Drug Research最新文献

Protein kinases belong to the phosphor-transferases superfamily of enzymes, which "activate" enzymes via phosphorylation. The kinome of an organism is the total set of genes in the genome, which encode for all the protein kinases. Certain mutations in the kinome have been linked to dysregulation of protein kinases, which in turn can lead to several diseases and disorders including cancer. In this review, we have briefly discussed the role of protein kinases in various biochemical processes by categorizing cancer associated phenotypes and giving their protein kinase examples. Various techniques have also been discussed, which are being used to analyze the structure of protein kinases, and associate their roles in the oncogenesis. We have also discussed protein kinase inhibitors and United States Federal Drug Administration (USFDA) approved drugs, which target protein kinases and can serve as a counter to protein kinase dysregulation and mitigate the effects of oncogenesis. Overall, this review briefs about the importance of protein kinases, their roles in oncogenesis on dysregulation and how their inhibition via various drugs can be used to mitigate their effects.

The upsurge of cancer demands intense, rapid and effective intervention from the scientific society. Even though nanoparticles helped achieving this, maintaining its size without using toxic capping agents is challenging. Phytochemicals having reducing properties is a proper substitute and the efficiency of such nanoparticles could be further improved by grafting with suitable monomers. It could be further protected from rapid biodegradation by coating with suitable materials. This approach was utilized wherein, the green synthesized silver nanoparticles (AgNps) were initially functionalized with -COOH to couple with -NH₂ groups of ethylene diamine. It was then coated with polyethylene glycol (PEG) and hydrogen bonded with curcumin. The formed amide bonds could effectively uptake drug molecules and sensed environmental pH. Swelling studies and release profiles confirmed selective drug release. All these results along with those obtained from MTT assay, suggested the potential applicability of the prepared material in pH sensitive drug delivery of curcumin.

Malaria is one of the world's most devastating diseases, infecting well over 300 million people annually and killing between 2 and 3 million worldwide. Increasing parasite resistance to many existing drugs is exacerbating disease. Resistance to commonly used malarial drugs is increasing the need to develop new drugs urgently. Due to the slow pace and substantial costs of new drug development, repurposing of old drugs which is recently increasingly becoming an attractive proposition of highly efficient and effective way of drug discovery led us to study the drug rifampicin for this purpose. The present paper aims to investigate the route of Plasmodium falciparum apicoplast-targeted proteins that putatively encode β subunits of RNA polymerase with an objective to develop an effective antimalarial drug. Homology searching for conserved binding site to the rifampicin drug and the functional analysis of rpoB gene were done. Multiple Sequence alignment analysis of rpoB was compared with that in E.coli - rpoB and M. tuberculosis - rpoB. Docking studies of Rifampicin - rpoB complex was also done for finding binding affinity. The results of computational studies showed that rifampicin is a potential drug for malaria.

Introduction: This paper sought to scrutinize the role of microRNA-32 (miR-32) on the growth and migration as well as on the expression of metastatic genes in PC3 cells of prostate cancer in vitro.

Methods: Subsequent transfection of cells with miR-32 mimics, miR-32 inhibitor, negative control (NC), cell proliferation using MTT, and apoptosis by ELISA were performed. Furthermore, qRT-PCR was directed to measure the expression levels of matrix metalloproteinase 2 (MMP2) and vascular endothelial growth factors (VEGF) as metastatic and angiogenesis genes in the progression of PC3.

Results: miR-32 was overexpressed in PC3 cells compared to normal cells (P<0.001). Down-regulation of miR-32 obstructs in vitro proliferation and migration while intensifying the apoptosis rate in PC3 cells. Also, we found that miR-32 negatively modulates the expression of VEGF and MMP2 in PC3 cells.

Conclusion: These results indicate that the suppression of miR-32 might offer an auxiliary treatment procedure for addressing the invasion, progression, and metastasis in PCa patients by improving cell apoptosis.

Oximes, as classical acetylcholinesterase (AChE) reactivators, have some pharmacokinetics/pharmacodynamics disadvantages. During the synthesis of non-oxime compounds, we encountered the compound 2-formylbenzoic acid (2-FBA) with promising in vitro and in vivo cholinesterase (ChE) reactivating properties in the acute exposure to diazinon (DZN). For in vitro experiments, the healthy mice serum and brain homogenate were freshly prepared and exposed to DZN (160 µg/mL). After 10 minutes, 2-FBA was added to the poisoned samples, and ChE activity was measured afterward. For the in vivo assay, the mice were poisoned with DZN subcutaneous (SC) injection (50 mg/kg), and after 1 hour, either 2-FBA or Pralidoxime (2-PAM) was injected intravenously (IV). After 3 h, ChE activity was measured in the serum and brain homogenate samples. The LD50 (IV) for 2-FBA in mice was measured as well. 2-FBA effectively reactivated the inhibited ChE in serum and brain homogenate samples in vitro. In the in vivo experiments, while 2-FBA could significantly reactivate the brain ChE even better than 2-PAM, they failed to reactivate the serum ChE by single IV injection. LD50 of 2-FBA was calculated to be 963 mg/kg. There were no general toxicity signs in any treatment groups. The in silico results support the potential ability of 2-FBA efficacy via possibly Witting reaction mechanism. Our findings indicate that 2-FBA seems to be a suitable non-oxime candidate for AChE reactivation with minimal side effects. Further toxicokinetic studies on this compound are strongly recommended to be performed before conducting the clinical trial in humans.

Imatinib mesylate (IM) is the gold standard for treatment of Chronic Myeloid Leukemia (CML). This study aimed to gain more knowledge of the altered PK, pharmacogenetic factors, and gene expression leading to variable IM levels. Fifty patients with chronic phase-CML were enrolled in this study and divided as 25 responders and 25 non-responders (patients are directly recruited after response assessment). HPLC/MS/MS was used to determine trough and peak concentration of imatinib and N-desmethyl imatinib in the blood. PCR-RFLP technique was used to detect IDH1 gene mutation (R132). The median value of IM trough level was significantly higher, the P/T ratio was significantly lower and the α-1-acid glycoprotein (AGP) was significantly higher among responders compared to non-responders (P=0.007, 0.009 and 0.048, respectively). Higher N-desmethyl imatinib peak plasma concentration was observed with low mRNA expression of ABCG2 and OCT1 (P=0.01 and 0.037, respectively). IDH1 R132 gene mutation was associated with a significant increase in toxicities (P=0.028). In conclusion, IM trough level, P/T ratio and AGP was significantly higher in responders. In addition, ABCG2 and OCT1 gene expression may affect the interindividual PK variation. Although a prospective study with a larger patient population is necessary to validate these findings. IDH1 mutation is a predictor of increased toxicity with IM treatment.

Curcumin has a wide range of pharmacological activities, including antioxidant, anti-inflammatory and tissue protective. In here we hypothesized that curcumin-loaded chitosan-coated solid lipid nanoparticles (CuCsSLN) are able to increase its overall bioavailability and hence its antioxidant and mitochondria;/lysosomal protective properties of curcumin. CuCsSLN were prepared using solvent diffusion technique for formation of solid lipid nanoparticles (SLNs) and electrostatic coating of positive-charged chitosan to negative surface of SLNs. CuCsSLN showed the encapsulation efficiency of 91.4±2.7%, the mean particle size of 208±9 nm, the polydispersity index of 0.34±0.07, and the zeta potential of+53.5±3.7 mV. The scanning electron microscope (SEM) images of nanoparticles verified their nanometric size and also spherical shape. Curcumin was released from CuCsSLN in a sustain release pattern up to 24 hours. Then isolated cardiomyocytes and mitochondria were simultaneously treated with (1) control (0.05% ethanol), (2) celecoxib (20 µg/ml) treatment, (3) celecoxib (20 µg/ml)+++CuCsSLN (1 µg/ml) treatment, (4) CuCsSLN (1 µg/ml) treatment, (5) celecoxib (20 µg/ml)+++curcumin (10 µM) treatment and (6) curcumin (10 µM) treatment for 4 h at 37°C. The results showed that celecoxib (20 µg/ml) induced a significant increase in cytotoxicity, reactive oxygen species (ROS) formation, mitochondria membrane potential (ΔΨm) collapse, lipid peroxidation, oxidative stress and mitochondrial swelling while CuCsSLN and curcumin reverted the above toxic effect of celecoxib. Our data indicated that the effect of CuCsSLN in a number of experiments, is significantly better than that of curcumin which shows the role of chitosan nanoparticles in increasing effect of curcumin.

Background: Ischemia/reperfusion has been reported to further damage the intestine reperfusion injury (IRI) and cause multiple distal organ dysfunction through oxidative stress, inflammation, and apoptosis. Cysteamine is known to inhibit oxidative stress, inflammatory cytokines and apoptosis. This experiment was designed to evaluate the role of cysteamine against IRI in rats METHODS: Thirty-two Wistar rat strains were assigned to four groups: sham, Intestinal-reperfusion injury (IRI), 50 mg/kg and 100 mg/kg cysteamine treatment IRI. A 5 cm segment of terminal ileum was twisted 360° clockwise along the mesentery for 45 minutes to induce ischemia before detorsion. Tissues were preserved for biochemical evaluation and histology 4 hours after detorsion. Activities of GPx, GSH, protein and non-protein thiol, H₂O₂, MDA were evaluated. Serum concentration of nitrite, MPO, ALT, AST TNF-alpha and IL-6 were measured. Caspase 3 and bax were evaluated by immunohistochemistry. Statistical significance was set as p<0.05 RESULTS: Significant (p<0.05) increase in H₂O_2, MDA and nitrite but reduction in GPx, GSH, protein thiol and non-protein thiol in the IRI rats was reversed by 50 and 100 mg/kg cysteamine. Serum MPO, TNF-α, IL6, AST and ALT was significantly elevated in IRI while the rats treated with cysteamine showed a significant decrease (p<0.05) in the activities of these inflammatory and hepatic injury markers.

Conclusion: Cysteamine mitigate IRI by enhancing intracellular antioxidant defense system, inhibiting inflammatory mediators and intestinal tissue expression of pro-apoptotic protein.

Background: Chronic pain represents a significant and costly healthcare problem especially in the older patient. Transdermal opioid therapy is easy to apply and ensures constant supply of active ingredients. However, skin irritation, poor adhesion and systemic side effects complicate transdermal pain therapy.

Methods: In the Relief study, comprising 54 centers, all in Germany, 252 patients were recruited and data about the general care situation as well as the characteristics, effects and side effects of the Aloe vera fentanyl patch were collected. 92 patients had a prior treatment with fentanyl patch without Aloe vera, allowing a comparative analysis.

Results: Compared to patches without Aloe vera, the new fentanyl patch showed better adhesion. Systemic and local tolerance and pain reduction were also significantly better. Patients also reported improvements in side effects and central parameters of quality of life. The data regarding the care situation in Germany showed remarkably low use of coanalgetics and laxatives in pain patients.

Discussion: Aloe vera in transdermal pain treatment improves adhesion and local tolerance of the patch. Pain control and quality of life were also improved. Regional care data concerning cotreatment in pain therapy from this study indicate a lack of penetration of existing guidelines in general practitioners' pain therapy.