Tectona grandis leaf extract ameliorates hepatic fibrosis: Modulation of TGF- ß /Smad signaling pathway and upregulating MMP3/TIMP1 ratio.

ETHNOBOTANICAL RELEVANCE: Tectona grandis L.f (or syn: Jatus grandis (L.f.) Kuntze Revis), from family Lamiaceae, also known as Teak, is widely recognized in ayurvedic system of medicine and confer curative potential against inflammation, liver disorders, biliousness, diabetes, bronchitis, leprosy and dysentery. Its leaves are rich source of edible food colorant and reported nontoxic for liver and various organs. AIM OF STUDY: Hepatic injury progression to liver cirrhosis and cancer is a serious health issue across the world. Currently, anti-fibrotic therapeutic options are limited and expensive with no FDA approved direct anti-hepato-fibrotic drug validated in clinic. Thus, the aim of this study was to understand ameliorative effect of Tectona grandis L.f, leaves in early liver fibrosis. METHOD AND RESULTS: C57BL/6 mice suffering from CCl4 induced liver injury, were orally administered at three different doses (50, 100 & 200 mg/kg) of Tectona grandis L.f, leaf extract, thrice a week, up to 4 and 8 weeks. Anti-fibrotic effect was evaluated through animal body/liver weight measurements, serological tests (AST, ALT, GSH, MDA and LDH assays), tissue hydroxyproline content, and histochemical analysis (H&E, Masson trichrome, Sirius red and αSMA localization). Moreover, transcriptional and post-transcriptional expression of fibrosis associated biomarkers and TGF-ß/Smad cascade were analyzed. It was observed that 100 mg/kg dose optimally downregulated TGF-ß1/Smad2 with upregulation of Smad7 and regulated αSMA, Col 1, PDGF, TIMP1 and MMP3 expression, post 8 weeks of treatment. In addition, MMP3/TIMP1 ratio was upregulated to 0.7, 2.5 and 1.7 fold at 50 mg/kg, 100 mg/kg & 200 mg/kg treatments respectively, in comparison to untreated liver fibrosis models. The extract contains gallic acid, caffeic acid, sinapinic acid and myricetin when analyzed through high performance liquid chromatography. CONCLUSION: Tectona grandis L.f, leaves have potential to ameliorate liver fibrosis induced by CCl4 in mice via modulation of TGF-ß1/Smad pathway and upregulated MMP3/TIMP1 ratio.

Clofazimine analogs with efficacy against experimental tuberculosis and reduced potential for accumulation.

The global tuberculosis crisis urgently demands new, efficacious, orally available drugs with the potential to shorten and simplify the long and complex treatments for drug-sensitive and drug-resistant disease. Clofazimine, a riminophenazine used for many years to treat leprosy, demonstrates efficacy in animal models of tuberculosis via a novel mode of action. However, clofazimine's physicochemical and pharmacokinetic properties contribute to side effects that limit its use; in particular, an extremely long half-life and propensity for tissue accumulation together with clofazimine's dye properties leads to unwelcome skin discoloration. We recently conducted a systematic structure-activity study of more than 500 riminophenazine analogs for anti-Mycobacterium tuberculosis activity. We describe here the characteristics of 12 prioritized compounds in more detail. The new riminophenazine analogs demonstrated enhanced in vitro activity compared to clofazimine against replicating M. tuberculosis H37Rv, as well as panels of drug-sensitive and drug-resistant clinical isolates. The new compounds demonstrate at least equivalent activity compared to clofazimine against intracellular M. tuberculosis and, in addition, most of them were active against nonreplicating M. tuberculosis. Eleven of these more water-soluble riminophenazine analogs possess shorter half-lives than clofazimine when dosed orally to mice, suggesting that they may accumulate less. Most importantly, the nine compounds that progressed to efficacy testing demonstrated inhibition of bacterial growth in the lungs that is superior to the activity of an equivalent dose of clofazimine when administered orally for 20 days in a murine model of acute tuberculosis. The efficacy of these compounds, along with their decreased potential for accumulation and therefore perhaps also for tissue discoloration, warrants further study.