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.

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.

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.

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.

[Total ginsenosides fought against right ventricular hypertrophy through inhibiting calcineurin signal pathway].

OBJECTIVE: To observe the effect of total ginsenosides (TG) on monocrotaline (MCT) induced right ventricular hypertrophy rats, and to explore its correlation with calcineurin (CaN) pathway. METHODS: Fifty male Sprague Dawley rats were randomly divided into the normal control group, the MCT model group, and the low, middle, high dose TG treatment groups, 10 in each group. All medication was performed by peritoneal injection for 18 days. Right ventricular peak systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), and right ventricular weight/body weight (RVW/BW) were measured. Intracellular free calcium concentrations were measured by Ca2+ fluorescence indicator Fura2/AM. The atrial natriuretic factor (ANF) and CaN mRNA expression of the myocardial tissue were quantitatively analyzed by Real-time PCR. The protein expression of CaN was detected by Western blot. RESULTS: Compared with the MCT model group, preventive treatment of TG at the 3 doses could significantly reduce RVSP, RVHI, RVW/BW, and ANF mRNA expression, and decrease Ca2+ concentration in myocardial cells, CaN mRNA and protein expression in the myocardial tissue. CONCLUSION: TG could obviously improve MCT-induced right ventricular hypertrophy, which was possibly achieved through suppressing MCT-activated CaN signal transduction.

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.

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.

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.

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.

Inhibitory Effect of Ginsenoside Rg1 on Vascular Smooth Muscle Cell Proliferation Induced by PDGF-BB Is Involved in Nitric Oxide Formation.

Ginsenoside Rg1 (Rg1) has been reported to suppress the proliferation of vascular smooth muscle cells (VSMCs). This study aimed to observe the role of nitric oxide (NO) in Rg1-antiproliferative effect. VSMCs from the thoracic aorta of SD rats were cultured by tissue explant method, and the effect of Rg1 (20 mg·L(-1), 60 mg·L(-1), and 180 mg·L(-1)) on platelet-derived growth factor-BB (PDGF-BB)-induced proliferation was evaluated by MTT assay. The cell cycle was analyzed by flow cytometry. For probing the mechanisms, the content of NO in supernatant and cGMP level in VSMCs was measured by nitric oxide kit and cGMP radio-immunity kit, respectively; the expressions of protooncogene c-fos and endothelial NO synthase (eNOS) mRNA in the VSMCs were detected by real-time RT-PCR; the intracellular free calcium concentration ([Ca2(+)](i)) was detected with Fura-2/AM-loaded VSMCs. Comparing with that in normal group, Rg1 180 mg·L(-1) did not change the absorbance of MTT and cell percent of G(0)/G(1), G(2)/M, and S phase in normal cells (P > 0.05). Contrarily, PDGF-BB could increase the absorbance of MTT (P < 0.01) and the percent of the S phase cells but decrease the G(0)/G(1) phase cell percent in the cell cycle, accompanied with an upregulating c-fos mRNA expression (P < 0.01), which was reversed by additions of Rg1(20 mg·L(-1), 60 mg·L(-1), and 180 mg·L(-1)). Rg1 administration could also significantly increase the NO content in supernatant and the cGMP level in VSMCs, as well as the eNOS mRNA expression in the cells, in comparison of that in the group treated with PDGF-BB alone (P < 0.01). Furthermore, Rg1 caused a further increase in the elevated [Ca(2+)](i) induced by PDGF-BB. It was concluded that Rg1 could inhibit the VSMC proliferation induced by PDGF-BB through restricting the G(0)/G(1) phase to S-phase progression in cell cycle. The mechanisms may be related to the upregulation of eNOS mRNA and the increase of the formation of NO and cGMP.

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.

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.

Role of nitric oxide in ginsenoside Rg(1)-induced protection against left ventricular hypertrophy produced by abdominal aorta coarctation in rats.

Ginsenoside Rg(1) (Rg(1)), one of the active components of Panax ginseng, has been reported to promote endogenous nitric oxide (NO) production in some tissues, and to inhibit left ventricular (LV) hypertrophy in rats. This study aimed to investigate whether Rg(1)-induced inhibition of rat LV hypertrophy is mediated by NO-production. Rat LV hypertrophy was induced by abdominal aorta coarctation. Rg(1) 15 mg/kg/d, L-arginine 200 mg/kg/d, and the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine-methyl ester (L-NAME) 100 mg/kg/d used with the same dose of L-arginine or Rg(1) were given starting from 1 d after surgery for 21 consecutive days. LV hypertrophy was evidenced by determining LV weight and mRNA expression of atrial natriuretic peptide, a marker of cardiac hypertrophic response, as well as by histopathology. Rg(1) and L-arginine administration significantly reduced the elevated LV hypertrophic parameters independent of LV systolic pressure changing, and ameliorated the histopathology of LV myocardium and LV diastolic function. All the beneficial effects of Rg(1) and L-arginine were abolished or blunted by L-NAME. Further to examine the role of NO in Rg(1) inhibition on LV hypertrophy, expression of endothelial NOS was determined at the transcript levels. In our experimental conditions endothelial NOS mRNA expression in LV tissue was lowered by abdominal aorta coarctation, and upregulated by Rg(1) administration. These results demonstrate that Rg(1)-induced protection against LV hypertrophy elicited by abdominal aorta coarctation in rats is mediated, at least in part, via endogenous NO production and release.

Protective effects of icariin on cognitive deficits induced by chronic cerebral hypoperfusion in rats.

1. Icariin is a major constituent of flavonoids derived from the Chinese medicinal herb Epimedium revicornum Maxim. The aim of the present study was to investigate whether icariin has protective effects on learning ability and memory in a rat model of chronic cerebral hypoperfusion. 2. Chronic cerebral hypoperfusion was induced by permanent ligation of the common carotid artery in Wistar rats for 4 months. One month after permanent artery occlusion, rats were adminitered icariin at doses of 0, 30, 60 or 120 mg/kg per day, p.o., for 3 months. Neurobehavioural and neurobiochemical parameters were examined to evaluate the effects of icariin on cognitive deficits induced by chronic cerebral hypoperfusion. 3. The Morris water maze test revealed that learning ability and memory were severely impaired in untreated rats, but were significantly improved in icariin-treated rats. Icariin treatment also ameliorated chronic cerebral hypoperfusion-induced oxidative stress in the brain, as evidenced by reduced malondialdehyde formation and maintained superoxide dismutase activity. In addition, the decreased hippocampal levels of acetylcholine, acetylcholinesterase and choline acetyltransferase associated with chronic cerebral hypoperfusion were significantly prevented by icariin treatment. 4. In conclusion, icariin protects against cognitive deficits induced by chronic cerebral hypoperfusion in rats. These effects appear to be mediated through its anti-oxidant effects, as well as its effects on the circulatory and cholinergic systems.

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.

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.