An Updated Review on Glycoprotein IIb/IIIa Inhibitors as Antiplatelet Agents: Basic and Clinical Perspectives.

The glycoprotein (GP) IIb/IIIa receptor is found integrin present in platelet aggregations. GP IIb/IIIa antagonists interfere with platelet cross-linking and platelet-derived thrombus formation through the competition with fibrinogen and von Willebrand factor. Currently, three parenteral GP IIb/IIIa competitors (tirofiban, eptifibatide, and abciximab) are approved for clinical use in patients affected by percutaneous coronary interventions (PCI) in the location of acute coronary syndrome (ACS). GP IIb/IIIa antagonists have their mechanism of action in platelet aggregation prevention, distal thromboembolism, and thrombus formation, whereas the initial platelet binding to damage vascular areas is preserved. This work is aimed to provide a comprehensive review of the significance of GP IIb/IIIa inhibitors as a sort of antiplatelet agent. Their mechanism of action is based on factors that affect their efficacy. On the other hand, drugs that inhibit GP IIb/IIIa already approved by the FDA were reviewed in detail. Results from major clinical trials and regulatory practices and guidelines to deal with GP IIb/IIIa inhibitors were deeply investigated. The cardiovascular pathology and neuro-interventional surgical application of GP IIb/IIIa inhibitors as a class of antiplatelet agents were developed in detail. The therapeutic risk/benefit balance of currently available GP IIb/IIa receptor antagonists is not yet well elucidated in patients with ACS who are not clinically evaluated regularly for early cardiovascular revascularization. On the other hand, in patients who have benefited from PCI, the antiplatelet therapy intensification by the addition of a GP IIb/IIIa receptor antagonist (intravenously) may be an appropriate therapeutic strategy in reducing the occurrence of risks of thrombotic complications related to the intervention. Development of GP IIb/IIIa inhibitors with oral administration has the potential to include short-term antiplatelet benefits compared with intravenous GP IIb/IIIa inhibitors for long-term secondary preventive therapy in cardiovascular disease. But studies showed that long-term oral administration of GP IIb/IIIa receptor inhibitors has been ineffective in preventing ischemic events. Paradoxically, they have been linked to a high risk of side effects by producing prothrombotic and pro-inflammatory events.

NMDA Inhibitors: A Potential Contrivance to Assist in Management of Alzheimer's Disease.

Alzheimer's disease (AD) is an increasingly common neurodegenerative disease that attracts the attention of researchers and medical community in order to develop new, safe and more effective drugs. Currently available drugs could only slow the AD progression and relieve the symptoms, in addition to being linked to moderate-to-severe side effects. N-methyl D-aspartate (NMDA) receptors antagonists were reported to have the ability to block the glutamate-mediated excitotoxic activity being good therapeutic targets for several neurodegenerative diseases, including AD. Based on data obtained so far, this review provides an overview over the use of NMDA antagonists for AD treatment, starting with a key emphasis on present features and future aspects regarding the use of NMDA antagonists for AD, and lastly a key focus is also given on its use in precision medicine.

Naturally-Occurring Bioactives in Oral Cancer: Preclinical and Clinical Studies, Bottlenecks and Future Directions.

Oral cancer (OC) is the eighth most common cancer, particularly prevalent in developing countries. Current treatment includes a multidisciplinary approach, involving chemo, radio, and immunotherapy and surgery, which depends on cancer stage and location. As a result of the side effects of currently available drugs, there has been an increasing interest in the search for naturally-occurring bioactives for treating all types of cancer, including OC. Thus, this comprehensive review aims to give a holistic view on OC incidence and impact, while highlights the preclinical and clinical studies related to the use of medicinal plants for OC prevention and the recent developments in bioactive synthetic analogs towards OC management. Chemoprophylactic therapies connect the use of natural and/or synthetic molecules to suppress, inhibit or revert the transformation of oral epithelial dysplasia (DOK) into oral squamous cell carcinoma (OSCC). Novel searches have underlined the promising role of plant extracts and phytochemical compounds, such as curcumin, green tea extract, resveratrol, isothiocyanates, lycopene or genistein against this malignancy. However, poor bioavailability and lack of in vivo and clinical studies and complex pharmacokinetic profiles limit their huge potential of application. However, recent nanotechnological and related advances have shown to be promising in improving the bioavailability, absorption and efficacy of such compounds.

An Updated Review on The Properties of Melissa officinalis L.: Not Exclusively Anti-anxiety.

Melissa officinalis L. is a plant of the Lamiaceae family known in numerous countries for its medicinal activities. This plant has been used since ancient times to treat different disorders, including gastrointestinal, cardiovascular, neurological, psychological conditions. M. officinalis contains several phytochemicals such as phenolic acids, flavonoids, terpenoids, and many others at the basis of its pharmacological activities. Indeed, the plant can have antioxidant, anti-inflammatory, antispasmodic, antimicrobial, neuroprotective, nephroprotective, antinociceptive effects. Given its consolidated use, M. officinalis has also been experimented with clinical settings, demonstrating interesting properties against different human diseases, such as anxiety, sleeping difficulties, palpitation, hypertension, depression, dementia, infantile colic, bruxism, metabolic problems, Alzheimer's disease, and sexual disorders. As for any natural compound, drug, or plant extract, also M. officinalis can have adverse effects, even though the reported events are very rare and the plant can be considered substantially safe. This review has been prepared with a specific research strategy, interrogating different databases with the keyword M. officinalis. Moreover, this work analyzes the properties of this plant updating currently available literature, with a special emphasis on human studies.

Common bean (Phaseolus vulgaris L.) α-amylase inhibitors as safe nutraceutical strategy against diabetes and obesity: An update review.

Overweight and obesity are constantly increasing, not only in Western countries but also in low-middle-income ones. The decrease of both the intake of carbohydrates and their assimilation are among the main dietary strategies to counter these conditions. α-Amylase, a key enzyme involved in the digestion of carbohydrates, is the target enzyme to reduce the absorption rate of carbohydrates. α-Amylase inhibitors (α-AIs) can be found in plants. The common bean, Phaseolus vulgaris is of particular interest due to the presence of protein-based α-AIs which, through a protein-protein interaction, reduce the activity of this enzyme. Here we describe the nature of the various types of common bean seed extracts, the type of protein inhibitors they contain, reviewing the recent Literature about their molecular structure and mechanism of action. We also explore the existing evidence (clinical trials conducted on both animals and humans) supporting the potential benefits of this protein inhibitors from P. vulgaris, also highlighting the urgent need of further studies to confirm the clinical efficacy of the commercial products. This work could contribute to summarize the knowledge and application of P. vulgaris extract as a nutraceutical strategy for controlling unwanted weight gains, also highlighting the current limitations.

State of knowledge on chemical, biological and nutritional properties of olive mill wastewater.

The Mediterranean olive oil industries are producing annually a massive quantity of olive mill wastewater (OMWW). Unfortunately, the OMWW is released arbitrarily in the nature without any pretreatment. Thus, it exhibits a high toxicity against the whole natural ecosystem including, microorganisms, plants and animals. In order to eliminate or reduce its pollution, OMWW must be properly treated prior to its release in the nature. In this regard, different treatment methods have been developed by researchers, but some of them were costly and others were inappropriate. Thus, more efforts should be made to save the nature from this pollutant. In the light of that, the current work summaries the state of knowledge regarding the OMWW from a chemical, biological, nutraceutical point of view, and the treatment methods that were used to eliminate its risk of pollution.

Immune Checkpoint Inhibitors in the Treatment of Cancer.

BACKGROUND: Immunotherapy drugs, known as immune checkpoint inhibitors (ICIs), work by blocking checkpoint proteins from binding with their partner proteins. The two main pathways that are specifically targeted in clinical practice are cytotoxic T-lymphocyte antigen-4 (CTLA- 4) and programmed cell death protein 1 (PD-1) that showed potent immune-modulatory effects through their function as negative regulators of T cell activation. METHODS: In view of the rapid and extensive development of this research field, we conducted a comprehensive review of the literature and updated on the use of CTLA-4, PD-1, and PD-L1 targeted therapy in the treatment of several types of cancer, including melanoma, non-small-cell lung carcinoma, breast cancer, hepatocellular carcinoma, Hodgkin lymphoma, cervical cancer, and head and neck squamous cell carcinoma. RESULTS: Based on the last updated list released on March 2019, seven ICIs are approved by the FDA, including ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and cemiplimab. CONCLUSION: This review highlighted the most common adverse effects caused by ICIs which affect people in different ways.

Chimeric Antigen Receptor T-cells (CARs) in Cancer Treatment.

BACKGROUND: Cancer is one of the leading causes of death worldwide. Chemotherapy, radiation therapy, and stem cell transplantation were the main cancer treatment approaches for several years but due to their limited effectiveness, there was a constant search for new therapeutic approaches. Cancer immunotherapy that utilizes and enhances the normal capacity of the patient's immune system was used to fight against cancer. Genetically engineered T-cells that express Chimeric Antigen Receptors (CARs) showed remarkable anti-tumor activity against hematologic malignancies and are now being investigated in a variety of solid tumors. The use of this therapy in the last few years has been successful, achieving great success in improving the quality of life and prolonging the survival time of patients with a reduction in remission rates. However, many challenges still need to be resolved in order for this technology to gain widespread adoption. OBJECTIVE: This review summarizes various experimental approaches towards the use of CAR T-- cells in hematologic malignancies and solid tumors. CONCLUSION: Finally, we address the challenges posed by CAR T-cells and discuss strategies for improving the performance of these T-cells in fighting cancers.

Plant Natural Compounds in the Treatment of Adrenocortical Tumors.

Plant natural products are a plethora of diverse and complex molecules produced by the plant secondary metabolism. Among these, many can reserve beneficial or curative properties when employed to treat human diseases. Even in cancer, they can be successfully used and indeed numerous phytochemicals exert antineoplastic activity. The most common molecules derived from plants and used in the fight against cancer are polyphenols, i.e., quercetin, genistein, resveratrol, curcumin, etc. Despite valuable data especially in preclinical models on such compounds, few of them are currently used in the medical practice. Also, in adrenocortical tumors (ACT), phytochemicals are scarcely or not at all used. This work summarizes the available research on phytochemicals used against ACT and adrenocortical cancer, a very rare disease with poor prognosis and high metastatic potential, and wants to contribute to stimulate preclinical and clinical research to find new therapeutic strategies among the overabundance of biomolecules produced by the plant kingdom.

Phenolic Bioactives as Antiplatelet Aggregation Factors: The Pivotal Ingredients in Maintaining Cardiovascular Health.

Cardiovascular diseases (CVD) are one of the main causes of mortality in the world. The development of these diseases has a specific factor-alteration in blood platelet activation. It has been shown that phenolic compounds have antiplatelet aggregation abilities and a positive impact in the management of CVD, exerting prominent antioxidant, anti-inflammatory, antitumor, cardioprotective, antihyperglycemic, and antimicrobial effects. Thus, this review is intended to address the antiplatelet activity of phenolic compounds with special emphasis in preventing CVD, along with the mechanisms of action through which they are able to prevent and treat CVD. In vitro and in vivo studies have shown beneficial effects of phenolic compound-rich plant extracts and isolated compounds against CVD, despite that the scientific literature available on the antiplatelet aggregation ability of phenolic compounds in vivo is scarce. Thus, despite the current advances, further studies are needed to confirm the cardioprotective potential of phenolic compounds towards their use alone or in combination with conventional drugs for effective therapeutic interventions.

Ginkgolic Acids Confer Potential Anticancer Effects by Targeting Pro- Inflammatory and Oncogenic Signaling Molecules.

BACKGROUND: Medicinal plants and herbal preparations in the form of traditional medicines have been used in healthcare worldwide. The extracts of Ginkgo biloba L. seeds and leaves contain a complex mixture of numerous components, such as flavonol glycosides, terpene lactones, and a group of alkylphenols (anacardic or ginkgolic acids, cardanols and cardols) that have been a part of traditional Chinese medicine. These extracts are also sold as dietary supplements worldwide. G. biloba extract (EGb 761 and LI 1370) represent the standard form of G. biloba extract. Six different 6-alkylsalicylic acids (syn. ginkgolic acids) with alkyl substituents (C13:0, C15:0, C15:1, C17:0, C17:1, and C17:2) have been identified. OBJECTIVE: The aim of this review is to unravel scientific evidence on anti-inflammatory and anticancer activities of ginkgolic acids to understand its therapeutic potential against inflammatory and oncologic diseases. METHODS: A structured literature search was independently performed by the authors on PubMed, ScienceDirect, Scopus, and Web of Science. Accordingly, this review article critically analyses available scientific evidence on anti-inflammatory and anticancer activities of ginkgolic acids. Moreover, the review only included articles written in the English language. RESULTS: Several forms of ginkgolic acids, especially C13:0, C15:0 and C17:1, isolated from the leaves of G. biloba exhibited cytotoxic activity against a variety of human cancers by suppressing various pro-inflammatory signaling cascades and oncogenic transcription factors through multiple modes of action in various in vitro and in vivo preclinical models. Ginkgolic acids have also been reported to be potent post-translational small ubiquitin-related modifiers (SUMO)ylation inhibitors. CONCLUSION: In this review, we present updated information on the anti-inflammatory and anticancer properties of ginkgolic acids both in vitro and in vivo. Although ginkgolic acids show significant therapeutic potential in inflammatory and oncologic diseases, more investigations regarding the safety and efficacy of these natural agents are warranted before the clinical transition.

Antioxidant potential of family Cucurbitaceae with special emphasis on Cucurbita genus: A key to alleviate oxidative stress-mediated disorders.

Oxidative stress is the imbalance between reactive oxygen species (ROS) production, and accumulation and the ability of a biological system to clear these reactive products. This imbalance leads to cell and tissue damage causing several disorders in human body, such as neurodegeneration, metabolic problems, cardiovascular diseases, and cancer. Cucurbitaceae family consists of about 100 genera and 1,000 species of plants including mostly tropical, annual or perennial, monoecious, and dioecious herbs. The plants from Cucurbita species are rich sources of phytochemicals and act as a rich source of antioxidants. The most important phytochemicals present in the cucurbits are cucurbitacins, saponins, carotenoids, phytosterols, and polyphenols. These bioactive phyto-constituents are responsible for the pharmacological effects including antioxidant, antitumor, antidiabetic, hepatoprotective, antimicrobial, anti-obesity, diuretic, anti-ulcer activity, and antigenotoxic. A wide number of in vitro and in vivo studies have ascribed these health-promoting effects of Cucurbita genus. Results of clinical trials suggest that Cucurbita provides health benefits for diabetic patients, patients with benign prostate hyperplasia, infertile women, postmenopausal women, and stress urinary incontinence in women. The intend of the present review is to focus on the protective role of Cucurbita spp. phytochemicals on oxidative stress-related disorders on the basis of preclinical and human studies. The review will also give insights on the in vitro and in vivo antioxidant potential of the Cucurbitaceae family as a whole.

The Warburg Effect on Cancer Cells Survival: The Role of Sugar Starvation in Cancer Therapy.

BACKGROUND: Cancer is not just one disease; it is a group of diseases either genetic or metabolic due to the malfunction of mitochondria. Thus, metabolic pathways are reprogrammed to satisfy tumor cell proliferation and survival requirements. METHODS: We undertook a structured search of bibliographic databases for peer-reviewed research literature dealing with these metabolic pathways. RESULTS: It was found that cancer cells prefer fermentation as a source of energy even in the presence of oxygen, this altered metabolism of cancer cells may confer a selective advantage for survival and proliferation according to the Warburg effect. Furthermore, some molecules like HIF, PKM2, NADPH and others are essential to the survival of cancer cells in the hypoxic abnormal environment which has limited glucose sources. CONCLUSION: As cancer cells use glucose for aerobic glycolysis as a preferred substrate for energyyielding metabolism, we discuss in this review the Warburg effect and a strategy of starving cancer cells from glucose to prevent cancer cell survival and induce apoptosis in various types of cancer which could be the key to future treatment.

Turmeric and Its Major Compound Curcumin on Health: Bioactive Effects and Safety Profiles for Food, Pharmaceutical, Biotechnological and Medicinal Applications.

Curcumin, a yellow polyphenolic pigment from the Curcuma longa L. (turmeric) rhizome, has been used for centuries for culinary and food coloring purposes, and as an ingredient for various medicinal preparations, widely used in Ayurveda and Chinese medicine. In recent decades, their biological activities have been extensively studied. Thus, this review aims to offer an in-depth discussion of curcumin applications for food and biotechnological industries, and on health promotion and disease prevention, with particular emphasis on its antioxidant, anti-inflammatory, neuroprotective, anticancer, hepatoprotective, and cardioprotective effects. Bioavailability, bioefficacy and safety features, side effects, and quality parameters of curcumin are also addressed. Finally, curcumin's multidimensional applications, food attractiveness optimization, agro-industrial procedures to offset its instability and low bioavailability, health concerns, and upcoming strategies for clinical application are also covered.

Ex Vivo Study of Laban's Role in Decreasing Hemolysis Crisis in G6PD-Deficient Patients.

In spite of the vast nutritional and environmental benefits provided by fava bean (Vicia faba), the ingestion of vicine/convicine provokes an acute hemolytic anemia called favism in individuals with a glucose-6-phosphate dehydrogenase (G6PD) deficiency. The elimination of these glycosides is a goal that could be accomplished using different processing methods including bacteriological treatment. Laban as a good source of lactic acid bacteria was tested in an ex vivo assay on human blood samples in order to determine its capacity in decreasing the hemolysis crisis induced by the ingestion of fava beans. Results indicate a significant decrease in human blood cell hemolysis after the treatment of fava beans by Laban. This decrease in hemolysis was also correlated with the G6PD deficiency categorization. The highest hemolysis level (mean: 23.11 ± 0.76%) was observed in samples with G6PD activity between 10 and 30%, while the lowest hemolysis level (mean: 5.75 ± 0.64%) was observed in samples with G6PD activity more than 60%. This decrease was correlated with a high antioxidant capacity of Laban (51.61 ± 1.13% expressed by the percentage inhibition of DPPH radical). The counts of isolates from MRS and M17 culture plates were 6.75 ± 0.095 and 7.91 ± 0.061 log cfu ml-1, respectively. In conclusion, the synergy between the antioxidant properties of Laban and the possible decrease of vicine and convicine concentrations by lactobacillus found in the fermented dairy products could explain the ability of Laban to reduce the hemolysis crisis ex vivo.

Phytosterols: From Preclinical Evidence to Potential Clinical Applications.

Phytosterols (PSs) are plant-originated steroids. Over 250 PSs have been isolated, and each plant species contains a characteristic phytosterol composition. A wide number of studies have reported remarkable pharmacological effects of PSs, acting as chemopreventive, anti-inflammatory, antioxidant, antidiabetic, and antiatherosclerotic agents. However, PS bioavailability is a key issue, as it can be influenced by several factors (type, source, processing, preparation, delivery method, food matrix, dose, time of administration into the body, and genetic factors), and the existence of a close relationship between their chemical structures (e.g., saturation degree and side-chain length) and low absorption rates has been stated. In this sense, the present review intends to provide in-depth data on PS therapeutic potential for human health, also emphasizing their preclinical effects and bioavailability-related issues.

Current Trends on Seaweeds: Looking at Chemical Composition, Phytopharmacology, and Cosmetic Applications.

Seaweeds have received huge interest in recent years given their promising potentialities. Their antioxidant, anti-inflammatory, antitumor, hypolipemic, and anticoagulant effects are among the most renowned and studied bioactivities so far, and these effects have been increasingly associated with their content and richness in both primary and secondary metabolites. Although primary metabolites have a pivotal importance such as their content in polysaccharides (fucoidans, agars, carragenans, ulvans, alginates, and laminarin), recent data have shown that the content in some secondary metabolites largely determines the effective bioactive potential of seaweeds. Among these secondary metabolites, phenolic compounds feature prominently. The present review provides the most remarkable insights into seaweed research, specifically addressing its chemical composition, phytopharmacology, and cosmetic applications.

Gut Microbiota as a Prospective Therapeutic Target for Curcumin: A Review of Mutual Influence.

BACKGROUND: Turmeric is a spice that has recently received much interest and has been widely used in Ayurvedic medicine. Turmeric products are diarylheptanoids and have been characterized as safe. They are termed as curcuminoids that consists essentially of three major compounds: curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Curcumin is a lipophilic polyphenol that has poor systemic bioavailability and suffers from biotransformation by human intestinal microflora to yield different metabolites that are easily conjugated to glucuronides and sulfate O-conjugated derivatives. Recently, an increasing number of studies have indicated that dysbiosis is linked with many metabolic diseases, though gut microbiota could be a novel potential therapeutic target. SCOPE AND APPROACH: Thus, it is suspected that curcumin and its derivatives exert direct regulative effects on the gut microbiota which could explain the paradox between curcumin's poor systemic bioavailability and its widely reported pharmacological activities. KEY FINDINGS AND CONCLUSIONS: This article summarizes a range of studies that highlight the interaction between curcumin and gut microbiota and considers opportunities for microbiome-targeting therapies using turmeric extract.