Polydatin Alleviates Small Intestine Injury during Hemorrhagic Shock as a SIRT1 Activator.

OBJECTIVE: To evaluate the role of SIRT1 in small intestine damage following severe hemorrhagic shock and to investigate whether polydatin (PD) can activate SIRT1 in shock treatment. RESEARCH DESIGN AND METHODS: The severe hemorrhagic shock model was reproduced in Sprague Dawley rats. MAIN OUTCOME MEASURES: Two hours after drug administration, half of the rats were assessed for survival time evaluation and the remainder were used for small intestinal tissue sample collection. RESULTS: Bleeding and swelling appeared in the small intestine with epithelial apoptosis and gut barrier disturbance during hemorrhagic shock. SIRT1 activity and PGC-1α protein expression of the small intestine were decreased, which led to an increase in acetylated SOD2 and decreases in the expression and activity of SOD2, resulting in severe oxidative stress. The decreased SIRT1 activity and expression were partially restored in the PD administration group, which showed reduced intestine injury and longer survival time. Notably, the effect of PD was abolished after the addition of Ex527, a selective inhibitor of SIRT1. CONCLUSIONS: The results collectively suggest a role for the SIRT1-PGC-1α-SOD2 axis in small intestine injury following severe hemorrhagic shock and that PD is an effective SIRT1 activator for the shock treatment.

Polydatin: a new therapeutic agent against multiorgan dysfunction.

BACKGROUND: Polydatin (PD), a monocrystalline and polyphenolic drug isolated from a traditional Chinese herb (Polygonum cuspidatum), is protective against mitochondrial dysfunction and has been approved for clinical trials in the treatment of shock. However, whether the administration of PD has a therapeutic effect on multiple-organ dysfunction syndrome (MODS) requires investigation. MATERIAL AND METHODS: MODS was induced in Sprague-Dawley rats via hemorrhage and ligation and puncture of cecum-induced sepsis. The rats were divided into three groups as follows: MODS + PD, MODS + normal saline, and a control group (no treatment). Survival time, blood biochemical indexes, and histopathologic changes in various organs were evaluated; serum oxidative stress (advanced oxidative protein products [AOPPs]) and proinflammatory cytokines (tumor necrosis factor-α, interleukin 1ß, and interleukin 6) were assayed using enzyme-linked immunosorbent assay. Apoptosis-related protein expression (B-cell lymphoma-2 [Bcl-2] and Bax) was assayed by immunohistochemical and Western blotting methods, whereas caspase-3 activity was assayed by spectrophotometry. RESULTS: PD improved organ function, prolonged survival time, and reduced MODS incidence and serum levels of AOPPs and proinflammatory cytokines. It also decreased Bax levels and caspase-3 activity and increased Bcl-2 levels in the kidney and liver. CONCLUSIONS: PD may serve as a potential therapeutic for MODS, as it suppresses oxidative stress, inhibits inflammatory response, attenuates apoptosis, and protects against mitochondrial dysfunction.

Polydatin--a new mitochondria protector for acute severe hemorrhagic shock treatment.

OBJECTIVE: The aim of the study was find out whether neuronal mitochondrial injury does take place in severe shock and to explore effective therapy for severe shock. RESEARCH DESIGN AND METHODS: Rats were divided in the following group: sham, shock + normal saline (NS), shock + cyclosporine A (CsA), shock + resveratrol (Res) and shock + polydatin (PD). Rats were subjected to shock for 2 h, followed by administration of NS, CsA, Res and PD, and infusion of shed blood. Morphology, metabolism and function of mitochondria were measured. RESULTS: Increased lipid peroxides (LPO) levels, lysosomal injury and mitochondrial permeability transition pore opening took place in neurons, resulting in swollen mitochondria with poorly defined cristae, decreased mitochondrial membrane potential (ΔΨ) and reduced ATP content in shock + NS group, indicating mitochondrial dysfunction. Mitochondrial protectors, such as CsA, Res and PD, partially inhibited these alterations, especially following PD protection, ATP level increased from 44.14 ± 13.81% in shock + NS group to 89.57 ± 9.21% and the survival time was prolonged from 6.3 ± 5.9 h in the shock + NS group to 31.6 ± 13.7 h in shock + PD group. CONCLUSIONS: The study shows that neuronal mitochondrial injury is involved in the genesis of severe shock and PD may be the best choice for protection of neuron against mitochondrial injury in severe shock.

Hypotensive resuscitation combined with polydatin improve microcirculation and survival in a rabbit model of uncontrolled hemorrhagic shock in pregnancy.

BACKGROUND: Obstetric hemorrhage remains a leading cause of maternal death internationally. Polydatin is an effective drug in ameliorating microcirculatory insufficiency and increasing survival rate in non-pregnant animal model of controlled hemorrhagic shock. In the present study, we investigated the effects of hypotensive resuscitation combined with Polydatin administration on microcirculation and survival rate in a clinically relevant model of uncontrolled hemorrhagic shock in pregnancy. MATERIALS AND METHODS: Twenty anesthetized New Zealand white rabbits at mid and late gestation were anesthetized, and an ear chamber was prepared to examine microvessels by intravital microscopy. Shock was induced by transecting a small artery in mesometrium, followed by blood withdrawal via the femoral artery to a mean arterial pressure (MAP) of 40-45 mm Hg. Animals were randomly divided into two groups (n=10 per group): 30 min after hemorrhage induction, hypotensive resuscitation with Ringer's solution to MAP of 60 mm Hg, followed by a single volume infusion of 4 mL/Kg of normal saline or Polydatin at 60 min after hemorrhage induction (group NS, PD). Finally all the animals received hemorrhage control and resuscitated with half of the heparinized shed blood and Ringer's solution to MAP of 80 mm Hg. RESULTS: At the end of resuscitation, compared with group NS, group PD showed significantly improved capillary perfusion as indicated by increased arteriole diameter [0.95±0.02 of baseline (PD), 0.71±0.05 of baseline (NS); P=0.000] and higher functional capillary density[95.3% ± 2.6% (PD), 57.2% ± 4.1% (NS); P=0.000]. Median survival time was significantly longer in group PD than that in group NS [4 d (PD), 2 d (NS); P=0.000]. CONCLUSIONS: On the basis of hypotensive resuscitation, Polydatin administration improved microcirculation and prolonged survival time in pregnant rabbit model of uncontrolled hemorrhagic shock.

Hemorheologic events in severe shock.

Persistent low perfusion and low blood pressure are the two major events in the pathogenesis of irreversible shock. This review is focused on our recent study on the mechanism of, and a new therapeutic approach to the two events in IS. One of the main causes of persistent low perfusion are leukocyte adhesion on venule walls and plugging in capillaries which comes from the low wall shear stress or shear rate, and high leukocyte-endothelial adhesion force in IS. However, blockade of leukocyte adhesion by monoclonal antibodies against the adhesion molecules can only attenuate the number of sticking WBC in venules, but cannot make an appreciable improvement in capillary reflow and survival rate in IS, because it is difficult for the agents to flow into an obstructed capillary. We have shown that the administration of Polydatin, a crystalline product isolated from a traditional Chinese medicine, can restore the pulse pressure with high survival rate in irreversible shock. With an increase in pulse pressure, and the highly dispersive force resulting from pulsatile blood flow, the stationary blood cells can be pushed away from the obstructed capillary and thus promote capillary reflow. Therefore, enhancement of pulse pressure is a key factor for the treatment of low perfusion in irreversible shock. Hyperpolarization of arteriolar smooth muscle cells occurs in irreversible shock, which inhibits the potential-operated calcium channel and the influx of Ca2+ in arteriolar smooth muscle cells stimulated by norepinephrine, and finally leads to low vascular contractile responsiveness with refractory hypotension in irreversible shock. Activation of the potassium channels K(ATP) and BK(Ca) is involved in arteriolar smooth muscle cells hyperpolarization. In irreversible shock, ATP depletion, intracellular acidosis, ONOO- formation, and enhancement of a calcium spark results in activation of K(ATP) and BK(Ca) and consequent arteriolar smooth muscle cell hyperpolarization. Therefore, a new therapeutic strategy for refractory hypotension was suggested, including blockade of potassium channel activation to reconstitute vasoreactivity and the administration of vasopressors to elevate blood pressure in the treatment of irreversible shock.

The mechanism of Polydatin in shock treatment.

Polydatin is extracted from a traditional Chinese herbal medicine, Polygonum cuspidatum, and has a special effect in shock treatment. The aim of this study is to explain the cellular and molecular basis of Polydatin in shock treatment. The fluorescent probe techniques, patch clamp method, and cellular flow chamber were used to test intracellular variables of vascular smooth muscle cells (VSMC), myocardial cells (MC), endothelial cells (EC), and white blood cell (WBC). It was shown that Polydatin could inhibit ICAM-1 expression in EC stimulated by lipopolysaccharide (LPS), attenuate WBC-EC adhesion, increase [Ca2+]i in MC with enhancement of MC contraction extent, activate KATP channels of VSMC, and decrease pHi value and [Ca2+]i of VSMC in shock. The study suggests that Polydatin has multiple effects on VSMC, MC, WBC and EC, which are related to the enhancement of heart function and improvement of microcirculatory perfusion in shock.