Dicarboxylic Acid Dietary Supplementation Protects against AKI.

SIGNIFICANCE STATEMENT: In this study, we demonstrate that a common, low-cost compound known as octanedioic acid (DC 8 ) can protect mice from kidney damage typically caused by ischemia-reperfusion injury or the chemotherapy drug cisplatin. This compound seems to enhance peroxisomal activity, which is responsible for breaking down fats, without adversely affecting mitochondrial function. DC 8 is not only affordable and easy to administer but also effective. These encouraging findings suggest that DC 8 could potentially be used to assist patients who are at risk of experiencing this type of kidney damage. BACKGROUND: Proximal tubules are rich in peroxisomes, which are damaged during AKI. Previous studies demonstrated that increasing peroxisomal fatty acid oxidation (FAO) is renoprotective, but no therapy has emerged to leverage this mechanism. METHODS: Mice were fed with either a control diet or a diet enriched with dicarboxylic acids, which are peroxisome-specific FAO substrates, then subjected to either ischemia-reperfusion injury-AKI or cisplatin-AKI models. Biochemical, histologic, genetic, and proteomic analyses were performed. RESULTS: Both octanedioic acid (DC 8 ) and dodecanedioic acid (DC 12 ) prevented the rise of AKI markers in mice that were exposed to renal injury. Proteomics analysis demonstrated that DC 8 preserved the peroxisomal and mitochondrial proteomes while inducing extensive remodeling of the lysine succinylome. This latter finding indicates that DC 8 is chain shortened to the anaplerotic substrate succinate and that peroxisomal FAO was increased by DC 8 . CONCLUSIONS: DC 8 supplementation protects kidney mitochondria and peroxisomes and increases peroxisomal FAO, thereby protecting against AKI.

THE POTENTIAL RENOPROTECTIVE EFFECT OF TILIANIN IN RENAL ISCHEMIA REPERFUSION INJURY IN MALE RAT MODEL.

OBJECTIVE: The aim: To determine whether Tilianin (TIL) may have Nephroprotective effects on bilateral renal IRI in rats by analyzing kidney function biomarkers U and Cr, inflammatory cytokines like TNF α and IL-1ß, antioxidant marker total anti-oxidant Capacity (TAC), anti-apoptotic markers caspase-3, and histopathological scores. PATIENTS AND METHODS: Materials and methods: 20 rats divided into even 4 groups as: Sham group: Rats underwent median laparotomies without having their ischemia induced. Control group: Rats had bilateral renal ischemia for 30 minutes, followed by 2 hours of reperfusion. Vehicle group: 30 minutes prior to the onset of ischemia, rats were given a pretreatment of corn oil and DMSO. Tilianin treated group: Rats administered Tilianin 5 mg/kg for 30 min prior to ischemia induction, then IRI. RESULTS: Results: The study found that the serum levels of TNF, IL-1, caspase-3, urea and creatinine, as well as TNF and creatinine in the Tilianin group were significantly lower than those of the control and vehicle groups. On the other hand, it revealed that TAC levels are remarkably higher in the Tilianin group than they are in the control and vehicle groups. CONCLUSION: Conclusions: This study concluded that Tilianin have a Nephroprotective effect via multiple impacts as anti-inflammatory, anti-apoptotic, and anti-oxidant agents.

Novel gold-platinum nanoparticles serve as broad-spectrum antioxidants for attenuating ischemia reperfusion injury of the kidney.

Kidney ischemia reperfusion injury (IRI) is a common and inevitable pathological condition in routine urological practices, especially during transplantation. Severe kidney IRI may even induce systemic damage to peripheral organs, and lead to multisystem organ failure. However, no standard clinical treatment option is currently available. It has been reported that kidney IRI is predominantly associated with abnormally increased endogenous reactive oxygen species (ROS). Scavenging excessive ROS may reduce the damage caused by oxidative stress and subsequently alleviate kidney IRI. Here, we reported a simple and efficient one-step synthesis of gold-platinum nanoparticles (AuPt NPs) with a gold core having a loose and branched outer platinum shell with superior ROS scavenging capacity to possibly treat kidney IRI. These AuPt NPs exhibited multiple enzyme-like anti-oxidative properties simultaneously possessing catalase- and peroxidase-like activity. These particles showed excellent cell protective capability, and alleviated kidney IRI both in vitro and in vivo without obvious toxicity, by suppressing cell apoptosis, inflammatory cytokine release, and inflammasome formation. Meanwhile, AuPt NPs also had an effect on inhibiting the transition to chronic kidney disease by reducing kidney fibrosis in the long term. Thus, AuPt NPs might be a good therapeutic agent for kidney IRI management and may be helpful for the development of clinical treatments for kidney IRI.

Gastrodin Pretreatment Alleviates Renal Ischemia-Reperfusion Injury.

INTRODUCTION: This study aimed to investigate the possible effect of gastrodin in renal ischemia-reperfusion injury (IRI) and the mechanisms. METHODS: Forty-eight male Sprague Dawley rats were randomly divided into 3 groups: sham-operated group, saline-treated IRI group, and gastrodin-treated IRI group. Gastrodin or 0.9% saline (300 mg/kg/day) was intragastrically administrated for 8 days before operation. We analyzed renal function and histological change. The malondialdehyde level, antioxidant enzymes' activities, and markers of inflammation and apoptosis were measured. Statistical analysis was performed using 1-way analysis of variance (ANOVA) or Kruskal-Wallis ANOVA on ranks. RESULTS: Gastrodin pretreatment improved IRI-induced renal dysfunction and histologic injury. Mechanistically, gastrodin reversed the elevation of malondialdehyde level and the reduction of antioxidant enzymes' activities. Gastrodin also reduced the elevated myeloperoxidase activity, TNF-α and IL-1ß levels, and the activation of p38 MAPK. Moreover, gastrodin-treated rats exhibited a dramatic reduction in renal tubular apoptosis, along with a decrease in caspase-3 activation and an increase in the Bcl-2/Bax ratio. CONCLUSION: Gastrodin pretreatment may alleviate renal IRI via the amelioration of oxidative injury, inflammatory response, and renal tubular apoptosis.

Supplemental hydrogen sulfide in models of renal transplantation after cardiac death.

BACKGROUND: The increasing use of kidneys from donations after cardiac death (DCD) for renal transplantation is hindered by negative outcomes owing to organ injury after prolonged warm and cold ischemia-reperfusion. Recently, hydrogen sulfide (H2S) has shown cytoprotective effects against ischemia-reperfusion injury; however, its effectiveness in the context of DCD renal transplantation is unknown. METHODS: We tested a novel 30-day in vivo syngeneic murine model of DCD renal transplantation, in which the donor kidney was clamped for 30 minutes and stored for 18 hours in cold University of Wisconsin (UW) solution or UW with 150 µM sodium hydrogen sulfide (UW + NaHS) before transplantation. We also tested a 7-day in vivo porcine model of DCD renal autotransplantation, in which the left kidney was clamped for 60 minutes and preserved for 24 hours using hypothermic perfusion with UW or UW + 150 µM NaHS before autotransplantation. We collected blood and urine samples periodically, and collected kidney samples at the end point for histopathology and quantitative reverse transcription polymerase chain reaction. RESULTS: Rats that received H2S-treated kidneys showed significantly higher survival, faster recovery of graft function and significantly lower acute tubular necrosis than controls. Pig kidneys perfused with UW + NaHS showed significantly higher renal blood flow and lower renal resistance than control kidneys after 24 hours of perfusion. After autotransplantation, pigs that received H2S-treated kidneys showed significantly lower serum creatinine on days 1 and 7 after transplantation. Rat and pig kidneys treated with H2S also showed more protective gene expression profiles than controls. CONCLUSION: Our findings support the potential use of H2S-supplemented UW solution during cold storage as a novel and practical means to improve DCD graft survival and function.

Nitroglycerin ameliorates sperm parameters, oxidative stress and testicular injury following by testicular torsion/detorsion in male rats.

PURPOSE: This study was designed to determine the probable protection mechanisms of nitroglycerin, a widely used medication for treatment of heart failure and angina, in amelioration of testicular ischemia/reperfusion damage. METHODS: 24 adult male rats were randomly divided into three equal groups; with eight rats in each group: Group 1 (Sham) was sham-operated. Group 2 (T_D): 2 h testicular torsion was induced, afterward detorsion was performed and maintained for 2 h. Group 3 (NG): Nitroglycerin was administered immediately after detorsion. Sperm quality parameters such as viability, motility, morphology, and concentration, levels of antioxidant enzymes (glutathione peroxidase (GPX), catalase (CAT), and total antioxidant capacity (TAC)), and amount of malondialdehyde (MDA) in the blood plasma were examined in each group, thereafter histopathological parameters including germinal epithelial cell thickness (GECT), mean seminiferous tubular diameter (MSTD), Johnson's score and Cosentino's score were assessed. RESULTS: Testicular T_D significantly reduced sperm viability, motility, and normal morphology, whereas the NG administration remarkably increased the percentage of live, motile, and normal spermatozoa (p < 0.05). Levels of GPx, CAT, and TAC significantly reduced and the MDA level significantly increased in the T_D group in comparison to the sham group (p < 0.05). The NG treated group demonstrated significantly reduced MDA concentrations as well as elevated levels of GPx and CAT compared to the T_D group (p < 0.05). Induction of testicular torsion significantly reduced Johnson's score, GESCT (µm), and MSTD (µm), and remarkably increased the Cosentino's score (P < 0.05), while NG injection significantly increased Johnson's score, GESCT (µm), and MSTD (µm) and reduced the Cosentino's score (P < 0.05). CONCLUSION: According to the findings in this research, nitroglycerin was able to protect the testicular tissue from ischemia-reperfusion damage caused by induced torsion/detorsion.

The Role of O-GlcNAcylation for Protection against Ischemia-Reperfusion Injury.

Ischemia reperfusion injury (IR injury) associated with ischemic heart disease contributes significantly to morbidity and mortality. O-linked ß-N-acetylglucosamine (O-GlcNAc) is a dynamic posttranslational modification that plays an important role in numerous biological processes, both in normal cell functions and disease. O-GlcNAc increases in response to stress. This increase mediates stress tolerance and cell survival, and is protective. Increasing O-GlcNAc is protective against IR injury. Experimental cellular and animal models, and also human studies, have demonstrated that protection against IR injury by ischemic preconditioning, and the more clinically applicable remote ischemic preconditioning, is associated with increases in O-GlcNAc levels. In this review we discuss how the principal mechanisms underlying tissue protection against IR injury and the associated immediate elevation of O-GlcNAc may involve attenuation of calcium overload, attenuation of mitochondrial permeability transition pore opening, reduction of endoplasmic reticulum stress, modification of inflammatory and heat shock responses, and interference with established cardioprotective pathways. O-GlcNAcylation seems to be an inherent adaptive cytoprotective response to IR injury that is activated by mechanical conditioning strategies.

Melatonin role preventing steatohepatitis and improving liver transplantation results.

Liver steatosis is a prevalent process that is induced due to alcoholic or non-alcoholic intake. During the course of these diseases, the generation of reactive oxygen species, followed by molecular damage to lipids, protein and DMA occurs generating organ cell death. Transplantation is the last-resort treatment for the end stage of both acute and chronic hepatic diseases, but its success depends on ability to control ischemia-reperfusion injury, preservation fluids used, and graft quality. Melatonin is a powerful endogenous antioxidant produced by the pineal gland and a variety of other because of its efficacy in organs; melatonin has been investigated to improve the outcome of organ transplantation by reducing ischemia-reperfusion injury and due to its synergic effect with organ preservation fluids. Moreover, this indolamine also prevent liver steatosis. That is important because this disease may evolve leading to an organ transplantation. This review summarizes the observations related to melatonin beneficial actions in organ transplantation and ischemic-reperfusion models.

The effects of pituitary adenylate cyclase activating polypeptide in renal ischemia/reperfusion.

Pituitary adenylate cyclase activating polypeptide (PACAP ) is a multifunctional neuropeptide occurring in the nervous system as well as in the peripheral organs. Beneficial action of PACAP has been shown in different pathological processes. The strong protective effects of the peptide are probably due to its complex modulatory actions in antiapoptotic, anti-inflammatory and antioxidant pathways. In the kidney, PACAP is protective in models of diabetic nephropathy, myeloma kidney injury, cisplatin-, gentamycin- and cyclosporin-induced damages. Numerous studies have been published describing the protective effect of this peptide in renal ischemia/reperfusion. The present review focuses on the ischemia/reperfusion-induced kidney injury and gives a brief summary about the results published in this area.

Biological implications of extracellular adenosine in hepatic ischemia and reperfusion injury.

The purine nucleoside adenosine is clinically employed in the treatment of supraventricular tachycardia. In addition, it has direct coronary vasodilatory effects, and may influence platelet aggregation. Experimental observations mechanistically link extracellular adenosine to cellular adaptation to hypoxia. Adenosine generation has been implicated in several pathophysiologic processes including angiogenesis, tumor defenses and neurodegeneration. In solid organ transplantation, prolonged tissue ischemia and subsequent reperfusion injury may lead to profound graft dysfunction. Importantly, conditions of limited oxygen availability are associated with increased production of extracellular adenosine and subsequent tissue protection. Within the rapidly expanding field of adenosine biology, several enzymatic steps in adenosine production have been characterized and multiple receptor subtypes have been identified. In this review, we briefly examine the biologic steps involved in adenosine generation and chronicle the current state of adenosine signaling in hepatic ischemia and reperfusion injury.

Protective effects of recombinant human bone morphogenetic protein-7 on focal cerebral ischemia-reperfusion injury.

This study was to investigate the protective effect of recombinant human bone morphogenetic protein-7 (rhBMP-7) on focal cerebral ischemia-reperfusion (IR) injuries and their underlying mechanisms. An intraluminal suture method was used to generate a middle cerebral artery occlusion model in rats, which was followed by reperfusion. A sham operation (SO) group underwent the procedure without occlusion, whereas an IR group and rhBMP-7 treated group (RT) underwent occlusion in the absence and presence of rhBMP-7 (250 µg/kg) administered via a femoral vein injection 30 minutes prior to reperfusion. Twenty-four hours after reperfusion, neurological function, brain water content and morphological alterations were examined. Apoptosis was detected using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assays, and immunohistochemical staining and Western blot assays were used to detect nuclear nuclear factor-kappa B (NF-κB) p65 expression. Compared with the SO group, IR rats showed a decrease in neurological function, an increase in brain water content, and pathological and morphological damage (p < 0.05). Higher levels of apoptosis were also detected in the infarct region area. In contrast, RT rats had reduced injury after IR. In addition, while immunohistochemical staining and western blot assays consistently detected increased expression of nuclear NF-κB after IR, these levels were reduced in the RT group. Administration of rhBMP-7 prior to reperfusion effectively inhibited the extent of IR injury by attenuating cerebral edema and ameliorating ultrastructural damage. The underlying mechanisms responsible for these observations potentially involve the inhibition of apoptosis induced by IR by rhBMP-7 via an NF-κB-related signaling cascade.

Protective effects of passiflora incarnata on ovarian ischemia/reperfusion damage in rats with ovarian torsion.

BACKGROUND: This study aimed to investigate whether Passiflora Incarnata (PI) has a protective effect against ischemia-reperfu-sion (IR)-induced oxidative and inflammatory ovarian damage. METHODS: The effects of PI on ovarian ischemia-reperfusion injury were investigated in female Wistar albino rats. The animals were randomly divided into three groups: Group 1 (sham), Group 2 (IR), and Group 3 (IR+PI). RESULTS: The mean levels of Malondialdehyde (MDA), Myeloperoxidase (MPO), and Total Oxidant Status (TOS) were higher in the IR group (p=0.025, p<0.001, and p=0.016, respectively). The Total Antioxidant Status (TAS) levels were lower in the IR group (p=0.005). Immunostaining revealed significant differences across the groups for Tumor necrosis factor-alpha (TNF-α): 13.84%, 49.51%, and 22.51% for Groups 1, 2, and 3, respectively (p<0.01). Bax: 10.53%, 46.74%, and 26.46% for Groups 1, 2, and 3, respectively (p<0.01). Annexin V: 12.24%, 44.86%, and 23.28% for Groups 1, 2, and 3, respectively (p<0.01). The mean scores for hemorrhage, inflammation, follicular degeneration, and congestion showed significant variations among the groups, all registering p<0.001. CONCLUSION: Passiflora Incarnata exhibited antioxidant, anti-inflammatory, and anti-apoptotic properties, promoting cell survival, histologically protecting ovarian tissue, and ameliorating IR injury by reducing oxidative stress.

Artemisinin reduces acute ovarian ischemia-reperfusion injury in rats.

Artemisinin (ARS) is well known as an effective agent in the treatment of malaria through the rapid elimination of Plasmodium falciparum parasites. This study aims to investigate the effect of ARS in treating adnexal torsion, one of the most common gynecological surgical emergencies. ARS was administered intraperitoneally once 30 min before unilateral ovarian torsion in two different doses (10 mg/kg vs. 50 mg/kg). Torsion was maintained for 3 h and then held in the detorted state for 3 h. Bilateral adnexectomy was performed to measure antioxidant enzyme activities and oxidant levels on the ipsilateral ovary and to make histopathological and immunohistochemical analyses on the contralateral ovary. Ischemia-reperfusion (I/R) injury dramatically upregulated the activities of CAT, GST, and MDA levels in the ipsilateral ovary, which were all downregulated by ARS treatment. A significant increase in follicular cell degeneration, congestion, and edema in the contralateral ovary was seen in the I/R group, which was significantly reduced with ARS treatment. Furthermore, I/R injury resulted in a significant increase in apoptosis as shown by the increased levels of BAX and CASP-3, and decreased levels of BCL-2 whereas ARS significantly reduced the impact of the injury. Our data, based on a rat I/R injury model, show that both ipsilateral and contralateral ovaries are protected with ARS pretreatment, and 50 mg/kg ARS treatment demonstrates to be more effective than the 10 mg/kg ARS.

One Shoot, Two Birds: Alleviating Inflammation Caused by Ischemia/Reperfusion Injury to Reduce the Recurrence of Hepatocellular Carcinoma.

Inflammation is crucial to tumorigenesis and the development of metastasis. Hepatic ischemia/reperfusion injury (IRI) is an unresolved problem in liver resection and transplantation which often establishes and remodels the inflammatory microenvironment in liver. More and more experimental and clinical evidence unmasks the role of hepatic IRI and associated inflammation in promoting the recurrence of hepatocellular carcinoma (HCC). Meanwhile, approaches aimed at alleviating hepatic IRI, such as machine perfusion, regulating the gut-liver axis, and targeting key inflammatory components, have been proved to prevent HCC recurrence. This review article highlights the underlying mechanisms and promising therapeutic strategies to reduce tumor recurrence through alleviating inflammation induced by hepatic IRI.

The protective effect of roflumilast and ibuprofen on testicular ischemia reperfusion injury: An experimental study.

BACKGROUND: The aim of the present study is to investigate the efficiency of roflumilast and ibuprofen in an experimental rat testicular ischemia reperfusion injury model in the light of histological and biochemical data. METHODS: A total of 32 prepubertal male rats were randomly divided into four groups as G1: Control Group (testicular torsion/detorsion + saline (0.9% of 2 ml) was applied). G2: Sham Group only right scrotal incision was performed; G3: Ibuprofen Group (tes-ticular torsion/detorsion + ibuprofen administration); and G4 Roflumilast Group (testicular torsion/detorsion + roflumilast adminis-tration). Oxidative markers such as malondialdehyde (MDA), myeloperoxidase (MPO), total sulfhydryl (TSH), and nitrite (NO) levels as well as histopathological changes were analyzed. RESULTS: Tissue MPO, MDA, and NO levels were significantly higher and TSH levels significantly lower in control group compared to sham group (p<0.001). The histopathologic scores of drug groups (Groups 3 and 4) were significantly lower than group 1 (p<0.001). In comparison of Group 3 and Group 4 with each other, the mean values of MPO and MDA were statistically significantly lower in Group 4 (p<0.001). A higher mean value of TSH was found in Group 3 without statistically significance (p=0.32). There was also an insignificant decrease in mean NO values of Group 3 compared to Group 4 (p=0.44). In comparison of drug groups, Group 4 had statistically insignificant better scores. CONCLUSION: Our results indicate that administrating ibuprofen and roflumilast reduced testicular ischemia reperfusion injury in rat testis torsion model. In comparison, roflumilast is found to be more beneficial.

Role of the PI3K/Akt signaling pathway in liver ischemia reperfusion injury: a narrative review.

OBJECTIVE: To explore the role of phosphatidylinositol-3-kinase/protein kinase B and alpha serine/threonine protein kinase PI3K/PKB (also known as PI3K/Akt) signaling pathway in liver ischemia reperfusion injury. BACKGROUND: The PI3K/Akt signaling pathway is one of the major signal transduction pathways that regulates numerous cellular activities in vivo. The main functions of this pathway include induction of stem cell differentiation and metastasis, promotion of cell proliferation, inhibition of apoptosis, and regulation of tissue inflammation, tumor growth, and invasion. Liver ischemia reperfusion injury is an inevitable clinical problem that can occur during liver transplantation, liver resection, and various circulatory shock events, and it is one of the primary reasons for postoperative liver dysfunction, and poor disease outcome and patient prognosis. In recent years, it has been found that PI3K/Akt signaling pathway is closely related to liver ischemia reperfusion injury. METHODS: In this review, a large number of relevant literatures were collected to explain the biological basis of PI3K/Akt signaling pathway and its role in liver ischemia reperfusion injury. The review was based on a PubMed search using the terms "liver ischemia reperfusion injury", "PI3K/Akt signaling pathway", and "PI3K/Akt signaling pathway AND liver ischemia reperfusion injury", so as to understand the complex interaction between them. CONCLUSIONS: Activated PI3K/Akt signaling pathway can exert anti-inflammatory, antioxidant stress, anti-apoptosis and autophagy regulation effects through downstream related targeted pathways and proteins, thus alleviating liver ischemia-reperfusion injury. Therefore, the regulation of PI3K/Akt signaling pathway is expected to become an effective targeted pathway for clinical prevention and alleviation of liver ischemia reperfusion injury.

Astaxanthin Protects Testicular Tissue against Torsion/Detorsion-Induced Injury via Suppressing Endoplasmic Reticulum Stress in Rats.

BACKGROUND: The aim of this study was to investigate the effects of astaxanthin (ASX) on testicular torsion/detorsion (T/D) damage in rats in terms of oxidative stress and endoplasmic reticulum (ER) stress. METHODS: Eighteen male Sprague-Dawley rats were divided into three groups with six rats in each group: control, T/D and T/D + 20 mg/kg ASX. Torsion and detorsion times were applied as 4 h and 2 h, respectively. ASX application was performed 30 minutes before detorsion. At the end of the period, testicular tissues were removed and biochemical and histological analyzes were performed. To evaluate the degree of oxidative stress, tissue malondialdehyde (MDA), total oxidant status (TOS) and total antioxidant status (TAS) were determined using colorimetric methods, while tissue superoxide dismutase (SOD) levels were determined using ELISA kit. To evaluate the degree of ER stress, tissue glucose regulatory protein 78 (GRP78), activating transcription factor 6 (ATF6) and C/EBP homologous protein (CHOP) levels were determined using ELISA kits. Johnsen's testicle scoring system was used for histological evaluation. RESULTS: In the T/D group, it is determined that statistically significant decreasing in TAS, SOD levels and Johnsen score, and increasing in TOS, OSI, MDA, GRP78, ATF6 and CHOP levels (p < 0.001) compared with control group. ASX administration statistically significantly restored this T/D-induced damage (p < 0.01). CONCLUSION: This is the first study to show that ASX prevent T/D-induced testicular damage through its antioxidant activity. More comprehensive studies are needed to see the underlying mechanisms.

Palmatine Protects against Cerebral Ischemia/Reperfusion Injury by Activation of the AMPK/Nrf2 Pathway.

Palmatine (PAL), a natural isoquinoline alkaloid, possesses extensive biological and pharmaceutical activities, including antioxidative stress, anti-inflammatory, antitumor, neuroprotective, and gastroprotective activities. However, it is unknown whether PAL has a protective effect against ischemic stroke and cerebral ischemia/reperfusion (I/R) injury. In the present study, a transient middle cerebral artery occlusion (MCAO) mouse model was used to mimic ischemic stroke and cerebral I/R injury in mice. Our study demonstrated that PAL treatment ameliorated cerebral I/R injury by decreasing infarct volume, neurological scores, and brain water content. PAL administration attenuated oxidative stress, the inflammatory response, and neuronal apoptosis in mice after cerebral I/R injury. In addition, PAL treatment also decreases hypoxia and reperfusion- (H/R-) induced neuronal injury by reducing oxidative stress, the inflammatory response, and neuronal apoptosis. Moreover, the neuroprotective effects of PAL were associated with the activation of the AMP-activated protein kinase (AMPK)/nuclear factor E2-related factor 2 (Nrf2) pathway, and Nrf2 knockdown offsets PAL-mediated antioxidative stress and anti-inflammatory effects. Therefore, our results suggest that PAL may be a novel treatment strategy for ischemic stroke and cerebral I/R injury.

The Beneficial Effects of Saffron Extract on Potential Oxidative Stress in Cardiovascular Diseases.

Saffron is commonly used in traditional medicines and precious perfumes. It contains pharmacologically active compounds with notably potent antioxidant activity. Saffron has a variety of active components, including crocin, crocetin, and safranal. Oxidative stress plays an important role in many cardiovascular diseases, and its uncontrolled chain reaction is related to myocardial injury. Numerous studies have confirmed that saffron exact exhibits protective effects on the myocardium and might be beneficial in the treatment of cardiovascular disease. In view of the role of oxidative stress in cardiovascular disease, people have shown considerable interest in the potential role of saffron extract as a treatment for a range of cardiovascular diseases. This review analyzed the use of saffron in the treatment of cardiovascular diseases through antioxidant stress from four aspects: antiatherosclerosis, antimyocardial ischemia, anti-ischemia reperfusion injury, and improvement in drug-induced cardiotoxicity, particularly anthracycline-induced. Although data is limited in humans with only two clinically relevant studies, the results of preclinical studies regarding the antioxidant stress effects of saffron are promising and warrant further research in clinical trials. This review summarized the protective effect of saffron in cardiovascular diseases and drug-induced cardiotoxicity. It will facilitate pharmacological research and development and promote utilization of saffron.

Melatonin and its protective role in attenuating warm or cold hepatic ischaemia/reperfusion injury.

Although the liver is the only organ with regenerative capacity, various injury factors induce irreversible liver dysfunction and end-stage liver disease. Liver resection and liver transplantation (LT) are effective treatments for individuals with liver failure, liver cirrhosis and liver cancers. The remnant or transplanted liver tissues will undergo hepatic ischaemia/reperfusion (IR), which leads to oxidative stress, inflammation, immune injury and liver damage. Moreover, systemic ischaemia induced by trauma, stroke, myocardial ischaemia, haemorrhagic shock and other injury factors also induces liver ischaemia/reperfusion injury (IRI) in individuals. Hepatic IRI can be divided into warm IRI, which is induced by liver surgery and systemic ischaemia, and cold IRI, which is induced by LT. Multiple studies have shown that melatonin (MT) acts as an endogenous free radical scavenger with antioxidant capacity and is also able to attenuate hepatic IRI via its anti-inflammatory and antiapoptotic capacities. In this review, we discuss the potential mechanisms and current strategies of MT administration in liver surgery for protecting against warm or cold hepatic IRI. We highlight strategies to improve the efficacy and safety of MT for attenuating hepatic IRI in different conditions. After the potential mechanisms underlying the interactions between MT and other important cellular processes during hepatic IR are clarified, more opportunities will be available to use MT to treat liver diseases in the future.