SMND-309, a novel derivative of salvianolic acid B, protects rat brains ischemia and reperfusion injury by targeting the JAK2/STAT3 pathway.

SMND-309 is a novel derivative of salvianolic acid B, and has shown protective effects against rat cortical neuron damage in vitro and in vivo. However the molecular mechanisms through which SMND-309 affords this protection are unclear. The present study aimed to investigate the mechanisms associated with the protective activities of SMND-309 in a cerebral ischemia and reperfusion injury rat model. In this study, we used AG490, a specific inhibitor of the signaling pathway involving the Janus Kinase 2 (JAK2)/Signal Transducers and Activators of Transcription 3 (STAT3) signaling molecules and suramin, a potent inhibitor of vascular endothelial growth factor (VEGF), to investigate the mechanisms of SMND-309. The cerebral ischemia and reperfusion injury model was induced by performing middle cerebral artery occlusion (MCAO) in the rats. SMND-309 mitigated the effects of ischemia and reperfusion injury on brain by decreasing the infract volume, improving neurological function, increasing the survival of neurons and promoting angiogenesis by increasing the levels of erythropoietin (EPO), erythropoietin receptor (EPOR), phosphorylated JAK2 (P-JAK2), phosphorylated STAT3 (P-STAT3), VEGF and VEGF receptor 2 (Flk-1) in the brain. Our results suggest that SMND-309 provides significant neuroprotective effects against cerebral ischemia and reperfusion injury. The mechanisms of this protection may be attributed to the increased VEGF expression occurring from the JAK2/STAT3 pathway, activated by the increased EPO/EPOR expression in the brain.

Therapeutic effects of SMND-309, a new metabolite of salvianolic acid B, on experimental liver fibrosis.

(2E)-2-{6-[(E)-2-carboxylvinyl]-2,3-dihydroxyphenyl}-3-(3,4-dihydroxyphenyl) propenoic acid, a novel compound designated SMND-309, is a new metabolite of salvianolic acid B. The present study was carried out to investigate the effects of SMND-309 on experimental liver fibrosis in rats induced by subcutaneous injection of carbon tetrachloride and explore its possible mechanisms on the basis of biochemical, histopathologic and immunohistochemical studies. The results showed that intragastrical treatment with SMND-309 ameliorated liver function and decreased the elevation of serum hyaluronic acid, laminin, procollagen type III levels and hydroxyproline content in liver tissue. It also decreased the elevation in the malondialdehyde level and restored the decrease in superoxide dismutase and glutathione peroxidase activities. Upon histopathologic examination, the SMND-309-treated rats reduced the liver damage and the liver fibrosis grade. Moreover, the results of immunohistochemical examination showed that SMND-309 powerfully down-regulated the expression of connective tissue growth factor (CTGF) rather than transforming growth factor-beta1 (TGF-ß1) in serum and liver. Meanwhile, SMND-309 exhibits significantly higher potency compared with salvianolic acid B (Sal B) at the same dose. The antifibrotic mechanisms of SMND-309 might be associated with its ability to suppress the expression of CTGF as well as scavenge lipid peroxidation products and increase endogenous antioxidant enzyme activity.

Protections of SMND-309, a novel derivate of salvianolic acid B, on brain mitochondria contribute to injury amelioration in cerebral ischemia rats.

SMND-309, a novel compound named (2E)-2-{6-[(E)-2-carboxylvinyl]-2,3-dihydroxyphenyl}-3-(3,4-dihydroxyphenyl) propenoic acid, is a new derivate of salvianolic acid B. The present study was conducted to investigate whether SMND-309 has a protective effect on brain injury after focal cerebral ischemia, and if it did so, to investigate its effects on brain mitochondria. Adult male SD rats were subjected to middle cerebral artery occlusion (MCAO) by bipolar electro-coagulation. Behavioral tests and brain patho-physiological tests were used to evaluate the damage to central nervous system. Origin targets including mitochondria production of reactive oxygen species, antioxidant potentia, membrane potential, energy metabolism, mitochondrial respiratory enzymes activities and mitochondria swelling degree were evaluated. The results showed that SMND-309 decreased neurological deficit scores, reduced the number of dead hippocampal neuronal cells in accordance with its depression on mitochondria swelling degree, reactive oxygen species production, improvements on mitochondria swelling, energy metabolism, membrane potential level and mitochondrial respiratory chain complex activities. All of these findings indicate that SMND-309 exerted potent neuroprotective effects in the model of permanent cerebral ischemia, contributed to its protections on brain mitochondrial structure and function.

SMND-309, a novel derivate of salvianolic acid B, ameliorates cerebral infarction in rats: characterization and role.

(2E)-2-{6-[(E)-2-carboxylvinyl]-2,3-dihydroxyphenyl}-3-(3,4-dihydroxyphenyl) propenoic acid, a novel compound designated SMND-309, is a new degradation product of salvianolic acid B. The present study was conducted to evaluate whether SMND-309 has a protective effect on permanent focal cerebral ischemia in rats. The results showed that SMND-309 at doses higher than 4.0 mg/kg (i.v.) produced a significant neuroprotection in focal ischemia rats when administered 30 min after the onset of ischemia. SMND-309 (25.0 mg/kg, i.v.) demonstrated significant neuroprotective activity even after delayed administration at 1 h, 3 h and 6 h after ischemia. The neuroprotective effect of SMND-309 (25.0 mg/kg, bolus injection intravenous at 30 min after middle cerebral artery occlusion) was still present 7 days after ischemia. Meanwhile, SMND-309 significantly increased the brain ATP content, improved mitochondrial energy metabolism and mitochondrial respiratory chain complex activities and attenuated the elevation of malondialdehyde (MDA) content, the decrease in superoxide dismutase (SOD) and glutathione-peroxidase (GSH-Px) activity in brain mitochondria. All of these findings indicate that SMND-309 exerts potent and long-term neuroprotective effects with a favorable therapeutic time-window in the model of permanent cerebral ischemia, and its protective effects may be due to the amelioration of cerebral mitochondrial energy metabolism and the antioxidant property.

Paeoniflorin inhibits systemic inflammation and improves survival in experimental sepsis.

The present study was carried out to investigate the effects of paeoniflorin in cultured RAW264.7 cell line as well as in an experimental model of sepsis induced by cecal ligation and puncture, and intraperitoneal injection (i.p.) of lipopolysaccharide in rats. Results showed that paeoniflorin concentration-dependently down-regulated the levels of TNF-alpha, IL-6 and high-mobility group-box 1 protein in lipopolysaccharide-induced RAW264.7 cell, inhibited the IkappaB kinase pathway and modulated NF-kappaB. Intravenous injection (i.v.) of paeoniflorin alone or in combination with imipenem reduced i.p. of lipopolysaccharide or cecal ligation and puncture-induced lethality in rats. In addition, serum levels of TNF-alpha, IL-6, high-mobility group-box 1 protein, triggering receptor expressed on myeloid cells and endotoxin were down-regulated; by contrast, serum levels of IL-10 were up-regulated. Amelioration of hemodynamics, decrease of enzyme levels, decrease of myeloperoxidase in lung, liver, and small intestine were also found after paeoniflorin injection. These data indicate that the anti-sepsis effect of paeoniflorin was mediated by decreasing local and systemic levels of a wide spectrum of inflammatory mediators. This work provides the first evidence that paeoniflorin has the capacity to inactivate inflammatory response in sepsis and the anti-inflammatory mechanism of paeoniflorin may inhibit activation of the NF-kappaB pathway by inhibiting IkappaB kinase activity.

SMND-309, a novel derivate of salvianolic acid B, attenuates apoptosis and ameliorates mitochondrial energy metabolism in rat cortical neurons.

SMND-309, a novel compound (2E)-2-[6-[(E)-2-carboxyvinyl]-2,3-dihydroxyphenyl]-3-(3,4-dihydroxyphenyl) acrylic acid, is a new derivate of salvianolic acid B. The present study elucidates the effects of SMND-309 on the cultured rat cortical neuron damage induced by oxygen-glucose deprivation. The results show that SMND-309 treatment obviously attenuates apoptosis and ameliorates mitochondrial energy metabolism in rat cortical neurons by increasing cell survival rate, mitochondrial antioxidant enzyme activities, mitochondrial respiratory enzymes activities, mitochondrial respiratory control ratio and the adenosine triphosphate content, and by decreasing mitochondrial malondialdehyde content, lactate dehydrogenase release, intracellular Ca(2+) level and caspase-3 activity in a concentration-dependent manner. Moreover, SMND-309 exhibits significantly higher potency as compared to salvianolic acid B. These findings indicate that SMND-309 has a protective potential against cerebral ischaemic injury and its protective effects may be due to the suppression of intracellular Ca(2+) elevation and caspase-3 activity, and improvement of mitochondrial energy metabolism and antioxidant property.