In Vitro Evaluation of Biological and Anticancer Activities Exhibited by Five Varieties of Vitis vinifera L.

Vitis vinifera commonly known as grapevine is one of the most important fruit crops worldwide. Its cultivation started more than 7000 years ago in the Near East, and over the millennia was followed by the development of thousands of cultivars that were further selected and characterized for specific purposes. Its important pharmacological value and its richness in phytoconstituents were the triggers to perform this project. Seven extracts were prepared from five different V. vinifera varieties (V. vinifera 'Black Pearl' (BP), V. vinifera 'Red Glob' (RG), V. vinifera 'Crimson' (CR), V. vinifera 'Beitamouni' (BE) and V. vinifera 'Superior' (SU)) by separating the pulp from the seeds, followed by methanolic extraction. The phytochemical analysis showed that red colored grapes (RE, BP and CR), the seeds from V. vinifera 'Black Pearl' and V. vinifera 'Red Globe' contain higher amounts of primary and secondary metabolites such as polyphenols, anthocyanins and reducing sugars. In addition to their richness in phytoconstituents, these varieties/seeds possess an important antioxidant activity. The results of the cell viability assays showed that the red varieties have a potential anticancer activity against Capan-2 pancreatic cancer and MDA-MB231(TNBC) breast cancer cell lines, with the greatest promise when combined with the seeds.

Curcumin Modulates 1,2-dibehenoyl-sn-glycero-3-phosphocholine (DBPC) Liposomes: Chitosan Oligosaccharide Lactate Influences Membrane Fluidity But Does Not Alter Phase Transition Temperature of DBPC Liposomes.

1,2-dibehenoyl-sn-glycero-3-phosphocholine (DBPC) is one of the important phospholipids found in cell membrane but not studied well. Importance of curcumin as a dietary supplement and for its medicinal properites is getting widely recoginsed. The present study for the first time explores the effect of curcumin on properties of DBPC liposomes by monitoring the fluorescence properties of curcumin. The phase transition temperature (Tm) of DBPC is assessed which confirms increase in curcumin concentration causes a slight drop in the Tm value. Chitosan is being applied for various drug delivery uses. The study establishes new insight on effect of chitosan oligosaccharide lactate on DBPC liposomes. It is found that in the absence of chitosan oligosaccharide lactate, curcumin partitions more strongly in the liquids crystalline phase than in the solid gel phase, however, the opposite result is obtained with the presence of chitosan oligosaccharide lactate which penetrates into the DBPC liposomes membranes at higher temperature, blocking thus the passage of curcumin into the lipid bilayer. However, addition of chitosan oligosaccharide lactate had no effect on the Tm. Fluorescence quenching study of curcumin establishes that the location of curcumin to be in the hydrophobic cavity of DBPC membrane.

Ziziphus nummularia: A Comprehensive Review of Its Phytochemical Constituents and Pharmacological Properties.

Ziziphus nummularia, a small bush of the Rhamnaceae family, has been widely used in traditional folk medicine, is rich in bioactive molecules, and has many reported pharmacological and therapeutic properties. Objective: To gather the current knowledge related to the medicinal characteristics of Z. nummularia. Specifically, its phytochemical contents and pharmacological activities in the treatment of various diseases such as cancer, diabetes, and cardiovascular diseases, are discussed. Methods: Major scientific literature databases, including PubMed, Scopus, ScienceDirect, SciFinder, Chemical Abstracts, Medicinal and Aromatic Plants Abstracts, Henriette's Herbal Homepage, Dr. Duke's Phytochemical and Ethnobotanical Databases, were searched to retrieve articles related to the review subject. General web searches using Google and Google scholar were also utilized. The search period covered articles published between 1980 and the end of October 2021.The search used the keywords 'Ziziphus nummularia', AND ('phytochemical content', 'pharmacological properties, or activities, or effects, or roles', 'anti-inflammatory', 'anti-drought', 'anti-thermal', 'anthelmintic', 'antidiabetic',' anticancer', 'anticholinesterase', 'antimicrobial', 'sedative', 'antipyretic', 'analgesic', or 'gastrointestinal'). Results: This plant is rich in characteristic alkaloids, especially cyclopeptide alkaloids such as nummularine-M. Other phytochemicals, including flavonoids, saponins, glycosides, tannins, and phenolic compounds, are also present. These phytochemicals are responsible for the reported pharmacological properties of Z. nummularia, including anti-inflammatory, antioxidant, antimicrobial, anthelmintic, antidiabetic, anticancer, analgesic, and gastrointestinal activities. In addition, Z. nummularia has anti-drought and anti-thermal characteristics. Conclusion: Research into the phytochemical and pharmacological properties of Z. nummularia has demonstrated that this plant is a rich source of novel bioactive compounds. So far, Z. nummularia has shown a varied pharmacological profile (antioxidant, anticancer, anti-inflammatory, and cardioprotective), warranting further research to uncover the therapeutic potential of the bioactives of this plant. Taken together, Z. nummularia may represent a new potential target for the discovery of new drug leads.

Origanum syriacum Phytochemistry and Pharmacological Properties: A Comprehensive Review.

Herbal medicine has been gaining special interest as an alternative choice of treatment for several diseases, being generally accessible, cost-effective and safe, with fewer side-effects compared to chemically synthesized medicines. Over 25% of drugs worldwide are derived from plants, and surveys have shown that, when available, herbal medicine is the preferred choice of treatment. Origanum syriacum (Lamiaceae) is a widely used medicinal plant in the Middle East, both as a home and a folk remedy, and in the food and beverage industry. Origanum syriacum contains numerous phytochemical compounds, including flavonoids, phenols, essential oils, and many others. Because of its bioactive compounds, O. syriacum possesses antioxidant, antimicrobial, and antiparasitic capacities. In addition, it can be beneficial in the treatment of various diseases such as cancer, neurodegenerative disorders, and peptic ulcers. In this review, the chemical compositions of different types of extracts and essential oils from this herb will first be specified. Then, the pharmacological uses of these extracts and essential oils in various contexts and diseases will be discussed, putting emphasis on their efficacy and safety. Finally, the cellular and molecular mechanisms of O. syriacum phytochemicals in disease treatment will be described as a basis for further investigation into the plant's pharmacological role.

Ziziphus nummularia Attenuates the Malignant Phenotype of Human Pancreatic Cancer Cells: Role of ROS.

Pancreatic cancer (PC) is the fourth leading cause of all cancer-related deaths. Despite major improvements in treating PC, low survival rate remains a major challenge, indicating the need for alternative approaches, including herbal medicine. Among medicinal plants is Ziziphus nummularia (family Rhamnaceae), which is a thorny shrub rich in bioactive molecules. Leaves of Ziziphus nummularia have been used to treat many pathological conditions, including cancer. However, their effects on human PC are still unknown. Here, we show that the treatment of human pancreatic ductal adenocarcinoma cells (Capan-2) with Ziziphus nummularia ethanolic extract (ZNE) (100-300 µg/mL) attenuated cell proliferation in a time- and concentration-dependent manner. Pretreatment with N-acetylcysteine, an ROS scavenger, attenuated the anti-proliferative effect of ZNE. In addition, ZNE significantly decreased the migratory and invasive capacity of Capan-2 with a concomitant downregulation of integrin α2 and increased cell-cell aggregation. In addition, ZNE inhibited in ovo angiogenesis as well as reduced VEGF and nitric oxide levels. Furthermore, ZNE downregulated the ERK1/2 and NF-κB signaling pathways, which are known to drive tumorigenic and metastatic events. Taken together, our results suggest that ZNE can attenuate the malignant phenotype of Capan-2 by inhibiting hallmarks of PC. Our data also provide evidence for the potential anticancer effect of Ziziphus nummularia, which may represent a new resource of novel anticancer compounds, especially ones that can be utilized for the management of PC.

Flavonoids in adipose tissue inflammation and atherosclerosis: one arrow, two targets.

Flavonoids are polyphenolic compounds naturally occurring in fruits and vegetables, in addition to beverages such as tea and coffee. Flavonoids are emerging as potent therapeutic agents for cardiovascular as well as metabolic diseases. Several studies corroborated an inverse relationship between flavonoid consumption and cardiovascular disease (CVD) or adipose tissue inflammation (ATI). Flavonoids exert their anti-atherogenic effects by increasing nitric oxide (NO), reducing reactive oxygen species (ROS), and decreasing pro-inflammatory cytokines. In addition, flavonoids alleviate ATI by decreasing triglyceride and cholesterol levels, as well as by attenuating inflammatory mediators. Furthermore, flavonoids inhibit synthesis of fatty acids and promote their oxidation. In this review, we discuss the effect of the main classes of flavonoids, namely flavones, flavonols, flavanols, flavanones, anthocyanins, and isoflavones, on atherosclerosis and ATI. In addition, we dissect the underlying molecular and cellular mechanisms of action for these flavonoids. We conclude by supporting the potential benefit for flavonoids in the management or treatment of CVD; yet, we call for more robust clinical studies for safety and pharmacokinetic values.

Reactive Oxygen Species: Modulators of Phenotypic Switch of Vascular Smooth Muscle Cells.

Reactive oxygen species (ROS) are natural byproducts of oxygen metabolism in the cell. At physiological levels, they play a vital role in cell signaling. However, high ROS levels cause oxidative stress, which is implicated in cardiovascular diseases (CVD) such as atherosclerosis, hypertension, and restenosis after angioplasty. Despite the great amount of research conducted to identify the role of ROS in CVD, the image is still far from being complete. A common event in CVD pathophysiology is the switch of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic phenotype. Interestingly, oxidative stress is a major contributor to this phenotypic switch. In this review, we focus on the effect of ROS on the hallmarks of VSMC phenotypic switch, particularly proliferation and migration. In addition, we speculate on the underlying molecular mechanisms of these cellular events. Along these lines, the impact of ROS on the expression of contractile markers of VSMCs is discussed in depth. We conclude by commenting on the efficiency of antioxidants as CVD therapies.

The Role of Epac in Cancer Progression.

Cancer continues to be a prime contributor to global mortality. Despite tremendous research efforts and major advances in cancer therapy, much remains to be learned about the underlying molecular mechanisms of this debilitating disease. A better understanding of the key signaling events driving the malignant phenotype of cancer cells may help identify new pharmaco-targets. Cyclic adenosine 3',5'-monophosphate (cAMP) modulates a plethora of biological processes, including those that are characteristic of malignant cells. Over the years, most cAMP-mediated actions were attributed to the activity of its effector protein kinase A (PKA). However, studies have revealed an important role for the exchange protein activated by cAMP (Epac) as another effector mediating the actions of cAMP. In cancer, Epac appears to have a dual role in regulating cellular processes that are essential for carcinogenesis. In addition, the development of Epac modulators offered new routes to further explore the role of this cAMP effector and its downstream pathways in cancer. In this review, the potentials of Epac as an attractive target in the fight against cancer are depicted. Additionally, the role of Epac in cancer progression, namely its effect on cancer cell proliferation, migration/metastasis, and apoptosis, with the possible interaction of reactive oxygen species (ROS) in these phenomena, is discussed with emphasis on the underlying mechanisms and pathways.

EPAC in Vascular Smooth Muscle Cells.

Vascular smooth muscle cells (VSMCs) are major components of blood vessels. They regulate physiological functions, such as vascular tone and blood flow. Under pathological conditions, VSMCs undergo a remodeling process known as phenotypic switching. During this process, VSMCs lose their contractility and acquire a synthetic phenotype, where they over-proliferate and migrate from the tunica media to the tunica interna, contributing to the occlusion of blood vessels. Since their discovery as effector proteins of cyclic adenosine 3',5'-monophosphate (cAMP), exchange proteins activated by cAMP (EPACs) have been shown to play vital roles in a plethora of pathways in different cell systems. While extensive research to identify the role of EPAC in the vasculature has been conducted, much remains to be explored to resolve the reported discordance in EPAC's effects. In this paper, we review the role of EPAC in VSMCs, namely its regulation of the vascular tone and phenotypic switching, with the likely involvement of reactive oxygen species (ROS) in the interplay between EPAC and its targets/effectors.

MicroRNAs in Cardiac Hypertrophy.

Like other organs, the heart undergoes normal adaptive remodeling, such as cardiac hypertrophy, with age. This remodeling, however, is intensified under stress and pathological conditions. Cardiac remodeling could be beneficial for a short period of time, to maintain a normal cardiac output in times of need; however, chronic cardiac hypertrophy may lead to heart failure and death. MicroRNAs (miRNAs) are known to have a role in the regulation of cardiac hypertrophy. This paper reviews recent advances in the field of miRNAs and cardiac hypertrophy, highlighting the latest findings for targeted genes and involved signaling pathways. By targeting pro-hypertrophic genes and signaling pathways, some of these miRNAs alleviate cardiac hypertrophy, while others enhance it. Therefore, miRNAs represent very promising potential pharmacotherapeutic targets for the management and treatment of cardiac hypertrophy.

Cunninghamella blakesleeana-mediated biotransformation of a contraceptive drug, desogestrel, and anti-MDR-Staphylococcus aureus activity of its metabolites.

Staphylococcus aureus is one of the most infectious agents among staphylococcal bacteria. Currently many strains of S. aureus have developed resistance against available antibiotics. Therefore, the treatment of infections caused by them is a major challenge. During current study, desogestrel (1), a contraceptive drug, was found to be a potent growth inhibitor of drug resistant strains of S. aureus. Therefore, in search of new and effective agents against multi-drug resistant S. aureus strains, whole-cell bio-catalytic conversion of desogestrel (1) by Cunninghamella blakesleeana ATCC 8688A at pH 7.0 and 25 °C was carried out, yielding three new metabolites, 13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-6ß,15ß,17ß-triol (2), 13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-3ß,6ß,17ß-triol (3), and 13-ethyl-11-methylene-18,19-dinor-17α-pregn-20-yn-3α,5α,6ß,17ß-tetraol (4), along with a known metabolite, 13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-6ß,17ß-dihydroxy-3-one (5). Among them, compounds 1-2 showed a potent activity against S. aureus EMRSA-17, S. aureus NCTC 13277 (MRSA-252), and S. aureus NCTC 13143, and clinically isolated Pakistani strain of S. aureus in an in vitro Microplate Alamar Blue Assay (MABA). Vancomycin was used as the standard drug in this assay. In addition, compound 1 also showed a significant activity against vancomycin-resistant S. aureus (VRSA) ATCC 700699. Compounds 1-5 were also evaluated against 3T3 normal cell line (mouse fibroblast) where they all were identified as non-cytotoxic. The present study thus provides new leads for the development of anti-bacterial drugs against MDR S. aureus.

A Phytochemical Analysis and the Pharmacological Implications of the Seagrass Halodule uninervis: An Overview.

Seagrasses are marine angiosperms that inhabit tropical and subtropical regions around the world. They play a vital role in marine biodiversity and the ecosystem by providing habitats and food for several marine organisms, stabilizing sediments, and improving water quality. Halodule uninervis from the family Cymodoceaceae has been used in traditional folk medicine for the treatment of many ailments. Additionally, several identified bioactive metabolites have been shown to contribute to its pharmacological activities, including anticancer, anti-inflammatory, and antioxidant. As such, H. uninervis could contribute to the development of novel drugs for various diseases. This review aims to compile the phytochemical composition and pharmacological activities of H. uninervis. Furthermore, details about its botanical characteristics and ecological significance are also discussed. By providing valuable insights into the role of H. uninervis in both the marine ecosystem and biomedicine, this review helps to highlight its potential as a therapeutic agent for future drug discovery and development.

Halophila stipulacea: A Comprehensive Review of Its Phytochemical Composition and Pharmacological Activities.

Halophila stipulacea (Forsskål and Niebuhr) Ascherson is a small marine seagrass that belongs to the Hydrocharitaceae family. It is native to the Red Sea, Persian Gulf, and Indian Ocean and has successfully invaded the Mediterranean and Caribbean Seas. This article summarizes the pharmacological activities and phytochemical content of H. stipulacea, along with its botanical and ecological characteristics. Studies have shown that H. stipulacea is rich in polyphenols and terpenoids. Additionally, it is rich in proteins, lipids, and carbohydrates, contributing to its nutritional value. Several biological activities are reported by this plant, including antimicrobial, antioxidant, anticancer, anti-inflammatory, anti-metabolic disorders, and anti-osteoclastogenic activities. Further research is needed to validate the efficacy and safety of this plant and to investigate the mechanisms of action underlying the observed effects.

The Antioxidant Potential and Anticancer Activity of Halodule uninervis Ethanolic Extract against Triple-Negative Breast Cancer Cells.

Natural remedies have been indispensable to traditional medicine practices for generations, offering therapeutic solutions for various ailments. In modern times, these natural products continue to play a pivotal role in the discovery of new drugs, especially for cancer treatment. The marine ecosystem offers a wide range of plants with potential anticancer activities due to their distinct biochemical diversity and adaptation to extreme situations. The seagrass Halodule uninervis is rich in diverse bioactive metabolites that bestow the plant with various pharmacological properties. However, its anticancer activity against invasive triple-negative breast cancer (TNBC) is still poorly investigated. In the present study, the phytochemical composition of an ethanolic extract of H. uninervis (HUE) was screened, and its antioxidant potential was evaluated. Moreover, the anticancer potential of HUE against MDA-MB-231 cells was investigated along with the possible underlying mechanisms of action. Our results showed that HUE is rich in diverse phytochemicals that are known for their antioxidant and anticancer effects. In MDA-MB-231 cells, HUE targeted the hallmarks of cancer, including cell proliferation, adhesion, migration, invasion, and angiogenesis. The HUE-mediated anti-proliferative and anti-metastatic effects were associated with the downregulation of the proto-oncogenic STAT3 signaling pathway. Taken together, H. uninervis could serve as a valuable source for developing novel drugs targeting TNBC.

Comprehensive Review of Cyclamen: Development, Bioactive Properties, and Therapeutic Applications.

Plants are being researched as potential sources of novel drugs, which has led to a recent acceleration in the discovery of new bioactive compounds. Research on tissue culture technology for the synthesis and processing of plant compounds has skyrocketed, surpassing all expectations. These plants can be bought either raw or as extracts, where some of the chemicals are extracted by mashing the plant in water, alcohol, or another solvent. The use of herbal medicine may open new chances for reducing the onset of infections and treating different diseases including cancer. A perennial plant that blooms in the winter, Cyclamen, is one of the most widely used potted flowers in many nations. Alkaloids, flavonoids, phenols, tannins, saponins, sterols, and glycosides are the main active components of Cyclamen. Analgesic, cytotoxic, antioxidant, antimicrobial, and anti-inflammatory properties have all been demonstrated as potential effects of various extracts of Cyclamen tubers. However, the use of this medicinal plant in official medicine will require further research in the areas of pharmacology. Furthermore, it is necessary to create standard operating procedures for a crude herbal medication. In this regard, this review aims to highlight the key characteristics of the Cyclamen plant, such as its various parts, species, stages of development, and geographic range; pinpoint its intriguing bioactivities, its antioxidant, anti-inflammatory, and its anti-cancerous effects; and ascertain its potential medicinal uses and the main future perspectives.

Potential Anti-Tumorigenic Properties of Diverse Medicinal Plants against the Majority of Common Types of Cancer.

Globally, cancer is one of the primary causes of both morbidity and mortality. To prevent cancer from getting worse, more targeted and efficient treatment plans must be developed immediately. Recent research has demonstrated the benefits of natural products for several illnesses, and these products have played a significant role in the development of novel treatments whose bioactive components serve as both chemotherapeutic and chemo-preventive agents. Phytochemicals are naturally occurring molecules obtained from plants that have potential applications in both cancer therapy and the development of new medications. These phytochemicals function by regulating the molecular pathways connected to the onset and progression of cancer. Among the specific methods are immune system control, inducing cell cycle arrest and apoptosis, preventing proliferation, raising antioxidant status, and inactivating carcinogens. A thorough literature review was conducted using Google Scholar, PubMed, Scopus, Google Patent, Patent Scope, and US Patent to obtain the data. To provide an overview of the anticancer effects of several medicinal plants, including Annona muricata, Arctium lappa, Arum palaestinum, Cannabis sativa, Catharanthus roseus, Curcuma longa, Glycyrrhiza glabra, Hibiscus, Kalanchoe blossfeldiana, Moringa oleifera, Nerium oleander, Silybum marianum, Taraxacum officinale, Urtica dioica, Withania somnifera L., their availability, classification, active components, pharmacological activities, signaling mechanisms, and potential side effects against the most common cancer types were explored.

Enhancing Wastewater Depollution: Sustainable Biosorption Using Chemically Modified Chitosan Derivatives for Efficient Removal of Heavy Metals and Dyes.

Driven by concerns over polluted industrial wastewater, particularly heavy metals and dyes, this study explores biosorption using chemically cross-link chitosan derivatives as a sustainable and cost-effective depollution method. Chitosan cross-linking employs either water-soluble polymers and agents like glutaraldehyde or copolymerization of hydrophilic monomers with a cross-linker. Chemical cross-linking of polymers has emerged as a promising approach to enhance the wet-strength properties of materials. The chitosan thus extracted, as powder or gel, was used to adsorb heavy metals (lead (Pb2+) and copper (Cu2+)) and dyes (methylene blue (MB) and crystal violet (CV)). Extensive analysis of the physicochemical properties of both the powder and hydrogel adsorbents was conducted using a range of analytical techniques, including Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Brunauer-Emmett-Teller (BET), and scanning electron microscopy (SEM), as well as 1H and 13C nuclear magnetic resonance (NMR). To gain a comprehensive understanding of the sorption process, the effect of contact time, pH, concentration, and temperature was investigated. The adsorption capacity of chitosan powder for Cu(II), Pb(II), methylene blue (MB), and crystal violet (CV) was subsequently determined as follows: 99, 75, 98, and 80%, respectively. In addition, the adsorption capacity of chitosan hydrogel for Cu(II), Pb(II), MB, and CV was as follows: 85, 95, 85, and 98%, respectively. The experimental data obtained were analyzed using the Langmuir, Freundlich, and Dubinin-Radushkevich isotherm models. The isotherm study revealed that the adsorption equilibrium is well fitted to the Freundlich isotherm (R2 = 0.998), and the sorption capacity of both chitosan powder and hydrogel was found to be exceptionally high (approximately 98%) with the adsorbent favoring multilayer adsorption. Besides, Dubinin has given an indication that the sorption process was dominated by Van der Waals physical forces at all studied temperatures.

Antibacterial and Antifungal Activities of Cimbopogon winterianus and Origanum syriacum Extracts and Essential Oils against Uropathogenic Bacteria and Foodborne Fungal Isolates.

This study focused on testing the antibacterial and antifungal activity of Origanum syriacum (O. syriacum) and Cimbopogon winterianus (C. winterianus) extracts and their essential oils (EOs). The bacteria were isolated from urine samples and identified by a VITEK assay, and the fungi were isolated from spoiled food samples and further identified by MALDI-TOF. The susceptibility of the microbial isolates was assessed by determining the bacteriostatic and bactericidal/fungicidal effects by the minimum inhibitory concentration (MIC) and minimum bactericidal/fungicidal concentration (MBC/MFC) broth microdilution assay and time-kill test. The antibiofilm activities were assessed by the antibiofilm screening assays. The bacterial isolates included three Gram-negative isolates (Escherichia coli, Klebsiella pneumonia, and Citrobacter freundii) and two Gram-positive isolates (Staphylococcus aureus and Streptococcus intermedius). The fungal isolates included Candida albicans and Aspergillus niger. The O. syriacum and C. winterianus extracts exhibited bacteriostatic and fungistatic activities (MIC 1.25-2.5 mg/mL for the bacterial isolates and 2.5-5 mg/mL for the fungal isolates). However, their EOs exhibited bactericidal (MBC 5-20%) and fungicidal (MFC 1.25-10%) activities, meaning that the EOs had a better antimicrobial potential than the extracts. The antibiofilm activities of the mentioned extracts and their EOs were relatively weak. The O. syriacum extract inhibited S. aureus, S. intermedius, and K. pneumonia biofilms at a concentration of 0.3125 mg/mL and C. albicans and A. niger biofilms at 0.625 mg/mL. No antibiofilm activity was recorded for C. winterianus extract. In addition, the packaging of grapes with C. winterianus extract preserved them for about 40 days. The results reflect the significant antimicrobial activity of O. syriacum and C. winterianus extracts and their EOs, thus suggesting their potential in food packaging and preservation.

Fractionation and phytochemical composition of an ethanolic extract of Ziziphus nummularia leaves: antioxidant and anticancerous properties in human triple negative breast cancer cells.

Natural products have long been utilized in traditional medicine as remedies to improve health and treat illnesses, and have had a key role in modern drug discovery. Recently, there has been a revived interest in the search for bioactives from natural sources as alternative or complementary modalities to synthetic medicines; especially for cancer treatment, which incidence and mortality rates are on the rise worldwide. Ziziphus nummularia has been widely used in traditional medicine for the treatment of various diseases. Its traditional uses and numerous ethnopharmacological properties may be attributed to its richness in bioactive metabolites. However, its phytochemical composition or chemopreventive effects against the aggressive triple-negative breast cancer (TNBC) are still poorly explored. Here, phytochemical composition of an ethanolic extract of Z. nummularia leaves (ZNE) and its chromatographically isolated fractions was identified both qualitatively by spectrophotometric assays and analytically by HPLC-PDA-MS/MS. The anti-proliferative effects of ZNE were tested in several cancer cell lines, but we focused on its anti-TNBC effects since they were not explored yet. The anti-cancerous potential of ZNE and its fractions was tested in vitro in MDA-MB-231, a TNBC cell line. Results showed that ZNE and its Fraction 6 (F6) reduced the viability of MDA-MB-231 cells. F6 decreased MDA-MB-231 viability more than crude ZNE or its other fractions. ZNE and F6 are rich in phytochemicals and HPLC-PDA-MS/MS analysis identified several metabolites that were previously reported to have anti-cancerous effects. Both ZNE and F6 showed potent antioxidant capacity in the DPPH assay, but promoted reactive oxygen species (ROS) production in MDA-MB-231 cells; an effect which was blunted by the antioxidant N-acetyl cysteine (NAC). NAC also blunted ZNE- and F6-induced reduction in TNBC cell viability. We also demonstrated that ZNE and F6 induced an arrest of the cell cycle, and triggered apoptosis- and autophagy-mediated cell death. ZNE and F6 inhibited metastasis-related cellular processes by modifying cell migration, invasion, and adhesion. Taken together, our findings reveal that Z. nummularia is rich in phytochemicals that can attenuate the malignant phenotype of TNBC and may offer innovative avenues for the discovery of new drug leads for treatment of TNBC and other cancers.

Design and Synthesis of Novel Amino and Acetamidoaurones with Antimicrobial Activities.

The development of new and effective antimicrobial compounds is urgent due to the emergence of resistant bacteria. Natural plant flavonoids are known to be effective molecules, but their activity and selectivity have to be increased. Based on previous aurone potency, we designed new aurone derivatives bearing acetamido and amino groups at the position 5 of the A ring and managing various monosubstitutions at the B ring. A series of 31 new aurone derivatives were first evaluated for their antimicrobial activity with five derivatives being the most active (compounds 10, 12, 15, 16, and 20). The evaluation of their cytotoxicity on human cells and of their therapeutic index (TI) showed that compounds 10 and 20 had the highest TI. Finally, screening against a large panel of pathogens confirmed that compounds 10 and 20 possess large spectrum antimicrobial activity, including on bioweapon BSL3 strains, with MIC values as low as 0.78 µM. These results demonstrate that 5-acetamidoaurones are far more active and safer compared with 5-aminoaurones, and that benzyloxy and isopropyl substitutions at the B ring are the most promising strategy in the exploration of new antimicrobial aurones.