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This study mainly focuses on cardio protective anti-ﬁbrotic activity of PHE Of Momordica Charantia And Trigonella Foenum-Graecum against streptozotocin induced cardiac ﬁbrosis and high glucose induced collagen accumulation in cardiac ﬁbroblasts. Dys- regulation of matrix metalloproteinase especially 2 and 9 were considered to be responsible for the abnormal collagen deposition, which resulting improper cardiac contractile function in diabetic mice. Mice received a single dose of streptozotocin (100 mg/kg) through tail vein to induce diabetes. Normal and diabetic mice received PHE of Momordica charantia and Trigonella foenum-graecum orally (100 mg/kg/day) throughout the study period of 8 weeks. Cardiac ﬁbroblasts cultured and exposed to high glucose, PHE of Momordica charantia and Trigonella foenum-graecum and both for 48 h. Collagen quantitatively estimated in both in vivo and in vitro models. Altered structural changes were studied using the Masson tri-chrome staining, TEM images of cardiac sections. Increased collagen and metalloproteinase activities were conﬁrmed using gelatin zymography, western blotting and gene expression studies. The exact mechanism responsible for high glucose induced collagen up regulation in diabetic heart was incompletely understood. From this above in vivo and in vitro results, we conclude that, the cardio protective anti ﬁbrotic activity of amino guanidine was mainly attributed by exhibiting the inhibitory efﬁcacy against streptozotocin and high glucose induced collagen accumulation probably by inhibiting high glucose altered metalloproteinase-2 and -9 activities.