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Purpose: Currently, several disorders including burns, trauma, excisional and diabetic wounds, and bedsores threaten the human health. Application of mesenchymal stem cells (MSCs) is recommended for treatment of skin disorders. However, because of oxidative stress and inflammation after skin injury, survival of transplanted MSCs is low which in turn negatively affects the efficiency of the MSCs-based therapy. In an attempt to address the aforementioned challenge and introducing a novel potential therapeutic strategy, we employed combination therapy by Lipocalin (Lcn2)-engineered MSCs and a Metadichol (an inverse agonist of vitamin D receptor (VDR)) nanogel in a rat model of excisional wound. Methods: First, Human umbilical cord MSCs (hUC-MSCs) was transfected by a recombinant plasmid encoding Lipocalin 2 (Lcn2) gene. Next, a combination of Metadichol nanogel and the engineered MSCs was co-applied on wound in rat model of excision injury. Finally the improvement of wound healing in experimental groups was evaluated by photography and histological assessments (hematoxylin and eosin staining). Results: Our findings revealed that the repair rate was higher in the group received combination therapy comparing to control groups. Notably, Metadichol+Lcn2-MSCs showed significantly higher wound contraction rate compared to control group at all time points (p value< 0.001). Furthermore, wound repair rate was 95% 14 days after surgery, and 100% after 21 days in the treatment groups. Our results also revealed that the combination therapy improved and accelerated the wound healing process. Conclusion: Our findings suggest a novel potential therapeutic strategy i.e. Lcn2-engineered MSCs and Metadichol for wound healing. However, further preclinical and clinical studies are required.
Purpose: Currently, several disorders including burns, trauma, excisional and diabetic wounds, and bedsores threaten the human health. Application of mesenchymal stem cells (MSCs) is recommended for treatment of skin disorders. However, because of oxidative stress and inflammation after skin injury, survival of transplanted MSCs is low which in turn negatively affects the efficiency of the MSCs-based therapy. In an attempt to address the aforementioned challenge and introducing a novel potential therapeutic strategy, we employed combination therapy by Lipocalin (Lcn2)-engineered MSCs and a Metadichol (an inverse agonist of vitamin D receptor (VDR)) nanogel in a rat model of excisional wound. Methods: First, Human umbilical cord MSCs (hUC-MSCs) was transfected by a recombinant plasmid encoding Lipocalin 2 (Lcn2) gene. Next, a combination of Metadichol nanogel and the engineered MSCs was co-applied on wound in rat model of excision injury. Finally the improvement of wound healing in experimental groups was evaluated by photography and histological assessments (hematoxylin and eosin staining). Results: Our findings revealed that the repair rate was higher in the group received combination therapy comparing to control groups. Notably, Metadichol+Lcn2-MSCs showed significantly higher wound contraction rate compared to control group at all time points (p value< 0.001). Furthermore, wound repair rate was 95% 14 days after surgery, and 100% after 21 days in the treatment groups. Our results also revealed that the combination therapy improved and accelerated the wound healing process. Conclusion: Our findings suggest a novel potential therapeutic strategy i.e. Lcn2-engineered MSCs and Metadichol for wound healing. However, further preclinical and clinical studies are required.
Psoriasis affects 3% of the population worldwide, and there is no known cure. Psoriasis is associated with an increased risk of psoriatic arthritis, lymphomas, cardiovascular disease, and Crohn's disease. Psoriasis treatments today include steroid and vitamin D3 cream, ultraviolet light, and immune systemsuppressing medications such as methotrexate.The T cells responsible for psoriasis are Th1 and Th l7 cells. IL-22, produced by Th17 cells, is crucial for the proliferation of keratinocytes. IL-22 with the help of IL-17 can induce the critical events of psoriasis. To maintain Th17 cells, IL-23 is required, and it is released from tumor necrosis factor-alpha (TNF-alpha) induced pathways. The pathophysiology of psoriasis involves RORC (retinoic acid receptor-related orphan nuclear receptor gamma) as a critical transcription factor for the development of Th17 cells. FDA has approved an antibody Secukinumab ® targeting TNF-α for the treatment of psoriasis. Other FDA approved drugs are Tremfya ® targeting IL23 for treatment of moderate to severe plaque psoriasis and Taltz ® that blocks IL17 for treatment of plaque psoriasis.Metadichol ® a nanoformulation of long-chain lipid alcohols derived from food is a TNF-alpha inhibitor and also binds to Vitamin D receptor (VDR) that could have beneficial effects on Psoriasis. VDR modulates Th1-mediated inflammatory disease like psoriasis. We now present evidence that Metadichol is an inverse agonist of RORγt and AHR (Aryl Hydrocarbon Receptor) thus controlling Th17, IL17 and IL22. Being a TNF-alpha inhibitor, it can control IL23 thus blocking the significant pathways that exacerbate psoriasis. We present case studies of 7 patients afflicted with psoriasis and skin related conditions and how treatment with Metadichol resolved the underlying disease. Metadichol ® has properties that allow its use as a safe nontoxic, toxic solution to combating the growing number of psoriasis cases. TNF-a is implicated in the pathogenesis of multiple inflammatory and autoimmune conditions such as like Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, and psoriasis. The development of TNF-α inhibitors has improved therapeutic options for patients with these conditions. However, TNF-α inhibitors are paradoxically inducing the new onset of psoriasis or worsening preexisting quiescent psoriatic diseases [13].Genomic effects of 1, 25(OH)2D3 are controlled via binding to a nuclear receptor protein, VDR (vitamin D receptor). VDR is expressed in keratinocytes, fibroblasts, Langerhans cells, sebaceous gland cells, endothelial cells and almost the entire cell types related to the skin immune system [14]. Vitamin D and analogs display in the skin effects on cellular differentiation, proliferation, regulate psoriasis and represent a standard therapy. However, there is a need for highly antiproliferative or anti-inflammatory acting vitamin D analogs that exhibit only minor calcemic activity. Selective vitamin D signaling pathways that exert little calcemic activity would...
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