morphinans and Fibrosis

To study the effect of sinomenine (Sin) on isoproterenol (Iso, β-agonist)-induced cardiac hypertrophy (CH), we set up four mouse groups: control, Iso model, Iso+metoprolol (Met, β blocker) 60 mg/kg and Iso+Sin 120 mg/kg. CH was induced by Iso (s.c. for 28 days) in mice, and Sin or Met were orally administered by gavage for 28 days in total. Left ventricular diastolic anterior wall thickness (LVAWd), left ventricular diastolic posterior wall thickness (LVPWd), left ventricular ejection fraction (LVEF), and short axis shortening (FS) were measured by echocardiography. Malondialdehyde (MDA) and total superoxide dismutase (T-SOD) were measured by commercial kits. Lactate dehydrogenase (LDH), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) were measured by ELISA kits. Histological changes were observed using hematoxylin-eosin (HE) and Masson staining. Protein level of nuclear transcription factor-kappa B (NF-κB) was detected by immunohistochemistry. Compared with the control group, LVAWd, Left ventricular weight index (LVWI) and myocardial fibrosis of the Iso model group significantly increased, as well as NF-κB, LDH, MDA, TNF-α, and IL-1β levels. However, the activity of T-SOD decreased. Compared with the Iso model group, LVWI of Iso model+Sin or Iso model+Met group was improved, LVAWd, LVPWd and myocardial fibrosis decreased, and NF-κB, LDH, MDA, TNF-α and IL-1β levels decreased. T-SOD activity also increased. This study reveals that Sin inhibits the activation of NF-κB, lowers the levels of TNF-α and IL-1β, has anti-oxidative stress effect and inhibits myocardial inflammation in mouse heart, thereby demonstrating its efficacy in preventing Iso induced CH.

Topics: Animals; Cardiomegaly; Fibrosis; Isoproterenol; Mice; Morphinans; NF-kappa B; Stroke Volume; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Ventricular Function, Left

To investigate the therapeutic effects and potent mechanism of sinomenine (SIN) nanoliposomes on nephropathy in diabetic rats.. Cell viabilities of HK-2 cells with oxidative injury were obviously improved by incubating with SIN at 320 μg/mL for 92.9%. Significantly up-regulated GPX1, SOD2 and GSH contributed to the down-regulated ROS content in SIN-treated groups. Moreover, 6-week administration of SIN improved renal functions and worsening nephropathy morphology of DKD rats. SIN also ameliorated gradually increased renal cell apoptosis, suppressed expression levels of fibrosis-related proteins as well as IL-6 and ICAM-1, and regulated JAK2/STAT3/SOCS1 pathway, thereby exhibited protective effects on renal tissues of DKD rats.. SIN protects nephrocytes and decreases renal tissue injury via inhibiting oxidative stress, reducing renal cell apoptosis and fibrosis, regulating the JAK2/STAT3/SOCS1 pathway in DKD rats.

Topics: Animals; Apoptosis; Blood Glucose; Cell Line; Cell Survival; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dose-Response Relationship, Drug; Fibrosis; Humans; Hydrogen Peroxide; Janus Kinase 2; Male; Morphinans; Oxidative Stress; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor; Streptozocin; Suppressor of Cytokine Signaling 1 Protein

Renal fibrosis is the common feature of chronic kidney disease and mainly mediated by TGFβ-associated pro-fibrogenic signaling, which causes excessive extracellular matrix accumulation and successive loss of kidney functions. Sinomenine (SIN), an alkaloid derived from medicinal herb extensively used in treatment of rheumatoid arthritis and various inflammatory disorders, displays renal protective properties in experimental animals; however its pharmacological potency against renal fibrosis is not explored. In this study we report that SIN possesses strong anti-renal fibrosis functions in kidney cell and in mouse fibrotic kidney. SIN beneficially modulated the pro-fibrogenic protein expression in TGFβ-treated kidney cells and attenuated the renal fibrotic pathogenesis incurred by unilateral ureteral obstruction (UUO), which correlated with its activation of Nrf2 signaling - the key defender against oxidative stress with anti-fibrotic potentials. Further investigation on its regulation of Nrf2 downstream events revealed that SIN significantly balanced oxidative stress via improving the expression and activity of anti-oxidant and detoxifying enzymes, and interrupted the pro-fibrogenic signaling of TGFβ/Smad and Wnt/β-catenin. Even more impressively SIN achieved its anti-fibrotic activities in an Nrf2-dependent manner, suggesting that SIN regulation of Nrf2-associated anti-fibrotic activities constitutes a critical component of SIN's renoprotective functions. Collectively our studies have demonstrated a novel anti-fibrotic property of SIN and its upstream events and provided a molecular basis for SIN's potential applications in treatment of renal fibrosis-associated kidney disorders.

Topics: Animals; Antirheumatic Agents; Catalase; Fibrosis; Glutathione Peroxidase; HEK293 Cells; Humans; Kidney Diseases; Mice; Morphinans; NF-E2-Related Factor 2; Oxidative Stress; Signal Transduction; Superoxide Dismutase; Transforming Growth Factor beta1