Current Molecular Pharmacology - Volume 14, Issue 6, 2021

Background: The pseudo-cereal quinoa has attracted worldwide attention in recent years, due to it being considered a functional food. This stress-tolerant crop has historically been used by Andean cultures as a staple food. Nowadays, the consumption of quinoa in high-income countries is increasing due to it being associated with numerous health benefits, namely related to cardiovascular health. Objective: We have carried out an extensive review on quinoa, including its main uses, applications, and components (nutrients, antinutrients, and bioactives) and their relationship with biological activities and cardiovascular health. Key findings and Conclusions: Quinoa possesses numerous activities, including protection against cardiovascular, metabolic, and degenerative diseases, improvement of the immune system, reduction of symptoms associated with post-menopause, and promotion of muscle mass increase. Some of the quinoa’s activities are due to its balanced amino acid profile, high fiber content, presence of phosphorus, iron, potassium, magnesium, vitamin E, and B vitamins. A plethora of bioactives can also be found in quinoa, such as phytosterols, saponins, phenolics, bioactive peptides, and phytoecdysteroids. More research is needed to better understand the mechanisms of action involved in the biological/therapeutic action of some quinoa components, namely those related to the potential to reduce cardiovascular disease (CVD) risk markers. The knowledge of factors that affect quinoa variability, such as processing conditions, is also of great importance for being able to obtain more benefits from this crop.

Background: Hypertension is a highly prevalent chronic disease worldwide and a major cardiovascular risk factor. Oleanolic acid (3β-hydroxy-olea-12-en-28-oic acid) is a widely distributed bioactive pentacyclic triterpenoid with diverse biological activities such as anti-inflammatory, hepaprotective, anti-diabetic or anti-hypertensive. Objective: The aim of this study was to review and highlight the available data regarding the antihypertensive activity of oleanolic acid and the described mechanisms of action. Methods: Extensive searches were made in the available literature on oleanolic acid and the data investigating its antihypertensive effects were analysed. Results: Most of the research has been performed on animal models of hypertension, ex vivo studies with aortic ring and some in vitro tests with cell cultures, whereas clinical trials are still lacking. Treatment of hypertensive animals with oleanolic acid significantly ameliorated the rise in the systolic blood pressure. In addition, the hypotensive effects of oleanolic acid are also related to a potent diuretic-natriuretic activity and nephroprotection. In vitro studies have characterized the participation of various signalling pathways that modulate the release of vasodilation mediators. Conclusion: In vitro and in vivo studies suggest that oleanolic acid effectively reduces blood pressure and could be an interesting co-adjuvant to conventional treatment of hypertension.

Background: As a major cause of morbidity and mortality, cardiovascular diseases (CVDs) are globally increasing. In spite of recent development in the management of cardiovascular complications, CVDs have remained a medical challenge. Numerous conventional drugs are used to play cardioprotective roles; however, they are associated with several side effects. Considering the rich phytochemistry and fewer side effects of herbal medicines, they have gained particular attention to develop novel herbal drugs with cardioprotective potentials. Amongst natural entities, ginger is an extensively used and well-known functional food and condiment, possessing plentiful bioactivities, like anti-inflammatory, antioxidant, and antimicrobial properties in several disorders management. Objective: The current review deliberated phytochemical properties as well as the ginger/ginger constituents' biological activities and health benefits in several diseases, with particular attention to cardiovascular complications. Methods: A comprehensive search was conducted using multiple databases, including Scopus, PubMed, Medline, Web of Science, national database (Irandoc and SID), and related articles in terms of the health benefits and cardioprotective effects of ginger/ginger constituents. These data were collected from inception until August 2019. Results: In recent years, several herbal medicines were used to develop new drugs with more potency and also minor side effects. Amongst natural entities, ginger is used as a traditional medicine in several diseases. The crude extract, along with related pungent active constituents, is mostly attributed to heart health. The cardioprotective effects of ginger are contributed to its cardiotonic, anti- hypertensive, anti-hyperlipidemia, and anti-platelet effects. The signaling pathways and molecular mechanisms of ginger regarding its cardioprotective effects are also clarified. Conclusion: This study revealed the biological activities, health benefits, and cardioprotective properties of ginger/ginger constituents along with related mechanisms of action, which gave new insights to show new avenues in the treatment of CVDs.

Salvia miltiorrhiza, a traditional Chinese medicine, also named Danshen in China, is widely used for the treatment of cardiovascular disease. It demonstrates multiple biological functions, such as anti-oxidative stress, anti-inflammation and anti-thrombosis. Diabetic angiopathy is one of the diabetic complications with macro- and microangiopathy. Macroangiopathy mainly occurs in arteries, while the microangiopathy mainly includes diabetic retinopathy and nephropathy. Many factors associated with diabetes, such as metabolic abnormalities and oxidative stress, can induce vascular lesions. These factors promote the accumulation of lipids as well as inflammatory cytokines, increase the production of extracellular cell-matrix, and impair endothelium functions, thereby leading to vascular dysfunction. This review attempts to summarize the progress of the studies of Salvia miltiorrhiza on diabetic angiopathy, including improving endothelial function, anti- oxidative stress, reducing the risk of vascular blockage, inhibiting inflammation as well as regulating lipid metabolism. We also summarize the pharmacological activity of bioactive components in Salvia miltiorrhiza and the delivery systems. We made the conclusion that Salvia miltiorrhiza can be used as a potential auxiliary drug for the treatment of diabetic angiopathy.

Background: Cardiovascular disease is the leading cause of death in both developed and developing countries. Di'ao Xinxuekang (DAXXK) is a pure Chinese medicine herbal preparation refined from dioscin extracted from the roots of Dioscorea panthaica Prain et Burk and Diosorea nipponica Makino. Objective: To evaluate the application of DAXXK in Cardiovascular disease. Methods: We searched and summarized all the studies on DAXXK and Cardiovascular disease in Pubmed, Google, and CNKI. Results: Modern pharmacological studies have shown that DAXXK has pharmacological effects such as dilating blood vessels, lowering blood pressure and cardiac load, improving hemodynamics, lowering blood lipids and anti-platelet aggregation, and is widely used for the therapy of various kinds of cardiovascular diseases, including hypertension, atherosclerosis, coronary heart disease (CHD), angina pectoris (AP) and myocardial infarction. We provide an overview of the clinical efficacy, molecular mechanisms, safety and therapeutic potential of DAXXK in the treatment of cardiovascular disease, aiming to provide clues and evidence for clinical decision-making. Conclusion: DAXXK exerts cardiovascular protection by regulating a variety of cardiovascular disease- related signaling pathways.

Background: Waterpipe smoking has become a vitally important public health issue in the world with a false assumption that it has a less harmful effect. Objective: The aim of this study was to systematically review the association between waterpipe tobacco smoking and the risk of coronary artery disease (CAD). Methods: Up to September 25, 2018, we electronically searched the PubMed, Embase, and ISI Web of Science with no time restriction. We included observational studies and excluded conference abstracts, editorials, case reports, case series, and reviews. With the fixed model effect, we conducted a meta-analysis to evaluate the association between waterpipe smoking and coronary artery disease. Heterogeneity among studies was assessed by the I2 square test. Publication bias was assessed by Egger test. P<0.05 was set as significant level. Results: Among 248 paper records identified through a database search, 52 full texts were eligible for full text assessment whereas 49 papers were excluded. Additionally, three studies were eligible for meta-analysis, which involved 58,960 adults with 1334 in the water pipe smoker group. Risk of CAD was increased in water pipe smokers compared to individuals who had never smoked water pipe but the result did not reach a statistical significance (OR=1.18, 95% CI: 0.98-1.38, p=0.06). We found that heavy water pipe smoking (40 to 50 sessions of waterpipe smoking/year) was associated with CAD compared to lower smokers defined as less than 40 to 50 water pipe/year (OR=2.001, 95% CI: 1.13-2.87). Conclusion: Heavy Water pipe smoking was associated with coronary artery disease based on clinical findings. It seems very crucial to increase public awareness on adverse effects of water pipe smoking and its cessation in clinical setting.

Background: Substances present in nature have been a continuous source for the development of drugs for cardiovascular and infectious diseases, cancer, and many other diseases. As the literature concerning these natural products grows, it becomes more difficult for a reader to quickly grasp the essential facts and develop a well-informed impression of this field of research. Until now, it has also been difficult to determine which natural products and research objectives were gaining the most attention as measured by a number of citations. Objective: The current study of all published articles concerned with natural products sought to identify which natural products and which research objectives are connected with the major contributors to scientific journals based on the number of relevant publications and the number of times each publication was cited elsewhere. Methods: Bibliometric data, including citation data, were extracted from the Web of Science database using the search string TS=(“natural product*)” and analyzed by the VOSviewer software. Results: The search yielded 63,194 articles, with more than half of the manuscripts published since 2012. The ratio of original articles to reviews was 5.8:1. The major contributing countries were the United States, China, Germany, Japan, and India. Articles were published mainly in journals focused on chemistry, pharmacology or biochemistry. Curcumin, resveratrol, and terpenoids were the most frequently cited natural products. Conclusion: The results of the current study provide researchers from different backgrounds and healthcare professionals with a brief overview of the major trends in natural-product research in the form of a citation-based summary of the relevant literature.

Background: Malignant gliomas constitute a complex disease phenotype that demands optimum decision-making. Despite being the most common type of primary brain tumors, gliomas are highly heterogeneous when their pathophysiology and response to treatment are considered. Such inter-individual variability also renders differential and early diagnosis extremely difficult. Recent evidence highlight that the gene-environment interplay becomes of fundamental importance in oncogenesis and progression of gliomas. Objective: To unmask key features of the gliomas disease phenotype and map the inter-individual variability of patients, we explore genotype-to-phenotype associations. Emphasis is put on microRNAs as they regulate gene expression, have been implicated in the pathogenesis of gliomas and may serve as theranostics, empowering non-invasive strategies (circulating free or in exosomes). Methods: We mined text and omic datasets (as of 2019) and conducted a mixed-method content analysis. A novel framework was developed to meet the aims of our analysis, interrogating data in terms of content and context. We relied on literature data from PubMed/Medline and Scopus, as they are considered the largest abstract and citation databases of peer-reviewed literature. To avoid selection biases, both publicly available and private texts have been assessed. Both percent agreement and Cohen’s kappa statistic have been calculated to avoid biases by SAS® macro MAGREE with multicategorical ratings. Results: Gliomas serve as a paradigm for multifaceted datasets, despite data sparsity and scarcity. miRNAs and miRNA-based therapeutics are ready for prime time. Exosomal miRNAs empower non-invasive strategies, surpassing circulating free miRNAs, when accuracy and precision are considered. Conclusion: miRNAs hold promise as theranostics.

Ovarian cancer is an aggressive disease, and only a few cases are diagnosed at early stages due to the absence of symptoms. he majority of malignant ovarian tumors (>90%) are of epithelial origin and are subdivided into five histological sub types according to different molecular pathogenesis and clinical behavior. High-grade serous ovarian cancer is the most common subtype (70%). However, the different histotypes of ovarian cancer should be viewed as separate diseases both clinically and in biomarker studies. At present, surgical debulking and platinum/taxane - based chemotherapy is the standard of care for epithelial ovarian cancer. Most patients show an initial response to this therapeutic approach, but the majority of them experience disease recurrence at which point cure is no longer possible, due to acquired resistance in those chemotherapeutic regimens. Nevertheless, the current treatment model is still a “one-sizefits- all” approach. Epigenetic modifications represent heritable modifications in gene expression without alteration of the DNA sequence. DNA methylation is the best-studied epigenetic mechanism, and in epithelial ovarian cancer, the methylenome is widely altered. In addition, patterns of DNA methylation may represent potential diagnostic and prognostic markers as well as markers predictive of chemoresistance and potential therapeutic targets. This article systematically reviews the complex area of DNA methylation in ovarian carcinoma and summarizes the current implications and future perspectives of its use as a screening, diagnostic, prognostic and predictive tool as well as in personalized cancer therapy.

Background: Genetic events cannot account for the complexity of human carcinogenesis alone. Mutations of epigenetic regulators and aberrations of their expression patterns have been detected in various human malignancies. Methylation of histone H3 at lysine 4 (H3K4me), is an evolutionarily conserved histone modification that marks regions of active transcription and regulates cell growth, migration, and invasion. The MLL/KMT2 family of histone methyltransferases specifically methylate histone H3 at lysine 4. Objective: The aim of this study was to explore the role of KMT2C/MLL3 as well as key histone modification activating markers, such as H3K4me2 and H3K4me3 in a cohort of surgically resected human lung adenocarcinomas in an effort to reveal possible biomarkers for lung adenocarcinoma diagnosis and prognosis and potential therapeutic targets. Method: The immunohistochemical expression of KMT2C/MLL3, H3K4me2 and H3K4me3 was analyzed in formalin fixed paraffin embedded tissue from 96 patients with lung adenocarcinoma. Results were associated with clinicopathologic parameters and patient’s prognosis. Results: Nuclear expression of KMT2C/MLL3 in epithelial cells was independently associated with shorter overall survival. Cytoplasmic H3K4me2 expression was associated withT stage and nuclear H3K4me2 expression was associated with female gender and patients’ prognosis. The latter association persisted after multivariate analysis. No association was found between H3K4me3 expression and clinicopathological data or disease outcome in our cohort of patients. Conclusion: These results suggest that the pattern of histone modifications and KMT2C/MLL3 expression can be used as an independent prognostic factor in lung adenocarcinoma, revealing that chromatin remodeling is criticallyinvolved in cancer progression.

Stress is a condition that maintains the homeostasis of the organism through the activation of different neuroendocrine pathways and secretion of a wide array of chemical mediators, including corticotropin-releasing hormone (CRH), neurotransmitters and glucocorticoids hormones. These molecules fulfill important physiological functions, but under stressful conditions, they can induce or aggravate a pathological state depending on type, severity and duration of stress. For this reason, the search for compounds that modulate the activity of the neuroendocrine pathways is crucial for the control of diseases associated with stressful situations. Bovine lactoferrin (bLf) is an iron-binding multifunctional glycoprotein that exhibits modulatory properties on the neuroendocrine system. Bovine lactoferrin affects the production and secretion of neuroendocrine components of the hypothalamus-pituitary-adrenal (HPA) axis. Neuroendocrine mechanisms of bLf entail either the down- or up-modulation of adrenal corticosteroids via HPA pathway activation, nitric oxide (NO) generation and opioid nervous system pathway activation. This manuscript is focused on reviewing the current contributions of bLf modulatory actions on the response of hormones, neurotransmitters involved in stress and behavior. Sustained use of drugs for stress-associated dysfunctions loses efficacy and requires the dose increase by tolerance and drug dependence. Therefore, bLf may be included as a therapeutic and/or adjunctive agent of drugbased therapies for the treatment of stress-associated emotional-disturbances.

Minocycline and doxycycline both are second-generation tetracycline antibiotics with similar chemical structures and comparable antibacterial spectrum. Minocycline has also emerged as the tetracycline of choice for multidrug-resistant Acinetobacter baumannii infections, although doxycycline has also shown the activity. Minocycline showed promising results in experimental neurology, which was due to its highly lipophilic nature. It is clinically safe and effective adjunct to antipsychotic medications. The objective of the current review is to provide clinical and preclinical, non-antibiotic uses of minocycline as well as doxycycline. Relevant literature covers antibiotic actions but is more specifically concerned with the non-antibiotic biological aspect of tetracyclines. Non-antibiotic biological effects for both the antibiotics were identified through searching relevant databases including: PubMed, Scopus, and Web of Science up to 2020, using the keywords ‘minocycline and doxycycline’. Anti-inflammatory, anti-oxidant, anti-apoptotic neuroprotective, immunomodulatory and the number of other non-antibiotic effects were compiled for minocycline and doxycycline.

The role of mitochondria in the apoptosis signaling cell death pathway is regulated by extrinsic and intrinsic pathway, encompassing multiple components like the Bcl-2 family of proteins, death receptors, caspases, Smac/DIABLO, IAPs, Omi/HtrA2 and cytochrome c. These entities serve as effective molecular targets for numerous drugs targeting mitochondrial apoptotic pathways, mainly emphasizing oncology therapeutics. Defective apoptosis is an acquired hallmark of cancer cells, which promotes the establishment of apoptosis-targeting anti-cancer drugs in cancer treatment. The review provides an overview of the Bcl-2 inhibiting, IAPs antagonizing, caspase inhibiting and BH3 mimicking actions, mediated by anti-cancer drugs, rendering beneficial outcomes in different forms of cancer. The authors elaborate on the significance of synthetic and natural agents, targeting the mitochondrial apoptotic pathway, in ameliorating tumor cell growth in the body, and the specificity and effectiveness of these agents, motivating the researchers to explore mitochondrial apoptosis targeting of anti-tumor drugs of both herbal and synthetic origin. Thus, the review aims to predict this dynamic approach in oncology, simultaneously highlighting the challenges and future prospects, providing an opportunity to the experts to “go over with a fine tooth comb” in understanding this “programmed cell death pathway”, and establishing reliability and accuracy of this therapeutic paradigm in the upcoming future.

Thymoquinone (TQ) is one of the leading phytochemicals, which is abundantly found in Nigella sativa L. seeds. TQ exhibited various biological effects such as antioxidant, anti-inflammatory, antimicrobial, and anti-tumoral in several pre-clinical studies. Parkinson's disease (PD) is a long-term neurodegenerative disease with movement difficulties, and the common feature of neurodegeneration in PD patients is caused by dopaminergic neural damage in the substantia nigra pars compacta. The neuroprotective activity of TQ has been studied in various neurological disorders. TQ-mediated neuroprotection against PD is yet to be reported in a single frame; therefore, this review is intended to narrate the potentiality of TQ in the therapy of PD. TQ has been shown to protect against neurotoxins via amelioration of neuroinflammation, oxidative stress, and apoptosis, thereby protecting neurodegeneration in PD models. TQ could be an emerging therapeutic intervention in PD management, but mechanistic studies remain to be investigated to clarify its neuroprotective role.

Breast cancer is one of the leading causes of death worldwide. Breast cancer cells demonstrate uncontrolled proliferation and high metastatic capacity. They can obtain resistance to chemotherapy and radiotherapy. This has resulted in troublesome treatment of breast cancer. Nature as a rich source of plant derived-natural products with anti-tumor activity can be of interest in breast cancer therapy. Ginsenosides are triterpenoid saponins and considered as secondary metabolites exclusively found in Panax species. From immemorial times, ginsenosides have been applied in the treatment of various disorders such as diabetes, inflammatory diseases, neurological disorders, and particularly, cancer. In the present review, we highlight the anti-tumor activity of ginsenosides against breast cancer cells. Ginsenosides are able to induce apoptosis and cell cycle arrest. They interfere with breast cancer metastasis via inhibiting epithelial-to-mesenchymal transition, matrix metalloproteinase proteins and angiogenesis. Ginsenosides can promote the efficacy of chemotherapy via suppressing migration and proliferation. Molecular pathways such as phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), insulin-like growth factor-1, Wnt, microRNAs and long non-coding RNAs are affected by ginsenosides in suppressing breast cancer malignancy. Consequently, ginsenosides are versatile compounds in breast cancer therapy by suppressing the growth and invasion, as well as promoting their sensitivity to chemotherapy.

Flavonoids have been shown to target aromatase, suppressing the transformed cells' proliferation and growth. Such experimental data further promoted the usage of flavonoids as an aromatase inhibitor and helps prevent cancer, specifically breast and lung cancer. Conversely, flavonoids have certain limitations like low absorption, potency, and some side effects in addition to their tremendous advantages. The pharmacokinetics and toxicity of flavonoids are now being addressed by using advanced nanotechnological approaches. This review discusses the comprehensive aromatase signaling pathway in normal and cancer cells. It also draws attention to how do flavonoids modulate aromatase signaling pathways. Also, different flavonoid groups inhibiting aromatase activities are discussed and listed in the Table comprising flavonoids group, cancer type, clinical trials, IC50, and the assay employed. Moreover, nanoparticles-mediated improvement in the pharmacokinetics and toxicity issues of flavonoids in targeting aromatase are also deliberated. In conclusion, flavonoids act as a potential anticancer agent via targeting aromatase. Besides, nanotechnological approaches are useful in addressing the pharmacokinetics and toxicity of flavonoids.

Background: The fruits with the seeds of Dracunculus vulgaris Schott. (Araceae) are used against inflammatory diseases in Turkey. Objective: The present study was designed to justify this folkloric usage of the plant. Therefore, the aim of this study was to investigate the anti-inflammatory activity of D. vulgaris. Methods: Petroleum ether, ethyl acetate and methanol extracts were prepared from the fruits, successively. Carrageenan-, serotonin-, and prostaglandin E2-induced hind paw edema; acetic acid-induced capillary permeability and 12-O-tetradecanoyl-phorbol-13-acetate–induced mouse ear edema models were used to assess the anti-inflammatory activity of the extracts. The analgesic activity was observed by using p-benzoquinone-induced abdominal constriction test. Results: The petroleum ether extract displayed the highest activities in all of the used test models compared with the control group. Therefore, the constituents of this extract were determined by using gas chromatography-mass spectroscopy (GC–MS). Linoleic acid was found to be the major constituent of the petroleum ether extract of D. Vulgaris. Conclusion: This study has provided some justification for the folkloric use of the plant.

Background: Breast cancer (BC) produces bone resorptive cytokines and growth factors that accelerate the development of osteoclasts (OCs), leading to osteolytic bone metastases. In the Long-term Odanacatib Fracture Trial (LOFT), the skeletal-metastasized breast cancer subjects who received odanacatib (ODN) had a delayed tumour progression and skeletal tumour burden as a result of anti-resorptive effects through inhibition of cathepsin K (CTSK). In this study, we explored the effect of ODN, a CTSK inhibitor, on the paracrine pro-osteoclast activity of breast cancer cells. Methods: An immunohistochemistry study was performed to demonstrate CTSK and PTHrP expression in the samples of primary breast carcinoma. Expression of CTSK mRNA and protein was confirmed by the reverse transcription PCR and western blotting analysis in two human breast cancer cell lines, MDA-MB-231 and MCF-7 BC cell lines. Cells were incubated with sub-lethal amounts of ODN, and their conditioned supernatants were assessed for their capacity to differentiate PBMCs of healthy donors into osteoclast and its interference on bone-resorbing activities. We also measured the mRNA levels of major pro-osteoclast (pro-OC) factors in ODN-treated breast cancer cells and their secreted levels by semi-quantitative reverse transcription PCR and protein expression by immunoblotting. Results: Different staining intensity was observed in samples containing PTHrP and CTSK in various histological grades of breast carcinoma. A significant positive relationship was found between CTSK expression and histological grade of BC and presence or absence of distant metastasis. The present study results also indicate that ODN has no effects on OCs number, however, ODN decreases the mRNA expression of secreted pro-OC factors such as PTHrP, CXCR-4, and TNF-α. Immunoblot indicates that ODN treatment decreased the protein expression of CTSK, IL-6, and IL-1β, and thus lowered protein levels paralleled the defective phosphorylation of NF-ΚB. Moreover, there was a significant reduction in the level of growth factors such as IGF-1, PDGF, and TGFβ expression at transcriptional level after ODN treatment as compared to control. Conclusion: ODN has shown to prevent osteolytic metastasis by interacting with the NF-ΚB pathway, inhibiting bone resorptive cytokines and growth factors. This effect can also be taken into account the delayed development of metastatic bone disease found in the long-term odanacatib fracture trial (LOFT) study.