Photobiomodulation reduces neuropathic pain after spinal cord injury by downregulating CXCL10 expression.

BACKGROUND: Many studies have recently highlighted the role of photobiomodulation (PBM) in neuropathic pain (NP) relief after spinal cord injury (SCI), suggesting that it may be an effective way to relieve NP after SCI. However, the underlying mechanisms remain unclear. This study aimed to determine the potential mechanisms of PBM in NP relief after SCI. METHODS: We performed systematic observations and investigated the mechanism of PBM intervention in NP in rats after SCI. Using transcriptome sequencing, we screened CXCL10 as a possible target molecule for PBM intervention and validated the results in rat tissues using reverse transcription-polymerase chain reaction and western blotting. Using immunofluorescence co-labeling, astrocytes and microglia were identified as the cells responsible for CXCL10 expression. The involvement of the NF-κB pathway in CXCL10 expression was verified using inhibitor pyrrolidine dithiocarbamate (PDTC) and agonist phorbol-12-myristate-13-acetate (PMA), which were further validated by an in vivo injection experiment. RESULTS: Here, we demonstrated that PBM therapy led to an improvement in NP relative behaviors post-SCI, inhibited the activation of microglia and astrocytes, and decreased the expression level of CXCL10 in glial cells, which was accompanied by mediation of the NF-κB signaling pathway. Photobiomodulation inhibit the activation of the NF-κB pathway and reduce downstream CXCL10 expression. The NF-κB pathway inhibitor PDTC had the same effect as PBM on improving pain in animals with SCI, and the NF-κB pathway promoter PMA could reverse the beneficial effect of PBM. CONCLUSIONS: Our results provide new insights into the mechanisms by which PBM alleviates NP after SCI. We demonstrated that PBM significantly inhibited the activation of microglia and astrocytes and decreased the expression level of CXCL10. These effects appear to be related to the NF-κB signaling pathway. Taken together, our study provides evidence that PBM could be a potentially effective therapy for NP after SCI, CXCL10 and NF-kB signaling pathways might be critical factors in pain relief mediated by PBM after SCI.

Anaerobic degradation of thiobencarb by mixed culture of isolated bacteria.

Thiobencarb is a highly effective thiocarbamate herbicide frequently used in rice fields globally. In this study, three bacterial strains (Dechloromonas sp. Th1, Thauera sp. Th2, and Azoarcus sp. Th3) isolated from immobilized biomass were analyzed for thiobencarb degradation under anaerobic conditions, with nitrate serving as an electron acceptor. The experimental results showed that thiobencarb was transformed by Dechloromonas sp. Th1 and Thauera sp. Th2 to produce high concentrations of metabolites in a mineral medium. Dechloromonas sp. Th1 dechlorinated the herbicide to benzyl mercaptan, which was then degraded by Thauera sp. Th2 and Azoarcus sp. Th3. Azoarcus sp. Th3 effectively degraded intermediates, i.e. 4-chlorobenzyl alcohol, 4-chlorobenzoic acid, and benzoic acid, produced from the degradation by Dechloromonas sp. Th1 and Thauera sp. Th2. The cross-feeding, nutrient sharing, and cooperation of all isolates in the degradation process decreased the concentrations of intermediate products. The determination of the degradation kinetics showed that the utilization in the exponential phase of the mixed bacteria was consistent with the Michaelis-Menten model, with a maximum degradation rate of 1.56 ± 0.16 µM day-1. This study showed the degradation mechanisms in bacteria and the synergistic process in the degradation of thiobencarb and its metabolites.

Enhanced anaerobic degradation of thiobencarb using a horizontal-flow anaerobic immobilized biomass bioreactor.

Thiobencarb is a herbicide globally used in the agricultural sector, and its extensive application leads to severe environmental pollution. In this study, the thiobencarb supplementation caused a significant shift in the bacterial community in the sediment slurry. An analysis of the degradation metabolites of microorganisms from the sediment indicated that deschlorothiobencarb, S-4-chlorobenzyl ethylthiocarbamate, 4-chlorobenzyl mercaptan, 4-chlorobenzyl alcohol, 4-chlorobenzoic acid and chlorobenzene were the main intermediates. The degradation rates were significantly enhanced using a horizontal-flow anaerobic reactor with immobilized cells in polyurethane foam. The degradation rates at 2.6, 12.9 and 25.6 mg L-1 concentrations by suspended microorganisms from the sediment in the mineral medium supplemented with glucose were 0.085 ± 0.000, 0.383 ± 0.010 and 0.500 ± 0.045 mg day-1, respectively. The corresponding data for degradation in the reactor were 2.54 ± 0.03, 11.69 ± 0.72 and 18.58 ± 1.83 mg day-1 at the sixth operation period. Moreover, COD removal efficiencies were >90% achieved in the reactor. The proposed method facilitates degradation using a horizontal-flow anaerobic immobilized biomass bioreactor. Moreover, this study reveals the degradation of metabolites of thiobencarb under anaerobic conditions.

Synthesis, characterization of ruthenium(II), nickel(II), palladium(II), and platinum(II) triphenylphosphine-based complexes bearing an ONS-donor chelating agent: Interaction with biomolecules, antioxidant, in vitro cytotoxic, apoptotic activity and cell cycle analysis.

Four new transition metal complexes, [M(PPh3)(L)].CH3OH (M = Ni(II) (1), Pd(II) (2)) [Pt (PPh3)2(HL)]Cl (3) and [Ru(CO)(PPh3)2(L)] (4) (H2L = 2,4-dihydroxybenzaldehyde-S-methyldithiocarbazate, PPh3 = triphenylphosphine) have been synthesized and characterized by elemental analyses (C, H, N), FTIR, NMR (1H, 31P), ESI-MS and UV-visible spectroscopy. The molecular structure of (1) and (2) complexes was confirmed by single-crystal X-ray crystallography. It showed a distorted square planar geometry for both complexes around the metal center, and the H2L adopt a bi-negative tridentate chelating mode. The interaction with biomolecules viz., calf thymus DNA (ct DNA), yeast RNA (tRNA), and BSA (bovine serum albumin) was examined by both UV-visible and fluorescence spectroscopies. The antioxidant activity of all compounds is discussed on basis of DPPH• (2,2-diphenyl-1-picrylhydrazyl) scavenging activity and showed better antioxidant activity for complexes compared to the ligand. The in vitro cytotoxicity of the compounds was tested on human (breast cancer (MCF7), colon cancer (HCT116), liver cancer (HepG2), and normal lung fibroblast (WI38)) cell lines, showing that complex (1) the most potent against MCF7 and complex (4) against HCT116 cell lines based on IC50 and selective indices (SI) values. So, both complexes were chosen for further studies such as DNA fragmentation, cell apoptosis, and cell cycle analyses. Complex (1) induced MCF7 cell death by cellular apoptosis and arrest cells at S phase. Complex (4) induced HCT116 cell death predominantly by cellular necrosis and arrested cell division at G2/M phase due to DNA damage.

Dithiocarbamate derivatives inhibit α-glucosidase through an apparent allosteric site on the enzyme.

Dithiocarbamate derivatives possess diverse biological activities. This work further expands their activity profile by identifying seven benzylamine-containing dithiocarbamate derivatives with piperazine and piperidine substitutions at the main moiety, and five piperazine-containing dithiocarbamates with various substitutions at the piperazine moiety as new inhibitors of α-glucosidase. Compounds bearing the benzylamine moiety exhibited more potent inhibition of the enzyme than the piperazine derivatives. Majority of the compounds non-competitively inhibited α-glucosidase that led to the identification of a new allosteric site on the enzyme with the help of molecular dynamics and docking studies. These studies suggest that the compounds regulate inhibition of the enzyme by binding to an allosteric site that is located in the vicinity of the active site. This is the first report on the allosteric inhibition of α-glucosidase by dithiocarbamate derivatives that provides insights into the mechanism of inhibition of the enzyme at molecular level. Moreover, it also explores new avenues for drug development of α-glucosidase inhibitors as antidiabetic drugs.

An insight into the anticancer potential of carbamates and thiocarbamates of 10-demethoxy-10-methylaminocolchicine.

Colchicine shows very high antimitotic activity, therefore, it is used as a lead compound for generation of new anticancer agents. In the hope of developing novel, useful drugs with more favourable pharmacological profiles, a series of doubly modified colchicine derivatives has been designed, synthesized and characterized. These novel carbamate or thiocarbamate derivatives of 10-demethoxy-10-methylaminocolchicine have been tested for their antiproliferative activity against four human cancer cell lines. Additionally, their mode of action has been evaluated as colchicine binding site inhibitors, using molecular docking studies. Most of the tested compounds showed greater cytotoxicity (IC50 in a low nanomolar range) and were characterized by a higher selectivity index than standard chemotherapeutics such as cisplatin and doxorubicin as well as unmodified colchicine. Their pharmacological use in cancer therapy could possibly be accomplished with lower dosages and result in less acute toxicity problems than in the case of colchicine. In addition, we present a QSAR model for predicting the antiproliferative activity of doubly modified derivatives for two tumour cell lines.

Nitrosonium Cation as a Cytotoxic Component of Dinitrosyl Iron Complexes with Thiol-containing Ligands (based on the Experimental Work on MCF7 Human Breast Cancer Cell Culture).

Here we demonstrate that binuclear dinitrosyl iron complexes with thiol-containing ligands (glutathione and mercaptosuccinate, B-DNIC-GSH and B-DNIC-MS, respectively) exert cytotoxic effects on MCF7 human breast cancer cells. We showed that they are mediated by nitrosonium cations released from these complexes (NO+). This finding is supported by the cytotoxic effect of both B-DNICs on MCF7 cells evidenced to retain or was even promoted in the presence of N-Methyl-D-glucamine dithiocarbamate (MGD). MGD recruits an iron nitrosyl group [Fe(NO)] from the iron-dinitrosyl fragment [Fe(NO)2] of B-DNIC-MS forming stable mononitrosyl complexes of iron with MGD and releasing NO+ cations from a [Fe(NO)2] fragment.

Novel Coumarin Containing Dithiocarbamate Derivatives as Potent α-Glucosidase Inhibitors for Management of Type 2 Diabetes.

BACKGROUND: α-Glucosidase is a hydrolyzing enzyme that plays a crucial role in the degradation of carbohydrates and starch to glucose. Hence, α-glucosidase is an important target in carbohydrate mediated diseases such as diabetes mellitus. OBJECTIVE: In this study, novel coumarin containing dithiocarbamate derivatives 4a-n were synthesized and evaluated against α-glucosidase in vitro and in silico. METHODS: These compounds were obtained from the reaction between 4-(bromomethyl)-7- methoxy-2H-chromen-2-one 1, carbon disulfide 2, and primary or secondary amines 3a-n in the presence of potassium hydroxide and ethanol at room temperature. In vitro α-glucosidase inhibition and kinetic study of these compounds were performed. Furthermore, a docking study of the most potent compounds was also performed by Auto Dock Tools (version 1.5.6). RESULTS: Obtained results showed that all the synthesized compounds exhibited prominent inhibitory activities (IC50 = 85.0 ± 4.0-566.6 ± 8.6 µM) in comparison to acarbose as a standard inhibitor (IC50 = 750.0 ± 9.0 µM). Among them, the secondary amine derivative 4d with pendant indole group was the most potent inhibitor. Enzyme kinetic study of the compound 4d revealed that this compound competes with a substrate to connect to the active site of α-glucosidase and therefore is a competitive inhibitor. Moreover, a molecular docking study predicted that this compound interacted with the α-glucosidase active site pocket. CONCLUSION: Our results suggest that the coumarin-dithiocarbamate scaffold can be a promising lead structure for designing potent α-glucosidase inhibitors for the treatment of type 2 diabetes.

Inhibiting Protein Prenylation with Benzoxaboroles to Target Fungal Plant Pathogens.

Fungal pathogens pose an increasing threat to global food security through devastating effects on staple crops and contamination of food supplies with carcinogenic toxins. Widespread deployment of agricultural fungicides has increased crop yields but is driving increasingly frequent resistance to available agents and creating environmental reservoirs of drug-resistant fungi that can also infect susceptible human populations. To uncover non-cross-resistant modes of antifungal action, we leveraged the unique chemical properties of boron chemistry to synthesize novel 6-thiocarbamate benzoxaboroles with broad spectrum activity against diverse fungal plant pathogens. Through whole genome sequencing of Saccharomyces cerevisiae isolates selected for stable resistance to these compounds, we identified mutations in the protein prenylation-related genes, CDC43 and ERG20. Allele-swapping experiments confirmed that point mutations in CDC43, which encodes an essential catalytic subunit within geranylgeranyl transferase I (GGTase I) complex, were sufficient to confer resistance to the benzoxaboroles. Mutations in ERG20, which encodes an upstream farnesyl pyrophosphate synthase in the geranylgeranylation pathway, also conferred resistance. Consistent with impairment of protein prenylation, the compounds disrupted membrane localization of the classical geranylgeranylation substrate Cdc42. Guided by molecular docking predictions, which favored Cdc43 as the most likely direct target, we overexpressed and purified functional GGTase I complex to demonstrate direct binding of benzoxaboroles to it and concentration-dependent inhibition of its transferase activity. Further development of the boron-containing scaffold described here offers a promising path to the development of GGTase I inhibitors as a mechanistically distinct broad spectrum fungicide class with reduced potential for cross-resistance to antifungals in current use.

Preliminary Study of Multiple Stress Response Reactions in the Pond Snail Lymnaea stagnalis Exposed to Trace Metals and a Thiocarbamate Fungicide at Environmentally Relevant Concentrations.

Gastropod mollusks have achieved an eminent importance as biological indicators of environmental quality. In the present study, we applied a multibiomarker approach to evaluate its applicability for the pond snail Lymnaea stagnalis, exposed to common industrial and agricultural pollutants at environmentally relevant concentrations. The snails were exposed to copper (Cu2+, 10 µg L-1), zinc (Zn2+, 130 µg L-1), cadmium (Cd2+, 15 µg L-1), or the thiocarbamate fungicide "Tattoo" (91 µg L-1) during 14 days. Metal treatment and exposure to "Tattoo" caused variable patterns of increase or decrease of metal levels in the digestive gland, with a clear accumulation of only Cd and Zn after respective metal exposure. Treatment with Cu and "Tattoo" caused an increase of cytochrome P450-related EROD activity. Glutathione S-transferase was inhibited by exposure to Cu, Zn, and "Tattoo." Treatment with the "Tattoo" led to an inhibition of cholinesterase activity, whereas Cu and Cd increased its activity. Caspase-3 activity was enhanced by up to 3.3 times in all treatments. A nearly uniform inhibitory effect for oxidative stress response parameters was observed in all kinds of exposure, revealing an inhibition of superoxide dismutase (Mn-SOD) activity, a depression of glutathione (GSH and GSSG) and of protein carbonyl levels. Pollutant-specific effects were observed for the catalase activity, superoxide anion production, and lipid peroxidation levels. Due to the high response sensitivity of Lymnaea stagnalis to chemical impacts, we suggest our study as a contribution for biomarker studies with this species under field conditions.

Dithiocarbamate prodrugs activated by prostate specific antigen to target prostate cancer.

Disulfiram in conjunction with copper has been shown to be a potent anticancer agent. However, disulfiram's therapeutic potential in prostate cancer is hindered by off-target effects due to its reactive and nucleophilic thiol-containing component, diethyldithiocarbamate (DTC). To minimize undesirable reactivity, we have strategically blocked the thiol moiety in DTC with a cleavable p-aminobenzyl (pAB) group linked to peptide substrates recognized by prostate specific antigen (PSA). Here we report the synthesis and evaluation in cancer cell models of two PSA-activatable prodrugs: HPD (Ac-HSSKLQL-pAB-DTC and RPD (RSSYYSL-pAB-DTC). In vitro exposure to PSA was found to trigger activation of HPD and RPD to release diethyldithiocarbamate, and both prodrugs were found to induce toxicity in prostate cancer cells, with HPD showing the most promising selectivity. With copper supplementation, the IC50 of HPD was 1.4 µM in PSA-expressing LNCaP cells, and 11 µM in PC3 cells that do not express PSA. These studies demonstrate the utility of using peptide recognition handles to direct the activity of dithiocarbamate prodrugs for selective cytotoxicity of cancer cells.

Carbonyl Sulfide (COS) Donor Induced Protein Persulfidation Protects against Oxidative Stress.

The emergence of hydrogen sulfide (H2 S) as an important signalling molecule in redox biology with therapeutic potential has triggered interest in generating this molecule within cells. One strategy that has been proposed is to use carbonyl sulfide (COS) as a surrogate for hydrogen sulfide. Small molecules that generate COS have been shown to produce hydrogen sulfide in the presence of carbonic anhydrase, a widely prevalent enzyme. However, other studies have indicated that COS may have biological effects which are distinct from H2 S. Thus, it would be useful to develop tools to compare (and contrast) effects of COS and H2 S. Here we report enzyme-activated COS donors that are capable of inducing protein persulfidation, which is symptomatic of generation of hydrogen sulfide. The COS donors are also capable of mitigating stress induced by elevated reactive oxygen species. Together, our data suggests that the effects of COS parallel that of hydrogen sulfide, laying the foundation for further development of these donors as possible therapeutic agents.

Development and Application of Carbonyl Sulfide-Based Donors for H2S Delivery.

In addition to nitric oxide and carbon monoxide, hydrogen sulfide (H2S) has been recently recognized as an important biological signaling molecule with implications in a wide variety of processes, including vasodilation, cytoprotection, and neuromodulation. In parallel to the growing number of reports highlighting the biological impact of H2S, interest in developing H2S donors as both research tools and potential therapeutics has led to the growth of different H2S-releasing strategies. Many H2S investigations in model systems use direct inhalation of H2S gas or aqueous solutions of NaSH or Na2S; however, such systems do not mimic endogenous H2S production. This stark contrast drives the need to develop better sources of caged H2S. To address these limitations, different small organosulfur donor compounds have been prepared that release H2S in the presence of specific activators or triggers. Such compounds, however, often lack suitable  control compounds, which limits the use of these compounds in probing the effects of H2S directly. To address these needs, our group has pioneered the development of carbonyl sulfide (COS) releasing compounds as a new class of H2S donor motifs. Inspired by a commonly used carbamate prodrug scaffold, our approach utilizes self-immolative thiocarbamates to access controlled release of COS, which is rapidly converted to H2S by the ubiquitous enzyme carbonic anhydrase (CA). In addition, this design enables access to key control compounds that release CO2/H2O rather than COS/H2S, which enables delineation of the effects of COS/H2S from the organic donor byproducts. In this Account, we highlight a library of first-generation COS/H2S donors based on self-immolative thiocarbamates developed in our lab and also highlight challenges related to H2S donor development. We showcase the release of COS in the presence of specific triggers and activators, including biological thiols and bio-orthogonal reactants for targeted applications. We also demonstrate the design and development of a series of H2O2/reactive oxygen species (ROS)-triggered donors and show that such compounds can be activated by endogenous levels of ROS production. Utilizing approaches in bio-orthogonal activation, we establish that donors functionalized with an o-nitrobenzyl photocage can enable access to light-activated donors. Similar to endogenous production by cysteine catabolism, we also prepared a cysteine-selective COS donor activated by a Strongin ligation mechanism. In efforts to help delineate potential differences in the chemical biology of COS and H2S, we also report a simple esterase-activated donor, which demonstrated fast COS-releasing kinetics and inhibition of mitochondrial respiration in BEAS-2B cells. Additional investigations revealed that COS release rates and cytotoxicity correlated directly within this series of compounds with different ester motifs. In more recent and applied applications of this H2S donation strategy, we also highlight the development of donors that generate either a colorimetric or fluorescent optical response upon COS release. Overall, the work described in this Account outlines the development and initial application of a new class of H2S donors, which we anticipate will help to advance our understanding of the rapidly emerging chemical biology of H2S and COS.

Simultaneous determination of cartap and its metabolite in tea using hydrophilic interaction chromatography tandem mass spectrometry and the combination of dispersive solid phase extraction and solid phase extraction.

Risk assessment of cartap residue in tea should include the exposure of cartap and its metabolite due to rapid degradation of cartap into nereistoxin. Herein, a reliable method for determination of cartap and nereistoxin in tea was developed by hydrophilic interaction chromatography tandem mass spectrometry. Target compounds were extracted with water containing 1% formic acid and 5 mM ammonium formate. The use of dichloromethane effectively removed caffeine. Tea extracts were cleaned up by dispersive adsorbents of octadecylsilane and strong anion exchanger, then further purified using hydrophilic lipophilic balanced solid phase extraction cartridge. Isotopic internal standard was employed to calibrate the loss of analytes during sample preparation and compensate matrix effects. Method validation illustrated excellent linearity, with correlation coefficients (R2) higher than 0.999. Satisfactory recoveries of target compounds spiked in green tea, black tea and oolong tea ranged from 87.6% to 119.9% with intra- and inter-day precisions below 20%. Limits of quantification of cartap and nereistoxin were 10.0 µg kg-1, and limits of detection were 2.0 µg kg-1 for cartap and 4.0 µg kg-1 for nereistoxin. The developed method was applied to determine cartap and nereistoxin in thirty tea samples.

Pyrrolidine Dithiocarbamate Attenuates Cardiocyte Apoptosis and Ameliorates Heart Failure Following Coronary Microembolization in Rats

Background: Nuclear factor-kB is highly activated in cardiovascular disorders. However, few articles have targeted at the role of nuclear factor-kB inhibitor in heart failure. Aims: To evaluate the effects of nuclear factor-kB inhibitor pyrrolidine dithiocarbamate on cardiocyte apoptosis and cardiac function in a rat heart failure model. Study Design: Animal experiment. Methods: A stable and reproducible rat heart failure model (n=64) was prepared by injecting homologous microthrombotic particles into the left ventricle of Sprague­Dawley rats while obstructing the ascending aorta to produce coronary microembolization. Rats with heart failure were randomized into untreated (HFu) and pyrrolidine dithiocarbamate-treated (HFp) groups; the latter received an intraperitoneal injection of pyrrolidine dithiocarbamate (100 mg/kg/day) 1 h prior to surgery as well as on postoperative days 1-7. The sham group comprised 32 Sprague­Dawley rats. Eight rats from each group were sacrificed on days 1, 3, 7, and 14 postoperatively. Masson's trichrome staining was used to determine the micro-fibrotic area to indicate the severity of myocardial loss. Terminal transferase uridine triphosphate nick end labeling staining was used to detect apoptotic cardiomyocytes. Echocardiography and hemodynamics were performed to evaluate left ventricular function. Results: Rats with heart failure exhibited pathological changes evidenced by patchy myocardial fibrosis, remarkably elevated severity of myocardial loss, and persistently reduced left ventricular function. At the end of the study, compared with the HFu group, myocardial infarct size was reduced by 28% (p=0.001), cardiocyte apoptosis was suppressed (7.17%±1.47% vs 2.83%±0.75%, p<0.001), cardiac function parameters such as left ventricular ejection fraction (80%±4% vs 61%±6%), left ventricular + dP/dt max (4828±289 vs 2918±76 mmHg.s−1), left ventricular - dP/dt max (4398±269 vs 2481±365 mmHg.s−1), and left ventricular systolic pressure (126±13 vs 100±10 mmHg) were significantly increased, and left ventricular end-diastolic pressure was reduced (18±2 vs 13±1 mmHg) (p<0.001, for all) in the HFu group. Conclusion: Our rat model can adequately mimic heart failure via coronary vessel embolization. Moreover, pyrrolidine dithiocarbamate treatment can reduce cardiocyte apoptosis and improve cardiac function, which may be beneficial for patients with heart failure secondary to myocardial infarction.

Cytotoxicity, Pro-apoptotic Activity and in silico Studies of Dithiocarbamates and their Structure Based Design and SAR Studies.

BACKGROUND: Cancer is a far-reaching and lethal but curable disease. Researchers have investigated numerous anticancer agents with only a few commercially available effective drugs which are very costly. OBJECTIVE: Herein, we report the synthesis , characterization and anti cancer assays of a series of novel dithiocarbamates derivatives. METHODS: All compounds were synthesized from different secondary amines and substituted benzyl chlorides in a single step. The structures of newly synthesized dithiocarbamate derivatives were confirmed by spectroscopic techniques (IR, NMR and HR-MS). RESULTS: The synthesized compounds showed a significant anti-proliferative effect in cancer cells (HeLa) with the maximum inhibitory activity of compound SHD-2 with an IC50 = 0.31 ± 0.09 µM. However, the same compound exhibited 19.2% inhibition towards Baby Hamster Kidney fibroblasts (BHK-21), normal cell lines. Moreover, quantification of cellular DNA by flow cytometry for the evaluation of pro-apoptotic activity in HeLa cells demonstrates that arrest in cell cycle along with apoptosis advance towards drug cytotoxicity. However, molecular docking studies of the potent compound suggested that it binds to the major groove of the DNA. CONCLUSION: The cytotoxic and pro-apoptotic potential of the potent inhibitor may be further investigated in the animal models to advance their anti-cancer prospective.

Potential Angiotensin Converting Enzyme Inhibitors from Moringa oleifera.

BACKGROUND: Hypertension is the chronic medical condition and it affected billions of people worldwide. Natural medicines are the main alternatives to treatment for a majority of people suffering from hypertension. Niazicin-A, Niazimin-A, and Niaziminin-B compounds from Moringa oleifera ethanolic leave extract were reported to have potent antihypertensive activity. OBJECTIVE: These compounds were targeted with Angiotensin-converting enzyme [ACE] which is one of the main regulatory enzymes of the renin-angiotensin system. METHODS: Protein-ligand docking of these compounds with [ACE] [both domain N and C] was conceded out through Autodock vina and visualization was done by chimera. Pharmacokinetics study of these compounds was predicted by ADME-Toxicity Prediction. RESULTS: Niazicin-A, Niazimin-A, and Niaziminin-B showed high binding affinity with ACE and partially blocked the active sites of the enzyme. Niazicin-A, Niazimin-A and Niaziminin-B showed the estimated free binding energy of -7.6kcal/mol kcal/mol, -8.8kcal/mol and -8.0kcal/mol respectively with C-domain of ACE and -7.9kcal/mol, -8.5kcal/mol and -7.7kcal/mol respectively with N-domain of ACE. The compounds showed better binding energy with angiotensinconverting enzyme in comparison to Captopril -5.5kcal/mol and -5.6kcal/mol and Enalapril [standard] -8.4kcal/mol and -7.5kcal/mol with C and N domain, respectively. CONCLUSION: Computationally, the selected bioactive molecules have shown better binding energy to known standard drugs which have been already known for inhibition of ACE and can further act as a pharmacophore for in vitro and in vivo studies in the development of alternative medicine.

Esterase-Triggered Self-Immolative Thiocarbamates Provide Insights into COS Cytotoxicity.

Hydrogen sulfide (H2S) is an important gasotransmitter and biomolecule, and many synthetic small-molecule H2S donors have been developed for H2S-related research. One important class of triggerable H2S donors is self-immolative thiocarbamates, which function by releasing carbonyl sulfide (COS), which is rapidly converted to H2S by the ubiquitous enzyme carbonic anhydrase (CA). Prior studies of esterase-triggered thiocarbamate donors reported significant inhibition of mitochondrial bioenergetics and toxicity when compared to direct sulfide donors, suggesting that COS may function differently than H2S. Here, we report a suite of modular esterase-triggered self-immolative COS donors and include the synthesis, H2S release profiles, and cytotoxicity of the developed donors. We demonstrate that the rate of ester hydrolysis correlates directly with the observed cytotoxicity in cell culture, which further supports the hypothesis that COS functions as more than a simple H2S shuttle in certain biological systems.

Targeting microbial resistance: Synthesis, antibacterial evaluation, DNA binding and modeling study of new chalcone-based dithiocarbamate derivatives.

New dithiocarbamate chalcone-based derivatives were synthesized, their structures were elucidated using different spectroscopic techniques. They were subjected to antimicrobial screening against selected Gram negative bacteria focusing on microbial resistance. Bacterial resistance was targeted via phosphoethanolamine transferase enzyme. Most of the synthesized compounds showed equal or higher activity to colistin standard. Compound 24 proved to be the most active candidate with MIC of 8 µg/ml against both Ps12 and K4 and MBC of 32 µg/ml against Ps12 and 16 µg/ml against K4 Molecular docking study showed that 20, 22, 24 and 25 had good binding affinity with active site residues via Thr280. DNA macromolecule was further targeted. Compounds 28 and 34 were recorded to have better DNA binding than doxurubucin with IC50 of 27.48 and 30.97 µg/ml respectively, suggesting that it could have a role in their higher antibacterial effect. Their docking into DNA has shown a clear intercalation matching with antibacterial data. Pharmacokinetics parameters of active compounds showed that they have better absorption through GIT.

Comparison of 99mTc-UBI 29-41, 99mTc-ciprofloxacin, 99mTc-ciprofloxacin dithiocarbamate and 111In-biotin for targeting experimental Staphylococcus aureus and Escherichia coli foreign-body infections: an ex-vivo study.

BACKGROUND: Diagnosis of implant-associated infection is challenging. Several radiopharmaceuticals have been described but direct comparisons are limited. Here we compared in vitro and in an animal model 99mTc-UBI, 99mTc-ciprofloxacin, 99mTcN-CiproCS2 and 111In-DTPA-biotin for targeting E. coli (ATCC 25922) and S. aureus (ATCC 43335). METHODS: Stability controls were performed with the labelled radiopharmaceuticals during 6 hours in saline and serum. The in vitro binding to viable or killed bacteria was evaluated at 37 °C and 4 °C. For in vivo studies, Teflon cages were subcutaneously implanted in mice, followed by percutaneous infection. Biodistribution of i.v. injected radiolabelled radiopharmaceuticals were evaluated during 24 h in cages and dissected tissues. RESULTS: Labelling efficiency of all radiopharmaceuticals ranged between 94% and 98%, with high stability both in saline and in human serum. In vitro binding assays displayed a rapid but poor bacterial binding for all tested agents. Similar binding kinetic occurred also with heat-killed and ethanol-killed bacteria. In the tissue cage model, infection was detected at different time points: 99mTc-UBI and 99mTcN-CiproCS2 showed higher infected cage/sterile cage ratio at 24 hours for both E. coli and S. aureus; 99mTc-Ciprofloxacin at 24 hours for both E. coli and at 4 hours for S. aureus; 111In-DTPA-biotin accumulates faster in both E. coli and S. aureus infected cages. CONCLUSIONS: 99mTc-UBI, 99mTcN-CiproCS2 showed poor in vitro binding but good in vivo binding to E. coli only. 111In-DTPA-biotin showed poor in vitro binding but good in vivo binding to S. aureus and poor to E. coli. 99mTc-Ciprofloxacin showed poor in vitro binding but good in vivo binding to all tested bacteria. The mechanism of accumulation in infected sites remains to be elucidated.