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Diclofenac (Dic) was shown to increase in reactive oxygen species (ROS) levels thereby resulting oxidative stress and apoptotic cell death in colon cancer. The antioxidants can prevent and repair oxidative damage caused by ROS. The aim of this study was to assess the effect of chrysin (Chr) on Dic-induced toxicity in HT-29 and molecular mechanisms underlying its effect. Cell proliferation and cytotoxicity assays were carried out by WST-1 and LDH leakage assay, apoptotic index was calculated by TUNEL Assay, antioxidant parameters were studied by measurement of ROS, LPO and TAS levels and catalase activity, expression of caspase-3 protein levels were analyzed by immunohistochemical staining, mRNA levels of apoptotic and anti-apoptotic genes were studied by qRT-PCR. The cellular processes of Dic-triggered cell death was associated with increase in ROS, malondialdehyde levels and lactate dehydrogenase release, decrease in total antioxidant and catalase activity while pretreatment with Chr reversed these effects. The expression level of p53, cas-3, cas-8, Bax and cytochrome c increased in Dic-exposed group while they were reduced by Chr. The use of antioxidant nutritional supplements, and in particular of Chr, may reduce the efficacy of Dic in inducing apoptosis of colon cancer cells. [ABSTRACT FROM AUTHOR]

The glycolytic pathway of the enteric pathogen Campylobacter jejuni is incomplete; the absence of phosphofructokinase means that the suppression of futile cycling at this point in the glycolytic–gluconeogenic pathway might not be required, and therefore the mechanism for controlling pathway flux is likely to be quite different or absent. In this study, the characteristics of fructose-1,6-bisphosphatase (FBPase) of C.jejuni are described and the regulation of this enzyme is compared with the equivalent enzymes from organisms capable of glycolysis. The enzyme is insensitive to AMP inhibition, unlike other type I FBPases. Campylobacterjejuni FBPase also shows limited sensitivity to other glycolytic and gluconeogenic intermediates. The allosteric cooperative control of the enzyme's activity found in type I FBPases appears to have been lost. [ABSTRACT FROM AUTHOR]

Glucose-6-phosphate dehydrogenase (G6PD) plays a key function in various biochemical processes as they produce reducing power of the cell. Thus, metabolic reprogramming of nicotinamide adenine dinucleotide homeostasis is reported to be an important step in cancer progression as well as in combinational therapeutic approaches. In this study, the effects of the antibiotics, furosemide, cefazolin, cefuroxime, gentamicin and clindamycin on rat erythrocyte G6PD enzyme was studied in in vitro conditions. The enzyme was purified by 2', 5'-adenosine diphosphate Sepharose 4B affinity chromatography in a single purification step with 1825 fold and 83.7% yield. The specific activity of the enzyme was 29.2 EU/mg proteins. The inhibition studies of these antibiotics were carried out on the enzyme revealing that gentamicin, clindamycin and furosemide inhibited the activity of the G6PD with an IC50 of 1.75, 34.65 and 0.526 mM, respectively with Ki of 0.7, 39.8 and 0.860 mM, respectively. All inhibition types were analyzed by Lineweaver-Burk diagram showing noncompetitive inhibition for furosemide and gentamicin while clindamycin inhibited the activity competitively. On the other hand, cefazolin and cefuroxime increased the activity of the enzyme. [ABSTRACT FROM AUTHOR]

Natural and synthetic derivatives that contain an indole core are being used in medical treatments and technological processes. Therefore, the development of new synthetic methods for the synthesis of indole derivatives is very popular. In this study, new oxindoles with reaction of 4,7-dihydro-1H-indole (2) and isatin (4) were synthesized as analogs of natural product 3,3'-bis(indolyl)oxindole. The biological properties of the compounds obtained during this study were also studied, showing that compounds 5, 7, and 12 inhibited the activity of G6PD with an IC50 of 99 μM, 231 μM, and 304 μM respectively. The activity of rat erythrocyte 6PGD was increased in the presence of 5 and 7 and was inhibited in the presence of 12. As indole derivative 5 was an activator of 6PGD and inhibitor of G6PD, it was selected for docking studies to understand the mechanism of activation and inhibition. [ABSTRACT FROM AUTHOR]

• The crystal structure of the GAPDH from C. jejuni (cjGAPDH) in complex with NAD(P)+ was determined at 2.25 Å resolution with a space group of I4122. • The structure contains a typical coenzyme binding domain and a catalytic domain. • ADP binding resulted some local conformational changes. C ampylobacter jejuni is a pathogenic bacteria that causes gastrointestinal disorders and is thus of great importance. Phosphorylating Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a ubiquitous cellular enzyme that has a well-defined role in glycolysis and other pathways where it catalyses the oxidative phosphorylation of glyceraldehyde 3-phosphate (2-hydroxy-3-oxopropyl dihydrogen phosphate) to 1,3-Bisphosphoglycerate ((2-Hydroxy-3-phosphonooxy-propanoyloxy)phosphonic acid). The C. jejuni genome encodes a single GAPDH enzyme (CjGAPDH) which displays dual (NAD/NADP) coenzyme specificity. NAD-specific GAPDHs are given the EC classification of 1.2.1.12, whereas NADP-specific GAPDHs are classed as 1.2.1.13. GAPDH's with dual specificity are in the class 1.2.1.59. Here we present the X-ray crystal structure of this enzyme (at 2.25 Å), this comprises superimposed structures of NAD- and NADP- complexes showing the structural adaptation that allows this dual specificity, and we consider this in the context of the pathogen's metabolism. There are no previous reports of EC 1.2.1.59 structures that compare the binding of the two co-enzymes. Furthermore, we also report the structure (at 2.05 Å) of the enzyme complexed with the nucleoside ADP and consider this with respect to the reported "moonlighting" activities of GAPDH. [ABSTRACT FROM AUTHOR]

The exposure to bisphenol A (BPA) is inevitable owing to its common use in the production of polycarbonate plastics. Studies to reduce side effects are gaining importance since BPA causes severe toxicities in important tissues such as testes, lungs, brain, liver and kidney. The current study was planned to study ameliorative effect of 18β-glycyrrhetinic acid (18β-GA) on BPA induced neurotoxicity. Fourty Wistar albino rats were divided into five equal groups as follows: I-Control group, II-18β-GA group (100 mg/kg), III- BPA group (250 mg/kg), IV-250 mg/kg BPA + 50 mg/kg 18β-GA group, V-250 mg/kg BPA + 100 mg/kg 18β-GA group. BPA intoxication was associated with increased MDA level while reduced GSH concentration, activities of glutathione peroxidase, superoxide dismutase, and catalase. BPA supplementation caused apoptosis in the brain by up-regulating caspase-3 and Bax levels and down-regulating Bcl-2. BPA also caused endoplasmic reticulum (ER) stress by increasing mRNA transcript levels of PERK, IRE1, ATF-6 and GRP78. Additionally, it was observed that BPA administration activated JAK1/STAT1 signaling pathway and levels of TNF-α, NF-κB, p38 MAPK and JNK in the brain. However, co-treatment with 18β-GA at a dose of 50 and 100 mg/kg considerably ameliorated oxidative stress, inflammation, apoptosis, ER stress and JAK1/STAT1 signaling pathway in brain tissue. Overall, the data of this study indicate that brain damage associated with BPA toxicity could be ameliorated by 18β-GA administration. [ABSTRACT FROM AUTHOR]

High dose of fluoride intake is associated with toxic effects on liver and kidney tissues. One approach to tackle these toxicities is using natural antioxidants as supplements. This study evaluated the ameliorative effects of hesperidin (HSP) against sodium fluoride (NaF)-induced hepatotoxicity and nephrotoxicity in wistar albino rats. In the present study, the rats were randomly allocated into five groups of seven male rats each group: control, NaF (600 ppm), HSP-200, NaF + HSP-100 and NaF + HSP 200. Hepatic and renal injuries induced by NaF were confirmed by the alteration in kidney function parameters in the serum (urea and creatinine), levels of liver enzymes (ALT, ALP and AST), activities of the antioxidant enzymes (SOD, CAT and GPx) and levels of inflammatory markers (NF-κB, IL-1β and TNF-α). NaF also inhibited PI3K/Akt/mTOR pathway, increased levels of autophagic markers (Beclin-1, LC3A and LC3B) and expression levels of apoptotic and anti-apoptotic proteins (Bax, Bcl-2, cytochrome c , p53 and procaspase-3) in the liver and kidney tissues. Administration of HSP concurrently with NaF significantly ameliorated the deviation in the above-studied parameters. The results of the current study revealed that HSP could be used as a beneficial adjuvant that confers protection against NaF-induced liver and kidney damage through antioxidant, anti-inflammatory, anti-apoptotic and anti-autophagic mechanisms. • Hesperidin prevented NaF-induced hepatotoxicity and nephrotoxicity. • Hesperidin attenuated NaF-induced oxidative stress and inflammation. • Hesperidin reduced NaF-induced apoptosis and autophagy. [ABSTRACT FROM AUTHOR]

Vancomycin (VCM) is a glycopeptide antibiotic widely used to treat serious infections caused by methicillin-resistant Staphylococcus aureus and has been associated with some severe side effects such as hepatotoxicity and nephrotoxicity. However, the underlying mechanism of VCM-induced hepatotoxicity is not yet fully understood. Therefore, the current study was designed to evaluate the protective effects of zingerone (Zin) against VCM-induced hepatotoxicity in rats. VCM was intraperitoneally administered at a dose of 200 mg/kg body weight (b.w.) for 7 days alone and in combination with the orally administered Zin (25 and 50 mg/kg b.w). Zin treatment significantly improved VCM-induced hepatic lipid peroxidation, glutathione depletion, reduced antioxidant enzyme (superoxide dismutase, catalase and glutathione peroxidase) activities and liver function markers (aspartate aminotransferase, alkaline phosphatase and alanine aminotransferase). Histopathological integrity and immunohistochemical expression of 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the VCM-induced liver tissue were ameliorated after Zin administration. In addition, Zin reversed the changes in levels and/or activities of inflammatory and apoptotic parameters such as nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), p53, cysteine aspartate specific protease-3 (caspase-3), cysteine aspartate specific protease-8 (caspase-8), cytochrome c , Bcl-2 associated X protein (Bax) and B-cell lymphoma-2 (Bcl-2) in the VCM-induced hepatotoxicity. Collectively, these results reveal probable ameliorative role of Zin against VCM-induced hepatotoxicity. [ABSTRACT FROM AUTHOR]