Ahmed Esmat

Chrysin alleviates acute doxorubicin cardiotoxicity in rats via suppression of oxidative stress, inflammation and apoptosis.

Doxorubicin (DOX) is one of the most effective chemotherapeutic drugs; however, its incidence of cardiotoxicity compromises its therapeutic index. Chrysin, a natural flavone, possesses multiple biological activities, such as antioxidant, anti-inflammatory and anti-cancer. The present study was designed to investigate whether chrysin could protect against DOX-induced acute cardiotoxicity; and if so, unravel the molecular mechanisms of this protective effect. Chrysin was administered to male albino rats once daily for 12 consecutive days at doses of 25 and 50mg/kg orally. DOX (15 mg/kg; i.p.) was administered on day 12. Chrysin pretreatment significantly protected against DOX-induced myocardial damage which was characterized by conduction abnormalities, increased serum creatine kinase isoenzyme-MB (CK-MB), and lactate dehydrogenase (LDH) and myofibrillar disarrangement. As indicators of oxidative stress, DOX caused significant glutathione depletion, lipid peroxidation and reduction in activities of antioxidant enzymes; catalase (CAT) and superoxide dismutase (SOD). Chrysin pretreatment significantly attenuated DOX-induced oxidative injury. Additionally, DOX provoked inflammatory responses by increasing the expressions of nuclear factor kappa-B (NF-κB), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and the levels of tumor necrosis factor-alpha (TNF-α) and nitric oxide while chrysin pretreatment significantly inhibited these inflammatory responses. Furthermore, DOX induced apoptotic tissue damage by increasing Bax and cytochrome c expressions and caspase-3 activity while decreasing the expression of Bcl-2. Chrysin pretreatment significantly ameliorated these apoptotic actions of DOX. Collectively, these findings indicate that chrysin possesses a potent protective effect against DOX-induced acute cardiotoxicity via suppressing oxidative stress, inflammation and apoptotic tissue damage.

Caffeic acid phenethyl ester synergistically enhances docetaxel and paclitaxel cytotoxicity in prostate cancer cells

Evidence is growing for the beneficial role of selective estrogen receptor modulators (SERM) in prostate diseases. Caffeic acid phenethyl ester (CAPE) is a promising component of propolis that possesses SERM activity. This study aimed at investigating the modulatory impact of CAPE on docetaxel (DOC) and paclitaxel (PTX) cytotoxicity in prostate cancer cells and exploring the possible underlying mechanisms for this chemomodulation. CAPE significantly increased DOC and PTX potency in PC‐3, DU‐145 and LNCaP prostate cancer cells. Combination index calculations showed synergistic interaction of CAPE/DOC and CAPE/PTX cotreatments in all the tested cell lines. Subsequent mechanistic studies in PC‐3 cells indicated that cyclin D1 and c‐myc were significantly reduced in the combined treatment groups with concurrent increase in p27kip. DNA‐ploidy analysis indicated a significant increase in the percentage of cells in pre‐G1 in CAPE/DOC and CAPE/PTX cotreatments. Decreased Bcl‐2/Bax ratio together with increased caspase‐3 activity and protein abundance were observed in the same groups. Estrogen receptor‐β (ER‐β) and its downstream tumor suppressor forkhead box O1 levels were significantly elevated in CAPE and combination groups compared to DOC or PTX‐alone. ER‐α and insulin‐like growth factor‐1 receptor protein abundance were reduced in the same groups. CAPE significantly reduced AKT, ERK and ER‐α (Ser‐167) phosphorylation in PC‐3 cells. CAPE‐induced inhibition of AKT phosphorylation was more prominent (1.7‐folds higher) in cells expressing ER‐α such as PC‐3 compared to LNCaP. In conclusion, CAPE enhances the antiproliferative and cytotoxic effects of DOC and PTX in prostate cancer cells. This can be, at least partly, attributed to CAPE augmentation of DOC and PTX proapoptotic effects in addition to CAPE‐induced alterations in ER‐α and ER‐β abundance.

Genistein improves 3-NPA-induced memory impairment in ovariectomized rats: impact of its antioxidant, anti-inflammatory and acetylcholinesterase modulatory properties.

Huntington’s disease (HD) is a progressive neurodegenerative disorder. The pre-motor symptomatic stages of the disease are commonly characterized by cognitive problems including memory loss. 3-Nitropropionic acid (3-NPA) is a mitochondrial toxin that produces selective lesions in the brain similar to that of HD and was proven to cause memory impairment in rodents. Phytoestrogens have well-established neuroprotective and memory enhancing effects with fewer side effects in comparison to estrogens. This study investigated the potential neuroprotective and memory enhancing effect of genistein (5, 10 and 20 mg/kg), a phytoestrogen, in ovariectomized rats challenged with 3-NPA (20 mg/kg). These potential effects were compared to those of 17β-estradiol (2.5 mg/kg). Systemic administration of 3-NPA for 4 consecutive days impaired locomotor activity, decreased retention latencies in the passive avoidance task, decreased striatal, cortical and hippocampal ATP levels, increased oxidative stress, acetylcholinesterase (AChE) activity, cycloxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions. Pretreatment with genistein and 17β-estradiol attenuated locomotor hypoactivity, increased retention latencies in the passive avoidance task, increased ATP levels, improved the oxidative stress profile, attenuated the increase in AChE activity and decreased the expression of COX-2 and iNOS. Overall, the higher genistein dose (20 mg/kg) was the most effective. In conclusion, this study suggests neuroprotective and memory enhancing effects for genistein in a rat model of HD. These effects might be attributed to its antioxidant, anti-inflammatory and cholinesterase inhibitory activities.

The effect of pomegranate fruit extract on testosterone-induced BPH in rats

Benign prostatic hyperplasia (BPH) affects many men after the age of 50 years. Inflammation and oxidative stress along with apoptotic changes are thought to play an important role in the pathology of BPH. Pomegranate contains a variety of polyphenolic compounds that have been studied in a medley of diseases for their anti‐oxidant, anti‐inflammatory and pro‐apoptotic properties. Therefore, this study examined the effect of Pomegranate Fruit Extract (PFE) on the development of BPH using a testosterone‐induced BPH model in rats.

Mechanistic clues to the protective effect of chrysin against doxorubicin-induced cardiomyopathy: Plausible roles of p53, MAPK and AKT pathways

Doxorubicin (DOX) is the mainstay chemotherapeutic agent against a variety of human neoplasmas. However, its clinical utility is limited by its marked cardiotoxicity. Chrysin, is a natural flavone which possesses antioxidant, anti-inflammatory and anti-cancer properties. The current study aimed to investigate the potential protective effect of chrysin against DOX-induced chronic cardiotoxicity and the underlying molecular mechanisms. Male Sprague-Dawley rats were treated with either DOX (5 mg/kg, once a week) and/or chrysin (50 mg/kg, four times a week) for four weeks. Chrysin prevented DOX-induced cardiomyopathy which was evident by conduction abnormalities, elevated serum CKMB and LDH and histopathological changes. Chrysin also ameliorated DOX-induced oxidative stress by decreasing lipid peroxidation and upregulating the antioxidant enzymes. Moreover, chrysin attenuated DOX-induced apoptosis via decreasing expression of p53, Bax, Puma, Noxa, cytochrome c and caspase-3 while increasing expression of Bcl-2. DOX induced activation of MAPK; p38 and JNK and increased expression of NF-κB. Meanwhile, DOX suppressed AKT pathway via decreasing expression of its upstream activator VEGF and increasing expression of PTEN. Conversely, chrysin effectively neutralised all these effects. Collectively, these findings indicate that chrysin effectively protected against DOX-induced cardiomyopathy via suppressing oxidative stress, p53-dependent apoptotic pathway, MAPK and NF-κB pathways while augmenting the VEGF/AKT pathway.

Anti-Inflammatory Activity of Pistacia khinjuk in Different Experimental Models: Isolation and Characterization of Its Flavonoids and Galloylated Sugars

The present study aimed at isolating and elucidating the structure of the main components of Pistacia khinjuk L. and exploring its potential anti-inflammatory effect in different experimental models. The extract was evaluated for anti-inflammatory activity by measuring paw volume in three experimental models. Then, prostaglandin E₂ (PGE₂) level, ear edema, tissue myeloperoxidase (MPO) activity, histopathology, nitric oxide (NO) level, and tumor necrosis factor-α (TNF-α) level were assessed. Seven phenolic compounds, mainly flavonoids and galloylated compounds, were isolated from the aqueous methanol extract: gallic acid (1), methyl gallate (2), quercetin-3-O-β-D-⁴C₁-galactopyranoside (hyperin) (3), myricetin-3-O-α-L-¹C₄-rhamnopyranoside (myricitrin) (4), 1,6-digalloyl-β-D-glucose (5), 1,4-digalloyl-β-D-glucopyranoside (6), and 2,3-di-O-galloyl-(α/β)-⁴C₁-glucopyranose (nilocitin) (7). The anti-inflammatory activity was evidenced by decreased carrageenan-induced rat paw edema and PGE₂ elevation. In the croton oil-induced ear edema model, MPO activity was significantly inhibited, and inflammatory histopathological changes were ameliorated. In the rat air pouch model, NO generation and TNF-α release were significantly inhibited. The isolation and nuclear magnetic resonance spectral data of compound 6 from the genus Pistacia are revealed for the first time. Also, P. khinjuk L. aqueous methanol extract possesses anti-inflammatory activity in several experimental models.

Metformin Attenuates Testosterone-Induced Prostatic Hyperplasia in Rats: A Pharmacological Perspective

Benign prostatic hyperplasia (BPH) is uncontrolled proliferation of prostate tissue. Metformin, a widely prescribed anti-diabetic agent, possesses anticancer activity through induction of apoptotic signaling and cell cycle arrest. This study aimed to investigate the protective effect of metformin against experimentally-induced BPH in rats. Treatment with 500 and 1000 mg/kg metformin orally for 14 days significantly inhibited testosterone-mediated increase in the prostate weight & prostate index (prostate weight/body weight [mg/g]) and attenuated the pathological alterations induced by testosterone. Mechanistically, metformin significantly protected against testosterone-induced elevation of estrogen receptor-α (ER-α) and decrease of estrogen receptor-β (ER-β) expression, with no significant effect of androgen receptor (AR) and 5α-reductase expression. It decreased mRNA expression of IGF-1 and IGF-1R and protein expression ratio of pAkt/total Akt induced by testosterone. Furthermore, it significantly ameliorated testosterone–induced reduction of mRNA expression Bax/Bcl-2 ratio, P21 and phosphatase and tensin homolog (PTEN) and AMPK [PT-172] activity. In conclusion, these findings elucidate the effectiveness of metformin in preventing testosterone-induced BPH in rats. These results could be attributed, at least partly, to its ability to enhance expression ratio of ER-β/ER-α, decrease IGF-1, IGF-1R and pAkt expressions, increase P21, PTEN, Bax/Bcl-2 expressions and activate AMPK with a subsequent inhibition of prostate proliferation.

Discovery of Potent VEGFR-2 Inhibitors based on Furopyrimidine and Thienopyrimidne Scaffolds as Cancer Targeting Agents

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. In this study, a series of novel furo[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine based-derivatives were designed and synthesized as VEGFR-2 inhibitors, in accordance to the structure activity relationship (SAR) studies of known type II VEGFR-2 inhibitors. The synthesized compounds were evaluated for their ability to in vitro inhibit VEGFR-2 kinase enzyme. Seven compounds (15b, 16c, 16e, 21a, 21b, 21c and 21e) demonstrated highly potent dose-related VEGFR-2 inhibition with IC50 values in nanomolar range, of which the thieno[2,3-d]pyrimidine based-derivatives (21b, 21c and 21e) exhibited IC50 values of 33.4, 47.0 and 21 nM respectively. Moreover, furo[2,3-d]pyrimidine-based derivative (15b) showed the strongest inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 99.5% inhibition at 10 μM concentration. Consistent with our in vitro findings, compounds (21b and 21e) orally administered at 5 and 10 mg/kg/day for 8 consecutive days demonstrated potent anticancer activity in Erhlich ascites carcinoma (EAC) solid tumor murine model. Such compounds blunted angiogenesis in EAC as evidenced by reduced percent microvessel via decreasing VEGFR-2 phosphorylation with subsequent induction of apoptotic machinery. Furthermore, Miles vascular permeability assay confirmed their antiangiogenic effects in vivo. Intriguingly, such compounds showed no obvious toxicity.

Anti-inflammatory sesquiterpenes from Costus speciosus rhizomes

ETHNOPHARMACOLOGICAL RELEVANCE Costus speciosus (Koen ex. Retz.) Sm. (crepe ginger, family Costaceae) is an ornamental plant used in traditional medicine for the treatment of inflammation, rheumatism, bronchitis, fever, headache, asthma, flatulence, constipation, helminthiasis, leprosy, skin diseases, hiccough, anemia, as well as burning sensation on urination. AIM OF THE STUDY The present study is designed to isolate and identify the active compounds from C. speciosus rhizomes and measure their anti-inflammatory activities. MATERIALS AND METHODS The n-hexane-CHCl3 soluble fraction of the MeOH extract of C. speciosus rhizomes has been subjected to a repeated column chromatography, including normal silica gel and RP-18 column to give eight compounds. The structures of these compounds were established by UV, IR, 1D ((1)H and (13)C), and 2D ((1)H-(1)H COSY, NOESY, HSQC, and HMBC) NMR experiments and HRESIMS data. In addition, the anti-inflammatory activity of compounds 1-8 was evaluated by measuring the levels IL-6, IL-1β, TNF-α, COX-2, lipoxgenase-5, and PGE2 using enzyme-linked immunosorbent assay. RESULTS The n-hexane-CHCl3 soluble fraction afforded a new eudesmane acid, specioic acid (8), along with seven known compounds, 22,23-dihydrospinasterone (1), dehydrodihydrocostus lactone (mokko lactone) (2), dehydrocostus lactone (3), stigmasterol (4), arbusculin A (5), santamarine (douglanin) (6), and reynosin (7). Compounds 1, 4, and 5-7 were isolated for the first time C. speciosus. Compounds 1-4 displayed potent anti-inflammatory activity, while 7 and 8 showed moderate activity. Compounds 1-8 exhibited a concentration-related decrease in the levels of IL-1β, IL-6, TNF-α, PGE2, lipoxgenase-5, and COX-2. Compounds 5 and 6 did not significantly decrease levels of different cytokines, PGE2, lipoxgenase-5, and COX-2 from PHA treatment at 1 µM. However, all tested compounds significantly decreased cytokines, PGE2, lipoxgenase-5, and COX-2 levels at concentration 100 µM. It is noteworthy that compounds 1-4 had the highest activity, where it lowered levels of cytokines, PGE2, lipoxgenase-5, and COX-2 to the extent that was no statistical difference from the control group. Thus, they decreased proinflammatory cytokines (IL-1β, IL-6, and TNF-α) with decreased level of the target enzymes (COX-2 and lipoxgenase-5) and subsequent reduction of its inflammatory product (PGE2). CONCLUSION Good anti-inflammatory activities exhibited of the isolated compounds from C. speciosus corroborate the usefulness of this plant in the traditional treatment of inflammation and related symptoms.

A Systemic Review on Aloe arborescens Pharmacological Profile: Biological Activities and Pilot Clinical Trials

Since ancient times, plants and herbal preparations have been used as medicine. Research carried out in the last few decades has verified several such claims. Aloe arborescens Miller, belonging to the Aloe genus (Family Asphodelaceae), is one of the main varieties of Aloe used worldwide. The popularity of the plant in traditional medicine for several ailments (antitumor, immunomodulatory, antiinflammatory, antiulcer, antimicrobial and antifungal activity) focused the investigators interest on this plant. Most importantly, the reported studies have shown the plant effectiveness on various cancer types such as liver, colon, duodenal, skin, pancreatic, intestinal, lung and kidney types. These multiple biological actions make Aloe an important resource for developing new natural therapies. However, the biological activities of isolated compounds such as glycoprotein, polysaccharides, enzyme and phenolics were insufficient. Considering all these, this contribution provides a systematic review outlining the evidence on the biological efficacy of the plant including the pharmacology and the related mechanisms of action, with specific attention to the various safety precautions, and preclinical and clinical studies, indicating the future research prospects of this plant. Copyright