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1.
Article in English | MEDLINE | ID: mdl-36125533

ABSTRACT

The 4,4'-diaminodiphenyl sulfone (DDS), also known as dapsone, is traditionally used as a potent anti-bacterial agent in clinical management of leprosy. For decades, dapsone has been among the first-line medications used in multidrug treatment of leprosy recommended by the World Health Organization (WHO). Shortly after dapsone's discovery as an antibiotic in 1937, the dual function of dapsone (anti-microbial and anti-inflammatory) was elucidated. Dapsone exerts its anti-bacterial effects by inhibiting dihydrofolic acid synthesis, leading to inhibition of bacterial growth, while its anti-inflammatory properties are triggered by inhibiting reactive oxygen species (ROS) production, reducing the effect of eosinophil peroxidase on mast cells and downregulating neutrophil-mediated inflammatory responses. Among the leading mechanisms associated with its anti-microbial/anti-protozoal effects, dapsone clearly has multiple antioxidant, anti-inflammatory, and anti-apoptotic functions. In this regard, it has been described in treating a wide variety of inflammatory and infectious skin conditions. Previous reports have explored different molecular targets for dapsone and provided insight into the anti-inflammatory mechanism of dapsone. This article reviews several basic, experimental, and clinical approaches on anti-inflammatory effect of dapsone.

2.
Front Biosci (Landmark Ed) ; 27(8): 237, 2022 Aug 10.
Article in English | MEDLINE | ID: mdl-36042178

ABSTRACT

BACKGROUND AND AIMS: Experimental models using carbon tetrachloride (CCl4) and D-galactosamine (D-GalN) can be used in preclinical assessment of acute liver failure (ALF) therapies. Unfortunately, these models are characterized by different dynamics of liver injury depending on the animal strain, administered hepatotoxin, and its dose. The aim of this study was to compare known rat and mouse models of ALF with a view to their future introduction into preclinical cell therapy experiments. In particular, based on histopathological and molecular changes, we suggested experimental time cut-off points for an effective stem cell therapeutic intervention. METHODS: ALF was induced by a single intraperitoneal injection of CCl4 in mice (50 µL/100 g b.w.) and rats (200 µL/100 g b.w.) and D-GalN in mice (150 mg/100 g b.w.) and rats (50 mg/100 g b.w.). Blood and liver samples were collected 12 h, 24 h, 48 h and 7 days after intoxication. Blood morphology, liver function blood tests, histopathological changes, proliferation activity, apoptosis, fibrosis, and gene expression were analysed to assess liver damage. RESULTS: At 12 h, 24 h, and 48 h after CCl4 injection, mouse livers showed moderate inflammatory infiltration and massive pericentral necrosis. In rats treated with CCl4, minor lymphocytic infiltration in the liver parenchyma was seen at 12 h, followed by necrosis that appeared around central veins at 24 h and persisted to 48 h. In D-GalN-injected mice, the first histopathological signs of liver injury appeared at 48 h. In the livers of D-GalN-treated rats, moderate pericentral inflammatory infiltration occurred after 12 h, 24 h, and 48 h, accompanied by increased proliferation and apoptosis. All histological changes were accompanied by decreasing expression of certain genes. In most experimental groups of rats and mice, both histological and molecular parameters returned to the baseline values between 48 h and 7 days after intoxication. CONCLUSIONS: In mice and rats with CCl4-induced ALF, signs of liver failure can be seen as early as 12 h and develop to 48 h. In the D-GalN-induced model, mice are more resistant to the hepatotoxic effect than rats (after 12 h), and the early hepatitis phase can be observed much later, after 48 h. These cut-off points seem to be optimal for suppressing inflammation and applying effective stem cell therapy for acute liver injury.


Subject(s)
Chemical and Drug Induced Liver Injury , Liver Failure, Acute , Animals , Cell- and Tissue-Based Therapy , Chemical and Drug Induced Liver Injury/pathology , Chemical and Drug Induced Liver Injury/therapy , Disease Models, Animal , Galactosamine/toxicity , Lipopolysaccharides/pharmacology , Liver/metabolism , Liver Failure, Acute/chemically induced , Liver Failure, Acute/metabolism , Liver Failure, Acute/therapy , Mice , Necrosis/pathology , Rats
3.
J Cent Nerv Syst Dis ; 14: 11795735221102231, 2022.
Article in English | MEDLINE | ID: mdl-35783991

ABSTRACT

Coronavirus disease 2019 (COVID-19) has raised serious concerns worldwide due to its great impact on human health and forced scientists racing to find effective therapies to control the infection and a vaccine for the virus. To this end, intense research efforts have focused on understanding the viral biology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COVID-19. The ever-expanding list of cases, reporting clinical neurological complications in COVID-19 patients, strongly suggests the possibility of the virus invading the nervous system. The pathophysiological processes responsible for the neurological impact of COVID-19 are not fully understood. Some neurodegenerative disorders sometimes take more than a decade to manifest, so the long-term pathophysiological outcomes of SARS-CoV-2 neurotropism should be regarded as a challenge for researchers in this field. There is no documentation on the long-term impact of SARS-CoV-2 on the human central nervous system (CNS). Most of the data relating to neurological damage during SARS-CoV-2 infection have yet to be established experimentally. The purpose of this review is to describe the knowledge gained, from experimental models, to date, on the mechanisms of neuronal invasion and the effects produced by infection. The hope is that, once the processes are understood, therapies can be implemented to limit the damage produced. Long-term monitoring and the use of appropriate and effective therapies could reduce the severity of symptoms and improve quality of life of the most severely affected patients, with a special focus on those have required hospital care and assisted respiration.

4.
CNS Neurosci Ther ; 28(10): 1492-1508, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35896511

ABSTRACT

OBJECTIVES: To systematically review studies using remote ischemia postconditioning (RIPostC) for ischemic stroke in experimental models and obtain factors that significantly influence treatment outcomes. MATERIALS AND METHODS: Peer-reviewed studies were identified and selected based on the eligibility criteria, followed by extraction of data on potentially influential factors related to model preparation, postconditioning, and measure time based on outcome measures including infarct size, neurological scales, and cell tests with autophagy, apoptosis, normal-neuron, and damaged-neuron counting. Then, all data were preprocessed, grouped, and meta-analyzed with the indicator of the standardized mean difference. RESULTS: Fifty-seven studies with 224 experiments (91 for infarct size, 92 for neurological scales, and 41 for cell-level tests) were included. There was little statistical difference between different model preparations, treated body parts, number of treatments, and sides. And treatment effect was generally a positive correlation with the duration of conditioning time to stroke onset with exceptions at some time points. Based on infarct size, the number of cycles per treatment, duration of occlusion, and release per cycle showed significant differences. Combined with the effect sizes by other measures, the occlusion/release duration of 8-10 min per cycle is better than 5 min, and three cycles per treatment were most frequently used with good effects. Effect also varied when measuring at different times, showing statistical differences in infarct size and most neurological scales. RIPostC is confirmed as an effective therapeutic intervention for ischemic stroke, while the RIPostC-mediated autophagy level being activated or inhibited remained conflicting. CONCLUSIONS: Conditioning time, number of cycles per treatment, duration of occlusion, and release per cycle were found to influence the treatment effects of RIPostC significantly. More studies on the relevant influential factors and autophagy mechanisms are warranted.


Subject(s)
Ischemic Postconditioning , Ischemic Stroke , Stroke , Autophagy/physiology , Humans , Infarction , Stroke/therapy
6.
iScience ; 25(8): 104688, 2022 Aug 19.
Article in English | MEDLINE | ID: mdl-35847555

ABSTRACT

Metabolic perturbations can affect gene expression, for instance to rewire metabolism. While numerous efforts have measured gene expression in response to individual metabolic perturbations, methods that determine all metabolic perturbations that affect the expression for a given gene or set of genes have not been available. Here, we use a gene-centered approach to derive a first-pass metabolic regulatory network for Caenorhabditis elegans by performing RNAi of more than 1,400 metabolic genes with a set of 19 promoter reporter strains that express a fluorescent protein in the animal's intestine. We find that metabolic perturbations generally increase promoter activity, which contrasts with transcription factor (TF) RNAi, which tends to repress promoter activity. We identify several TFs that modulate promoter activity in response to perturbations of the electron transport chain and explore complex genetic interactions among metabolic pathways. This work provides a blueprint for a systems-level understanding of how metabolism affects gene expression.

7.
Int J Mol Sci ; 23(14)2022 Jul 15.
Article in English | MEDLINE | ID: mdl-35887167

ABSTRACT

In amyotrophic lateral sclerosis (ALS) patients, loss of cellular homeostasis within cortical and spinal cord motor neurons triggers the activation of the integrated stress response (ISR), an intracellular signaling pathway that remodels translation and promotes a gene expression program aimed at coping with stress. Beyond its neuroprotective role, under regimes of chronic or excessive stress, ISR can also promote cell/neuronal death. Given the two-edged sword nature of ISR, many experimental attempts have tried to establish the therapeutic potential of ISR enhancement or inhibition in ALS. This review discusses the complex interplay between ISR and disease progression in different models of ALS, as well as the opportunities and limitations of ISR modulation in the hard quest to find an effective therapy for ALS.


Subject(s)
Amyotrophic Lateral Sclerosis , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/therapy , Cell Death , Disease Progression , Humans , Motor Neurons/metabolism
8.
Microorganisms ; 10(6)2022 Jun 06.
Article in English | MEDLINE | ID: mdl-35744683

ABSTRACT

The physiology of an organism in the environment reflects its interactions with the diverse physical, chemical, and biological properties of the surface. These principles come into consideration during model selection to study biofilm-host interactions. Biofilms are communities formed by beneficial and pathogenic bacteria, where cells are held together by a structured extracellular matrix. When biofilms are associated with a host, chemical gradients and their origins become highly relevant. Conventional biofilm laboratory models such as multiwall biofilm models and agar plate models poorly mimic these gradients. In contrast, ex vivo models possess the partial capacity to mimic the conditions of tissue-associated biofilm and a biofilm associated with a mineralized surface enriched in inorganic components, such as the human dentin. This review will highlight the progress achieved using these settings for two models of persistent infections: the infection of the lung tissue by Pseudomonas aeruginosa and the infection of the root canal by Enterococcus faecalis. For both models, we conclude that the limitations of the conventional in vitro systems necessitate a complimentary experimentation with clinically relevant ex vivo models during therapeutics development.

9.
iScience ; 25(6): 104483, 2022 Jun 17.
Article in English | MEDLINE | ID: mdl-35712079

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a major research focus because of its poor therapy response and dismal prognosis. PDAC cells adapt their metabolism to the surrounding environment, often relying on diverse nutrient sources. Because traditional experimental techniques appear exhaustive to find a viable therapeutic strategy, a highly curated and omics-informed PDAC genome-scale metabolic model was reconstructed using patient-specific transcriptomics data. From the model-predictions, several new metabolic functions were explored as potential therapeutic targets in addition to the known metabolic hallmarks of PDAC. Significant downregulation in the peroxisomal beta oxidation pathway, flux modulation in the carnitine shuttle system, and upregulation in the reactive oxygen species detoxification pathway reactions were observed. These unique metabolic traits of PDAC were correlated with potential drug combinations targeting genes with poor prognosis in PDAC. Overall, this study provides a better understanding of the metabolic vulnerabilities in PDAC and will lead to novel effective therapeutic strategies.

10.
J Hepatol ; 77(4): 1109-1123, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35605741

ABSTRACT

The hepatitis E virus (HEV) was initially thought to exclusively cause acute hepatitis. However, the first diagnosis of chronic hepatitis E in transplant recipients in 2008 profoundly changed our understanding of this pathogen. We have now begun to understand that specific HEV genotypes can cause chronic infection in certain immunocompromised populations. Over the past decade, dedicated clinical and experimental research has substantiated knowledge on the epidemiology, transmission routes, pathophysiological mechanisms, diagnosis, clinical features and treatment of chronic HEV infection. Nevertheless, many gaps and major challenges remain, particularly regarding the translation of knowledge into disease prevention and improvement of clinical outcomes. This article aims to highlight the latest developments in the understanding and management of chronic hepatitis E. More importantly, we attempt to identify major knowledge gaps and discuss strategies for further advancing both research and patient care.


Subject(s)
Hepatitis E virus , Hepatitis E , Hepatitis E/diagnosis , Hepatitis E/epidemiology , Hepatitis E/prevention & control , Hepatitis E virus/genetics , Hepatitis, Chronic/diagnosis , Hepatitis, Chronic/epidemiology , Hepatitis, Chronic/therapy , Humans , Immunocompromised Host , Patient Care , Persistent Infection
11.
Biomedicines ; 10(5)2022 Apr 19.
Article in English | MEDLINE | ID: mdl-35625672

ABSTRACT

Pregnancy-associated disorders affect around 20% of pregnancies each year around the world. The risk associated with pregnancy therapeutic management categorizes pregnant women as "drug orphan" patients. In the last few decades, nanocarriers have demonstrated relevant properties for controlled drug delivery, which have been studied for pregnancy-associated disorders. To develop new drug dosage forms it is mandatory to have access to the right evaluation models to ensure their usage safety and efficacy. This review exposes the various placental-based models suitable for nanocarrier evaluation for pregnancy-associated therapies. We first review the current knowledge about nanocarriers as drug delivery systems and how placenta can be used as an evaluation model. Models are divided into three categories: in vivo, in vitro, and ex vivo placental models. We then examine the recent studies using those models to evaluate nanocarriers behavior towards the placental barrier and which information can be gathered from these results. Finally, we propose a flow chart on the usage and the combination of models regarding the nanocarriers and nanoparticles studied and the intended therapeutic strategy.

12.
Cancers (Basel) ; 14(10)2022 May 19.
Article in English | MEDLINE | ID: mdl-35626107

ABSTRACT

Although advances have been made in cancer therapy, cancer remains the second leading cause of death in the U.S. and Europe, and thus efforts to continue to study and discover better treatment methods are ongoing. Three-dimensional (3D) tumor models have shown advantages over bi-dimensional (2D) cultures in evaluating the efficacy of chemotherapy. This commentary aims to highlight the potential of combined application of biomaterials with patient-derived cancer cells as a 3D in vitro model for the study and treatment of cancer patients. Five studies were discussed which demonstrate and provided early evidence to create 3D models with accurate microenvironments that are comparable to in vivo tumors. To date, the use of patient-derived cells for a more personalized approach to healthcare in combination with biomaterials to create a 3D tumor is still relatively new and uncommon for application in clinics. Although highly promising, it is important to acknowledge the current limitations and challenges of developing these innovative in vitro models, including the need for biologists and laboratory technicians to become familiar with biomaterial scaffolds, and the effort for bioengineers to create easy-to-handle scaffolds for routine assessment.

14.
J Neuroimmunol ; 367: 577874, 2022 06 15.
Article in English | MEDLINE | ID: mdl-35490443

ABSTRACT

Neuroinflammation contributes to neuronal degeneration in Parkinson's disease (PD). However, how brain inflammatory factors mediate the progression of neurodegeneration is still poorly understood. Experimental models of PD have shed light on the understanding of this phenomenon, but the exploration of inflammation-driven models is necessary to better characterize this aspect of the disorder. The use of lipopolysaccharide (LPS) to induce a neuroinflammation-mediated neuronal loss is useful to induce reliable elimination of dopaminergic neurons. Nevertheless, how this model parallels the PD-like neuroinflammation is uncertain. In the present work, we used the direct LPS injection as a model inductor to eliminate dopaminergic neurons of the substantia nigra pars compacta (SNpc) in rats and reevaluated the inflammatory reaction. High-resolution 3D histological examination revealed that, although LPS induced a reliable elimination of SNpc dopaminergic neurons, it also generated a massive inflammatory response. This inflammation-mediated injury was characterized by corralling, a damaged parenchyma occupied by a vast population of lesion-associated microglia and macrophages (LAMMs) undertaking wound compaction and scar formation, surrounded by highly reactive astrocytes. LAMMs tiled the entire lesion and engaged in long-standing phagocytic activity to resolve the injury. Additionally, modeling LPS inflammation in a cell culture system helped to understand the role of phagocytosis and cytotoxicity in the initial phases of dopaminergic degeneration and indicated that LAMM-mediated toxicity and phagocytosis coexist during LPS-mediated dopaminergic elimination. However, this type of severe inflammatory-mediated injury, and subsequent resolution appear to be different from the ageing-related PD scenario where the architectural structure of the parenchyma is mostly preserved. Thus, the necessity to explore new experimental models to properly mimic the inflammatory compound observed in PD degeneration.


Subject(s)
Microglia , Parkinson Disease , Animals , Dopamine , Inflammation/metabolism , Lipopolysaccharides/metabolism , Lipopolysaccharides/toxicity , Macrophages/metabolism , Microglia/metabolism , Parkinson Disease/pathology , Phagocytosis , Rats , Substantia Nigra/metabolism , Wound Healing
15.
Theranostics ; 12(7): 3329-3344, 2022.
Article in English | MEDLINE | ID: mdl-35547744

ABSTRACT

CRISPR-Cas9 is a Nobel Prize-winning robust gene-editing tool developed in the last decade. This technique enables a stable genetic engineering method with high precision on the genomes of all organisms. The latest advances in the technology include a genome library screening approach, which can detect survival-essential and drug resistance genes via gain or loss of function. The versatile machinery allows genomic screening for gene activation or inhibition, and targets non-coding sequences, such as promoters, miRNAs, and lncRNAs. In this review, we introduce the emerging high-throughput CRISPR-Cas9 library genome screening technology and its working principles to detect survival and drug resistance genes through positive and negative selection. The technology is compared with other existing approaches while focusing on the advantages of its variable applications in anti-cancer drug discovery, including functions and target identification, non-coding RNA information, actions of small molecules, and drug target discoveries. The combination of the CRISPR-Cas9 system with multi-omic platforms represents a dynamic field expected to advance anti-cancer drug discovery and precision medicine in the clinic.


Subject(s)
Antineoplastic Agents , Neoplasms , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , CRISPR-Cas Systems/genetics , Gene Editing/methods , Genetic Engineering , Humans , Neoplasms/drug therapy , Neoplasms/genetics
16.
Article in English | MEDLINE | ID: mdl-35445924

ABSTRACT

Progeria is a rare genetic disease which is characterised by accelerated ageing and reduced life span. There are differing types of progeria, but the classic type is Hutchinson-Gilford progeria syndrome (HGPS). Within a year of birth, people suffering from it start showing several features such as very low weight, scleroderma, osteoporosis and loss of hair. Their life expectancy is highly reduced and the average life span is around 14.6 years. Research is going on to understand the genetic and molecular level causes of this disease. Apart from that, several studies are also going on to discover therapeutic techniques and drugs to treat this disease but the success rate is very low. To gain a better understanding about research developments of progeria more experimental models, drugs and molecular technologies are under trial. Different important aspects and recent developments in epidemiology, genetic causes, symptoms, diagnosis and treatment options of progeria are discussed in this review.

17.
Biomolecules ; 12(4)2022 04 01.
Article in English | MEDLINE | ID: mdl-35454125

ABSTRACT

Cardiovascular diseases are the leading cause of death and the main cause of disability. In the last decade, homocysteine has been found to be a risk factor or a marker for cardiovascular diseases, including myocardial infarction (MI) and heart failure (HF). There are indications that vitamin B6 plays a significant role in the process of transsulfuration in homocysteine metabolism, specifically, in a part of the reaction in which homocysteine transfers a sulfhydryl group to serine to form α-ketobutyrate and cysteine. Therefore, an elevated homocysteine concentration (hyperhomocysteinemia) could be a consequence of vitamin B6 and/or folate deficiency. Hyperhomocysteinemia in turn could damage the endothelium and the blood vessel wall and induce worsening of atherosclerotic process, having a negative impact on the mechanisms underlying MI and HF, such as oxidative stress, inflammation, and altered function of gasotransmitters. Given the importance of the vitamin B6 in homocysteine metabolism, in this paper, we review its role in reducing oxidative stress and inflammation, influencing the functions of gasotransmitters, and improving vasodilatation and coronary flow in animal models of MI and HF.


Subject(s)
Gasotransmitters , Heart Failure , Hyperhomocysteinemia , Myocardial Infarction , Animals , Folic Acid , Heart Failure/complications , Homocysteine , Hyperhomocysteinemia/etiology , Inflammation/complications , Models, Theoretical , Vitamin B 6 , Vitamins
18.
Nanomaterials (Basel) ; 12(8)2022 Apr 14.
Article in English | MEDLINE | ID: mdl-35458054

ABSTRACT

The growing development and applications of nanomaterials lead to an increasing release of these materials in the environment. The adverse effects they may elicit on ecosystems or human health are not always fully characterized. Such potential toxicity must be carefully assessed with the underlying mechanisms elucidated. To that purpose, different approaches can be used. First, experimental toxicology consisting of conducting in vitro or in vivo experiments (including clinical studies) can be used to evaluate the nanomaterial hazard. It can rely on variable models (more or less complex), allowing the investigation of different biological endpoints. The respective advantages and limitations of in vitro and in vivo models are discussed as well as some issues associated with experimental nanotoxicology. Perspectives of future developments in the field are also proposed. Second, computational nanotoxicology, i.e., in silico approaches, can be used to predict nanomaterial toxicity. In this context, we describe the general principles, advantages, and limitations especially of quantitative structure-activity relationship (QSAR) models and grouping/read-across approaches. The aim of this review is to provide an overview of these different approaches based on examples and highlight their complementarity.

19.
Animal Model Exp Med ; 5(2): 108-119, 2022 04.
Article in English | MEDLINE | ID: mdl-35412027

ABSTRACT

Inflammation is a common disease involved in the pathogenesis, complications, and sequelae of a large number of related diseases, and therefore considerable research has been directed toward developing anti-inflammatory drugs for the prevention and treatment of these diseases. Traditional Chinese medicine (TCM) has been used to treat inflammatory and related diseases since ancient times. According to the review of abundant modern scientific researches, it is suggested that TCM exhibit anti-inflammatory effects at different levels, and via multiple pathways with various targets, and recently a series of in vitro and in vivo anti-inflammatory models have been developed for anti-inflammation research in TCM. Currently, the reported classic mechanisms of TCM and experimental models of its anti-inflammatory effects provide reference points and guidance for further research and development of TCM. Importantly, the research clearly confirms that TCM is now and will continue to be an effective form of treatment for many types of inflammation and inflammation-related diseases.


Subject(s)
Drugs, Chinese Herbal , Medicine, Chinese Traditional , Anti-Inflammatory Agents/pharmacology , Drugs, Chinese Herbal/pharmacology , Humans , Inflammation/drug therapy , Models, Theoretical
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