Heavy metal associated health hazards: An interplay of oxidative stress and signal transduction.

Arsenic induces pancreatic dysfunction and ferroptosis via mitochondrial ROS-autophagy-lysosomal pathway.

Exosomes are lipid-bilayer enclosed nano-sized vesicles that transfer functional cellular proteins, mRNA and miRNAs. Mesenchymal stem cells (MSCs) derived exosomes have been demonstrated to prevent memory deficits in the animal model of Alzheimer’s disease (AD). However, the intravenously injected exosomes could be abundantly tracked in other organs except for the targeted regions in the brain. Here, we proposed the use of central nervous system-specific rabies viral glycoprotein (RVG) peptide to target intravenously-infused exosomes derived from MSCs (MSC-Exo) to the brain of transgenic APP/PS1 mice. MSC-Exo were conjugated with RVG through a DOPE-NHS linker. RVG-tagged MSC-Exo exhibited improved targeting to the cortex and hippocampus after being administered intravenously. Compared with the group administered MSC-Exo, in the group administered RVG-conjugated MSC-Exo (MSC-RVG-Exo) plaque deposition and Aβ levels were sharply decreased and activation of astrocytes was obviously reduced. The brain targeted exosomes derived from MSCs was better than unmodified exosomes to improve cognitive function in APP/PS1 mice according to Morris water maze test. Additionally, although MSC-Exo injected intravenously reduced the expression of pro-inflammatory mediators TNF-α, IL-β, and IL-6, but the changes of anti-inflammatory factors IL-10 and IL-13 were not obvious. However, administration of MSC-RVG-Exo significantly reduced the levels of TNF-α, IL-β, and IL-6 while significantly raised the levels of IL-10, IL-4 and IL-13. Taken together, our results demonstrated a novel method for increasing delivery of exosomes for treatment of AD. By targeting exosomes to the cortex and hippocampus of AD mouse, there was a significant improvement in learning and memory capabilities with reduced plaque deposition and Aβ levels, and normalized levels of inflammatory cytokines.

/pdf/rvg-modified-exosomes-derived-from-mesenchymal-stem-cells-4yenar12ui.pdf

RVG-modified exosomes derived from mesenchymal stem cells rescue memory deficits by regulating inflammatory responses in a mouse model of Alzheimer’s disease

Environmental arsenic exposure and its contribution to human diseases, toxicity mechanism and management.

Nrf2: Redox and Metabolic Regulator of Stem Cell State and Function.

Arsenic poisoning is a global health problem. Chronic exposure to arsenic has been associated with the development of a wide range of diseases and health problems in humans. Arsenic exposure induces the generation of intracellular reactive oxygen species (ROS), which mediate multiple changes to cell behavior by altering signaling pathways and epigenetic modifications, or cause direct oxidative damage to molecules. Antioxidants with the potential to reduce ROS levels have been shown to ameliorate arsenic-induced lesions. However, emerging evidence suggests that constructive activation of antioxidative pathways and decreased ROS levels contribute to chronic arsenic toxicity in some cases. This review details the pathways involved in arsenic-induced redox imbalance, as well as current studies on prophylaxis and treatment strategies using antioxidants.

https://www.mdpi.com/2218-273X/10/2/240/pdf

The Role of Reactive Oxygen Species in Arsenic Toxicity.

In vitro culture of mesenchymal stem cells (MSCs) from mouse bone marrow (BM) has been hampered because of the low yield of MSCs during isolation and the contamination of hematopoietic cells during expansion. The lack of specific mouse BM-MSC markers increases the difficulty. Several techniques have been reported to improve the purity and in vitro growth of mouse BM-MSCs. However, systematic report on comparison of characteristics in primary BM-MSCs between different culture conditions is rare. Here, we studied the effects of oxygen concentrations and initial medium replacement intervals, along with cell passages, on mouse BM-MSCs isolated with differential adhesion method. BM-MSCs exhibited elevated proliferative and clonogenic abilities in 5% oxygen compared with 10% and 21% oxygen, as well as a better expression of the MSC marker Sca-1. Adipogenic and osteogenetic differentiation of BM-MSCs can be observed in both 21% and 5% oxygen. Adipogenic differentiation appeared stronger under normoxia conditions. BM-MSCs showed increased proliferative capacity and adipogenic/osteogenetic differentiation potential when initial medium replacement interval was 4 days compared with 1 day. As passage number increased, cells were more MSC-like in morphology and in expression of surface markers (positive for CD29, CD44, and Sca-1 and negative for CD11b, CD19, and CD45). These data provide new insight into optimizing the culture method and understanding the biological characteristics of mouse BM-MSCs during in vitro expansion.

Comparative Study on In Vitro Culture of Mouse Bone Marrow Mesenchymal Stem Cells.

Deficiency of long isoforms of Nfe2l1 sensitizes MIN6 pancreatic β cells to arsenite-induced cytotoxicity

Nrf2 in keratinocytes protects against skin fibrosis via regulating epidermal lesion and inflammatory response.

Chronic exposure to high levels of arsenic has been associated with high risks for many cancers, including renal cell carcinoma (RCC). However the underlying mechanisms are not clear. In the present study, chronic arsenite exposure (2 μM or 5 μM, 30 weeks) induced malignant transformation of HK-2 human renal epithelial cells as indicated by elevated colony formation (6.2- and 5.4-fold increase, respectively), secreted MMP-9 activity (10.1- and 11.3-fold increase, respectively) and proliferation rate (1.2- and 1.3-fold increase in 72 h, respectively). Lipid accumulation, typical of clear cell RCC, was observed in arsenic-transformed (As-TM) cells. Overexpression of hypoxia-inducible factor 2α (HIF2α) and suppression of carnitine palmitoyltransferase 1A (CPT1A) were found at the level of mRNA (1.5- and 0.49-fold of control, respectively) and protein (4.0- and 0.28-fold of control, respectively) after exposure to 2 μM arsenite for 20 weeks. Silencing of HIF2α significantly attenuated arsenite-induced malignant phenotypes and lipid accumulation. Inactivation of Von Hippel-Lindau (VHL) and impaired protein degradation of HIF2α were not found in As-TM cells. Expression of miR-182-5p and miR-802 in As-TM cells was 42.4% and 54.0% of control, respectively (p < 0.05). The levels of mRNA and protein of HIF2α were increased 2.4 folds and 1.6 folds of negative control in response to the miR-182-5p inhibitor, respectively, but decreased to 58.1% and 50.1% of negative control in response to miR-182-5p mimics, respectively. No significant alteration was observed in HIF2α expression when miR-802 was silenced. Our data provide further evidence for the carcinogenic role of arsenic in the kidney. Moreover, the miR-182-5p/HIF2α pathway is indicated to be involved in malignant transformation of human renal epithelial cells under arsenite exposure.

Yuxin Hu

Papers

The Role of Reactive Oxygen Species in Arsenic Toxicity.

Comparative Study on In Vitro Culture of Mouse Bone Marrow Mesenchymal Stem Cells.

Deficiency of long isoforms of Nfe2l1 sensitizes MIN6 pancreatic β cells to arsenite-induced cytotoxicity

Nrf2 in keratinocytes protects against skin fibrosis via regulating epidermal lesion and inflammatory response.

miRNA-182-5p, via HIF2α, contributes to arsenic carcinogenesis: evidence from human renal epithelial cells