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Mangalathettu Binumon, Thankachan
- Cholesterolgenic Inhibition Causes Permanent Hair Follicle Damage by Activating Fibrosis Via the Angiotensin Receptor .
Abstract Views :233 |
PDF Views:0
Authors
Shahul Hameed Najeeb
1,
Thankachan Mangalathettu Binumon
1,
Suresh Surya
1,
Leemon Nikhila
1,
Parameswara Panicker Sreejith
1
Affiliations
1 Department of Zoology, Advanced Centre for Regenerative Medicine and Stem cell in Cutaneous Research (AcREM-Stem), University of Kerala, Thiruvananthapuram – 695581, Kerala, India ., IN
1 Department of Zoology, Advanced Centre for Regenerative Medicine and Stem cell in Cutaneous Research (AcREM-Stem), University of Kerala, Thiruvananthapuram – 695581, Kerala, India ., IN
Source
Artificial Intelligent Systems and Machine Learning, Vol 26, No 3 (2022), Pagination: 188 - 204Abstract
Primary Cicatricial Alopecia (PCA) is a type of inflammatory hair loss disorder resulting in the permanent damage of the pilosebaceous structure due to fibrosis. Various internal and environmental stimuli caused the breakdown of hair follicle cells. Cholesterol is a crucial component in the formation and differentiation of hair follicles and the skin’s overall health. The loss of hair follicles and aberrant cycles were caused by inhibiting or obstructing the cholesterol biosynthetic pathways. This study suggests that cholesterologenic changes like precursor formation and inhibition in the hair follicle, trigger inflammation, fibrogenic signaling and lead to fibrosis. TGFβ-SMAD pathways related to the fibrogenic process were significantly expressed during the experimental condition. Angiotensin II receptor, AGTR1, showed a profound effect on the hair follicle cells. Real-time PCR analysis and immunohistochemistry of the patient’s scalp biopsies, HHFORS cells, and mice tissue sample revealed that the fibrotic genes were significantly activated after the treatment of BM15766, a cholesterol biosynthesis inhibitor, and 7-DHC, a sterol precursor. Our study confirmed that fibrosis is developed in the late stage of PCA by the dysregulation of cholesterol biosynthesis pathways in the hair follicle cells.Keywords
Aryl hydrocarbon Receptor, Angiotensin II, Primary Cicatricial Alopecia, Autoimmune Disorder, Peroxisome Proliferator-Activated Receptors γ, Transforming Growth Factor β .References
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- Tsuruoka H, Khovidhunkit W, Brown BE, et al. Scavenger Receptor Class B Type I is Expressed in Cultured Keratinocytes and Epidermis regulation in response to changes in cholesterol homeostasis and barrier. 2002; 277(4):2916-22. https://doi.org/10.1074/ jbc.M106445200 PMid:11707442
- Schallreuter KU, Hasse S, Rokos H, et al. Cholesterol regulates melanogenesis in human epidermal melanocytes and melanoma cells. Exp Dermatol. 2009; 18(8):680-8. https://doi.org/10.1111/j.1600-0625.2009.00850.x PMid:19469904
- Palmer M, Palmer MA, Blakeborough L, et al. Cholesterol homeostasis : Links to hair follicle biology and hair disorders.Exp Dermatol. 2020; 29(3):299-311. https://doi.org/10.1111/exd.13993 PMid:31260136
- Panicker SP, Ganguly T, Consolo M, et al. Sterol intermediates of cholesterol biosynthesis inhibit hair growth and trigger an innate immune response in cicatricial alopecia. PLoS One. 2012; 7(6):e38449:. https://doi.org/10.1371/journal.pone.0038449 PMid:22685570 PMCid:PMC3369908
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- Shapira KE, Ehrlich M, Henis YI. Cholesterol depletion enhances TGF-β Smad signaling by increasing c-Jun expression through a PKR-dependent mechanism. Mol Biol Cell. 2018; 29(20):2494-507. https://doi.org/10.1091/mbc.E18-03-0175 PMid:30091670 PMCid:PMC6233055
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- Budi EH, Duan D, Derynck R. Transforming Growth Factor- b Receptors and Smads :Regulatory complexity and functional versatility. Trends Cell Biol. 2017; 27(9):658-672. https://doi.org/10.1016/j.tcb.2017.04.005 PMid:28552280
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- Murphy AM, Wong AL, Bezuhly M. Modulation of angiotensin II signaling in the prevention of fibrosis.Fibrogenesis Tissue Repair. 2015; 23;8:7. https://doi.org/10.1186/s13069-015-0023-z PMid:25949522 PMCid:PMC4422447
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- Zuo W, Zhao X, Chen YG. SARS Coronavirus and Lung Fibrosis. Molecular Biology of the SARS-Coronavirus. 2009; 22:247-58. https://doi.org/10.1007/978-3-642-03683-5_15 PMCid:PMC7176214
- Karnik P, Tekeste Z, McCormick TS, et al. Hair follicle stem cell-specific PPARγ deletion causes scarring alopecia. J Invest Dermatol 2009; 129(5):1243-57. https://doi.org/10.1038/jid.2008.369 PMid:19052558 PMCid:PMC3130601
- Shi-wen X, Eastwood M, Stratton RJ, et al. Rosiglitazone alleviates the persistent fibrotic phenotype of lesional skin scleroderma fibroblasts. Rheumatology 2010; 49(2):259-63. https://doi.org/10.1093/rheumatology/kep371 PMid:20007285
- Vallée A, Lecarpentier Y. TGF β in fibrosis by acting as a conductor for contractile properties of myofibroblasts. Cell Biosci. 2019; 1-15. https://doi.org/10.1186/s13578-019-0362-3 PMid:31827764 PMCid:PMC6902440
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- Cholesterolgenic Inhibition Causes Permanent Hair Follicle Damage by Activating Fibrosis Via the Angiotensin Receptor
Abstract Views :143 |
PDF Views:0
Authors
Shahul Hameed Najeeb
1,
Thankachan Mangalathettu Binumon
2,
Suresh Surya
2,
Leemon Nikhila
2,
Parameswara Panicker Sreejith
2
Affiliations
1 Department of Zoology, Advanced Centre for Regenerative Medicine and Stem cell in Cutaneous Research (AcREM-Stem), University of Kerala, Thiruvananthapuram – 695581, Kerala, India, IN
2 Department of Zoology, Advanced Centre for Regenerative Medicine and Stem cell in Cutaneous Research (AcREM-Stem), University of Kerala, Thiruvananthapuram – 695581, Kerala, India ., IN
1 Department of Zoology, Advanced Centre for Regenerative Medicine and Stem cell in Cutaneous Research (AcREM-Stem), University of Kerala, Thiruvananthapuram – 695581, Kerala, India, IN
2 Department of Zoology, Advanced Centre for Regenerative Medicine and Stem cell in Cutaneous Research (AcREM-Stem), University of Kerala, Thiruvananthapuram – 695581, Kerala, India ., IN
Source
Journal of Endocrinology and Reproduction, Vol 26, No 3 (2022), Pagination: 188 - 204Abstract
Primary Cicatricial Alopecia (PCA) is a type of inflammatory hair loss disorder resulting in the permanent damage of the pilosebaceous structure due to fibrosis. Various internal and environmental stimuli caused the breakdown of hair follicle cells. Cholesterol is a crucial component in the formation and differentiation of hair follicles and the skin’s overall health. The loss of hair follicles and aberrant cycles were caused by inhibiting or obstructing the cholesterol biosynthetic pathways. This study suggests that cholesterologenic changes like precursor formation and inhibition in the hair follicle, trigger inflammation, fibrogenic signaling and lead to fibrosis. TGFβ-SMAD pathways related to the fibrogenic process were significantly expressed during the experimental condition. Angiotensin II receptor, AGTR1, showed a profound effect on the hair follicle cells. Real-time PCR analysis and immunohistochemistry of the patient’s scalp biopsies, HHFORS cells, and mice tissue sample revealed that the fibrotic genes were significantly activated after the treatment of BM15766, a cholesterol biosynthesis inhibitor, and 7-DHC, a sterol precursor. Our study confirmed that fibrosis is developed in the late stage of PCA by the dysregulation of cholesterol biosynthesis pathways in the hair follicle cells .Keywords
Aryl hydrocarbon Receptor, Angiotensin II, Primary Cicatricial Alopecia, Autoimmune Disorder, Peroxisome Proliferator-Activated Receptors γ, Transforming Growth Factor βReferences
- Inoue T, Miki Y, Abe K, et al. Sex steroid synthesis in human skin in situ : The roles of aromatase and steroidogenic acute regulatory protein in the homeostasis of human skin. Mol Cell Endocrinol. 2012; 362(1-2):19-28. https://doi.org/10.1016/j.mce.2012.05.005 PMid:22634420
- Tsuruoka H, Khovidhunkit W, Brown BE, et al. Scavenger Receptor Class B Type I is Expressed in Cultured Keratinocytes and Epidermis regulation in response to changes in cholesterol homeostasis and barrier. 2002; 277(4):2916-22. https://doi.org/10.1074/ jbc.M106445200 PMid:11707442
- Schallreuter KU, Hasse S, Rokos H, et al. Cholesterol regulates melanogenesis in human epidermal melanocytes and melanoma cells. Exp Dermatol. 2009; 18(8):680-8. https://doi.org/10.1111/j.1600-0625.2009.00850.x PMid:19469904
- Palmer M, Palmer MA, Blakeborough L, et al. Cholesterol homeostasis : Links to hair follicle biology and hair disorders.Exp Dermatol. 2020; 29(3):299-311. https://doi.org/10.1111/exd.13993 PMid:31260136
- Panicker SP, Ganguly T, Consolo M, et al. Sterol intermediates of cholesterol biosynthesis inhibit hair growth and trigger an innate immune response in cicatricial alopecia. PLoS One. 2012; 7(6):e38449:. https://doi.org/10.1371/journal.pone.0038449 PMid:22685570 PMCid:PMC3369908
- Ozyurt K, Uzak A, Ozturk P, et al. Emopamil binding protein mutation in Conradi-Hünermann-Happle syndrome representing plaque-type psoriasis. Indian J Dermatol. 2015; 60(2):216.
- Frangogiannis NG. Transforming growth factor-ß in tissue fibrosis. J Exp Med. 2020; 217(3):1-16. https://doi.org/10.1084/ jem.20190103 PMid:32997468 PMCid:PMC7062524 8.
- Wei J, Ghosh AK, Sargent JL, et al. PPARγ downregulation by TGF in fibroblast and impaired expression and function in systemic sclerosis: A novel mechanism for progressive fibrogenesis. PLoS One. 2010; 5(11):e13778. https://doi.org/10.1371/ journal.pone.0013778 PMid:21072170 PMCid:PMC2970611
- Inagaki Y, Okazaki I. Emerging insights into transforming growth factor β Smad signal in hepatic fibrogenesis. Gut. 2007; 56(2):284-92. https://doi.org/10.1136/gut.2005.088690 PMid:17303605 PMCid:PMC1856752
- Kagami S, Border WA, Miller DE, Noble NA. Angiotensin 11 Stimulates extracellular matrix protein synthesis through induction of transforming growth factor- β expression in rat glomerular mesangial cells. J Clin Invest. 1994; 93(6):2431-7. https://doi. org/10.1172/JCI117251 PMid:8200978 PMCid:PMC294451
- Suresh S, Leemon N, Najeeb S, Panicker SP. Cytokine profiling in primary cicatricial alopecia : androgenic alopecia and leptin connections. Journal of Endocrinology and Reproduction. 2020; 24:87-96.
- Shapira KE, Ehrlich M, Henis YI. Cholesterol depletion enhances TGF-β Smad signaling by increasing c-Jun expression through a PKR-dependent mechanism. Mol Biol Cell. 2018; 29(20):2494-507. https://doi.org/10.1091/mbc.E18-03-0175 PMid:30091670 PMCid:PMC6233055
- Ito T, Ito N, Saathoff M, et al. Interferon-γ is a potent inducer of catagen-like changes in cultured human anagen hair follicles. Br J Dermatol. 2005; 152(4):623-31. https://doi.org/10.1111/j.1365-2133.2005.06453.x PMid:15840090
- Imanishi H, Ansell DM, Chéret J, et al. Epithelial-to-mesenchymal stem cell transition in a human organ: lessons from lichen planopilaris. J Invest Dermatol. 2018; 138(3):511-9. https://doi.org/10.1016/j.jid.2017.09.047 PMid:29106928
- Budi EH, Duan D, Derynck R. Transforming Growth Factor- b Receptors and Smads :Regulatory complexity and functional versatility. Trends Cell Biol. 2017; 27(9):658-672. https://doi.org/10.1016/j.tcb.2017.04.005 PMid:28552280
- Roberts AB, Sporn MB. Mini-Review: Physiological actions and clinical applications of transforming growth factor beta ( TGFBeta ). Growth Factors. 1993; 8:1-9. https://doi.org/10.3109/08977199309029129 PMid:8448037
- Lu L, Saulis AS, Liu WR, et al. The temporal effects of anti-TGF-β1, 2, and 3 monoclonal antibody on wound healing and hypertrophic scar formation. J Am Coll Surg. 2005; 201(3):391-7. https://doi.org/10.1016/j.jamcollsurg.2005.03.032 PMid:16125072
- Pakyari M, Farrokhi A, Maharlooei MK, Ghahary A. Critical role of transforming growth factor beta in different phases of wound healing. Adv Wound Care. 2013; 2(5):215-24. https://doi.org/10.1089/wound.2012.0406 PMid:24527344 PMCid:PMC3857353
- Hitraya EG, Varga J, Artlett CM, Jimenjz SA. Identification of elements in the promoter region of the alpha1(1) procollagen gene involved in its up-regulated expression in systemic sclerosis. Arthritis Rheum. 1998; 41(11):2048-58. https://doi.org/10.1002/15290131(199811)41:11<2048::AID-ART21>3.0.CO;2-X
- Tang H, Cheng D, Jia Y, et al. Angiotensin II induces type I collagen gene expression in human dermal fibroblasts through an AP-1 / TGF- b 1-dependent pathway. Biochem Biophys Res Commun. 2009; 385(3):418-23. https://doi.org/10.1016/j.bbrc.2009.05.081 PMid:19465003
- Namazi MR, Ashraf A, Handjani F, et al. Angiotensin converting enzyme activity in alopecia areata. Enzyme Res. 2014; 2014:694148. https://doi.org/10.1155/2014/694148 PMid:25349723 PMCid:PMC4198813
- Murphy AM, Wong AL, Bezuhly M. Modulation of angiotensin II signaling in the prevention of fibrosis.Fibrogenesis Tissue Repair. 2015; 23;8:7. https://doi.org/10.1186/s13069-015-0023-z PMid:25949522 PMCid:PMC4422447
- Gabriel VA. Transforming growth factor- β and angiotensin in fibrosis and burn injuries. J Burn Care Res. 2009; 30(3):471-481. https://doi.org/10.1097/BCR.0b013e3181a28ddb PMid:19349880
- Zuo W, Zhao X, Chen YG. SARS Coronavirus and Lung Fibrosis. Molecular Biology of the SARS-Coronavirus. 2009; 22:247-58.https://doi.org/10.1007/978-3-642-03683-5_15 PMCid:PMC7176214
- Karnik P, Tekeste Z, McCormick TS, et al. Hair follicle stem cell-specific PPARγ deletion causes scarring alopecia. J Invest Dermatol 2009; 129(5):1243-57. https://doi.org/10.1038/jid.2008.369 PMid:19052558 PMCid:PMC3130601
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- Inhibition of Cholesterol Biosynthesis Modulates Epithelial-Mesenchymal Transition in Primary Cicatricial Alopecia Through TGFβ and Angiotensin Receptors
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Authors
Leemon Nikhila
1,
Suresh Surya
1,
Shahul Hameed Najeeb
1,
Thankachan Mangalathettu Binumon
1,
Parameswara Panicker Sreejith
1
Affiliations
1 Department of Zoology, University of Kerala, Thiruvananthapuram - 695581, Kerala, IN
1 Department of Zoology, University of Kerala, Thiruvananthapuram - 695581, Kerala, IN
Source
Journal of Endocrinology and Reproduction, Vol 27, No 1 (2023), Pagination: 40-53Abstract
Introduction: Primary Cicatricial Alopecia (PCA) is an autoimmune condition that affects the skin and causes hair loss in patients. In PCA the hair follicles of the patients are irreversibly damaged and replaced with fibrous tissue. This diseased condition lends relevance to our work since the fibrosis raises the potential that PCA may be affected in some way by the Epithelial Mesenchymal Transition (EMT). We used small interfering RNAs (siRNA) of TGFβ, AGTR and their regulators to identify the EMT modulation. Because these molecules mediate the induction of EMT. This study explores the idea of lowering PCA fibrosis by modifying EMT markers. Methods: We chose 7 DHC and BM15766 to investigate the function of cholesterol biosynthesis inhibition. We employed the HFORS in vitro and the mouse in vivo model system to examine EMT regulation PCA. Quantitative real-time PCR was utilised to examine the expression of genes in PCA scalp samples, compound-treated HFORS, and mouse tissues; immunohistochemistry was used to confirm the protein estimate in the scalp samples; and small interfering RNA (siRNA) transfection was used to identify the functional analysis of TGFβ and AGTR. Results: Reduced cholesterol production in PCA patients leads to permanent hair follicle damage. The in vitro and in vivo study using 7DHC and BM15766 revealed cells were positive for the EMT markers. PPARγ, AhR, and AGTR together can act as vital EMT regulators. As a result, the PPARγ agonist, AhR, and AGTR antagonist significantly downregulate the expression of CDH1, SNAIL1, and SMA. The markers of EMT are likewise deregulated by the transfection of siRNA for TGFβ and AGTR. Conclusion: We clarify how EMT is regulated in hair loss circumstances by suppressing cholesterol biosynthesis. We further confirm that EMT modulators (PPARγ, AhR, AGTR, and TGFβ) and siRNA can be employed as potentially effective strategies to slow the advancement of EMT. As a result, we propose these cholesterol and EMT modulators as potential inhibitors in PCA etiology.Keywords
Cholesterol, Fibrosis, Hair, PPARγ, Pioglitazone, Transfection.References
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