METHODS: 3c-induced inhibition of proliferation was measured in the absence and presence NAC using MTT in HT-29 and SW620 cells and xCELLigence RTCA DP instrument. 3c-induced apoptotic studies were performed using flow cytometry. 3c-induced redox alterations were measured by ROS production using fluorescence plate reader and flow cytometry and mitochondrial membrane potential by flow cytometry; NADPH and GSH levels were determined by colorimetric assays. Bcl2 family protein expression and cytochrome c release and PARP activation was done by western blotting. Caspase activation was measured by ELISA. Cell migration assay was done using the real time xCELLigence RTCA DP system in SW620 cells and wound healing assay in HT-29.
RESULTS: Many anticancer therapeutics exert their effects by inducing reactive oxygen species (ROS). In this study, we demonstrate that 3c-induced inhibition of cell proliferation is reversed by the antioxidant, N-acetylcysteine, suggesting that 3c acts via increased production of ROS in HT-29 cells. This was confirmed by the direct measurement of ROS in 3c-treated colorectal cancer cells. Additionally, treatment with 3c resulted in decreased NADPH and glutathione levels in HT-29 cells. Further, investigation of the apoptotic pathway showed increased release of cytochrome c resulting in the activation of caspase-9, which in turn activated caspase-3 and -6. 3c also (i) increased p53 and Bax expression, (ii) decreased Bcl2 and BclxL expression and (iii) induced PARP cleavage in human colorectal cancer cells. Confirming our observations, NAC significantly inhibited induction of apoptosis, ROS production, cytochrome c release and PARP cleavage. The results further demonstrate that 3c inhibits cell migration by modulating EMT markers and inhibiting TGFβ-induced phosphorylation of Smad2 and Samd3.
CONCLUSIONS: Our findings thus demonstrate that 3c disrupts redox balance in colorectal cancer cells and support the notion that this agent may be effective for the treatment of colorectal cancer.
METHODS: The title amides (4a-j) were obtained by simple nucleophilic substitution reaction of dexibuprofen acid chloride with substituted amines in good yield and chemical structures were confirmed by FTIR, 1H NMR, 13C NMR and mass spectral data.
RESULTS: The brine shrimp lethality assay results showed that all of the synthesized compounds are non-toxic to shrimp larvae. The inhibitory effects on tumor growth were evaluated and it was observed that N-(2,5-dichlorophenyl)-2-(4-isobutylphenyl) propionamide (4e) and N-(2-chlorophenyl)-2-(4-isobutylphenyl) propionamide (4g) exhibited excellent antitumor activity compared to all other derivatives. The compound 4e bearing 2,5-dichloro substituted phenyl ring and 4g possesses 2-chloro substituted phenyl ring exhibited 100% inhibition of the tumor growth. The anticancer activity was evaluated against breast carcinoma cell line (MCF-7) and it was observed that derivative 4e exhibited excellent growth inhibition of cancer cells with IC50 value of 0.01±0.002 µm, which is better than the standard drugs. The docking studies against breast cancer type 1 susceptibility protein BRCA1 (PDBID 3K0H) exhibited good binding affinities, which are in good agreement with the wet lab results. The compounds 4e and 4g showed the binding energy values of -6.39 and -6.34 Kcal/mol, respectively. The molecular dynamic (MD) simulation was also carried out to evaluate the residual flexibility of the best docking complexes of compounds 4e and 4g. The MD simulation analysis assured that the 4e formed a more stable complex with the target protein than the 4g. The synthesized amide derivatives exhibited were devoid of gastrointestinal side effects and no cytotoxic effects against human normal epithelial breast cell line (MCF-12A) were found.
CONCLUSION: Based upon our wet lab and dry lab findings we propose that dexibuprofen analogue 4e may serve as a lead structure for the design of more potent anticancer drugs.
METHODS: Both patients had features of difficult airway, American Society of Anesthesiologists (ASA) physical status class III and central venous occlusive disease. The common approach, i.e., ultrasound-guided supraclavicular brachial plexus block was technically difficult with inherent risk of vascular puncture due to dilated venous collaterals at the supraclavicular area possibly compromising block quality. The risk of general anesthesia (GA) was significant as patients were morbidly obese with possible risk of obstructive sleep apnea postoperatively. As an alternative, we performed the ultrasound-guided costoclavicular approach infraclavicular brachial plexus block with 20 mL local anesthetic (LA) ropivacaine 0.5% delivered at the identified costoclavicular space using in-plane needling technique. Another 10 mL of LA was infiltrated along the subcutaneous fascia of the proximal medial aspect of arm.
RESULTS: Both surgeries of >2 hours' duration were successful, without the need of further local infiltration at surgical site or conversion to GA.
CONCLUSIONS: Ultrasound-guided costoclavicular approach can be an alternative way of providing effective analgesia and safe anesthesia for vascular access surgery of the upper limb.
METHODS: Five APT quantification methods, including asymmetry analysis and its variants as well as two Lorentzian model-based methods, were applied to data acquired from six rats that underwent middle cerebral artery occlusion scanned at 9.4T. Diffusion and perfusion-weighted images, and water relaxation time maps were also acquired to study the relationship of these conventional imaging modalities with the different APT quantification methods.
RESULTS: The APT ischemic area estimates had varying sizes (Jaccard index: 0.544 ≤ J ≤ 0.971) and had varying correlations in their distributions (Pearson correlation coefficient: 0.104 ≤ r ≤ 0.995), revealing discrepancies in the quantified ischemic areas. The Lorentzian methods produced the highest contrast-to-noise ratios (CNRs; 1.427 ≤ CNR ≤ 2.002), but generated APT ischemic areas that were comparable in size to the cerebral blood flow (CBF) deficit areas; asymmetry analysis and its variants produced APT ischemic areas that were smaller than the CBF deficit areas but larger than the apparent diffusion coefficient deficit areas, though having lower CNRs (0.561 ≤ CNR ≤ 1.083).
CONCLUSION: There is a need to further investigate the accuracy and correlation of each quantification method with the pathophysiology using a larger scale multi-imaging modality and multi-time-point clinical study. Future studies should include the magnetization transfer ratio asymmetry results alongside the findings of the study to facilitate the comparison of results between different centers and also the published literature.
OBJECTIVE: The objective of this study is to evaluate the anti-cancer potential of the novel class of quinazoline tethered acetamide derivatives against six different cancer cell lines.
METHOD: A novel series of various substituted quinazolinone acetamides were synthesized through a feasible scheme. The synthetic scheme involves the conversion of benzoxazinone (from anthranilic acid and benzoyl chloride) intermediate to 3-amino quinazoline-4-one which is further converted to the final amide by tethering with the propionyl chloride employing Schotten-Baumann Reaction conditions. All the synthesized derivatives characterized by IR, 1HNMR and MASS spectral methods and anti-cancer activity evaluated by employing MTT assay for six cancer cell lines and one normal human cell line.
RESULTS: All the synthesized compounds were screened for anti-cancer activity against six cancer cell lines, including A 549 (lung), DU 145 (prostate), HT 29 (colon), MCF-7 (breast), SiHA (cervical), B16F10 (mouse skin melanoma) and one normal human fibroblast cell lines. All the compounds displayed a decent cytotoxicity profile when compared with the standard drug, doxorubicin. Among the synthesized compounds (5a to 5n) tested, two compounds, 5f and 5g have demonstrated excellent cytotoxicity against SiHA and MCF-7 cancer cell lines.
CONCLUSION: Comparatively, most of the compounds displayed decent cytotoxicity potential relative to the standard drug, doxorubicin. Further investigations are needed to establish the detailed mechanism of action of the developed novel quinazolinone acetamides.
Methods: This study analyzed all suspected ADEs related to favipiravir reported from 2015. The reports were analyzed based on age, gender, and seriousness of ADEs at the System Organ Classification (SOC) level and the individual Preferred Term (PT) level.
Results: This study is based on 194 ADEs reported from 93 patients. Most frequent ADEs suspected to be caused by the favipiravir included increased hepatic enzymes, nausea and vomiting, tachycardia, and diarrhea. Severe and fatal ADEs occurred more frequently in men and those over the age of 64 years. Blood and lymphatic disorders, cardiac disorders, hepatobiliary disorders, injury poisoning, and procedural complications were more common manifestations of severe ADEs.
Conclusion: This study revealed that favipiravir appears to be a relatively safe drug. An undiscovered anti-inflammatory activity of favipiravir may explain the improvement in critically ill patients and reduce inflammatory markers. Currently, the data is based on very few patients. A more detailed assessment of the uncommon ADEs needs to be analyzed when more information will be available.