Given the high mortality rate and clinical impact associated with sinusoidal obstruction syndrome (SOS), many studies have attempted to better characterize the disease and potential treatment strategies. However, the unpredictability of SOS onset represents a major obstacle when developing reproducible and controlled clinical trials in humans. Similarly, although in vitro studies have elucidated many of the molecular and cellular mechanisms of SOS, they often lack clinical relevance and translatability, highlighting the importance of experimental in vivo research. Animal models have greatly varied in the approach used to induce SOS in accordance with the numerous causes of human disease. Thus far, the most common and prevalent model is the monocrotaline-induced model in rats, which has served as the basis for both new diagnostic and treatment studies and has been revised over the last 20 years to optimize its use. Furthermore, radiotherapy, oxaliplatin-based chemotherapy, and even hematopoietic stem cell transplantation have been recently used to better replicate human SOS in animals. Nevertheless, because of the novelty of such research, further studies should be conducted to better understand the reproducibility and applicability of these newer models. Thus, this review seeks to summarize the methods and results of experimental in vivo models of SOS and compare the efficacy of these various adaptations.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

There is a new public health crisis threatening the world with the emergence and spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease was later named novel coronavirus disease or COVID-19. It was then declared a pandemic by the World Health Organization on March 11, 2020. The virus originated in bats and was transmitted to humans through unknown intermediary animals in Wuhan, Hubei province, China, in December 2019. As of February 5, 2021, 103 million laboratory-confirmed cases and nearly 2.3 million deaths were reported globally. The number of death tolls continues to rise, and a large number of countries have been forced to maintain social distance in public place and enforce lockdown. As per literature, coronavirus is transmitted human to human or human to animal via airborne droplets. Coronavirus enters the human cell through the membrane ACE-2 exopeptidase receptor. WHO, ECDC, and ICMR advised avoiding public places and close contact with infected persons and pet animals. To date, there is no evidence of any effective treatment for COVID-19. The main therapies being used to treat the disease are antiviral drugs, chloroquine/hydroxychloroquine, and respiratory therapy. Although several therapies have been proposed, quarantine is the only intervention that appears to be effective in decreasing the contagion rate. We conducted a literature review of publicly available information to summarize knowledge about the pathogen and the current epidemic. In the present literature review, the causative agent of the pandemic, epidemiology, pathogenesis, and diagnostic techniques are discussed. Further, currently used treatment, preventive strategies along with vaccine trials and computational tools are all described in detail.

• MeSH
• COVID-19 * MeSH
• hydroxychlorochin MeSH
• kontrola infekčních nemocí MeSH
• lidé MeSH
• pandemie MeSH
• SARS-CoV-2 * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Arylbenzimidazoles have been synthesized as antimycobacterial agents. An efficient synthesis has been developed for 2-arylbenzimidazoles from o-phenylenediamines and aromatic aldehydes in molecular sieves-methanol system. The methodology is straightforward to get 2-arylbenzimidazoles (3a-3z) in excellent yields with high chemoselectivity over 2-aryl-1-benzylbenzimidazoles (4a-4z). All these benzimidazole analogues were evaluated against M. tuberculosis in BACTEC radiometric assay. The compounds 4y and 4z exhibited potential antitubercular activity against M. tuberculosis H37RV, MIC at 16 µM and 24 µM respectively. The best compound of the series i.e. compound 4y was well tolerated by Swiss-albino mice in acute oral toxicity. Compound 4y possessing a diarylbenzimidazole core, can further be optimized for better activity.

• MeSH
• antituberkulotika chemická syntéza   farmakologie   MeSH
• aplikace orální MeSH
• bakteriální proteiny antagonisté a inhibitory   metabolismus   MeSH
• DNA gyráza chemie   metabolismus   MeSH
• imidazoly chemie   farmakologie   MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• myši MeSH
• simulace molekulového dockingu MeSH
• tělesná hmotnost účinky léků   MeSH
• terciární struktura proteinů MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

This study was designed to assess both the quality and cost aspects of various branded and generic formulations of angiotensin receptor blockers, specifically Irbesartan, Losartan Potassium, Olmesartan Medoxomil, Telmisartan, and Valsartan. The collected samples underwent distinct quality evaluations using the methods outlined in different global Pharmacopoeias (British Pharmacopoeia/European Pharmacopoeia, Indian Pharmacopoeia and United States Pharmacopoeia). These drugs were characterized using Fourier-Transform Infrared Spectroscopy and Nuclear Magnetic Resonance techniques, while their quality and concentration were analysed using High Performance Liquid Chromatography. The release profile of the drugs was examined through dissolution testing. Additionally, a cost comparison analysis was carried out by determining the prevailing market prices of the drugs. The evaluated branded and generic angiotensin receptor blockers were found to meet the established standards for impurities, active drug content, and dissolution as set by these Pharmacopoeias, indicating their optimal quality. Notably, the generic drugs exhibited significantly lower costs compared to their branded counterparts. This study confirms that the quality of generic angiotensin receptor blockers is equivalent to that of their branded counterparts. Consequently, these findings support the practicality of utilizing generic drugs as a more economically sustainable and cost-effective approach to managing diseases, especially those of chronic nature.

• Publikační typ
• časopisecké články MeSH

The purpose of the present study was to study the synergy potential of gallic acid-based derivatives in combination with conventional antibiotics using multidrug resistant cultures of Escherichia coli. Gallic acid-based derivatives significantly reduced the MIC of tetracycline against multidrug resistant clinical isolate of E. coli. The best representative, 3-(3',4,'5'-trimethoxyphenyl)-4,5,6-trimethoxyindanone-1, an indanone derivative of gallic acid, was observed to inhibit ethidium bromide efflux and ATPase which was also supported by in silico docking. This derivative extended the post-antibiotic effect and decreased the mutation prevention concentration of tetracycline. This derivative in combination with TET was able to reduce the concentration of TNFα up to 18-fold in Swiss albino mice. This derivative was nontoxic and well tolerated up to 300 mg/kg dose in subacute oral toxicity study in mice. This is the first report of gallic acid-based indanone derivative as drug resistance reversal agent acting through ATP-dependent efflux pump inhibition.

• MeSH
• antibakteriální látky farmakologie   MeSH
• aplikace orální MeSH
• Escherichia coli účinky léků   MeSH
• indany aplikace a dávkování   škodlivé účinky   farmakologie   MeSH
• inhibitory enzymů farmakologie   MeSH
• kyselina gallová aplikace a dávkování   škodlivé účinky   farmakologie   MeSH
• makrofágy účinky léků   MeSH
• mikrobiální testy citlivosti MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nežádoucí účinky léčiv MeSH
• septický šok prevence a kontrola   MeSH
• simulace molekulového dockingu MeSH
• synergismus léků * MeSH
• tetracyklin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Colorectal cancer (CRC) is one of the most deaths causing diseases worldwide. Several risk factors including hormones like insulin and insulin like growth factors (e.g., IGF-1) have been considered responsible for growth and progression of colon cancer. Though there is a huge advancement in the available screening as well as treatment techniques for CRC. There is no significant decrease in the mortality of cancer patients. Moreover, the current treatment approaches for CRC are associated with serious challenges like drug resistance and cancer re-growth. Given the severity of the disease, there is an urgent need for novel therapeutic agents with ideal characteristics. Several pieces of evidence suggested that natural products, specifically medicinal plants, and derived phytochemicals may serve as potential sources for novel drug discovery for various diseases including cancer. On the other hand, cancer cells like colon cancer require a high basal level of reactive oxygen species (ROS) to maintain its own cellular functions. However, excess production of intracellular ROS leads to cancer cell death via disturbing cellular redox homeostasis. Therefore, medicinal plants and derived phytocompounds that can enhance the intracellular ROS and induce apoptotic cell death in cancer cells via modulating various molecular targets including IGF-1 could be potential therapeutic agents. Alkaloids form a major class of such phytoconstituents that can play a key role in cancer prevention. Moreover, several preclinical and clinical studies have also evidenced that these compounds show potent anti-colon cancer effects and exhibit negligible toxicity towards the normal cells. Hence, the present evidence-based study aimed to provide an update on various alkaloids that have been reported to induce ROS-mediated apoptosis in colon cancer cells via targeting various cellular components including hormones and growth factors, which play a role in metastasis, angiogenesis, proliferation, and invasion. This study also provides an individual account on each such alkaloid that underwent clinical trials either alone or in combination with other clinical drugs. In addition, various classes of phytochemicals that induce ROS-mediated cell death in different kinds of cancers including colon cancer are discussed.

• MeSH
• alkaloidy * terapeutické užití   MeSH
• hormony terapeutické užití   MeSH
• insulinu podobný růstový faktor I MeSH
• lidé MeSH
• nádory tračníku * farmakoterapie   metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Roxadustat (RXD) is an approved drug substances for the treatment of renal anemia. It has poor aqueous solubility and photochemical stability. This study employs a comprehensive approach to enhance the stability and physicochemical properties RXD through coformer selection and characterization. The investigation integrates delta pKa analysis, molecular complementary assessment, molecular electrostatic potential surface analysis, and machine learning techniques to predict potential co-crystal formation and binding interactions between drug molecules and coformers. The co-crystal screening which lead to in a novel RXD-nicotinamide co-crystal (RXD-NA). Experimental characterization underscores the physical and chemical stability of the co-crystals. To elucidate the supramolecular synthons and understand the intermolecular interactions in the RXD-NA co-crystal, Hirshfeld surfaces analysis, quantum theory of atoms in molecules (QTAIM) analysis and non-covalent interaction (NCI) analysis were performed. Computational analysis of photo-isomer formation aligns with experimental observations, further enhancing our understanding of RXD-coformer interactions. RXD-NA co-crystal was found photo-chemically stable as compared to free base API drug substance. This integrated methodology provides a systematic framework for informed co-crystal design, holding promise for optimizing RXD formulations based on molecular interactions and stability considerations. Consequently, this study contributes valuable insights to the field of rational drug design and formulation optimization.

• MeSH
• glycin * MeSH
• rozpustnost MeSH
• Publikační typ
• časopisecké články MeSH

Organophosphate (OP)-based pesticides and nerve agents are highly toxic compounds which interrupt the catalytic mechanism of acetylcholinesterase (AChE) by phosphorylating the hydroxyl moiety of serine residue. The inhibited enzyme can be reactivated by the nucleophilic action of oxime reactivators. To analyze the effect of different AChE sources on reactivation efficacy of reactivators, several in vivo studies have carried out using variety of AChE sources like pig, rat and monkey. Investigations on species differences provide a better insight for the development of new reactivators. Hence, present study was mainly targeted on comparative analysis of the reactivation of electric eel and human AChE inhibited by different OP. A series of butene-linked bis-pyridinium mono oximes which vary in functional groups present at the second pyridinium ring have been examined against sarin, VX, tabun and ethyl-paraoxon-poisoned AChE. In case of tabun-inhibited AChEs, tested oximes were better than reference oximes. For VX-poisoned human AChE, reactivator K251 (kr2;1.51 mM (-) (1 )min (-) (1)) showed good reactivation efficacy with standard oximes. Studies stipulated that butene-linked oximes consisting of different functional moieties are good reactivators and found to have better efficacy to reactivate nerve agent-inhibited human AChE in comparison to eel AChE.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• časové faktory MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• dospělí MeSH
• Electrophorus MeSH
• erytrocytární membrána účinky léků   enzymologie   MeSH
• kinetika MeSH
• lidé MeSH
• organofosfáty farmakologie   MeSH
• oximy farmakologie   MeSH
• reaktivátory cholinesterasy farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: In patients with colorectal liver metastases, the possibility for radical liver resection can be limited by oxaliplatin-induced sinusoidal obstruction syndrome (SOS). This study investigates the potential of mesenchymal stem cells (MSC) to improve the outcome of liver resections in pigs with SOS. MATERIALS AND METHODS: SOS was induced in all animals (n=20) on day 0. Animals in the experimental group (n=8) received allogeneic MSC on day 7. Liver resection was performed in all animals on day 14 and the animals were observed until day 28. Ultrasound volumetry, biochemical analysis and histological examination of liver parenchyma was performed during the follow-up period. RESULTS: Six animals from the control group died prematurely, while all animals survived in the experimental group. According to histology, biochemical analysis and ultrasound volumetry, there were no significant differences between the groups documenting the effect of MSC. CONCLUSION: Single dose allogeneic MSC administration improved survival of animals with SOS undergoing partial liver resection. Further experiments with different timing of liver resection and MSC administration should be performed to investigate the effect of MSC in more detail.

• MeSH
• biologické markery MeSH
• hepatektomie * metody   MeSH
• imunofenotypizace MeSH
• imunohistochemie MeSH
• jaterní žilní okluze etiologie   patologie   terapie   MeSH
• kolorektální nádory patologie   MeSH
• kombinovaná terapie MeSH
• mezenchymální kmenové buňky * cytologie   MeSH
• modely nemocí na zvířatech MeSH
• nádory jater komplikace   sekundární   MeSH
• prasata MeSH
• transplantace mezenchymálních kmenových buněk * MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

In recent years, considerable progress has been made in topologically and functionally characterizing integral outer membrane proteins (OMPs) of Treponema pallidum subspecies pallidum, the syphilis spirochete, and identifying its surface-exposed β-barrel domains. Extracellular loops in OMPs of Gram-negative bacteria are known to be highly variable. We examined the sequence diversity of β-barrel-encoding regions of tprC, tprD, and bamA in 31 specimens from Cali, Colombia; San Francisco, California; and the Czech Republic and compared them to allelic variants in the 41 reference genomes in the NCBI database. To establish a phylogenetic framework, we used T. pallidum 0548 (tp0548) genotyping and tp0558 sequences to assign strains to the Nichols or SS14 clades. We found that (i) β-barrels in clinical strains could be grouped according to allelic variants in T. pallidum subsp. pallidum reference genomes; (ii) for all three OMP loci, clinical strains within the Nichols or SS14 clades often harbored β-barrel variants that differed from the Nichols and SS14 reference strains; and (iii) OMP variable regions often reside in predicted extracellular loops containing B-cell epitopes. On the basis of structural models, nonconservative amino acid substitutions in predicted transmembrane β-strands of T. pallidum repeat C (TprC) and TprD2 could give rise to functional differences in their porin channels. OMP profiles of some clinical strains were mosaics of different reference strains and did not correlate with results from enhanced molecular typing. Our observations suggest that human host selection pressures drive T. pallidum subsp. pallidum OMP diversity and that genetic exchange contributes to the evolutionary biology of T. pallidum subsp. pallidum They also set the stage for topology-based analysis of antibody responses to OMPs and help frame strategies for syphilis vaccine development.IMPORTANCE Despite recent progress characterizing outer membrane proteins (OMPs) of Treponema pallidum, little is known about how their surface-exposed, β-barrel-forming domains vary among strains circulating within high-risk populations. In this study, sequences for the β-barrel-encoding regions of three OMP loci, tprC, tprD, and bamA, in T. pallidum subsp. pallidum isolates from a large number of patient specimens from geographically disparate sites were examined. Structural models predict that sequence variation within β-barrel domains occurs predominantly within predicted extracellular loops. Amino acid substitutions in predicted transmembrane strands that could potentially affect porin channel function were also noted. Our findings suggest that selection pressures exerted within human populations drive T. pallidum subsp. pallidum OMP diversity and that recombination at OMP loci contributes to the evolutionary biology of syphilis spirochetes. These results also set the stage for topology-based analysis of antibody responses that promote clearance of T. pallidum subsp. pallidum and frame strategies for vaccine development based upon conserved OMP extracellular loops.

• MeSH
• fylogeneze MeSH
• genetická variace MeSH
• lidé MeSH
• molekulární evoluce * MeSH
• molekulární sekvence - údaje MeSH
• proteinové domény MeSH
• proteiny vnější bakteriální membrány chemie   genetika   metabolismus   MeSH
• sekvence aminokyselin MeSH
• sekvence nukleotidů MeSH
• sekvenční seřazení MeSH
• Spirochaetales klasifikace   genetika   růst a vývoj   izolace a purifikace   MeSH
• syfilis mikrobiologie   MeSH
• Treponema pallidum klasifikace   genetika   růst a vývoj   izolace a purifikace   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH