Current Pharmaceutical Design - Volume 22, Issue 3, 2016

Monoamine oxidase (MAO, E.C. 1.4.3.4) is a flavin-adenine type of enzyme with two isoforms referred to MAO-A and MAO-B that function for oxidation of monoamines. While MAO-A inhibitors are effective as antidepressant and anxiolytic drugs (e.g. chlorgyline, moclobemide, and lazabemide), inhibitors of MAO-B (e.g. Ldeprenyl, pargyline, and rasagiline) are used against neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. Considering the need for novel MAO inhibitors due to side effects of the current ones, natural products have become attractive targets for researchers. Up till now, many studies revealed strong MAO inhibitory activity of flavonoid, xanthone, alkaloid, and coumarin derivatives from herbal sources, which also become good models for the synthetic MAO inhibitors. For this purpose, the present review focuses on examples of in vitro and in vivo MAO-inhibiting natural compounds of plant origin from a wide variety of chemical classes isolated mainly between 2000 – 2015.

Autism is a comprehensive growth abnormality in which social skills, language, communication, and behavioral skills are developed with delay and as diversionary. The reasons for autism are unclear, but various theories of genetics, immunity, biological, and psychosocial factors have been proffered. In fact, autism is a complex disorder with distinct causes that usually co-occur. Although no medicine has been recognized to treat this disorder, pharmacological treatments can be effective in reducing its signs, such as self-mutilation, aggression, repetitive and stereotyped behaviors, inattention, hyperactivity, and sleeping disorders. Recently, complementary and alternative approaches have been considered to treat autism. Ginkgo biloba is one of the most effective plants with an old history of applications in neuropsychological disorders which recently is used for autism. The present review discusses the recent findings, pathophysiology, and etiology of autism and thereafter addresses the promising results of herbal remedies.

Hepatitis B virus (HBV) is inherently a hepatotropic virus that causes acute and chronic hepatitis in about one-third of world population. Of the estimated 360 million chronically infected individuals, more than one million die of liver cirrhosis, fulminant liver failure or hepatocellular carcinoma (HCC) every year. Though there is an effective vaccine available, failure to protection because of vaccine-escape viral mutants in some population is also reported. Moreover, all the currently approved antiviral drugs have their limitations, too. Interferon (IFN-α) has limited efficacy and a high incidence of adverse side-effects in a proportion of chronic patients. Nucleos(t)ide analogs like, lamivudine, adefovir, tenofovir and entecavir are very effective in treating chronic hepatitis B (CHB), but long-term therapy eventually leads to drug-resistance. As an alternative approach, natural or plant products have provided promising therapeutics in modern pharma industry. Owing to their characteristics of high chemical diversity and biochemical specificity, natural products offer great promises as potentially effective antiviral drugs. A broad spectrum of phytochemicals including flavonoids (e.g., Vogonin), terpenes (e.g., Artemisinin), alkaloids (e.g., Oxymatrine), polyphenolics (e.g., geraniin), saponins (e.g., Astragaloside IV) and lignans (e.g., Helioxanthin) has been isolated and investigated for anti-HBV activities in vitro as well as in vivo. Nevertheless, these promising compounds have different and overlapping mechanisms of action by either inhibiting viral antigens secretion or suppression of DNA replication. The present article reviews the recent developments in anti-HBV natural products.

Guggulsterone [4, 17(20)-pregnadiene-3, 16-dione] is a plant sterol derived from the gum resin of the tree Commiphora wightii. The gum resin of the guggul tree has been used in traditional medicine for centuries to treat obesity, liver disorders, internal tumors, malignant sores, ulcers, urinary complaints, intestinal worms, leucoderma, sinus, edema and sudden paralytic seizures. Guggulsterone has been shown to modulate the nuclear receptors, farnesoid X receptor, pregnane X receptor, CYP 2b10 gene expression, and the bile salt export pump for cholesterol elimination. Recent research indicates that the active components of gum guggul, E- and Zguggulsterone have the potential to both prevent and treat cancers. Guggulsterone inhibits the growth of a wide variety of tumor cells and induces apoptosis through down regulation of antiapoptotic gene products (IAP1, xIAP, Bfl-1/A1, Bcl-2, cFLIP, and survivin), modulation of cell cycle proteins (cyclin D1 and c-Myc), activation of caspases, inhibition of Akt, and activation of JNK. Guggulsterone modulates the expression of gene products involved in metastasis (MMP-9, COX-2, and VEGF) of tumor cells. Guggulsterone mediates gene expression through the modulation of several transcription factors, including NF-κB, STAT3, C/EBPα, androgen receptor, and glucocorticoid receptors. This review describes the anti-cancer properties, molecular targets, and the apoptotic effects of guggulsterone.

Esophageal adenocarcinoma (EAC) is the second frequent cancer of the esophagus. Barrett’s esophagus (BE) takes precedence over EAC. BE is a metaplastic change of the stratified squamous epithelium to the intestinal columnar epithelium due to the acidic gastrointestinal reflux. Further, the disease takes the hyperplastic stage followed by EAC. An initial immune response is an essential reaction of a body to an occurrence of alien/modified cells to be removed. It has been appreciated that an inflammatory reaction occurs in the early stages of EAC or even in BE. Dendritic cells (DCs) play a key role in a frontier of an immune response due to their advanced ability to recognize foreign antigens and mobilize naive T cells to effectors. However, in a cancer condition, tumor-delivered immunosuppression occurs in a variety of mechanisms that alter/switch the functionality of DCs from immune activating to immune suppressive cells. In this brief review, we consider tumor-induced paths of a capacity of tumor cells to down-regulate DCs, with a focus on EAC, and also discuss a possibility to use DCs for immunotherapeutic approaches. Indeed, DCs represent a promising tool for developing new immunotherapeutic approaches for cancer treatment including EAC. It has been reported to achieve effective DC-mediated immune responses by raising anti-tumor cytotoxic T cell responses against multiple cancer antigens through loading DCs with total tumor RNA. However, more studies should be performed in order to understand a precise role in tumor-induced mechanisms of DC suppression in BE/EAC. Likely, these mechanisms should involve general carcinogenic and EAC-specific pathways.

Traditional Chinese medicine (TCM) is a theoretical based system and is completely different from western medicine and states that numerous diseases, especially chronic diseases, are cured or relieved. “Zheng” (syndrome) is a summarization of the pathological changes which take place during the different stages of the development of a disease, including its location, cause and nature as well as the state of both Xie-qi (pathogenic factors) and Zheng-qi (healthy energy). Compared to a single symptom, syndrome can demonstrate the nature of a disease more extensively, completely and correctly. However, it is difficult to compare “Zheng” to the western medicine theory, which is based on scientific evidence for the diagnosis and treatment of a specific disease. Estrogen deficiency is a major pathogenetic factor in bone loss after menopause and oophorectomy with the subsequent risk of developing osteoporosis. According to TCM theory, the kidney stores essence and this can transform into bone marrow to nourish the bones, strenghthen the skeleton by promoting growth and repair. The kidney deficiency can decrease the estrogen level adjusted by the gonadal axis, causing osteoporosis. Traditional Chinese medicines tonifying the kidney can significantly enhance the level of estrogen to alleviate osteoporosis. In combination with other evidence, we further deduce that the syndrome as defined within TCM has a similar pathological mechanism to that defined by western medicine. If TCM theory is to be understood and accepted, and further fused with the western medicine theory, the micro pathological basis of TCM syndrome must be investigated extensively, which will lead to bridging the two theories together. The fusion of TCM with western medicine will pay more attention to analyzing the common nature and difference of disease and syndrome. This paper reviews the way forward for new translational advances.

Objective: To search major Islamic Traditional Medicine (ITM) textbooks for definition, etiology and medicinal plants used to manage ‘khadar’ or ‘paresthesia’, a common sensory symptom of multiple sclerosis (MS) and peripheral neuropathies. In addition, the conformity of the efficacy of ITM-suggested plants with the findings from modern pharmacological research on MS will be discussed. Methods: Data on the medicinal plants used to treat ‘khadar’ were obtained from major ITM texts. A detailed search in PubMed, ScienceDirect, Scopus and Google Scholar databases was performed to confirm the effects of ITM-mentioned medicinal plants on MS in view of identified pharmacological actions. Results: Moringa oleifera Lam., Aloe vera (L.) Burm.f., Euphorbia species, Citrullus colocynthis (L.) Schrad., and Costus speciosus (Koen ex. Retz) Sm. are among the most effective ITM plants for the management of ‘khadar’. Recent experimental evidence confirms the effectiveness of the mentioned plants in ameliorating MS symptoms. Moreover, according to ITM, prolonged exposure to cold and consuming foodstuff with cold temperament might be involved in the etiopathogenesis of MS. Conclusions: The use of traditional knowledge can help finding neglected risk factors as well as effective and safe therapeutic approaches, phytomedicines and dietary habits for the management of paresthesia and related disorders such as MS.

Herba Epimedii (HEP) known as YinYangHuo in Chinese is the dried leaf of the Epimediium, and has been historically used in combination with other herbs to treat skeletal diseases in traditional Chinese medicine (TCM). Here, we review the historical TCM interpretation of the action of HEP, its use in clinical trials, its main phytochemical constituents and its pharmacological findings. 85 clinical trials were identified which used HEP in TCM prescriptions with other herbs to treat primary and secondary osteoporosis from 2005 to now. More than 60 individual compounds were isolated and characterized from HEP and studied in various animal and cell models. HEP and its constituents exhibited a variety of anti-resorptive and bone formation-stimulating effects, which target different pathways in the bone remodeling cycle. These compounds may provide new perspectives in alternative treatment regimes and reveal novel chemical scaffolds for the development of anti-osteoporotic drugs. These approaches are also useful for guiding our research to employ an integrative therapeutic approach to treat complex diseases such as osteoporosis diseases which could be superior to the conventional single target – single drug approach.

Regarding limited effectiveness of many hepatic medical approaches, seeking for novel treatment strategies is crucial to improve outcomes. Hence, the current study aims to compile a concise but critical review over reported liver diseases and related medicinal plants from the Persian medicine perspectives. To this end, five main pharmaceutical manuscripts of Persian medicine from 9th-18th A.D. as well as the latest and largest medical textbook of Persian medicine were studied. By searching through databases such as PubMed and ScienceDirect, mechanisms or pharmacological activities of reported medicinal plants in the field of liver diseases were cited and discussed. In all, seventeen different liver diseases, mainly chronic, were cited in Persian medicine. Ninety three medicinal plants with liver tonic, hepatoprotective and related effectiveness belonging to 49 families were derived and authenticated from these studied manuscripts. More than 75% of the herbs showed related hepatoprotectivity and antioxidant activities. However, none of them have been examined clinically. Besides historical clarification, the current investigation compiled an evidence- based study on reported liver herbal remedies from the standpoints of Persian scholars. Conducting attributable clinical trials against the backdrops of proven in vitro and in vivo studies may result in new treatment discoveries for liver diseases.

AIMS: High levels of plasma triglycerides (TG) are a risk factor for cardiovascular diseases often associated with anomalies in other lipids or lipoproteins. However, results from randomized trials, suggesting that low high density lipoprotein cholesterol (HDLc) might not cause cardiovascular disease, as originally thought, have generated renewed interest in increased concentrations of TG. The objective has been to determine the prevalence and factors associated with hypertrigliceridemia (HTG) and with low HDLc. Methods: Patients, included in the HTG Registry of the Spanish Association of Atherosclerosis, have been analyzed and anthropometric as well as metabolic data have been collected from them. Results: 1349 patients have been evaluated. Low HDLc has been found in 60.86% (821). Factors significantly associated with low HDLc and HTG were the female sex, being overweight with an increase in the body mass index, using tobacco, diabetes mellitus, low-alcohol consumption and a low exercise rate. Among them, two types of association may be identified with anthropometric variables (especially in men) and metabolic variables (diabetes mellitus and metabolic syndrome). No significant differences have been found insofar as the prevalence of cardiovascular illness between both groups. Conclusions: HTG - low HDLc association is very frequent and it is related to overweight-obesity and other metabolic disorders such as diabetes mellitus with or without metabolic syndrome. In addition, these findings underscore the intricate relationship between HDLc, TG, and glucose metabolism that need to be studied simultaneously. In this context, TG lowering treatment is suggested to be more strongly recommended to address the residual risk of atherosclerotic cardiovascular disease.

Cardiovascular diseases (CVD) are considered the leading cause of morbidity and mortality from chronic diseases in the world. In addition, about 20% of first and recurrent acute myocardial infarctions (MI) are silent. In this context, subclinical atherosclerosis culminates in evident CVD, through the evolution of early risk factors such as hypercholesterolemia, hypertriglyceridemia and others. The main problem in CVD is related to the long-time between the start of the subclinical atherosclerosis and the manifestation of the disease. The identification of subjects at risk of such events is obviously substantial, since identification leads to implementation and compliance with effective preventive measures that reduce such risk. In this sense, this review demonstrates biomarkers as an alternative to early detection of subclinical atherosclerosis. One of the proposed biomarkers is the Ischemia-modified albumin (IMA), being considered a promising biochemical biomarker for atherosclerotic conditions. Another marker that is gaining strength and is associated with the IMA are the advanced oxidation protein products (AOPP), its measurement provides information on the level of exposure to potentially harmful changes to proteins and metabolic control. And last but not least we have nitric oxide as an early marker mainly related to endothelial dysfunction. In this review also is evidenced the use of the Campomanesia xanthocarpa, a plant native to southern region from Brazil extensively used as complementary and alternative medicine, and natural products to reduce protein oxidation and improve the availability of nitric oxide and consequently vascular function, reducing the risk for development of CVD.

Recent studies have shown that visit-to-visit blood pressure (BP) variability was emerging as an independent risk factor for stroke. Although the mechanism is not fully understood, artery remodeling would be closely associated with the relationship between visit-to-visit BP variability and stroke. In addition, the class of antihypertensive agents is suggested to be an important determinant of visit-to-visit BP variability. This review article summarizes the recent literature on these topics. In the elderly hypertensives, strict BP control using calcium channel blockade would play a crucial role to prevent stroke via reducing the visit-to-visit BP variability.

Cardiovascular diseases are currently a basic cause of mortality in highly developed countries. The major reason for genesis and development of cardiovascular diseases is atherosclerosis. At the present time high technology methods of molecular genetic diagnostics can significantly simplify early presymptomatic recognition of patients with atherosclerosis, to detect risk groups and to perform a family analysis of this pathology. A Next-Generation Sequencing (NGS) technology can be characterized by high productivity and cheapness of full genome analysis of each DNA sample. We suppose that in the nearest future NGS methods will be widely used for scientific and diagnostic purposes, including personalized medicine. In the present review article literature data on using NGS technology were described in studying mitochondrial genome mutations associated with atherosclerosis and its risk factors, such as mitochondrial diabetes, mitochondrial cardiomyopathy, diabetic nephropathy and left ventricular hypertrophy. With the use of the NGS technology it proved to be possible to detect a range of homoplasmic and heteroplasmic mutations and mitochondrial genome haplogroups which are associated with these pathologies. Meanwhile some mutations and haplogroups were detected both in atherosclerosis and in its risk factors. It conveys the suggestion that there are common pathogenetic mechanisms causing these pathologies. What comes next? New paradigm of crosstalk between non-pharmaceutical (including molecular genetic) and true pharmaceutical approaches may be developed to fill the niche of effective and pathogenically targeted pretreatment and treatment of preclinical and subclinical atherosclerosis to avoid the development of chronic life-threatening disease.

MicroRNAs (miRNAs) are a class of small regulatory RNAs that control several cellular processes that may contribute to development of cardiovascular disease (CVD) and the pathophysiological consequences of myocardial infarction (MI). Only a very small-numbers of biomarkers in MI (e.g., Troponin) have been identified, which are sufficiently sensitive, specific and robust. There is growing evidence of an association between specific miRNAs in the pathogenesis of MI. miRNAs are transported within the systemic circulation via exosomes and microparticles, and are therefore detectable in blood, urine, saliva, and other fluid compartments. Dysregulation of myocardial-derived miRNAs, such as miR-1, miR-133, miR-499, and miR-208, have been identified as potential biomarkers in MI. Furthermore, alteration of the levels of some miRNAs during stress-induced apoptosis is reported as a novel therapeutic strategy for cardiac disease. Modulation of mir-24 appears to inhibit cardiomyocyte apoptosis, attenuate infarct size, and reduce cardiac dysfunction. A greater knowledge on the molecular mechanism underlying the functional role of emerging miRNAs, could provide novel insights into identifying of new biomarkers. This review highlights several recent preclinical and clinical studies on the role of miRNAs in myocardial infarction; novel miRNA-based therapeutic approaches for therapeutic intervention, and potential circulating miRNA to be served as biomarkers in patients with suspected MI.