Vitamin D3 promotes oligodendrogenesis and modulates synucleinopathy in lead-induced nigral pars compacta neurotoxicity in rats.

BACKGROUND: Lead-induced neurotoxicity was marked with locomotor and Parkinsonian-like changes. Oligodendrocytes and synucleinopathy were signed to in the pathophysiology of some neurodegenerative diseases. Vitamin D3's (D3) role in substantia nigra pars compacta (SNpc) disorders is debated between neuroscientists. The aim of the study was to investigate lead-induced SNpc neurotoxic changes and explore the possible neuroprotective role of D3 and the possible involvement of oligodendrocytes and α-synuclein. MATERIALS AND METHODS: This study included 40 adult Wistar rats assigned into four equal groups: control, lead (Pb) (in drinking water, 1,000 mg/L), Pb + D3 (D3 injection, 1,000 IU/kg IM; 3 days/week), and D3. After 8 weeks, the rats were sacrificed, and their midbrain underwent biochemical and immunoblotting analysis. Midbrain paraffin blocks were stained for histological and immunohistochemical assessment. RESULTS: Lead (Pb) had increased significantly (p < 0.05) nigral α-synuclein and caspase-11 by immunoblotting analysis. Histologically, it induced neurodegeneration in SNpc and significantly decreased neuronal cell density by cresyl violet staining. Pb also significantly reduced SNpc tyrosine hydroxylase immunoreaction, significantly elevated glial fibrillatory acid protein (GFAP) and α-synuclein immunoreaction associated with a mild but significant increase in caspase-3. In the Pb + D3 group, all the previous deleterious changes were significantly alleviated in addition to significant upregulation of anti-oligodendrocytes immunoexpression. CONCLUSIONS: Lead (Pb) may induce SNpc neurotoxicity presumably via activation of caspase-11 and α-synuclein. D3 may modulate this neurotoxicity probably through an oligodendrogenic effect.

Potential therapeutic role of microvesicles derived from mesenchymal stem cells and platelet-rich plasma in murine burn wound healing: scar regulation and antioxidant mechanism.

BACKGROUND: Microvesicles (MVs) derived from mesenchymal stem cells exhibited an emerging promising therapy in many animal model diseases. Post-burn scars represent one of the significant challenges in wound healing processes. The present study investigated the possible role of MVs derived from mesenchymal stem cells vs. platelet-rich plasma (PRP) in murine burn wound healing. MATERIALS AND METHODS: Wistar rats (n = 40) were assigned into four equal groups (control, burn, burn + PRP, burn + MVs). Small-sized burns were induced, morphologically followed for 3 weeks, then rats were sacrificed and skin lesions were analysed biochemically and immunohistochemically. RESULTS: Both MVs and PRP modulated the burn healing process with better results in the MVs group than in PRP. MVs significantly (p < 0.05) accelerated burn wound size healing and dramatically modulated tissue interleukin (IL)-10, IL-6, and hyaluronidase. Both MVs and PRP significantly downregulated gene expression of miRNA203 and alpha smooth muscle actin and immunoblotting analysis of matrix metalloproteinases 3 and transforming growth factor beta compared with the burn group. The immune-staining intensity of tumour necrosis factor alpha was dramatically reversed in the MVs group compared with the burn group, whereas that of connective tissue growth factor, collagen I and III was significantly reduced in both groups. The antioxidant Nrf2 immune-staining intensity had been dramatically enhanced particularly in MVs. CONCLUSIONS: Microvesicles derived from mesenchymal stem cells and PRP may improve burn wound healing via regulating scar formation and antioxidant mechanism.

Cadmium-induced adrenal cortical autophagy in rats: possible modulation by sildenafil.

BACKGROUND: The link between autophagy, inflammatory bowel disease, ischaemic injury and cancer had been established. Reasonable evidence is available for cadmium to be related to certain cancers. Sildenafil had been investigated to modulate oxidative stress mechanisms. The aim of this study is to investigate cadmium-induced adrenal cortical autophagy and to declare possible modulation by sildenafil. MATERIALS AND METHODS: Twenty four Wistar rats weighing 150-200 g were randomly and equally assigned into: control group, sildenafil (20 mg/kg/day orally) exposed group, cadmium group (cadmium chloride 1 mg/kg/day SC), cadmium + sildenafil group (rats received cadmium concomitant with sildenafil). Euthanasia was done 4 weeks from the beginning of experiment; adrenal glands were subjected to biochemical, histological, ultrastructural and immunnohistochemical assessment. RESULTS: Control and sildenafil exposed groups exhibited nearly similar results. Cadmium had produced adrenal cortical apoptosis and ultrastructural derangement of cell organelles. Cadmium-induced autophagy was detected by ultrastructural abundance of enlarged lysosomes and significant (p < 0.05) increase in the optical density of lysosomal associated membrane protein 2 immunoexpression. Sildenafil taken with cadmium had decreased adrenal cortical autophagy, significantly modulated the adrenal gland superoxide dismutase and malondialdehyde compared to cadmium group. Also, the optical density of nuclear factor kappa B (NF-kB) and caspase-3 immunoexpression was significantly decreased in cadmium + sildenafil compared to cadmium group. CONCLUSIONS: Cadmium might induce adrenal cortical autophagy in rats and sildenafil might show an ameliorating effect probably through enhancement of antioxidant defence mechanism and modulation of NF-kB.

Efficacy of erythropoietin-pretreated mesenchymal stem cells in murine burn wound healing: possible in vivo transdifferentiation into keratinocytes.

BACKGROUND: Stem cells have shown promising potential to treat burn wounds. Erythropoietin was capable of promoting in vitro transdifferentiation of mesenchymal stem cells (MSCs). The aim of the study was to investigate possible role of erythropoietin-pretreated mesenchymal stem cells (EPOa/MSCs) in burn wounds healing and to evaluate its in vivo differentiation into keratinocytes. MATERIALS AND METHODS: Forty rats were utilised in this study divided into four groups (n = 10 for each). Control group (I), burn group (II), burn + MSCs, group (III), burn + EPOa/MSCs. 1 × 106 cells were injected locally for each 1 cm² of burn areas. Burn areas were followed-up morphologically. After 21 days of the experiment, the rats were euthanised, skin specimens were assessed biochemically, histologically and immunohistochemically. RESULTS: EPOa/MSCs enhanced significantly (p < 0.05) burn wound vimentin gene expression and level of interleukin (IL)-10 while decreased IL-1 and COX2 as compared to the burn group. Histologically, EPOa/MSCs improved epithelialisation despite stem cells' differentiation into keratinocytes was rarely detected by PKH26 red fluorescence. EPOa/MSCs promoted angiogenesis as detected by significant increase in VEGF and PDGF immunoexpression as compared to burn group. CONCLUSIONS: EPOa/MSCs may improve burn wound healing, probably through anti-inflammatory, immunomodulatory and angiogenic action. However, in vivo transdifferentiation into keratinocytes was rarely detected.

Mesenchymal stem cells pretreated with platelet-rich plasma modulate doxorubicin-induced cardiotoxicity.

The cardiotoxic adverse effect of doxorubicin (DOX) is the major factor limiting its use. Recently, mesenchymal stem cells (MSCs) have been implicated in the preclinical studies of treatment of DOX-induced cardiotoxicity. The question is MSCs pretreated with platelet-rich plasma (PRP) have a better influence on DOX-induced cardiotoxicity compared to the influence of MSCs alone. Twenty-four Wistar rats were categorized into control, DOX-treated, MSC-treated, and PRP/MSC-treated groups. DOX was injected for two consecutive weeks. Light microscopic, biochemical markers (interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-α), and creatine kinase-MB (CK-MB)), immunohistochemical (Bax, Bcl2, vascular endothelial growth factor (VEGF), and cardiac troponin-I (CT-I)), and oxidative/antioxidative markers (malondialdehyde (MDA)/superoxide dismutase (SOD)) were measured. Degenerative cardiac changes were detected in the DOX-treated group with complete loss of the architecture and coagulative necrosis. These changes were accompanied with the elevation of the serum level of CK-MB and loss of CT-I immunoreactivity. The major factors in the DOX-induced cardiotoxicity were the oxidative stress (elevated MDA/decreased SOD), inflammation (elevated TNF-α/decreased IL-10), and cardiac apoptosis (lower Bcl2, higher Bax, and lower Bcl2/Bax ratio). MSCs and PRP/MSCs attenuate DOX-induced cardiotoxicity. Better attenuation was observed in the PRP/MSC-treated group. PRP/MSC combination reduced greatly the MDA and TNF-α and increased IL-10, Bcl2/Bax ratio, and VEGF. PRP had no significant influence over the Bcl2, Bax, and SOD. In conclusion, DOX in its toxic dose induced myocardial injury. This destructive effect is related to oxidative stress, inflammation, and cardiac apoptosis. PRP/MSC possesses a better attenuation over the DOX-induced toxicity compared to MSC alone.

Acrylamide-induced adverse cerebellar changes in rats: possible oligodendrogenic effect of omega 3 and green tea.

BACKGROUND: Humans are widely exposed to acrylamide (ACR) and its neurotoxicity is a significant public health issue attracting wide attention. The aim of the study was to investigate ACR-induced adverse cerebellar changes in rats and study the possible oligodendrogenic effect of omega 3 and green tea. MATERIALS AND METHODS: Twenty-four adult albino rats weighing 150-200 g were randomly divided into four equal groups (6 rats each): control group (Group I), the rats that received ACR 45 mg/kg/day (Group II), the rats that received ACR concomitant with omega 3 at a dosage of 200 mg/kg/day (Group III), the rats that received ACR concomitant with green tea dissolved in drinking water at a dosage of 5 g/L (Group IV). The rats were euthanized after 8 weeks of the experiment. Malondialdehyde (MDA) and glutathione (GSH) were measured in cerebellar homogenates. Sections of 5 µm thickness from specimens from the cerebellum were stained with haematoxylin and eosin, silver stain and immunohistochemical stains: platelet-derived growth factor alpha (PDGFα; for oligodendrocytes), glial fibrillary acidic protein (GFAP; for astrocytes) and BCL2 (antiapoptotic). RESULTS: Omega 3 and green tea had improved MDA and GSH as compared to the ACR group. Histologically, the ACR group showed variable degrees of cellular degeneration. Omega 3 had induced oligodendrogenesis in Group III. The optical density of silver stain was significantly (p < 0.05) increased in Groups III and IV as compared to the ACR group. Area per cent of positive PDGFα was significantly increased in the ACR + omega 3 group as compared to the ACR group. Area per cent of positive GFAP was significantly decreased in Groups III and IV as compared to the ACR group. Area per cent of positive BCL2 was significantly increased in the omega 3-trated group as compared to the ACR group. CONCLUSIONS: Concomitant administration of omega 3 or green tea with ACR might mitigate the adverse cerebellar changes caused by ACR thanks to an oligodendrogenic effect of omega 3.