Response of lead-induced oxidative stress and alterations in biogenic amines in different rat brain regions to combined administration of DMSA and MiADMSA

The present study was planned to investigate if combined administration of meso-2,3-dimercaptosuccinic acid (DMSA) and monoisoamyl DMSA (MiADMSA) could achieve better recovery in the altered biochemical parameters suggestive of brain oxidative stress and depletion of lead from blood and brain following acute lead exposure. Male Wistar rats were exposed to lead nitrate (50 mg/kg, i.p., once daily for 5 days) followed by treatment with the above chelating agents using two different doses of 25 or 50 mg/kg (orally) either alone and in combination once daily for five consecutive days. Lead exposure resulted in the significant inhibition of δ-aminolevulinic acid dehydratase activity and depletion of glutathione (GSH) in blood. These changes were accompanied by significant reduction in blood hemoglobin, RBC levels and superoxide dismutase and catalase activities. Significant increase in blood reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS) levels were noted. We observed marked increase in brain ROS level while GSH/oxidized glutathione ratio showed significant decrease accompanied by a significant increase in blood and brain lead concentration. The levels of norepinephrine, dopamine and serotonin in different brain regions were also altered on lead exposure. Co-administration of DMSA and MiADMSA particularly at the lower dose was most effective in the recovery of lead-induced changes in the hematological variables and oxidative stress and resulted in more pronounced depletion of lead from blood and brain compared to monotherapy with these chelators. On the other hand, combined administration of MiADMSA (50 mg/kg) in combination with DMSA (25 mg/kg each) had additional beneficial effect over the individual effect of chelating agent in the recovery of altered levels of brain biogenic amines. The study suggests that administration of MiADMSA is generally a better lead chelator than DMSA while combined administration of DMSA and MiADMSA might be a better treatment option compared to monotherapy at least in the removal of lead from the target tissues.     

Pharmacoinformatics and molecular docking reveal potential drug candidates against Schizophrenia to target TAAR6

Schizophrenia (SZ) is a complex disabling disorder that leads to the mental disability and afflicts 1% of the world's total population and placed in top ten medical disorders. In current work, bioinformatics analyses were carried out on Trace amine (TA)-associated receptor 6 (TAAR6) to recognize the potential drugs and compounds against SZ. Comparative modeling and threading-based approaches were utilized for the structure prediction of TAAR6. Fifty-nine predicted structures were evaluated by various model assessment techniques and final model having only eight amino acids in the outlier region and 98.5% overall quality factor was chosen for further pharmacoinformatics and molecular docking analyses. From an extensive literature review, 11 Food and Drug Administration (FDA) approved drugs were analyzed by computational techniques and Aripiprazole was found as the most effective drug against SZ by targeting TAAR6. Here, we report five novel molecules which exhibited the highest binding affinity, effective drug properties, and interestingly, observed better results than the approved selected drugs against SZ by targeting TAAR6. The docking analyses revealed that Arg-92, Trp-98, Gln-191, Thr-192, Ala-290, Cys-291, Tyr-293, and Glu-294 residues were observed as critical interacting residues in receptor-ligand interactions. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, Lipinski rule of five, highest binding affinity coupled with virtual screening (VS), and pharmacophore modeling approach illustrated that aripiprazole (−8.6 kcal/mol) and TAAR6_0094 (−9.3 kcal/mol) are potential inhibitors for targeting TAAR6. It is suggested that schizophrenic patients have to use Aripiprazole for the medication of SZ by targeting TAAR6 and develop effective therapies by utilizing scrutinized novel compound.     

Crystal structures of CbpF complexed with atropine and ipratropium reveal clues for the design of novel antimicrobials against Streptococcus pneumoniae

Background

Streptococcus pneumoniae is a major pathogen responsible of important diseases worldwide such as pneumonia and meningitis. An increasing resistance level hampers the use of currently available antibiotics to treat pneumococcal diseases. Consequently, it is desirable to find new targets for the development of novel antimicrobial drugs to treat pneumococcal infections. Surface choline-binding proteins (CBPs) are essential in bacterial physiology and infectivity. In this sense, esters of bicyclic amines (EBAs) such as atropine and ipratropium have been previously described to act as choline analogs and effectively compete with teichoic acids on binding to CBPs, consequently preventing in vitro pneumococcal growth, altering cell morphology and reducing cell viability.

Methods

With the aim of gaining a deeper insight into the structural determinants of the strong interaction between CBPs and EBAs, the three-dimensional structures of choline-binding protein F (CbpF), one of the most abundant proteins in the pneumococcal cell wall, complexed with atropine and ipratropium, have been obtained.

Results

The choline analogs bound both to the carboxy-terminal module, involved in cell wall binding, and, unexpectedly, also to the amino-terminal module, that possesses a regulatory role in pneumococcal autolysis.

Conclusions

Analysis of the complexes confirmed the importance of the tropic acid moiety of the EBAs on the strength of the binding, through π–π interactions with aromatic residues in the binding site.

General significance

These results represent the first example describing the molecular basis of the inhibition of CBPs by EBA molecules and pave the way for the development of new generations of antipneumococcal drugs.     

Synthesis and in vitro antitumor evaluation of primary amine substituted quinazoline linked benzimidazole

By combining the structural features of quinazoline and benzimidazole, new hybrid regioisomeric molecules with substituted primary amines have been synthesized. Evaluation of these molecules over 60 cancer cell line panel has identified three molecules as most potent anticancer agents. Compound 10 showed ten and eleven folds more activity than respective quinazoline and benzimidazole class of compounds with GI₅₀ value of 1.64 μM. Compound 11 (GI₅₀ value of 0.81 μM) showed almost twenty and twenty-two fold more activity than quinazoline and benzimidazole analogue, respectively while compound 12 (GI₅₀ value of 4.52 μM) has four fold more activity than quinazoline and benzimidazole analogue. In vitro evaluation of compound 11 exhibited remarkable anticancer activity towards colon cancer cell lines and prostate cancer cell lines at five dose concentrations with GI₅₀ values of 0.34 and 0.31 μM, respectively.     

Anti-cancer activity of carbamate derivatives of melampomagnolide B

Melampomagnolide B (MMB) is a natural sesquiterpene structurally related to parthenolide (PTL). We have shown that MMB exhibits anti-leukemic properties similar to PTL. Unlike PTL, the presence of a primary hydroxyl group in the MMB molecule allows the opportunity for examining the biological activity of a variety of conjugated analogs of MMB. We have now synthesized a series of carbamate analogs of MMB and evaluated these derivatives for anti-cancer activity against a panel of sixty human cancer cell lines. Analogs 6a and 6e exhibited promising anti-leukemic activity against human leukemia cell line CCRF-CEM with GI₅₀ values of 680 and 620 nM, respectively. Analog 6a also showed GI₅₀ values of 1.98 and 1.38 μM respectively, against RPMI-8226 and SR leukemia cell lines and GI₅₀ values of 460 and 570 nM against MDA-MB-435 melanoma and MDA-MB-468 breast cancer cell lines, respectively. Analog 6e had GI₅₀ values of 650 and 900 nM against HOP-92 non-small cell lung and RXF 393 renal cancer cell lines.     

Degradation of biogenic amines by vineyard ecosystem fungi. Potential use in winemaking

Aims: To evaluate the ability of grapevine ecosystem fungi to degrade histamine, tyramine and putrescine in synthetic medium and in wines. Methods and Results: Grapevine and vineyard soil fungi were isolated from four locations of Spain and were subsequently identified by PCR. A total of 44 fungi were evaluated for in vitro amine degradation in a microfermentation system. Amine degradation by fungi was assayed by reversed‐phase (RP)‐HPLC. All fungi were able to degrade at least two different primary amines. Species of Pencillium citrinum, Alternaria sp., Phoma sp., Ulocladium chartarum and Epicoccum nigrum were found to exhibit the highest capacity for amine degradation. In a second experiment, cell‐free supernatants of P. citrinum CIAL‐274,760 (CECT 20782) grown in yeast carbon base with histamine, tyramine or putrescine, were tested for their ability to degrade amines in three different wines (red, white and synthetic). The highest levels of biogenic amine degradation were obtained with histamine‐induced enzymatic extract. Conclusion: The study highlighted the ability of grapevine ecosystem fungi to degrade biogenic amines and their potential application for biogenic amines removal in wine. Significance and Impact of Study: The fungi extracts described in this study may be useful in winemaking to reduce the biogenic amines content of wines, thereby preventing the possible adverse effects on health in sensitive individuals and the trade and export of wine.     

Genetic variants in epoxide hydrolases modify the risk of oligozoospermia and asthenospermia in Han-Chinese population

Objectives

Epoxide hydrolases are involved in detoxifying and excreting the environmental chemicals, which are associated with decreased semen quality and male infertility. We hypothesized that polymorphisms in epoxide hydrolases may be associated with risk of oligozoospermia and asthenospermia.

Design and methods

In this study, 468 fertile controls and 672 idiopathic male infertile patients were recruited. SNPstream and TaqMan assay were used to genotype four single nucleotide polymorphisms in EPHX1 and EPHX2. The semen analysis was performed by computer-assisted semen analysis system.

Results

Our results demonstrated that rs1042064 of EPHX2 was significantly associated with decreased risk of oligozoospermia (OR = 0.65, 95% CI: 0.44–0.98) and asthenospermia (OR = 0.66, 95% CI: 0.46–0.94).

Conclusions

Our results provided evidence that genetic variants in epoxide hydrolases may modify the risk of oligozoospermia and asthenospermia in Han-Chinese population.     

New amphiphilic chlorins of the chlorophyll <Emphasis Type="Italic">a</Emphasis> series

We treated by nucleophiles derivatives of chlorophyll a with additional six-membered cycles: δ-lactone at pyrrole D and anhydride at pyrrole C bearing a γ-meso-bridge. In the first case, this led to the formation of substituted amides at the propionic acid residue and the introduction of hydroxy group at position 18 of the macrocycle, and, in the second case, to N-substituted cycloimides of chlorin p6.     

Studies on the antimutagenesis of Phyllanthus orbicularis: mechanisms involved against aromatic amines

Phyllanthus orbicularis is a medicinal plant, endemic to Cuba, whose aqueous extract has proven antiviral properties. This plant extract is being studied for treatment of viral diseases in animals and humans. Antimutagenic activities of this plant aqueous extract have been investigated as an additional and possible valuable property. Antimutagenesis was assayed against the mutagenic activity of m-phenylenediamine (m-PDA), 2-aminofluorene (2-AF), 1-aminopyrene (1-AP), 2-aminoanthracene (2-AA) and 9-aminophenantrene (9-AP) in Salmonella typhimurium (S. typhimurium) YG1024, in different co-treatment approaches. This plant extract produced a significant decrease of the mutagenesis mediated by these aromatic amines (AA) in the following order: m-PDA>2-AA>2-AF>9-AP>1-AP. Interactions with S9 enzymes and transformation of promutagenic amines and their mutagenic metabolites by chemical reactions to non-mutagenic compounds are proposed as possible mechanisms of antimutagenesis. Mutagenesis mediated by m-PDA was almost completely abolished when S9 mixture was co-incubated with the plant extract during 40 min, previous to the addition of the m-PDA and bacterial cells to the assay. Similar results were found with 2-AA and 1-AP, but the reduction of the mutation rate was not so dramatic. In contrast, the most significant antimutagenic effect against 2-AF and 9-AP was seen when these chemicals were co-incubated with the plant extract, before addition of the S9 mixture and bacterial cells to the assay. Therefore, inhibition or competition for S9 enzymes seems to be the main antimutagenic mechanism of this plant extract against m-PDA, 2-AA and 1-AP, whilst a chemical modification of 2-AF and 9-AP into non-promutagenic derivatives is likely to be the main mechanism of antimutagenesis against both compounds.     

Green synthesis,inhibition studies of yeast α-glucosidase and molecular docking of pyrazolylpyridazine amines

An efficient and environmentally benign simple fusion reaction of 3-chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine (1a) or 3-chloro-6-(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)pyridazine (2a) with different aliphatic/aromatic amines have produced a series of novel pyrazolylpyridazine amines (4a–4c & 5a–5m). All compounds exhibited moderate in vitro yeast α-glucosidase inhibition except m-chloro derivative 5g, which was found potent inhibitor of this enzyme with IC₅₀ value of 19.27 ± 0.005 µM. The molecular docking further helped in understanding the structure activity relationship of these compounds including 5g.