Blocking CIRP protects against acute pancreatitis by improving mitochondrial function and suppressing pyroptosis in acinar cells.

Acute pancreatitis (AP) continues to pose a major challenge as targeted therapeutic interventions are absent. Mitochondrial dysfunction and inflammasome-dependent pyroptosis are involved in the pathogenic mechanisms of AP. CIRP is a stress-response protein and a damage-associated molecular pattern (DAMP) molecule. In our previous studies, we discovered that excessive CIRP can directly damage pancreatic acinar cells. Nonetheless, the precise involvement of CIRP in AP is still unexplored. The primary aim of this study was to examine the potential involvement of CIRP in the development of pyroptosis and mitochondrial dysfunction in AP. To study this, an L-arginine-induced AP mouse model was used. Our results showed that Caspase-1-mediated pyroptosis and mitochondria-derived reactive oxygen species (ROS) were crucial factors in the occurrence of tissue damage and inflammation in AP. A substantial increase in the CIRP serum levels was observed in AP mice. Blocking CIRP by either CIRP gene knockout or systemic administration of C23, a competing inhibitor of CIRP, reduced ROS accumulation and pyroptosis in AP mice. These effects were associated with attenuated pancreatic injury and inflammation. In addition, CIRP-triggered mitochondrial dysfunction, autophagy impairment, and pyroptosis in pancreatic acinar cells were prevented by TAK242, an inhibitor of CIRP receptor TLR4. In conclusion, CIRP can induce mitochondrial dysfunction and pyroptosis in pancreatic acinar cells, and blocking CIRP may be a valuable approach to treating patients with AP.

MFG-E8 induces epithelial-mesenchymal transition and anoikis resistance to promote the metastasis of pancreatic cancer cells.

Pancreatic cancer is an extremely malignant tumor, and only a few clinical treatment options exist. MFG-E8 and kindlin-2 all play an important role in cancer progression. However, the specific mechanism occurring between MFG-E8, kindlin-2 and the migration and invasion of pancreatic cancer cells remains unelucidated. To unravel the specific mechanism, this study assessed the potential association between MFG-E8 and kindlin-2 as well as the involvement of MFG-E8 in pancreatic cancer using two pancreatic cancer cell lines (MiaPaCa-2 and PANC-1). Pancreatic cancer cells were treated with 0, 250, and 500 ng/ml MFG-E8, and the effects of MFG-E8 on the migration, invasion, and anoikis of pancreatic cancer cells were observed. To investigate the role of kindlin-2 in pancreatic cancer, kindlin-2-shRNAi was transfected to knock down its expression level in the two pancreatic cancer cell lines. Furthermore, cilengitide, a receptor blocker of MFG-E8, was used to explore the relationship between MFG-E8, kindlin-2, and pancreatic cancer progression. Our findings demonstrated that MFG-E8 promotes the migration and invasion of pancreatic cancer cells and induces cell anoikis resistance in a dose-dependent manner, which was effectively counteracted by cilengitide, a receptor blocker. Additionally, the knockdown of kindlin-2 expression nullified the effect of MFG-E8 on the migration and invasion of pancreatic cancer cells. Consequently, this study provides insights into the specific mechanism underlying the interplay between MFG-E8 and kindlin-2 in the progression of pancreatic cancer cells.

Sex-determining region Y gene promotes liver fibrosis and accounts for sexual dimorphism in its pathophysiology.

BACKGROUND & AIMS: Men are more prone to develop and die from liver fibrosis than women. In this study, we aim to investigate how sex-determining region Y gene (SRY) in hepatocytes promotes liver fibrosis. METHODS: Hepatocyte-specific Sry knock-in (KI), Sry knockout (KO), and Sry KI with platelet-derived growth factor receptor α (Pdgfrα) KO mice were generated. Liver fibrosis was induced in mice by bile duct ligation for 2 weeks or carbon tetrachloride treatment for 6 weeks. In addition, primary hepatocytes, hepatic stellate cells (HSCs), and immortalized cell lines were used for in vitro studies and mechanistic investigation. RESULTS: Compared to females, the severity of toxin- or cholestasis-induced liver fibrosis is similarly increased in castrated and uncastrated male mice. Among all Y chromosome-encoded genes, SRY was the most significantly upregulated and consistently increased gene in fibrotic/cirrhotic livers in male patients and in mouse models. Sry KI mice developed exacerbated liver fibrosis, whereas Sry KO mice had alleviated liver fibrosis, compared to age- and sex-matched control mice after bile duct ligation or administration of carbon tetrachloride. Mechanistically, both our in vivo and in vitro studies illustrated that SRY in hepatocytes can transcriptionally regulate Pdgfrα expression, and promote HMGB1 (high mobility group box 1) release and subsequent HSC activation. Pdgfrα KO or treatment with the SRY inhibitor DAX1 in Sry KI mice abolished SRY-induced HMGB1 secretion and liver fibrosis. CONCLUSIONS: SRY is a strong pro-fibrotic factor and accounts for the sex disparity observed in liver fibrosis, suggesting its critical role as a potentially sex-specific therapeutic target for prevention and treatment of the disease. IMPACT AND IMPLICATION: We identified that a male-specific gene, sex-determining region Y gene (SRY), is a strong pro-fibrotic gene that accounts for the sex disparity observed in liver fibrosis. As such, SRY might be an appropriate target for surveillance and treatment of liver fibrosis in a sex-specific manner. Additionally, SRY might be a key player in the sexual dimorphism observed in hepatic pathophysiology more generally.

Targeting extracellular CIRP with an X-aptamer shows therapeutic potential in acute pancreatitis.

Severe acute pancreatitis (AP) is associated with a high mortality rate. Cold-inducible RNA binding protein (CIRP) can be released from cells in inflammatory conditions and extracellular CIRP acts as a damage-associated molecular pattern. This study aims to explore the role of CIRP in the pathogenesis of AP and evaluate the therapeutic potential of targeting extracellular CIRP with X-aptamers. Our results showed that serum CIRP concentrations were significantly increased in AP mice. Recombinant CIRP triggered mitochondrial injury and ER stress in pancreatic acinar cells. CIRP-/- mice suffered less severe pancreatic injury and inflammatory responses. Using a bead-based X-aptamer library, we identified an X-aptamer that specifically binds to CIRP (XA-CIRP). Structurally, XA-CIRP blocked the interaction between CIRP and TLR4. Functionally, it reduced CIRP-induced pancreatic acinar cell injury in vitro and L-arginine-induced pancreatic injury and inflammation in vivo. Thus, targeting extracellular CIRP with X-aptamers may be a promising strategy to treat AP.

The traditional Chinese medicine and non-small cell lung cancer: from a gut microbiome perspective.

Non-small cell lung cancer (NSCLC) is one of the most serious diseases affecting human health today, and current research is focusing on gut flora. There is a correlation between intestinal flora imbalance and lung cancer, but the specific mechanism is not clear. Based on the "lung and large intestine being interior-exteriorly related" and the "lung-intestinal axis" theory. Here, based on the theoretical comparisons of Chinese and western medicine, we summarized the regulation of intestinal flora in NSCLC by active ingredients of traditional Chinese medicine and Chinese herbal compounds and their intervention effects, which is conducive to providing new strategies and ideas for clinical prevention and treatment of NSCLC.

Overexpression of HSF2 binding protein suppresses endoplasmic reticulum stress via regulating subcellular localization of CDC73 in hepatocytes.

BACKGROUND: Endoplasmic reticulum (ER) stress plays an important role in the occurrence and development of various liver diseases. However, there are no effective prevention and treatment strategies. We aimed to determine the role of heat shock factor 2 binding protein (HSF2BP) in ER stress. METHODS: HSF2BP expression in mice and cultured hepatocytes was measured during ER stress induced by tunicamycin, and its importance in ER stress was evaluated in hepatocyte-specific HSF2BP transgenic (TG) and knockout (KO) mice. The effects and mechanisms of HSF2BP on ER stress were further probed in hepatic ischemia-reperfusion (I/R) injury. RESULTS: HSF2BP expression was significantly upregulated during tunicamycin-induced ER stress in mice and cultured hepatocytes. Liver injury and ER stress were reduced in HSF2BP overexpressing mice after treating with tunicamycin, but were aggravated in HSF2BP knockout mice compared to the controls. In hepatic I/R injury, HSF2BP expression was significantly upregulated, and HSF2BP overexpressing mice had reduced liver injury and inflammation. These improvements were associated with ER stress inhibition. However, these results were reversed in hepatocyte-specific HSF2BP knockout mice. HSF2BP overexpression increased cytoplasmic CDC73 levels and inhibited the JNK signaling pathway. CDC73 knockdown using siRNA eliminated the protection exerted by HSF2BP overexpression in hypoxia/reoxygenation (H/R)-induced ER stress in hepatocytes. CONCLUSION: HSF2BP is a previously uncharacterized regulatory factor in ER stress-likely acts by regulating CDC73 subcellular localization. The feasibility of HSF2BP-targeted treatment in ER stress-related liver disease deserves future research.

Efficient Iodine Removal by Porous Biochar-Confined Nano-Cu2O/Cu0: Rapid and Selective Adsorption of Iodide and Iodate Ions.

Iodine is a nuclide of crucial concern in radioactive waste management. Nanomaterials selectively adsorb iodine from water; however, the efficient application of nanomaterials in engineering still needs to be developed for radioactive wastewater deiodination. Artemia egg shells possess large surface groups and connecting pores, providing a new biomaterial to remove contaminants. Based on the Artemia egg shell-derived biochar (AES biochar) and in situ precipitation and reduction of cuprous, we synthesized a novel nanocomposite, namely porous biochar-confined nano-Cu2O/Cu0 (C-Cu). The characterization of C-Cu confirmed that the nano-Cu2O/Cu0 was dispersed in the pores of AES biochar, serving in the efficient and selective adsorption of iodide and iodate ions from water. The iodide ion removal by C-Cu when equilibrated for 40 min exhibited high removal efficiency over the wide pH range of 4 to 10. Remarkable selectivity towards both iodide and iodate ions of C-Cu was permitted against competing anions (Cl-/NO3-/SO42-) at high concentrations. The applicability of C-Cu was demonstrated by a packed column test with treated effluents of 1279 BV. The rapid and selective removal of iodide and iodate ions from water is attributed to nanoparticles confined on the AES biochar and pore-facilitated mass transfer. Combining the advantages of the porous biochar and nano-Cu2O/Cu0, the use of C-Cu offers a promising method of iodine removal from water in engineering applications.

HSF2BP protects against acute liver injury by regulating HSF2/HSP70/MAPK signaling in mice.

Heat shock proteins (HSPs) depletion and protein misfolding are important causes of hepatocyte death and liver regeneration disorder in liver injury. HSF2BP, as its name implies, is a binding protein of HSF2, but the specific role of HSF2BP in heat shock response (HSR) remains unknown. The aim of this study is to identify the role of HSF2BP in HSR and acute liver injury. In this study, we found that HSF2BP expression increased significantly within 24 h after APAP administration, and the trend was highly consistent with that of HSP70. hsf2bp-KO and hsf2bp-TG mouse models demonstrated HSF2BP reduced hepatocyte death, ameliorated inflammation, and improved liver function in APAP- or D-GalN/LPS- induced liver injury. Meanwhile, a significant increase of the survival rate was observed in hsf2bp-TG mice after APAP administration. Further studies showed that HSF2BP upregulated the expression of HSF2 and HSP70 and inhibited the activation of Jnk1/2 and P38 MAPK. Additionally, HSP70 siRNA pretreatment abolished the effect of HSF2BP on the MAPK pathway in APAP-treated hepatocytes. The results reveal that HSF2BP is a protective factor in acute liver injury, and the HSF2BP/HSP70/MAPK regulatory axis is crucial for the pathogenesis of liver injury. HSF2BP is a potential therapeutic target for liver injury.

Clinical Significance of Serum Albumin/Globulin Ratio in Patients With Pyogenic Liver Abscess.

Pyogenic liver abscess (PLA) remains a significant challenge for modern clinicians. Serum albumin/globulin ratio (AGR) can reflect the progress of many diseases. However, the clinical significance of AGR in PLA has not been evaluated. The aim of this study was to explore the effect of AGR on the clinical characteristic and prognosis in PLA patients. This retrospective study included 392 PLA patients who admitted to the First Affiliated Hospital of Xi'an Jiaotong University from January, 2007 to December, 2016. The medical records on admission were collected. Compared with the healthy controls and the patients with extraperitoneal infection or non-infectious liver disease, PLA patients had lower levels of AGR. The mean level of AGR in PLA patients was 1.02 ± 0.25. There were 179 (45.4%) patients with AGR > 1.02 and 213 (54.6%) patients with AGR ≤ 1.02. The baseline data and treatment plans of PLA patients with high or low AGR were comparative. However, PLA patients with a low AGR had higher body temperature, leukocytes and neutrophils, lower hemoglobin, poorer liver and coagulation function, larger abscess diameter, higher positive rate of pus culture and proportion of Escherichia coli, and were more susceptible to multiple bacteria. Moreover, PLA patients with a low AGR had more complications, including systemic inflammatory response syndrome (SIRS), peritoneal effusion and pleural effusion. And it also needs longer time for temperature normalization and hospital stay. In conclusion, PLA patients have lower AGR and lower AGR is associated with worse clinical manifestations, more complications and poorer prognosis. Thus, monitoring of AGR is of great clinical significance for evaluating the progress of PLA patients.

T-tube vs no T-tube for biliary tract reconstruction in adult orthotopic liver transplantation: An updated systematic review and meta-analysis.

BACKGROUND: Whether to use a T-tube for biliary anastomosis during orthotopic liver transplantation (OLT) remains a debatable question. Some surgeons chose to use a T-tube because they believed that it reduces the incidence of biliary strictures. Advances in surgical techniques during the last decades have significantly decreased the overall incidence of postoperative biliary complications. Whether using a T-tube during OLT is still associated with the reduced incidence of biliary strictures needs to be re-evaluated. AIM: To provide an updated systematic review and meta-analysis on using a T-tube during adult OLT. METHODS: In the electronic databases MEDLINE, PubMed, Scopus, ClinicalTrials.gov, the Cochrane Library, the Cochrane Hepato-Biliary Group Controlled Trails Register, and the Cochrane Central Register of Controlled Trials, we identified 17 studies (eight randomized controlled trials and nine comparative studies) from January 1995 to October 2020. The data of the studies before and after 2010 were separately extracted. We chose the overall biliary complications, bile leaks or fistulas, biliary strictures (anastomotic or non-anastomotic), and cholangitis as outcomes. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to describe the results of the outcomes. Furthermore, the test for overall effect (Z) was used to test the difference between OR and 1, where P ≤ 0.05 indicated a significant difference between OR value and 1. RESULTS: A total of 1053 subjects before 2010 and 1346 subjects after 2010 were included in this meta-analysis. The pooled results showed that using a T-tube reduced the incidence of postoperative biliary strictures in studies before 2010 (P = 0.012, OR = 0.62, 95%CI: 0.42-0.90), while the same benefit was not seen in studies after 2010 (P = 0.60, OR = 0.76, 95%CI: 0.27-2.12). No significant difference in the incidence of overall biliary complications (P = 0.37, OR = 1.41, 95%CI: 0.66-2.98), bile leaks (P = 0.89, OR = 1.04, 95%CI: 0.63-1.70), and cholangitis (P = 0.27, OR = 2.00, 95%CI: 0.59-6.84) was observed between using and not using a T-tube before 2010. However, using a T-tube appeared to increase the incidence of overall biliary complications (P = 0.049, OR = 1.49, 95%CI: 1.00-2.22), bile leaks (P = 0.048, OR = 1.91, 95%CI: 1.01-3.64), and cholangitis (P = 0.02, OR = 7.21, 95%CI: 1.37-38.00) after 2010. A random-effects model was used in biliary strictures (after 2010), overall biliary complications (before 2010), and cholangitis (before 2010) due to their heterogeneity (I 2 = 62.3%, 85.4%, and 53.6%, respectively). In the sensitivity analysis (only RCTs included), bile leak (P = 0.66) lost the significance after 2010 and a random-effects model was used in overall biliary complications (before 2010), cholangitis (before 2010), bile leaks (after 2010), and biliary strictures (after 2010) because of their heterogeneity (I 2 = 92.2%, 65.6%, 50.9%, and 80.3%, respectively). CONCLUSION: In conclusion, the evidence gathered in our updated meta-analysis showed that the studies published in the last decade did not provide enough evidence to support the routine use of T-tube in adults during OLT.

Milk fat globule EGF factor 8 restores mitochondrial function via integrin-medicated activation of the FAK-STAT3 signaling pathway in acute pancreatitis.

Acute pancreatitis (AP) remains a significant clinical challenge. Mitochondrial dysfunction contributes significantly to the pathogenesis of AP. Milk fat globule EGF factor 8 (MFG-E8) is an opsonizing protein, which has many biological functions via binding to αvß3/5 integrins. Ligand-dependent integrin-FAK activation of STAT3 was reported to be of great importance for maintaining a normal mitochondrial function. However, MFG-E8's role in AP has not been evaluated. METHODS: Blood samples were acquired from 69 healthy controls and 134 AP patients. Serum MFG-E8 levels were measured by ELISA. The relationship between serum concentrations of MFG-E8 and disease severity were analyzed. The role of MFG-E8 was evaluated in experimental models of AP. RESULTS: Serum concentrations of MFG-E8 were lower in AP patients than healthy controls. And serum MFG-E8 concentrations were negatively correlated with disease severity in AP patients. In mice, MFG-E8 administration decreased L-arginine-induced pancreatic injury and mortality. MFG-E8's protective effects in experimental AP were associated with improvement in mitochondrial function and reduction in oxidative stress. MFG-E8 knockout mice suffered more severe pancreatic injury and greater mitochondrial damage after l-arginine administration. Mechanistically, MFG-E8 activated the FAK-STAT3 pathway in AP mice. Cilengitide, a specific αvß3/5 integrin inhibitor, abolished MFG-E8's beneficial effects in AP. PF00562271, a specific FAK inhibitor, blocked MFG-E8-induced STAT3 phosphorylation. APTSTAT3-9R, a specific STAT3 antagonist, also eliminated MFG-E8's beneficial effects under such a condition. CONCLUSIONS: MFG-E8 acts as an endogenous protective mediator in the pathogenesis of AP. MFG-E8 administration protects against AP possibly by restoring mitochondrial function via activation of the integrin-FAK-STAT3 signaling pathway. Targeting the action of MFG-E8 may present a potential therapeutic option for AP.

Involvement of GPX4 in irisin's protection against ischemia reperfusion-induced acute kidney injury.

Ischemia reperfusion (I/R)-induced acute kidney injury (AKI) is a common and serious condition. Irisin, an exercise-induced hormone, improves mitochondrial function and reduces reactive oxygen species (ROS) production. Glutathione peroxidase 4 (GPX4) is a key regulator of ferroptosis and its inactivation aggravates renal I/R injury by inducing ROS production. However, the effect of irisin on GPX4 and I/R-induced AKI is still unknown. To study this, male adult mice were subjected to renal I/R by occluding bilateral renal hilum for 30 min, which was followed by 24 hr reperfusion. Our results showed serum irisin levels were decreased in renal I/R mice. Irisin (250 µg/kg) treatment alleviated renal injury, downregulated inflammatory response, improved mitochondrial function, and reduced ER stress and oxidative stress after renal I/R, which were associated with upregulation of GPX4. Treated with RSL3 (a GPX4 inhibitor) abolished irisin's protective effect. Thus, irisin attenuates I/R-induced AKI through upregulating GPX4.

Involvement of kindlin-2 in irisin's protection against ischaemia reperfusion-induced liver injury in high-fat diet-fed mice.

Liver steatosis is associated with increased ischaemia reperfusion (I/R) injury. Our previous studies have shown that irisin, an exercise-induced hormone, mitigates I/R injury via binding to αVß5 integrin. However, the effect of irisin on I/R injury in steatotic liver remains unknown. Kindlin-2 directly interacts with ß integrin. We therefore suggest that irisin protects against I/R injury in steatotic liver via a kindlin-2 dependent mechanism. To study this, hepatic steatosis was induced in male adult mice by feeding them with a 60% high-fat diet (HFD). At 12 weeks after HFD feeding, the mice were subjected to liver ischaemia by occluding partial (70%) hepatic arterial/portal venous blood for 60 minutes, which was followed by 24 hours reperfusion. Our results showed HFD exaggerated I/R-induced liver injury. Irisin (250 µg/kg) administration at the beginning of reperfusion attenuated liver injury, improved mitochondrial function, and reduced oxidative and endoplasmic reticulum stress in HFD-fed mice. However, kindlin-2 inhibition by RNAi eliminated irisin's direct effects on cultured hepatocytes. In conclusion, irisin attenuates I/R injury in steatotic liver via a kindlin-2 dependent mechanism.

Identification of irisin as a therapeutic agent that inhibits oxidative stress and fibrosis in a murine model of chronic pancreatitis.

BACKGROUND: Abnormal activation of pancreatic stellate cells (PSCs) plays a crucial role in the pathogenesis of chronic pancreatitis (CP). Irisin, an exercise-induced hormone, has been shown to mitigate liver fibrosis by inhibiting the activation of hepatic stellate cells. However, the effect of irisin in CP has not been evaluated. METHODS: This study aimed to determine whether irisin is protective in CP. CP was induced by 6 IP injections of cerulein (50 µg/kg/body weight). HPSCs were treated with 5 ng/ml TGF-ß1 as in vitro experiment. RESULTS: Our results showed that repeated cerulein injection induced severe pancreatic injury and fibrosis in mice and the serum irisin level in cerulein-treated mice decreased as in CP patients. Excessive oxidative and ER stress was also present in the pancreas of cerulein-treated mice. Irisin treatment significantly alleviated pancreatic injury and fibrosis, which was associated with reduced oxidative and ER stress. In cultured PSCs, irisin directly inhibited TGF-ß-induced α-SMA and collagen I expression. This effect appears to be mediated through downregulation of kindlin-2 and inhibition of the SMAD2/3 pathway. CONCLUSIONS: Irisin alleviated pancreatic injury and fibrosis, which was associated with reduced oxidative and ER stress. Thus, irisin may offer therapeutic potential for patients with CP.

Irisin Improves Autophagy of Aged Hepatocytes via Increasing Telomerase Activity in Liver Injury.

An aged liver has decreased reparative capacity during ischemia-reperfusion (IR) injury. A recent study showed that plasma irisin levels predict telomere length in healthy adults. The aim of the present study is to clarify the role of irisin, telomerase activity, and autophagy during hepatic IR in the elderly. To study this, hepatic IR was established in 22-month- and 3-month-old rats and primary hepatocytes were isolated. The results showed that the old rats exhibited more serious liver injury and lower levels of irisin expression, telomerase activity, autophagy ability, and mitochondrial function than young rats during hepatic IR. Irisin activated autophagy and improved mitochondrial function via increasing telomerase activity in aged hepatocytes. Inhibition of telomerase activity by BIBP1532 abolished the protective role of irisin in hepatocytes during hypoxia and reoxygenation. Additionally, this study proved irisin increased the telomerase activity via inhibition of the phosphorylation of JNK during hepatic IR. Administration of exogenous irisin significantly mitigated the inflammation, oxidative stress, apoptosis, and liver injury in an old rat model of hepatic IR. In conclusion, irisin improves autophagy of aged hepatocytes via increasing telomerase activity in hepatic IR. Irisin exhibits conspicuous benefits in increasing reparative capacity of an aged liver during hepatic IR.

Irisin reverses intestinal epithelial barrier dysfunction during intestinal injury via binding to the integrin αVß5 receptor.

Disruption of the gut barrier results in severe clinical outcomes with no specific treatment. Metabolic disorders and destruction of enterocytes play key roles in gut barrier dysfunction. Irisin is a newly identified exercise hormone that regulates energy metabolism. However, the effect of irisin on gut barrier function remains unknown. The therapeutic effect of irisin on gut barrier dysfunction was evaluated in gut ischemia reperfusion (IR). The direct effect of irisin on gut barrier function was studied in Caco-2 cells. Here, we discovered that serum and gut irisin levels were decreased during gut IR and that treatment with exogenous irisin restored gut barrier function after gut IR in mice. Meanwhile, irisin decreased oxidative stress, calcium influx and endoplasmic reticulum (ER) stress after gut IR. Moreover, irisin protected mitochondrial function and reduced enterocyte apoptosis. The neutralizing antibody against irisin significantly aggravated gut injury, oxidative stress and enterocyte apoptosis after gut IR. Further studies revealed that irisin activated the AMPK-UCP 2 pathway via binding to the integrin αVß5 receptor. Inhibition of integrin αVß5, AMPK or UCP 2 abolished the protective role of irisin in gut barrier function. In conclusion, exogenous irisin restores gut barrier function after gut IR via the integrin αVß5-AMPK-UCP 2 pathway.

Irisin attenuates intestinal injury, oxidative and endoplasmic reticulum stress in mice with L-arginine-induced acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is often associated with intestinal injury, which in turn exaggerates the progression of AP. Our recent study has shown that a low level of serum irisin, a novel exercise-induced hormone, is associated with poor outcomes in patients with AP and irisin administration protects against experimental AP. However, the role of irisin in intestinal injury in AP has not been evaluated. AIM: To investigate the effect of irisin administration on intestinal injury in experimental AP. METHODS: AP was induced in male adult mice by two hourly intraperitoneal injections of L-arginine. At 2 h after the last injection of L-arginine, irisin (50 or 250 µg/kg body weight) or 1 mL normal saline (vehicle) was administered through intraperitoneal injection. The animals were sacrificed at 72 h after the induction of AP. Intestinal injury, apoptosis, oxidative and endoplasmic reticulum (ER) stress were evaluated. RESULTS: Administration of irisin significantly mitigated intestinal damage, reduced apoptosis, and attenuated oxidative and ER stress in AP mice. In addition, irisin treatment also effectively downregulated serum tumor necrosis factor-alpha and interleukin-6 levels and alleviated injury in the pancreas, liver and lung of AP mice. CONCLUSION: Irisin-mediated multiple physiological events attenuate intestinal injury following an episode of AP. Irisin has a great potential to be further developed as an effective treatment for patients with AP.

Low Serum Irisin Concentration Is Associated with Poor Outcomes in Patients with Acute Pancreatitis, and Irisin Administration Protects Against Experimental Acute Pancreatitis.

Aims: Severe acute pancreatitis (AP) is a serious condition without specific treatment. Mitochondrial dysfunction plays a crucial role in the pathogenesis of AP. Irisin, a novel exercise-induced hormone, contributes to many health benefits of physical activity. We and others have shown that irisin protects against ischemia reperfusion-induced organ injury by alleviating mitochondrial damage. However, the role of irisin in AP has not been evaluated. The purpose of this study was to investigate the role of serum irisin levels in patients with AP and the effect of irisin administration in experimental AP. Results: Serum irisin levels were decreased in AP patients, and low serum irisin levels were associated with worse outcomes in these patients. Treatment with exogenous irisin increased survival and mitigated pancreatic injury in experimental AP. The protective effects of irisin in AP were associated with improvement in mitochondrial function and reduction in ER stress. Moreover, irisin upregulated UCP2 expression in the pancreas, and administration of genipin, a specific UCP2 antagonist, abolished irisin's beneficial effects in L-arginine-induced AP. Innovation and Conclusion: Low serum irisin was associated with poor outcomes in AP patients, and irisin administration protected against experimental AP by restoring mitochondrial function via activation of UCP2. Restoration of mitochondrial function by irisin may offer therapeutic potential for patients with AP. Antioxid. Redox Signal. 31, 771-785.

Stereoselective Syntheses of ( E)-γ',δ-Bisboryl-Substituted syn-Homoallylic Alcohols via Chemoselective Aldehyde Allylboration.

The development of a novel ( Z)-α,δ-bisboryl-substituted crotylboron reagent is reported. Ni-catalyzed 1,4-diboration of dienylboronate provided the targeted crotylboronate in good yield with high regio- and stereoselectivity. Chemo- and stereoselective addition of this crotylboron reagent to aldehydes followed by protection of the resulting secondary hydroxyl group gave TES-protected homoallylic alcohols bearing an alkyl and a vinyl boronate groups with high stereoselectivities.