Notably we observed that GPR activation induced by PA an
Notably, we observed that GPR35 activation induced by PA, an in vivo GPR35 agonist , significantly decreased DAI, colon weight, and histological score, while increasing colon length in mice with DSS-induced colitis. Furthermore, fibronectin and integrin α5 were co-localized with GPR35 on the colonic epithelium in DSS-induced mice treated with PA, indicating that GPR35 stimulation promoted the migration of colonic epithelial cells via upregulation of fibronectin and its cognate receptor. Thus, a GPR35 agonist may be a candidate therapeutic agent in IBD. One of the current approaches to treat IBD is the blockage of TNFα, which is upregulated in IBD along with other proinflammatory cytokines . However, for many patients with IBD, TNFα antibodies as well as other therapeutic agents do not cause complete remission, underscoring the need for novel, more potent therapeutic approaches to treat IBD. In our experiments, the treatment with PA not only improved the status of the damaged colonic mucosa by inducing the migration of epithelial cells but also significantly inhibited the production of proinflammatory cytokines TNFα, IL-1β, and IL-6. The mechanism underlying the inhibitory effect of PA on the production of proinflammatory cytokines is still unknown, but there is an indication that GPR35 agonists may have the ability to directly inhibit cytokine release by inflammatory cells. Thus, GPR35 activation by kynurenic beta adrenergic receptors caused anti-inflammatory effects by downregulating the synthesis of proinflammatory cytokines, including TNFα and IFN-γ in mononuclear cells , .
Conflict of interest
Acknowledgements This work was supported by Japan Society for the Promotion of Science [JSPS] under the Grant-in-Aid for Scientific-Research Program [KAKENHI; grant number 15H06727 to TT and 16K08287 to KM], and Takeda Science Foundation to KM. The authors would like to thank Dr. Robert Whitehead for providing YAMC cells.
Methods GPR35-/-, UCP2-/-, GPR35-/-UCP2-/-and wild-type (WT) littermates were separately divided into two groups: the control group; the experimental group (T2DM with hyperuricemia). Interstitial fibrosis and impaired diastolic relaxation were examined in in vivo study. Mouse myocardial cell lines (MCM) were assigned into two groups: the normal group; high glucose(HG)+high uric acid (HUA) group. Cells were harvested for biochemical or molecular assays.
Results Interstitial fibrosis and impaired diastolic relaxation were aggravated, compared with the control group(P<0.05). The levels of GPR35 expression and of ROS were showed an obviously increase in HG+HUA group(P<0.05). In experimental group, interstitial fibrosis and impaired diastolic relaxation were clearly alleviated by GPR35 knockout (P<0.05). Moreover, ROS and mitochondrial disorder have a significance decrease by the application of the GPR35 antagonist CID2745687 (P<0.05). Interestingly, those effects of GPR35 siRNA was reversed in UCP2-/- mice (P<0.05). And CID2745687 significantly enhanced the expression of UCP2 and reduced oxidative stress in in-vitro studies(P<0.05). However melatonin, a powerful anti-oxidant, could reverse the effect of GPR35(P<0.05).
Introduction Flavonoid glycosides are attracting considerable attention owing to their good bioactivities and low toxicities, which have been widely used as medicines and nutraceuticals . As documented, flavonoid glycosides possess a wide spectrum of biological activities, such as antioxidation, immunomodulatory and anti-cancer activities . As a fold remedy in traditional Chinese medicines (TCMs), Lobelia chinensis Lour (L. chinensis) is rich in flavonoids, which has been used to treat snakebite, edema, jaundice and diarrhea in folk . Modern pharmacological studies have revealed that L. chinensis exhibit various biological properties, including anti-bacterial, anti-venom, and anticancer properties . However, due to the complex chemical compositions of L. chinensis extract, it is still a challenge to isolate new flavonoid glycosides and evaluate their bioactivities.