ginkgetin and Inflammation

Apoptosis, inflammation, and the extracellular matrix (ECM) synthesis and catabolism are compromised with intervertebral disc degeneration (IDD). Ginkgetin (GK) has been demonstrated to alleviate several diseases; however, its effect on IDD remains unknown.. The nucleus pulposus cells (NPCs) were stimulated with interleukin (IL)-1β to construct the IDD models. GK increased the cell viability and upregulated the expressions of anti-apoptosis and ECM synthesis markers in NPCs treated with IL-1β. GK also decreased apoptosis rate, and downregulated the expressions of proteins related to pro-apoptosis, ECM catabolism, and inflammation in vitro. Mechanically, GK reduced the expression of nucleotide binding oligomeric domain like receptor protein 3 (NLRP3) inflammasome-related proteins. Overexpression of NLRP3 reversed the effect of GK on the proliferation, apoptosis, inflammation, and ECM degradation in IL-1β-induced NPCs. Moreover, GK attenuated the pathological manifestations, inflammation, ECM degradation, and NLRP3 inflammasome expression in IDD rats.. GK suppressed apoptosis, inflammation, and ECM degradation to alleviate IDD via the inactivation of NLRP3 inflammasome.

Topics: Animals; Extracellular Matrix; Inflammasomes; Inflammation; Intervertebral Disc Degeneration; NLR Family, Pyrin Domain-Containing 3 Protein; Rats

Diabetic nephropathy constitutes the leading cause for end-stage kidney disease. Ginkgetin is a common natural non-toxic biflavone and fulfills pleiotropic pharmacological characterizations, such as anti-inflammation and kidney injury. Nevertheless, its efficacy in diabetic nephropathy remains elusive. Here, ginkgetin exhibited little cytotoxicity in glomerular mesangial cells. Of note, ginkgetin restrained high glucose (HG)-induced mesangial cell proliferation and oxidative stress by inhibiting ROS and malonaldehyde levels, but enhancing antioxidant SOD activity. Additionally, ginkgetin suppressed HG-evoked transcript and release of inflammatory cytokine TNF-α, IL-1β, and IL-6. Concomitantly, the increased extracellular matrix (ECM) deposition in HG-treated glomerular mesangial cells was attenuated by ginkgetin via decreasing expression of collagen IV, fibronectin, and laminin. Intriguingly, ginkgetin-restored HG-impaired autophagy; whereas blocking autophagy by its inhibitor 3-MA overturned ginkgetin function against HG-evoked mesangial cell dysfunction. Mechanistically, ginkgetin-mediated AMPK/mTOR axis accounted for HG-impaired autophagy. Importantly, blockage of AMPK signaling reversed ginkgetin-restored autophagy and its protective efficacy against HG-induced dysfunction in mesangial cells. Thus, these findings highlight that ginkgetin may attenuate HG-evoked mesangial cell hyperplasia, oxidative stress, inflammation, and ECM accumulation by activating AMPk/mTOR-mediated autophagy pathway. Therefore, ginkgetin may alleviate the progression of diabetic nephropathy by regulating glomerular mesangial cell dysfunction, supporting a promising therapeutic agent against diabetic nephropathy.

Topics: AMP-Activated Protein Kinases; Anti-Inflammatory Agents; Antioxidants; Autophagy; Biflavonoids; Collagen; Diabetic Nephropathies; Extracellular Matrix; Fibronectins; Glucose; Humans; Inflammation; Malondialdehyde; Mesangial Cells; Oxidative Stress; Signal Transduction; Superoxide Dismutase; TOR Serine-Threonine Kinases

The present investigation evaluates the protective effect of Ginkgetin aglycone (GA) against ischemic stroke-induced neuronal injury. Ischemic stroke was produced by the middle cerebral artery occlusion (MCAO) model and animals were a group that received GA 100 and 200 mg/kg, i.p. five days before the induction of MCAO. The effect of GA against stroke was determined by estimating the neurological deficit score and brain water content was also observed. Moreover terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay was done for determining the neuronal apoptosis and Western blot assay also performed for estimating the expression of several proteins. Results of the study suggest that the neurological deficit score and brain water content was found to be lower in the GA treated group than the ischemia/reperfusion (I/R) group of rats. Moreover the number of TUNEL positive cells was found to be lower in the GA treated group than in the I/R group of rats. There was a significant (p < 0.01) decrease in the oxidative stress parameters and cytokine in the tissue homogenate of the GA treated group compared to the I/R group of rats. Further treatment with GA attenuates altered expression of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), protein kinase B (Akt), B-cell lymphoma 2 (Bcl-2), signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa light chain enhancer of activated B cells (NF-B), toll-like receptor 4 (TLR-4), Janus kinase 2 (JAK-2) and sirtuin-1 (SIRT-1) protein in the brain tissues of stroke rats. In conclusion, data of the report reveal that treatment with Ginkgetin aglycone protects the neuronal injury against stroke in rats by reducing oxidative stress and inflammation.

Topics: Animals; Anti-Inflammatory Agents; Biflavonoids; Inflammation; Janus Kinase 2; Male; Neurons; Neuroprotective Agents; Rats; Rats, Wistar; Signal Transduction; Sirtuin 1; STAT3 Transcription Factor; Stroke

Ginkgetin, a biflavone from Ginkgo biloba leaves, was previously reported to be a phospholipase A2 inhibitor and this compound showed the potent antiarthritic activity in rat adjuvant-induced arthritis as well as analgesic activity. This investigation was carried out to find effects on cyclooxygenase (COX)-1 and -2 including an in vivo effect. Ginkgetin (1 - 10 microM) and the biflavonoid mixture (10 - 50 microg/ml), mainly a 1 : 1 mixture of ginkgetin and isoginkgetin, from G. biloba leaves, inhibited production of prostaglandin E2 from lipopolysaccharide-induced RAW 264.7 cells. This inhibition was mediated, at least in part, by down-regulation of COX-2 expression, but not by direct inhibition of COX-1 or COX-2 activity. Down-regulation of COX-2 by ginkgetin was also proved in the dorsal skin of ICR mouse treated by 12-O-tetradecanoylphorbol 13-acetate (TPA). At total doses of 1,000 microg/site on the dorsal skin (15 mm x 15 mm), ginkgetin inhibited prostaglandin E2 production by 65.6 % along with a marked suppression of COX-2 induction. In addition, ginkgetin and the biflavonoid mixture (100 - 1,000 microg/ear) dose-dependently inhibited skin inflammation of croton oil induced ear edema in mice by topical application. The present study suggests that ginkgetin from G. biloba leaves down-regulates COX-2 induction in vivo and this down-regulating potential is associated with an anti-inflammatory activity against skin inflammatory responses.

Topics: Animals; Biflavonoids; Blotting, Western; Cell Line; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Dose-Response Relationship, Drug; Flavonoids; Ginkgo biloba; Indomethacin; Inflammation; Isoenzymes; Macrophages; Male; Membrane Proteins; Mice; Mice, Inbred ICR; Monocytes; Nitrobenzenes; Phospholipases; Plant Extracts; Plant Leaves; Prostaglandin-Endoperoxide Synthases; Skin; Sulfonamides