ABSTRACT
There has been a steady growth of interest in proton-conductive metal-organic frameworks (MOFs) due to their potential utility in proton-exchange membrane fuel cells. To attain a super proton conductivity (>1 × 10-2 S cm-1) in a MOF-based proton conductor is a key step toward practical application. Currently, most studies are focused on enhancing the proton conductivity of porous MOFs by controlling a single factor, such as the type of protons or hydrophilic pore or hydrogen bond. However, a limited contribution from a single factor cannot afford to remarkably increase the proton conductivity of the MOF and form a super proton conductor. Herein, we constructed two distinct porous MOFs, {(H3O+)4[Cu12(ci)12(OH)4(H2O)12]·3H2O·9DMF} (Cu-ci-3D, H2ci = 1H-indazole-5-carboxylic acid, DMF = N,N'-dimethylformamide) and {[Co(Hppca)2]·2HN(CH3)2·CH3OH·2H2O} (Co-ppca-2D, H2ppca = 5-(pyridin-3-yl)-1H-pyrazole-3-carboxylic acid), to tune their proton conductivities at high relative humidity (RH) using the combined effect of hydrophilic pore and the type of protons, ultimately achieving super proton conduction. Excitingly, Cu-ci-3D indeed harvests a super proton conductivity of 1.37 × 10-2 S cm-1 at 353 K and â¼97% RH, superior to some previously reported MOF-based proton conductors. The results present a unique perspective for developing high-performance MOF-based proton conductors and understanding their structure-performance relationships.
ABSTRACT
BACKGROUND: Piebaldism is a rare, autosomal dominant, and congenital pigmentary disorder characterized by stable depigmentation of the skin and white forelock. Mutations in KIT or SLUG genes result in piebaldism. Most individuals with piebaldism have a family history of the disorder. METHODS: In this paper, we report a case of piebaldism with café-au-lait macules resulting from a novel mutation of KIT gene c.1982C > T (p.Thr661Ile) in a three-generation Chinese family. The whole-exome sequencing, mitochondrial gene 3000X, and bioinformatics tools were used to identify the mutation in this new-found pedigree. In addition, we searched the databases of "Punmed, Chinese National Knowledge Infrastructure, CMJD, WANFANG MED ONLINE", reviewed 88 cases of piebaldism caused by KIT gene mutation, and summarized the relationship between clinical phenotype and genotype of piebaldism through logistic regression and other statistical methods. RESULTS: The proband and her affected mother carried a heterozygous c.1982C > T missense mutation (p.Thr661Ile) on KIT gene. Bioinformatics analysis hinted that it had potential pathogenicity. The data showed that piebaldism patients with cafè-au-lait macules had KIT mutations almost located in the intracellular tyrosine kinase domain and were mostly related to the severe clinical phenotype of piebaldism. CONCLUSION: The new heterozygous c.1982C > T missense mutation on KIT caused piebaldism with café-au-lait macules in this Chinese family. This study provides a new reference index for clinicians to judge the severity of clinical phenotypes of piebaldism, broadens the understanding of the correlation between clinical phenotypes and genotypes of piebaldism, and provides reference of genetic counseling and prenatal diagnosis for affected families.
Subject(s)
Piebaldism , Pigmentation Disorders , Humans , Female , Piebaldism/genetics , Proto-Oncogene Proteins c-kit/genetics , Cafe-au-Lait Spots/diagnosis , Cafe-au-Lait Spots/genetics , Mutation/geneticsABSTRACT
Sarsasapogenin-AA13(AA13), a sarsasapogenin derivative, exhibited good neuroprotective and anti-inflammatory activities in vitro and therapeutic effects on learning and memory dysfunction in amyloid-ß-injected mice. A sensitive UPLC-MS/MS method was developed and validated to quantitatively determine AA13 in rat plasma and was further applied to evaluate the pharmacokinetic behaviour of AA13 in rats that were administered AA13 intravenously and orally. This method was validated to exhibit excellent linearity in the concentration range of 1-1000 ng/mL. The lower limit of quantification was 1 ng/mL for AA13 in rat plasma. Intra-day accuracy for AA13 was in the range of 90-114%, and inter-day accuracy was in the range of 97-103 %. The relative standard deviation of intra-day and inter-day assay was less than 15%. After a single oral administration of AA13 at the dose of 25 mg/kg, Cmax of AA13 was 1266.4 ± 316.1 ng/mL. AUC0-48 h was 6928.5 ± 1990.1 h·ng/mL, and t1/2 was 10.2 ± 0.8 h. Under intravenous administration of AA13 at a dosage of 250 µg/kg, AUC0-48 h was 785.7 ± 103.3 hâ ng/mL, and t1/2 was 20.8 ± 7.2 h. Based on the results, oral bioavailability (F %) of AA13 in rats at 25 mg/kg was 8.82 %.
Subject(s)
Chromatography, High Pressure Liquid/methods , Neuroprotective Agents/blood , Spirostans/blood , Tandem Mass Spectrometry/methods , Animals , Limit of Detection , Linear Models , Male , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacokinetics , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Spirostans/chemistry , Spirostans/pharmacokineticsABSTRACT
Depression is partially caused by inflammation in central nervous system. This study investigated the ameliorative effects of phenol glycosides (PG) from Ligustrum lucidum Ait. (Oleaceae) on neuroinflammation and depressive-like behavior in mice hypothalamus as well as the molecular mechanism. Mice were administered with PG extract for 2 weeks prior to treatment with LPS. The mice treated with PG extract showed resistance to LPS-induced reduction in body weight and LPS-induced depressive-like behaviors shown by sucrose preference, tail suspension test, forced swimming test and open field test. LPS-induced activation of microglial cells and elevation in protein expression of inflammatory cytokines including IL-1ß, RANTES and MCP-1 in hypothalamus of mice were abrogated by pre-treatment with PG extract. This extract down-regulated expression of TLR4, MyD88, NLRP3, renin and angiotensin II and decreased proportional area of Iba-1+ microglias in hypothalamus. Pre-treatment with PG extract inhibited LPS-triggered activation of CaSR/Gα11 signaling, stimulated 1-OHase expression in hypothalamus, and enhanced circulating 1,25(OH)2 D3 level. Overall, pre-treatment with PG extract ameliorated LPS-induced depressive-like behaviors by repressing neuroinflammation in mice hypothalamus which was attributed to its suppression on activation of microglia and production of inflammatory cytokines via acting on TLR4 pathway, CaSR and RAS cascade associated with improving vitamin D metabolism.
Subject(s)
Chromatography, High Pressure Liquid/methods , Depression/drug therapy , Fruit/chemistry , Glycosides/therapeutic use , Hypothalamus/drug effects , Inflammation/drug therapy , Ligustrum/chemistry , Plant Extracts/chemistry , Animals , Glycosides/pharmacology , Male , MiceABSTRACT
A sarsasapogenin derivative, sarsasapogenin-AA22 (AA22), with cyclobutylamine at the 3-hydroxyl position of sarsasapogenin, has great neuroprotective activity in PC12 cells and NO production inhibitory activity in RAW264.7 cell lines. A method was developed to determine AA22 in rat plasma which was further applied to evaluate the pharmacokinetics of AA22 after taking a single dose of AA22. Liquid chromatography tandem mass spectrometry was used in the method, while diosgenin was used as internal standard. A simple protein precipitation based on acetonitrile was utilized. A simple sample cleanup promoted the throughput of the method considerably. The method was validated over the range of 1-1000 ng/mL with a correlation coefficient > 0.99. The lower limit of quantification was 1 ng/mL for AA22 in plasma. Intra- and inter-day accuracies for AA22 were 92-111 and 100-103%, respectively, and the inter-day precision was <15%. After a single oral dose of 25 mg/kg of AA22, the mean peak plasma concentration of AA22 was 2114 ± 362 ng/mL at 6 h. The area under the plasma concentration-time curve was 196,098 ± 69,375 h ng/mL, and the elimination half-life was 8.7 ± 2.2 h.
Subject(s)
Chromatography, Liquid/methods , Spirostans/blood , Spirostans/pharmacokinetics , Tandem Mass Spectrometry/methods , Animals , Drug Stability , Male , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Sensitivity and Specificity , Spirostans/chemistryABSTRACT
Objective To observe the effect of Shengqing Capsule (SC) on serum contents of TC, LDL-C, and HDL-C, hepatic scavenger receptor B I (SRB I ) , and CD36 in rats with cholesterol cal- culus. Methods Totally 80 mice were divided into 4 groups according to random number table, i.e., the normal group, the model group, the Western medicine (WM) group, and the Chinese medicine (CM) group, 20 in each group. Mice in the normal group were fed with common forage, while mice in the other 3 groups were fed with lithogenic diet. Mice in the CM group and the WM group were fed with SC (at the daily dose of 0.35 g/kg) and Ursodeoxycholic Acid Tablet (UDCA, at the daily dose of 39. 55 mg/kg) re- spectively for 7 weeks. The general condition and gallstone formation rate were observed. Serum contents of TC, LDL-C, and HDL-C, and protein expressions of SBR I and CD36 were detected by oxidase meth- od and Western blot respectively. Results No gallbladder stone formed in the normal group, and gall- stone formed in 15 mice of the model group with gallstone formation rate of 75%. Compared with the nor- mal group, serum contents of TC and LDL-C and protein expressions of SRB I and CD36 increased, HDL-C content decreased in the model group (P <0. 01). The gallstone formation rate was 35% (7 mice) in the WM group and 30% (6 mice) in the CM group, lower than that of the model group (75%; P <0. 05). Contents of TC and LDL-C, and protein expressions of SRB I and CD36 decreased, HDL-C content in- creased in the WM group and the CM group (P <0.01). Compared with the WM group, TC content and protein expressions of SRB I and CD36 decreased in the CM group (P <0.01). Conclusion SC could prevent and treat gallbladder stone possibly through lowering expression levels of SRB I and CD36.
Subject(s)
Cholesterol , Drugs, Chinese Herbal , Gallstones , Receptors, Scavenger , Animals , Calculi , Cholesterol/blood , Drugs, Chinese Herbal/pharmacology , Gallstones/drug therapy , Gallstones/prevention & control , Mice , Rats , Receptors, Scavenger/drug effectsABSTRACT
Inflammatory pseudotumour (IP) is a rare proliferative disease characterized by a dense infiltrate of plasma cells, lymphocytes, eosinophils and neutrophils in the fibrous stroma. It primarily affects the lungs of pediatric patients or young adults. Cutaneous IP is an extremely rare condition, with limited documentation in the English literature. In this case report, we presented an unusual instance of a 62-year-old male endured recalcitrant cutaneous IP for 8 years and exhibited poor response to topical glucocorticoid therapy, as well as intralesional injections of pingyangmycin and/or corticosteroid. Notably, after undergoing four sessions of 5-aminolevulinic acid photodynamic therapy (ALA-PDT), the patient experienced a significant reduction in erythema and nodules. This observation suggests that ALA-PDT may represent a promising and safe treatment option for cutaneous IP.
Subject(s)
Granuloma, Plasma Cell , Photochemotherapy , Male , Young Adult , Humans , Child , Middle Aged , Photochemotherapy/methods , Photosensitizing Agents/therapeutic use , Granuloma, Plasma Cell/drug therapy , Aminolevulinic Acid/therapeutic use , SkinABSTRACT
Background: Psoriasis is a chronic inflammatory skin disease that has no cure. While the specific cause of psoriasis is unknown, interactions between immune cells and inflammatory cytokines are believed to be important in its pathogenesis. Thymic stromal lymphopoietin (TSLP) is a cytokine produced by epithelial cells that profoundly affects dendritic cells (DCs) and is involved in allergy and inflammatory diseases. In some studies, its expression is higher in the skin of psoriasis patients, whereas it is increased in treated psoriasis patients when compared with untreated patients in others. Aims: To investigate the role of TSLP in the pathogenesis of psoriasis. Study Design: In vitro and in vivo study. Methods: To investigate the effect of TSLP on psoriasis in vivo, a mouse psoriasis model and shRNA targeting TSLP to reduce its expression were used. Mouse primary bone marrow dendritic cells (BMDCs) were cultured in vitro and used to investigate the signaling pathways activated by TSLP. Results: We found that reducing TSLP expression in psoriasis skin alleviated disease severity. TSLP activated the Janus kinase (JAK)/SYK pathway in psoriatic skin. In vitro studies with BMDCs demonstrated that TSLP increased DC maturation through the JAK/SYK pathway and activated DCs-secreted cytokines that stimulated CD4+ T cells to develop into T helper 17 (Th17) cells by activating STAT3 signaling. The JAK/SYK pathway inhibitor reduced the effect of TSLP on activating BMDCs and promoting Th17 differentiation by CD4+ T cells. Conclusion: These findings indicated that TSLP exerted its immune-modulating effect in psoriasis through the JAK/SYK pathway.
Subject(s)
Cytokines , Dendritic Cells , Psoriasis , Th17 Cells , Thymic Stromal Lymphopoietin , Animals , Humans , Mice , Cytokines/metabolism , Cytokines/drug effects , Dendritic Cells/drug effects , Dendritic Cells/immunology , Disease Models, Animal , Janus Kinases , Signal Transduction/drug effects , Syk Kinase , Th17 Cells/drug effects , Th17 Cells/immunologyABSTRACT
To provide theoretical support for the safety control of rectangular pipe jacking tunnels crossing an existing expressway, a method for predicting the surface settlement of a rectangular pipe jacking tunnel is proposed in this study. Therefore, based on the high approximation of the BP neural network to any function under the multiparameter input, the PSO-BP mixed prediction model of the ground subsidence of the ultrashallow buried large section rectangular pipe jacking tunnel is established by taking into account the adaptive mutation method, adopting the improved particle swarm optimization (IPSO) algorithm with adaptive inertia weight and mutation particles in the later stage to determine the optimal hyperparameters of the prediction model. Through the case study of an ultrashallow large cross-section rectangular pipe jacking tunnel, this algorithm is compared with the traditional algorithm and combined with field monitoring data for analysis and prediction. The prediction results show that compared with the traditional BP neural network prediction model, AWPSO-BP model and PWPSO-BP model, the improved PSO-BP mixed prediction model shows a more stable prediction effect when the change in surface subsidence is gentle and the concavity and convexity are large. The predicted subsidence value is close to the actual value, and the accuracy and robustness of the prediction are significantly improved.
ABSTRACT
Exploitation of solid-state proton-conducting materials with high anhydrous proton conductivity from subzero temperature (<273 K) to moderate temperature (>353 K) is a great challenge. Here, Brönsted acid-dopped zirconium-organic xerogels (Zr/BTC-xerogels) are prepared for anhydrous proton conduction from subzero to moderate temperature. Abundant acid sites and strong H-bonding interactions make the CF3SO3H (TMSA)-introduced xerogel gain high proton conductivity from 9.0 × 10-4 S cm-1 (253 K) to 1.40 × 10-2 S cm-1 (363 K) under anhydrous conditions, which are in the leading level. This provides a new possibility to develop wide-operating-temperature conductors.
ABSTRACT
There exists a challenge to develop solid-state proton conductors with high conductivity not only at high working temperatures (>353â¯K) but at start-up temperature and even at subzero temperature (<273â¯K) in cold climates or high-altitude drones. Here we present a series of zirconium-organic xerogels (Zr/Fum-xerogels) with porosity and defectivity, supported by N2 sorption, thermogravimetric analysis (TGA) and X-ray photoelectron spectroscopy (XPS), exhibiting a high anhydrous proton conductivity over the temperature range of 233 to 433â¯K. The anhydrous conductivity of Zr/Fum-xerogel-0.04 reaches 5.68â¯×â¯10-4 (233â¯K) and 2.5â¯×â¯10-2 S cm-1 (433â¯K), situating in the leading level of all anhydrous conductors reported to date. Further, the defective effects on acidities and conductive mechanisms of xerogels, especially structural changes of water clusters generated by varying temperatures are investigated by ion exchange capacity (IEC), X-ray photoelectron spectroscopy (XPS), temperature programmed desorption of NH3 (NH3-TPD) and in-situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). The zirconium-organic xerogels with outstanding conducting performance is further implemented as impedance sensor towards formic acid.
ABSTRACT
Pancreatic cancer is a highly fatal malignant tumor of the digestive system. It is characterized by early metastasis and high mortality rates. Solasonine, a steroidal alkaloid, is derived from Solanum nigrum L., a natural herb. Solasonine is associated with excellent anti-tumor effects, however, its effects on pancreatic cancer have not been fully established. Pancreatic cancer cells (PANC-1 and CFPAC-1) were used to verify the in vitro and in vivo effects of solasonine. Metabolomics were used to evaluate its underlying mechanisms. Solasonine promoted PANC-1 and CFPAC-1 cell apoptosis while inhibiting their proliferation, migration and invasion. Mouse xenograft models and metastasis models of ANC-1 and CFPAC-1 confirmed that solasonine blocked tumor formation and metastasis. Metabolomics confirmed the effects of solasonine on glutathione metabolism and SLC7A11-mediated ferroptosis. Furthermore, Co-Immunoprecipitation and Duolink® in situ PLA confirmed that OTUB1, a deubiquitylating enzyme, interacted with SLC7A11 and solasonine to enhance ubiquitinated degradation of SLC7A11 in PANC-1 and CFPAC-1 cells. Besides, molecular docking confirmed that solasonine directly bound TFAP2A and suppressed its protein levels. Bioinformatics and luciferase assays revealed that TFAP2A binds the OTUB1 promoter region, thereby promoting its transcription. In summary, solasonine inhibits the TFAP2A/OTUB1 SLC7A11 axis to activate ferroptosis and suppress pancreatic cancer cell progression.
ABSTRACT
The development of proton-conducting materials in cold regions is still at the initial stage due to the challenge in breaking the subzero temperature limit, especially in covalent organic frameworks (COFs). Herein, we fabricated a series of proton-conductive COFs as self-standing, highly flexible combined membranes (ssc-COFMs) composed of a processable TpBD-Me2 and a conductive Tp-TGCl, in-situ encapsulated proton-conducting ionic liquids (PCILs) as additional proton sources into backbones. Compositions and microstructures of ssc-COFMs are monitored by XRD, FTIR, nitrogen adsorption and elemental analysis. Comparison to other porous organic conductors, a great advance propelled renders the combined COF membranes to have a high protonic conductivities at medium and subzero temperatures (243 to 353 K), owing to the resultant multifaceted synergistic effect of multiple proton units. Specifically, the proton conductivities of the ssc-COFMs loaded with -SO4H functionalized PCILs reaches 2.87 × 10-4 S cm-1 (~58% RH) and 9.93 × 10-4 S cm-1 (~98% RH) at 243 K, together with 6.84 × 10-2 S·cm-1 under 353 K and ~ 98% RH.
ABSTRACT
BACKGROUND: Metastasis is the leading cause of death among breast cancer patients. MicroRNA-134 has been reported to have a tumor-suppressive role in breast cancer. Ruyiping (RYP), a traditional Chinese formula, has been shown with the ability to reduce breast cancer metastasis in pre-clinical studies. This present study was designed to examine whether miR-134 was involved in RYP-inhibited breast cancer metastasis. METHODS: The expression of SLUG, E-Cadherin, N-Cadherin and miR-134 in MDA-MB-231 and 4 T1 cells treated with RYP or vehicle control were determined by quantitative realtime-PCR and western blot. Invasiveness determined by transwell assay as well as SLUG gene expression determined by qPCR were detected in cells transfected with chemically synthesized miR-134 mimics or inhibitors. BALB/c mice were injected with 4 T1 cells orthotopically and fed with RYP through gavage. Breast tumor growth, metastasis and tumor expression of EMT markers were detected. RESULTS: Compared with the control, Ruyiping formula significantly inhibited SLUG-regulated breast cancer cells invasion. MiR-134 was induced by RYP in vitro and in vivo and was able to suppress SLUG by targeting its 3'UTR. RYP suppressed SLUG expression and cell invasion through miR-134. In 4 T1 tumor-bearing mice, RYP significantly inhibited 4 T1 tumor growth and lung metastasis, increased the levels of miR-134 and epithelial marker while decreased the levels of SLUG and mesenchymal marker. CONCLUSION: Our data uncovered that Ruyiping formula exerts an anti-metastatic activity against breast cancer cells by regulating SLUG through miR-134. MiR-134-SLUG axis might be a promising strategy in breast cancer therapy.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Breast Neoplasms/drug therapy , Drugs, Chinese Herbal/pharmacology , MicroRNAs/metabolism , Snail Family Transcription Factors/metabolism , Animals , Breast Neoplasms/pathology , Female , Mice, Inbred BALB C , Neoplasm Invasiveness , Neoplasm Metastasis , Snail Family Transcription Factors/drug effectsABSTRACT
BACKGROUND: In Traditional Chinese Medicine (TCM), Dahuang Danshen decoction (DD) is used to treat pancreatic fibrosis. Pancreatic fibrosis is a typical manifestation of chronic pancreatitis (CP), which affects the digestive system. The therapeutic mechanisms of DD in pancreatic fibrosis are unclear. AIM: This study aimed to investigate the regulatory mechanisms of DD on oxidative stress and endoplasmic reticulum stress in CP. MATERIALS AND METHODS: Experimental rats were intraperitoneally injected with 500 mg/kg BW of diethyldithiocarbamate (DDC) twice a week for six weeks to induce CP. At the same time, DD was administered orally at daily doses of 1.37 g/kg BW, 2.74 g/kg BW, and 5.48 g/kg BW to evaluate its treatment effects on CP. After all treatments, pancreatic tissues were harvested and subjected to H&E staining. Transmission electron microscopy (TEM) was also performed to show the endoplasmic reticulum structure in the pancreatic tissues. Immunohistochemistry was used to detect the α-SMA expression level in the pancreatic tissues. Metabolomics analysis of the serum and proteomics analysis of the pancreatic tissues were performed to reveal the changes of endogenous metabolites and proteins, respectively. Concentrations of GSH, MDA, SOD, ROS, col-1, and col-3 were determined using corresponding kits. The western blotting method was used to determine the protein levels of Keap-1, HO-1, NQO1, Nrf2, GRP, JNK, and caspase 12. The pancreatic mRNA levels of NQO1, GPX1, HO-1, GST-π, GRP, JNK, and caspase 12 were also determined by quantitative PCR. The interactions between TCM components and Keap-1 were investigated by molecular docking modeling. RESULTS: The pathohistological results demonstrated that DD could ameliorate DDC-induced CP in vivo, indicated by reduction of α-SMA, col-1, col-3, TNF-α, and IL-6. DD increased serum levels of GSH and SOD but reduced pancreatic ROS. DD decreased cytoplasmic Keap-1 and increased Nrf2 nuclear localization. Correspondingly, DD increased the expression levels of Nrf2 downstream antioxidant genes NQO1, GPX1, HO-1, and GST-π. DD also decreased ERS hallmarks caspase 12 cleavage and GRP expression. Eventually, DD inhibited PSC activation by reducing JNK phosphorylation and MMK-3/p38 expression. Molecular docking analysis showed that salvianolic acid B and emodin had a good binding affinity toward Keap-1. CONCLUSIONS: These results demonstrated that DD could ameliorate the oxidative and endoplasmic reticulum stress through releasing Nrf2 from Keap-1 binding and inducing the downstream antioxidant enzymes. As a result, DD could thwart pancreatic fibrosis by inhibiting PSCs activation, which was induced by OS and ERS through JNK and MMK3/p38 pathways.
ABSTRACT
Overuse of acetaminophen (APAP) is a major cause of drug-induced liver failure at the clinics. Apigenin (API) is a natural flavonoid derived from Matricaria chamomilla. The aim of the present study was to investigate the amelioration function of API in APAP-induced hepatotoxicity both in vitro and in vivo and investigate its potential mechanisms. Analysis results of the activities of serum alanine and aspartate aminotransferases (ALT and AST), malondialdehyde, myeloperoxidase (MPO), and reactive oxygen species (ROS) demonstrated therapeutic effects of API. MTT assay results revealed that API attenuated APAP and its metabolic product, N-acetyl-p-benzoquinone imine (NAPQI) induced cytotoxicity in a dose-dependent manner in human liver cells, L-02 cells. Subsequently, metabolomic results of cells and serum analyses demonstrated an aberrant level of carnitine palmitoyltransferase I (CPT1A). We established that API stimulated CPT1A activity in mice liver tissues and L-02 cells. Molecular docking analyses revealed potential interaction of API with CPT1A. Further investigation of the role of CPT1A in L0-2 cells revealed that API reversed cytotoxicity via the AMP-activated protein kinase (AMPK)/GSK-3ß signaling pathway and compound C, which is a selective AMPK inhibitor, inhibited activation of CPT1A induced by API. API was bound to the catalytic region of AMPK as indicated by molecular docking results. In addition, compound C suppressed nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) that is enhanced by API and inhibited the antioxidative function of API. In summary, the study demonstrates that API attenuates APAP-induced hepatotoxicity by activating the AMPK/GSK-3ß signaling pathway, which subsequently promotes CPT1A activity and activates the NRF2 antioxidant pathway.
ABSTRACT
Severe acute pancreatitis (SAP) is a non-bacterial inflammatory disease that clinically causes a very high rate of mortality. Dihydrokaempferol (DHK) is a natural flavonoid extracted from Bauhinia championii. Our research aimed to establish the treatment function of DHK on SAP-induced pancreas injury and delve into its potential mechanism. In this study, SAP was induced by caerulein (CER) and Lipopolysaccharide (LPS). DHK was administered orally at different doses of 20, 40, or 80 mg/kg. Results from serum amylase/lipase, pancreas hematoxylin-eosin staining technique, pancreas malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) showed the therapeutic effect of DHK in a mice SAP model. MTT revealed DHK alleviated CER + LPS induced cytotoxicity in a dose-dependent manner in the pancreatic acinar cells of mice. Next, we verified DHK suppressed the level of Keap1 and promoted transcriptional activation of nuclear Nrf2 in the presence of CER + LPS. The molecular docking study suggested that there is a potential interaction between DHK and Keap1. To further look at the role of Keap1 using in vitro and in vivo models, Keap1 overexpression adenovirus (ad-Keap1) was performed. The results revealed that ad-Keap1suppressed the nuclear translocation of Nrf2 which is enhanced by DHK, and suppressed the antioxidative functionality of DHK both in mice and cell models. Collectively, this research demonstrated that DHK bettered the SAP induced pancreas injury by regulating the Keap1/Nrf2 pathway and regulating oxidative stress injury.
Subject(s)
Flavonoids/pharmacology , Kelch-Like ECH-Associated Protein 1/metabolism , NF-E2-Related Factor 2/metabolism , Pancreatitis/drug therapy , Animals , Ceruletide , Disease Models, Animal , Dose-Response Relationship, Drug , Flavonoids/administration & dosage , Glutathione/metabolism , Lipopolysaccharides , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , Oxidative Stress/drug effects , Pancreatitis/physiopathology , Reactive Oxygen Species/metabolism , Severity of Illness IndexABSTRACT
A series of composites have been fabricated by introducing ionic liquid (IL) (ship) into chromium terephthalate MIL-101 (bottle) by ship-in-bottle method (IL@MIL-101s), the resulting IL@MIL-101s are endowed to high water retention, which is essential to proton conducting on multiple energy-involved applications at the low relative humidity (RH). The humidifying IL can lower water loss and increase water uptake, and thus improves water retention properties of the composites aided by the mesoporous MIL-101 at low RH. The hydropenic proton transfer pathways are modeled inside MOF and between IL-MOF, diminishing energy barrier routes for proton hopping, and thus a promotive proton transfer is rendered via Grotthuss mechanism. Specially, the IL@MIL-101 (SIB-3) unfolds a high proton conductivity (σ = 4.4 × 10-2 S cm-1) at RH as low as ~23%, five orders of magnitude increase than that of parent MIL-101 (1.1 × 10-7 S cm-1) at 323 K. Besides, IL@MIL-101s as fillers are incorporated into polymer blends to form hybrid membranes, appearing the relatively high proton conductivity (4.3 × 10-3 S cm-1) under ~23% RH at 323 K.
ABSTRACT
Reduction of ferric methemoglobin (metHb) to its ferrous form is observed by short-time ultraviolet A (UVA) irradiation of metHb together with nicotinamide adenine dinucleotide (NADH). And, severely structural destruction of metHb occurs when long-time UVA irradiation is exerted. However, neither reduction nor destruction can be observed in the absence of NADH under otherwise the same experimental conditions. Accordingly, the O2-binding ability of the protein increases by short-time UVA irradiation of metHb together with NADH, which corresponds with the reduction of metHb, while it decreases by long-time UVA irradiation, which corresponds with the structural destruction. Besides, it is found that the reduction reaction and the conformational destruction proceed more rapidly with higher concentrations of NADH.
Subject(s)
Hemoglobins/chemistry , Hemoglobins/radiation effects , NAD/chemistry , Ultraviolet Rays , Humans , Oxygen/chemistry , SpectrophotometryABSTRACT
OBJECTIVE: To observe the effects of Qingdan Capsule (QDC) and Yanggan Lidan Granule (YGLDG), two kinds of compound traditional Chinese herbal medicines, on biochemical parameters in guinea-pigs with pigment gallstones. METHODS: An animal model of pigment gallstones was established in male guinea-pigs by hypodermic injection of lincomycin. The guinea-pigs were randomly divided into blank control group, untreated group, QDC group and YGLDG group. There were 8 guinea-pigs in each group. After ten-day treatment, animals were sacrificed and sampled to calculate the rate of stone formation, total bilirubin (TB), unconjugated bilirubin (UCB) and Ca2+ density in bile of the four groups. RESULTS: In comparison with the untreated group, the rates of stone formation in the QDC and YGLDG groups were significantly decreased (P<0.01). TBIL, UCB and Ca2+ content of bile in both QDC and YGLD groups was also significantly decreased (P<0.05, P<0.01). CONCLUSION: QDC and YGLD have good effects on biochemical changes of animal model of pigment gallstone in reversing the lithogenesity of bile by reducing the content of TB, UCB and Ca2+, hence resulting in clinical treatment and prevention of pigment gallstone disease.