Probing the hierarchical dynamics of DNA-sperm nuclear transition protein complexes through fuzzy interaction and mesoscale condensation.

Nuclear transition protein TNP1 is a crucial player mediating histone-protamine exchange in condensing spermatids. A unique combination of intrinsic disorder and multivalent properties turns TNP1 into an ideal agent for orchestrating the formation of versatile TNP-DNA assemblies. Despite its significance, the physicochemical property and the molecular mechanism followed by TNP1 for histone replacement and DNA condensation are still poorly understood. This study reports the first-time in vitro expression and purification of human TNP1 and investigates the hierarchical dynamics of TNP1-DNA interaction using a combination of computational simulations, biochemical assays, fluorescence imaging, and atomic force microscopy. We explored three crucial facets of TNP1-DNA interactions. Initially, we delve into the molecular binding process that entails fuzzy interactions between TNP1 and DNA at the atomistic scale. Subsequently, we analyze how TNP1 binding affects the electrostatic and mechanical characteristics of DNA and influences its morphology. Finally, we study the biomolecular condensation of TNP1-DNA when subjected to high concentrations. The findings of our study set the foundation for comprehending the potential involvement of TNP1 in histone replacement and DNA condensation in spermatogenesis.

Raf promotes dimerization of the Ras G-domain with increased allosteric connections.

Ras dimerization is critical for Raf activation. Here we show that the Ras binding domain of Raf (Raf-RBD) induces robust Ras dimerization at low surface densities on supported lipid bilayers and, to a lesser extent, in solution as observed by size exclusion chromatography and confirmed by SAXS. Community network analysis based on molecular dynamics simulations shows robust allosteric connections linking the two Raf-RBD D113 residues located in the Galectin scaffold protein binding site of each Raf-RBD molecule and 85 Å apart on opposite ends of the dimer complex. Our results suggest that Raf-RBD binding and Ras dimerization are concerted events that lead to a high-affinity signaling complex at the membrane that we propose is an essential unit in the macromolecular assembly of higher order Ras/Raf/Galectin complexes important for signaling through the Ras/Raf/MEK/ERK pathway.

A proteome-scale analysis of vertebrate protein amino acid occurrence: Thermoadaptation shows a correlation with protein solvation but less so with dynamics.

Despite differences in behaviors and living conditions, vertebrate organisms share the great majority of proteins, often with subtle differences in amino acid sequence. Here, we present a simple way to analyze the difference in amino acid occurrence by comparing highly homologous proteins on a subproteome level between several vertebrate model organisms. Specifically, we use this method to identify a pattern of amino acid conservation as well as a shift in amino acid occurrence between homeotherms (warm-blooded species) and poikilotherms (cold-blooded species). Importantly, this general analysis and a specific example further establish a broad correlation, if not likely connection between the thermal adaptation of protein sequences and two of their physical features: on average a change in their protein dynamics and, even more strongly, in their solvation. For poikilotherms, such as frog and fish, the lower body temperature is expected to increase the protein-protein interaction due to a decrease in protein internal dynamics. In order to counteract the tendency for enhanced binding caused by low temperatures, poikilotherms enhance the solvation of their proteins by favoring polar amino acids. This feature appears to dominate over possible changes in dynamics for some proteins. The results suggest that a general trend for amino acid choice is part of the mechanism for thermoadaptation of vertebrate organisms at the molecular level.

Laparoscopic versus open central pancreatectomy: a propensity score-matched analysis in a single centre.

PURPOSE: Laparoscopic central pancreatectomy (LCP) has been implemented in pancreatic surgery; however, open surgery is still the predominant approach for central pancreatectomy (CP). Our objective was to compare LCP with open CP (OCP). METHODS: Data were collected from patients with tumours located in the pancreatic neck and proximal body who underwent CP in the Department of Pancreatic Surgery West China Hospital from January 1, 2010, to June 30, 2019. A comparison between the LCP and OCP groups was performed. RESULTS: Fifteen patients underwent CP via the laparoscopic approach, and 96 patients underwent CP via the open approach. Using 1:2 propensity score matching (PSM), 12 patients in the LCP group were matched to 21 in the OCP group. Regarding safety, postoperative pancreatic fistula (POPF) was not significantly different between the two groups (13.3% vs. 12.5%, P = 1.000), even with PSM (16.7% vs. 14.3%, P = 1.000). However, regarding effectiveness, the operative time in the OCP group was significantly shorter than that in the LCP group before (307.0 ± 92.3 ml vs. 220.6 ± 63.6 ml, P < 0.000) and after (300.3 ± 90.2 ml vs. 212.7 ± 44.4 ml, P = 0.002) PSM. Regarding length of stay (LOS), there was no difference between the two groups before (13.1 ± 13.7 days vs. 12.7 ± 10.1 days, P = 0.376) and after PSM (14.4 ± 15.1 days vs. 14.5 ± 16.2 days, P = 0.985). The length of the resected pancreas was shorter in the OCP group than in the LCP group before PSM (50.0 ± 13.2 mm vs. 41.1 ± 11.1 mm, P = 0.043). However, there was no difference between the two groups after PSM (47.9 ± 12.5 mm vs. 37.9 ± 10.4 mm, P = 0.084). Moreover, the other variables showed no difference between the two groups before and after PSM. CONCLUSION: LCP can demonstrate similar safety and effectiveness to OCP, even in the early stages of the learning curve.

LncRNA GAS8-AS1 is a Novel Prognostic and Diagnostic Biomarker for Pancreatic Cancer.

BACKGROUND: LncRNA GAS8-AS1 inhibits thyroid carcinoma, but its function in other malignancies is unknown. The present study aimed to investigate the involvement of GAS8-AS1 in pancreatic cancer (PC). METHODS: The present study included 68 PC patients (38 males and 30 females, 42-66 years, 52.1 ± 4.5) and 62 healthy volunteers (28 males and 24 females, 43-67 years, 52.3 ± 4.9). Real-time quantitative PCR, transient cell transfection, and in vitro cell migration and invasion assays were applied for the research. RESULTS: The study showed that plasma GAS8-AS1 was lower in PC patients than in healthy controls. Downregulation of plasma GAS8-AS1 distinguished early-stage PC patients from healthy controls. Patients with low GAS8-AS1 plasma levels showed a significantly lower 5-year overall survival rate. Plasma miR-1179 levels were also significantly lower in PC patients than in healthy controls and were positively correlated with plasma GAS8-AS1 levels in PC patients but not healthy controls. GAS8-AS1 overexpression upregulated miR-1179, and MiR-1179 overexpression increased GAS8-AS1 level. Overexpression of both GAS8-AS1 and miR-1179 inhibited PC cell migration and invasion. CONCLUSION: GAS8-AS1 may promote PC by positively interacting with miR-1179.

Plexin-Bs enhance their GAP activity with a novel activation switch loop generating a cooperative enzyme.

Plexins receive guidance cues from semaphorin ligands and transmit their signal through the plasma membrane. This family of proteins is unique amongst single-pass transmembrane receptors as their intracellular regions interact directly with several small GTPases, which regulate cytoskeletal dynamics and cell adhesion. Here, we characterize the GTPase Activating Protein (GAP) function of Plexin-B1 and find that a cooperative GAP activity towards the substrate GTPase, Rap1b, is associated with the N-terminal Juxtamembrane region of Plexin-B1. Importantly, we unveil an activation mechanism of Plexin-B1 by identifying a novel functional loop which partially blocks Rap1b entry into the plexin GAP domain. Consistent with the concept of allokairy developed for other systems, Plexin-B activity is increased by an apparent substrate-mediated cooperative effect. Simulations and mutagenesis suggest the repositioned JM conformation is stabilized by the new activation switch loop when the active site is occupied, giving rise to faster enzymatic turnover and cooperative behavior. The biological implications, essentially those of a threshold behavior for cell migration, are discussed.

[Variation of COL7A1 gene in dystrophic epidermolysis bullosa pruriginosa].

OBJECTIVE: To perform gene mutation analysis in a Chinese pedigree with dystrophic epidermolysis bullosa pruriginosa (DEB-Pr), and explore phetotype, genotype, and genotypes-phenotypes relationship of DEB-Pr. METHODS: Potential variants of the COL7A1 gene were detected by skin targeted sequencing panel and verified by Sanger sequencing. The pathogenicity of the variation was analyzed. RESULTS: Compound heterozygous variants, c.4128delT and c.8234G>A, were detected in the COL7A1 gene of the two patients. The c.4128delT(p.Pro1376fs) variant was derived from their mother and unreported previously. According to the American College of Medical Genetics and Genomics Standards and Guidelines, it was suggested to be a pathogenic mutation. The c.8234G>A(p.Arg2745Gln) variant was derived from their father, and possibly is a pathogenic variation. CONCLUSION: In this study, the compound heterozygous variants of c.4128delT(p.Pro1376fs) and c.8234G>A(p.Arg2745Gln) of the COL7A1 gene probably underlies the disease in this patient and his sister. And our study expands the database on mutations of DEB-Pr.

Neuropilin-1 assists SARS-CoV-2 infection by stimulating the separation of Spike protein S1 and S2.

The cell surface receptor Neuropilin-1 (Nrp1) was recently identified as a host factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry. The Spike protein of SARS-CoV-2 is cleaved into two segments, the S1 (residues (res.) 1-685) and the S2 (res. 686-1273) domains by furin protease. Nrp1 predominantly binds to the C-terminal RRAR amino acid motif (res. 682-685) of the S1 domain. In this study, we firstly modeled the association of an Nrp1 protein (consisting of domains a2-b1-b2) with the Spike protein. Next, we studied the separation of S2 from the S1 domain, with and without Nrp1 bound, by utilizing molecular dynamics pulling simulations. During the separation, Nrp1 stabilizes the S1 C-terminal region (res. 640-685) and thereby assists the detachment of S2 N-terminal region (res. 686-700). Without Nrp1 bound, S1 tends to become stretched, whereas the bound Nrp1 stimulates an earlier separation of S2 from the S1 domain. The liberated S2 domain is known to mediate the fusion of virus and host membranes; thus, Nrp1 likely increases virus infectivity by facilitating the S1 and S2 separation. We further analyzed the possible topological structure of the SARS-CoV-2 Spike protein when bound with Nrp1 and angiotensin-converting enzyme 2 (ACE2). Understanding of such an Nrp1-assisted viral infection opens the gate for the generation of protein-protein inhibitors, such as antibodies, which could attenuate the infection mechanism and protect certain cells in a future Nrp1-ACE2 targeted combination therapy.

[Genetic testing and genotype-phenotype analysis for a child with X-linked hypohidrotic ectodermal dysplasia].

OBJECTIVE: To carry out genetic testing for a Chinese patient with X-linked hypohidrotic ectodermal dysplasia (XLHED) and explore its genotype-phenotype correlation. METHODS: Clinical data of the patient was collected. Peripheral blood samples were taken from the patient, his parents and 100 unrelated healthy controls. Genetic variants were detected by using next-generation sequencing using a skin-disease panel through targeted capture and next generation sequencing. Candidate variant was verified by Sanger sequencing. All literature related to genetic testing of XLHED patients in China was searched in the database, and the genotypes and phenotypes of patients in the literature and the correlation between them were statistically analyzed. RESULTS: A novel splice site variant c.655_689del was detected in the patient but not among his parents and the 100 unrelated healthy controls. So far 61 variants of the EDA gene have been identified among Chinese patients with XLHED, which suggested certain degree of genotype-phenotype correlation. CONCLUSION: A novel c.655_689del variant has been identified in the EDA gene, which has expanded the spectrum of EDA gene variant and facilitated delineation of the genotype-phenotype correlation of XLHED.

K-Ras G-domain binding with signaling lipid phosphatidylinositol (4,5)-phosphate (PIP2): membrane association, protein orientation, and function.

Ras genes potently drive human cancers, with mutated proto-oncogene GTPase KRAS4B (K-Ras4B) being the most abundant isoform. Targeted inhibition of oncogenic gene products is considered the "holy grail" of present-day cancer therapy, and recent discoveries of small-molecule KRas4B inhibitors were made thanks to a deeper understanding of the structure and dynamics of this GTPase. Because interactions with biological membranes are key for Ras function, Ras-lipid interactions have become a major focus, especially because such interactions evidently involve both the Ras C terminus for lipid anchoring and its G-protein domain. Here, using NMR spectroscopy and molecular dynamics simulations complemented by biophysical- and cell-biology assays, we investigated the interaction between K-Ras4B with the signaling lipid phosphatidylinositol (4,5)-phosphate (PIP2). We discovered that the ß2 and ß3 strands as well as helices 4 and 5 of the GTPase G-domain bind to PIP2 and identified the specific residues in these structural elements employed in these interactions, likely occurring in two K-Ras4B orientation states relative to the membrane. Importantly, we found that some of these residues known to be oncogenic when mutated (D47K, D92N, K104M, and D126N) are critical for K-Ras-mediated transformation of fibroblast cells, but do not substantially affect basal and assisted nucleotide hydrolysis and exchange. Moreover, the K104M substitution abolished localization of K-Ras to the plasma membrane. The findings suggest that specific G-domain residues can critically regulate Ras function by mediating interactions with membrane-associated PIP2 lipids; these insights that may inform the future design of therapeutic reagents targeting Ras activity.

miR-103a-3p regulates mitophagy in Parkinson's disease through Parkin/Ambra1 signaling.

Parkin is a crucial protein that promotes the clearance of damaged mitochondria via mitophagy in neuron, and parkin mutations result in autosomal-recessive Parkinson's disease (AR-PD). However, the exact mechanisms underlying the regulation of Parkin-mediated mitophagy in PD remain unclear. In this study, PD models were generated through incubation of SH-SY5Y cells with 1-methyl-4-phenylpyridinium ion (MPP+, 1.5 mM for 24 h) and intraperitoneal injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg for five consecutive days) in mice. A Bioinformatics database was used to identify Parkin-targeting microRNAs (miRNAs). Then, miR-103a-3p agomir, miR-103a-3p antagomir and Parkin siRNA were used to assess the effects of miR-103a-3p/Parkin/Ambra1 signaling-mediated mitophagy in PD in vitro and in vivo. The protein and mRNA levels of Parkin and Ambra1 were significantly decreased, while miR-103a-3p, which is a highly expressed miRNA in the human brain, was obviously increased in PD mouse and SH-SY5Y cell models. Moreover, miR-103a-3p suppressed Parkin expression by targeting a conserved binding site in the 3'-untranslated region (UTR) of Parkin mRNA. Importantly, miR-103a-3p inhibition resulted in neuroprotective effects and improved mitophagy in vitro and in vivo, whereas Parkin siRNA strongly abolished these effects. These findings suggested that miR-103a-3p inhibition has neuroprotective effects in PD, which may be involved in regulating mitophagy through the Parkin/Ambra1 pathway. Modulating miR-103a-3p levels may be an applicable therapeutic strategy for PD.

Computational Design of Myristoylated Cell-Penetrating Peptides Targeting Oncogenic K-Ras.G12D at the Effector-Binding Membrane Interface.

A number of small inhibitors have been developed in recent years to target the cancer-driving protein, K-Ras. In this study, we propose and design a novel way of targeting oncogenic K-Ras4B.G12D with myristoylated cell-penetrating peptides which become membrane-anchored and lock the protein into an inactive state. In all atom molecular dynamics simulations, such peptides associate with K-Ras4B exclusively at the effector-binding region, which, in turn, is expected to hinder the binding of downstream effector proteins (e.g., C-Raf). The myristoylated R9 (Arg9) peptide locks K-Ras4B.G12D into orientations that are unfavorable for effector binding. After breaking the cyclic structure and myristoylation, a cell-penetrating peptide cyclorasin 9A5, which was designed for targeting the Ras/Raf interface, is also found to be effective in targeting the Ras/membrane interface. The myristoylated peptides likely have high cell permeability because of their mixed cationic/hydrophobic character at the N-terminus, while simultaneously the subsequent multiple charges help to maintain a close association of the peptide with the K-Ras4B.G12D effector-binding lobe. Targeting protein-membrane interfaces is starting to attract attention very recently, thanks to our understanding of the signaling mechanism of an increased number of peripheral membrane proteins. The strategy used in this study has potential applications in the design of drugs against K-Ras4B-driven cancers. It also provides insights into the general principles of targeting protein-membrane interfaces.

lncRNA TINCR participates in ALA-PDT-induced apoptosis and autophagy in cutaneous squamous cell carcinoma.

This study aims to investigate whether terminal differentiation-induced ncRNA (TINCR) has an effect on apoptosis and autophagy induced by ALA-PDT in cutaneous squamous cell carcinoma (CSCC). A431 cells were treated with 5-aminolevulinic acid (ALA) solution at different concentrations and for different duration time. A431 cell viability was detected by Cell Counting Kit-8 (CCK-8) assay, relative TINCR messenger RNA expression was detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). A431 cell apoptosis was examined by flow cytometry. Relative apoptosis/autophagy-related protein expression was analyzed by Western blot analysis. The effect of TINCR on cell autophagy was detected by RFP-LC3 immunofluorescence assay. Reactive oxygen species concentration was detected by 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probe. Relative expressions of ERK1/2 and specificity protein 3 (Sp3) in A43 cells were detected by Western blot analysis and qRT-PCR. Sp3 binding sites were analyzed by ChIP-qPCR. The relative transcription activity was measured with luciferase reporter assay. ALA-PDT treatment at 3.2 mmol/L for 120 minutes significantly promoted TINCR expression in CSCC A431 cells, and TINCR promoted ALA-PDT-induced apoptosis and cell autophagy. Furthermore, ALA-PDT promoted TINCR expression through ERK1/2-SP3 pathway. Sp3 promoted TINCR transcription by binding TINCR promoters. Our data indicated that TINCR involves in ALA-PDT-induced apoptosis and autophagy in CSCC.

Inhibition of the ubiquitination of HSF1 by FBXW7 protects the intestine against ischemia-reperfusion injury.

Epithelial apoptosis is an important factor in intestinal ischemia-reperfusion (I/R) injury. Heat shock factor 1 (HSF1) is a classical stress response factor that directly regulates the transcription of heat shock proteins (HSPs) under stress conditions. Although HSPs are involved in protecting the intestine against I/R, the mechanism whereby HSF1 is regulated in I/R is poorly understood. Here, we show that the ubiquitin ligase FBXW7 targets HSF1 for ubiquitination and degradation in intestinal I/R. In this study, we found that FBXW7 expression was upregulated at the transcriptional level in intestinal mucosae subjected to I/R. In Caco-2 and IEC-6 cells subjected to hypoxia/reoxygenation (H/R), a high FBXW7 level led to excessive HSF1 ubiquitination and degradation. FBXW7 knockdown attenuated HSF1 ubiquitination and downregulation and accelerated HSPB1 and HSP70 expression. In addition, FBXW7 deletion alleviated the apoptosis of intestinal epithelial cells, as evidenced by decreased activation of caspase-3 and caspase-9. The results suggest that FBXW7 suppression protects against intestinal I/R, at least partly through the HSF1/HSP pathway. These findings indicate that FBXW7 may be a potential therapeutic target for inhibiting intestinal mucosa apoptosis during intestinal I/R.

Microarray Analysis of Differentially Expressed Profiles of Circular RNAs in a Mouse Model of Intestinal Ischemia/Reperfusion Injury with and Without Ischemic Postconditioning.

BACKGROUND/AIMS: Ischemic postconditioning (iPoC) represents a promising strategy to mitigate ischemia/reperfusion (I/R) injury of the intestine, yet the mechanisms of this treatment remain to be elucidated. Circular RNAs (circRNAs), a novel class of endogenous non-coding RNAs, have recently been recognized as important regulators of gene expression and pathological processes. Here, we aimed to investigate the expression patterns of circRNAs after intestinal I/R with and without iPoC and, furthermore, to explore the potential mechanisms of iPoC in relation to the differentially expressed circRNAs. METHODS: The global circRNA and mRNA expression profiles in mouse intestinal mucosa were initially screened by microarray (n = 3 per group) and quantitative real-time PCR was used to validate the expression pattern of circRNAs and mRNAs. Bioinformatics analysis including Gene ontology, KEGG pathway analysis, microRNA binding sites identification and circRNA-miRNA-mRNA network construction were utilized for in-depth mechanism exploration. RESULTS: There were 4 up- and 58 downregulated circRNAs as well as 322 up- and 199 downregulated mRNAs in the intestinal I/R group compared with the sham group, whereas compared with I/R, iPoC treatment significantly upregulated 12 circRNAs and 129 mRNAs and downregulated 21 circRNAs and 174 mRNAs. The expression levels of a randomly selected set of 6 circRNAs and 5 mRNAs were successfully validated by qRT-PCR. Through a systematic comparison of the direction of circRNA expression changes in all groups, we identified two circRNAs, circRNA_012412 and circRNA_016863, that may be closely associated with the protective mechanisms of iPoC. Finally, four possible circRNA_012412/circRNA_016863-miRNA-mRNA pathways were predicted, which may play important roles in endogenous protective signaling in iPoC. CONCLUSIONS: This study was the first to comprehensively delineate the expression profiles of circRNAs in a mouse model of intestinal I/R and iPoC and provides novel clues for understanding the mechanisms of iPoC against intestinal I/R injury.

Salvianolic acid A alleviates chronic ethanol-induced liver injury via promotion of ß-catenin nuclear accumulation by restoring SIRT1 in rats.

In recent years, alcoholic liver disease (ALD) has emerged as a growing public health problem worldwide. ß-catenin plays an important role in the growth, development, regeneration and metabolic activity of the liver. Salvianolic acid A (SalA) is a water-soluble component from the root extract of Salvia miltiorrhiza Bunge, and its effect on ALD has not yet been investigated. This study aimed to investigate the effect of SalA on chronic alcohol-induced liver injury and to explore the role of SIRT1-mediated ß-catenin deacetylation in such an effect. In this study, SalA treatment significantly alleviated the accumulation of lipid droplets and reduced the plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), alcohol and ammonia levels in rats. SalA enhanced ethanol and ammonia metabolism and maintained mitochondrial homeostasis. Moreover, SalA restored the activity of the major ethanol-metabolizing enzymes and oxidative stress functions in the liver. Importantly, we found that SalA treatment effectively inhibited the ethanol-mediated decrease in nuclear ß-catenin by upregulating SIRT1 in the liver. SIRT1 then deacetylated ß-catenin to promote its accumulation in the nucleus, thereby preventing alcohol-induced liver injury. The results demonstrate that the SIRT1/ß-catenin pathway is a key therapeutic target in liver injury caused by chronic alcohol exposure and that SalA protects against alcohol-induced liver injury via the SIRT1-mediated deacetylation of ß-catenin.

Inhibition of p66Shc-mediated mitochondrial apoptosis via targeting prolyl-isomerase Pin1 attenuates intestinal ischemia/reperfusion injury in rats.

Intestinal epithelial oxidative stress and apoptosis constitute key pathogenic mechanisms underlying intestinal ischemia/reperfusion (I/R) injury. We previously reported that the adaptor 66 kDa isoform of the adaptor molecule ShcA (p66Shc)-mediated pro-apoptotic pathway was activated after intestinal I/R. However, the upstream regulators of the p66Shc pathway involved in intestinal I/R remain to be fully identified. Here, we focused on the role of a prolyl-isomerase, peptidyl-prolyl cis-trans isomerase (Pin1), in the regulation of p66Shc activity during intestinal I/R. Intestinal I/R was induced in rats by superior mesenteric artery (SMA) occlusion. Juglone (Pin1 inhibitor) or vehicle was injected intraperitoneally before I/R challenge. Caco-2 cells were exposed to hypoxia/reoxygenation (H/R) in vitro to simulate an in vivo I/R model. We found that p66Shc was significantly up-regulated in the I/R intestine and that this up-regulation resulted in the accumulation of intestinal mitochondrial reactive oxygen species (ROS) and massive epithelial apoptosis. Moreover, intestinal I/R resulted in elevated protein expression and enzyme activity of Pin1 as well as increased interaction between Pin1 and p66Shc. This Pin1 activation was responsible for the translocation of p66Shc to the mitochondria during intestinal I/R, as Pin1 suppression by juglone or siRNA markedly blunted p66Shc mitochondrial translocation and the subsequent ROS generation and cellular apoptosis. Additionally, Pin1 inhibition alleviated gut damage and secondary lung injury, leading to improvement of survival after I/R. Collectively, our findings demonstrate for the first time that Pin1 inhibition protects against intestinal I/R injury, which could be partially attributed to the p66Shc-mediated mitochondrial apoptosis pathway. This may represent a novel prophylactic target for intestinal I/R injury.