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Tay-Sachs disease (TSD) is a progressive neurodegenerative disorder that occurs due to a deficiency of a β hexosaminidase A (HexA) enzyme, resulting in the accumulation of GM2 gangliosides. In this work, we analyzed the effect of umbilical cord blood cell transplantation (UCBCT) and curcumin administration on the course of the disease in a patient with adult TSD. The patient's serum cytokine profile was determined using multiplex analysis. The level of GM2 gangliosides in plasma was determined using mass spectrometry. The enzymatic activity of HexA in the plasma of the patient was assessed using a fluorescent substrate assay. The HexA α-subunit (HexA) concentration was determined using ELISA. It was shown that both UCBCT and curcumin administration led to a change in the patient's cytokine profile. The UCBCT resulted in an increase in the concentration of HexA in the patient's serum and in an improvement in the patient's neurological status. However, neither UCBCT nor curcumin were able to alter HexA activity and the level of GM2 in patient's plasma. The data obtained indicate that UCBCT and curcumin administration can alter the immunity of a patient with TSD, reduce the level of inflammatory cytokines and thereby improve the patient's condition. [ABSTRACT FROM AUTHOR]

Simple Summary: Almost all human cells release extracellular vesicles participating in intercellular communication. Extracellular vesicles are rounded structures surrounded by the cytoplasmic membrane, which embody cytoplasmic contents of the parental cells, which makes extracellular vesicles a promising therapeutic tool for cell-free cancer therapy. In this study, human mesenchymal stem cells were genetically modified to overexpress human interleukin-2 (IL2), a cytokine which regulates the proliferation and activation of immune cells. Membrane vesicle release from native and genetically modified stem cells was induced by cytochalasin B treatment to increase the yield of membrane vesicles. To evaluate the immunomodulating properties of isolated membrane vesicles, immune cells were isolated from human peripheral blood and co-cultured with membrane vesicles from native or IL2 overexpressing stem cells. To analyze the anti-tumor activity of immune cells after interaction with IL2-enriched membrane vesicles, immune cells were co-cultured with triple negative breast cancer cells. As a result, IL2-enriched membrane vesicles were able to activate and stimulate the proliferation of immune cells, which in turn were able to induce apoptosis in breast cancer cells. Therefore, the production of IL2-enriched membrane vesicles represents a unique opportunity to meet the potential of extracellular vesicles to be used in clinical applications for cancer therapy. Interleukin 2 (IL2) was one of the first cytokines used for cancer treatment due to its ability to stimulate anti-cancer immunity. However, recombinant IL2-based therapy is associated with high systemic toxicity and activation of regulatory T-cells, which are associated with the pro-tumor immune response. One of the current trends for the delivery of anticancer agents is the use of extracellular vesicles (EVs), which can carry and transfer biologically active cargos into cells. The use of EVs can increase the efficacy of IL2-based anti-tumor therapy whilst reducing systemic toxicity. In this study, human adipose tissue-derived mesenchymal stem cells (hADSCs) were transduced with lentivirus encoding IL2 (hADSCs-IL2). Membrane vesicles were isolated from hADSCs-IL2 using cytochalasin B (CIMVs-IL2). The effect of hADSCs-IL2 and CIMVs-IL2 on the activation and proliferation of human peripheral blood mononuclear cells (PBMCs) as well as the cytotoxicity of activated PBMCs against human triple negative cancer MDA-MB-231 and MDA-MB-436 cells were evaluated. The effect of CIMVs-IL2 on murine PBMCs was also evaluated in vivo. CIMVs-IL2 failed to suppress the proliferation of human PBMCs as opposed to hADSCs-IL2. However, CIMVs-IL2 were able to activate human CD8+ T-killers, which in turn, killed MDA-MB-231 cells more effectively than hADSCs-IL2-activated CD8+ T-killers. This immunomodulating effect of CIMVs-IL2 appears specific to human CD8+ T-killer cells, as the same effect was not observed on murine CD8+ T-cells. In conclusion, the use of CIMVs-IL2 has the potential to provide a more effective anti-cancer therapy. This compelling evidence supports further studies to evaluate CIMVs-IL2 effectiveness, using cancer mouse models with a reconstituted human immune system. [ABSTRACT FROM AUTHOR]

GM2 gangliosidoses are a group of autosomal-recessive lysosomal storage disorders. These diseases result from a deficiency of lysosomal enzyme β-hexosaminidase A (HexA), which is responsible for GM2 ganglioside degradation. HexA deficiency causes the accumulation of GM2-gangliosides mainly in the nervous system cells, leading to severe progressive neurodegeneration and neuroinflammation. To date, there is no treatment for these diseases. Cell-mediated gene therapy is considered a promising treatment for GM2 gangliosidoses. This study aimed to evaluate the ability of genetically modified mesenchymal stem cells (MSCs-HEXA-HEXB) to restore HexA deficiency in Tay-Sachs disease patient cells, as well as to analyze the functionality and biodistribution of MSCs in vivo. The effectiveness of HexA deficiency cross-correction was shown in mutant MSCs upon interaction with MSCs-HEXA-HEXB. The results also showed that the MSCs-HEXA-HEXB express the functionally active HexA enzyme, detectable in vivo, and intravenous injection of the cells does not cause an immune response in animals. These data suggest that genetically modified mesenchymal stem cells have the potentials to treat GM2 gangliosidoses., Competing Interests: None

Passaged cell lines represent currently an integral component in various studies of malignant neoplasms. These cell lines are utilized for drug screening both in monolayer cultures or as part of three-dimensional (3D) tumor models. They can also be used to model the tumor microenvironment in vitro and in vivo through xenotransplantation into immunocompromised animals. However, immortalized cell lines have some limitations of their own. The homogeneity of cell line populations and the extensive passaging in monolayer systems make these models distant from the original disease. Recently, there has been a growing interest among scientists in the use of primary cell lines, as these are passaged directly from human tumor tissues. In this case, cells retain the morphological and functional characteristics of the tissue from which they were derived, an advantage often not observed in passaged cultures. This review highlights the advantages and limitations of passaged and primary cell cultures, their similarities and differences, as well as existing test systems that are based on primary and passaged cell cultures for drug screening purposes., Competing Interests: The authors declare that they have no conflicts of interest., (© The Author(s) 2024.)

Background: Several studies have highlighted the role of host-microbiome interactions in the pathogenesis of inflammatory bowel disease (IBD), resulting in an increasing amount of data mainly focusing on Western patients. Because of the increasing prevalence of IBD in newly industrialized countries such as those in Asia, the Middle East, and South America, there is mounting interest in elucidating the gut microbiota of these populations. We present a comprehensive analysis of several IBD-related biomarkers and gut microbiota profiles and functions of a unique population of patients with IBD and healthy patients from Kazan (Republic of Tatarstan, Russia)., Methods: Blood and fecal IBD biomarkers, serum cytokines, and fecal short-chain fatty acid (SCFA) content were profiled. Finally, fecal microbiota composition was analyzed by 16S and whole-genome shotgun sequencing., Results: Fecal microbiota whole-genome sequencing confirmed the presence of classic IBD dysbiotic features at the phylum level, with increased abundance of Proteobacteria, Actinobacteria, and Fusobacteria and decreased abundance of Firmicutes, Bacteroidetes, and Verrucomicrobia. At the genus level, the abundance of both fermentative (SCFA-producing and hydrogen (H2)-releasing) and hydrogenotrophic (H2-consuming) microbes was affected in patients with IBD. This imbalance was confirmed by the decreased abundance of SCFA species in the feces of patients with IBD and the change in anaerobic index, which mirrors the redox status of the intestine., Conclusions: Our analyses highlighted how IBD-related dysbiotic microbiota-which are generally mainly linked to SCFA imbalance-may affect other important metabolic pathways, such as H2 metabolism, that are critical for host physiology and disease development., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Extracellular vesicles, including exosomes and microvesicles, play a fundamental role in the activity of the nervous system, participating in signal transmission between neurons and providing the interaction of central nervous system with all body systems. In many neurodegenerative diseases, neurons pack toxic substances into vesicles and release them into the extracellular space, which leads to the spread of misfolded neurotoxic proteins. The contents of neuron-derived extracellular vesicles may indicate pathological changes in the central nervous system, and the analysis of extracellular vesicle molecular content contributes to the development of non-invasive methods for the diagnosis of many central nervous system diseases. Extracellular vesicles of neuronal origin can be isolated from various biological fluids due to their ability to cross the blood-brain barrier. Today, the diagnostic potential of almost all toxic proteins involved in nervous system disease pathogenesis, specifically α-synuclein, tau protein, superoxide dismutase 1, FUS, leucine-rich repeat kinase 2, as well as some synaptic proteins, has been well evidenced. Special attention is paid to extracellular RNAs mostly associated with extracellular vesicles, which are important in the onset and development of many neurodegenerative diseases. Depending on parental cell type, extracellular vesicles may have different therapeutic properties, including neuroprotective, regenerative, and anti-inflammatory. Due to nano size, biosafety, ability to cross the blood-brain barrier, possibility of targeted delivery and the lack of an immune response, extracellular vesicles are a promising vehicle for the delivery of therapeutic substances for the treatment of neurodegenerative diseases and drug delivery to the brain. This review describes modern approaches of diagnosis and treatment of central nervous system diseases using extracellular vesicles., Competing Interests: None