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Experimental & Molecular Medicine Jun 2023Sphingolipids, which are components of cellular membranes and organ tissues, can be synthesized or degraded to modulate cellular responses according to environmental... (Review)
Review
Sphingolipids, which are components of cellular membranes and organ tissues, can be synthesized or degraded to modulate cellular responses according to environmental cues, and the balance among the different sphingolipids is important for directing immune responses, regardless of whether they originate, as intra- or extracellular immune events. Recent progress in multiomics-based analyses and methodological approaches has revealed that human health and diseases are closely related to the homeostasis of sphingolipid metabolism, and disease-specific alterations in sphingolipids and related enzymes can be prognostic markers of human disease progression. Accumulating human clinical data from genome-wide association studies and preclinical data from disease models provide support for the notion that sphingolipids are the missing pieces that supplement our understanding of immune responses and diseases in which the functions of the involved proteins and nucleotides have been established. In this review, we analyze sphingolipid-related enzymes and reported human diseases to understand the important roles of sphingolipid metabolism. We discuss the defects and alterations in sphingolipid metabolism in human disease, along with functional roles in immune cells. We also introduce several methodological approaches and provide summaries of research on sphingolipid modulators in this review that should be helpful in studying the roles of sphingolipids in preclinical studies for the investigation of experimental and molecular medicines.
Topics: Humans; Sphingolipids; Genome-Wide Association Study; Cell Membrane; Homeostasis
PubMed: 37258585
DOI: 10.1038/s12276-023-01018-9 -
Current Opinion in Microbiology Oct 2023Laboratory studies of host-microbe interactions have historically been carried out using transformed cell lines and animal models. Although much has been learned from... (Review)
Review
Laboratory studies of host-microbe interactions have historically been carried out using transformed cell lines and animal models. Although much has been learned from these models, recent advances in the development of multicellular, physiologically active, human intestinal organoid (HIO) cultures are allowing unprecedented discoveries of host-microbe interactions. Here, we review recent literature using HIOs as models to investigate the pathogenesis of clinically important enteric bacteria and viruses and study commensal intestinal microbes. We also discuss limitations of current HIO culture systems and how technical advancesĀ and innovative engineering approaches are providing new directions to improve the model. The studies discussed here highlight the potential of HIOs for studying microbial pathogenesis, host-microbe interactions, and for preclinical development of therapeutics and vaccines.
Topics: Animals; Humans; Gastrointestinal Microbiome; Intestines; Organoids; Viruses; Intestinal Mucosa
PubMed: 37536261
DOI: 10.1016/j.mib.2023.102362 -
British Journal of Pharmacology May 2019The endocannabinoid system has emerged as an important target for the treatment of many diverse diseases. In addition to the well-established palliative effects of... (Review)
Review
The endocannabinoid system has emerged as an important target for the treatment of many diverse diseases. In addition to the well-established palliative effects of cannabinoids in cancer therapy, phytocannabinoids, synthetic cannabinoid compounds and inhibitors of endocannabinoid degradation have attracted attention as possible systemic anticancer drugs. Results emerging from preclinical studies suggest cannabinoids elicit effects at different levels of cancer progression, including inhibition of proliferation, neovascularization, invasion and chemoresistance, induction of apoptosis and autophagy as well as enhancement of tumour immune surveillance. Although the clinical use of cannabinoid receptor ligands is limited by their psychoactivity, non-psychoactive compounds, such as cannabidiol, have gained attention due to preclinically established anticancer properties and a favourable risk-to-benefit profile. Thus, cannabinoids may complement the currently used collection of chemotherapeutic agents, as a broadly diversified option for cancer treatment, while counteracting some of their severe side effects. LINKED ARTICLES: This article is part of a themed section on 8 European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Cannabinoid Receptor Agonists; Cannabinoids; Cell Line, Tumor; Cell Survival; Clinical Trials as Topic; Endocannabinoids; Humans; Neoplasms; Receptors, Cannabinoid
PubMed: 30019449
DOI: 10.1111/bph.14426 -
Journal of Cerebral Blood Flow and... Dec 2016Obesity is a risk factor for stroke and is consequently one of the most common co-morbidities found in patients. There is therefore an identified need to model... (Review)
Review
Obesity is a risk factor for stroke and is consequently one of the most common co-morbidities found in patients. There is therefore an identified need to model co-morbidities preclinically to allow better translation from bench to bedside. In preclinical studies, both diet-induced and genetically obese rodents have worse stroke outcome, characterised by increased ischaemic damage and an altered inflammatory response. However, clinical studies have reported an 'obesity paradox' in stroke, characterised by reduced mortality and morbidity in obese patients. We discuss the potential reasons why the preclinical and clinical studies may not agree, and review the mechanisms identified in preclinical studies through which obesity may affects stroke outcome. We suggest inflammation plays a central role in this relationship, as obesity features increases in inflammatory mediators such as C-reactive protein and interleukin-6, and chronic inflammation has been linked to worse stroke risk and outcome.
Topics: Animals; Humans; Inflammation; Obesity; Rodentia; Stroke; Translational Research, Biomedical
PubMed: 27655337
DOI: 10.1177/0271678X16670411 -
Current Opinion in Anaesthesiology Oct 2014Chronic pain is often accompanied by mood, sleep and cognitive complications affecting the patient's quality of life. This reviews aims to provide a synthesis of the... (Review)
Review
PURPOSE OF REVIEW
Chronic pain is often accompanied by mood, sleep and cognitive complications affecting the patient's quality of life. This reviews aims to provide a synthesis of the recent clinical and preclinical findings concerning the chronic pain and mood disorder comorbidity.
RECENT FINDINGS
The possible mechanisms underlying the presence of anxiety and/or depression in neuropathic pain, chronic widespread pain (fibromyalgia) and inflammatory pain are reviewed based on recent evidences from neuroimaging, anatomical, behavioral, pharmacological, genetic and biochemical studies. Clinical data from patients and preclinical findings from pain models in rodents are considered.
SUMMARY
The epidemiological studies report a high prevalence of mood disorders in patients with chronic pain, and these consequences of pain can be preclinically modeled. This comorbidity may be explained by shared morphological and functional alterations observed in both chronic pain and mood disorders. However, mechanistic studies also highlight differences in such alterations depending on the type of chronic pain. Better understanding of the genetic and environmental determinants of pain-induced mood disorders and of the various neurobiological bases of this comorbidity depending on the pain subtype could provide the clinician with important diagnosis and treatment tools. Such progress benefits from translational effort between clinical and preclinical research.
Topics: Anxiety Disorders; Chronic Pain; Comorbidity; Depressive Disorder; Humans; Prevalence
PubMed: 25188218
DOI: 10.1097/ACO.0000000000000116 -
Cancer Chemotherapy and Pharmacology Mar 2017The benefits of asparaginase (ASNASE) in the treatment of ALL and NHL are indisputable and new ASNASE preparations are under clinical development to overcome limitations... (Review)
Review
PURPOSE
The benefits of asparaginase (ASNASE) in the treatment of ALL and NHL are indisputable and new ASNASE preparations are under clinical development to overcome limitations of the actual ASNASE therapy, especially immunogenicity. Apart from ALL and NHL further indications of ASNASE are preclinically and clinically evaluated.
METHODS
We reviewed ASNASE literature and especially focused on the mechanism of action, on biomarker, which determine ASNASE sensitivity and resistance, and on ASNASE pharmacodynamics in vivo.
RESULTS
More than 40 years after the clinical introduction of ASNASE its mechanism of action is yet not fully understood. Studies on asparagine synthetase (ASNS) as biomarker for ASNASE resistance are contradictory and complicated by methodological obstacles. The role of glutamine hydrolysis for ASNASE efficacy is still debated, other mechanisms are possibly not yet identified. In addition, individual pharmacokinetic/-dynamic relationships cannot be properly addressed because of methodological limitations.
CONCLUSION
More sophisticated preclinical models and suitable methods for monitoring of ASNASE pharmacodynamics are urgently needed (1) to understand the mechanism of action, (2) to establish valid biomarkers for ASNASE sensitivity and resistance, (3) to evaluate the pharmacokinetics/-dynamics of ASNASEs in individual patients, and (4) to compare the bioequivalence of clinically established, as well as new ASNASE preparations.
Topics: Animals; Antineoplastic Agents; Asparaginase; Humans; Lymphoma, Non-Hodgkin; Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 28197753
DOI: 10.1007/s00280-016-3236-y -
Nanotheranostics 2022Novel targeted therapies are rapidly emerging for the treatment of cancer. With the advent of new immune targeting agents, understanding the changes in the tumor... (Review)
Review
Novel targeted therapies are rapidly emerging for the treatment of cancer. With the advent of new immune targeting agents, understanding the changes in the tumor microenvironment (TME) is critical. Given the complexity and several cellular mechanisms and factors that play a role in the TME, novel imaging methods to assess and evaluate the dynamic changes in the TME during treatment are needed. Several techniques are being developed for imaging TME including optical, fluorescence and photoacoustic methods. Positron emission tomography (PET) imaging can be used to track the dynamics of different molecular targets in the TME in live animals and in humans. Several novel PET imaging probes including radiolabeled antibodies, antibody fragments, and small molecules have been developed with many more that are under development preclinically and in early human studies. This review is a brief overview of some of the PET agents that are either in the preclinical developmental phase or undergoing early clinical studies.
Topics: Animals; Neoplasms; Positron-Emission Tomography; Tumor Microenvironment
PubMed: 35223381
DOI: 10.7150/ntno.66556 -
Molecular Aspects of Medicine Feb 2024Glaucoma, one of the leading causes of irreversible blindness worldwide, is a complex and heterogenous disease. While environmental factors are important, it is... (Review)
Review
Glaucoma, one of the leading causes of irreversible blindness worldwide, is a complex and heterogenous disease. While environmental factors are important, it is well-recognized that the disease has a strong heritable component. With the advent of large-cohort genome wide association studies, a myriad of genetic risk loci has been linked to different forms of glaucoma. Animal models have been an indispensable tool in characterizing these loci, especially if they lie within coding regions in the genome. Not only do these models connect genotype to phenotype, advancing our understanding of glaucoma pathogenesis in the process, they also have valuable utility as a platform for the pre-clinical testing of potential therapies. In this review, we will outline genetic models used for studying the major forms of glaucoma, including primary open angle glaucoma, normal tension glaucoma, primary angle closure glaucoma, pigmentary glaucoma, pseudoexfoliation glaucoma, and early onset glaucoma, including congenital and developmental glaucoma, and how studying these models have helped shed light on human glaucoma.
Topics: Animals; Humans; Glaucoma, Open-Angle; Genome-Wide Association Study; Genetic Predisposition to Disease; Glaucoma; Genotype
PubMed: 38039744
DOI: 10.1016/j.mam.2023.101229 -
Brain, Behavior, and Immunity Oct 2023Human immunodeficiency virus (HIV) remains a persistent public health concern throughout the world. Substance use disorders (SUDs) are a common comorbidity that can... (Review)
Review
Human immunodeficiency virus (HIV) remains a persistent public health concern throughout the world. Substance use disorders (SUDs) are a common comorbidity that can worsen treatment outcomes for people living with HIV. The relationship between HIV infection and SUD outcomes is likely bidirectional, making clear interrogation of neurobehavioral outcomes challenging in clinical populations. Importantly, the mechanisms through which HIV and addictive drugs disrupt homeostatic immune and CNS function appear to be highly overlapping and synergistic within HIV-susceptible reward and motivation circuitry in the central nervous system. Decades of animal research have revealed invaluable insights into mechanisms underlying the pathophysiology SUDs and HIV, although translational studies examining comorbid SUDs and HIV are very limited due to the technical challenges of modeling HIV infection preclinically. In this review, we discuss preclinical animal models of HIV and highlight key pathophysiological characteristics of each model, with a particular emphasis on rodent models of HIV. We then review the implementation of these models in preclinical SUD research and identify key gaps in knowledge in the field. Finally, we discuss how cutting-edge behavioral neuroscience tools, which have revealed key insights into the neurobehavioral mechanisms of SUDs, can be applied to preclinical animal models of HIV to reveal potential, novel treatment avenues for comorbid HIV and SUDs. Here, we argue that future preclinical SUD research would benefit from incorporating comorbidities such as HIV into animal models and would facilitate the discovery of more refined, subpopulation-specific mechanisms and effective SUD prevention and treatment targets.
Topics: Animals; Humans; HIV Infections; Substance-Related Disorders; Comorbidity
PubMed: 37567486
DOI: 10.1016/j.bbi.2023.07.021 -
World Journal of Oncology Apr 2024Pigs are playing an increasingly vital role as translational biomedical models for studying human pathophysiology. The annotation of the pig genome was a huge step... (Review)
Review
Pigs are playing an increasingly vital role as translational biomedical models for studying human pathophysiology. The annotation of the pig genome was a huge step forward in translatability of pigs as a biomedical model for various human diseases. Similarities between humans and pigs in terms of anatomy, physiology, genetics, and immunology have allowed pigs to become a comprehensive preclinical model for human diseases. With a diverse range, from craniofacial and ophthalmology to reproduction, wound healing, musculoskeletal, and cancer, pigs have provided a seminal understanding of human pathophysiology. This review focuses on the current research using pigs as preclinical models for cancer research and highlights the strengths and opportunities for studying various human cancers.
PubMed: 38545477
DOI: 10.14740/wjon1763