Protective effects of polydatin on multiple organ ischemia-reperfusion injury

Journal Pre-proofs Protective effects of polydatin on multiple organ ischemia-reperfusion injury Zhicheng Sun, Xiyang Wang PII: DOI: Reference:

S0045-2068(19)31947-9 https://doi.org/10.1016/j.bioorg.2019.103485 YBIOO 103485

To appear in:

Bioorganic Chemistry

Received Date: Revised Date: Accepted Date:

14 November 2019 23 November 2019 26 November 2019

Please cite this article as: Z. Sun, X. Wang, Protective effects of polydatin on multiple organ ischemiareperfusion injury, Bioorganic Chemistry (2019), doi: https://doi.org/10.1016/j.bioorg.2019.103485

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Protective effects of polydatin on multiple organ ischemia-reperfusion injury Zhicheng Suna,b,[email protected], Xiyang Wanga,b,*,[email protected] aDepartment

of Spine Surgery, Xiangya Hospital, Central South University, Changsha 410008,

Hunan, People’s Republic of China bHunan

Engineering Laboratory of Advanced Artificial Osteo-Materials, Xiangya Hospital, Central

South University, Changsha 410008, Hunan, People’s Republic of China

*Corresponding

author.

Highlights 

Polydatin has a protective effect on multiple organ ischemia-reperfusion injury.



Polydatin is a new drug with great potential for anti-ischemic reperfusion injury.



The protective effect of polydatin on ischemia-reperfusion injury may be achieved through anti-oxidant, anti-inflammatory, improving mitochondrial damage, inhibiting Ca2+ overload, anti-apoptosis and enhancing autophagy. etc.



4. The protective effect of polydatin on ischemia-reperfusion injury is a synergistic effect of various mechanisms and needs further exploration and verification.

Abstract: Polydatin(PD), a natural active ingredient isolated from traditional Chinese herb Polygonum cuspidatum, is also found in daily foods such as grapes and red wine. It might play a potential therapeutic role in human health through its anti-inflammatory, anti-oxidant, anti-ischemia injury, anti-apoptosis, conditioning blood lipids and other effects, which makes it increasingly become a hotspot of research. Various studies have shown that PD has a protective effect in the ischemia-reperfusion injury of heart, lungs, kidneys, gastrointestinal tract, cerebra and other organs. However, the specific mechanism of action is less and not completely clear. In this study, we aim to review the protective mechanism of PD in the ischemia-reperfusion injury of various organs, and provide inspiration for future studies.

Keywords: polydatin

ischemia-reperfusion injury

and autophagy 1

inflammatory

oxidative stress

apoptosis

Background Traditional Chinese herb plays an increasingly important role in the treatment of diseases, especially cardiovascular diseases, and other chronic diseases, etc.[51]. The medicinal value of traditional Chinese herb and the separation and extraction of active ingredients are also becoming more of a concern. In particular, the artemisinin extracted from the Chinese herb by Tu Youyou, the 2015 Nobel Prize-winner, has achieved extremely high benefits in the treatment of malaria. Polydatin (PD, C20H22O8), also known as pieced, a natural active ingredient, is a single crystal compound isolated from the Chinese herbal medicine Polygonum cuspidatum Sieb. et Zucc.[8,44,117]. In nature, it is mainly derived from the dried roots and stems of Polygonum cuspidatum Sieb. et Zucc., but also in daily foods such as grapes, peanuts, and wine[22,91,92]. PD is a

glycoside

form

of

resveratrol

with

the

structural

formula:

3,4,5-trihydroxystilbene-3-β-mono-D-glucoside (Figure1), and it has two isomers of cis-PD and trans-PD. The efficacy of resveratrol has been extensively studied, including anti-inflammatory[20], anti-tumor[119], weakening chemotherapy drug resistance[58], promoting nerve regeneration[21] and improving mitochondrial function[28], etc.. Although PD has similar pharmacological effects to resveratrol in some respects compared to resveratrol, it still has its own specificity. PD is traditionally used for antitussive, antiasthmatic, expectorant, conditioning blood lipid, reducing cholesterol, etc., but with the in-depth study of its chemical extraction[104,105,107], drug metabolism, pharmacology and toxicology[22,60,102,116,120], it has been found that it also has some unique effects such as anti-microbial[4], anti-inflammatory[41], anti-oxidant[2,66,94], scavenging free radicals, anti-ischemia injury[95], liver protection[26,118], anti-apoptosis[38], etc.. Therefore, the research on its special effects, especially its mechanism of anti-ischemic injury and reperfusion injury, has become a hotspot.

Ischemia-reperfusion(I/R) injury refers to the phenomenon that tissue damage is aggravated and 2

even irreversible damage occurs when blood flow is restored on the basis of tissue ischemia[76]. Under certain conditions, it can occur in many organs such as heart, cerebra, lungs, kidneys, intestine, stomach, testis, spinal cord, and skeletal muscles[18]. It often occurs after the blood supply of the ischemic tissues and organs is restored, such as shock treatment, coronary artery bypass

surgery,

thrombolytic

therapy,

transplantation, spinal decompression,

cardiopulmonary

etc.[25].The

cerebral

resuscitation,

organ

length of the ischemic time is a key factor in its

occurrence. Namely, I/R injury is not prone to occur if the time is too long or too short. In addition, the oxygen-dependent degree of tissues is also an important factor in determining whether an organ is susceptible to I/R injury. However, up to now, the mechanism of I/R injury remains unclear. By reviewing existing studies, it is found that many complex processes involve I/R injury, including ion accumulation, destruction of mitochondrial membrane potential, the formation of reactive oxygen species(ROS), dysregulation of nitric oxide metabolism, endothelial dysfunction, platelet aggregation, immune activation, apoptosis and autophagy[45,98]. Under each major mechanism, there are more specific and more subtle mechanisms, which makes the mechanism of I/R injury more complicated. Although many studies support the protective effect of PD on the organ I/R injury, the most comprehensive review of the molecular mechanisms of its protective effects on I/R injury has not yet been published. In this study, we aim to review the protective mechanism of PD in the I/R injury of various organs, and provide inspiration for future studies. 1. Polydatin and myocardial I/R injury. Myocardial I/R can cause different levels of damage to the heart in terms of myocardial ultrastructure, energy metabolism, and cardiac function. The mechanism of myocardial I/R injury is quite complicated and not completely clear. The energy metabolism disorder, free radical production, Ca2+ overload and leukocyte action play a crucial role in the occurrence and development of myocardial I/R injury[11,24,45,78]. To relieve myocardial I/R injury, it is especially important to restore blood flow as soon as possible. In general, low-pressure, low-flow and low-temperature reperfusion is recommended. At the same time, improving mitochondrial function, scavenging free radicals, reducing inflammation and the use of calcium antagonists, to some extent, can also protect the heart from I/R injury. At present, the research on the protective effect of PD on myocardial I/R injury has become more and more popular in the world, but the clarification of the relevant mechanism is still not perfect, and some even require further experimental verification. 1.1 Activating PKC-KATP-dependent signaling and eliminate free radicals: Miao Q et al.[65] established a rat model of myocardial I/R injury and verified that intravenous injection of PD could protect the myocardium from I/R injury, significantly inhibit myocardial infarction area and myocardial enzyme leakage, increase superoxide dismutase(SOD) activity and reduce 3

malondialdehyde(MDA) levels. In the presence of PKC inhibitors and mito KATP channel blockers, cardiac function retention and myocardial enzyme leakage limitation of PD disappeared. However, the oxidative stress-related metabolites SOD activity and MDA levels were not affected. Thus, it can be considered that the cardioprotective effect of PD is mediated by two different pathways: activation of PKC-KATP-dependent signaling and the mechanism of free radical elimination. When it comes to the removal of free radicals and antioxidant stress, Zhang LP et al.[115] have also confirmed this point, and believe that this effect is mainly related to the increase of nitric oxide(NO) mediated by constitutive nitric oxide synthase(NOS). 1.2 Enhancing autophagy: Ling

YN

et

al.[54]

established

a

myocardial

I/R

injury

model

in

mice

and

a

hypoxia-reoxygenation(H/R) model in vitro. Further studies found that PD-treated mice had significantly smaller myocardial infarct size, higher left ventricular shortening fraction, and ejection fraction than the control group. In the cardiomyocyte model, the PD group showed that PD promoted the degradation of autolysosomes and reduced the production of mitochondrial membrane potential and cellular reactive oxygen species, all of which were inhibited or antagonized by autophagy inhibitors. These findings suggest that PD protects myocardial I/R injury by promoting autophagy flux to clear damaged mitochondria to reduce ROS and cell death. 1.3 Regulating intracellular Ca2+ treatment: Studies have shown that PD could reversely regulate the activity of two calcium channels LCC and RyR in cardiomyocytes, increase the sensitivity of myofilament to calcium ions, reduce calcium ion transients and increase myocardial contractility, and it could also regulate cardiac EC binding by regulating the production of NO[19]. However, whether this effect is still effective in myocardial ischemia-reperfusion injury is still unknown. Moreover, the effect of PD on cardiomyocyte Ca2+ signaling is different under normal and diseased state, which seems to depend on the intracellular oxidation state[57]. However, this remains controversial. In the treatment of acute heart failure, PD could inhibit the excessively active RyR-mediated sarcoplasmic reticulum Ca2+ leakage in cardiomyocytes, thereby restoring the sarcoplasmic reticulum Ca2+ content, increasing Ca2+ transients and myocardial cell contractility. In a failing heart with excessive ROS accumulation, PD could reduce oxidative stress by increasing antioxidant proteins and neutralize ROS by increasing NO production, thereby preventing hyperactive RyR induced by oxidative stress[42]. The continued increase in Ca2+ overload plays a key role in I/R-induced cardiac injury[30,33]. Inhibiting sarcoplasmic reticulum Ca2+ recirculation and increasing diastolic sarcoplasmic reticulum Ca2+ leakage could induce Ca2+ overload[97]. In summary, a reasonable hypothesis can be made: PD may protect against myocardial I/R injury through anti-oxidative stress and anti-Ca2+ overload. This hypothesis needs further exploration in the model of myocardial I/R injury. 4

1.4 Activation of Pten/Akt signaling mediated by Notch1/Hes1: Yu LM et al.[109] established a model of myocardial I/R injury in diabetic rats. Further studies found that PD can maintain cardiac function and reduce myocardial infarct size. In addition, PD can improve myocardial oxidative and nitrative stress damage, which is manifested by the decrease of myocardial superoxide production, MDA level, iNOS expression, NO metabolite level, and nitrotyrosine level and the increase of phosphorylation level of eNOS. However, these effects can be antagonized by γ-secretase inhibitors and PI3K/Akt inhibitors. In summary, it can be proved that PD can effectively reduce myocardial I/R injury in diabetic patients by improving oxidation and nitrification stress damage. Moreover, the activation of Notch1/Hes1-mediated Pten/Akt signaling plays a crucial role in this process. 1.5 Inhibition of the renin-angiotensin system (RAS) and Rho-associated kinase (ROCK) activity: Ming D et al.[67] found that trans-PD could reduce myocardial infarct size, myocardial fibrosis and apoptosis and improve left ventricular function in mice after myocardial I/R injury. It also inhibited the activity of RAS and ROCK in cardiomyocytes after myocardial I/R injury, especially the ROCK pathway activated by angiotensin I receptor. And it is concluded that trans-PD might play a cardioprotective effect on myocardial I/R injury by inhibiting RAS and its downstream ROCK activity. 1.6 Other possible mechanisms：Zhang LP et al.[113] found that the protective effect of PD on rat I/R injury might be related to the opening of ATP-sensitive potassium channels on both cell membrane and mitochondrial membrane, and the inhibition of mitochondrial permeability transition pore opening. At the same time, they also found that PD could inhibit I/R-induced apoptosis by increasing Bcl-2 protein expression and decreasing Bax protein expression in rat myocardium[114].

2. Polydatin and renal I/R injury. Renal ischemia-reperfusion injury often occurs after renal transplantation, often leading to postoperative renal insufficiency[31,82]. It can also occur in trauma, sepsis, and hypovolemic shock. In this process, oxidative stress caused by excess reactive oxygen species triggers subsequent lipid peroxidation, and deoxyribonucleic acid(DNA) and protein damage, leading to apoptosis in ischemic tissue[63,69,74]. In addition, the inflammatory response is not negligible during renal ischemia-reperfusion and often leads to excessive production of pro-inflammatory cytokines in the kidney, which leads to leukocyte infiltration and tissue damage[9,40]. Therefore, anti-oxidative stress and anti-apoptosis are particularly important in the prevention and treatment of renal I/R injury. And PD has exactly this effect, he may be a useful supplementary treatment for kidney disease such as kidney damage. 5

At present, the protective mechanism of PD in renal I/R injury is still unclear, but it is mainly concentrated in the following aspects: 2.1 Shh signaling pathway: Sonic hedgehog(Shh) is a secreted extracellular signaling protein that plays an important role in a range of cellular processes such as differentiation, proliferation and apoptosis in a variety of tissues[3,16]. It has been proved that PD can enhance the anti-oxidation and anti-apoptotic ability of renal tissue by activating the Shh signaling pathway, thereby providing a protective effect on renal ischemia-reperfusion injury[64]. 2.2 PI3K/Akt signaling pathway: The phosphatidylinositol 3-kinase(PI3K) family activates its downstream signaling protein, the serine/threonine kinase Akt, to regulate cell proliferation, survival, apoptosis, and various biological responses, including oxidative stress, inflammation, and chemotaxis[5,13]. It has been proved that PD can resist oxidative stress and inflammation through PI3-K/Akt-dependent molecular mechanism, which has a significant protective effect on renal I/R injury[56]. 2.3 Mitigating mitochondrial dysfunction by SIRT1 activation and p53 deacetylation pathway: Silent information regulator (SIRT)1, a nicotinamide adenine dinucleotide- (NAD+-) dependent histone deacetylase, can deacetylate P53 protein and reduce the activity of P53[49,59,100]. Zeng ZH et al.[110] simulated the renal I/R model in vitro by establishing an H/R model of renal tubular epithelial cells(RTECs). Further studies found that PD can increase SIRT1 activity, decrease acetylated p53 levels, and mitigate mitochondrial disfunction in RTECs. Based on this, it can be concluded that the protective effect of PD on renal I/R injury is partly achieved by activating the SIRT1-p53 pathway to attenuate mitochondrial dysfunction. 2.4 Regulating TLR4 / NF-κB signaling pathway: Li Ying et al.[53] used the H/R model of NRK-52E cells to simulate renal I/R injury in vitro. Further studies found that PD can down-regulate I/R-induced TLR4 mRNA and protein expression and reduce the protein expression of NF-κB, TNF-α and IL-1β, and this effect can be antagonized by TLR4 receptor blockers. Based on this, It can be concluded that PD may protect the NRK-52E cells from I/R injury by regulating the TLR4/NF-κB signaling pathway to alleviate the inflammatory response.

3. Polydatin and cerebral I/R injury. Cerebral ischemia is one of the most serious neurological diseases, often leading to cerebral ischemic tissue cell death, resulting in adverse outcomes such as stroke, dementia, decreased 6

learning and memory, and therefore, effective treatment is required immediately after it occurs. At present, thrombolytic therapy is the main treatment strategy for the timely recovery of cerebral perfusion after cerebral ischemic injury[106]. However, during reperfusion, it is easy to cause intracellular ROS production, calcium overload, mitochondrial damage, cell death and other biochemical metabolic processes, which may eventually lead to cerebral I/R injury[27,73]. The mechanisms of cerebral I/R injury are complex and include cellular responses such as oxidative stress, inflammation, and apoptosis[27,73,106]. As an antioxidant, polyphenols such as PD have been shown to have important protective effects in brain injury[6,48,89]. Therefore, Whether PD can protect against cerebral I/R injury has attracted the attention of researchers. Gao, Youguang et al[32] used rat middle cerebral artery occlusion to induce ischemia, and then reperfusion to construct a rat model of cerebral I/R injury. Further studies revealed that PD can improve rat neurological function after cerebral I/R injury, reduce infarct size, improve mitochondrial dysfunction, increase Bcl-2 expression, and reduce expression of Bcl-2 related protein X apoptosis regulators. PD also prevents the release of cytochrome-c from the mitochondria into the cytoplasm and attenuates the activity of caspase-9 and caspase-3. In addition, PD reduced the amount of ROS in neuronal cells compared to the control group. It can be inferred that PD has a dual protective effect on cerebral I/R injury, which can improve oxidative stress and mitochondria-dependent apoptosis. In addition, Cheng, YF et al[14,15] used the same method to construct a cerebral I/R injury model in rat, and found that PD inhibited the expression of CAMs(especially VCAM-1, L-selectin, integrinα5 and VLA-4) induced by cerebral I/R injury in rats. It is shown that PD protects the brain injury induced by I/R at least in part by its inhibition of CAM.

4. Polydatin and pulmonary I/R injury. Pulmonary I/R injury is one of the main causes of pulmonary dysfunction after cardiopulmonary surgery and thoracic organ transplantation. Although the exact mechanism of lung injury caused by I/R is not fully clear, the infiltration of polymorphonuclear leukocytes, the separation of macrophages and the excessive production of ROS such as superoxide and peroxide may be associated with lung injury[12]. In addition, studies have shown that pulmonary I/R injury may be related to lung mitochondrial dysfunction[90]. Jin XF et al.[43] showed that PD may inhibit the release of ICAM-1 inflammatory mediators by down-regulating TLR4 and NF-κB expression, thereby protecting lung I/R injury. In addition, Wang FY et al.[103] constructed a model of lung I/R injury in rabbits. Further studies found that PD treatment group can increase SOD activity, decrease MDA level, and significantly attenuate lung tissue ultrastructure injury compared with the control group. And it is further found that PKC may be involved in its protection mechanism in pulmonary I/R injury. 7

It can be seen from these two studies that the protective mechanism of PD on lung ischemia-reperfusion injury is only carried out from two aspects: inflammation and oxidative stress. The specific mechanism still needs more experimental evidence. Whether PD can affect the structure of lung mitochondria still requires more scientific and rigorous experiments to explore.

5. Polydatin and gastric I/R injury. Gastric I/R injury can occur in a variety of surgical procedures, may also be due to a variety of pathological factors such as vascular rupture, gastrointestinal disease[70]. Inflammatory response and oxidative stress play an important role in the pathogenesis of gastric I/R injury[71], while oxygen-derived free radicals and lipid peroxidation may play an important role in the pathogenesis of acute gastric mucosal injury induced by I/R during oxidative stress[99,108]. Therefore, anti-inflammatory and anti-oxidative stress have become an entry point for our treatment and prevention of gastric I/R injury. In previous studies, many antioxidants and anti-inflammatory drugs were found and tried to be effective against gastric I/R injury[7], such as methionine[17,71], melatonin, glucagon-like peptide-1α receptor-agonist[68], estradiol and progesterone[47], etc., but due to their own different limitations, it is still rare to be truly used in the clinic. The protective mechanism of PD in gastric I/R injury is extremely rare internationally. Guo LY et al.[35] established a model of gastric I/R injury in rats by clamping the celiac artery with a small artery clamp for 30 min and reperfusion for 60 min. The gastric mucosal injury index and the changes of MDA, SOD, glutathione peroxidase(GSH-Px), NO and NOS were observed. The results showed that PD can significantly reduce the gastric mucosal injury index in the injury model, reduce the MDA content, increase the levels of SOD, GSH-Px, NO and NOS in gastric tissue. According to this, it is judged that PD can inhibit the production of oxygen free radicals during gastric I/R injury and improve the antioxidant capacity of tissues, which has a certain protective effect on gastric I/R injury. However, it is worth noting that the role of PD in gastric I/R injury seems to have another effect. Brzozowski T et al. found that resveratrol can be used as a specific cyclooxygenase-1 inhibitor, which can reduce the production of prostaglandin E2, prolong the healing time of gastric injury induced by ischemia-reperfusion, and enhance gastric injury[10]. Since resveratrol is one of the active metabolites of PD in the body, PD may be similar to resveratrol, producing a detrimental effect on gastric I/R injury by inhibiting prostaglandin E2 production. Of course, based on the research results of Guo LY et al. and our conjecture, we cannot rule out the dual role of PD exist at the same time, and the different results are dependent on who plays the leading role. However, this requires more scientific and rigorous experiments to explore and validate.

6. Polydatin and intestinal I/R injury. The role of PD in the intestinal tract has been repeatedly reported, including anti-radiation 8

damage[52], protective effects of ulcerative colitis[55] and anti-intestinal epithelial cell proliferation[93], etc., but less in intestinal I/R injury. Intestinal I/R injury often occurs in intestinal hemorrhagic shock, intestinal transplantation, mesenteric thrombosis and their treatment process, and is also a common complication in the intensive care process. Although its specific mechanism is still unclear, the large-scale production of ROS, depletion of antioxidant defense mechanisms in vivo, mitochondrial dysfunction, and systemic inflammatory response are involved in this process, leading to intestinal epithelial damage and mucosal barrier dysfunction[86-88,101]. Zeng ZH et al.[111] explored the role of PD in intestinal I/R injury by establishing a model of severe hemorrhagic shock in rats. It was found that PD can enhance SIRT1 activity, increase the expression of SOD2 protein, enhance SOD2 activity, reduce intestinal injury caused by oxidative stress during hemorrhagic shock, and inhibits cell apoptosis and histological changes in the small intestine. In addition, PD can also alleviate systemic inflammatory response during severe hemorrhagic shock in rats and prolong their survival time. Therefore, it can be preliminarily believed that PD plays an important protective role in the SIRT1-PGC-1α-SOD2 axis mechanism of small intestine injury, and it is an effective SIRT1 activator. However, in addition to the SIRT1-mediated mechanism, SOD2 activity is regulated by a variety of different cellular mechanisms[96], and SIRT3-mediated mechanisms are one of them. Studies have shown that SIRT3 can activate SOD2 activity and reduce oxidative stress[84], and can reduce autophagy through the SIRT3-SOD2-mROS mechanism[77]. Inspired by this, Zeng ZH et al. continued to establish H2O2-induced oxidative stress model and hemorrhagic shock model in rats, and found that PD can significantly restore SIRT3 activity, reduce acetylated SOD2 level, enhance SOD2 activity, improve mitochondrial dysfunction, thereby reducing I/R injury during hemorrhagic shock[112]. These studies indicate that PD plays an important protective role in intestinal I/R injury, but in addition to the mechanism of SOD2 activity mediated by SIRT1/3, there are still other possible molecular mechanisms that have not yet been found or reported. 7. Polydatin and testicular I/R injury. Testicular I/R injury often occurs in the process of testicular torsion and detorsion(T/D) injury. It is one of the most important pathophysiological processes of testicular T/D injury. Testicular torsion injury is more common in young people under the age of 25[79], especially 13-15 years old adolescents and 1-year-old infants[80]. The best treatment after testicular torsion is to reset as soon as possible, including manual reduction and operative reduction, and in this process, reperfusion injury may gradually occur[1,29,85]. Lipid peroxidation, large-scale production of ROS, and activation of the enzymatic antioxidant defense system are thought to be associated with testicular I/R injury[34,81]. 9

A previous study showed that polydatin can improve oxidative stress in testicular injury, reduce lipid peroxidation, enhance its antioxidant defense mechanism, and partially regenerate damaged testicular tissue[39]. However, at present, there are few reports on the application of PD in testicular I/R injury. Qiao HL et al.[83] established a rat model of testicular T/D injury and studied the benefits of PD. It was found that PD pretreatment significantly improved morphological damage, lowered Cosentino histological score, decreased MDA levels, up-regulated catalase, glutathione peroxidase and SOD activity. PD can also reduce T/D-induced germ cell-specific apoptosis, reduce the activation of caspase-3, caspase-8, caspase-9 and poly(ADP-ribose) polymerase, and increase the Bcl-2/Bax ratio. According to the results of this study, PD suggests a protective effect on testicular T/D injury, especially in histological, anti-oxidative stress and anti-apoptotic levels. However, due to the lack of clinical application data and more experimental evidence of PD in this field, the results are still not convincing. 8. Polydatin and spinal cord I/R injury. Spinal cord ischemia/reperfusion (I/R) injury is a serious and unpredictable complication that occurs in many operations, including thoracoabdominal aortic surgery, trauma surgery, and spinal surgery, often leading to some serious adverse consequences such as neurological damage and paraplegia[36,37]. Studies have shown that about 32% of patients with thoracic or thoracoabdominal aortic surgery will have spinal cord I/R injury, and the incidence of paraplegia is as high as 5%[50,75]. The specific mechanism of spinal cord I/R injury is still unclear, but oxygen free radical-mediated lipid peroxidation, calcium overload, excitatory amino acids, prostaglandins and other factors play an important role in the mechanism of spinal cord injury[23,72]. By now, the study of PD in the spinal cord is quite rare, and mainly focused on spinal cord injury. Studies have shown that PD can inhibit oxidative stress and microglia apoptosis through the Nrf2/ HO-1 pathway, thereby reducing spinal cord injury in rats[61]. It can also alleviate microglial inflammation and reduce traumatic spinal cord injury by regulating iNOS and NLRP3 inflammatory bodies[62]. In addition, studies have also shown that PD can enhance spinal cord regeneration and prevent the excitatory and inhibitory afferent loss of motor neurons after spinal cord injury[46]. In the aspect of spinal cord I/R injury, there is still no report on the protective effect of PD on it. However, because PD has anti-inflammatory, anti-oxidation, mitigating mitochondrial dysfunction, anti-apoptosis and other pharmacological action, the research of PD on spinal cord injury and ischemia-reperfusion injury is promising.

Conclusion PD has been shown to have protective effects in multiple organ I/R injury. Its protective mechanism cannot be simply attributed to its anti-inflammatory and anti-oxidative stress 10

properties, and a variety of signaling pathways and molecular mechanisms may be also involved, including anti-mitochondrial injury, anti-apoptosis, anti-autophagy, anti-Ca2+ Overloaded, etc.. In addition, the protective mechanism of PD on I/R injury may have the cross-section of tissues and organs, that is, the molecular mechanism that has been confirmed to exist in a tissue may also exist in another tissue. What is more worthy of scrutiny is that each mechanism of action can be mediated by multiple signal paths, which is similar to a huge network. Therefore, research on the mechanism of PD in I/R injury still has a long way to go, and more scientific and rigorous experiments are needed to further explore and prove. However, it is undeniable that PD is likely to be a very promising drug that is expected to be used clinically for the benefit of patients suffering from ischemia-reperfusion injury.

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