Fernando Ezquer  Ya-Lin Huang  Marcelo Ezquer 《International journal of molecular sciences》2022,23(5)

Drug-induced liver injury (DILI) is one of the leading causes of acute liver injury. Many factors may contribute to the susceptibility of patients to this condition, making DILI a global medical problem that has an impact on public health and the pharmaceutical industry. The use of mesenchymal stem cells (MSCs) has been at the forefront of regenerative medicine therapies for many years, including MSCs for the treatment of liver diseases. However, there is currently a huge gap between these experimental approaches and their application in clinical practice. In this concise review, we focus on the pathophysiology of DILI and highlight new experimental approaches conceived to improve cell-based therapy by the in vitro preconditioning of MSCs and/or the use of cell-free products as treatment for this liver condition. Finally, we discuss the advantages of new approaches, but also the current challenges that must be addressed in order to develop safer and more effective procedures that will allow cell-based therapies to reach clinical practice, enhancing the quality of life and prolonging the survival time of patients with DILI.  相似文献   

    

Manuel Gacitúa  Alexander Carreo  Rosaly Morales-Guevara  Dayn Pez-Hernndez  Jorge I. Martínez-Araya  Eyleen Araya  Marcelo Preite  Carolina Otero  María Macarena Rivera-Zaldívar  Andrs Silva  Juan A. Fuentes 《International journal of molecular sciences》2022,23(5)

Searching for adequate and effective compounds displaying antimicrobial activities, especially against Gram-positive bacteria, is an important research area due to the high hospitalization and mortality rates of these bacterial infections in both the human and veterinary fields. In this work, we explored (E)-4-amino-3-((3,5-di-tert-butyl-2-hydroxybenzylidene)amino) benzoic acid (SB-1, harboring an intramolecular hydrogen bond) and (E)-2-((4-nitrobenzilidene)amino)aniline (SB-2), two Schiff bases derivatives. Results demonstrated that SB-1 showed an antibacterial activity determined by the minimal inhibitory concentration (MIC) against Staphylococcus aureus, Enterococcus faecalis, and Bacillus cereus (Gram-positive bacteria involved in human and animal diseases such as skin infections, pneumonia, diarrheal syndrome, and urinary tract infections, among others), which was similar to that shown by the classical antibiotic chloramphenicol. By contrast, this compound showed no effect against Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, and Salmonella enterica). Furthermore, we provide a comprehensive physicochemical and theoretical characterization of SB-1 (as well as several analyses for SB-2), including elemental analysis, ESMS, ¹H and ¹³C NMR (assigned by 1D and 2D techniques), DEPT, UV-Vis, FTIR, and cyclic voltammetry. We also performed a computational study through the DFT theory level, including geometry optimization, TD-DFT, NBO, and global and local reactivity analyses.  相似文献   

    

Oscar O. Solis-Castro  Marcelo N. Rivolta  Fiona M. Boissonade 《International journal of molecular sciences》2022,23(5)

Evidence from dental-related stem cells (DRSCs) suggests an enhanced potential for ectodermal lineage differentiation due to their neural crest origin. Growing evidence that DRSC cultures can produce cells with a neural crest-derived stem cell (NCSC)-like phenotype supports their potential for future therapeutic approaches for neurodegenerative diseases and nerve injuries. However, most of the evidence is limited to the characterization of DRSCs as NCSCs by detecting the expression of neural crest markers. Only a few studies have provided proof of concept of an improved neuro-glial differentiation or direct applicability in relevant models. In addition, a current problem is that several of the existing protocols do not meet manufacturing standards for transferability to a clinical scenario. This review describes the current protocols to obtain NCSCs from DRSCs and their characterization. Also, it provides important considerations from previous work where DRSCs were established and characterized as mesenchymal stromal cells but studied for their neuro-glial differentiation potential. The therapeutic advancement of DRSCs would depend on establishing protocols that can yield a neural crest-like phenotype efficiently, using appropriate manufacturing standards and testing them in relevant models of disease or injury. Achieving these conditions could then facilitate and validate the therapeutic potential of DRSC-NCSCs in regenerative therapies.  相似文献   

    

Natlia Lins da Silva-Gomes  Leonardo Alexandre de Souza Ruivo  Claudia Moreira  Marcelo Meuser-Batista  Cristiane Frana da Silva  Denise da Gama Jaen Batista  Stênio Fragoso  Gabriel Melo de Oliveira  Maria de Nazar Correia Soeiro  Otacilio C. Moreira 《International journal of molecular sciences》2022,23(23)

Ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) are enzymes located on the surface of the T. cruzi plasma membrane, which hydrolyze a wide range of tri-/-diphosphate nucleosides. In this work, we used previously developed genetically modified strains of Trypanosoma cruzi (T. cruzi), hemi-knockout (KO +/−) and overexpressing (OE) the TcNTPDase-1 gene to evaluate the parasite infectivity profile in a mouse model of acute infection (n = 6 mice per group). Our results showed significantly higher parasitemia and mortality, and lower weight in animals infected with parasites OE TcNTPDase-1, as compared to the infection with the wild type (WT) parasites. On the other hand, animals infected with (KO +/−) parasites showed no mortality during the 30-day trial and mouse weight was more similar to the non-infected (NI) animals. In addition, they had low parasitemia (45.7 times lower) when compared with parasites overexpressing TcNTPDase-1 from the hemi-knockout (OE KO +/−) group. The hearts of animals infected with the OE KO +/− and OE parasites showed significantly larger regions of cardiac inflammation than those infected with the WT parasites (p < 0.001). Only animals infected with KO +/− did not show individual electrocardiographic changes during the period of experimentation. Together, our results expand the knowledge on the role of NTPDases in T. cruzi infectivity, reenforcing the potential of this enzyme as a chemotherapy target to treat Chagas disease (CD).  相似文献   

    

Thatiana Corrêa de Melo  Dilza Trevisan-Silva  Miryam P. Alvarez-Flores  Renata Nascimento Gomes  Marcelo Medina de Souza  Hellen Paula Valerio  Douglas S. Oliveira  Carlos DeOcesano-Pereira  Viviane Fongaro Botosso  Soraia Attie Calil Jorge  Mirta Schattner  Ricardo M. Gomez  Ana Marisa Chudzinski-Tavassi 《International journal of molecular sciences》2022,23(18)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for the severe pandemic of acute respiratory disease, coronavirus disease 2019 (COVID-19), experienced in the 21st century. The clinical manifestations range from mild symptoms to abnormal blood coagulation and severe respiratory failure. In severe cases, COVID-19 manifests as a thromboinflammatory disease. Damage to the vascular compartment caused by SARS-CoV-2 has been linked to thrombosis, triggered by an enhanced immune response. The molecular mechanisms underlying endothelial activation have not been fully elucidated. We aimed to identify the proteins correlated to the molecular response of human umbilical vein endothelial cells (HUVECs) after exposure to SARS-CoV-2, which might help to unravel the molecular mechanisms of endothelium activation in COVID-19. In this direction, we exposed HUVECs to SARS-CoV-2 and analyzed the expression of specific cellular receptors, and changes in the proteome of HUVECs at different time points. We identified that HUVECs exhibit non-productive infection without cytopathic effects, in addition to the lack of expression of specific cell receptors known to be essential for SARS-CoV-2 entry into cells. We highlighted the enrichment of the protein SUMOylation pathway and the increase in SUMO2, which was confirmed by orthogonal assays. In conclusion, proteomic analysis revealed that the exposure to SARS-CoV-2 induced oxidative stress and changes in protein abundance and pathways enrichment that resembled endothelial dysfunction.  相似文献   

    

Wanderson Gonalves e Gonalves  Marcelo Henrique Paula dos Santos  Leonardo Miranda Brito  Helber Gonzales Almeida Palheta  Fbio Manoel Frana Lobato  Samia Demachki  ndrea Ribeiro-dos-Santos  Gilderlanio Santana de Araújo 《International journal of molecular sciences》2022,23(23)

Emerging deep learning-based applications in precision medicine include computational histopathological analysis. However, there is a lack of the required training image datasets to generate classification and detection models. This phenomenon occurs mainly due to human factors that make it difficult to obtain well-annotated data. The present study provides a curated public collection of histopathological images (DeepHP) and a convolutional neural network model for diagnosing gastritis. Images from gastric biopsy histopathological exams were used to investigate the performance of the proposed model in detecting gastric mucosa with Helicobacter pylori infection. The DeepHP database comprises 394,926 histopathological images, of which 111 K were labeled as Helicobacter pylori positive and 283 K were Helicobacter pylori negative. We investigated the classification performance of three Convolutional Neural Network architectures. The models were tested and validated with two distinct image sets of 15% (59K patches) chosen randomly. The VGG16 architecture showed the best results with an Area Under the Curve of 0.998%. The results showed that CNN could be used to classify histopathological images from gastric mucosa with marked precision. Our model evidenced high potential and application in the computational pathology field.  相似文献   

    

Giulia Sierri  Roberta Dal Magro  Barbara Vergani  Biagio Eugenio Leone  Beatrice Formicola  Lorenzo Taiarol  Stefano Fagioli  Marcelo Kravicz  Lucio Tremolizzo  Laura Calabresi  Francesca Re 《International journal of molecular sciences》2022,23(1)

The cerebral synthesis of cholesterol is mainly handled by astrocytes, which are also responsible for apoproteins’ synthesis and lipoproteins’ assembly required for the cholesterol transport in the brain parenchyma. In Alzheimer disease (AD), these processes are impaired, likely because of the astrogliosis, a process characterized by morphological and functional changes in astrocytes. Several ATP-binding cassette transporters expressed by brain cells are involved in the formation of nascent discoidal lipoproteins, but the effect of beta-amyloid (Aβ) assemblies on this process is not fully understood. In this study, we investigated how of Aβ_1-42-induced astrogliosis affects the metabolism of cholesterol in vitro. We detected an impairment in the cholesterol efflux of reactive astrocytes attributable to reduced levels of ABCA1 transporters that could explain the decreased lipoproteins’ levels detected in AD patients. To approach this issue, we designed biomimetic HDLs and evaluated their performance as cholesterol acceptors. The results demonstrated the ability of apoA-I nanodiscs to cross the blood–brain barrier in vitro and to promote the cholesterol efflux from astrocytes, making them suitable as a potential supportive treatment for AD to compensate the depletion of cerebral HDLs.  相似文献   

    

Marcelo Ozu  Juan Jos Alvear-Arias  Miguel Fernandez  Agustín Caviglia  Antonio Pea-Pichicoi  Christian Carrillo  Emerson Carmona  Anselmo Otero-Gonzalez  Jos Antonio Garate  Gabriela Amodeo  Carlos Gonzalez 《International journal of molecular sciences》2022,23(20)

Aquaporins (AQPs) are small transmembrane tetrameric proteins that facilitate water, solute and gas exchange. Their presence has been extensively reported in the biological membranes of almost all living organisms. Although their discovery is much more recent than ion transport systems, different biophysical approaches have contributed to confirm that permeation through each monomer is consistent with closed and open states, introducing the term gating mechanism into the field. The study of AQPs in their native membrane or overexpressed in heterologous systems have experimentally demonstrated that water membrane permeability can be reversibly modified in response to specific modulators. For some regulation mechanisms, such as pH changes, evidence for gating is also supported by high-resolution structures of the water channel in different configurations as well as molecular dynamics simulation. Both experimental and simulation approaches sustain that the rearrangement of conserved residues contributes to occlude the cavity of the channel restricting water permeation. Interestingly, specific charged and conserved residues are present in the environment of the pore and, thus, the tetrameric structure can be subjected to alter the positions of these charges to sustain gating. Thus, is it possible to explore whether the displacement of these charges (gating current) leads to conformational changes? To our knowledge, this question has not yet been addressed at all. In this review, we intend to analyze the suitability of this proposal for the first time.  相似文献   

    

Giulia Minniti  Letícia Maria Pescinini-Salzedas  Guilherme Almeida dos Santos Minniti  Lucas Fornari Laurindo  Sandra Maria Barbalho  Renata Vargas Sinatora  Lance Alan Sloan  Rafael Santos de Argollo Haber  Adriano Cressoni Araújo  Karina Quesada  Jesselina F. dos Santos Haber  Marcelo Dib Bechara  Katia Portero Sloan 《International journal of molecular sciences》2022,23(21)

Sarcopenia is a disease that becomes more prevalent as the population ages, since it is directly linked to the process of senility, which courses with muscle atrophy and loss of muscle strength. Over time, sarcopenia is linked to obesity, being known as sarcopenic obesity, and leads to other metabolic changes. At the molecular level, organokines act on different tissues and can improve or harm sarcopenia. It all depends on their production process, which is associated with factors such as physical exercise, the aging process, and metabolic diseases. Because of the seriousness of these repercussions, the aim of this literature review is to conduct a review on the relationship between organokines, sarcopenia, diabetes, and other metabolic repercussions, as well the role of physical exercise. To build this review, PubMed-Medline, Embase, and COCHRANE databases were searched, and only studies written in English were included. It was observed that myokines, adipokines, hepatokines, and osteokines had direct impacts on the pathophysiology of sarcopenia and its metabolic repercussions. Therefore, knowing how organokines act is very important to know their impacts on age, disease prevention, and how they can be related to the prevention of muscle loss.  相似文献   

    

Julieta H. Sepulveda-Yanez  Diego Alvarez-Saravia  Jose Fernandez-Goycoolea  Jacqueline Aldridge  Cornelis A. M. van Bergen  Ward Posthuma  Roberto Uribe-Paredes  Hendrik Veelken  Marcelo A. Navarrete 《International journal of molecular sciences》2021,22(23)

Activation-induced deaminase (AID) is required for somatic hypermutation in immunoglobulin genes, but also induces off-target mutations. Follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL), the most frequent types of indolent B-cell tumors, are exposed to AID activity during lymphomagenesis. We designed a workflow integrating de novo mutational signatures extraction and fitting of COSMIC (Catalogue Of Somatic Mutations In Cancer) signatures, with tridimensional chromatin conformation data (Hi-C). We applied the workflow to exome sequencing data from lymphoma samples. In 33 FL and 30 CLL samples, 42% and 34% of the contextual mutations could be traced to a known AID motif. We demonstrate that both CLL and FL share mutational processes dominated by spontaneous deamination, failures in DNA repair, and AID activity. The processes had equiproportional distribution across active and nonactive chromatin compartments in CLL. In contrast, canonical AID activity and failures in DNA repair pathways in FL were significantly higher within the active chromatin compartment. Analysis of DNA repair genes revealed a higher prevalence of base excision repair gene mutations (p = 0.02) in FL than CLL. These data indicate that AID activity drives the genetic landscapes of FL and CLL. However, the final result of AID-induced mutagenesis differs between these lymphomas depending on chromatin compartmentalization and mutations in DNA repair pathways.  相似文献