Comprehensive overview of how to fade into succinate dehydrogenase dysregulation in cancer cells by naringenin-loaded chitosan nanoparticles.

Mitochondrial respiration complexes play a crucial function. As a result, dysfunction or change is intimately associated with many different diseases, among them cancer. The epigenetic, evolutionary, and metabolic effects of mitochondrial complex IΙ are the primary concerns of our review. Provides novel insight into the vital role of naringenin (NAR) as an intriguing flavonoid phytochemical in cancer treatment. NAR is a significant phytochemical that is a member of the flavanone group of polyphenols and is mostly present in citrus fruits, such as grapefruits, as well as other fruits and vegetables, like tomatoes and cherries, as well as foods produced from medicinal herbs. The evidence that is now available indicates that NAR, an herbal remedy, has significant pharmacological qualities and anti-cancer effects. Through a variety of mechanisms, including the induction of apoptosis, cell cycle arrest, restriction of angiogenesis, and modulation of several signaling pathways, NAR prevents the growth of cancer. However, the hydrophobic and crystalline structure of NAR is primarily responsible for its instability, limited oral bioavailability, and water solubility. Furthermore, there is no targeting and a high rate of breakdown in an acidic environment. These shortcomings are barriers to its efficient medical application. Improvement targeting NAR to mitochondrial complex ΙΙ by loading it on chitosan nanoparticles is a promising strategy.

Synthesis and Anti-Breast Cancer Potency of Mono- and Bis-(pyrazolyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine) Derivatives as EGFR/CDK-2 Target Inhibitors.

The target mono- and bis-(6-pyrazolyltriazolo-thiadiazine) derivatives 4a-c and 6a-d were synthesized using a straightforward protocol via reaction of 3-bromoacetylpyrazole 2 with 4-amino-s-triazole-3-thiols 3a-c and bis(4-amino-5-mercapto-s-triazol-3-yl)alkanes 5a-d, respectively. The bis(6-pyrazolyl-s-triazolo[3,4-b][1,3,4]thiadiazine) derivatives 8a,b and 10 were also constructed by reaction of the triazolo[3,4-b][1,3,4]thiadiazine-3-thiol 4c with the proper dibromo compounds 7a,b and 9, respectively. Structures of the new substances were determined by spectroscopic and analytical data. Compounds 4b, 4c, and 6a showed potent cytotoxicity against MCF-7 (IC50 = 3.16, 2.74, and 0.39 µM, respectively) and were safe against the MCF-10A cells. Compounds 4b, 4c, and 6a also showed promising dual EGFR and CDK-2 inhibition activities, particularly 6a was the most effective (IC50 = 19.6 and 87.9 nM, respectively), better than Erlotinib and Roscovitine. Compound 6a treatment induced EGFR and CDK-2 enzyme inhibition by 97.18% and 94.11%, respectively, at 10 µM (the highest concentration). Compound 6a notably induced cell apoptosis in MCF-7 cells, increasing the cell population by total apoptosis 43.3% compared to 1.29% for the untreated control group, increasing the cell population at the S-phase by 39.2% compared to 18.6% (control).

Synthesis of novel mono- and bis-pyrazolylthiazole derivatives as anti-liver cancer agents through EGFR/HER2 target inhibition.

3-Bromoacetyl-4-(2-naphthoyl)-1-phenyl-1H-pyrazole (6) was synthesized from 2-acetylnaphthalene and was used as a new key building block for constructing the title targets. Thus, the reaction of 6 with the thiosemicarbazones 7a-d and 9-11 afforded the corresponding simple naphthoyl-(3-pyrazolyl)thiazole hybrids 8a-d and 12 ~ 14. The symmetric bis-(2-naphthoyl-pyrazol-3-yl)thiazol-2-yl)hydrazono)methyl)phenoxy)alkanes 18a-c and 21a-c were similarly synthesized from reaction of 6 with the appropriate bis-thiosemicarbazones 17a-c and 19a-c, respectively. The synthesized two series of simple and symmetrical bis-molecular hybrid merging naphthalene, thiazole, and pyrazole were evaluated for their cytotoxicity. Compounds 18b,c and 21a showed the most potent cytotoxicity (IC50 = 0.97-3.57 µM) compared to Lapatinib (IC50 = 7.45 µM). Additionally, they were safe (non-cytotoxic) against the THLE2 cells with higher IC50 values. Compounds 18c exhibited promising EGFR and HER-2 inhibitory activities with IC50 = 4.98 and 9.85 nM, respectively, compared to Lapatinib (IC50 = 6.1 and 17.2 nM). Apoptosis investigation revealed that 18c significantly activated apoptotic cell death in HepG2 cells, increasing the death rate by 63.6-fold and arresting cell proliferation at the S-phase. Compound 18c upregulated P53 by 8.6-fold, Bax by 8.9-fold, caspase-3,8,9 by 9, 2.3, and 7.6-fold, while it inhibited the Bcl-2 expression by 0.34-fold. Thereby, compound 18c exhibited promising cytotoxicity against EGFR/HER2 inhibition against liver cancer.

Synthesis and Evaluation of Thioamide and Bromo Derivatives of 1,3-Diphenylpropane-1,3-dione as 5α-Reductase Inhibitors.

BACKGROUND: 1,3-Diphenylpropane-1,3-dione (1) is an acetylacetone ß-diketone in which both of the methyl groups have been replaced with phenyl groups. It is a component of licorice root extract (Glycyrrhiza glabra) and has anti-mutagenic and anti-cancer properties. It functions as a metabolite, an anti-mutagen, and an anti-neoplastic agent. It is an aromatic ketone and a ß-diketone. 1,3-Diphenylpropane-1,3-dione (1) is primarily used in PVC hard and soft materials, including plates, films, profiles, pipes, and fittings. OBJECTIVES: This research aims to examine the utility of 1,3-diphenylpropane-1,3-dione (1) for the synthesis of a variety of new heterocyclic compounds, such as thioamide, thiazolidine, thiophene-2-carbonitrile, phenylthiazole, thiadiazole-2-carboxylate, 1,3,4-thiadiazole derivatives, 2-bromo-1,3-diphenylpropane-1,3-dione, new substituted benzo[1,4]thiazines, phenylquinoxalines, and imidazo[1,2-b][1,2,4]triazole derivatives of potential biological activity Methods: 1,3-Diphenylpropane-1,3-dione (1) was used as a starting compound for the synthesis of 3-oxo-N,3-diphenyl-2-(phenylcarbonyl)propanethioamide (3) and 2-bromo-1,3-diphenylpropane-1,3-dione (25), which can be used for further preparations. The 5α-reductase inhibitor activity of some of the synthesized compounds was also tested in vivo; the ED50 and LD50 data were established, Results: Using IR, 1H-NMR, mass spectroscopy, and elemental analysis, the structures of all produced compounds were elucidated. Some of these prepared compounds were reported as 5α-reductase inhibitors. CONCLUSION: New heterocyclic compounds can be formed via 1,3-diphenylpropane-1,3-dione (1), and some of these compounds can act as 5α-reductase inhibitors.

Impairment of electron transport chain and induction of apoptosis by chrysin nanoparticles targeting succinate-ubiquinone oxidoreductase in pancreatic and lung cancer cells.

BACKGROUND: Flavonoids may help ameliorate the incidence of the major causes of tumor-related mortality, such as pancreatic ductal adenocarcinoma (PDAC) and lung cancer, which are predicted to steadily increase between 2020 to 2030. Here we compared the effect of chrysin and chrysin nanoparticles (CCNPs) with 5-fluorouracil (5-FLU) on the activity and expression of mitochondrial complex II (CII) to induce apoptosis in pancreatic (PANC-1) and lung (A549) cancer cells. METHODS: Chrysin nanoparticles (CCNPs) were synthesized and characterized, and the IC50 was evaluated in normal, PANC-1, and A549 cell lines using the MTT assay. The effect of chrysin and CCNPs on CΙΙ activity, superoxide dismutase activity, and mitochondria swelling were evaluated. Apoptosis was assessed using flow cytometry, and expression of the C and D subunits of SDH, sirtuin-3 (SIRT-3), and hypoxia-inducible factor (HIF-1α) was evaluated using RT-qPCR. RESULTS: The IC50 of CII subunit C and D binding to chrysin was determined and used to evaluate the effectiveness of treatment on the activity of SDH with ubiquinone oxidoreductase. Enzyme activity was significantly decreased (chrysin < CCNPs < 5-FLU and CCNPs < chrysin < 5-FLU, respectively), which was confirmed by the significant decrease of expression of SDH C and D, SIRT-3, and HIF-1α mRNA (CCNPs < chrysin < 5-FLU). There was also a significant increase in the apoptotic effects (CCNPs > chrysin > 5-FLU) in both PANC-1 and A549 cells and a significant increase in mitochondria swelling (CCNPs < chrysin < 5-FLU and CCNPs > chrysin > 5-FLU, respectively) than that in non-cancerous cells. CONCLUSION: Treatment with CCNPs improved the effect of chrysin on succinate-ubiquinone oxidoreductase activity and expression and therefore has the potential as a more efficient formulation than chemotherapy to prevent metastasis and angiogenesis by targeting HIF-1α in PDAC and lung cancer.

Therapeutic potential of chrysin nanoparticle-mediation inhibition of succinate dehydrogenase and ubiquinone oxidoreductase in pancreatic and lung adenocarcinoma.

Pancreatic adenocarcinoma (PDAC) and lung cancer are expected to represent the most common cancer types worldwide until 2030. Under typical conditions, mitochondria provide the bulk of the energy needed to sustain cell life. For that inhibition of mitochondrial complex ΙΙ (CΙΙ) and ubiquinone oxidoreductase with natural treatments may represent a promising cancer treatment option. A naturally occurring flavonoid with biological anti-cancer effects is chyrsin. Due to their improved bioavailability, penetrative power, and efficacy, chitosan-chrysin nano-formulations (CCNPs) are being used in medicine with increasing frequency. Chitosan (cs) is also regarded as a highly versatile and adaptable polymer. The cationic properties of Cs, together with its biodegradability, high adsorption capacity, biocompatibility, effect on permeability, ability to form films, and adhesive properties, are advantages. In addition, Cs is thought to be both safe and economical. CCNPs may indeed be therapeutic candidates in the treatment of pancreatic adenocarcinoma (PDAC) and lung cancer by blocking succinate ubiquinone oxidoreductase.

Design and synthesis of new bis(1,2,4-triazolo[3,4-b][1,3,4]thiadiazines) and bis((quinoxalin-2-yl)phenoxy)alkanes as anti-breast cancer agents through dual PARP-1 and EGFR targets inhibition.

A number of new 1,ω-bis((acetylphenoxy)acetamide)alkanes 5a-f were prepared then their bromination using NBS furnished the novel bis(2-bromoacetyl)phenoxy)acetamides 6a-f. Reaction of 6a-f with 4-amino-5-substituted-4H-1,2,4-triazole-3-thiol 7a-d and with o-phenylenediamine derivatives 9a and b afforded the corresponding bis(1,2,4-triazolo[3,4-b][1,3,4]thiadiazine) derivatives 8a-l and bis(quinoxaline) derivatives 10a-e in good yields. The cytotoxicity of the synthesized compounds as well as apoptosis induction through PARP-1 and EGFR as molecular targets was evaluated. Three compounds, 8d, 8i and 8l, exhibited much better cytotoxic activities against MDA-MB-231 than the drug Erlotinib. Interestingly, compound 8i induced apoptosis in MDA-MB-231 cells by 38-fold compared to the control arresting the cell cycle at the G2/M phase, and its treatment upregulated P53, Bax, caspase-3, caspase-8, and caspase-9 gene levels, while it downregulated the Bcl2 level. Compound 8i exhibited promising dual enzyme inhibition of PARP-1 (IC50 = 1.37 nM) compared to Olaparib (IC50 = 1.49 nM), and EGFR (IC50 = 64.65 nM) compared to Erlotinib (IC50 = 80 nM). These results agreed with the molecular docking studies that highlighted the binding disposition of compound 8i inside the PARP-1 and EGFR protein active sites. Hence, compound 8i may serve as a potential anti-breast cancer agent.

Antiviral activity of chitosan nanoparticles encapsulating silymarin (Sil-CNPs) against SARS-CoV-2 (in silico and in vitro study).

To develop a specific treatment against COVID-19, we investigated silymarin-chitosan nanoparticles (Sil-CNPs) as an antiviral agent against SARS-CoV-2 using in silico and in vitro approaches. Docking of Sil and CNPs was carried out against SARS-CoV-2 spike protein using AutoDock Vina. CNPs and Sil-CNPs were prepared by the ionic gelation method and characterized by TEM, FT-IR, zeta analysis, and the membrane diffusion method to determine the drug release profile. Cytotoxicity was tested on both Vero and Vero E6 cell lines using the MTT assay. Minimum binding energies with spike protein and ACE2 were -6.6, and -8.0 kcal mol-1 for CNPs, and -8.9, and -9.7 kcal mol-1 for Sil, respectively, compared to -6.6 and -8.4 kcal mol-1 respectively for remdesivir (RMV). CNPs and Sil-CNPs were prepared at sizes of 29 nm and 82 nm. The CC50 was 135, 35, and 110 µg mL-1 for CNPs, Sil, and Sil-CNPs, respectively, on Vero E6. The IC50 was determined at concentrations of 0.9, 12 and 0.8 µg mL-1 in virucidal/replication assays for CNPs, Sil, and Sil-CNPs respectively using crystal violet. These results indicate antiviral activity of Sil-CNPs against SARS-CoV-2.

Study of the inhibitory effects of chrysin and its nanoparticles on mitochondrial complex II subunit activities in normal mouse liver and human fibroblasts.

BACKGROUND: Mitochondrial complex ΙΙ has a unique biological role owing to its participation in both the citric acid cycle and the electron transport chain. Our goal was to evaluate the succinate dehydrogenase and ubiquinone oxidoreductase activity of mitochondrial complex II in the presence of chrysin and chrysin-chitosan nanoparticles. Chrysin chitosan nanoparticles were synthesized and characterized using ultraviolet spectroscopy, Fourier transform-infrared spectroscopy, X-ray diffraction, transmission electron microscopy, scanning electron microscopy, drug release, and zeta potential. The binding affinity of chrysin to complex II subunits was assessed by molecular docking. The IC50 values were measured in a suspension of mouse mitochondria, and the inhibitory effect of chrysin and chrysin chitosan nanoparticles on mitochondrial complex ΙΙ was determined. RESULTS: The free energy of binding between chrysin and complex ΙΙ subunits A, B, C, and D was -4.9, -5, -8.2, and -8.4 kcal/mol, respectively. The characteristic peak of chrysin was confirmed at 348 nm. The chrysin chitosan nanoparticles contained characteristic bands of both chrysin and chitosan. The crystalline nature of chrysin chitosan nanoparticles was confirmed by X-ray powder diffraction measurements showing the characteristic Bragg peaks of (11.2°), (32.2°), (19.6°), (27.6°), and (31.96°). Transmission and scanning electron microscopy revealed their spherical shape and an average particle size of 49.7 ± 3.02 nm. Chrysin chitosan nanoparticles showed a burst release within the initial 2 h followed by a steady release at 8 h. Their zeta potential was positive, between +35.5 and +80 mV. The IC50 of chrysin, chitosan nanoparticles, chrysin chitosan nanoparticles, and 5-fluorouracil was 34.66, 184.1, 12.2, and 0.05 µg/mL, respectively, in adult mice liver and 129, 311, 156, and 8.07 µg/mL, respectively, in normal human fibroblasts. When comparing the inhibitory effects on complex ΙΙ activity, application of the IC50 of chrysin, chitosan nanoparticles, chrysin chitosan nanoparticles, and 5-fluorouracil resulted in 40.14%, 90.9%, 86.7%, and 89% decreases in SDH activity and 70.09%, 86.74%, 60.8%, and 80.23% decreases in ubiquinone oxidoreductase activity in normal adult mice, but 80.9%, 89.06%, and 90% significant decreases in SDH activity, and 90%, 85%, and 95% decreases in ubiquinone reductase after treatment with chrysin, chrysin chitosan nanoparticles, and 5-fluorouracil, in normal human fibroblasts, respectively. CONCLUSIONS: Chrysin and CCNPs exhibit potent inhibitory effects on SDH activity ubiquinone oxidoreductase activity.

Design and characterization of PANI/starch/Fe2O3 bio composite for wastewater remediation.

A new synthesized polyaniline/starch/hematite bio composite (PANI/S/Fe2O3 BC) has been studied as an effective material for on-site water remediation. PANI/S/Fe2O3 BC was developed by combining the techniques of co-precipitation and interfacial polymerization in the presence of aqueous starch solution in an acidic medium under ultrasonic irradiation. The nano-morphologies and structures of the designed PANI/S/Fe2O3 BC were evaluated by various techniques relative to PANI and Fe2O3 nanoparticles. In single and multiple systems, PANI/S/Fe2O3 BC was evaluated as a possible adsorbent for different heavy metals, including As3+, Zn2+, and Co2+, relative to PANI and Fe2O3 nanoparticles. In terms of pH value, operating temperature, initial heavy metal concentration, contact time, adsorbent dose and competitive ions in the solutions, the adsorption process was optimized. For 92% overall adsorption of Co2+ and 100% overall adsorption of both As3+ and Zn2+, the adsorption equilibrium was achieved within 60 and 120 min, respectively. In addition, adsorption thermodynamic analysis shows that the As3+ ions adsorption process was not random and the pseudo-second-order fitted with experimental results. Moreover, PANI/S/Fe2O3 BC was evaluated as an antibacterial agent against Gram-negative bacteria (Salmonella typhimurium) and Gram-positive bacteria (S. aureus, Methicillin-Resistant Staphylococcus, Aureus Clinical isolate and Bacillus subtilis). The reported performances indicated that the PANI/S/Fe2O3 BC is a potent candidate for industrial water bioremediation.

Ecoepidemiology and Potential Transmission of Vibrio cholerae among Different Environmental Niches: An Upcoming Threat in Egypt.

Cholera is a negative public health event caused by Vibrio cholerae. Although V. cholerae is abundant in natural environments, its pattern and transmission between different niches remain puzzling and interrelated. Our study aimed to investigate the occurrence of nonpathogenic V. cholerae in the natural environment during endemicity periods. It also aimed to highlight the role of molecular ecoepidemiology in mapping the routes of spread, transmission, and prevention of possible future cholera outbreaks. V. cholerae was detected in different aquatic environments, waterfowl, and poultry farms located along the length of the Nile River in Giza, Cairo, and Delta provinces, Egypt. After polymerase chain reaction amplification of the specific target outer membrane gene (Omp W) of suspected isolates, we performed sequence analysis, eventually using phylogenetic tree analysis to illustrate the possible epidemiological relationships between different sequences. Data revealed a significant variation in the physicochemical conditions of the examined Nile districts related to temporal, spatial, and anthropogenic activities. Moreover, data showed an evident association between V. cholerae and the clinically diseased Synodontis schall fish. We found that the environmental distress triggered by the salinity shift and elevated temperature in the Middle Delta of the Nile River affects the pathogenesis of V. cholerae, in addition to the characteristics of fish host inhabiting the Rosetta Branch at Kafr El-Zayat, El-Gharbia province, Egypt. In addition, we noted a significant relationship between V. cholerae and poultry sources that feed on the Nile dikes close to the examined districts. Sequence analysis revealed clustering of the waterfowl and broiler chicken isolates with human and aquatic isolated sequences retrieved from the GenBank databases. From the obtained data, we hypothesized that waterfowl act as a potential vector for the intermediate transmission of cholera. Therefore, continuous monitoring of Nile water quality and mitigation of Nile River pollution, in addition to following good managemental practices (GMPs), general hygienic guidelines, and biosecurity in the field of animal production and industry, might be the way to break this cyclic transmission between human, aquatic, and animal sectors.

In Vivo and In Vitro Assessments of the Antibacterial Potential of Chitosan-Silver Nanocomposite Against Methicillin-Resistant Staphylococcus aureus-Induced Infection in Rats.

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most threatening multidrug-resistant bacteria worldwide. Owing to their efficient antimicrobial properties, nanoparticles have been widely used as an alternative approach for combating the antibiotic-resistant bacteria. Consequently, this study was designed to compare in between the bactericidal effect of low doses (5 mg/kg bwt) of nanoparticles of chitosan (Ch-NPs), silver (Ag-NPs), and chitosan-silver nanocomposites (Ch-Ag NCs) both in vitro and in vivo against experimentally chronic infection induced by methicillin-resistant Staphylococcus aureus (MRSA). The three forms of nanoparticles were tested for their in vitro antimicrobial potential against MRSA by detection of MICs and MBCs using microdilution method. In vivo, thirty-five male albino Wistar rats were used and divided into five groups (n = 7). Group l (negative control), group 2 (MRSA infected and untreated), groups 3, 4, and 5 (MRSA infected then treated with Ch-NPs, Ag-NPs, and Ch-Ag NCs respectively for 7 days). After 6 weeks, blood samples were collected then rats were euthanized to collect different organs (liver, spleen, lungs, and kidneys). Some of them were kept in 10% formalin for histopathological investigations while others used for bacterial re-isolation. Ch-Ag NCs showed the lowest MIC and MBC among the tested nanoparticles. Moreover, the highest histopathological scoring was observed in the infected and untreated group while the lowest scoring was detected in groups treated with Ch-Ag NCs in comparison with the negative control group. The highest bacterial count was noticed in the infected and untreated group followed by those treated with Ch-NPs while the lowest count was observed in group treated with Ch-Ag NCs. Depending on these results, it can be concluded that Ch-Ag NCs have a strong bactericidal effect against MRSA and may be used as alternative option to antibiotics.

Efficacy of a prepared tissue culture-adapted vaccine against Chlamydia psittaci experimentally in mice.

BACKGROUND AND AIM: Chlamydia psittaci is an intracellular pathogen with a broad range of hosts and endemic in nearly all bird species as well as many mammalian species. Outbreaks contribute to economic losses, especially due to infection of pet birds, poultry, and livestock. Worse, the organism has a zoonotic effect, and transmission to humans results in severe illness. Therefore, proper control measures need to be applied. We conducted a trial for the preparation and evaluation of inactivated vaccine against C. psittaci. MATERIALS AND METHODS: Three C. psittaci strains (accession nos.: KP942827, KP942828, and KP942829) were grown in embryonated chicken eggs and then propagated for purification in Vero cells. The immunization experiment was experimentally performed in mice, which then were challenged with a virulent C. psittaci strain. RESULTS: The immunization trial revealed nearly 100% protection after the challenge. The histopathological and immunofluorescence examinations of internal organs revealed that the prepared killed vaccines can effectively reduce chlamydial infection and shedding in animals with the proper level of protection. CONCLUSION: Our vaccine can be used to control economic and financial losses resulting from avian chlamydiosis, especially those in poultry industries. The zoonotic transmission risk highlights the need for proper control measures.

Assessment of Thyroid Function and Oxidative Stress State in Foundry Workers Exposed to Lead.

BACKGROUND: Exposure to lead (Pb) has been associated with endocrine, hematological, gastrointestinal, renal and neurological problems in humans. However, effects on the thyroid gland are controversial. OBJECTIVES: The aim of the present study was to assess thyroid function in foundry workers occupationally exposed to Pb and the mechanism of oxidative-antioxidant imbalance. METHODS: Thyroid function parameters and markers of oxidative stress were examined in 59 adult males who had been occupationally exposed to Pb. The results were then compared to those of 28 male subjects who had no history of Pb exposure or thyroid abnormalities and served as a control group. RESULTS: Mean blood lead levels (16.5±1.74 µg/dl) were significantly higher among the exposed workers compared to those of the control group (12.8±1.16 µg/dl, (p <0.001)). The exposed group had significantly increased free triiodothyronine (FT3), free thyroxine (FT4) and significantly decreased thyroid stimulating hormone (TSH) (1.77±0.44 µIU/ml), whereas the control group had a TSH level of 2.61±0.94 µIU/ml (p< 0.0001). A state of oxidative stress was indicated by the significant increase in mean levels of malondialdehyde (MDA) and significant decrease in glutathione (GSH) (p < 0.0001). There was a significant positive correlation (r=0.358, p <0.05) between blood lead levels (BLL) and duration of employment, while BLL showed a significant negative correlation with TSH (r =-0.486, p <0.001), and GSH (r =-0.336, p <0.05). Of the occupationally exposed workers, 32.76% had elevated thyroid hormones. The results showed a significant positive relationship between GSH and TSH (ß coefficient=0.274, p < 0.05), MDA with FT3 (ß coefficient=0.355, p < 0.05) and FT4 (ß coefficient = 0.491, p < 0.0001) among exposed workers. CONCLUSIONS: Workers exposed to Pb dust proved to be at risk for hyperthyroidism, which was found to have a significant role in oxidative-antioxidant imbalance present among workers with increasing duration of exposure. PARTICIPANT CONSENT: Obtained. ETHICS APPROVAL: This study was approved by the Ethical Committee of the National Research Centre in Egypt (NRC) under the registration number 15225. COMPETING INTERESTS: The authors declare no competing financial interests.

Single or combined exposure to chlorpyrifos and cypermethrin provoke oxidative stress and downregulation in monoamine oxidase and acetylcholinesterase gene expression of the rat's brain.

The extensive uses of organophosphates and pyrethroids have made it necessary to investigate the neurotoxicity of their combination as they may implicate in the neurodegenerative syndromes. Monoamine oxidase-A (MAO-A) and acetylcholinesterase (AChE) gene expression in the rat brain were evaluated after independent and combined intoxications with chlorpyrifos and cypermethrin. Twenty-four mature male rats were equally distributed into four groups. The first one was kept as a control group, whereas the second, third and fourth were orally gavage with chlorpyrifos (16.324 mg/kg), cypermethrin (25.089 mg/kg) and their combination (9.254 mg/kg), respectively, for 4 weeks. As compared to the control group, intoxications with chlorpyrifos and/or cypermethrin revealed significant (P < 0.05) declines in the levels of brain neurotransmitters (dopamine and serotonin) plus the enzymatic activities of MAO-A, AChE and sodium-potassium adenosine triphosphatase. The mRNA genes expression of MAO-A and AChE have also confirmed the enzymatic actions. Moreover, the oxidative injury recorded as the levels of malondialdehyde and nitric oxide markedly increased (P < 0.01), while the total thiol content reduced and the histopathological outcomes have confirmed these impacts. In conclusion, chlorpyrifos and cypermethrin revealed antagonistic inhibitions on the brain MAO-A and AChE gene regulation through neurotransmission deteriorations and oxidative damage, which could describe their contributions in the neuropathological progressions.

Genotyping and antimicrobial resistance patterns of Helicobacter pylori in human and dogs associated with A2142G and A2143G point mutations in clarithromycin resistance.

BACKGROUND: Routes of transmission of Helicobacter pylori a class I carcinogen bacterium and the roles of animals have not been yet well determined. This study was carried out to investigate H. pylori phenotypically and genotypically in human and dogs to determine the antibiotic resistance patterns. As eradication therapy depends mainly on clarithromycin we evaluated 23S rRNA gene mutations associated with its resistance. RESULTS: A total of 150 human stool samples and 60 canine gastric biopsies were examined by nested PCR for the presence of H. pylori, 60% and 76.6% were positive respectively. Only 20 (22.2%) and 41 (89.1%) isolates were successfully cultured from human and canine samples respectively. Genotyping revealed a total of cagA+vacA+ combinations 76.6% (69/90) and 65.2% (30/46) in human and dogs, respectively. Allelic diversity in vacA gene was obviously observed, while cagA-vacA+ combinations were 23.3% (21/90) and 34.7% (16/46) in human and dogs, respectively. The antimicrobial susceptibility patterns of human exhibited the highest levels of resistance against Clarithromycin (60%), Trimethoprim (55%), metronidazole (45%), amoxicillin (45%) and cefsulodin (60%) antibiotics and comparatively lower for spiramycin (10%) and tetracycline (15%). Dogs strains showed the highest levels of resistance against Clarithromycin (53.6%), metronidazole (51.2%) and erythromycin (43.9%) antibiotics, on the other hand, the percent of resistant canine strains were comparatively lower for spiramycin (9.7%). Single point mutation of A2143G was detected as 25% (3/12), 18.1% (4/22) in human and dogs respectively. Single point mutation of A2142G was detected as 16.6% (2/12), 13.6% (3/22) in human and dogs, respectively. While dual mutations of both A2142G and A2143G were detected as 50% (6/12), 40.9% (9/22) in human and dogs, respectively. CONCLUSION: occurrence of elevated rates of A2142G and A2143G point mutations in clarithromycin resistant H. pylori isolates from human and dogs causing failure in treatment and eradication of the pathogen. The roles of animals need attention and further investigations.

Synthesis and antimicrobial evaluation of some new cyclooctanones and cyclooctane-based heterocycles.

The versatile synthon (E)-2-((dimethyl amino)methylene)cyclooctanone (2) was used as a key intermediate for the synthesis of cyclooctanones and cyclooctane-based heterocycles with pyrazole, isoxazole, pyrimidine, pyrazolopyrimidine, triazolopyrimidine and imidazopyrimidine derivatives via its reactions with several nitrogen nucleophiles. The newly synthesized compounds were screened in vitro for their antimicrobial activity against pathogenic microorganisms (Listeria monocytogenes, methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans). Most of the tested compounds showed moderate to high antibacterial and antifungal effects against the tested pathogenic microorganisms. Among the synthesized compounds, 2-((p-sulfonamidophenyl)methylene)cyclooctanone (5) showed excellent activity against Listeria monocytogenes.

Synthesis of new functionalized 3-substituted [1,2,4]triazolo [4,3-a]pyrimidine derivatives: potential antihypertensive agents.

A convenient synthesis of a series of thiosemicarbazide, 1,3,4-oxadiazole, 1,3,4-thiadiazole, thiazole, 1,2,4-triazole, pyrazole and dioxoisoindoline derivatives incorporating 1,2,4-triazolo[4,3-a]pyrimidine via the reaction of the readily accessible 1,5-dihydro-5-oxo-1.7-diphenyl-1,2.4-triazolo[4,3-a]pyrimidine-3-carbohydrazide (2) with the appropriate reagents is described. The newly synthesized compounds were found to possess antihypertensive and diuretic activities compared to captopril and furosemide as reference controls, respectively.

Synthesis, anti-HCV, antioxidant, and peroxynitrite inhibitory activity of fused benzosuberone derivatives.

Reaction of benzosuberone 1 with dimethylformamide-dimethylacetal (DMF-DMA) gives 2-dimethylamino-methylenebenozosuberone 2 which in turn reacts with heterocyclic amines to furnish new heterocyclic ring systems 6-9. Moreover, enaminone 2 reacts with hydrazine hydrate and hydroxylamine hydrochloride to afford the corresponding benzo[6,7]cyclohepta[1,2-c]pyrazole (10) and benzo[6,7]cyclohepta[2,1-d]isoxazole (12), respectively. In addition, the reactions of enaminone 2 with active methylene compounds afforded benzo[6,7]cyclohepta[1,2-b]pyridines (13-18). The X-ray crystallographic analysis of compounds 6 and 16, were recorded. We demonstrated the ability of nine new synthesized compounds to inhibit Hepatitis C Virus (HCV) and Subacute Sclerosing Panencephalitis (SSPE) due to structural similarity between ribavirin and some of the newly synthesized compounds were they contain triazoles and its bioisosters. In addition, the ability of ten synthesized compounds to react with the biologically relevant reactive nitrogen species, peroxynitrite was investigated indirectly by measurement of their ability to inhibit ONOO(-)-induced tyrosine nitration. The antioxidant activity of these ten compounds was also studied using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay.

Synthesis and biological evaluation of new 3-substituted indole derivatives as potential anti-inflammatory and analgesic agents.

Treatment of 3-cyanoacetyl indole 1 with the diazonium salts of 3-phenyl-5-aminopyrazole and 2-aminobenzimidazole afforded the corresponding hydrazones 4 and 5. 3-Cyanoacetyl indole reacted with phenylisothiocyanate to give the corresponding thioacetanilide derivative 7. Treatment of 7 with hydrazonoyl chlorides afforded the corresponding 1,3,4-thiadiazole derivatives 8a-f and 9. Also, the thioacetanilide reacted with alpha-haloketones to afford thiophene derivatives 10a,b (tenidap analogues), or thiazolidin-4-one derivative 11. The newly synthesized compounds were found to possess potential anti-inflammatory and analgesic activities.