naphthoquinones and Diabetic-Nephropathies

In diabetes mellitus, diabetic nephropathy (DN) is a typical complication and pivotal cause of chronic kidney disease. The DN disease burden is among the highest in the world and is associated with high morbidity, mortality, and disease burden. Safe and effective medications are urgently needed for the treatment of DN. Interest has been increasing in Shikonin, extracted from the naphthoquinone plant, particularly in determining its renal protective effect.. In this study, we explored Shikonin's effects and potential mechanisms on a streptozotocin (STZ)-induced DN experimental model. An STZ-induced rat diabetic model was established, and the rats were treated with different doses of Shikonin (10/50 mg/kg) for 4 weeks. Blood, urine, and renal tissue samples were collected after the last administration. Renal tissues were examined to detect each group's physiologic, biochemical, histopathologic, and molecular changes.. The results showed that Shikonin administration could significantly alleviate the STZ-induced elevation of blood urea nitrogen, serum creatinine, urinary protein content, and renal pathologic injury. Furthermore, Shikonin significantly decreased oxidative stress, inflammation, and Toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor-κB expression levels in DN kidney tissues. Shikonin showed a dose-dependent effect, with the best outcome at 50 mg/kg.. Shikonin could effectively alleviate DN-related nephropathy damage and reveal the underlying pharmacologic mechanism. Based on the results, a Shikonin combination can be used in clinical treatment.

Topics: Albuminuria; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Urea Nitrogen; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Male; Naphthoquinones; Oxidative Stress; Rats; Rats, Sprague-Dawley; Streptozocin

In this present study, rhinacanthins-rich extract (RRE) and rhinacanthin C (RC) the main bioactive constituent of Rhinacanthus nasutus was investigated for their protective effect against diabetic nephropathy (DN). Diabetes was induced by administering nicotinamide (100 mg/kg, i.p.)/streptozotocin (60 mg/kg, i.p.) and diabetic rats were orally administered with RRE and RC for 4 weeks. RRE and RC significantly reduced the kidney index, renal oxidative stress markers, and pro-inflammatory cytokines. Furthermore, RRE and RC increased renal levels of glutathione, superoxide dismutase, catalase, and attenuated diabetic induced renal damages. In conclusion, RRE and RC confer protective effect against DN through the inhibition of oxidative stress and inflammation and could be a potential medicinal or nutritional supplement for the prevention of DN. PRACTICAL APPLICATIONS: Rhinacanthus nasutus is a medicinal plant that is extensively used in Thai traditional medicine as an antibacterial, antifungal, antidiabetic, and anti-inflammatory agent. The plant is rich in naphthoquinones, which confer it with several excellent bioactivities. The rich extract of the leaves was prepared with three major bioactive components and the extract was evaluated for its renoprotective effect in diabetic rats. The results from this study provides valuable pharmacological information that supports the use of the plant, especially the rich extract in the prevention and treatment of diabetes and diabetic complications.

Topics: Animals; Anti-Inflammatory Agents; Catalase; Diabetic Nephropathies; Glutathione; Humans; Male; Naphthoquinones; Oxidative Stress; Rats; Rats, Wistar; Streptozocin; Superoxide Dismutase

Hyperglycemia-induced oxidative stress is thought to play a critical role in the pathogenesis of diabetic nephropathy (DN). Treating high-glucose (HG)-induced proximal tubule injury has become a patential therapeutic option to attenuate the onset and progression of DN. The present study aimed to investigate the renoprotective effect of shikonin, the chief active compound extracted from the roots of the traditional Chinese herb Lithospermum erythrorhizon, on HG-induced cytotoxicity in NRK-52E cells. Treating cells with HG significantly reduce cell viability while also significantly increasing content of reactive oxygen species (ROS). Treating the cells with shikonin improved these changes induced by HG. Shikonin strongly stabilized mitochondrial membrane potential in HG-induced NRK-52E cells. In addition, treatment with shikonin upregulated antioxidant system in response to ROS by increasing levels of SOD and CAT. Furthermore, shikonin also strongly decreased the levels of activated caspase-3, Bax and p-GSK-3β while increased the p-AKT level. These findings provide that the renoprotective effects of shikonin against HG-induced cytotoxicity in NRK-52E cells may be mediated in inhibiting oxidative stress through activating of the AKT signalling pathway.

Topics: Animals; Antioxidants; Apoptosis; Caspase 3; Cell Line; Cell Survival; Diabetic Nephropathies; Epithelial Cells; Glucose; Glycogen Synthase Kinase 3 beta; Kidney Tubules, Proximal; Membrane Potential, Mitochondrial; Naphthoquinones; Oxidative Stress; Protective Agents; Rats; Reactive Oxygen Species; Signal Transduction

NADPH oxidase 4 (Nox4) is reported to be the major source of reactive oxygen species (ROS) in the kidneys during the early stages of diabetic nephropathy. It has been shown to mediate TGFβ1-induced differentiation of cardiac fibroblasts into myofibroblasts. Despite TGFβ1 being recognised as a mediator of renal fibrosis and functional decline role in diabetic nephropathy, the renal interaction between Nox 4 and TGFβ1 is not well characterised. The aim of this study was to investigate the role of Nox4 inhibition on TGFβ1-induced fibrotic responses in proximal tubular cells and in a mouse model of diabetic nephropathy. Immortalised human proximal tubular cells (HK2) were incubated with TGFβ1 ± plumbagin (an inhibitor of Nox4) or specific Nox4 siRNA. Collagen IV and fibronectin mRNA and protein expression were measured. Streptozotocin (STZ) induced diabetic C57BL/6J mice were administered plumbagin (2 mg/kg/day) or vehicle (DMSO; 50 µl/mouse) for 24 weeks. Metabolic, physiological and histological markers of nephropathy were determined. TGFβ1 increased Nox4 mRNA expression and plumbagin and Nox4 siRNA significantly inhibited TGF-β1 induced fibronectin and collagen IV expression in human HK2 cells. STZ-induced diabetic C57BL/6J mice developed physiological features of diabetic nephropathy at 24 weeks, which were reversed with concomitant plumbagin treatment. Histologically, plumbagin ameliorated diabetes induced upregulation of extracellular matrix protein expression compared to control. This study demonstrates that plumbagin ameliorates the development of diabetic nephropathy through pathways that include Nox4 signalling.

Topics: Animals; Base Sequence; Cell Line, Transformed; Collagen Type IV; Diabetic Nephropathies; DNA Primers; Fibronectins; Glucose; Humans; Mice; Mice, Inbred C57BL; NADPH Oxidases; Naphthoquinones; Real-Time Polymerase Chain Reaction; RNA, Messenger; Streptozocin; Superoxide Dismutase; Transforming Growth Factor beta1