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Bioisosterism is a useful strategy in rational drug design to improve pharmacodynamic and pharmacokinetic properties of lead compounds. Imidazolidinones have been reported as potent kinase inhibitors and antileishmanial agents. In this study, bioisosteres of imidazolidinones (compounds 1-3) were evaluated for their antileishmanial properties. The modified imidazolidinones exhibited potent antileishmanial activity against extracellular as well as intracellular Leishmania donovani parasites in nanomolar concentrations. The selectivity index of these compounds on host cells was found to be more than 1000, emphasizing their specificity toward the parasite. Using SwissTargetPrediction software, we assessed the potential targets of these compounds and found MAPK as the most probable target. To in vitro validate, we developed a novel in vitro kinase assay that mimics the in vivo nature of the functional kinome. Compounds 1-3 displayed specific inhibition of parasite kinase activity accompanied by an increase in intracellular sodium levels in the parasites. This might be the effect of kinase inhibition that regulates sodium homeostasis through Na-ATPases. Finally, the compound-treated parasites underwent apoptosis-like death. This study represents bioisoterism as a novel approach for drug design to establish the structure-activity relationship, which in turn helps to improve the therapeutic activity of lead compounds.
Assuntos
Antiprotozoários/farmacologia , Desenho de Fármacos , Imidazolidinas/farmacologia , Leishmania donovani/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Apoptose/efeitos dos fármacos , Imidazolidinas/síntese química , Imidazolidinas/química , Estrutura Molecular , Sódio/metabolismo , Relação Estrutura-AtividadeRESUMO
Most obturator hernias are diagnosed intraoperatively due to their vague signs and symptoms. However, they are associated with a high mortality rate mainly because of the patient's age, comorbidities, and late diagnosis. We present three cases of obturator hernia in patients admitted under our care with signs of acute intestinal obstruction. All the patients were elderly with comorbidities, and they underwent open surgery with anatomical repair of the hernial defect with or without resection of any gangrenous bowel. They were discharged in good health, and during the limited follow-up period, there has been no recurrence. We would like to emphasize that obturator hernia should be considered in the differential diagnosis when an elderly, thinly built woman presents with acute intestinal obstruction. Though the outcome of such cases depends on the clinical status and comorbidities of the patient, early diagnosis and treatment can help in reducing postoperative morbidity and mortality.
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Fournier's gangrene, which is a necrotizing fasciitis of the perineal region, requires prompt control of infection with emergent surgical debridement. The shameful exposure of gonads, which occurs following debridement, can cause both physiological and psychological impairment to the patient. These can be avoided by the use of this novel technique for testicular preservation. Following debridement of necrotic scrotal skin, this technique involves creation of inguinal pouch by blunt dissection and placement of the testes in the pouch created. Once healthy granulation tissue is achieved in the scrotal wound, closure of the scrotum is performed after bringing down the testes. The advantages of this technique include development of a relatively physiological position to preserve the testes before definitive reconstruction of the scrotum and the easy reproducibility of the technique. A holistic approach to management of Fournier's gangrene should include resuscitation, administration of antibiotics, debridement, and scrotal reconstruction. However, the psychological impact of shameful exposure of the gonads must also be borne in mind during the management. Our technique represents one of the ways to reduce the stigma and discomfort associated with shameful exposure of the testes.
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Coronavirus disease 2019 (COVID-19) is caused due to infection by severe acute respiratory syndrome virus coronavirus 2 (SARS-CoV-2). It is highly infective virus resulting in recent on-going pandemic and causing multisystem involvement predominantly affecting respiratory system. The most common presenting symptoms are fever, dry cough and breathlessness. The role of Computerized tomography (CT) is crucial especially in those patient having negative (rRT-PCR) but with high clinical suspicion, for prognosis and follow up. CT imaging findings mainly consists of multiple patchy bilateral ground-glass opacity (GGO) with or without consolidation and interlobular septal thickening with a peripheral or posterior distribution, mainly involving the lower lobes, depending upon the stage of disease. We present two case report of high CT severity score COVID-19 infection on non-invasive ventilation (NIV) having rare complication of pneumomediastinum and subcutaneous emphysema apart from typical COVID pattern lung findings during their course of admission in the hospital.
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Yield and productivity are critical for the economics and viability of a bioprocess. In metabolic engineering the main objective is the increase of a target metabolite production through genetic engineering. Metabolic engineering is the practice of optimizing genetic and regulatory processes within cells to increase the production of a certain substance. In the last years, the development of recombinant DNA technology and other related technologies has provided new tools for approaching yields improvement by means of genetic manipulation of biosynthetic pathway. Industrial microorganisms like Escherichia coli, Actinomycetes, etc. have been developed as biocatalysts to provide new or to optimize existing processes for the biotechnological production of chemicals from renewable plant biomass. The factors like oxygenation, temperature and pH have been traditionally controlled and optimized in industrial fermentation in order to enhance metabolite production. Metabolic engineering of bacteria shows a great scope in industrial application as well as such technique may also have good potential to solve certain metabolic disease and environmental problems in near future.