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Cureus Jul 2023Septic shock is a life-threatening condition characterized by systemic inflammation resulting from a severe infection. Although the primary focus of sepsis research has... (Review)
Review
Septic shock is a life-threatening condition characterized by systemic inflammation resulting from a severe infection. Although the primary focus of sepsis research has traditionally been on the dysfunctional immune response, recent studies have highlighted the important role of bone marrow in the pathophysiology of septic shock. The bone marrow, traditionally regarded as the hematopoietic organ responsible for blood cell production, undergoes significant changes during sepsis, contributing to the overall immune dysregulation observed in this condition. This comprehensive review aims to provide a detailed overview of the bone marrow changes associated with septic shock. It explores the alterations in the bone marrow microenvironment, hematopoietic progenitor cells, and the subsequent effects on leukocyte production and function. Key cellular and molecular mechanisms involved in bone marrow dysfunction during septic shock are discussed, including the dysregulation of cytokines, chemokines, growth factors, and signaling pathways. Furthermore, this review highlights the clinical implications of bone marrow changes in septic shock. It emphasizes the impact of altered hematopoiesis on immune cell populations, such as neutrophils, monocytes, and lymphocytes, and their role in the progression and outcome of sepsis. The potential prognostic value of bone marrow parameters and the therapeutic implications of targeting bone marrow dysfunction are also addressed. The review summarizes relevant preclinical and clinical studies to comprehensively understand the current knowledge of bone marrow changes in septic shock. The limitations and challenges of studying bone marrow in the context of sepsis are acknowledged, and future directions for research are proposed.
PubMed: 37637609
DOI: 10.7759/cureus.42517 -
Radiological Physics and Technology Mar 2024Magnetic resonance imaging (MRI) is an indispensable diagnostic imaging technique used in the clinical setting. MRI is advantageous over X-ray and computed tomography... (Review)
Review
Magnetic resonance imaging (MRI) is an indispensable diagnostic imaging technique used in the clinical setting. MRI is advantageous over X-ray and computed tomography (CT), because the contrast provided depends on differences in the density of various organ tissues. In addition to MRI systems in hospitals, more than 100 systems are used for research purposes in Japan in various fields, including basic scientific research, molecular and clinical investigations, and life science research, such as drug discovery, veterinary medicine, and food testing. For many years, additional preclinical imaging studies have been conducted in basic research in the fields of radiation technology, medical physics, and radiology. The preclinical MRI research includes studies using small-bore and whole-body MRI systems. In this review, we focus on the animal study using small-bore MRI systems as "preclinical MRI". The preclinical MRI can be used to elucidate the pathophysiology of diseases and for translational research. This review will provide an overview of previous preclinical MRI studies such as brain, heart, and liver disease assessments. Also, we provide an overview of the utility of preclinical MRI studies in radiological physics and technology.
Topics: Animals; Technology, Radiologic; Magnetic Resonance Imaging; Spectrum Analysis; Radiology; Physics
PubMed: 38351261
DOI: 10.1007/s12194-024-00785-y -
Nutrition Reviews Jun 2024Intermittent fasting (IF), one of the most popular diets, can regulate inflammation and promote health; however, the detailed molecular mechanisms are not fully... (Review)
Review
Intermittent fasting (IF), one of the most popular diets, can regulate inflammation and promote health; however, the detailed molecular mechanisms are not fully understood. The present review aims to provide an overview of recent preclinical and clinical studies that have examined the effect of IF on inflammasome signaling, and to discuss the translational gap between preclinical and clinical studies. Three databases (PubMed, Web of Science, and Embase) were searched to identify all relevant preclinical and clinical studies up to October 30, 2022. A total of 1544 studies were identified through the database searches, and 29 preclinical and 10 clinical studies were included. Twenty-three of the 29 preclinical studies reported that IF treatment could reduce inflammasome activation in neurological diseases, metabolic and cardiovascular diseases, immune and inflammatory diseases, gastrointestinal diseases, and pulmonary diseases, and 7 of the 10 clinical studies demonstrated reduced inflammasome activation after IF intervention in both healthy and obese participants. Among various IF regimens, time-restricted eating seemed to be the most effective one in terms of inflammasome regulation, and the efficacy of IF might increase over time. This review highlights the regulatory effect of IF on inflammasome activation in health and disease. Future studies using different IF regimens, in various populations, are needed in order to evaluate its potential to be used alone or as an adjunct therapy in humans to improve health and counteract diseases.
Topics: Humans; Inflammasomes; Fasting; Animals; Inflammation; Intermittent Fasting
PubMed: 37634143
DOI: 10.1093/nutrit/nuad104 -
Biomedicines Oct 2023One of the major goals in the advancement of basic cancer research focuses on the development of new anticancer therapies. To understand the molecular mechanisms of... (Review)
Review
One of the major goals in the advancement of basic cancer research focuses on the development of new anticancer therapies. To understand the molecular mechanisms of cancer progression, acquired drug resistance, and the metastatic process, the use of preclinical in vitro models that faithfully summarize the properties of the tumor in patients is still a necessity. The tumor is represented by a diverse group of cell clones, and in recent years, to reproduce in vitro preclinical tumor models, monolayer cell cultures have been supplanted by patient-derived xenograft (PDX) models and cultured organoids derived from the patient (PDO). These models have proved indispensable for the study of the tumor microenvironment (TME) and its interaction with tumor cells. Prostate cancer (PCa) is the most common neoplasia in men in the world. It is characterized by genomic instability and resistance to conventional therapies. Despite recent advances in diagnosis and treatment, PCa remains a leading cause of cancer death. Here, we review the studies of the last 10 years as the number of papers is growing very fast in the field. We also discuss the discovered limitations and the new challenges in using the organoid culture system and in using PDXs in studying the prostate cancer phenotype, performing drug testing, and developing anticancer molecular therapies.
PubMed: 37893116
DOI: 10.3390/biomedicines11102743 -
Nature Communications Oct 2023Recent advancements in artificial intelligence have witnessed human-level performance; however, AI-enabled cognitive assistance for therapeutic procedures has not been...
Recent advancements in artificial intelligence have witnessed human-level performance; however, AI-enabled cognitive assistance for therapeutic procedures has not been fully explored nor pre-clinically validated. Here we propose AI-Endo, an intelligent surgical workflow recognition suit, for endoscopic submucosal dissection (ESD). Our AI-Endo is trained on high-quality ESD cases from an expert endoscopist, covering a decade time expansion and consisting of 201,026 labeled frames. The learned model demonstrates outstanding performance on validation data, including cases from relatively junior endoscopists with various skill levels, procedures conducted with different endoscopy systems and therapeutic skills, and cohorts from international multi-centers. Furthermore, we integrate our AI-Endo with the Olympus endoscopic system and validate the AI-enabled cognitive assistance system with animal studies in live ESD training sessions. Dedicated data analysis from surgical phase recognition results is summarized in an automatically generated report for skill assessment.
Topics: Animals; Female; Humans; Endoscopic Mucosal Resection; Artificial Intelligence; Workflow; Endoscopy; Learning; Endometriosis
PubMed: 37865629
DOI: 10.1038/s41467-023-42451-8 -
Biology of Sex Differences Jul 2023Biological factors are known to influence disease trajectories and treatment effectiveness in alcohol addiction and preclinical and clinical evidence suggests that sex...
BACKGROUND
Biological factors are known to influence disease trajectories and treatment effectiveness in alcohol addiction and preclinical and clinical evidence suggests that sex is an important factor influencing disease dynamics in alcohol dependence. Another critical factor is age at first intoxicating drink, which has been identified as a risk factor for later alcohol binging. Preclinical research allows prospective monitoring of rodents throughout the lifespan, providing very detailed information that cannot be acquired in humans. Lifetime monitoring in rodents can be conducted under highly controlled conditions, during which one can systematically introduce multiple biological and environmental factors that impact behaviors of interest.
METHODS
Here, we used the alcohol deprivation effect (ADE) rat model of alcohol addiction in a computerized drinkometer system, acquiring high-resolution data to study changes over the course of addictive behavior as well as compulsive-like drinking in cohorts of adolescent vs. adult as well as male vs. female rats.
RESULTS
Female rats drank more alcohol than male rats during the whole experiment, drinking much more weak alcohol (5%) and similar amounts of stronger alcohol solutions (10%, 20%); female rats also consumed more alcohol than male rats during quinine taste adulteration. Increased consumption in females compared to males was driven by larger access sizes of alcohol. Differences in circadian patterns of movement were observed between groups. Early age of onset of drinking (postnatal day 40) in male rats had surprisingly little impact on the development of drinking behavior and compulsivity (quinine taste adulteration) when compared to rats that started drinking during early adulthood (postnatal day 72).
CONCLUSIONS
Our results suggest that there are sex-specific drinking patterns, not only in terms of total amount consumed, but specifically in terms of solution preference and access size. These findings provide a better understanding of sex and age factors involved in the development of drinking behavior, and can inform the preclinical development of models of addiction, drug development and exploration of options for new treatments.
Topics: Humans; Rats; Male; Female; Animals; Adolescent; Adult; Alcoholism; Alcohol Drinking; Quinine; Prospective Studies; Behavior, Addictive; Ethanol; Age Factors
PubMed: 37420305
DOI: 10.1186/s13293-023-00529-4 -
Journal of Controlled Release :... Mar 2024Systemic drug delivery is the current clinically preferred route for cancer therapy. However, challenges associated with tumor localization and off-tumor toxic effects... (Review)
Review
Systemic drug delivery is the current clinically preferred route for cancer therapy. However, challenges associated with tumor localization and off-tumor toxic effects limit the clinical effectiveness of this route. Locoregional drug delivery is an emerging viable alternative to systemic therapies. With the improvement in real-time imaging technologies and tools for direct access to tumor lesions, the clinical applicability of locoregional drug delivery is becoming more prominent. Theoretically, locoregional treatments can bypass challenges faced by systemic drug delivery. Preclinically, locoregional delivery of drugs has demonstrated enhanced therapeutic efficacy with limited off-target effects while still yielding an abscopal effect. Clinically, an array of locoregional strategies is under investigation for the delivery of drugs ranging in target and size. Locoregional tumor treatment strategies can be classified into two main categories: 1) direct drug infusion via injection or implanted port and 2) extended drug elution via injected or implanted depot. The number of studies investigating locoregional drug delivery strategies for cancer treatment is rising exponentially, in both preclinical and clinical settings, with some approaches approved for clinical use. Here, we highlight key preclinical advances and the clinical relevance of such locoregional delivery strategies in the treatment of cancer. Furthermore, we critically analyze 949 clinical trials involving locoregional drug delivery and discuss emerging trends.
Topics: Humans; Drug Delivery Systems; Neoplasms; Injections
PubMed: 38325716
DOI: 10.1016/j.jconrel.2024.01.072 -
American Journal of Translational... 2023An evaluation of the inflammatory enzymatic interactions related to pulmonary function can help identify biomarkers for interventions or prophylactic measures to improve... (Review)
Review
Soluble epoxide hydrolase inhibitors for smoking-associated inflammatory lung diseases and chronic obstructive pulmonary disease: a meta-analytical systematic review of preclinical and clinical studies.
An evaluation of the inflammatory enzymatic interactions related to pulmonary function can help identify biomarkers for interventions or prophylactic measures to improve patient prognosis. This study aimed to determine the effect of epoxide hydrolase inhibition by GSK2256294 in different pulmonary inflammation models. A secondary search was performed using Medline/PubMed, Web of Science, SciELO, Cochrane Library, Embase, Academic Google, and gray literature by two independent reviewers, who analyzed the methodological quality and consistency of the data. Different variables were compared using a meta-analysis. A total of 86 studies were found, 4 of which were selected from the gray literature. Based on the eligibility criteria, two clinical and one preclinical studies were evaluated. GSK2256294 inhibited the soluble epoxide hydrolase enzyme in both clinical and preclinical models, exhibiting greater effectiveness in clinical studies and contributing to the anti-inflammatory activity mediated by the eicosatrienoic pathway by reducing the levels of dihydroxyeicosatrienoic acids and leukotoxin-diol. Overall, GSK2256294 was identified as a promising drug for controlling the deleterious manifestations of lung inflammation. Further clinical and preclinical studies are required to ensure consistency among the evidence and identify other biological activities mediated by GSK2256294.
PubMed: 38074809
DOI: No ID Found -
European Journal of Nuclear Medicine... Dec 2023The integrin αβ and aminopeptidase N (APN/CD13) play vital roles in the tumor angiogenesis process. They are highly expressed in a variety of tumor cells and...
PURPOSE
The integrin αβ and aminopeptidase N (APN/CD13) play vital roles in the tumor angiogenesis process. They are highly expressed in a variety of tumor cells and proliferating endothelial cells during angiogenesis, which have been considered as highly promising targets for tumor imaging. Arginine-glycine-aspartic (RGD) and asparagine-glycine-arginine (NGR) are two peptides specifically binding to the integrin αβ and CD13, respectively. In this study, we optimized our previously developed probe and preclinically evaluated the new integrin αβ and CD13 dual-targeted probe, NOTA-RGD-NGR (denoted as HX01) radiolabeled with Ga, in 10 different subcutaneous and orthotopic tumor models.
METHODS
The specific activity and radiochemical purity of [Ga]Ga-HX01 were identified. The dual-receptor targeting ability was confirmed by a series of blocking studies and partly muted tracers using BxPC-3 xenograft model. The dynamic imaging study and dose escalation study were explored to determine the optimal imaging time point and dosage in the BxPC-3 xenograft model. Next, we established a variety of subcutaneous and orthotopic tumor models including pancreas (BxPC-3), breast (MCF-7), gallbladder (NOZ), lung (HCC827), ovary (SK-OV-3), colorectal (HCT-8), liver (HuH-7), stomach (NUGC-4), and glioma (U87) cancers. All models underwent [Ga]Ga-HX01 PET/CT imaging about 2 weeks post-inoculation, with a subset of them undergoing [F]FDG PET/CT scan performed concurrently, and their results were compared. In addition, ex vivo biodistribution studies were also performed for verifying the semi-quantitative results of the non-invasive PET images.
RESULTS
[Ga]Ga-HX01 significantly outperformed single target probes in the BxPC-3 xenograft model. All blocking and single target groups exhibited significantly descending tumor uptake. The high tumor uptakes were found in BxPC-3, MCF-7, and NOZ subcutaneous tumors (%ID/g > 1.1), while middle uptakes were observed in HCC827, SK-OV-3, HCT-8, and HuH-7 subcutaneous tumor (%ID/g 0.7-1.0). Due to the low background, the tumor-to-muscle and tumor-to-blood ratios of [Ga]Ga-HX01 were higher than that of [F]FDG.
CONCLUSIONS
[Ga]Ga-HX01, as a dual target imaging agent, exhibited superior in vivo performance in different subcutaneous and orthotopic mice models of human tumors over [F]FDG and its respectively mono-receptor targeted agents, which warrants the future clinical translation for tumor imaging.
Topics: Female; Humans; Animals; Mice; Positron Emission Tomography Computed Tomography; Gallium Radioisotopes; Fluorodeoxyglucose F18; Tissue Distribution; Endothelial Cells; Cell Line, Tumor; Positron-Emission Tomography; Oligopeptides; Integrins; Integrin alphaVbeta3
PubMed: 37642706
DOI: 10.1007/s00259-023-06412-z -
GeroScience Feb 2024Aging is associated with cellular and physiological changes, which significantly reduce the quality of life and increase the risk for disease. Geroprotectors improve... (Review)
Review
Aging is associated with cellular and physiological changes, which significantly reduce the quality of life and increase the risk for disease. Geroprotectors improve lifespan and slow the progression of detrimental aging-related changes such as immune system senescence, mitochondrial dysfunction, and dysregulated nutrient sensing and metabolism. Emerging evidence suggests that gut microbiota dysbiosis is a hallmark of aging-related diseases and microbiome modulators, such as probiotics (live bacteria) or postbiotics (non-viable bacteria/bacterial byproducts) may be promising geroprotectors. However, because they are strain-specific, the geroprotective effects of probiotics and postbiotics remain poorly understood and understudied. Drosophila melanogaster, Caenorhabditis elegans, and rodents are well-validated preclinical models for studying lifespan and the role of probiotics and/or postbiotics, but each have their limitations, including cost and their translation to human aging biology. C. elegans is an excellent model for large-scale screening to determine the geroprotective potential of drugs or probiotics/postbiotics due to its short lifecycle, easy maintenance, low cost, and homology to humans. The purpose of this article is to review the geroprotective effects of microbiome modulators and their future scope, using C. elegans as a model. The proposed geroprotective mechanisms of these probiotics and postbiotics include delaying immune system senescence, preventing or reducing mitochondrial dysfunction, and regulating food intake (dietary restriction) and metabolism. More studies are warranted to understand the geroprotective potential of probiotics and postbiotics, as well as other microbiome modulators, like prebiotics and fermented foods, and use them to develop effective therapeutics to extend lifespan and reduce the risk of debilitating aging-related diseases.
Topics: Humans; Animals; Caenorhabditis elegans; Drosophila melanogaster; Quality of Life; Senotherapeutics; Microbiota; Mitochondrial Diseases
PubMed: 37561384
DOI: 10.1007/s11357-023-00901-7