experimental rodent models. The mechanism of the pathogenesis of IBD is complex involving both environmental and genetic factors. IBD is considered as a consequence of impaired epithelial barrier function, gut microbiota dysbiosis, and aberrant immune response. Studies have demonstrated that herbal medicine can improve epithelial proliferation and barrier integrity, restore microbiota homeostasis, and suppress hyper-immune reaction. This review is to summarize current understanding of the molecular basis of herbal treatment of IBD at the levels of epithelial, microbial, and immune regulation.

Depression is a common psychiatric disorder and a leading cause of disability worldwide. Traditional Chinese medicine is one of the commonly used complementary and alternative medicine therapies for depression. Clinical trials have been carried out to assess the efficacy and safety of Chinese herbal medicine currently. The exploration of herbal mechanisms of action used for the treatment of depression has also received great attention. This study is performed to summarize the frequently used formulae, patent drugs and single herbs in treating depression, review the literatures of clinical trials in treating depressive disorders, and to list the possible mechanisms involved during the treatment. Besides, we will analyze the limitations of present studies and the obstacles in the modernization of traditional Chinese medicine.

Background: This review focuses on the treatment of pulmonary arterial hypertension (PAH) with selexipag and compares its drug-related therapeutic effects with those of prostacyclin analogues. Methods: We searched the relevant literature and summarized the current clinical trials concerning selexipag and PAH. Results: With only few cases per million, PAH is a rare disease, but when untreated it can be life-threatening. PAH is linked to elevated levels of endothelin (ET-1) and decreased levels of nitric oxide (NO) and prostacyclin (PGI2). PAH-specific therapeutic approaches concentrate on these characteristics with drugs targeting the endothelin- receptor (e.g. bosentan), phosphodiesterase-5 (e.g. sildenafil) or the prostacyclin-receptor (e.g. treprostinil). Recently, the new drug selexipag acting as a non-prostanoid IP2-receptor agonist has been approved for PAH therapy. The active form of selexipag (ACT-333679) was designed by the help of a medicinal chemistry program and it was further modified by replacing the terminal carboxyl group with an N-acylsulfonamide group to form the more stable oral drug, selexipag. Selexipag has a high selectivity for the IP2-receptor and differs from conventional prostacyclin analogues in its chemical structure. In the GRIPHON trial selexipag was demonstrated to significantly improve the primary composite endpoint of death or complications related to PAH (hazard ratio 0.6, 99% confidence interval, 0.46 to 0.78; P < 0.001) as well as exercise capacity in the form of the 6-minute walk distance (12.0 m treatment effect, 99% confidence interval, 1 to 24; P = 0.003). However, no significant reduction in all-cause mortality was achieved. Selexipag has also shown promising results in combination therapy with phosphodiesterase-5 inhibitors (PDE-5i) and/or endothelin receptor antagonists (ERA). The most common adverse effects (AEs), associated with selexipag, are headache, diarrhea, jaw pain, and nausea. Nevertheless, Selexipag was generally well tolerated during the GRIPHON trial. Conclusions: Selexipag is a valuable addition to PAH therapeutics especially by reducing the PAH-related hospitalizations and thus improving quality of life in PAH patients.

Insulin resistance indicates a deregulated set of biochemical pathways and physiological functions involved in the pathogenesis of a number of diseases, including type 2 diabetes and cancer. Conversely, a number of synthetic and natural insulin sensitizers, including inositol, have been recognized to exert both anti-diabetic as well as anti-cancer properties. Inositol participates in insulin transduction signaling, and deregulated inositol metabolism has been ascertained in several conditions associated with insulin resistance. Two distinct inositolphosphoglycans released upon insulin stimulation act as insulin-mimetic by counteracting hyperinsulinemia, hyperglycemia and their metabolic complications. Additionally, inositol may directly interfere with both glucose metabolism and carcinogenesis by modulating a number of critical processes downstream of insulin stimulation, including anti-oxidant defenses, oxidative glucose metabolism and endocrine modulation. A selected cluster of biochemical factors (PI3K/Akt, PDH and AMPK-related pathways), that are presently considered putative targets for anticancer treatments, are also specifically modulated by inositol or its derivatives. What is more, studies on inositol mechanism of action paved the way in understanding that both insulin resistance and cancer share a few perturbed, critical biochemical pathways. Asides from the basic investigations, preliminary studies in vivo demonstrated the beneficial effect of inositol in fostering glucose homeostasis as well as in antagonizing cancer growth. Thereby, inositol fulfills the requirement to target both insulin resistance and cancer, and its clinical usefulness deserves to be adequately addressed by specific, randomized trials.