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Drug research

Thieme

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    In silico Investigation of Lon Protease as a Promising Therapeutic Target

    Parisa AsadollahiIraj PakzadSobhan GhafourianHossein Kazemian...
    9页
    查看更多>>摘要：Considering the widespread occurrence of antibiotic resistance, the need for new therapeutic strategies is inevitable. Bacterial proteases are a broad set of enzymes that play a vital role in cell survival, stress response, and pathogenicity. This in silico study was aimed to focus on the crucial role of Lon protease in the regulation of toxin-antitoxin systems in E. coli and to design inhibitory peptides against the action of this protease. With the help of relevant servers and softwares, the communication network, the evolutionary history, and the interaction of Lon with the corresponding antitoxins were examined, following which the inhibitory peptides were designed against these interactions. The results showed that Lon protease plays a central role in the control of these systems and is a conserved protein, especially among the Enterobacteriaceae family. The docking results of the designed peptides with the Lon protease were significant. This study showed that Lon protease may have the characteristics of a new therapeutic target.
      原文链接:
    • NSTL
    • Thieme Medical Publishers

    Decipher the inhibitory potential of phytocompounds from Leptadenia reticulata on dopamine D2 receptor to enhance prolactin secretion

    Roshan Kumar SharmaSunil S JalalpureMahendra Kumar ChouhanSanjay Deshpande...
    8页
    查看更多>>摘要：Dopamine is secreted by the hypothalamus, which inhibits the proliferation and effectiveness of lactotroph cells that release prolactin via dopamine D2 receptor (D2R). D2R activation inhibits lactotroph cell prolactin synthesis and regulates prolactin gene expression. Although, commercial medications are available for hypogalactia and agalactia, various plant sources significantly alleviate these problems. Leptadenia reticulata (Jivanti) is one of the important medicinal plants often consumed by nursing mothers to improve breast milk production. However, mechanism and chemical constituents involved in the inhibition of D2R by Jivanti is unclear. Therefore, in this study the phytocompounds reported from Jivanti were used for in-silico analysis to predict D2R inhibitory potential. The binding affinity value of campesterol and β-sitosterol (??10.1 and ?10.0?kcal/mol) with D2R has high revealed by molecular docking and stable interaction reveled by molecular dynamics simulation. Thus, these lead compounds could exert more D2R inhibitory activity resulting into prolactin release, which may lead to an increase in breast milk production. Although all selected compounds had fine permeation, non-toxic, and non-carcinogenic characteristics predicted by ADMET, campesterol had good solubility, absorption characteristics compared to other. Therefore, Jivanti, which is traditionally known medicinal plant, could be explored as a medication candidate to boost breast milk production.
      原文链接:
    • NSTL
    • Thieme Medical Publishers

    Toxicity of Hydrogen Sulfide on Rat Brain Neurons

    Enayatollah SeydiZahra IrandoostMahmoud Ghazi KhansariParvaneh Naserzadeh...
    6页
    查看更多>>摘要：Hydrogen sulfide (H2S) is a toxic compound known as a member of the gasotransmitter family. H2S has the ability to inhibit the cytochrome c oxidase enzyme in the mitochondrial respiratory chain. Mitochondria play an important role in energy production and the brain needs energy for normal function. Mitochondrial dysfunction is associated with neurodegenerative diseases. This study investigated the mechanisms of cytotoxicity induced by H2S in brain neurons. thioacetamide has been used to produce H2S in water solutions. The results of the study showed that thioacetamide at concentrations of 116, 232 and 464?μg/ml was able to increase the level of reactive oxygen species (ROS), collapse in mitochondrial membrane potential (MMP), damage to the lysosomal membrane, increase in the level of oxidized glutathione (GSSG) and decrease in the level of reduced glutathione (GSH) in brain neurons. The results of the study suggested that H2S causes damage to mitochondria and lysosomes in brain neurons that could be associated with neurodegenerative diseases.
      原文链接:
    • NSTL
    • Thieme Medical Publishers

    Carvacrol Enhance Apoptotic Effect of 5-FU on MCF-7 Cell Line via inhibiting P-glycoprotein: An In-silco and In-vitro Study

    Vajihe GhorbanzadehKarwan Anwar Hassan AljafHunar Mustafa WasmanLale Pirzeh...
    6页
    查看更多>>摘要：Background P-glycoprotein (P-gp), is an ATP-dependent efflux transporter and overexpressed in cancer cells which is responsible for drug resistance and transportation of anticancer agents out of cells. Hence, P-gp inhibition is a promising way to reverse multi-drug resistance, finding a suitable inhibitor is essential. Carvacrol, an active compound of thyme, has been shown anticancer properties in several types of cancers but the mechanisms underlying this effect remain unclear. Here, we evaluated the inhibitory effects of carvacrol on P-gp by In-silco and in-vitro studies. Method carvacrol was docked against P-gp via autodock vina software to identify the potential binding of this agent. Verapamil, a well-known P-gp inhibitor, was selected as the control ligands. Cell proliferation and apoptosis were assessed using MTT assay and ELISA cell death assay, respectively. Results It was observed that carvacrol exhibited appropriate affinity (?7?kcal/mol) to drug binding pocket of P-gp when compared with verapamil that showed binding affinities of ?8?kcal/mol. The result of MTT assay showed a dose-dependent inhibitory effect of carvacrol and 5-FU. Data of apoptosis assay showed that combining carvacrol with 5-FU increased apoptotic effect of 5-FU 6.7-Fold rather than the control group. This ability to enhance apoptosis is more than the combination of verapamil and 5-FU (4.26-Fold). Conclusion These results provide important evidence that carvacrol may be a promising agent able to overcome P-gp-mediated MDR.
      原文链接:
    • NSTL
    • Thieme Medical Publishers

    Administration of Orexin-A into the Rat Thalamic Paraventricular Nucleus Enhances the Naloxone Induced Morphine Withdrawal

    Fatemeh BabaieMasoumeh Kourosh-AramiMona Farhadi
    6页
    查看更多>>摘要：Objective Orexin neuropeptides are implicated in physical dependence on opioids and expression of withdrawal symptoms in drug abuse. The paraventricular nucleus of the midline thalamus (PVT) has a high expression of orexin receptors. The current research studied the effect of orexin-A in the PVT area on the development of behavioral indices produced by morphine withdrawal in rats. Methods Male Wistar rats weighing 250–300 gr were utilised. To produce drug dependence, morphine (6, 16, 26, 36, 46, 56, and 66?mg/kg, 2?ml/kg) was injected at an interval of 24 hrs for 7 days. To assess the involvement of the orexin in withdrawal syndrome, we injected orexin-A (100?μM, 200?nl) into the PVT for 7 days before each morphine injection. On the day after the last injection of morphine, naloxone (2.5?mg/kg, i.p.) was injected to elicit the morphine withdrawal symptoms which were observed and checked for 25?min. Results The results of the current research showed that the orexin-A in PVT enhances the severity of behavioral symptoms prompted by the injection of naloxone in drug-dependent rats. Conclusions These observations imply that targeting the orexin receptors in PVT might exhibit a new therapeutic strategy for the future treatment of dependence.
      原文链接:
    • NSTL
    • Thieme Medical Publishers

    Preclinical Safety Evaluation: Acute and Repeated-Dose Toxicity of a New Intranasal Recombinant Vector Vaccine TB/FLU-04L Against Tuberculosis

    Kira StosmanKonstantin SivakAndrey AleksandrovZhanna Buzitskaya...
    5页
    查看更多>>摘要：Background Vaccination against tuberculosis is one of the most successful medical measures to reduce morbidity and mortality. The BCG vaccine has been in use for more than 100 years, but its efficacy is still controversial. New vaccine candidates may offer better protection than available BCG vaccine. In this work, we studied the acute and the repeated-dose toxicity study of a new vector vaccine TB/Flu-04L against tuberculosis. Materials and Methods The study was conducted on 60 BALB/c mice and 150 Wistar rats. The vaccine was administered intranasally and intravenously for the acute toxicity study. For the repeated-dose toxicity study, rats were intranasally immunized by 6.5 log10 TCID50 or 7.5 log10 TCID50 three times with 21-day intervals. Mortality, temperature, body weight, food and water consumption, hematological and biochemical parameters, urine analysis, as well as cardiovascular, respiratory, and central nervous system parameters were evaluated. A macroscopic examination of internal organs was performed. Results The TB/FLU-04L vaccine did not cause death among the mice and rats in the acute toxicity study. There were no pathological abnormalities in animal condition, behavior, food and water consumption, temperature, and body weight during the observation period. The results suggest that intranasal repeated-dose administration of the TB/FLU-04L vaccine does not exhibit significant toxicity in rats. Hematological and biochemistry analysis and the histological examination identified no toxicity-associated changes. Conclusions The toxicity study in mice and rats showed that the intranasal vector vaccine TB/FLU-04L had no toxic effect. The tests confirm no adverse effects for laboratory animals in the studied parameters.
      原文链接:
    • NSTL
    • Thieme Medical Publishers

    Thymoquinone Augments Methotrexate-Induced Apoptosis on Osteosarcoma Cells

    Darioush ShanebandiNiloufar TarghazehBahman YousefiJafar Soleimanpour...
    6页
    查看更多>>摘要：Background Osteosarcoma (OS) as the most frequent primary bone malignancy in children and adolescents has a short survival rate in advanced stages. Alternative herbal medicines with fewer side effects or the potency to protect common therapy’s side effects can be helpful in combinational therapies. Herein, we aim to explore the effects of Thymoquinone (TQ) combined with Methotrexate (MTX) on Saos-2 cells apoptosis. Methods The effects of TQ and MTX alone or in combination on Saos-2 cell viability were measured by MTT assay. Real-time PCR was applied for the measurement of Bax, BCL-2, and caspase-9 mRNA expression. Apoptosis evaluation was conducted by flow cytometry. Results TQ improves the cytotoxic effects of MTX on Saos-2 cells proliferation at lower doses. Indeed, the IC50 of MTX decreased from 26 μM to 15 μM when it combined with TQ. TQ and MTX can induce the expression level of pro-apoptotic factors, Bax and caspase-9 while inhibiting anti-apoptotic protein BCL-2. Moreover, the combination of TQ and MTX potentiates apoptosis to 73%, compared to either TQ (48%) or MTX (53%) treated cells. Conclusion The co-treatment of TQ and MTX is associated with the up-regulation of apoptotic factors and down-regulation of anti-apoptotic factors, conducting apoptosis aggravation and OS cell death.
      原文链接:
    • NSTL
    • Thieme Medical Publishers

    Quercetin and Methotrexate in Combination have Anticancer Activity in Osteosarcoma Cells and Repress Oncogenic MicroRNA-223

    Erfan MohammadiForough AlemiMasomeh MalekiFaezeh Malakoti...
    8页
    查看更多>>摘要：Introduction Osteosarcoma (OS) is one of the most common bone neoplasms in adolescents. Notable short- and long-term toxic effects of OS chemotherapy regimens have been reported. Hence, new chemotherapeutic agents with the ability to potentiate OS chemotherapy drugs and protect non-tumorous tissues are required. Methods Saos-2 cells were treated with Methotrexate (MTX) and Quercetin (Que) (a polyphenolic flavonoid with anti-tumor effects) alone and in combination. MTT assay was performed to investigate the cytotoxicity of the drugs. Moreover, apoptosis-involved genes, including miR-223, p53, BCL-2, CBX7, and CYLD expression were analyzed via qRT-PCR. Annexin V-FITC/PI kit was employed to assess the apoptosis rate. Results The MTT results showed that Que increases MTX cytotoxicity on OS cells. The measured IC50s are 142.3?μM for QUE and 13.7?ng/ml for MTX. A decline in MTX IC50 value was observed from 13.7?ng/ml to 8.45?ng/ml in the presence of Que. Moreover, the mRNA expression outcomes indicated that the combination therapy significantly up-regulates the tumor suppressor genes, such as p53, CBX7, and CYLD, and declines anti-apoptotic genes BCL-2 and miR-223, which can lead to proliferation inhibition and apoptosis inducement. Furthermore, the apoptosis rate increased significantly from 6.03% in the control group to 38.35% in Saos-2 cells that were treated with the combination of MTX and Que. Conclusion Que, with the potential to boost the anticancer activity of MTX on Saos-2 cancer cells through proliferation inhibition and apoptosis induction, is a good candidate for combination therapy.
      原文链接:
    • NSTL
    • Thieme Medical Publishers