Environmental stimulus-responsive mesoporous silica nanoparticles as anticancer drug delivery platforms.

Currently, cancer poses a significant health challenge in the medical community. Traditional chemotherapeutic agents are often accompanied by toxic side effects and limited therapeutic efficacy, restricting their application and advancement in cancer treatment. Therefore, there is an urgent need for developing intelligent drug release systems. Mesoporous silica nanoparticles (MSNs) have many advantages, such as a large specific surface area, substantial pore volume and size, adjustable mesoporous material pore size, excellent biocompatibility, and thermodynamic stability, making them ideal carriers for drug delivery and release. Additionally, they have been widely used to develop novel anticancer drug carriers. Recently, MSNs have been employed to design responsive systems that react to the tumor microenvironment and external stimuli for controlled release of anticancer drugs. This includes factors within the intratumor environment, such as pH, temperature, enzymes, and glutathione as well as external tumor stimuli, such as light, magnetic field, and ultrasound, among others. In this review, we discuss the research progress on environmental stimulus-responsive MSNs in anticancer drug delivery systems, including internal and external environment single stimulus-responsive release and combined stimulus-responsive release. We also summarize the current challenges associated with environmental stimulus-responsive MSNs and elucidate future directions, providing a reference for the functionalization modification and practical application of these MSNs.

Dual effects of endogenous formaldehyde on the organism and drugs for its removal.

Endogenous formaldehyde (FA) is produced in the human body via various mechanisms to preserve healthy energy metabolism and safeguard the organism. However, endogenous FA can have several negative effects on the body through epigenetic alterations, including cancer growth promotion; neuronal, hippocampal and endothelial damages; atherosclerosis acceleration; haemopoietic stem cell destruction and haemopoietic cell production reduction. Certain medications with antioxidant effects, such as glutathione, vitamin E, resveratrol, alpha lipoic acid and polyphenols, lessen the detrimental effects of endogenous FA by reducing oxidative stress, directly scavenging endogenous FA or promoting its degradation. This study offers fresh perspectives for managing illnesses associated with endogenous FA exposure.

Effects of Shenling Baizhu powder on intestinal microflora metabolites and liver mitochondrial energy metabolism in nonalcoholic fatty liver mice.

Background & purpose: Non-alcoholic fatty liver disease (NAFLD) is characterised by the excessive accumulation of triglycerides in the liver. Shenling Baizhu powder (SLBZP) is formulated from various natural medicinal plants that protect the liver and are used to treat intestinal diseases. SLBZP improves the symptoms of NAFLD. However, its mechanism of action remains unclear. Herein, we investigated the ameliorative effect of SLBZP on model mice with high-fat-diet (HFD)-induced NAFLD. Additionally, we evaluated the impact of SLBZP on the intestinal flora and its metabolites and mitochondrial energy metabolism in NAFLD. Methods: We used HFD to establish a mouse model of NAFLD. Different drug interventions were administered. We measured serum biochemical indices. Liver sections were visualised with hematoxylin-eosin and oil red O staining. 16S rDNA amplicon sequencing technology was used to analyse the diversity and abundance of the intestinal flora. Short-chain fatty acids (SCFAs) in the intestinal contents were detected using GC-MS. Liver tissue was sampled to detect mitochondrial membrane functional indices. Western blotting was used to determine the levels of mitochondrial pathway-related proteins, namely, uncoupling protein 2 (UCP2), adenosine monophosphate-activated protein kinase (AMPK) and inhibitory factor 1 (IF1) of F1Fo ATP synthesis/hydrolase, in the liver. Results: The spleen-invigorating classic recipe of SLBZP reduced liver lipid deposition in mice with HFD-induced NAFLD. Additionally, SCFAs produced by intestinal flora metabolism regulated the UCP2/AMPK/IF1 signalling pathway involved in liver mitochondrial energy metabolism to improve the liver mitochondrial membrane permeability, respiratory state and oxidative phosphorylation efficiency of mice with NAFLD. Finally, SLBZP increased the liver ATP level. Conclusion: Our results suggest that the therapeutic effect of SLBZP on NAFLD is related to the regulation of hepatic mitochondrial energy metabolism by intestinal flora and its metabolites and is possibly associated with the UCP2/AMPK/IF1 signalling pathway.

A multifunctional nanocomposite coated with a BSA membrane for cascaded nitric oxide therapy.

Gas therapy based on nitric oxide (NO) has emerged as a potential therapeutic approach for cancer, and in conjunction with multi-mode combination therapy, offers new possibilities for achieving significant hyperadditive effects. In this study, an integrated AI-MPDA@BSA nanocomposite for diagnosis and treatment was constructed for PDA based photoacoustic imaging (PAI) and cascade NO release. Natural NO donor L-arginine (L-Arg) and photosensitizer (PS) IR780 were loaded into mesoporous polydopamine (MPDA). Bovine serum albumin (BSA) was conjugated to the MPDA to increase the dispersibility and biocompatibility of the nanoparticles, as well as to serve as a gatekeeper controlling IR780 release from the MPDA pores. The AI-MPDA@BSA produced singlet oxygen (1O2) and converted it into NO through a chain reaction based on L-Arg, enabling a combination of photodynamic therapy and gas therapy. Moreover, due to the photothermal properties of MPDA, the AI-MPDA@BSA performed good photothermal conversion, which allowed photoacoustic imaging. As expected, both in vitro and in vivo studies have confirmed that the AI-MPDA@BSA nanoplatform has a significant inhibitory effect on cancer cells and tumors, and no apparent systemic toxicity or side effects were detected during the treatment period.

[Advances in traditional Chinese medicine treatment of non-alcoholic fatty liver disease via farnesoid X receptor].

Non-alcoholic fatty liver disease(NAFLD) is a chronic metabolic condition with rapidly increasing incidence, becoming a public health issue of worldwide concern. Studies have shown that farnesoid X receptor(FXR)-based modulation of downstream targets can improve liver function and metabolic status in the patients with NAFLD and may be a potential drug target for treating this di-sease. Great progress has been achieved in the development of drugs targeting FXR for the treatment of NAFLD. A number of studies have explored the traditional Chinese medicine and their active ingredients for the treatment of NAFLD via FXR considering the high safety and efficacy and mild side effects. This paper systematically describes the mechanism of traditional Chinese medicines in the treatment of NAFLD via FXR and the downstream targets, aiming to provide precise targets for the drug development and clinical treatment of NAFLD.

[Prevention and treatment of non-alcoholic fatty liver disease by regulation of mitochondrial function with Chinese medicine].

Non-alcoholic fatty liver disease(NAFLD), as a metabolic stress liver injury disease, is one of the most common chronic liver diseases, which seriously threatens people's health. The pathogenesis of NAFLD is very complex. A large number of studies show that the hepatic mitochondrial dysfunction leads to the disorder of hepatic glucose and lipid metabolism, oxidative stress, and inflammation, thus inducing hepatocyte apoptosis, which plays an important role in the progression of NAFLD. In recent years, researchers have begun to focus on developing drugs that slowed the progression of NAFLD by regulating the hepatic mitochondrial function. Chinese medicine has a good curative effect on the treatment of NAFLD, with the advantages of high safety and few side effects. Various studies have shown that Chinese medicine prevented and treated NAFLD by regulating the mitochondrial function. Therefore, this paper summarized the relationship between NAFLD and mitochondria, and the mechanism of Chinese medicine(single Chinese medicine, Chinese medicine monomer, and Chinese medicine compound prescription) in the prevention and treatment of NAFLD by regulating mitochondrial function. This paper is expected to provide references for clinical application of traditional Chinese medicine in the treatment of NAFLD by regulating mitochondrial function.

Nanomaterials Respond to Lysosomal Function for Tumor Treatment.

The safety and efficacy of tumor treatment are difficult problems to address. Recently, lysosomes have become an important target for tumor treatment because of their special environment and function. Nanoparticles have unique physicochemical properties which have great advantages in tumor research. Therefore, in recent years, researchers have designed various types of nanoparticles to treat tumors based on lysosomal function and environment. In this review, we summarize and analyze different perspectives of tumor treatment, including direct destruction of lysosomes or lysosomal escape, drug delivery by nanoparticles, response to endogenous or exogenous stimuli, and the targeting of tumor cells or other cells. We describe the advantages and disadvantages of these approaches as well as the developmental prospects in this field. We hope to provide new ideas for better tumor treatment.

Platelet-Activating Factor Promotes the Development of Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a multifaceted clinicopathological syndrome characterised by excessive hepatic lipid accumulation that causes steatosis, excluding alcoholic factors. Platelet-activating factor (PAF), a biologically active lipid transmitter, induces platelet activation upon binding to the PAF receptor. Recent studies have found that PAF is associated with gamma-glutamyl transferase, which is an indicator of liver disease. Moreover, PAF can stimulate hepatic lipid synthesis and cause hypertriglyceridaemia. Furthermore, the knockdown of the PAF receptor gene in the animal models of NAFLD helped reduce the inflammatory response, improve glucose homeostasis and delay the development of NAFLD. These findings suggest that PAF is associated with NAFLD development. According to reports, patients with NAFLD or animal models have marked platelet activation abnormalities, mainly manifested as enhanced platelet adhesion and aggregation and altered blood rheology. Pharmacological interventions were accompanied by remission of abnormal platelet activation and significant improvement in liver function and lipids in the animal model of NAFLD. These confirm that platelet activation may accompany a critical importance in NAFLD development and progression. However, how PAFs are involved in the NAFLD signalling pathway needs further investigation. In this paper, we review the relevant literature in recent years and discuss the role played by PAF in NAFLD development. It is important to elucidate the pathogenesis of NAFLD and to find effective interventions for treatment.

Cu2+-Chelating Mesoporous Silica Nanoparticles for Synergistic Chemotherapy/Chemodynamic Therapy.

In this study, a pH-responsive controlled-release mesoporous silica nanoparticle (MSN) formulation was developed. The MSNs were functionalized with a histidine (His)-tagged targeting peptide (B3int) through an amide bond, and loaded with an anticancer drug (cisplatin (CP)) and a lysosomal destabilization mediator (chloroquine (CQ)). Cu2+ was then used to seal the pores of the MSNs via chelation with the His-tag. The resultant nanoparticles showed pH-responsive drug release, and could effectively target tumor cells via the targeting effect of B3int. The presence of CP and Cu2+ permits reactive oxygen species to be generated inside cells; thus, the chemotherapeutic effect of CP is augmented by chemodynamic therapy. In vitro and in vivo experiments showed that the nanoparticles are able to effectively kill tumor cells. An in vivo cancer model revealed that the nanoparticles increase apoptosis in tumor cells, and thereby diminish the tumor volume. No off-target toxicity was noted. It thus appears that the functionalized MSNs developed in this work have great potential for targeted, synergistic anticancer therapies.

Literature Review on the Use of Herbal Extracts in the Treatment of Non- Alcoholic Fatty Liver Disease.

BACKGROUND: Non-alcoholic fatty liver disease is a common chronic liver injury disease, and its incidence is rapidly increasing across the globe, thus becoming a serious threat to human health. So far, the clinical prevention and treatment of non-alcoholic fatty liver disease mainly include single-targeted drug therapy, surgical treatment and lifestyle changes. However, these treatments cannot completely address the complex pathogenesis of non-alcoholic fatty liver disease and have various side effects. Recent studies reveal that many herbal extracts are found to have potential anti-non-alcoholic fatty liver disease activities. OBJECTIVE: This paper presents a review on herbal extracts used for the treatment of non-alcoholic fatty liver disease in experimental studies to provide a theoretical basis for their clinical application in the treatment of non-alcoholic fatty liver disease and for new drug development. METHODS: Scientific papers were retrieved by searching the PubMed database up to Feb 2021 using the following keywords: 'non-alcoholic fatty liver disease', 'herbal extracts' ('flavonoids', 'saponins', 'quinones', 'phenolic compounds', 'alkaloids', 'polysaccharides', 'ginkgolide B', 'schizandrin B', 'ursolic acid') and 'mechanism'. RESULTS: The pharmacological effects and mechanisms of many herbal extracts can reverse the adverse health effects of non-alcoholic fatty liver disease. CONCLUSION: In vitro and in vivo experimental studies indicated that herbal extracts can improve the symptoms of non-alcoholic fatty liver disease by inhibiting inflammation, antioxidant stress, improvement of lipid metabolism and insulin sensitivity and regulating intestinal bacteria flora. However, there needs to be sufficient data from human clinical trials to prove their efficacy and safety.

Construction of Biomimetic-Responsive Nanocarriers and their Applications in Tumor Targeting.

BACKGROUND: At present, tumors are leading cause of death. Biomimetic nanocarriers for precision cancer therapy are attracting increasing attention. Nanocarriers with a good biocompatible surface could reduce the recognition and elimination of nanoparticles as foreign substances by the immune system, offer specific targeting, and improve the efficacy of precision medicine for tumors, thereby providing outstanding prospects for application in cancer therapy. In particular, cell membrane biomimetic camouflaged nanocarriers have become a research hotspot because of their excellent biocompatibility, prolonged circulation in the blood, and tumor targeting. OBJECTIVE: The objective of this study is to summarize the biological targeting mechanisms of different cell membraneencapsulated nanocarriers in cancer therapy. In this article, the characteristics, applications, and stages of progress of bionic encapsulated nanocarriers for different cell membranes are discussed, as are the field's developmental prospects. METHODS: The findings on the characteristics of bionic encapsulated nanocarriers for different cell membranes and tumor treatment have been analyzed and summarized. RESULTS: Biomimetic nanosystems based on various natural cell and hybrid cell membranes have been shown to efficiently control targeted drug delivery systems. They can reduce immune system clearance, prolong blood circulation time, and improve drug loading and targeting, thereby enhancing the diagnosis and treatment of tumors and reducing the spread of CTCs. CONCLUSION: With advances in the development of biomimetic nanocarrier DDSs, novel ideas for tumor treatment and drug delivery have been emerged. However, there are still some problems in biomimetic nanosystems. Therefore, it needs to be optimized through further research, from the laboratory to the clinic to benefit a wide range of patients.

Novel glucose-responsive nanoparticles based on p-hydroxyphenethyl anisate and 3-acrylamidophenylboronic acid reduce blood glucose and ameliorate diabetic nephropathy.

An insulin delivery system that self-regulates blood sugar levels, mimicking the human pancreas, can improve hyperglycaemia. At present, a glucose-responsive insulin delivery system combining AAPBA with long-acting slow release biomaterials has been developed. However, the safety of sustained-release materials and the challenges of preventing diabetic complications remain. In this study, we developed a novel polymer slow release material using a plant extract-p-hydroxyphenylethyl anisate (HPA). After block copolymerisation with AAPBA, the prepared nanoparticles had good pH sensitivity, glucose sensitivity, insulin loading rate and stability under physiological conditions and had high biocompatibility. The analysis of streptozotocin-induced diabetic nephropathy (DN) mouse model showed that the insulin-loaded injection of nanoparticles stably regulated the blood glucose levels of DN mice within 48 â€‹h. Importantly, with the degradation of the slow release material HPA in vivo, the renal function improved, the inflammatory response reduced, and antioxidation levels in DN mice improved. This new type of nanoparticles provides a new idea for hypoglycaemic nano-drug delivery system and may have potential in the prevention and treatment of diabetic complications.

Downregulation of ATP1A1 Expression by Panax notoginseng (Burk.) F.H. Chen Saponins: A Potential Mechanism of Antitumor Effects in HepG2 Cells and In Vivo.

The Na+/K+-ATPase α1 subunit (ATP1A1) is a potential target for hepatic carcinoma (HCC) treatment, which plays a key role in Na+/K+ exchange, metabolism, signal transduction, etc. In vivo, we found that Panax notoginseng saponins (PNS) could inhibit tumor growth and significantly downregulate the expression and phosphorylation of ATP1A1/AKT/ERK in tumor-bearing mice. Our study aims to explore the potential effects of PNS on the regulation of ATP1A1 and the possible mechanisms of antitumor activity. The effects of PNS on HepG2 cell viability, migration, and apoptosis were examined in vitro. Fluorescence, Western blot, and RT-PCR analyses were used to examine the protein and gene expression. Further analysis was assessed with a Na+/K+-ATPase inhibitor (digitonin) and sorafenib in vitro. We found that the ATP1A1 expression was markedly higher in HepG2 cells than in L02 cells and PNS exhibited a dose-dependent effect on the expression of ATP1A and the regulation of AKT/ERK signaling pathways. Digitonin did not affect the expression of ATP1A1 but attenuated the effects of PNS on the regulation of ATP1A1/AKT/ERK signaling pathways and enhanced the antitumor effect of PNS by promoting nuclear fragmentation. Taken together, PNS inhibited the proliferation of HepG2 cells via downregulation of ATP1A1 and signal transduction. Our findings will aid a data basis for the clinical use of PNS.

Nanoparticles prepared from pterostilbene reduce blood glucose and improve diabetes complications.

BACKGROUND: Diabetes complications are the leading cause of mortality in diabetic patients. The common complications are decline in antioxidant capacity and the onset of micro-inflammation syndrome. At present, glucose-responsive nanoparticles are widely used, as they can release insulin-loaded ultrafine particles intelligently and effectively reduce blood sugar. However, the toxicology of this method has not been fully elucidated. The plant extracts of pterostilbene (PTE) have a wide range of biological applications, such as antioxidation and inflammatory response improvement. Therefore, we have proposed new ideas for the cross application of plant extracts and biomaterials, especially as part of a hypoglycaemic nano-drug delivery system. RESULTS: Based on the PTE, we successfully synthesised poly(3-acrylamidophenyl boric acid-b-pterostilbene) (p[AAPBA-b-PTE]) nanoparticles (NPs). The NPs were round in shape and ranged between 150 and 250 nm in size. The NPs possessed good pH and glucose sensitivity. The entrapment efficiency (EE) of insulin-loaded NPs was approximately 56%, and the drug loading (LC) capacity was approximately 13%. The highest release of insulin was 70%, and the highest release of PTE was 85%. Meanwhile, the insulin could undergo self-regulation according to changes in the glucose concentration, thus achieving an effective, sustained release. Both in vivo and in vitro experiments showed that the NPs were safe and nontoxic. Under normal physiological conditions, NPs were completely degraded within 40 days. Fourteen days after mice were injected with p(AAPBA-b-PTE) NPs, there were no obvious abnormalities in the heart, liver, spleen, lung, or kidney. Moreover, NPs effectively reduced blood glucose, improved antioxidant capacity and reversed micro-inflammation in mice. CONCLUSIONS: p(AAPBA-b-PTE) NPs were successfully prepared using PTE as raw material and effectively reduced blood glucose, improved antioxidant capacity and reduced the inflammatory response. This novel preparation can enable new combinations of plant extracts and biomaterials to adiministered through NPs or other dosage forms in order to regulate and treat diseases.

Bioresponsive Functional Phenylboronic Acid-Based Delivery System as an Emerging Platform for Diabetic Therapy.

The glucose-sensitive self-adjusting drug delivery system simulates the physiological model of the human pancreas-secreting insulin and then precisely regulates the release of hypoglycemic drugs and controls the blood sugar. Thus, it has good application prospects in the treatment of diabetes. Presently, there are three glucose-sensitive drug systems: phenylboronic acid (PBA) and its derivatives, concanavalin A (Con A), and glucose oxidase (GOD). Among these, the glucose-sensitive polymer carrier based on PBA has the advantages of better stability, long-term storage, and reversible glucose response, and the loading of insulin in it can achieve the controlled release of drugs in the human environment. Therefore, it has become a research hotspot in recent years and has been developed very rapidly. In order to further carry out a follow-up study, we focused on the development process, performance, and application of PBA and its derivatives-based glucose-sensitive polymer drug carriers, and the prospects for the development of this field.

Glucose-Sensitive Nanoparticles Based On Poly(3-Acrylamidophenylboronic Acid-Block-N-Vinylcaprolactam) For Insulin Delivery.

BACKGROUND: Compared with random copolymers, block copolymerization is easier to prepare for nanoparticles with core-shell structure, and they will have better glucose sensitivity and higher insulin loading. PURPOSE: In our study, insulin-loaded poly (3-acrylamidophenylboronic acid-block-N-vinyl caprolactam) p(AAPBA-b-NVCL) nanoparticles were successfully prepared and were glucose-sensitive, which could effectively lower the blood sugar levels within 72 hrs. METHODS: The polymer of p(AAPBA-b-NVCL) was produced by reversible addition-fragmentation chain transfer polymerization based on different ratios of 3-acrylamidophenylboronic acid (AAPBA) and N-vinylcaprolactam (NVCL), and its structure was discussed by Fourier transform infrared spectroscopy and 1H-nuclear magnetic resonance . Next, the polymer was manufactured into the nanoparticles, and the characteristics of nanoparticles were detected by dynamic light scattering, lower critical solution temperature, and transmission electron microscopy. After that, the cell and animal toxicity of nanoparticles were also investigated. RESULTS: The results demonstrated that p(AAPBA-b-NVCL) was successfully synthesized, and can be easily self-assembled to form nanoparticles. The new nanoparticles included monodisperse submicron particles, with the size of the nanoparticle ranged between 150 and 300nm and are glucose- and temperature-sensitive. Meanwhile, insulin can be easily loaded by p(AAPBA-b-NVCL) nanoparticles and an effective sustained release of insulin was observed when the nanoparticles were placed in physiological saline. Besides, MTT assay revealed that cell viability was more than 80%, and mice demonstrated no negative impact on blood biochemistry and heart, liver, spleen, lung, and kidney after intraperitoneal injection of 10 mg/kg/d of nanoparticles. This suggested that the nanoparticles were low-toxic to both cells and animals. Moreover, they could lower the blood sugar level within 72h. CONCLUSION: Our research suggested that these p(AAPBA-b-NVCL) nanoparticles might have the potential to be applied in a delivery system for insulin or other hypoglycemic proteins.

Discovery of rafoxanide as a dual CDK4/6 inhibitor for the treatment of skin cancer.

Since cyclin­dependent kinases 4/6 (CDK4/6) play pivotal roles in cell cycle regulation and are overexpressed in human skin cancers, CDK4/6 inhibitors are potentially effective drugs for skin cancer. In the present study, we present a mixed computational and experimental study attempting to repurpose approved small­molecule drugs as dual CDK4/6 inhibitors for skin cancer treatment. We performed structure­based virtual screening using the docking software idock, targeting an ensemble of CDK4/6 structures. We identified and selected nine compounds with significant predicted scores, and evaluated their cytotoxic effects in vitro in A375 and A431 human skin cancer cell lines. Rafoxanide was found to exhibit the highest cytotoxic effects (IC50: 1.09 µM for A375 and 1.31 µM for A431 cells). Consistent with the expected properties of CDK4/6 inhibitors, rafoxanide significantly increased the G1 phase population. Notably, we revealed that rafoxanide specifically decreased the expression of CDK4/6, cyclin D, retinoblastoma protein (Rb) and the phosphorylation of CDK4/6 and Rb. Furthermore, the anticancer effect of rafoxanide was demonstrated in vivo in BALB/C nude mice subcutaneously xenografted with human skin cancer A375 cells. Rafoxanide (40 mg/kg, i.p.) exhibited significant antitumor activity, comparable to that of oxaliplatin (5 mg/kg, i.p.). The combined administration of rafoxanide and oxaliplatin produced a synergistic therapeutic effect. To the best of our knowledge, the present study is the first to indicate that rafoxanide inhibits CDK4/6 activity and is a potential candidate drug for the treatment of human skin cancer.

Tetrahydrobiopterin ameliorates hepatic ischemia-reperfusion Injury by coupling with eNOS in mice.

BACKGROUND: In the liver, eNOS appears to have a central role in protecting against ischemia/reperfusion (I/R) injury. We hypothesized that tetrahydrobiopterin (BH4) would protect livers subjected to I/R injury by coupling with eNOS. METHODS: Chinese Kun Ming (KM) mice were subjected to 60 min of 70% hepatic ischemia 30 min after the administration of BH4 or saline. After reperfusion, survival was evaluated. The histologic appearance and ALT, BH4, nitrite/nitrate, 8-isoprostane, and eNOS protein expression levels were measured. RESULTS: The 1-wk survival rate was 66.67% in the BH4 group and 33.33% in the saline group. The serum ALT values in the BH4 group 1, 3, 6, 12, and 24 h after reperfusion were significantly lower than those of the saline group. A histologic examination of the liver revealed only a small necrotic area in the BH4 group as opposed to massive necrosis in the saline group. The percentage values of the hepatic necrotic area 24 h after reperfusion were significantly less for the BH4 group than for the saline group. The nitrite/nitrate levels in the liver tissue were significantly increased by ~2-fold in the BH4 group compared with the saline group. The free radical indicator 8-isoprostane was reduced approximately 50% in the BH4 group compared with the saline group. Western blotting showed that the level of eNOS protein between the groups was not significantly different. CONCLUSIONS: BH4 significantly improved the survival rate by reducing liver failure. This was supported by the histologic findings, and the mechanism was explored. According to the results, we suggest that BH4 prevents liver damage from I/R injury by attenuating reactive oxygen species and increasing NO synthesis, and might provide a novel and promising therapeutic option for preventing I/R injury.