Author: Wang, Jie ; Wang, Shan ; He, Anxu ; Chen, Yidi ; Qian, Minyi ; Wang, Jiaying ; Li, Honglin ; Li, Shiliang ; Shen, Xu ; Lu, Jian ; Zhao, Tong ; Lv, Jianlu

INTRODUCTIONType 2 diabetes mellitus (T2DM) is a chronic disease with hallmarks of hyperglycemia and hyperlipidemia. Long-term hyperglycemia damages the functions of multiple tissues and organs leading to a series of complications and disability or even death. Nuclear receptor farnesoid X receptor (FXR) antagonism has been recently discovered to exhibit beneficial effect on glucose metabolism in T2DM mice, although the underlying mechanisms remain unclear. Here, we performed the study on the discovery of new FXR antagonist and investigated the mechanism underlying the amelioration of FXR antagonism on glucose homeostasis in T2DM mice by using the determined FXR antagonist as a probe.METHODSFXR antagonist Mebhydrolin was discovered by screening against the lab in-house FDA approved drug library through surface plasmon resonance (SPR), microscale thermophoresis (MST), AlphaScreen, mammalian one-hybrid and transactivation assays. Activity of Mebhydrolin in improving glucose homeostasis was evaluated in db/db and HFD/STZ-induced T2DM mice, and the mechanisms governing the regulation of Mebhydrolin were investigated by assays of immunostaining, Western blot, ELISA, RT-PCR against liver tissues of both T2DM mice and the T2DM mice with liver-specific FXR knockdown injected via adeno-associated-virus AAV-FXR-RNAi and mouse primary hepatocytes. Finally, molecular docking and molecular dynamics (MD) technology-based study was performed to investigate the structural basis for the antagonistic regulation of Mebhydrolin against FXR at an atomic level.FINDINGSMebhydrolin ameliorated blood glucose homeostasis in T2DM mice by both suppressing hepatic gluconeogenesis via FXR/miR-22-3p/PI3K/AKT/FoxO1 pathway and promoting glycogen synthesis through FXR/miR-22-3p/PI3K/AKT/GSK3β pathway. Structurally, residues L291, M332 and Y373 of FXR were required for Mebhydrolin binding to FXR-LBD, and Mebhydrolin induced H2 and H6 shifting of FXR potently affecting the regulation of the downstream target genes.CONCLUSIONSOur work has revealed a novel mode for the regulation of FXR against glucose metabolism in T2DM mice and highlighted the potential of Mebhydrolin in the treatment of T2DM.

01 May 2008·Clinical and Experimental DermatologyQ4 · MEDICINE

Subcorneal pustular dermatosis: 50 years on

Q4 · MEDICINE

Review

Author: M. Ben-Gashir ; E. Edmonds ; S. Cheng ; R. C. Yu

We review the key developments in our understanding of subcorneal pustular dermatosis (SCPD, also known as Sneddon-Wilkinson disease) over the past 50 years. SCPD is a rare, chronic, sterile pustular eruption that was first described by Sneddon and Wilkinson in 1956. The primary lesions are pea-sized pustules classically described as half-pustular, half-clear flaccid fluid blisters. Histologically the salient feature is a subcorneal accumulation of neutrophils, suggesting the presence of chemoattractants such as tumour necrosis factor (TNF)alpha in the uppermost epidermis. However, to date its exact pathophysiology is unknown. Cases in association with pyoderma gangrenosum, benign monoclonal IgA gammopathy and multiple myeloma are well documented. There are anecdotal reports of SCPD associated with other internal malignancies such as chronic lymphocytic leukaemia, thymoma, apudoma and epidermoid carcinoma of the lung. The treatment of choice is dapsone. Therapeutic alternatives include retinoids, phototreatment with psoralen ultraviolet (UV) A, broadband or narrow band UVB and corticosteroids. Anecdotal uses of tacalcitol, ketoconazole, azithromycin, tetracycline, minocycline, vitamin E, ciclosporin, colchicine, mizoribine, mebhydrolin, infliximab and adalimumab with mycophenolate mofetil have all been reported.

01 Mar 1993·Clinical and Experimental DermatologyQ4 · MEDICINE

Exacerbation of psoriasis, liver dysfunction and thrombocytopenia associated with mebhydrolin

Q4 · MEDICINE

Article

Author: K. E. Mckenna ; J. C. Mcmillan

Two patients with psoriasis, whose skin condition deteriorated in association with disturbed liver function are reported; one case developed thrombocytopenia, following administration of mebhydrolin (Fabahistin, Bayer)a commonly prescribed oral antihistamine

100 Deals associated with Mebhydrolin Napadisilate

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KEGG	Wiki	ATC	Drug Bank
D01786	Mebhydrolin Napadisilate	R06AX15	DB13808

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