Herbal Medicine, Hachimi-jio-gan, and Its Component Cinnamomi Cortex Activate the Peroxisome Proliferator-activated Receptor Alpha in Renal Cells

Abstract

Abstract. Hachimi-jio-gan is widely used to improve several disorders associated with diabetes, but its mechanism remains poorly understood. In an attempt to clarify the mechanism of Hachimi-jio-gan, we investigated the effects of this herbal medicine and its components in transfection studies of CV1 cells, especially nuclear receptor-mediated actions. One half (0.5) mg/ml of Hachimi-jio-gan activated peroxisome proliferator-activated receptor (PPARα), mediating the activation by 3.1-fold on DR1 response elements; however, it did not affect PPARγ, thyroid hormone receptor, androgen receptor, estrogen receptor or RXR. In addition, this activation was observed in a dose-dependent manner. Next, to determine which components of Hachimi-jio-gan activate PPARα-mediated transcription, 8 of its components (rehmanniae radix, orni fructus, dioscoreae rhizoma, alismatis rhizoma, hoelen, moutan cortex, cinnamomi cortex, aconiti) were tested. Only cinnamomi cortex (1.0 mg/ml) increased PPARα-mediated transcription by 4.1-fold, and this activation was specific for PPARα, and not for other nuclear receptors. Moreover, this PPARα-related activation by cinnamomi cortex is specifically observed in renal cells. Taken together, these findings indicate that Hachimi-jio-gan and cinnamomi cortex may have a pharmacological effect through the target site for PPARα. IN Japan and China, traditional herbal medicines (Kampo) have often been used for diabetes mellitus to treat symptoms such as fever, numbness, and edema. In particular, Hachimi-jio-gan is used clinically to improve diabetic nephropathy [1][2][3][4]. Recently, Hachimijio-gan was reported to suppress hyperglycemia via insulin production and secretion from the pancreas [5]. In addition, Hachimi-jio-gan has been widely used for the treatment of many chronic diseases such as renal nephritis [6], vegetative ataxia [7], major depressive disorder [8,9], hyperprolactinemia [10], and hyperlipidemia [11]; however, the mechanisms of Hachimijio-gan remain unclear. The objective of this study was to investigate whether Hachimi-jio-gan has functions related to hormonal effects using transfection assays with thyroid hormone receptor, androgen receptor, estrogen receptor, estrogen receptor, RXR, PPARγ, and PPARα into several cell lines. Moreover, Hachimi-jio-gan is composed of eight ingredients, rehmanniae radix, orni fructus, dioscoreae rhizoma, alismatis rhizoma, hoelen, moutan cortex, cinnamomi cortex and aconiti; therefore, we identified which components of Hachimi-jio-gan are responsible for pharmacological effects such as hormonal ligands for nuclear receptors.

The potential of natural products for targeting PPAR α

“…However, it is undoubted that several still unexplored natural sources of potential PPAR α modulators are available. Thus, the list reported in Table 175, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112 is should encourage natural product chemists to make efforts aimed at the detailed characterization of the active principle(s) responsible for the action of these extract.…”

Botanical compounds and their regulation of nuclear receptor action: The case of traditional Chinese medicine

“…Another interesting case is cinnamomi cortex, a compound isolated from the Japanese traditional medicine Hachimi-jio-gan, which is used to improve several metabolic disorders such as diabetes. This molecule activates PPARα, but not PPARγ (Monden et al, 2008). The most thorough study identified two agonists from Tithonia diversifolia, a plant used in Chinese medicine to treat diabetes and hepatitis.…”

Proliferative effect of Hachimijiogan, a Japanese herbal medicine, in C2C12 skeletal muscle cells

“…21 HJG and Cinnamomi cortex could activate peroxisome proliferator-activated receptor alpha (PPARα) in kidney cells. 22 Considering that PPARα agonist WY-14,643 could activate ERK1/2 signaling in C2C12 cells, 23 it may be possible that such a PPARα and ERK signaling pathway may be involved in the proliferative effect of HJG in C2C12 cells.…”