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Background: Mutations in keratin proteins have been vastly associated with a wide array of genodermatoses; however, mutations of keratins in psoriasis have not been fully investigated. The main aim of the current research was to identify the mutation in K14, K10, K16, and K17 genes in two stages of psoriasis patients., Methods: Ninety-six psoriatic skin biopsies were collected. mRNA transcript of K14, K10, K16, and K17 was prepared, amplified, and sequenced. Sanger sequences of all keratins were further validated for mutational analysis using Mutation Surveyor and Alamut Visual. Then, in silico analysis of protein stability and protein and gene expression of all keratins was performed and validated., Results: Out of 44 mutations, about 75% of keratins are highly pathogenic and deleterious. Remaining 25% mutations are less pathogenic and tolerated in nature. In these 33 deleterious mutations were immensely found to decrease keratin protein stability. We also found a correlation between keratin and Psoriasis Area and Severity Index score which added that alteration in keratin gene in skin causes severity of psoriasis., Conclusions: We strongly concluded that acanthosis and abnormal terminal differentiation was mainly due to the mutation in epidermal keratins. In turn, disease severity and relapsing of psoriasis are mainly due to the mutation of hyperproliferative keratins. These novel keratin mutations in psoriatic epidermis might be one of the causative factors for psoriasis.

Psoriasis is a chronic inflammatory skin disease characterized by hyper proliferation of keratinocytes. Recent data show that the epidermis thickening in psoriasis may be related to imbalance of homeostasis caused by abnormal apoptotic process. Maintenance of keratinocyte apoptotic process is very important in psoriasis. Methotrexate (MTX) has been used for many years to restore the normal skin in psoriasis condition. However, the exact mechanism of MTX in psoriasis condition is poorly understood. The aim of this study was to examine the role of MTX on keratinocyte apoptosis pathway in psoriasis patients. A total of 58 psoriasis vulgaris patients were recruited for this study. Nonlesional skin biopsies served as control. Skin biopsies of psoriatic patients were collected and analyzed for cytosolic, mitochondria and total cytochrome c by ELISA. Expression of caspase-9, NFκBp65, pAkt1 by western blot, real-time PCR and immunohistochemical analysis of c-FLIP protein was analyzed in nonlesional and lesional skin biopsies before (day 0) and after (at the end of 6 and 12 weeks) MTX treatment. After MTX treatment, a significant increase in cytochrome c was observed when compared with before MTX treatment in psoriasis patients (p < 0.001). Protein and gene expression of cleaved caspase-9 were significantly increased after MTX treatment, whereas the expression of Bcl-xL, c-FLIP, NFκBp65, pAkt1 significantly downregulated after MTX treatment. In conclusion, these results showed that intrinsic apoptotic pathway induced by MTX eventually adds the beneficial therapeutic role of MTX in psoriasis by controlling the acanthosis.

Background: Caspase-1 induces the proinflammatory cytokines which appears to be a promising target in Th1-type inflammatory diseases, like psoriasis. We determined the effect of MTX on caspase-1, TNF-α and IL-18 in psoriasis patients., Methods: We recruited 45 control subjects and 58 psoriasis patients for this study. The patients were treated with 7.5mg of MTX per week for 12weeks. Folic acid was given at 5mg once daily except on the day of MTX for 12weeks. Blood samples and lesional skin biopsy were taken. Histological examination has been done. IL-18 and TNF-α levels were analyzed by using ELISA. Caspase-1 expression was analyzed by western blot and Real Time PCR., Results: Histological examinations showed MTX decreased acanthosis in psoriasis skin. Plasma IL-18 level and serum TNF-α were increased in psoriasis and deduced significantly (P<0.001) after MTX treatment. Protein and mRNA expression of caspase-1 in skin biopsy were higher in psoriasis and reduced significantly (P<0.001) after MTX treatment., Conclusion: Decreasing inflammatory caspase and proinflammatory cytokines by MTX, inhibits the Th1 response in psoriasis. This shows the therapeutic effect of MTX in controlling the immunopathogenesis of psoriasis., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: In psoriatic skin, epidermal keratinocytes undergo deregulated inflammatory response that leads to prolonged expression of inflammatory mediators as well as abnormal keratins. Methotrexate (MTX) is an immunosuppressive agent used as a standard drug to treat severe psoriasis. The aim of the study is to find the pharmacological effect of MTX on abnormal keratin and deregulated inflammatory mediators., Methods: Fifty-eight psoriasis vulgaris patients were recruited for this study. Skin biopsies of psoriatic patients were collected and analyzed for activation signal such as TNF-α and IFN-γ and deactivation signal such as TGF-β1. Also, protein and gene expression of normal keratins K14 and K10 and abnormal keratins K16 and K17 were analyzed in skin biopsies before (day 0) and after (at the end of 6 and 12 weeks) MTX treatment., Results: Results show a significant decrease in tissue TNF-α and IFN-γ and increase in TGF-β1 after MTX treatment when compared with before MTX treatment in psoriasis patients (p<0.001). Protein and gene expression of K14, K16 and K17 decreased after MTX treatment, whereas the expression of differentiation marker K10 increased after MTX treatment., Conclusion: MTX resolves deregulated inflammatory markers and maintains normal keratin phenotype on hyperproliferating KC, thereby controlling acanthosis in psoriasis patients., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Propylthiouracil (PTU), an anti-thyroid thioureylene, has been shown to be effective in chronic plaque psoriasis. Involucrin is a precursor protein that is upregulated in psoriasis., Objectives: This study evaluated the expression of involucrin in the epidermis of skin in psoriatic plaques before and after treatment with PTU., Methods: This was an open-label, prospective study in which 25 psoriasis patients underwent skin biopsies prior to treatment with oral PTU 100 mg three times per day for 12 weeks. Patients were assessed at 2, 6, and 12 weeks. Skin biopsies were repeated at the same sites at 12 weeks. Pre- and post-treatment specimens were subjected to immunohistochemical staining and real-time polymerase chain reaction for involucrin., Results: Mean ± standard deviation (SD) scores on the Psoriasis Area and Severity Index reduced significantly from 17.86 ± 9.9 at baseline to 4.63 ± 4.1 at week 12 (P < 0.001). Histomorphometric analysis revealed marked decreases in numbers of positively stained cells and intensity of staining. Staining became localized to the upper granular layers after therapy. Immunohistochemical scoring for involucrin reduced from a mean ± SD of 9.00 ± 0.67 at baseline to 3.90 ± 0.88 at week 12 (P < 0.0001)., Conclusions: In psoriasis, there is increased expression of involucrin, which leads to abnormal keratinocyte differentiation and hence to the formation of psoriatic plaques. The therapeutic effect of PTU in psoriasis may be attributable to the downregulation of involucrin. Larger trials should further elucidate the mechanism and therapeutic potential of PTU in psoriasis., (© 2014 The International Society of Dermatology.)

Methotrexate (MTX), a cytotoxic chemotherapeutic agent, is considered an effective drug in the treatment of psoriasis. The aim of this study was to find out whether the effect of MTX treatment in psoriasis is due to oxidative stress-induced apoptosis. Psoriasis vulgaris patients (58 in number) were recruited for this study. Healthy volunteers (45 in number) served as control. Samples of psoriatic patients were collected and analyzed for total reactive oxygen species (ROS), malondialdehyde (MDA) levels, nitrite, nitrate levels and the activities of antioxidants like superoxide dismutase (SOD), catalase (CAT) and total antioxidant status (TAS) and also the protein expression of caspase-3, before (Day 0) and after (at the end of 6 and 12 weeks) MTX treatment. Our results show a significant increase in tissue ROS and plasma MDA after MTX treatment when compared with before MTX treatment in psoriasis patients (p < 0.001). The levels of serum nitrite and nitrate were decreased significantly after MTX treatment (p < 0.001). The activities of plasma SOD, TAS and serum CAT levels were decreased, but not significantly after 12 weeks of treatment. The expression of caspase-3 was increased after MTX treatment. In conclusion, MTX induce apoptosis through oxidative stress by reducing NO and increasing caspase-3 levels. MTX-induced apoptosis may account for the beneficial effect of MTX treatment in psoriasis patients, which is characterized by acanthosis.

Background: Psoriasis is a chronic autoimmune hyperproliferative skin disease. In psoriasis, the cutaneous and systemic overexpression of various proinflammatory cytokines, such as interleukin-6 (IL-6) has been demonstrated. Methotrexate (MTX) has been used in the treatment of psoriasis. The aim of this study is to assess the effect of MTX on serum IL-6 levels and also to find the association between PASI score and IL-6 levels in psoriatic patients during MTX therapy., Methods: We recruited 20 control subjects and 22 Psoriasis vulgaris patients for this study. The patients were treated with 7.5mg of methotrexate per week for 12 weeks. Folic acid was given at 5mg once daily except on the day of MTX for 12 weeks. There were 2 dropouts, because of increased liver enzyme levels. Blood samples were collected at three intervals (i.e., Day 0, 6 weeks, 12 weeks) from psoriatic patients and only once from control subjects. PASI score, biochemical and hematological parameters were assessed. Serum IL-6 level was analyzed by using ELISA., Results: Biochemical and hematological parameters showed no significant changes. Serum IL-6 level and PASI score declined significantly (p<0.001) from Day 0 to 12 weeks of MTX treatment and also showed positive correlation before (r=0.992; p<0.000) and after (r=0.987; p<0.000) treatment with MTX. Out of 4 clinical indices of PASI, only 2 indices namely Infiltration (I) and Desquamation (D) showed positive correlation with IL-6 before and after MTX treatment., Conclusion: The treatment response with MTX in psoriatic patients can be seen both at clinical and molecular levels., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: Propylthiouracil (PTU) is an effective drug for psoriasis treatment. Prolactin (PRL) is increased during psoriasis which has hyperproliferative effect on keratinocytes. Hence, the objective is to find the effect of PTU on PRL level in psoriatic patients., Design and Methods: 25 psoriatic patients and 10 control subjects were involved in the study. Serum PRL, hematological and biochemical parameters, thyroid profile and histopathological examination were performed., Results: PTU treatment for 6 weeks and 12 weeks cleared psoriatic lesions indicated by decreased PASI score (p<0.001). Patients before treatment showed significantly increased PRL levels (male p<0.01, female p<0.001) when compared to controls, which was found to decrease significantly (male p<0.01, female p<0.001) after 12 weeks. Hematological and biochemical parameters showed no significant change. Histopathology showed reduced thickening of the epidermis and acanthosis after PTU treatment., Conclusion: Since PRL is a growth hormone involved in hyperproliferation of keratinocytes, this study reveals the antiproliferative effect of PTU. Furthermore, no major side effects were observed following PTU treatment., (Copyright © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Psoriasis greatly impacts the quality of life (QOL) of patients including several dermatological conditions that are listed in the Dermatology Life Quality Index (DLQI). Decrease in psoriatic lesion as measured by Psoriasis Area Severity Index (PASI) score is associated with improvement in QOL. Propylthiouracil (PTU) was found to be clinically efficient in clearing psoriatic lesions. Our objective is to find the extent of improvement in QOL in psoriatic patients treated with PTU., Materials and Methods: Twenty-three psoriatic patients who were taking 300 mg PTU/day were involved in the study. Clinical improvement was assessed by PASI score and QOL was assessed by DLQI questionnaire at baseline, 6 th and 12 th week of PTU treatment., Results: Psoriatic patients before treatment showed significantly increased DLQI score when compared with 6 and 12 weeks of PTU treatment which was found to be decreased significantly (P < 0.001) after PTU treatment. There was a positive correlation between DLQI and PASI score at all three intervals of treatment period at P < 0.001 (r = 0.793, r = 0.834, r = 0.801), respectively., Conclusion: Since PTU was found to improve the QOL of psoriasis patients, this study adds an advantage of using it as treatment option in psoriasis.