Due to high relative blood flow the kidney is prone to drug-induced damage. Aminoglycoside type antibiotic gentamicin is one of the leading cause of drug-induced nephrotoxicity. In recent years ...gentamicin nephrotoxicity is significantly reduced by shifting to once daily dosage as well as by eliminating known risk factors. Application of gentamicin is still related to serious side effects which are reported more often compared to other antibiotics. Because gentamicin is still heavily used and is highly efficient in treating infections, it is important to find mechanisms to reduce its nephrotoxicity. This aim can only be achieved through better understanding of kidney metabolism of gentamicin. This problem has been extensively researched in the last 20 years. The experimental results have provided evidence for almost complete understanding of mechanisms responsible for gentamicin nephrotoxicity. We now have well described morphological, biochemical and functional changes in kidney due to gentamicin application. During the years, this model has become so popular that now it is used as an experimental model for nephrotoxicity per se. This situation can mislead an ordinary reader of scientific literature that we know everything about it and there is nothing new to discover here. But quite opposite is true. The precise and complete mechanism of gentamicin nephrotoxicity is still point of speculation and an unfinished story. With emerge of new and versatile technics in biomedicine we have an opportunity to reexamine old beliefs and discover new facts. This review focuses on current knowledge in this area and gives some future perspectives.
Direct-acting antivirals are effective tools to control viral infections. SARS-CoV-2 is a coronavirus associated with the epidemiological outbreak in late 2019. Previous reports showed that HIV-1 ...protease inhibitors could block SARS-CoV main protease. Based on that and using an
approach, we evaluated SARS-CoV-2 main protease as a target for HIV-1 protease inhibitors to reveal the structural features related to their antiviral effect. Our results showed that several HIV inhibitors such as lopinavir, ritonavir, and saquinavir produce strong interaction with the active site of SARS-CoV-2 main protease. Furthermore, broad library protease inhibitors obtained from PubChem and ZINC (www.zinc.docking.org) were evaluated. Our analysis revealed 20 compounds that could be clustered into three groups based on their chemical features. Then, these structures could serve as leading compounds to develop a series of derivatives optimizing their activity against SARS-CoV-2 and other coronaviruses. Altogether, the results presented in this work contribute to gain a deep understanding of the molecular pharmacology of SARS-CoV-2 treatment and validate the use of protease inhibitors against SARS-CoV-2.
Molecular mechanisms of etoposide Montecucco, Alessandra; Zanetta, Francesca; Biamonti, Giuseppe
EXCLI journal,
01/2015, Letnik:
14
Journal Article
Recenzirano
Odprti dostop
Etoposide derives from podophyllotoxin, a toxin found in the American Mayapple. It was first synthesized in 1966 and approved for cancer therapy in 1983 by the U.S. Food and Drug Administration ...(Hande, 199825). Starting from 1980s several studies demonstrated that etoposide targets DNA topoisomerase II activities thus leading to the production of DNA breaks and eliciting a response that affects several aspects of cell metabolisms. In this review we will focus on molecular mechanisms that account for the biological effect of etoposide.
Recently, bioinformatics has advanced to the level that it allows almost accurate prediction of molecular interactions that hold together a protein and a ligand in the bound state. For instance, the ...program AutoDock has been developed to provide a procedure for predicting the interaction of small molecules with macromolecular targets which can easily separate compounds with micromolar and nanomolar binding constants from those with millimolar binding constants and can often rank molecules with finer differences in affinity. AutoDock can be used to screen a variety of possible compounds, searching for new compounds with specific binding properties or testing a range of modifications of an existing compound. The present work is a detailed outline of the protocol to use AutoDock in a more user-friendly manner. The first step is to retrieve required Ligand and Target.pdb files from major databases. The second step is preparing PDBQT format files for Target and Ligand (Target.pdbqt, Ligand.pdbqt) and Grid and Docking Parameter file (a.gpf and a.dpf) using AutoDock 4.2. The third step is to perform molecular docking using Cygwin and finally the results are analyzed. With due confidence, this is our humble claim that a researcher with no previous background in bioinformatics research would be able to perform molecular docking using AutoDock 4.2 program by following stepwise guidelines given in this article.
Animal experimentation helps us to understand human biology. Rodents and, in particular, rats are among the most common animals used in animal experiments. Reporting data on animal age, animal body ...weight, and animal postnatal developmental stages is not consistent, which can cause the failure to translate animal data to humans. This review summarizes age-related postnatal developmental stages in rats by addressing age-related changes in their body weights. The age and body weight of animals can affect drug metabolism, gene expression, metabolic parameters, and other dependent variables measured in animal studies. In addition, considering the age and the body weight of the animals is of particular importance in animal modeling of human diseases. Appropriate reporting of age, body weight, and the developmental stage of animals used in studies can improve animal to human translation.
Obesity is a disorder of lipid metabolism and continues to be a global problem, ranking fifth for deaths worldwide. It also leads to diabetes, cardiovascular disorders, musculoskeletal disorders and ...some types of cancer. Obesity is regarded as the output of a long-term imbalance between energy intake and energy expenditure. Digestion and absorption of dietary lipids by pancreatic lipase, a major source of excess calorie intake, can be targeted for development of anti-obesity agents. Being the major factor of concern, food materials and edible plants are most widely studied for the anti-obesity activity, so that they can be incorporated in the routine diet. In this review, an attempt was made to present a current scenario of the bioactive compounds from plant and microbial origin that have been investigated for their pancreatic lipase inhibition. Compounds belonging to various classes of natural products such as alkaloids, carotenoids, glycosides, polyphenols, polysaccharides, saponins and terpenoids are well studied while lipophilic compounds from microbial sources are the most active against the pancreatic lipase. Few studies on the synthetic analogues, structurally similar to the triglycerides have been described in the review. Despite of tremendous research on the finding of potential pancreatic lipase inhibitor, very few compounds have entered the clinical studies and no new molecule after orlistat has been marketed. Along with HTS based screening, detailed structure-activity relationship studies on semi-synthetic and synthetic derivatives might also provide a direction for the development of potential lead(s) or pharmacophore for pancreatic lipase inhibition in order to treat and/or prevent obesity and related disorders.
This review will concentrate on the clinical pharmacology, in particular pharmacodynamic data, related to atypical antipsychotics, clozapine, risperidone, paliperidone, olanzapine, que¬tiapine, ...amisulpride, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone and cariprazine. A summary of their acute pharmacokinetics properties are also reported. Four new second-generation antipsychotics are available: iloperidone, asenapine, lurasidone and in the next future cariprazine. Similar to ziprasidone and aripiprazole, these new agents are advisable for the lower propensity to give weight gain and metabolic abnormalities in comparison with older second-generation antipsychotics such as olanzapine or clozapine. Actually lurasidone seems to be best in terms of minimizing unwanted alterations in body weight and metabolic variables. Therapeutic drug monitoring is not strictly necessary for all of the new antipsychotic drugs because there are no unequivocal data supporting a relationship between plasma drug levels and clinical outcomes or side effects. The exception can be represented by clozapine for which plasma levels of 350-420 ng/ml are reported to be associated with an increased probability of a good clinical response. Also for olanzapine an established therapeutic range (20-50 ng/ml) is proposed to yield an optimal response and minimize side effects.
Cancer imposes a global health burden as it represents one of the leading causes of morbidity and mortality while also giving rise to significant economic burden owing to the associated expenditures ...for its monitoring and treatment. In spite of advancements in cancer therapy, the low success rate and recurrence of tumor has necessitated the ongoing search for new therapeutic agents. Aside from drugs based on small molecules and protein-based biopharmaceuticals, there has been an intense effort geared towards the development of peptide-based therapeutics owing to its favorable and intrinsic properties of being relatively small, highly selective, potent, safe and low in production costs. In spite of these advantages, there are several inherent weaknesses that are in need of attention in the design and development of therapeutic peptides. An abundance of data on bioactive and therapeutic peptides have been accumulated over the years and the burgeoning area of artificial intelligence has set the stage for the lucrative utilization of machine learning to make sense of these large and high-dimensional data. This review summarizes the current state-of-the-art on the application of machine learning for studying the bioactivity of anticancer peptides along with future outlook of the field. Data and R codes used in the analysis herein are available on GitHub at https://github.com/Shoombuatong2527/anticancer-peptides-review.
is a South American plant, the cultivation of which is increasing worldwide due to its high content of sweet compounds.
sweetness is mainly due to steviol glycosides, that are ~250-300 times sweeter ...than sucrose. Many studies have suggested the benefits of
extract over sugar and artificial sweeteners, but it is still not a very popular sugar substitute. This review summarizes current data on the biological activities of
extract and its individual glycosides, including anti-hypertensive, anti-obesity, anti-diabetic, antioxidant, anti-cancer, anti-inflammatory, and antimicrobial effects and improvement of kidney function. Possible side effects and toxicity of
extract are also discussed.
Nanoparticles (NPs) have become an important field of research over the past several decades with applications in various sectors, such as biomedical, cosmetic, food and many others, because of their ...unique characteristics. The green synthesis of nanoparticles has been preferred because of the naturally occurring reductants present in biological systems that decreases exposure to toxic chemicals compared with physico-chemical methods and is eco-friendly. Zinc oxide (ZnO) NPs exhibit broad and potential applications in different fields with their specific characteristics such as surface area, size, shape, low toxicity, optical properties, high binding energy and large band gap. This paper focuses on the bio-synthesis of ZnO NPs by utilizing extracts of different plant parts (stem, flower, fruit, peel, and leaves) through efficient, economical, simple, pure, and eco-friendly green routes. In this process, zinc salts have been used as precursor and phytochemicals in the plant extract reduce the metal salt to lower oxidation state as well as stabilize the ZnO NPs. The morphological and physico-chemical properties of obtained NPs analyzed by various characterization techniques have been discoursed. Further, antimicrobial activity and potential photocatalytic application in terms of the degradation of dyes have also been reviewed in addition to the toxicity aspects of these NPs on human beings and animals.
