Ursonic acid from Artemisia montana exerts anti-diabetic effects through anti-glycating properties, and by inhibiting PTP1B and activating the PI3K/Akt signaling pathway in insulin-resistant C2C12 cells

Diabetes mellitus (DM) is predicted to affect more than 642 million people worldwide by 2040 [1,2]. DM is a chronic metabolic disease characterized by consistently high sugar levels in the bloodstream due to insulin deficiency, insulin resistance, or both [3,4]. Many biochemical and physiological reactions within the diabetic body are altered, and insulin resistance is caused by glucose metabolic disorders. Further, excess glucose in the blood damages blood vessels and nerves, resulting in a variety of conditions such as hypertension, cardiovascular disease, blindness, stroke, amputations, kidney disease, and dental disease [[4], [5], [6]]. There are currently few insulin-sensitizing or optimum glycemic control medicines available, and it is important to find new drug candidates with no side-effects [7].

The pathology of DM is complex, but members of the protein tyrosine phosphatase (PTP) family play an important role in the regulation of insulin function by dephosphorylating protein tyrosine residues and have been implicated in DM [8]. PTP1B is a member of the PTP family and is involved in insulin and leptin signaling [9,10]. PTP1B dephosphorylates the activated insulin receptor and insulin receptor substrates to attenuate the cellular response to insulin binding [11,12]. PTP1B knockout mice have enhanced insulin sensitivity and low body weight, even when fed a high-fat diet [13,14]. For these reasons, PTP1B has become an active therapeutic target for treatment of type 2 diabetes mellitus (T2DM).

Another enzyme implicated in the pathogenesis of T2DM is α-glucosidase, a membrane-bound enzyme capable of converting starch and disaccharides into monosaccharides, the latter of which are released into the blood stream, resulting in postprandial hyperglycemia [15]. Glucose absorption can be reduced by inhibition of this enzyme, as can postprandial blood glucose levels [16]. In addition, α-glucosidase inhibitors can delay the absorption of glucose and efficiently mitigate postprandial hyperglycemia in diabetic patients [17]. Therefore, inhibition of α-glucosidase is effective for the treatment of DM. Advanced glycation end-products (AGEs) are produced in a complex reaction known as the Maillard reaction in which sugars undergo several non-enzymatic reactions resulting in glycoxidation of nucleic acids, proteins, and lipids [[18], [19], [20]]. The enhanced production of AGEs in patients with DM may result from a “cyclic event” whereby glycated albumin disturbs the metabolism of glucose in fat and muscle tissues, reducing insulin-mediated glucose take-up and causing hyperglycemia [3,21,22]. Therefore, inhibition of AGE formation and AGE cross-linking is a potentially effective strategy to treat diabetic complications.

Artemisia is one of the largest genera in the family Asteraceae, with 500 species [23]. Numerous species in this family have long been used in traditional herbal medicine, particularly for the treatment of hepatitis, cancer, malaria, hypertension, inflammation, blood diseases, cough, pain, and microbial or viral infection [24]. Among the various Artemisia species, A. montana is a perennial plant that grows in woods and grassy fields in Korea, Japan, and China [25], where it is used. A. montana is used in cuisine and in moxibustion, a traditional heat therapy in China and Korea, which involves the burning of mugwort on the body to facilitate healing [26,27].

In addition, aerial parts of A. montana have been used in folk medicine as antihypertensive, anti-hepatotoxic, and anti-hemorrhoid agents [28]. Previous studies have shown that A. montana has anti-inflammatory, antioxidant, and anti-obesity activities [26,29,30]. Recently, an essential oil prepared from the leaves of A. montana was reported to have beneficial effects on atopic dermatitis, and its application in aromatherapy has attracted attention [31]. A. montana contains a variety of phytochemicals including sesquiterpene lactones, flavonoids, coumarins, caffeoylquinic acids, and glycosides [26,29,[32], [33], [34], [35]]. In our previous studies, we reported that whole-plant extracts and constituents of A. montana exhibited anti-diabetic activity by inhibiting rat lens aldose reductase [26]. Additionally, we demonstrated that an extract of the aerial parts of the plant and the constituents of this extract showed antioxidant activity by scavenging 1,1-diphenyl-2-picrylhydrazyl (DPPH) [29].

Although several studies of the biological activities of A. montana have been conducted, the effects of A. montana and its constituents on PTP1B and α-glucosidase have not been elucidated. As part of our ongoing efforts to identify potent PTP1B, α-glucosidase, and AGEs agents from natural sources, we investigated the anti-diabetic properties of UNA derived from A. montana. The mode of inhibition or molecular interactions of UNA with corresponding enzymes such as PTP1B, α-glucosidase, and HSA were investigated. Further, the inhibitory effects of UNA on AGE formation were assessed through fluorescence assays. Additionally, we investigated the glucose uptake stimulatory effects of UNA and its effects on activation of the IRS-1/PI3K/Akt and GSK-3β insulin signaling pathways in insulin-resistant C2C12 cells.

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