Adipose Tissue-Derived Mesenchymal Stem Cells Alter Metabolites of Brain Cholesterol Homeostasis in An Alzheimer's Model.

OBJECTIVE: Disruption of cholesterol homeostasis in Alzheimer's disease (AD) plays a crucial role in disease pathogenesis, making it a potential therapeutic target. Mesenchymal stem cells (MSCs) show promise in treating cognitive impairment and provide a novel therapeutic approach. This study aims to investigate the effects of MSCs on specific metabolites associated with brain cholesterol homeostasis in an AD rat model. MATERIALS AND METHODS: In this experimental study, animals were divided into three groups: control, AD, and AD+MSCs. AD was induced using amyloid beta (Aß) and confirmed through the Morris water maze (MWM) behavioural test and Congo red staining. MSCs were extracted, characterised via flow cytometry, subjected to osteoblast and adipose differentiation, and injected intraventricularly. The cholesterol metabolite levels were measured using gas chromatography-mass spectrometry (GC)-MS and compared among the groups. RESULTS: Treatment with MSCs significantly improved memory function in the AD+MSCs group compared to the AD group and the number of beta-amyloid plaques decreased according to histological assessment. Disturbances in the brain cholesterol metabolites that included desmosterol, 7-dehydrocholesterol, 24S-hydroxycholesterol, 27-hydroxycholesterol and cholesterol were observed in the AD group compared to the control group. Treatment with MSCs resulted in significant alterations in the levels of these metabolites. CONCLUSION: The findings indicate that MSC therapy has the potential to improve AD by modulating brain cholesterol homeostasis and promoting the differentiation of stem cells into nerve cells. The results emphasize the importance of investigating the role of cholesterol metabolites in the context of MSC therapy to gain deeper insights into underlying mechanisms of the therapeutic efficacy of MSCs in AD.

Amyloid Beta Alters the Expression of microRNAs Regulating HMGCR and ABCA1 Genes in Astrocytes of C57BL/6J Mice.

Dysregulation of brain cholesterol homeostasis causes the accumulation of extracellular protein deposits called amyloid plaques in the hippocampus which eventually leads to neuronal death, memory and learning deficits. The aim of the present study was to investigate the effect of beta amyloid on miRNAs regulating HMGCR and ABCA1 as cholesterol synthesis and homeostasis genes. Primary astrocytes were isolated from C57BL/6J mice, and were treated with 0.5 µM amyloid beta (Aß). Expression levels of genes and miRNAs were measured by real-time PCR. In comparison to control, Aß treatment resulted in a significant decrease in miR-96-5p expression as a positive and negative regulator of HMGCR and ABCA1, respectively. There was no significant increase in miR-27a-3p expression as a negative regulator of HMGCR. miR- 106b- 5p and miR-143-3p expressions were also dramatically decreased as ABCA1 negative regulators. Amyloid beta can alter the expression of major genes in the cholesterol homeostasis pathway via their regulatory miRNAs.

Organochlorine pesticides, oxidative stress biomarkers, and leukemia: a case-control study.

Exposure to pesticides has been linked to an elevated risk of leukemia. The present research aimed to evaluate the relationship between organochlorine (OC) pesticides and biomarkers of oxidative stress in leukemia patients. This work was conducted on 109 patients with leukemia and 109 healthy controls. The serum concentrations of seven derivatives of OCs including alpha-HCH, beta-HCH, gamma-HCH, 2,4-DDT, 4,4-DDT, 2,4-DDE, and 4,4-DDE along with acetylcholinesterase (AChE), glutathione peroxidase (GPx), superoxide dismutase (SOD), paraoxonase-1 (PON1), and catalase (CAT) activities as well as total antioxidant capacity (TAC), nitric oxide (NO), protein carbonyl (PC), and malondialdehyde (MDA) levels were measured in all the subjects. Levels of OCs were remarkably higher in leukemia patients compared to the controls (p < 0.05). In addition, levels of SOD, AChE, GPx, PON-1, and TAC were remarkably lower in leukemia patients compared to controls (p < 0.05). In contrast, MDA, NO, and PC concentrations were higher in leukemia patients than in the controls (p < 0.05). Moreover, the serum level of 4,4-DDE was negatively associated with GPx activity (p = 0.038). Our findings suggest that OCs may play a role in the development of leukemia by disrupting the oxidant/antioxidant balance.

Mesenchymal Stem Cells Therapy Led to the Improvement of Spatial Memory in Rats with Alzheimer's disease Through Changing the Expression of LncRNA TUSC7/ miR-449a/ PPARγ and CD36 Genes in the Brain Tissue.

Mesenchymal stem cells (MSCs) have the ability to phagocytize amyloid beta (Aß) plaques and lower inflammation through the activity of microglia. Peroxisome proliferator-activated receptor gamma (PPARγ) is a protein involved in reducing inflammation through the activity of microglia and the phagocytosis of Aß plaques by scavenger receptor CD36, in this study, the effect of MSCs therapy on memory function and plaques was investigated. A total of 24 adult male Wistar rats were randomly divided into three groups:1) the control group, 2) the Aß-treated group (Alzheimer's disease (AD)), and 3) the MSC-treated group (AD + MSC). After the treatment with Aß and MSCs, western blotting and real-time polymerase chain reaction (PCR) techniques were used to assess protein and gene expression levels, respectively. MSCs improved spatial learning and memory in the AD group (p ≤0.05). The expression levels of PPARγ, lncRNA TUSC7, and CD36 genes were significantly elevated in the group receiving MSCs compared to the AD group (p≤0.0001). Also, the expression level of miR-449a significantly decreased in the AD + MSC group (p≤0.0001). Moreover, western blot analysis revealed that PPARγ and CD36 protein levels were enhanced in the AD + MSC group compared to the AD group (p≤0.0001). MSC treatment led to the positive regulation of the PPARγ gene and its protein expression by ncRNAs, which could have a beneficial impact on CD36 protein levels, and subsequently, reduce the number of plaques in the cell recipient.

High Levels of Organochlorines Are Associated with Induction of ABL1 Promoter Methylation in Children with Acute Lymphoblastic Leukemia.

Exposure to organochlorines is associated with epigenetic changes, including methylation change in the promoter of tumor suppressor genes, thereby leading to cancer induction. The aim of this study was to investigate the relationship between organochlorine pesticides (OCPs) and ABL1 promoter methylation in child patients with acute lymphoblastic leukemia (ALL) and the control group. The methylation rate of the ABL1 promoter was evaluated using the methylation-specific polymerase chain reaction method, and the level of OCPs in patients with ALL and healthy children was measured using gas chromatography. ABL1 promoter hypermethylation was observed in 64% of ALL patients and 28.5% of children in the control group. The level of OCPs in children with methylated ABL1 promoters was significantly higher than that in children with nonmethylated ABL1 promoters (p < 0.05). Our findings suggest that OCPs, especially alpha-hexachlorocyclohexane, beta-hexachlorocyclohexane, gamma-hexachlorocyclohexane, 2,4 dichlorodiphenyldichloroethylene, and 4,4 dichlorodiphenyltrichloroethane may induce methylation at the ABL1 promoter level, thereby preventing the normal expression of the ABL1 gene. As a result, the reduced expression of ABL1 (a tumor suppressor) gene due to the hypermethylation of its promoter leads to the disruption of normal biological processes, thus making cells vulnerable to oncogenic factors.

Organochlorine pesticides, oxidative stress biomarkers, and leukemia: a case-control study.

Exposure to pesticides has been linked to an elevated risk of leukemia. The present research aimed to evaluate the relationship between organochlorine (OC) pesticides and biomarkers of oxidative stress in patients with leukemia. This work was conducted on 109 patients with leukemia and 109 healthy controls. The serum concentrations of seven derivatives of OCs including alpha-hexachlorocyclohexane (HCH), beta-HCH, gamma-HCH, 2,4-dichlorodiphenyltrichloroethane (DDT), 4,4-DDT, 2,4-dichlorodiphenyldichloroethylene (DDE), and 4,4-DDE along with acetylcholinesterase (AChE), glutathione peroxidase (GPx), superoxide dismutase (SOD), paraoxonase-1 (PON1), and catalase (CAT) activities as well as total antioxidant capacity (TAC), nitric oxide (NO), protein carbonyl (PC), and malondialdehyde (MDA) levels were measured in all the subjects. Levels of OCs were remarkably higher in patients with leukemia compared with the controls (p<0.05). In addition, levels of SOD, AChE, GPx, PON1, and TAC were remarkably lower in patients with leukemia compared with controls (p<0.05). In contrast, MDA, NO, and PC concentrations were higher in patients with leukemia than in the controls (p<0.05). Moreover, the serum level of 4,4-DDE was negatively associated with GPx activity (p=0.038). Our findings suggest that OCs may play a role in the development of leukemia by disrupting the oxidant/antioxidant balance.