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Cells May 2021Alzheimer's disease (AD) is the number one neurovegetative disease, but its treatment options are relatively few and ineffective. In efforts to discover new strategies... (Review)
Review
Alzheimer's disease (AD) is the number one neurovegetative disease, but its treatment options are relatively few and ineffective. In efforts to discover new strategies for AD therapy, natural products have aroused interest in the research community and in the pharmaceutical industry for their neuroprotective activity, targeting different pathological mechanisms associated with AD. A wide variety of natural products from different origins have been evaluated preclinically and clinically for their neuroprotective mechanisms in preventing and attenuating the multifactorial pathologies of AD. This review mainly focuses on the possible neuroprotective mechanisms from natural products that may be beneficial in AD treatment and the natural product mixtures or extracts from different sources that have demonstrated neuroprotective activity in preclinical and/or clinical studies. It is believed that natural product mixtures or extracts containing multiple bioactive compounds that can work additively or synergistically to exhibit multiple neuroprotective mechanisms might be an effective approach in AD drug discovery.
Topics: Alzheimer Disease; Animals; Biological Products; Drug Discovery; Humans; Neuroprotective Agents
PubMed: 34070275
DOI: 10.3390/cells10061309 -
Cancers Apr 2021In the quest to advance neuroblastoma therapeutics, there is a need to have a deeper understanding of the tumor microenvironment (TME). From extracellular matrix... (Review)
Review
In the quest to advance neuroblastoma therapeutics, there is a need to have a deeper understanding of the tumor microenvironment (TME). From extracellular matrix proteins to tumor associated macrophages, the TME is a robust and diverse network functioning in symbiosis with the solid tumor. Herein, we review the major components of the TME including the extracellular matrix, cytokines, immune cells, and vasculature that support a more aggressive neuroblastoma phenotype and encumber current therapeutic interventions. Contemporary treatments for neuroblastoma are the result of traditional two-dimensional culture studies and in vivo models that have been translated to clinical trials. These pre-clinical studies are costly, time consuming, and neglect the study of cofounding factors such as the contributions of the TME. Three-dimensional (3D) bioprinting has become a novel approach to studying adult cancers and is just now incorporating portions of the TME and advancing to study pediatric solid. We review the methods of 3D bioprinting, how researchers have included TME pieces into the prints, and highlight present studies using neuroblastoma. Ultimately, incorporating the elements of the TME that affect neuroblastoma responses to therapy will improve the development of innovative and novel treatments. The use of 3D bioprinting to achieve this aim will prove useful in developing optimal therapies for children with neuroblastoma.
PubMed: 33915765
DOI: 10.3390/cancers13071629 -
Transplant International : Official... 2023Considering recent clinical and experimental evidence, expectations for using DCD-derived intestines have increased considerably. However, more knowledge about DCD...
Considering recent clinical and experimental evidence, expectations for using DCD-derived intestines have increased considerably. However, more knowledge about DCD procedure and long-term results after intestinal transplantation (ITx) is needed. We aimed to describe in detail a DCD procedure for ITx using normothermic regional perfusion (NRP) in a preclinical model. Small bowel was obtained from pigs donors after 1 h of NRP and transplanted to the recipients. Graft Intestinal samples were obtained during the procedure and after transplantation. Ischemia-reperfusion injury (Park-Chiu score), graft rejection and transplanted intestines absorptive function were evaluated. Seven of 8 DCD procedures with NRP and ITx were successful (87.5%), with a good graft reperfusion and an excellent recovery of the recipient. The architecture of grafts was well conserved during NRP. After an initial damage of Park-chiu score of 4, all grafts recovered from ischemia-reperfusion, with no or very subtle alterations 2 days after ITx. Most recipients (71.5%) did not show signs of rejection. Only two cases demonstrated histologic signs of mild rejection 7 days after ITx. Interestingly intestinal grafts showed good absorptive capacity. The study's results support the viability of intestinal grafts from DCD using NRP, contributing more evidence for the use of DCD for ITx.
Topics: Animals; Swine; Humans; Perfusion; Reperfusion; Tissue Donors; Graft Rejection; Reperfusion Injury
PubMed: 37745640
DOI: 10.3389/ti.2023.11518 -
Annals of Translational Medicine Dec 2020In recent decades, great interest in the off-label use of metformin has arisen as a result of its broad effects on different signaling pathways, with only a few side... (Review)
Review
In recent decades, great interest in the off-label use of metformin has arisen as a result of its broad effects on different signaling pathways, with only a few side effects, and low cost. Metformin has been shown to have multiple, dose-dependent preclinical anticancer effects, which can be roughly divided into either direct effects via inhibition of mitochondrial respiratory chain complex I, or indirect effects through lowered glucose, insulin and insulin-like growth factor levels. Further details on and anticancer effects specifically in ovarian cancer are continuously reported. Preclinically metformin has clear chemosensitizing effects in ovarian cancer and it is an effective negative regulator of angiogenesis. There are also some epidemiological studies on metformin use in ovarian cancer, but the results of these studies are not as promising as those preclinical studies would indicate. Most preclinical studies have involved metformin concentrations that are many times higher than the pharmacological doses used in patients, which might confound the clinical use of metformin as regards the above-mentioned aspects. In this review we evaluate preclinical and clinical evidence concerning metformin in ovarian cancer treatment.
PubMed: 33490223
DOI: 10.21037/atm-20-1060 -
Heliyon Dec 2022In vivo imaging in preclinical and clinical settings can enhance knowledge of the host-microbiome interactions. Imaging techniques are a crucial node between findings at... (Review)
Review
In vivo imaging in preclinical and clinical settings can enhance knowledge of the host-microbiome interactions. Imaging techniques are a crucial node between findings at the molecular level and clinical implementation in diagnostics and therapeutics. The purpose of this study was to review existing knowledge on the microbiota in the field of imaging and provide guidance for future research, emphasizing the critical role that molecular imaging plays in increasing understanding of the host-microbe interaction. Preclinical microbiota animal models lay the foundation for the clinical translatability of novel microbiota-based therapeutics. Adopting animal models in which factors such as host genetic landscape, microbiota profile, and diet can be controlled enables investigating how the microbiota contributes to immunological dysregulation and inflammatory disorders. Current preclinical imaging of gut microbiota relies on models where the bacteria can be isolated, labelled, and re-administered. , optical imaging, ultrasound and magnetic resonance imaging define the bacteria's biodistribution in preclinical models, whereas nuclear imaging investigates bacterial metabolic activity. For the clinical investigation of microbe-host interactions, molecular nuclear imaging is increasingly becoming a promising approach. Future microbiota research should develop selective imaging probes to investigate microbiota profiles and individual strains of specific microbes. Preclinical knowledge can be translated into the molecular imaging field with great opportunities for studying the microbiome.
PubMed: 36593827
DOI: 10.1016/j.heliyon.2022.e12511 -
European Journal of Nuclear Medicine... Jul 2023FAP is a membrane-bound protease under investigation as a pan-cancer target, given its high levels in tumors but limited expression in normal tissues. FAP-2286 is a...
PURPOSE
FAP is a membrane-bound protease under investigation as a pan-cancer target, given its high levels in tumors but limited expression in normal tissues. FAP-2286 is a radiopharmaceutical in clinical development for solid tumors that consists of two functional elements: a FAP-targeting peptide and a chelator used to attach radioisotopes. Preclinically, we evaluated the immune modulation and anti-tumor efficacy of FAP-2287, a murine surrogate for FAP-2286, conjugated to the radionuclide lutetium-177 (Lu) as a monotherapy and in combination with a PD-1 targeting antibody.
METHODS
C57BL/6 mice bearing MCA205 mouse FAP-expressing tumors (MCA205-mFAP) were treated with Lu-FAP-2287, anti-PD-1, or both. Tumor uptake of Lu- FAP-2287 was assessed by SPECT/CT scanning, while therapeutic efficacy was measured by tumor volume and survival. Immune profiling of tumor infiltrates was evaluated through flow cytometry, RNA expression, and immunohistochemistry analyses.
RESULTS
Lu-FAP-2287 rapidly accumulated in MCA205-mFAP tumors leading to significant tumor growth inhibition (TGI) and longer survival time. Significant TGI was also observed from anti-PD-1 and the combination. In flow cytometry analysis of tumors, Lu-FAP-2287 increased CD8 T cell infiltration which was maintained in the combination with anti-PD-1. The increase in CD8 T cells was accompanied by an induction of STING-mediated type I interferon response and higher levels of co-stimulatory molecules such as CD86.
CONCLUSION
In a preclinical model, FAP-targeted radiotherapy enhanced anti-PD-1-mediated TGI by modulating the TME and increasing the recruitment of tumor-infiltrating CD8 T cells. These findings provide a rationale for clinical studies of combined Lu-FAP-2286 radiotherapy and immune checkpoint inhibition in FAP-positive tumors.
Topics: Animals; Mice; Immune Checkpoint Inhibitors; CD8-Positive T-Lymphocytes; Tumor Microenvironment; Cell Line, Tumor; Mice, Inbred C57BL; Fibroblasts
PubMed: 37086273
DOI: 10.1007/s00259-023-06211-6 -
Revista de Investigacion Clinica;... 2023Since the dawn of civilization, ancient cultures have utilized hallucinogens from plants and fungi in the context of religious and healing practices. Recently, their use... (Review)
Review
Since the dawn of civilization, ancient cultures have utilized hallucinogens from plants and fungi in the context of religious and healing practices. Recently, their use has expanded to other cultures. Hallucinogens are natural or synthetic substances that alter the perception of reality at nontoxic doses, producing intense psychological and physiological effects. The initial research on hallucinogens began in the 1950s. However, their non-medical use, studies without proper controls, and negative social opinion resulted in legal restrictions that limited their use for clinical and preclinical research for more than two decades. A renewed interest in studying hallucinogens as potential therapeutic agents for treating different psychiatric conditions has recently re-emerged. This review summarizes the effects of main hallucinogen drugs and their therapeutic potential. Classic hallucinogens such as LSD, dimethyltryptamine, psilocin, and mescaline have chemical structures similar to serotonin and directly activate 5-hydroxy-tryptamine (5-HT) receptors. Ketamine is a dissociative anesthetic with antagonist effects at the glutamatergic N-methyl-D-aspartate receptor, indirectly activating 5-HT receptors. Ketamine has rapid antidepressant effects and reduces suicidal ideation, but its effects are short-lasting. Other hallucinogens are under study. It is necessary to continue this research with a more rigorous methodology and include studying the long-term effects of psychedelics use.
Topics: Humans; Hallucinogens; Ketamine; Serotonin; Mescaline; N,N-Dimethyltryptamine
PubMed: 37441761
DOI: 10.24875/RIC.23000108 -
Frontiers in Oncology 2017The limited effectiveness of conventional therapy for malignant pleural mesothelioma demands innovative approaches to this difficult disease. Even with aggressive... (Review)
Review
The limited effectiveness of conventional therapy for malignant pleural mesothelioma demands innovative approaches to this difficult disease. Even with aggressive multimodality treatment of surgery, radiation, and/or chemotherapy, the median survival is only 1-2 years depending on stage and histology. Oncolytic viral therapy has emerged in the last several decades as a rapidly advancing field of immunotherapy studied in a wide spectrum of malignancies. Mesothelioma makes an ideal candidate for studying oncolysis given the frequently localized pattern of growth and pleural location providing access to direct intratumoral injection of virus. Therefore, despite being a relatively uncommon disease, the multitude of viral studies for mesothelioma can provide insight for applying such therapy to other malignancies. This article will begin with a review of the general principles of oncolytic therapy focusing on antitumor efficacy, tumor selectivity, and immune system activation. The second half of this review will detail results of preclinical models and human studies for oncolytic virotherapy in mesothelioma.
PubMed: 28884088
DOI: 10.3389/fonc.2017.00179 -
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 -
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