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.

Ethnopharmacology and therapeutic potential of Anchusa strigosa: a comprehensive review.

Anchusa strigosa Banks and Sol. is a rough flowering plant of the Boraginaceae family native to Eastern Mediterranean region that is widely used in traditional herbal medicine, mainly for the treatment of wounds, abdominal pain, and arthritis, to name a few. This article aims to gather knowledge related to the medicinal properties of A. strigosa. Specifically, it summarizes its traditional uses and pharmacological activities in the treatment of various diseases. Moreover, its botanical, ecological, and phytochemical characteristics are also discussed. Research showed that this plant is rich in pyrrolizidine alkaloids, particularly in the leaves. Other bioactive metabolites identified in this plant include flavonoids, phenolic acids, triterpenes, organic acids, and volatile organic compounds. These phytochemicals are responsible for the reported pharmacological properties of A. strigosa, including antimicrobial, antioxidant, anticancer, anti-inflammatory, antiarthritic, gastric protective, antidiabetic, and pro-wound healing. This warrants further investigation into the molecular mechanism of action behind the observed effects to elucidate its therapeutic potential. Nevertheless, more research on this plant is needed to ensure its efficacy and safety.

Study of the antioxidant and anti-pancreatic cancer activities of Anchusa strigosa aqueous extracts obtained by maceration and ultrasonic extraction techniques.

Pancreatic cancer is a highly aggressive malignancy and a leading cause of cancer-related deaths worldwide. Moreover, the incidence and mortality rates for pancreatic cancer are projected to keep increasing. A major challenge in the treatment of pancreatic cancer is the lack of effective screening approaches, which contributes to its poor prognosis, indicating the need for new treatment regimens and alternative therapies, such as herbal medicine. The medicinal plant A. strigosa, which is widely distributed in the Eastern Mediterranean region, is a short prickly plant from the Boraginaceae family that has been widely used in traditional medicine for treating various diseases. Nevertheless, its effect on human pancreatic cancer remains poorly investigated. In the present study, we screened the phytochemical content of Anchusa strigosa aqueous extracts obtained by maceration and ultrasound-assisted methods (ASM and ASU, respectively) and evaluated their antioxidant effects. We also investigated their anticancer effects and possible underlying mechanisms. The results show that both extracts were rich in bioactive molecules, with slight differences in their composition. Both extracts exhibited remarkable antioxidant potential and potent radical-scavenging activity in vitro. Additionally, non-cytotoxic concentrations of both extracts attenuated cell proliferation in a time- and concentration-dependent manner, which was associated with a decrease in the proliferation marker Ki67 and an induction of the intrinsic apoptotic pathway. Furthermore, the extracts increased the aggregation of pancreatic cancer cells and reduced their migratory potential, with a concomitant downregulation of integrin ß1. Finally, we showed that the ASM extract caused a significant decrease in the levels of COX-2, an enzyme that has been linked to inflammation, carcinogenesis, tumor progression, and metastasis. Taken together, our findings provide evidence that A. strigosa extracts, particularly the extract obtained using the maceration method, have a potential anticancer effect and may represent a new resource for the design of novel drugs against pancreatic cancer.

Ethanolic extract of Origanum syriacum L. leaves exhibits potent anti-breast cancer potential and robust antioxidant properties.

Background: Breast cancer (BC) is the second most common cancer overall. In women, BC is the most prevalent cancer and the leading cause of cancer-related mortality. Triple-negative BC (TNBC) is the most aggressive BC, being resistant to hormonal and targeted therapies. HYPOTHESIS/PURPOSE: The medicinal plant Origanum syriacum L. is a shrubby plant rich in bioactive compounds and widely used in traditional medicine to treat various diseases. However, its therapeutic potential against BC remains poorly investigated. In the present study, we screened the phytochemical content of an ethanolic extract of O. syriacum (OSEE) and investigated its anticancer effects and possible underlying mechanisms of action against the aggressive and highly metastatic human TNBC cell line MDA-MB-231. METHODS: MTT, trans-well migration, and scratch assays were used to assess cell viability, invasion, or migration, respectively. Antioxidant potential was evaluated in vitro using the DPPH radical-scavenging assay and levels of reactive oxygen species (ROS) were assessed in cells in culture using DHE staining. Aggregation assays were used to determine cell-cell adhesion. Flow cytometry was used to analyze cell cycle progression. Protein levels of markers of apoptosis (BCL-2, pro-Caspase3, p53), proliferation (p21, Ki67), cell migration, invasion, or adhesion (FAK, E-cadherin), angiogenesis (iNOS), and cell signaling (STAT3, p38) were determined by immunoblotting. A chorioallantoic Membrane (CAM) assay evaluated in ovo angiogenesis. RESULTS: We demonstrated that OSEE had potent radical scavenging activity in vitro and induced the generation of ROS in MDA-MB-231 cells, especially at higher OSEE concentrations. Non-cytotoxic concentrations of OSEE attenuated cell proliferation and induced G0/G1 cell cycle arrest, which was associated with phosphorylation of p38 MAPK, an increase in the levels of tumor suppressor protein p21, and a decrease of proliferation marker protein Ki67. Additionally, only higher concentrations of OSEE were able to attenuate inhibition of proliferation induced by the ROS scavenger N-acetyl cysteine (NAC), indicating that the anti-proliferative effects of OSEE could be ROS-dependent. OSEE stimulated apoptosis and its effector Caspase-3 in MDA-MB-231 cells, in correlation with activation of the STAT3/p53 pathway. Furthermore, the extract reduced the migration and invasive properties of MDA-MB-231 cells through the deactivation of focal adhesion kinase (FAK). OSEE also reduced the production of inducible nitric oxide synthase (iNOS) and inhibited in ovo angiogenesis. CONCLUSION: Our findings reveal that OSEE is a rich source of phytochemicals and has robust anti-breast cancer properties that significantly attenuate the malignant phenotype of MD-MB-231 cells, suggesting that O. syriacum may not only act as a rich source of potential TNBC therapeutics but may also provide new avenues for the design of novel TNBC drugs.

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.

Origanum syriacum L. Attenuates the Malignant Phenotype of MDA-MB231 Breast Cancer Cells.

Breast cancer is the leading cause of cancer-related deaths among women. Among breast cancer types, triple negative breast cancer (TNBC) is the most aggressive, and is resistant to hormonal and chemotherapeutic treatments. As such, alternative approaches that may provide some benefit in fighting this debilitating pathology are critically needed; hence the utilization of herbal medicine. Origanum syriacum L., one of the most regularly consumed plants in the Mediterranean region, exhibits antiproliferative effect on several cancer cell lines. However, whether this herb modulates the malignant phenotype of TNBC remains poorly investigated. Here, we show that in MDA-MB-231, a TNBC cell line, Origanum syriacum L. aqueous extract (OSE) inhibited cellular viability, induced autophagy determined by the accumulation of lipidized LC3 II, and triggered apoptosis. We also show that OSE significantly promoted homotypic cell-cell adhesion while it decreased cellular migration, adhesion to fibronectin, and invasion of MDA-MB-231 cells. This was supported by decreased activity of focal adhesion kinase (FAK), reduced α2 integrin expression, and downregulation of secreted PgE2, MMP2 and MMP-9, in OSE-treated cells. Finally, we also show that OSE significantly inhibited angiogenesis and downregulated the level of nitric oxide (NO) production. Our findings demonstrate the ability of OSE to attenuate the malignant phenotype of the MDA-MB-231 cells, thus presenting Origanum syriacum L. as a promising potential source for therapeutic compounds for TNBC.

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.

The hypertensive potential of estrogen: An untold story.

Cardiovascular disease (CVD) is the major cause of morbidity and mortality worldwide. The implication of estrogen in this disease has been extensively studied. While the vast majority of published research argue for a cardioprotective role of estrogen in vascular inflammation such as in atherosclerosis, the role of estrogen in hypertension remains far from being resolved. The vasorelaxant effect of estrogen has already been well-established. However, emerging evidence supports a vasoconstrictive potential of this hormone. It has been proposed that the microenvironment dictates the effect of estrogen-induced type 1 nitric oxide synthase-1 (nNOS) on vasotone. Indeed, depending on nNOS product, nitric oxide or superoxide, estrogen can induce vasodilation or vasoconstriction, respectively. In this review, we discuss the evidence supporting the vasorelaxant effects of estrogen, and the molecular players involved. Furthermore, we shed light on recent reports revealing a vasoconstrictive role of estrogen, and speculate on the underlying signaling pathways. In addition, we identify certain factors that can account for the discrepant estrogenic effects. This review emphasizes a yin-yang role of estrogen in regulating blood pressure.

Marjoram Relaxes Rat Thoracic Aorta Via a PI3-K/eNOS/cGMP Pathway.

Despite pharmacotherapeutic advances, cardiovascular disease (CVD) remains the primary cause of global mortality. Alternative approaches, such as herbal medicine, continue to be sought to reduce this burden. Origanum majorana is recognized for many medicinal values, yet its vasculoprotective effects remain poorly investigated. Here, we subjected rat thoracic aortae to increasing doses of an ethanolic extract of Origanummajorana (OME). OME induced relaxation in a dose-dependent manner in endothelium-intact rings. This relaxation was significantly blunted in denuded rings. N(ω)-nitro-l-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) significantly reduced the OME-induced vasorelaxation. Cyclic guanosine monophosphate (cGMP) levels were also increased by OME. Moreover, wortmannin or LY294002 significantly reduced OME-induced vasorelaxation. Blockers of ATP-sensitive or Ca2+-activated potassium channels such as glibenclamide or tetraethylamonium (TEA), respectively, did not significantly affect OME-induced relaxation. Similarly, verapamil, a Ca2+ channel blocker, indomethacin, a non-selective cyclooxygenase inhibitor, and pyrilamine, a H1 histamine receptor blocker, did not significantly modulate the observed relaxation. Taken together, our results show that OME induces vasorelaxation via an endothelium-dependent mechanism involving the phosphoinositide 3-kinase (PI3-K)/ endothelial nitric oxide (NO) synthase (eNOS)/cGMP pathway. Our findings further support the medicinal value of marjoram and provide a basis for its beneficial intake. Although consuming marjoram may have an antihypertensive effect, further studies are needed to better determine its effects in different vascular beds.