In Vitro Cytotoxic Potential of Selected Jordanian Flora and Their Associated Phytochemical Analysis.

Traditional medicines are a significant source of phytochemicals with potential anticancer effects. Ten Jordanian plants were chosen to be tested for cytotoxicity on human colorectal (HT-29) and breast adenocarcinoma (MCF-7) cell lines. The ethanol extracts were screened for their potential cytotoxic effects using a Sulforhodamine B (SRB) colorimetric assay, using doxorubicin as positive control. Plants extracts exhibiting marked cytotoxic activity were further investigated by qualitative and quantitative phytochemical methods. Total phenolics were quantified using the Folin-Ciocalteu reagent, while flavonoids were quantified using aluminum chloride. The total saponins of the n-butanol fraction were estimated using diosgenin as a standard. The total alkaloids and total terpenoids were also evaluated using the gravimetric method. As results, Senecio leucanthemifolius (IC50: 13.84 µg/mL) and Clematis cirrhosa (IC50: 13.28 µg/mL) exhibited marked cytotoxic effects on human colorectal adenocarcinoma (HT-29) cell lines. Total phenolics, flavonoids, saponins, alkaloids, and terpenoids found in Senecio leucanthemifolius were (91.82, 14.90, 14.27, 101, and 135.4 mg/g of dry extract), respectively. They were revealed to be (68.18, 7.16, 31.25, 73.6, and 180 mg/g of dry extract) in Clematis cirrhosa, respectively. Senecio leucanthemifolius and Clematis cirrhosa have been found to possess cytotoxicity against colorectal (HT-29). In conclusion, the findings of this study offer a new perspective on Jordanian plant extracts anticancer activity research.

Natural Reno-Protective Agents against Cyclosporine A-Induced Nephrotoxicity: An Overview.

CA (cyclosporine A) is a powerful immunosuppressing agent that is commonly utilized for treating various autoimmune illnesses and in transplantation surgery. However, its usage has been significantly restricted because of its unwanted effects, including nephrotoxicity. The pathophysiology of CA-induced kidney injury involves inflammation, apoptosis, tubular injury, oxidative stress, and vascular injury. Despite the fact that exact mechanism accountable for CA's effects is inadequately understood, ROS (reactive oxygen species) involvement has been widely proposed. At present, there are no efficient methods or drugs for treating CA-caused kidney damage. It is noteworthy that diverse natural products have been investigated both in vivo and in-vitro for their possible preventive potential in CA-produced nephrotoxicity. Various extracts and natural metabolites have been found to possess a remarkable potential for restoring CA-produced renal damage and oxidative stress alterations via their anti-apoptosis, anti-inflammatory, and antioxidative potentials. The present article reviews the reported studies that assess the protective capacity of natural products, as well as dietary regimens, in relation to CA-induced nephrotoxicity. Thus, the present study presents novel ideas for designing and developing more efficient prophylactic or remedial strategies versus CA passive influences.

Anti-adhesive activity of Aframomum melegueta major phenolics on lower respiratory tract pathogens.

Recent studies have raised interest in the potential health effect of Aframomum melegueta, which is related to the phenolic content of its seeds. The methanolic extract of A. melegueta seeds showed a significant anti-adhesive effect against Staphylococcus aureus to lung carcinoma cell line in a concentration-dependent manner. The n-butanol and the chloroform fractions exhibited a significant antiadhesive activity against S. aureus. The chloroform fraction exhibited an antiadhesive effect of 49.53%, 40.15% and 70.34% at concentrations 25, 50 and 100 µg/mL, respectively. Through a biologically guided isolation, the chloroform fraction yielded a new diarylheptanoid identified using 1D, 2D NMR and HREIMS and named 3-(S)-acetyl-1-(4',5'-dihydroxy-3'- methoxyphenyl)-7-(3″,4″-dihydroxyphenyl)heptane(1), in addition to eight known compounds (2-9). Compounds (1), 6-paradol (5), [6]-shogaol (7), [8]-gingerol(8) and dihydro[6]paradol (9) exhibited a significant anti-adhesive activity against S. aureus with a % of inhibition of adhesion of 60.58, 50, 70.07, 85.4, 59.85% at 50 µg/mL, respectively. Additionally, the extract's capacity to reduce adhesion without reducing bacterial growth reduces the likeliness of resistance development.

Characterization and Pharmacological Evaluation of Anti-Cellulite Herbal Product(s) Encapsulated in 3D-Fabricated Polymeric Microneedles.

Skin health is vital for a healthy body. Herbal remedies have long been used for skin care, and their global use has tremendously increased over the past three decades. Although cellulite is seen as a normal condition by the medical community, it is considered a serious cosmetic concern for most affected women. Many topical anti-cellulite creams are available on the market, but unfortunately, their efficacy has not been proven scientifically. Microneedles (MNs) represent a new approach to enhance the permeation of loaded medication through the skin. In this study, the anti-cellulite effects of Vitex agnus-castus and Tamarindus indica extracts were compared using safe and effective polymeric MNs. This delivery system offers a painless alternative to the combined treatment strategy of microneedling devices and anti-cellulite products. The selected standardized extracts were evaluated for their mineral, phenolic and flavonoid contents, which are correlated to a promising antioxidant effect, as demonstrated by an in vitro radical scavenging activity assay. 3D-printing techniques were chosen for fabrication of a micromold, which is inexpensive for mass production. To ensure that MNs were sufficiently strong to perforate the skin without breaking, axial failure force was measured using a micro-mechanical test machine. The anticellulite effects of MNs were assessed using an in vivo diet-induced obesity guinea pig model. Skin properties, histopathology and inflammatory markers were examined. MNs loaded with plant extracts were statistically comparable in normalizing the oxidative state and reducing inflammation, while myeloperoxidase levels were more significantly reduced by T. indica than by V. agnus-castus. This novel delivery system opens the door for new transdermal strategies for cellulite management.

Metabolomic profiling of five Agave leaf taxa via UHPLC/PDA/ESI-MS inrelation to their anti-inflammatory, immunomodulatory and ulceroprotective activities.

Agave plants are popular for their myriad applications in traditional medicine attributed to their reported anti-inflammatory, immunomodulatory, cytotoxic and antifungal activities. The aim of this study was to examine the anti-inflammatory, immunomodulatory and ulceroprotective activity of Agave species in relation to their metabolite fingerprint via a metabolome based ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) approach coupled to chemometrics. The metabolomic differences among five examined Agave leaves viz. Agave americana L., A. americana var. marginata Trel, A. angustifolia Haw. cv. marginata, A. desmettiana Jacobi, A. pygmaea Gentry were determined via a total of 56 annotated metabolites. Identification based on MSn and UV spectra revealed 25 steroidal saponins and sapogenins, 6 flavonoids, 2 homoisoflavonoids, 7 phenolic acids, 6 fatty acids and 3 fatty acid amides, some of which are reported for the first time in Agave. Metabolites heterogeneity was assessed among leaf taxa via multivariate data analyses for samples classification, showing that saponins is the major metabolite contributing to their classification. The carrageenan induced acute inflammatory rat model was used to assess the anti-inflammatory activity of Agave extracts via monitoring of blood cytokine levels. Additionally, their effects on ethanol-induced gastric ulcer in rats were evaluated. A. pygmaea showed the most significant anti-inflammatory and immunomodulatory activity, while A. angustifolia var. marginata possessed the highest ulceroprotective activity, which could be attributable to the high abundance of various saponins and homoisoflavonoids in those taxa.

Natural Peroxisome Proliferator-Activated Receptor γ (PPARγ) Activators for Diabetes.

CONTEXT: Metabolic syndrome (MetS) represents a worldwide problem. Drugs used in MetS target different symptoms, like excessive body weight, insulin resistance, hyperglycemia, dyslipidemia, or hypertension. Peroxisome proliferator-activated receptors (PPAR) regulate the gene expression involved in lipid metabolism, inflammation, and adipogenesis. Activation of PPARγ has become a target of interest to counter hyperglycemia linked with MetS and type 2 diabetes (T2DM). OBJECTIVE: The current review intended to summarize reported research on medicinal plants, or their bioactive constituents, with PPARγ-activating potential. DESIGN: The research team searched the literature up to 2016 using electronic databases- ScienceDirect, PubMed, Google-Scholar, SpringerLink, Scopus, and Wiley-for publications on medicinal plants with promising PPARγ modulators using keywords diabetes mellitus, natural products, peroxisome proliferator-activated receptors, metabolic syndrome, adipogenesis. SETTING: This study was conducted in the Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia, Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt, and Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al Madinah, Al Munawwarah, Saudi Arabia. RESULTS: Several natural products were considered to be good ligands for PPARγ. The PPARγ agonistic activity of over 100 plants covered in this review was supported by experimental evidence. Some of the plants and their constituents had been studied for their possible mechanisms of action. CONCLUSIONS: Findings discussed in this review highlighted PPARγ's role as an organizer of lipid metabolism and glucose homeostasis, thus supporting its function as a target for antidiabetic agents. The discovery that some natural compounds and plants could activate PPARγ opens up the prospect for future development of strategies to take advantage of its therapeutic potential in diabetes. Therefore, the current review could provide significant information for biotechnological or pharmaceutical applications in targeted drug delivery and design.

Russelioside B, a pregnane glycoside ameliorates hyperglycemia in streptozotocin induced diabetic rats by regulating key enzymes of glucose metabolism.

An alternative strategy to treat diabetes mellitus is the use of various natural agents possessing hypoglycemic effect. Caralluma quadrangula has been used in Saudi traditional medicine in cases of thirst and hunger and for the treatment of diabetes. The present study was designed to evaluate the improving effect of russelioside B, a pregnane glycoside isolated from Caralluma quadrangula on glucose metabolism in the liver of streptozotocin-induced diabetic rats. Diabetes mellitus was induced in rats by a single intraperitoneal injection of streptozotocin (50 mg/kg body weight). Experimental rats were administered russelioside B at a dose of 50 mg/kg body weight once a day for 30 days. The results showed that RB improved the fasting serum glucose level, glycated hemoglobin percent, serum insulin level and lipid profile. A significant improvement was observed upon the administration of russelioside B on the activities of the key enzymes of carbohydrate metabolism (glucokinase, glucose-6-phosphatase, glucose-6-phosphate dehydrogenase, and glycogen phosphorylase) in the liver of diabetic rats. Further, russelioside B administration to diabetic rats reverted gene expression of glucokinase, glucose-6-phosphatase, glycogen synthase and glycogen synthase kinase-3ß to near normal levels. In conclusion, russelioside B possess antidiabetic and antihyperlipidemic effect in streptozotocin induced diabetic rats. Hence, administration of russelioside B may represent a potentially useful strategy for the management of diabetes.

P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review.

Resistance of solid tumors to treatment is significantly attributed to pharmacokinetic reasons at both cellular and multi-cellular levels. Anticancer agent must be bio-available at the site of action in a cytotoxic concentration to exert its proposed activity. P-glycoprotein (P-gp) is a member of the ATP-dependent membrane transport proteins; it is known to pump substrates out of cells in ATP-dependent mechanism. The over-expression of P-gp in tumor cells reduces the intracellular drug concentrations, which decreases the cytotoxicity of a broad spectrum of antitumor drugs. Accordingly, P-gp inhibitors/blockers are potential enhancer for the cellular bioavailability of several clinically important anticancer drugs such as, anthracyclines, taxanes, vinca alkaloids, and podophyllotoxins. Besides several chemically synthesized P-gp inhibitors/blockers, some naturally occurring compounds and plant extracts were reported for their modulation of multidrug resistance; however, this review will focus only on major classes of naturally occurring inhibitors viz., flavonoids, coumarins, terpenoids, alkaloids and saponins.

Protective effect of Aframomum melegueta phenolics against CCl4-induced rat hepatocytes damage; role of apoptosis and pro-inflammatory cytokines inhibition.

Aframomum melegueta is a commonly used African spice. Through a hepatoprotective bioassay-guided isolation, the chloroform fraction of A.melegueta seeds yielded one new diarylheptanoid named 3-(S)-acetyl-1-(4'-hydroxy-3', 5'-di methoxyphenyl)-7-(3″,4″, 5″-trihydroxyphenyl)heptane (1), and two new hydroxyphenylalkanones, [8]-dehydrogingerdione (2) and [6]-dehydroparadol (3), in addition to six known compounds (4-9). The hepatoprotective effect of A. melegueta methanol extract, sub-fractions and isolated compounds was investigated using carbon tetrachloride (CCl4)-induced liver injury in a rat hepatocytes model. The methanol, chloroform extracts and compounds 1, 5, 8 and 9 of A. melegueta significantly inhibited the elevated serum alanine aminotransferase (ALT), thiobarbituric acid reactive substances (TBARS), tumor necrosis factor (TNFα), interleukin-1beta (Il-1ß), caspase3 and 9 and enhanced the reduced liver glutathione (GSH) level caused by CCl4 intoxication. These results indicate that A.melegueta extracts, and isolated compounds play a protective role in CCl4 induced acute liver injury which might be due to elevated antioxidative defense potentials, suppressed inflammatory responses and apoptosis of liver tissue.

New bioactive metabolites from a crown gall induced on an Eucalyptus tereticornis Sm. tree.

Applying a bioactivity-guided isolation strategy for the ethanolic extract of crown gall tumours induced on an Eucalyptus tereticornis tree, two new compounds in addition to a known one were isolated. The new compounds were identified as an amino acid derivative named 1-ethyl-6-(1'-methyl-1'-phenylethyl) piperidin-2-one (1) and a lanostane tetracyclic triterpene named 3beta-hydroxy-24-methyllanosta-8,17(20),24(28)-trien-22-oic acid (2), together with stigmasterol-3-O-glucoside (3). The three compounds exhibited significant cytotoxic activity against two human cell lines, breast (MCF7) and colon (HCT116), with IC50 values of 1.01, 1.54, and 2.15 microg/ml, respectively, against MCF7 and 3.49, 3.83, and 3.39 microg/ ml, respectively, against HCT116. Furthermore, in rats elevated levels of blood cholesterol, triglycerides, and low-density lipoprotein (LDLc) were significantly reduced, while the level of high-density lipoprotein (HDLc) was significantly increased by administration of the ethanolic extract as well as of 3. These results support a correlation between the reduction of blood cholesterol levels and improvement of colorectal cancer.

Screening for estrogenic and antiestrogenic activities of plants growing in Egypt and Thailand.

BACKGROUND: There is a growing demand for the discovery of new phytoestrogens to be used as a safe and effective hormonal replacement therapy. MATERIALS AND METHODS: The methanol extracts of 40 plants from the Egyptian and Thailand folk medicines were screened for their estrogen agonist and antagonist activities. The estrogenic and antiestrogenic effects of the tested extracts were carried out using the yeast two-hybrid assay system expressing ERα and ERß. In addition, all the extracts were subjected to a naringinase treatment and retested for their estrogenic activity. RESULTS: The methanol extracts of Derris reticulata and Dracaena lourieri showed the most potent estrogenic activity on both estrogen-receptor subtypes, while, the methanol extracts of Butea monosperma, Erythrina fusca, and Dalbergia candenatensis revealed significant estrogenic activity on ERß only. Nigella sativa, Sophora japonica, Artabotrys harmandii, and Clitorea hanceana showed estrogenic effect only after naringinase treatment. The most potent antiestrogenic effect was revealed by Aframomum melegueta, Dalbergia candenatensis, Dracena loureiri, and Mansonia gagei.

Inhibition of the dimerization and active site of HIV-1 protease by secondary metabolites from the Vietnamese mushroom Ganoderma colossum.

A new farnesyl hydroquinone, ganomycin I (1), was isolated along with ganomycin B (2) from the chloroform extract of the fruiting bodies of the Vietnamese mushroom Ganoderma colossum. These compounds inhibited HIV-1 protease with IC50 values of 7.5 and 1.0 microg/mL, respectively. Kinetic studies using Zhang-Poorman and Lineweaver plots revealed that compound 2 competitively inhibited the active site of the enzyme, whereas the tetracyclic triterpene schisanlactone A, previously isolated from the same fungus, was a dimerization inhibitor, with an IC50 value of 5.0 microg/mL. The previous findings were also confirmed by the virtual docking of both compounds with HIV-1 protease crystal structure.

Computer based design, synthesis and biological evaluation of novel indole derivatives as HCV NS3-4A serine protease inhibitors.

A series of novel indoles were designed and their molecular modeling simulation study including fitting to a 3D pharmacophore model using CATALYST program and their docking into the NS3 active site was examined as HCV NS3 protease inhibitor. Several compounds showed significant high simulation docking score and fit values. The designed compounds were synthesized and biologically evaluated in vitro using an NS3 protease binding assay, where compounds 10a-k showed significant inhibitory activity (> or =67% inhibition at 100 microg/mL). Of these, compounds 10c and 10f demonstrated potent HCV NS3 protease inhibitors with IC(50) values of 15 and 13 microM, respectively. Enantio-selective Michael addition of an indole derivative in the presence of catalytic amount of AlCl(3) and quinine at room temperature afforded the adduct 7e in excellent yield with 73% ee. The product was converted into 10l, which showed lower activity than the mixture of the corresponding diastereoisomers.

Anti-HIV-1 protease activity of lanostane triterpenes from the vietnamese mushroom Ganoderma colossum.

Four new lanostane triterpenes, colossolactone V (1), colossolactone VI (2), colossolactone VII (3), and colossolactone VIII (4), were isolated from the fruiting bodies of the Vietnamese mushroom Ganoderma colossum, together with the known compound colossolactone E (5). The structures of 1- 4 were assigned on the basis of spectroscopic evidence, and their absolute configurations were determined by CD spectroscopy and the Mosher ester method. Compounds 1- 5, as well as two previously isolated compounds [schisanlactone A (6) and colossolactone G (7)] from the same mushroom, were evaluated for inhibition of HIV-1 protease, with IC 50 values for the most potent compounds ranging from 5 to 13 microg/mL.

New lanostane triterpene lactones from the Vietnamese mushroom Ganoderma colossum (FR.) C. F. BAKER.

Four new lanostane triterpene lactones (colossolactone I, colossolactone II, colossolactone III and colossolactone IV) were isolated from the Vietnamese mushroom Ganoderma colossum (FR.) C. F. BAKER along with five known compounds. The structures of the new compounds were determined on the basis of MS, NMR and circular dichroism.