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Colon cancer is the commonest cancer worldwide. α-Hederin is a monodesmosidic triterpenoid saponin possessing diverse pharmacological activities. The running experiment was designed to test the chemopreventive activity of α-hederin when used as an adjuvant to carboplatin in an experimental model of mouse colon hyperplasia induced by 1,2-dimethylhydrazine (DMH). Fifty male Swiss albino mice were classified into five groups: group (I): saline group, group (II): DMH-induced colon hyperplasia control group, group (III): DMH + carboplatin (5 mg/kg) group, group (IV): DMH + α-hederin (80 mg/kg) group, and group (V): DMH + carboplatin (5 mg/kg)+α-hederin (80 mg/kg) group. Analyzing of colonic tissue indicated that the disease control group showed higher colon levels of phospho-PI3K to total-PI3K, phospho-AKT to total-AKT and cyclin D1 concurrent with lower phospho-JNK/total JNK ratio and caspase 3. However, treatment with α-hederin, in combination with carboplatin, favorably ameliorated phosphorylation of PI3K/AKT/JNK proteins, increased colon caspase 3 and downregulated cyclin D1. Microscopically, α-hederin, in combination with carboplatin, produced the most reduction in the histologic hyperplasia score, enhanced the goblet cell survival in periodic acid Schiff staining and reduced proliferation (Ki-67 immunostaining) in the current colon hyperplasia model. Collectively, the current study highlighted for the first time that using α-hederin as an adjuvant to carboplatin enhanced its chemopreventive activity, improved JNK signaling and increased apoptosis. Hence, further studies are warranted to test α-hederin as a promising candidate with chemotherapeutic agents in treating colon cancer.

Vicia faba L. is a legume from the family Fabaceae. Ancient Egyptians consumed fava beans thousands of years ago and they are still one of the most popular foods in Egypt. The current study examined the anti-Parkinson effect of 80% methanolic extracts of seeds or sprouts of the fava ‘Sakha 3 ‘cultivar which has been selected based on the total phenol content among three cultivars tested. In addition, the extracts were characterized by reversed-phase high-performance liquid chromatography coupled with diode array detection and quadrupole-time-of-flight-mass spectrometry (RP-HPLC–DAD-QTOF-MS). Three doses (200, 400, and 600 mg/kg) of 80% methanol extracts of seeds or sprouts of the Sakha 3 cultivar were evaluated in rotenone–Parkinsonian mice from behavioral, biochemical, and histopathological aspects. The extract of fava sprouts (600 mg/kg dose) showed the most beneficial effect. It improved motor activity, enhanced striatal dopamine level, and decreased the striatal malondialdehyde, as well as the expression of the inflammatory markers, compared with the rotenone control group and groups receiving lower therapeutic doses of the extracts or l-Dopa. In addition, these findings were supported by a histopathological investigation which indicated that mice treated with the 600-mg/kg dose of the sprout extract showed a low number of degenerated neurons. The application of RP-HPLC–DAD-QTOF-MS and mass/mass spectroscopy enabled the metabolic profiling of the sprouts and seeds of the ‘Sakha 3′ cultivar. It is obvious that germination increased the amounts of phenolic acids, saponins, and aromatic amino acids, together with a dramatic increase in flavonoids. In conclusion, the 80% methanolic extract of sprouts of the fava “Sakha 3” cultivar may be a promising candidate for treating Parkinsonism if appropriate safety data are available.

In this study, the acid chlorides of pyrazolo[3,4-d]pyrimidine compounds were prepared and reacted with a number of nucleophiles. The novel compounds were experimentally tested via enzyme assay and they showed cyclooxygenase-2 inhibition activity in the middle micro molar range (4b had a COX-1 IC50 of 26 µM and a COX-2 IC50 of 34 µM, 3b had a COX-1 IC50 of 19 µM and a COX-2 IC50 of 31 µM, 3a had a COX-2 IC50 of 42 µM). These compounds were analyzed via docking and were predicted to interact with some of the COX-2 key residues. Our best hit, 4d (COX-1 IC50 of 28 µM, COX-2 IC50 of 23 µM), appears to adopt similar binding modes to the standard COX-2 inhibitor, celecoxib, proposing room for possible selectivity. Additionally, the resultant novel compounds were tested in several in vivo assays. Four compounds 3a (COX-2 IC50 of 42 µM), 3d, 4d and 4f were notable for their anti-inflammatory activity that was comparable to that of the clinically available COX-2 inhibitor celecoxib. Interestingly, they showed greater potency than the famous non-steroidal anti-inflammatory drug, Diclofenac sodium. In summary, these novel pyrazolo[3,4-d]pyrimidine analogues showed interesting anti-inflammatory activity and could act as a starting point for future drugs.

Objectives: The aim of this study was to prepare doxycycline polymeric nanoparticles (DOXY-PNPs) with hope to enhance its chemotherapeutic potential against solid Ehrlich carcinoma (SEC). Methods: Three DOXY-PNPs were formulated by nanoprecipitation method using hydroxypropyl methyl cellulose (HPMC) as a polymer. The prepared DOXY-PNPs were evaluated for the encapsulation efficiency (EE%), the drug loading capacity, particle size, zeta potential (ZP) and the in-vitro release for selection of the best formulation. PNP number 3 was selected for further biological testing based on the best pharmaceutical characters. PNP3 (5 and 10 mg/kg) was evaluated for the antitumor potential against SEC grown in female mice by measuring the tumor mass as well as the expression and immunohistochemical staining for the apoptosis markers, caspase 3 and BAX. Results: The biological study documented the greatest reduction in tumor mass in mice treated with PNP3. Importantly, treatment with 5 mg/kg of DOXY-PNPs produced a similar chemotherapeutic effect to that produced by 10 mg/kg of free DOXY. Further, a significant elevation in mRNA expression and immunostaining for caspase 3 and BAX was detected in mice group treated with DOXY-PNPs. Conclusions: The DOXY-PNPs showed greater antitumor potential against SEC grown in mice and greater values for Spearman&rsquo, s correlation coefficients were detected when correlation with tumor mass or apoptosis markers was examined, this is in comparison to free DOXY. Hence, DOXY-PNPs should be tested in other tumor types to further determine the utility of the current technique in preparing chemotherapeutic agents and enhancing their properties.

Rotenone is an insecticide that generates oxidative stress in the CNS and induces locomotor dysfunction and neurodegeneration in rodents. Biochanin A [BioA] is an isoflavone with antioxidant and anti-inflammatory actions. The antioxidant and the modulatory action of BioA on PI3K/Akt/mTOR signaling and autophagy were tested in rotenone-Parkinsonian mice. Mice were allocated into; Group I: oil control group, Group II: rotenone group [1-mg/kg/48h, subcutaneously], group III: rotenone and BioA [10-mg/kg]. Rotenone injection resulted in locomotor disturbances in mice, degeneration in dopaminergic neurons [tyrosine hydroxylase-immunoreactive cells], low striatal dopamine, increased malondialdehyde and decreased level of glutathione. Neuroinflammation was evidenced by upregulation of astrocytes [glia fibrillary acidic protein, GFAP] and elevated levels of cytokines. The phosphorylation of PI3K/Akt/mTOR and the autophagy-related protein, beclin-1, were decreased significantly as indicated by Western blot analysis. BioA treatment enhanced locomotor activity and afforded nigral neuroprotection. The mechanism by which BioA produced this effect includes increased antioxidant defenses, lessened proinflammatory cytokines, increased phosphorylation of PI3K/Akt/mTOR proteins and upregulated beclin-1. Importantly, BioA suppressed the striatal astrocyte marker [GFAP]. Overall, the currents study highlighted that BioA activates PI3K/Akt/mTOR signaling and enhances beclin-1 leading to neuroprotection for nigral dopaminergic neurons.

Vicia faba L. is a legume from the family Fabaceae. Ancient Egyptians consumed fava beans thousands of years ago and they are still one of the most popular foods in Egypt. The current study examined the anti-Parkinson effect of 80% methanolic extracts of seeds or sprouts of the fava 'Sakha 3 'cultivar which has been selected based on the total phenol content among three cultivars tested. In addition, the extracts were characterized by reversed-phase high-performance liquid chromatography coupled with diode array detection and quadrupole-time-of-flight-mass spectrometry (RP-HPLC-DAD-QTOF-MS). Three doses (200, 400, and 600 mg/kg) of 80% methanol extracts of seeds or sprouts of the Sakha 3 cultivar were evaluated in rotenone-Parkinsonian mice from behavioral, biochemical, and histopathological aspects. The extract of fava sprouts (600 mg/kg dose) showed the most beneficial effect. It improved motor activity, enhanced striatal dopamine level, and decreased the striatal malondialdehyde, as well as the expression of the inflammatory markers, compared with the rotenone control group and groups receiving lower therapeutic doses of the extracts or L-Dopa. In addition, these findings were supported by a histopathological investigation which indicated that mice treated with the 600-mg/kg dose of the sprout extract showed a low number of degenerated neurons. The application of RP-HPLC-DAD-QTOF-MS and mass/mass spectroscopy enabled the metabolic profiling of the sprouts and seeds of the 'Sakha 3' cultivar. It is obvious that germination increased the amounts of phenolic acids, saponins, and aromatic amino acids, together with a dramatic increase in flavonoids. In conclusion, the 80% methanolic extract of sprouts of the fava "Sakha 3" cultivar may be a promising candidate for treating Parkinsonism if appropriate safety data are available.

Doxorubicin (DXR) is a broad-spectrum anti-cancer. Doxorubicin irreversible toxicity resulting from oxidative damage limits its therapeutic use. Boswellic acids (BAs) are inhibitors of 5-lipoxygena...

Obesity is a public health burden disturbing all body functions and reproductive hormones. As obesity increases among females, there will be a rising challenge to physicians in care from fertility problems. Evening primrose oil (EPR oil) contains essential fatty acids including omega-6 linoleic acid with strong anti-inflammatory activity. Since EPR oil has utility in alleviating dysmenorrhea, this study aimed to ascertain its modulatory effect on systemic inflammation, reproductive hormones and estrus cycle irregularity in female obese rats. Thirty-two female rats were distributed to 4 groups: (i) normal, (ii) dietary obese-control female rats, and (iii and iv) dietary obese female rats treated with EPR oil (5 or 10 g/kg). Rats were examined for estrus regularity by taking vaginal smears daily during the last 2 weeks of the experiment. Serum level of insulin, leptin, adiponectin, and inflammatory cytokines was measured. In addition, serum lipid profile, and liver enzyme activities were estimated. Adipose tissues were taken for histopathologic examination as well as determination of gene expression for leptin, leptin receptors, adiponectin, and visfatin. Obese rats exhibited significant weight gain (90.69 ± 8.9), irregular prolonged estrus cycles (83.33%), increased serum levels of insulin, leptin, prolactin and testosterone and decreased gonadotropin levels. EPR oil exhibited a curative effect on obesity-related irregularity in estrus cycle and ovarian pathology. The underlying molecular mechanism may be related to reduction of systemic inflammation, alleviating insulin resistance and modulation of adipokine expression. EPR oil may be considered as a promising therapeutic intervention against obesity-related female hormonal disturbances and estrus irregularity.

Anti-epileptic medications are included in the international guidelines for managing neuropathic pain. Valproate sodium (VPS) was recently described as “the forgotten analgesic” and has been reported to relief pain in various models of neuropathic pain. Some studies reported anti-inflammatory and histone deacetylase 1 (HDA1) inhibitory properties for sodium valproate. The aim of the current study was to investigate the modulatory effect of VPS on pain behavior and inflammatory reactions in alloxan-induced diabetic neuropathy focusing on HDA1 inhibition and glia reactivity. 28 Male Swiss albino mice were allocated into four groups, (1) vehicle group, (2) alloxan-diabetic group, (3 & 4) alloxan+VPS (25 or 50 mg/kg) groups. VPS was given daily for 5 weeks by oral gavage. Pain behavior demonstrated increased allodynia (von-Frey filaments) and hyperalgesia (hot-plate test) in alloxan-diabetic mice that was reduced significantly by at least one of VPS doses. Sciatic nerves in diabetic mice showed increased histopathology score, increased silver staining for the nerves-indicating myelopathy- and a decrease in immunostaining for nerve growth factor. Spinal cord of diabetic mice showed greater histopathologic score, increased CD11b and glia fibrillary acidic protein (GFAP) immunostaining than vehicle treated mice. Molecular investigations highlighted greater content of spinal histone deacetylases, tumor necrosis factor-α (TNF-α) and interlukin-1β (IL1β) that were favorably modified by VPS. Overall, the current data confirmed that the pain killing and anti-inflammatory activity of VPS is at least partly mediated through inhibition of spinal HDA1 and glia reactivity. These findings support the view of inviting antiepileptics for treating neuropathies.

In this study, novel thiosemicarbazides and 1,3,4-oxadiazoles were synthesized and evaluated for their anticancer effects on human MCF-7 breast cancer cell lines. Among the synthesized derivatives studied, compound 2-(3-(4-chlorophenyl)-3-hydroxybutanoyl)-N-phenylhydrazinecarbothioamide 4c showed the highest cytotoxicity against MCF-7 breast cancer cells as it reduced cell viability to approximately 15% compared to approximately 25% in normal breast epithelial cells. Therefore, we focused on 4c for further investigations. Our data showed that 4c induced apoptosis in MCF-7 cells which was further confirmed by TUNEL assay. Western blotting analysis showed that compound 4c up-regulated the pro-survival proteins Bax, Bad and ERK1/2, while it down-regulated anti-apoptotic proteins Bcl-2, Akt and STAT-3. Additionally, 4c induced phosphorylation of SAPK/JNK in MCF-7 cells. Pretreatment of MCF-7 cells with 10 µM of JNK inhibitor significantly reduced 4c-induced apoptosis. Molecular docking results suggested that compound 4c showed a binding pattern close to the pattern observed in the structure of the lead fragment bound to JNK1. Collectively, the data of current study suggested that the thiosemicarbazide 4c might trigger apoptosis in human MCF-7 cells by targeting JNK signaling.

Small molecules that can target human cancers have been highly sought to increase the anticancer efficacy, the present work describes the design and synthesis of novel series of five quinuclidinone derivatives (2a-2e). Their anticancer activities were investigated against breast cancer cells MCF-7, MDA-MB-231 breast cancer cells harboring mutant p53 and normal breast counterpart MCF-12a. Derivative 2e reduced proliferation of MCF-7 and MCD-12a while it has no effect on MDA-MB-231. Derivative 2e induced apoptosis in MCF-7 cells which is further confirmed by TUNEL assay and it reduced the percentage of cell in G2/M phase as confirmed by increased expression of cyclin B and reduced expression of cyclinD1. Derivative 2e reduced expression levels of Mdm2, Akt and ERK1/2 by and increased expression level of p53. Moreover, the apoptosis induction by 2e was also inhibited by PFT-α as evidenced by non-significant induction of apoptosis after treatment of MCF-7 cells with both derivative 2e and PFT-α. In addition, docking study reveals that derivative 2e has a binding pattern close to the pattern observed in the structure of the lead fragment 5,6-dimethoxy-2-methylbenzothiazole bound to T-p53C-Y220C. The above findings demonstrate that derivative 2e induces apoptosis in MCF-7 cells via targeting p53 which merits further development.

In search of novel antiviral and anticancer agents with promising pharmacotoxicological profile, a study was initiated to synthesize new 2-thioxo-4-thiazolidinones as well as 2-phenylimino-4-thiazolidinones substituted with benzimidazole ring system. The compounds were screened primarily for their antiviral as well as anticancer activities. The synthesis of some novel 5-substituted thiazolidinones was also described. None of the tested compounds showed inhibitory activity against Hepatitis C virus replication. Two 2-phenylimino-4-thiazolidinone derivatives (9a and 10) exhibited significant antiproliferative activity against human colon carcinoma cell line HCT 116 and human hepatocellular carcinoma HEPG2 cell line, respectively. Results also indicated that six thiazolidinone derivatives (5a, 5d, 5e, 5f, 5h, and 9d) showed moderate antiproliferative activity against human breast adenocarcinoma cell line MCF7 in comparison to the standard drug Doxorubicin. Moreover, a docked pose of the most potent three cytotoxic compounds 5a, 5h, and 9d against MCF7 was obtained bound to Human N-acetyl transferase1 NAT1 binding pocket by molecular operating environment module.

Most of cancer chemotherapeutics and chemopreventives exert their effects by triggering apoptotic cell death. In this study, novel benzimidazole and benzothiazole derivatives have been synthesized to investigate their effects on HepG2 liver cancer cell lines after initial screening study. A dose response curve was constructed and the most active derivatives were further studied for apoptotic analysis. Six active benzimidazole derivatives (8, 9, 10, 12, 13 and 14) significantly induced apoptosis compared to control group. Two compounds 10 and 12 induced apoptosis by arresting cells in G1 phase of cell cycle which is confirmed by increased expression level of p21. The activity of caspase-3 which is well known as one of the key executioners of apoptosis was determined in the presence and absence of the tested derivatives. Our results indicated that compounds 10 and 12 significantly increased caspase-3 activity compared to control group. Moreover, a docked pose of compounds 10 and 12 was obtained bound to caspase-3 active site using Molecular Operating Environment module. This study demonstrated that benzimidazole derivatives 10 and 12 provoke cytotoxicity and induced apoptosis in liver cancer cells HepG2.

Novel benzimidazoles, benzothiazoles and benzofurans incorporating pyrazole moiety have been synthesized and screened for their antiangogenic activities, by testing their ability to inhibit human umbilical vein endothelial cell (HUVEC) proliferation, cord formation and migration in response to chemoattractant. 3 compounds 19, 23 and 26 showed antiangiogenic activities at non-cytotoxic concentrations. Compound 19 was the most active with chemotaxis activity data nearly comparable to that of the positive control, TNP-470. Compound 42 showed a significant cytotoxic effect on the tested cancer cell lines and less antiangiogenesis activity compared to compounds 19, 23 and 26. All the tested compounds, in contrary to TNP-470, interfered with the migratory function of HUVECs in response to vascular endothelial growth factor rather than the endothelial cells proliferation or cord formation. Moreover, a docked pose of compounds 19 and 26 was obtained bound to kinase insert domain receptor using Molecular Operating Environment module.

Intensive efforts are underway worldwide to develop anticancer and antimicrobial agents. Therefore, a novel series of pyrido[2,1-b]benzo [d]thiazole and 2-(benzo [d] thiazol-2-ylamino)pyrimidine derivatives was synthesized. The synthesized compounds were evaluated for their anticancer activity. Among the tested compounds, compounds 3a, 3b, and 7 exhibited more cytotoxic action than the control drug doxorubicin (CAS 23214-92-8; IC50: 52 microg/ml). Compound 7 was the most potent cytotoxic, with an IC50 of 42.55 pg/ ml, while compounds 3a and 3b induced high cytotoxic action with IC50 values of 50.15 pg/ml and 50.45 pg/ml, respectively. Moreover, the synthesized compounds were screened for their antibacterial and antifungal activities. Compound 6 exhibited moderate antifungal activity against C. albicans with a minimum inhibitory concentration of 125 pg/ml.

Pyrazole derivatives are well documented to possess anti-inflammatory activity but their effects on microglial activation are unknown. We determined the efficacy of the novel pyrazole compound 2-MBAPA (R/S-(±)-2-Methylbenzylamino 2-oxo-N-[4-cyano-1-phenyl-1H-pyrazol-5-yl] acetamide) on activated microglia under conditions relevant to inflammation in Alzheimer's disease (AD) brain. The compound at a non-toxic concentration inhibited secretion of tumor necrosis factor (TNF)-α by activated human microglia and attenuated toxicity of conditioned medium from activated human microglia towards human SH-SY5Y neuroblastoma cells in vitro. The 2-MBAPA neuroprotection was further demonstrated in vivo using an animal model of AD. The compound inhibited microgliosis, but not astrogliosis, in amyloid-β peptide (Aβ)(1-42)-injected rat brain. 2-MBAPA also diminished neuronal loss in the dentate gyrus caused by Aβ(1-42) injection. These results indicate that this novel pyrazole compound confers neuroprotection by inhibiting microglial activation. Therefore, further studies with 2-MBAPA and novel analogues based on this lead compound are warranted in an effort to develop new pharmacological agents that may be useful for slowing down progression of AD and other neuroinflammatory disorders associated with activated microglia.

Comparative acute toxicity studies of the latex and sequential extracts of Leptadenia pyrotechnica (Forsk.) Decne (Asclepiadaceae) were recorded using brine shrimp. The higher toxicities were exhibited in latex; methanol, methanol/dichloromethane (1:1), defatted methanol/dichloromethane (1:1), defatted methanol and dichloromethane extracts. The other extracts; aqueous, alkaloids, ethyl acetate and n-butanol exhibited less toxicities compared with the other extracts. The estimated LC50 and its 95% confidence limits for these extracts expressed in ppm were: methanol, latex 18.84 (11.22-31.61), methanol/dichloromethane 19.95 (7.76-53.70), defatted methanol/dichloromethane 21.38 (7.24-63.10), defatted methanol 28.19 (16.27-48.81) and dichloromethane 30.90 (11.75-79.43). The anti-tumor activities; potato disc assays of methanol, ethyl acetate and alkaloids extracts showed good activities as anti-tumor agent which represented-49.30,-43.20 an -33.60%, respectively. While latex and aqueous extract represented-30.80 and-28.17%, respectively.

Metformin is the most widely used antidiabetic drug for type II diabetes in the world. Recent studies provide clues that the use of metformin may be associated with reduced incidence and improved prognosis of certain cancers and there is increasing evidence of a potential efficacy of this agent as an anticancer drug. This observation led us to hypothesize that metformin might inhibit human breast cancer cells (MCF-7) growth. Here, we report that metformin induced apoptosis in human breast carcinoma cell lines MCF-7 cells via novel signaling pathway. Metformin induced apoptosis by arresting cells in G1 phase and reducing cyclin D level and increasing the expression of p21 and cyclin E. Molecular and cellular studies indicated that metformin significantly elevated p53 and Bax levels and reduced STAT3 and Bcl-2. Inhibitors of signaling proteins were used to study the mechanism(s) of metformin function. Receptor inhibitor studies indicated that p53 activation was mediated through insulin receptor (IR), not insulin-like growth factor-1 receptor (IGF-IR). Furthermore, MEK inhibitor significantly suppressed metformin-induced p53 and Bax elevation while ERK inhibitor generated a slight reduction in p53 levels. In contrast, PI3K inhibitor did not produce any effect on the metformin-elevated p53 levels. Finally, SAPK/JNK, known to be involved in apoptosis, was activated in cells treated with metformin and the activation appeared to occur downstream of ERK. All these results suggested that metformin activated p53, Bax, and induced tumor cell apoptosis through the ERK signaling pathway. This pathway has not been previously described for IR, p53, Bax activation, or apoptosis. Metformin, a novel inducer of apoptosis, and its analogs may offer a novel strategy for the treatment of cancer cells.

A novel dipyrazole ethandiamide compound and acid chloride of pyrazolo[3,4-d]pyrimidine 4(5H)-one were prepared and reacted with a number of nucleophiles. The resultant novel compounds were tested in several in vitro and in vivo assays. Three compounds inhibited the secretion of neurotoxins by human THP-1 monocytic cells at concentrations that were not toxic to these cells. They also partially inhibited both cyclooxygenase-1 and -2 isoforms. In animal studies, two compounds were notable for their anti-inflammatory activity that was comparable to that of the clinically available cyclooxygenase-2 inhibitor celecoxib. Modeling studies by using the molecular operating environment module showed comparable docking scores for the two enantiomers docked in the active site of cyclooxygenase-2.

GC-MS analysis of isolated alkaloids from aerial parts of Leptadenia pyrotechnica (Forsk.) Decne (Asclepiadaceae) was performed. Twenty-four alkaloids and six simple amines were detected for the first time in this plant. Almost all of the alkaloids belonged to pyridine, pyrrole, pyrazine, and indole types. The acute LC50 of the total alkaloids and alcohol extracts estimated by means of brine shrimp toxicity test were 63.09 and 11.89 ppm, respectively. The antitumor activities of these extracts, using potato disc screen, showed good activity represented by −33.6% and −49.3%, respectively.

Investigation of the chemical constituents of Leptadenia pyrotechnica (Forsk.) Decne (Asclepiadaceae) led to the isolation of three cardiac glycosides; 14,19-dihydroxycard-20 (22)-enolide-3-O-[β-d-glucopyranosyl-β-d-digitoxoside] C-I, 14,19-dihydroxycard-20 (22)-enolide-3-O-[β-d-glucopyranosyl-β-d-glucopyranoside] C-II and 14,19-dihydroxycard-20 (22)-enolide-3-O-β-d-digitoxoside C-III. The isolation and identification of these compounds were carried out using rotation locular counter current chromatography (RLCCC), high performance liquid chromatography (HPLC). The structures of the isolated compounds were established by fast-atom bombardment (FAB) and electrospray ionization (ESI) mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopic analysis. The acute toxicity studies of the cardiac glycosides and total alcohol extracts were examined by brine shrimp. Their lethal concentration 50 (LC50) were 18.84 and 11.89 ppm, respectively. The antitumor activity potato disk assays of the cardiac ...

An investigation of Leptadenia pyrotechnica (Forsk.) Decne (Asclepiadaceace) chemical constituents led to the isolation of six flavonoids, kaempferol-3-O-α- l-rhamnopyranosyl (1999→699)-O-β-d-glucopyranoside (E-I.1), kaempferol-3-O-β-d-rhamnopyranosyl (1999→699)-O-β-d-glucopyranoside (E-I.2), texasin-7-O-β-dglucopyranoside E-II.2, kaempferol-3-O-β-d-glucopyranoside (E-III.1), kaempferol (E-IV.1) and kaempferide3-O-α-l-rhamnopyranosyl (1999→699)-O-β-d-glucopyranoside (E-I.1a). The isolation of these compounds was carried out using Sephadex LH-20 low pressure liquid chromatography (LPLC), preparative paper chromatography (PC), and high performance liquid chromatography (HPLC). The chemical structures of the isolated compounds were established by mass spectrometry (FAB- and EI- techniques), nuclear magnetic resonance NMR ( 1 H-, 13 C- and COSY) spectral data and ultraviolet (UV) spectroscopic techniques. The acute toxicity of total alcoholic and total flavonoid extracts were examined by brine shrimp. The LC 50 values were 11.89 and 84.14 ppm for the total alcoholic and total flavonoid extracts, respectively. The mortality rates of the isolated flavonoid fractions of E-I, E-I.1, E-I.2 represent the higher percentages of mortality compared with the rest of the flavonoid fractions. The plant exhibited activity as an antitumor agent in the initial potato disc screen.

This work describes the synthesis of new series of compounds derived from methyl pyridyl- 2,4-dioxobutanoates that contain pyridine ring attached to substituted bioactive heterocyclic moieties in order to investigate their preliminary in vitro antibacterial and antifungal activities. The results revealed that most of the tested compounds exhibited significant activity against P. aeruginosa. and E. coli . They also displayed considerable activity against S. aureus and B. subtilis. On the other hand, the compounds displayed moderate antifungal activity.

A series of substituted pyridinylpyrazole (or isoxazole) derivatives were synthesized and evaluated for their anti-inflammatory (AI) activity using formalin-induced paw edema bioassays. Their inhibitory activities of cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) were also determined. The analgesic activity of the same compounds was evaluated using rat-tail withdrawal technique. Their antipyretic activity was also evaluated. The results revealed that compounds 4a,b, 6a, 8a, 14c and 15a exhibited significant AI and analgesic activities. Compounds 5a, 6a and 8a displayed good antipyretic activity. Compounds 14c and 15a showed good COX-2 inhibitory activity and weak inhibition of COX-1. Additionally, the most active compounds were shown to have a large safety margin (ALD 50 >300-400 mg / Kg) and minimal ulcerogenic potentialities when administered orally at a dose of 300 mg/Kg. Docking studies for 14c and 15a with COX-2 showed good binding profile. Antimicrobial evaluation proved that most of the compounds exhibited distinctive activity against the gram negative bacteria, P. aeruginosa and E coli.

Fungal spore populations in the outdoor and indoor atmosphere of Ismailia have been studied during the period from March 1992 to May 1993. A total of 23 350 cfu and 73 species were recorded,Cladosporium cladosporioides, Aureobasidium pullulans andAspergillus flavus were the most abundant. The indoor and outdoor mycoflora showed marked quantitative and qualitative differences. In view of count, recorded species could be categorized into three groups as follows: (a) species showing higher counts in out- than indoor, (b) species showing the opposite trend i.e. lower counts in out-door than indoor, (c) species showing approximately equal counts in out- and indoor. Regarding seasonal periodicity, March and either September or October showed the highest count for both normal fungal flora (NFF) and opportunistic fungal flora (OFF). While January and July showed the lowest count of them both, May but not July was the lowest as for outdoor NFF.

Calotropis procera (Ait.) R.Br. (Asclepiadaceae) is a shrub or small tree that grows wild in Egypt. Calotropis acts as a purgative, anthelmintic, anticoagulant, palliative (in problems with respiration, blood pressure), antipyretic, and analgesic, and induces neuromuscular blocking activity. Little research has been done to study the electrophysiological effects of this plant's extracts on cardiac, smooth, and skeletal muscle activities.The present study was conducted to determine the phytochemical composition and the effect of the total alcohol extract of the shoot of the plant, which contains almost all of C. procera's cardiac glycosides, flavonoids, and saponins. Also, this study attempted to throw more light on the electrophysiological effects of the plant extracts on cardiac, smooth, and skeletal muscle activities and to clarify the mechanism(s) of their observed action(s).The aerial parts of the plant were air dried and their ethanol extracts partitioned with successive solvents. Cardiac, smooth, and skeletal muscles were used in this study to investigate the physiological and pharmacological effects of the plant extracts from different solvents. The data were analyzed by paired t-test.The phytochemical investigation of Calotropis procera revealed the presence of cardenolides, flavonoids, and saponins. The effects of ethanol, n-butanol, and ethyl acetate (EtOAc) extracts were each evaluated on isolated toad heart and their mechanisms of action determined. Perfusion with 2 μg/mL ethanol, 0.2 μg/mL butanol, and 0.2 μg/mL EtOAc extracts caused a significant decrease in heart rate (bradycardia), significant increase in the force of ventricular contraction, and increase in T-wave amplitude. In addition, the effects of different extracts of the studied plant on smooth muscle and skeletal muscle were investigated in this study. The different extracts and latex of C. procera induced a negative chronotropic effect and decreased the heart rate (HR) of isolated toad heart. The different extracts increased the power of contraction of the duodenum (trace a). Pretreatment with atropine sulfate as a muscarinic receptor blocker abolished the stimulatory effect of the different plant extracts and latex of C. procera (trace b).The present data suggest that ethanol, butanol, and EtOAc extracts of Calotropis procera have negative chronotropism and positive inotropism. Verapamil could abolish the inotropic effect of ethanol as well as that of butanol and EtOAc extracts. Meanwhile, atropine did not abolish the observed negative chronotropic effect. The ethanol extract increased the power of contraction of rabbit duodenum, but atropine abolished this effect. It also decreased the skeletal muscle contraction; this effect could be through blocking of the nicotinic receptors. Butanol and EtOAc extract data for smooth and skeletal muscles are very close to those for the corresponding ethanol extract of the studied plant. The present data for C. procera indicate its direct action on the myocardium, its increase of smooth muscle motility, and its relaxation of skeletal muscle contraction. The chemical constituents could directly affect the cell membrane probably through receptors coupling to G proteins. They regulate the ion channel physiology as in the myocardium.The present data on the extracts of C. procera indicate a direct action on the myocardium, stimulatory effect on smooth muscle motility, and relaxant action on skeletal muscle contraction. Chemical constituents could directly affect the cell membrane probably through receptors coupling to G proteins. They regulate the ion channel physiology as in the myocardium.

Novel pyrazolyl-2,4-thiazolidinediones were prepared via the reaction of appropriate pyrazolecarboxaldehydes with 2,4-thiazolidinediones and substituted benzyl-2,4-thiazolidinediones. The resultant compounds were first evaluated for their anti-inflammatory and neuroprotective properties in vitro. The active compounds were further studied in vivo by using the formalin-induced paw edema and the turpentine oil-induced granuloma pouch bioassays. We identified four novel compounds that showed protective effects in vitro at non-toxic concentrations, and were also effective in the animal models of acute and sub-acute inflammation.

Clusters of microcalcifications in mammograms are an important early sign of breast cancer in women. In this paper an approach is proposed to develop a computer-aided diagnosis (CAD) system that can be very helpful for radiologist in diagnosing microcalcifications' patterns in digitized mammograms earlier and faster than typical screening programs. The proposed method has been implemented in three stages: (a) the region of interest (ROI) selection of 32times32 pixels size which identifies clusters of microcalcifications, (b) the feature extraction stage is based on the wavelet decomposition of locally processed image (region of interest) to compute the important features of each cluster and (c) the classification stage, which classify between normal and microcalcifications' patterns and then classify between benign and malignant microcalcifications. In classification stage, four methods were used, the voting K-nearest neighbor classifier (K-NN), support vector machine (SVM) classifier, neural network (NN) classifier, and fuzzy classifier. The proposed method was evaluated using the Mammographic Image Analysis Society (MIAS) mammographic databases. The proposed system was shown to have the large potential for microcalcifications detection in digital mammograms.

We propose a novel data acquisition and image reconstruction method for parallel magnetic resonance imaging (MRI). The proposed method improves the GRAPPA (Generalized Auto-calibrating Partially Parallel Acquisitions) method by simultaneously collecting data using the body coil in addition to localized surface coils. The body coil data is included in the GRAPPA reconstruction as an additional coil. The reconstructed body coil image shows greater uniformity over the field of view than the conventional sum-of-squares reconstruction that is conventionally used with GRAPPA. The body coil image can also be used to correct for spatial inhomogeneity in the sum-of-squares image. The proposed method is tested using numerical and real MRI phantom data.

Prepulse inhibition (PPI) of acoustic startle response is a valuable paradigm for sensorimotor gating processes. Previous research showed that acute administration of St. John's wort extract (500 mg/kg, p.o.) to rats caused significant disruption of PPI while elevating monoamines levels in some brain areas. The cause-effect relationship between extract-induced PPI disruption and augmented monoaminergic transmission was studied using different serotoninergic, adrenergic and dopaminergic antagonists. The effects of hypericin and hyperforin, as the main active constituents of the extract, on PPI response were also tested. PPI disruption was prevented after blocking the serotoninergic 5-HT1A and 5-HT2A, alpha-adrenergic and dopaminergic D1 receptors. Results also demonstrated a significant PPI deficit after acute treatment of rats with hyperforin, and not hypericin. In some conditions manifesting disrupted PPI response, apoptosis coexists. Electrophoresis of DNA isolated from brains of hyperforin-treated animals revealed absence of any abnormal DNA fragmentation patterns. It is concluded that serotoninergic 5-HT1A and 5-HT2A, alpha-adrenergic and dopaminergic D1 receptors are involved in the disruptive effect of St. John's wort extract on PPI response in rats. We can also conclude that hyperforin, and not hypericin, is one of the active ingredients responsible for St. John's wort-induced PPI disruption with no relation to apoptotic processes.

Ethnopharmacological relevance St. John's wort extract is commonly used as a wound healing, anti-inflammatory, anxiolytic, diuretic, antibiotic, antiviral and cancer chemoprotective agent. It also has nootropic and/or antiamnestic effects. Aim of the study Prepulse inhibition (PPI) of startle response is a valuable paradigm for sensorimotor gating processes. A previous study indicated that single administration of St. John's wort extract (500 mg/kg) caused PPI disruption in rats. The effect of antiamnestic doses of the extract on PPI has not been investigated despite the coexistence of impaired memory and PPI deficit in some neurological disorders. Materials and methods The effects of acute (500 mg/kg) and chronic (200 mg/kg for 3 days) administration of St. John's wort extract were investigated for its antiamnestic activity. The effects of administration of the antiamnestic dose of the extract and hyperforin, its main active component, were tested on PPI of an acoustic startle response in rats. This study also investigated the proapoptotic effect of hyperforin in animals, demonstrating PPI deficit, by electrophoresis of DNA isolated from selected brain areas. Results Disruption of PPI resulted after treatment of rats with an antiamnestic dose of the extract (200 mg/kg for 3 days) and with hyperforin. Gel electrophoresis showed DNA fragmentation of the cortices of hyperforin-treated animals exhibiting PPI deficit. Conclusions The exacerbating effect of St. John's wort extract on PPI deficit may provide a limitation for using the extract to manage cognitive disturbance in psychotic and Huntington's disease patients manifesting PPI deficit.

A number of benzothiazole derivatives of 2-aminopyrimidines (3a-b, 5, 6a-b, and 7), benzothiazole-3-arylacrylonitriles (10a-c), and benzothiazol-2-yl-coumarins (18a c, and 20) were synthesized by reacting benzothiazole derivatives with dicarbonyl compounds, and aromatic aldehydes. The unexpected 2-(4-methoxyphenyl)benzo[d]thiazole (14) was obtained as a unique product via the reaction of 2-aminothiophenol with ethyl 3-(4-methoxyphenyl)-2-scyanoacrylate. 2-(Benzo[d]thiazol-2-yl)-3-(4-hydroxyphenyl)acrylonitrile (lOa) exhibited activity against Staphylococcus aureus. 2-(Benzo[d]thiazol-2-ylamino)pyrimidine-4,6-(1H,5H)-dione (3b) showed antibacterial activity selectivity against Corynebacterium xerosis. 2-(Benzo[d]thiazol-2-ylamino)-6-methylpyrimidin-4(3H)-one (5) showed weak anti-fungal activity against Candida albicans.

This study was designed to investigate the effect of chirality on the allosteric activity of a series of Hb allosteric modifiers. The chiral analogues were based on the lead compound (4), JP7, [1-[4-(((3,5-dimethylanilino)carbonyl)methyl)phenoxy]cyclopentanecarboxylic acid] with different D- and L-amino acids conjugated to the JP7 acid moiety. The D-isomers were the most potent in vitro effectors in Hb solutions as well as with whole blood. In general, this study demonstrated that the chirality of extended amino acid side chains in JP7 conjugates plays an important role in observed degree of allosteric activity. The binding site interactions for four analogues were determined by single crystallographic diffraction studies. Conclusions show that the chiral configuration of some of the D-isomers enable the effectors to bind with a greater number of interactions with the protein residues. D- and L-isomers with equivalent or near equivalent allosteric activity did not show any significant differences or interactions between their amino acid side chains and the protein. The most potent effectors, in vitro, were compounds 15 and 19, D-isomers of leucine and phenylalanine, respectively. Compounds 21, 22, 30, and32 were more potent in vitro in Hb solutions than JP7.

The adsorption of nitrogen at 78°K and 195°K, as well as adsorption of carbon dioxide at 78°K, 273°K and 298°K was measured on non-activated and activated Beda lignitous coals. The original lignite sample was thermally heated at 400°, 500°, 600° and 800°. The sample was activated either with 10 and 25 per cent zinc chloride or with steam to burn-outs of 10 and 25 per cent. Zinc chloride activation increases the adsorption capacity and micropore volume but does not affect the pore size. Steam activation on the other hand, produces the same effect as zinc chloride activation in its initial stages and at a certain stage, gasification with steam also widens the already existing pores altering thus the porous structure of the material.

The specific surface areas of two sub-bituminous coking coals and their carbonization products have been evaluated from the adsorption isotherms of methanol, benzene, cyclohexane and nitrogen. The specific surface area increases with carbonization temperature and reaches a maximum at about 600°C. Cokes prepared at temperatures above 800°C possess much lower surface areas due probably to sealing off of the micropore system. The coals and cokes exhibit molecular sieve effect, the specific surface area calculated from the adsorption data of methanol being much higher than the area derived from the adsorption of benzene and cyclohexane, except for cokes prepared above 900°C. The adsorption of nitrogen is an activated diffusion process. Zinc chloride activation produces cokes of much greater specific surface area.