A Mitochondria-Targeted Heptamethine Indocyanine Small Molecular Chelator for Attenuating Uranium Nephrotoxicity.

Radionuclide uranium has both a chemical and radioactive toxicity, leading to severe nephrotoxicity as it predominantly deposits itself in the kidneys after entering into human bodies. It crosses renal cell membranes, accumulates in mitochondria and causes mitochondrial oxidative damage and dysfunction. In this study, a mitochondria-targeted heptamethine indocyanine small molecule chelator modified with gallic acid (IR-82) is synthesized for uranium detoxication. Both gallic acid and sulfonic acid, as two hydrophilic endings, make IR-82, being excreted feasibly through kidneys. Gallic acid with polyphenol groups has a steady metal chelation effect and potent antioxidant ability, which may facilitate IR-82-alleviated uranium nephrotoxicity simultaneously by enhancing uranium decorporation from the kidneys and reducing mitochondrial oxidative damage. Cell viability assays demonstrate that IR-82 can significantly improve the cell viability of uranium-exposed human renal (HK-2) cells. It is also demonstrated to accumulate in mitochondria and reduce mitochondrial ROS and total intracellular ROS, as well as intracellular uranium content. In vivo imaging experiments in mice show that IR-82 could be excreted out through kidneys. ICP-MS tests further reveal that IR-82 can efficiently decrease the uranium deposition in mouse kidneys. IR-82 treatment improves the animal survival rate and renal function of experimental mice after high-dose uranium exposure. Collectively, our study may evidence that the development of uranium decorporation agents with kidney-mitochondrion dual targeting abilities is a promising strategy for attenuating uranium-induced nephrotoxicity.

Successful Treatment of Severe Case of Lipid Overload Syndrome with Pancreatitis and Pneumonia: A Case Report.

Background: Fat overload syndrome is a rare and severe adverse reaction triggered by the infusion of a single source of lipid emulsion, resulting in elevated blood triacylglycerol (TG) levels. The majority of literature reports focus on cases of fat overload syndrome in patients with mild symptoms. This case is significant because it demonstrates the diagnostic and therapeutic experience and provide valuable insights for the management for severe fat overload syndrome. Case Presentation: We present a case report of a female patient who developed fat overload syndrome following prolonged and excessive infusion of lipid emulsion after colon resection surgery. In the setting of compromised immune function and malnutrition, the patient's pulmonary infection and respiratory distress symptoms have further exacerbated. Hence, in addition to severe pancreatitis, the patient has also contracted severe pneumonia. Upon admission, tracheal intubation, plasma exchange and blood perfusion were performed. Subsequently, comprehensive treatment was provided, including anti-infection, antispasmodic, acid suppression, enzyme inhibition, as well as targeted supportive measures to stabilize electrolytes and nutritional status. After treatment, there was a progressive reduction in blood lipid levels. After assessing the relevant risks, it was deemed necessary to perform an emergency computed tomography (CT)-guided percutaneous drainage tube placement procedure targeting the necrotic area of the pancreas while the patient was still intubated. Finally, the patient was discharged from the hospital. Conclusion: The case highlights the association between fat overload syndrome and pancreatitis as well as the use of lipid emulsions and suggests the treatment strategies for severe fat overload syndrome.

The formation mechanism and textural properties of a complex gel based on soybean glycinin-chitosan complex coacervates: Effects of pH, heat treatment temperature and centrifugation.

The soybean glycinin (11S)-chitosan (CS) complex gels with various textural properties were successfully constructed. The process involved the initial formation of 11S-CS coacervates through electrostatic interactions, followed by a heating treatment to obtain the final complex gels. The impacts of pH, heating temperature, and centrifugation on 11S-CS complex gel properties were investigated. The results indicated that the pore arrangement of the gel formed at pH 7.3 was more tightly and uniformly packed than those formed at pH 6.8 and 7.8. Centrifugation facilitated denser and more ordered gel structures at the three pH values, while increasing the heating temperature exhibited the opposite trend at pH 6.8 and 7.8. These structural differences were also reflected in the rheological and textural properties of the gel. The 11S-CS complex gels exhibited an elasticity-based gel property. The textural properties of gels formed at pH 6.8 were stronger compared to those formed at pH 7.3 and 7.8. However, when the 11S-CS coacervates were heated without centrifugation, the resulting gels were weak. This study emphasizes the potential of using protein/polysaccharide associative interactions during gel formation to alter the microstructure of the gel, meeting various production requirements.

Regioselective Dearomative Amidoximation of Nonactivated Arenes Enabled by Photohomolytic Cleavage of N-nitrosamides.

Dearomative spirocyclization reactions represent a promising means to convert arenes into three-dimensional architectures; however, controlling the regioselectivity of radical dearomatization with nonactivated arenes to afford the spirocyclizative 1,2-difunctionalization other than its kinetically preferred 1,4-difunctionalization is exceptionally challenging. Here we disclose a novel strategy for dearomative 1,2- or 1,4-amidoximation of (hetero)arenes enabled by direct visible-light-induced homolysis of N-NO bonds of nitrosamides, giving rise to various highly regioselective amidoximated spirocycles that previously have been inaccessible or required elaborate synthetic efforts. The mechanism and origins of the observed regioselectivities were investigated by control experiments and density functional theory calculations.

A Mitochondria-Targeted Ferroptosis Inducer Activated by Glutathione-Responsive Imaging and Depletion for Triple Negative Breast Cancer Theranostics.

Ferroptosis is a new type of iron-dependent programmed cell death characterized by glutathione (GSH) depletion, selenoprotein glutathione peroxidase 4 (GPX4) inactivation, and lipid peroxides accumulation. Mitochondria, as the main source of intracellular energy supply and reactive oxygen species (ROS) generation, play a central role in oxidative phosphorylation and redox homeostasis. Therefore, targeting cancer-cell mitochondria and attacking redox homeostasis is expected to induce robust ferroptosis-mediated anticancer effects. In this work, a theranostic ferroptosis inducer (IR780-SPhF), which can simultaneously achieve the imaging and therapy of triple-negative breast cancer (TNBC) by targeting mitochondria is presented. It is developed from a mitochondria-targeting small molecule (IR780) with cancer-preferential accumulation, enabling it to react with GSH by nucleophilic substitution, resulting in mitochondrial GSH depletion and redox imbalance. More interestingly, IR780-SPhF exhibits GSH-responsive near-infrared fluorescence emission and photoacoustic imaging characteristics, further facilitating diagnosis and treatment with real-time monitoring of TNBC with a highly elevated GSH level. Both in vitro and in vivo results demonstrate that IR780-SPhF exhibits potent anticancer effect, which is significantly stronger than cyclophosphamide, a classic drug commonly recommended for TNBC patients in clinic. Hence, the reported mitochondria-targeted ferroptosis inducer may represent a promising candidate and a prospective strategy for efficient cancer treatment.

Rationally Designed Heptamethine Cyanine Photosensitizers that Amplify Tumor-Specific Endoplasmic Reticulum Stress and Boost Antitumor Immunity.

Cancer phototherapy activates immunogenic cell death (ICD) and elicits a systemic antitumor immune response, which is an emerging approach for tumor treatment. Most available photosensitizers require a combination of immune adjuvants or checkpoint inhibitors to trigger antitumor immunity because of the immunosuppressive tumor microenvironment and the limited phototherapeutic effect. A class of tumor-targeting heptamethine cyanine photosensitizers modified with an endoplasmic reticulum (ER)-targeting group (benzenesulfonamide) are synthesized. Phototherapy of tumor cells markedly amplifies ER stress and promotes tumor antigen release, as the ER is required for protein synthesis, secretion, and transport. More importantly, different electron-donating or -withdrawing substitutions are introduced into benzenesulfonamide to modulate the nonradiative decay pathways through intramolecular charge transfer, including singlet-triplet intersystem crossing (photodynamic effect) and internal thermal conversion (photothermal effect). Thus, a heptamethine cyanine photosensitizer containing a binitro-substituted benzenesulfonamide (ER-Cy-poNO2 ) is identified that preferentially accumulates in the ER of tumor cells. It significantly enhances the phototherapeutic effect by inducing excessive ER stress and robust ICD. Consequently, this small molecular photosensitizer triggers a sufficient antitumor immune response and effectively suppresses the growth of both primary and distant metastatic tumors, whereas no apparent toxicity is observed. This heptamethine cyanine photosensitizer has the potential to enhance cancer-targeted immunotherapy.

Synthesis of a versatile mitochondria-targeting small molecule for cancer near-infrared fluorescent imaging and radio/photodynamic/photothermal synergistic therapies.

Although as a mainstay modal for cancer treatment, the clinical effect of radiotherapy (RT) does not yet meet the need of cancer patients. Developing tumour-preferential radiosensitizers or combining RT with other treatments has been acknowledged highly necessary to enhance the efficacy of RT. The present study reported a multifunctional bioactive small-molecule (designated as IR-83) simultaneously exhibiting tumour-preferential accumulation, near-infrared imaging and radio/photodynamic/photothermal therapeutic effects. IR-83 was designed and synthesized by introducing 2-nitroimidazole as a radiosensitizer into the framework of heptamethine cyanine dyes inherently with tumour-targeting and photosensitizing effects. As results, IR-83 preferentially accumulated in tumours, suppressed tumour growth and metastasis by integrating radio/photodynamic/photothermal multimodal therapies. Mechanism studies showed that IR-83 accumulated in cancer cell mitochondria, induced excessive reactive oxygen species (ROS), and generated high heat after laser irradiation. On one hand, these phenomena led to mitochondrial dysfunction and a sharp decline in oxidative phosphorylation to lessen tissue oxygen consumption. On the other hand, excessive ROS in mitochondria destroyed the balance of antioxidants and oxidative stress balance by down-regulating the intracellular antioxidant system, and subsequently sensitized ionizing radiation-generated irreversible DNA double-strand breaks. Therefore, this study presented a promising radiosensitizer and a new alternative strategy to enhance RT efficacy via mitochondria-targeting multimodal synergistic treatment.

Design and Synthesis of a Mitochondria-Targeting Radioprotectant for Promoting Skin Wound Healing Combined with Ionizing Radiation Injury.

Wound healing is seriously retarded when combined with ionizing radiation injury, because radiation-induced excessive reactive oxygen species (ROS) profoundly affect cell growth and wound healing. Mitochondria play vital roles not only as cellular energy factories but also as the main source of endogenous ROS, and in this work a mitochondria-targeting radioprotectant (CY-TMP1) is reported for radiation injury-combined wound repair. It was designed, synthesized and screened out from different conjugates between mitochondria-targeting heptamethine cyanine dyes and a peroxidation inhibitor 2,2,6,6-tetramethylpiperidinyloxy (TEMPO). CY-TMP1 specifically accumulated in mitochondria, efficiently mitigated mitochondrial ROS and total intracellular ROS induced by 6 Gy of X-ray ionizing irradiation, thereby exhibiting a notable radioprotective effect. The mechanism study further demonstrated that CY-TMP1 protected mitochondria from radiation-induced injury, including maintaining mitochondrial membrane potential (MMP) and ATP generation, thereby reducing the ratio of cell apoptotic death. Particularly, an in vivo experiment showed that CY-TMP1 could effectively accelerate wound closure of mice after 6 Gy of whole-body ionizing radiation. Immunohistochemical staining further indicated that CY-TMP1 may improve wound repair through angiogenesis and re-epithelialization. Therefore, mitochondria-targeting ROS scavengers may present a feasible strategy to conquer refractory wound combined with radiation injury.

Predictive value of fibrinogen in identifying inflammatory bowel disease in active stage.

BACKGROUND: We aimed to externally validate for the first time the diagnostic ability of fibrinogen to identify active inflammatory bowel disease (IBD). METHODS: The research totally involved 788 patients with IBD, consisted of 245 ulcerative colitis (UC) and 543 Crohn' s disease (CD). The Mayo score and Crohn disease activity index (CDAI) assessed disease activity of UC and CD respectively. The independent association between fibrinogen and disease activity of patients with UC or CD was investigated by multivariate logistic regression analyses. Area under the receiver operating characteristic curve (AUROC) assessed the performance of various biomarkers in discriminating disease states. RESULTS: The fibrinogen levels in active patients with IBD significantly increased compared with those in remission stage (P < 0.001). Fibrinogen was an independent predictor to distinguish disease activity of UC (odds ratio: 2.247, 95% confidence interval: 1.428-3.537, P < 0.001) and CD (odds ratio: 2.124, 95% confidence interval: 1.433-3.148, P < 0.001). Fibrinogen was positively correlated with the Mayo score (r = 0.529, P < 0.001) and CDAI (r = 0.625, P < 0.001). Fibrinogen had a high discriminative capacity for both active UC (AUROC: 0.806, 95% confidence interval: 0.751-0.861) and CD (AUROC: 0.869, 95% confidence interval: 0.839-0.899). The optimum cut-off values of fibrinogen 3.22 was 70% sensitive and 77% specific for active UC, and 3.87 was 77% sensitive and 81% specific for active CD respectively. CONCLUSIONS: Fibrinogen is a convenient and practical biomarker to identify active IBD.

Synthesis of Mitochondria-Anchored Nitroimidazoles with a Versatile NIR Fluorophore for Hypoxic Tumor-Targeting Imaging and Chemoradiotherapy.

Nitroimidazoles are one of the most common radiosensitizers investigated to combat hypoxia-induced resistance to cancer radiotherapy. However, due to poor selectivity distinguishing cancer cells from normal cells, effective doses of radiosensitization are much closer to the doses of toxicity induced by nitroimidazoles, limiting their clinical application. In this work, a tumor-targeting near-infrared (NIR) cyanine dye (IR-808) was utilized as a targeting ligand and an NIR fluorophore tracer to chemically conjugate with different structures of hypoxia-affinic nitroimidazoles. One of the NIR fluorophore-conjugated nitroimidazoles (808-NM2) was identified to preferentially accumulate in hypoxic tumor cells, sensitively outline the tumor contour, and effectively inhibit tumor growth synergistically by chemotherapy and radiotherapy. More importantly, nitroimidazoles were successfully taken into cancer cell mitochondria via 808-NM2 conjugate to exert the synergistic effect of chemoradiotherapy. Regarding the important roles of mitochondria on cancer cell survival and metastasis under hypoxia, 808-NM2 may be hopeful to fight against hypoxic tumors.

Study on the ArI-catalyzed intramolecular oxy-cyclization of 2-alkenylbenzamides to benzoiminolactones.

A new intramolecular oxy-cyclization of 2-alkenylbenzamides catalyzed by ArI has been developed. This protocol is highlighted by its metal-free catalytic system and extremely short reaction time, providing efficient and straightforward access to various benzoiminolactones in good to excellent yields. Interestingly, a regioselective transformation occurred when using two different reaction systems. Mechanistic studies suggested that mCPBA acts as both oxidant and ligand at the IIII center, and the Lewis acid BF3 accelerated ligand exchange and reductive elimination in the catalytic process.

Data Mining the Prognostic Biomarkers: miRNAs Targeting the Chemotherapeutic Agent 5-Fluorouracil in Colon Cancer.

BACKGROUND: Colon cancer is one of the most common and has the highest mortality rate in the world. MicroRNAs (miRNAs) as potential biomarkers play crucial roles in diagnosis, prognosis, and drug-response prediction of colon cancer. METHODS: In this study, we collected miRNA expression data from the Broad GDAC Firehose and screened specific miRNA-gene pairs after treatment with 5-fluorouracil treatment and used COAD analysis to study the association of miRNAs and inhibitor of the inhibitory genes. Potential drug-related miRNAs were further extracted via hypergeometric testing. RESULTS: The results showed that 13,651 miRNA-gene pairs were retrieved, including 242 miRNAs and 5,179 genes. The association between miRNAs and the inhibitor of inhibitory genes DPYD, TYMS, UNG was indicated. We further extracted 4 potential drug-related miRNAs, including hsa-mir-551a, hsa-mir-144, hsa-mir-519b, hsa-mir-506. The miRNA-gene pairs associated with 5-fluorouracil exhibit better prognosis in patients with CRC. CONCLUSIONS: We expected that up-regulation of hsa-mir-551a, hsa-mir-144, and hsa-mir-506 and down-regulation of hsa-mir-519b would exhibit better prognosis. The findings would underpin the fundamental hypothesis of mi-RNAs being prognostic signal biomarkers in therapy of 5-fluorouracil in CRC.

Paeoniflorin Prevents Intestinal Barrier Disruption and Inhibits Lipopolysaccharide (LPS)-Induced Inflammation in Caco-2 Cell Monolayers.

Inflammatory bowel disease (IBD) in humans is closely related to bacterial infection and the disruption of the intestinal barrier. Paeoniflorin (PF), a bioactive compound from Paeonia lactiflora Pallas plants, exerts a potential effect of anti-inflammatory reported in various researches. However, the effect of PF on intestinal barrier function and its related mechanisms has not been identified. Here, we investigate the PF potential anti-inflammatory effect on lipopolysaccharide (LPS)-stimulated human Caco-2 cell monolayers and explore its underlying key molecular mechanism. In this context, PF significantly increased TEER value, decreased intestinal epithelium FITC-dextran flux permeability, and restored the expressions of occludin, ZO-1, and claudin5 in LPS-induced Caco-2 cell. In vitro, treatment of PF significantly inhibited LPS-induced expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and matrix metalloproteinase-9 (MMP-9). In addition, we found that PF suppressed nuclear factor kappa B (NF-κB) signaling via activating the Nrf2/HO-1 signaling pathways in ILPS-stimulated Caco-2 cells. Our findings indicate that PF has an inhibitory effect on endothelial injury. Our findings suggested that PF has an anti-inflammatory effect in ILPS-stimulated Caco-2 cells, which might be a potential therapeutic agent against IBD and intestinal inflammation.

Prognostic value of serum lactate kinetics in critically ill patients with cirrhosis and acute-on-chronic liver failure: a multicenter study.

Lactate clearance (Δ24Lac) was reported to be inversely associated with mortality in critically ill patients. The aim of our study was to assess the value of Δ24Lac for the prognosis of critically ill patients with cirrhosis and acute-on-chronic liver failure (ACLF). We analysed 954 cirrhotic patients with hyperlactatemia admitted to intensive care units (ICUs) in the United States and eastern China. The patients were followed up for at least 1 year. In the unadjusted model, we observed a 15% decrease in hospital mortality with each 10% increase in Δ24Lac. In the fully adjusted model, the relationship between the risk of death and Δ24Lac remained statistically significant (hospital mortality: odds ratio [OR] 0.84, 95% confidence interval [CI]: 0.78- 0.90, p < 0.001; 90-day mortality: hazard ratio [HR] 0.94, 95%CI 0.92- 0.97, p < 0.001; for Δ24Lac per 10% increase). Similar results were found in patients with ACLF. We developed a Δ24Lac-adjusted score (LiFe-Δ24Lac), which performed significantly better in the area under the receiver operating characteristic curves (AUROCs) than the original LiFe score for predicting mortality. Lactate clearance is an independent predictor of death, and the LiFe-Δ24Lac score is a practical tool for stratifying the risk of death.

Independent effect of alanine transaminase on the incidence of type 2 diabetes mellitus, stratified by age and gender: A secondary analysis based on a large cohort study in China.

BACKGROUND: Previous studies have revealed that alanine aminotransferase (ALT) may be one of the risk factors of developing diabetes. We aimed to demonstrate the independent effect of ALT on incident diabetes and to investigate whether the association between ALT and incident diabetes is modified by age and gender in the general Chinese population. METHODS: The present study was a retrospective cohort study, including 210,051 Chinese adult participants. The primary outcome was developing diabetes. The serum ALT activities were stratified by quintiles. We obtained data from 'DATADRYAD' website and used the data for secondary analysis. RESULTS: At a median follow-up of 3.0 y, 4144 of 210,051 (1.97%) participants developed diabetes. After adjustment for potential confounders, a significantly higher risk of the incident diabetes (HR: 1.43, 95% CI: 1.25-1.63) was found in participants in the fifth quintile (Q5, ≥31 U/L) compared to those in the first to fourth quintiles (Q1-4) for ALT activities. Among males aged 30 to 40 and 40 to 50 y with the fifth quintile of ALT activity had 2.4- and 1.5-fold increased odds of developing diabetes, respectively, in comparison with those in the lower ALT activities. Among females with age 30 to 40 and ≥ 70 y, the fifth quintile of ALT activity had 4.9- and 2.2-fold increased odds for incident diabetes. CONCLUSION: Our result indicated that the ALT activity was positively associated with the incident diabetes among Chinese persons. Moreover, 30-40 y individuals, whether male or female, with elevated ALT activities had the greatest increased risk for diabetes compared with persons with lower ALT activities in the same age group.

Theoretical study of the intermolecular recognition mechanism between Survivin and substrate based on conserved binding mode analysis.

Survivin is the smallest member of IAP (inhibitor of apoptosis protein) family, which plays important roles in both mitosis and apoptosis. It has become an attractive drug target due to its overexpression in many human cancers. Survivin has been proven to bind to Smac/DIABLO protein that indirectly inhibits apoptosis. Meanwhile, it is the key subunit of chromosome passenger complex (CPC) which bind to the N-terminal tail of phosphorylated histone H3T3ph during mitosis. Up to now, Survivin directly targeting inhibitor has yet to merge since the difficulty of disrupting the protein-protein interactions (PPIs) between Survivin and its substrate proteins. Nevertheless, currently known binding partners of Survivin provide crucial information about conserved recognition mechanism, which can assist in the detection of some uncharted substrates and also the Survivin inhibitors. Herein, we adopted a method that using four substrates to analyze the common binding mode of Survivin. To accomplish this, conventional molecular dynamics (MD) simulations, molecular mechanics/generalized born surface area (MM-GBSA) binding free energy calculations and energy decomposition were carried out to assess the binding affinity and per-residue contributions. We found that there are two anchor sites of Survivin responsible for maintaining the binding conformation and one sub-pocket for intermolecular recognition. The results of this study synthetically describe the binding mechanism and provide valuable guidance for rational drug design of PPI inhibitor.

Iguratimod ameliorates inflammatory responses by modulating the Th17/Treg paradigm in dextran sulphate sodium-induced murine colitis.

Inflammatory bowel disease (IBD) is an autoimmune disease with an abnormal and persistent immune response. Iguratimod, a novel anti-rheumatic drug, exhibits anti-inflammatory effects and regulates immune response. The role of iguratimod in intestinal mucosal inflammation and immunity has not been examined. The aim of this study was to investigate whether iguratimod ameliorates dextran sulphate sodium (DSS)-induced murine colitis and its potential regulatory mechanism. Murine colitis was induced by administering 2.5% DSS for 5days. Some mice were administered iguratimod (5, 30mg/kg) by oral gavage once daily for 7days, beginning on the day 3 after colitis induction. Our study showed that iguratimod alleviates the symptoms of colitis and suppresses intestinal tissue damage, including macroscopic and histopathological manifestations. Moreover, iguratimod reduced interleukin (IL)-6, IL-17, and tumour necrosis factor-α levels, and increased the expression levels of IL-10 and TGF-ß. In addition, iguratimod downregulated the proportion of Th17 cells, the level of transcription factor retinoic acid-related orphan receptor γt (RORγt), and the phosphorylation of signal transducer and activator of transcription-3 (STAT3), and upregulated the proportion of Treg cells, the level of transcription factor forkhead box p3 (Foxp3), and the phosphorylation of STAT5 in the colonic tissues. In conclusion, iguratimod plays a protective role in mice with DSS-induced colitis via anti-inflammatory effects and regulation of Th17/Treg cells. Therefore, use of iguratimod may serve as a novel therapeutic strategy for the treatment of IBD.

Efficacy and safety of carbon dioxide insufflation versus air insufflation for endoscopic retrograde cholangiopancreatography: A meta-analysis update.

BACKGROUND AND OBJECTIVE: Endoscopic retrograde cholangiopancreatography (ERCP) is essential for visualising the biliary tree and pancreatic ducts, and carbon dioxide (CO2) insufflation during ERCP is considered an alternative technique to air insufflation for relieving post-procedural abdominal discomfort (abdominal pain and distension). The aim of the present study was to evaluate the effect of CO2 insufflation on the remission of abdominal discomfort and the potential side effects by conducting a meta-analysis. METHODS: The method recommended by the Cochrane Collaboration was employed to conduct a meta-analysis of randomised controlled trials (RCTs) of CO2 insufflation versus air insufflation during ERCP. The PubMed, EMBASE, Cochrane Library, ISI Web of Science and China Biology Medicine disc (CBMdisc) databases were comprehensively searched. RESULTS: Nine high-quality RCTs were reviewed. The updated meta-analysis showed that the CO2 groups achieved a lower abdominal pain score [1-hour (SMD: -1.44, 95% CI: -2.76, -0.15), 3-hour (SMD: -1.17, 95% CI: -2.18, -0.16) and 6-hour (SMD: -1.39, 95% CI: -2.68, -0.10)], a lower abdominal distension score [1-hour (SMD: -1.05, 95% CI: -1.73, -0.38), 3-hour (SMD: -0.63, 95% CI: -1.10, -0.16) and 6-hour (SMD: -0.54, 95% CI: -0.99, -0.08)] and a lower overall rate of complications (OR: 0.59; 95% CI: 0.37, 0.93). There was no significant difference between the groups regarding abdominal discomfort immediately after recovery or 24-hour post-procedure. There was no evidence to indicate higher pressure of CO2 (pCO2) values in the CO2 groups during the procedure when the patients were under sedation anaesthesia. CONCLUSIONS: Compared to air insufflation, CO2 insufflation is currently the preferred method for ERCP and decreases post-procedural abdominal pain and distension without significant side effects.

Tolvaptan regulates aquaporin-2 and fecal water in cirrhotic rats with ascites.

AIM: To investigate the role of tolvaptan in regulating aquaporin (AQP)-2 expression and fecal water content in cirrhotic rats with ascites. METHODS: Cirrhosis with ascites was induced in rats by repetitive dorsal injection of CCl4 for 14 wk. In total, 84 cirrhotic rats with ascites divided into three groups (vehicle, 3 mg/kg and 5 mg/kg tolvaptan), and then further divided into five subgroups (days 1, 2, 3, 4, and 5). Blood samples were obtained to measure vasopressin and sodium concentrations. Rats were killed and colonic mucosa was scraped for analysis of protein expression and AQP-2 transcriptional level. The whole layer was fixed for hematoxylin&eosin (HE) staining and feces were collected for determination of fecal water content. CONCLUSION: Compared with vehicle, vasopressin decreased significantly in the tolvaptan groups from day 2 to a similar level in each treatment group. AQP-2 showed significant upregulation in cirrhotic rats with ascites compared with an untreated control group (100% ± 22.9% vs 22.2% ± 10.23%, P < 0.01). After administration of tolvaptan, AQP-2 expression began to decrease significantly from day 2 in each treatment group, but no significant difference was finally found between the treatment groups. Fecal water content in the distal colon was increased by 5 mg/kg tolvaptan on day 1 (66.8% ± 9.3% vs 41.4% ± 6.3%, in the vehicle group, P < 0.05). Fecal water content returned to baseline at day 4 at the latest in both treatment groups, and did not correspond to the change in AQP-2 expression. HE staining of the colonic mucosa showed no mucosal damage related to tolvaptan. CONCLUSION: Upregulation of AQP-2 in the distal colon is found in cirrhotic rats with ascites. Tolvaptan inhibits its expression and may decrease water reabsorption and induce diarrhea.

Genetic Variants Associated with Gestational Hypertriglyceridemia and Pancreatitis.

Severe hypertriglyceridemia is a well-known cause of pancreatitis. Usually, there is a moderate increase in plasma triglyceride level during pregnancy. Additionally, certain pre-existing genetic traits may render a pregnant woman susceptible to development of severe hypertriglyceridemia and pancreatitis, especially in the third trimester. To elucidate the underlying mechanism of gestational hypertriglyceridemic pancreatitis, we undertook DNA mutation analysis of the lipoprotein lipase (LPL), apolipoprotein C2 (APOC2), apolipoprotein A5 (APOA5), lipase maturation factor 1 (LMF1), and glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) genes in five unrelated pregnant Chinese women with severe hypertriglyceridemia and pancreatitis. DNA sequencing showed that three out of five patients had the same homozygous variation, p.G185C, in APOA5 gene. One patient had a compound heterozygous mutation, p.A98T and p.L279V, in LPL gene. Another patient had a compound heterozygous mutation, p.A98T & p.C14F in LPL and GPIHBP1 gene, respectively. No mutations were seen in APOC2 or LMF1 genes. All patients were diagnosed with partial LPL deficiency in non-pregnant state. As revealed in our study, genetic variants appear to play an important role in the development of severe gestational hypertriglyceridemia, and, p.G185C mutation in APOA5 gene appears to be the most common variant implicated in the Chinese population. Antenatal screening for mutations in susceptible women, combined with subsequent interventions may be invaluable in the prevention of potentially life threatening gestational hypertriglyceridemia-induced pancreatitis.