Activation of nuclear factor erythroid 2-related factor 2(Nrf2)by Kelch-like ECH-associated protein 1(Keap1)alkylation plays a central role in anti-inflammatory therapy.However,activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified.Deoxynyboquinone(DNQ)is a natural small molecule discovered from marine actinomycetes.The current study was designed to investigate the anti-inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1.DNQ exhibited signif-icant anti-inflammatory properties both in vitro and in vivo.The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be the α,β-unsaturated amides moieties by a chemical reaction between DNQ and N-acetylcysteine.DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway.Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation.The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry.DNQ triggered the ubiquitination and subsequent degra-dation of Keap1 by alkylation of the cysteine residue 489(Cys489)on Keap1-Kelch domain,ultimately enabling the activation of Nrf2.Our findings revealed that DNQ exhibited potent anti-inflammatory capacity through α,β-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain,suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ-like small molecules in inflammatory therapies.

Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.
Humans ; Female ; Blood Platelets/pathology* ; Biomarkers, Tumor/genetics* ; Ovarian Neoplasms/pathology* ; China

General anesthesia is an unconscious state induced by anesthetics for surgery. The molecular targets and cellular mechanisms of general anesthetics in the mammalian nervous system have been investigated during past decades. In recent years, K channels have been identified as important targets of both volatile and intravenous anesthetics. This review covers achievements that have been made both on the regulatory effect of general anesthetics on the activity of K channels and their underlying mechanisms. Advances in research on the modulation of K channels by general anesthetics are summarized and categorized according to four large K channel families based on their amino-acid sequence homology. In addition, research achievements on the roles of K channels in general anesthesia in vivo, especially with regard to studies using mice with K channel knockout, are particularly emphasized.
Anesthetics, General ; pharmacology ; therapeutic use ; Animals ; Humans ; Potassium Channels ; metabolism

Authors raised that staging based strategies and practice of integrative medicine (IM) by combining syndrome typing and disease identification, and choosing suitable measures in accordance with different persons and seasonal conditions after more than ten years' clinical practice and researches. Radical operation as prior (as evil eliminating) and strengthening vital qi in perioerative period are best strategy for promoting rapid rehabilitation of early stage prostate cancer patients. Strengthening body resistance to eliminate evil was used in treating advanced prostate cancer patients. For example, a comprehensive treatment program for hormone-dependent patients was combined with endocrinotherapy and Chinese herbs for synergisic efficacy-enhancing actions. In this way, these patients' quality of life (QOL) were improved and time to castration resistant prostate cancer (CRPC) was delayed, even some patients were clinically cured. There are lack of effective medicines and methods for CRPC patients. Greatly tonifying original qi is mainly used for improving their clinical symptoms and prolonging survivals. Practice has proved staging based strategies and practice of IM has favorable advantages in treating prostate cancer, especially showing prospect in prolonging survival and postponing progression of advanced prostate cancer patients. Besides, it also could provide beneficial considerations and inspiration for combination of syndrome typing and disease identification.
Disease Progression ; Humans ; Male ; Medicine, Chinese Traditional ; Neoplasm Staging ; Prostatic Neoplasms, Castration-Resistant ; diagnosis ; Quality of Life

OBJECTIVETo investigate the effects of silencing ADP-ribosylation factor 6 (Arf6) on the proliferation, migration, and invasion of prostate cancer cell line PC-3 and the possible molecular mechanisms.

METHODSThree Arf6-specific small interfering RNA (siRNA) were transfected into cultured prostate cancer cell line PC-3. Arf6 expression was examined by real-time PCR and Western blotting. MTT assay, wound healing assay, and Transwell migration and invasion assay were used to observe the effect of Arf6 silencing on the proliferation, migration, and invasion ability of PC-3 cells. The levels of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), ERK1/2, p-AKT, AKT and Rac1 were detected by Western blotting.

RESULTSTransfection of siRNA-3 resulted in significantly decreased Arf6 mRNA and protein expression with inhibition rates of (91.88±3.13)% and (86.37±0.57)%, respectively. Arf6 silencing by siRNA-3 markedly suppressed the proliferation, migration and invasion of PC-3 cells and reduced the expression levels of p-ERK1/2 and Rac1.

CONCLUSIONSilencing of Arf6 efficiently inhibits the proliferation, migration, and invasion of PC-3 cells in vitro, and the underlying mechanisms may involve the down-regulation of p-ERK1/2 and Rac1.

ADP-Ribosylation Factors ; genetics ; metabolism ; Cell Line, Tumor ; Cell Movement ; Down-Regulation ; Humans ; Male ; Mitogen-Activated Protein Kinase 1 ; metabolism ; Mitogen-Activated Protein Kinase 3 ; metabolism ; Neoplasm Invasiveness ; Prostatic Neoplasms ; pathology ; RNA Interference ; RNA, Messenger ; genetics ; metabolism ; RNA, Small Interfering ; genetics ; Real-Time Polymerase Chain Reaction ; Transfection ; Wound Healing ; rac1 GTP-Binding Protein ; metabolism

OBJECTIVETo assess the association between SIRT1 gene polymorphisms and the longevity phenomena in Yongfu region of Guangxi. In this case-control study, 500 individuals from Yongfu region of Guangxi were recruited. The subjects were divided into a longevity group (n=223, average age=93.17 U+00B1 3.08 yr) and a healthy control group (n=277, average age=46.92 U+00B1 17.12 yr). Polymerase chain reaction-high resolution melting curve (PCR-HRM) and DNA sequencing were used to determine the allelic and genotypic frequencies of rs3758391, rs3740051, rs2273773, rs4746720 and rs10997870 polymorphisms of SIRT1 gene in the two groups. The association between above polymorphisms and longevity was assessed.

RESULTSIn the longevity group, CT genotype of the rs4746720 locus was significantly more common than CC and TT genotypes (P=0.000, OR=2.098, 95%CI:1.412-4.117). However, no significant difference was found in the allelic and genotypic frequencies of rs3758391, rs3740051 and rs2273773 between the two groups.

CONCLUSIONThere is an association between rs4746720 of SIRT1 gene and longevity in Yongfu region of Guangxi.

Adult ; Aged ; Aged, 80 and over ; Alleles ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; Case-Control Studies ; China ; Female ; Gene Frequency ; Gene Order ; Genetic Association Studies ; Genotype ; Humans ; Longevity ; genetics ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Sirtuin 1 ; genetics ; Young Adult

OBJECTIVETo explore the molecular basis of an individual featuring an ABx variant of ABO blood group system.

METHODSSerological assays were used to characterize the erythrocyte phenotypes and salivary ABH secretors. All of the seven exons and flanking introns of ABO glycosyltransferase gene were amplified with polymerase chain reaction (PCR). And the products were sequenced bidirectionally following enzyme digestion. Exons 6 and 7 were also subcloned and analyzed for haplotypes of the ABO gene.

RESULTSErythrocytes of the proband have expressed a strong A antigen and a weak B antigen, which was identified as a rare ABx variant in addition with other serological features. Nine heterozygous sites in exon 6 (297A/G) and exon 7 (467C/T, 526C/G, 657C/T, 703G/A, 796C/A, 803G/C, 808T/A, 930G/A) of the coding region of the ABO gene were identified. Based on haplotype analysis, one allele was determined as common A102, whilst another was consistent with B101 except for an 808T>A mutation which has resulted in replacement of phenylalanine with isoleucine at position 270 of glycosyltransferase B.

CONCLUSIONThe 808T>A mutation of the glycosyltransferase B gene may decrease the enzymatic activity and result in the Bx variant.

ABO Blood-Group System ; genetics ; Adult ; Exons ; Female ; Glycosyltransferases ; genetics ; Haplotypes ; Humans ; Mutation

OBJECTIVETo evaluate the efficacy and safety of endoscopic mucous resection with transparent cap (EMR-Cap) and endoscopic multi-band mucosectomy (MBM) in the treatment of early esophageal cancer and precancerous lesion.

METHODSA retrospective study was performed to review 30 EMR-Cap cases from December 2008 to December 2009 and 32 MBM cases from January 2010 to January 2011 of early esophageal cancer and precancerous lesions. The differences between these two techniques in efficacy, safety, and cost were compared.

RESULTSIn EMR-Cap group, the median resection time was 26(10-56) min and median procedure time was 43(22-81) min, significantly longer than those in MBM group [10(7-18) min and 32(28-45) min, P=0.036 and 0.038, respectively]. There were no significant differences between the two groups in total thickness and depth of resected lesions (P>0.05). In EMR-Cap group, the median cost was significantly higher than that of MBM group [(5466±354) vs. (4014±368) RMB, P=0.008)].

CONCLUSIONSEMR-Cap and MBM are minimally invasive, safe and effective methods in the treatment of early esophageal cancer and precancerous lesions. Compared to the EMR-Cap, MBM is simple with shorter treatment time and lower cost.

Aged ; Endoscopy ; methods ; Esophageal Neoplasms ; surgery ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Mucous Membrane ; surgery ; Precancerous Conditions ; surgery ; Retrospective Studies ; Treatment Outcome

BACKGROUND: Hypothermia is associated with poor outcome in trauma patients; however, hemorrhagic shock (HS) model with anesthetized swine was different from that of clinical reality. To identify the effects of environmental hypothermia on HS, we investigated hemodynamics and oxygen dynamics in an unanesthetized swine model of HS under simulating hypothermia environment.METHODS: Totally 16 Bama pigs were randomly divided into ambient temperature group (group A) and low temperature group (group B), 8 pigs in each group. Venous blood (30 mL/kg) was continuously withdrawn for more than 15 minutes in conscious swine to establish a hemorrhagic shock model. Pulmonary arterial temperature (Tp), heart rate (HR), mean arterial pressure (MAP), pulmonary arterial pressure (PAP), pulmonary arterial wedge pressure (PAWP), central venous pressure (CVP), cardiac output (CO), hemoglobin (Hb), saturation of mixed venous blood (SvO2) and blood gas analysis were recorded at the baseline and different hemorrhagic shock time (HST). The whole body oxygen delivery indices, DO2I and VO2I, and the O2 extraction ratio (O2ER) were calculated.RESULTS: Core body temperature in group A decreased slightly after the hemorrhagic shock model was established, and environmental hypothermia decreased in core body temperature. The mortality rate was significantly higher in group B (50％) than in group A (0％). DO2I and VO2I decreased significantly after hemorrhage. No difference was found in hemodynamics, DO2I and VO2I between group A and group B, but the difference in pH, lactic acid and O2ER was significant between the two groups.CONCLUSION: Environmental hypothermia aggravated the disorder of oxygen metabolism after hemorrhagic shock, which was associated with poor prognosis.

OBJECTIVETo explore the recording method of the electrophysiological signals in corticospinal tract (CST) of adult rats by plugging microelectrodes and analyze the characteristics of these signals. These could provide some valuable and basic neural electrophysiological information for further research of recovering and refunctioning after spinal cord injury.

METHODSThe microelectrodes were plugged into the corticospinal tract at the T8 spinal section of Sprague-Dawley rats and the neuro-electrical signals were identified and recorded from CST by means of the Cerebus System. The characteristics of the recorded signals were described with the help of the Offline sorter and Neuroexplorer softwares, including the wavelength, amplitude, discharging frequency, the synchrony among the multi-discharging units from the same electrode and two different electrodes, analysis of interspike interval (ISI), etc.

RESULTSThe continuous and steady spontaneous electrophysiological signals were recorded from CST. Three or four types of discharging signals originated from different discharging units were collected with each electrode. The waveform of the signals appeared bidirectional. The wavelengths were 0.6 - 1.3 ms with wave amplitudes at a grade of hundred microvoltage and high signal-noise ratios. The LFB staining proved that the electrodes were accurately plugged into the corticospinal tract.

CONCLUSIONThe neuro-electrical signals at a grade of hundred microvoltage could be recorded stably from the corticospinal tract of rats by the Cerebus System with the microelectrodes, which provided valuable and basic neural electrophysiological information for further research on recovering and refunctioning after spinal cord injury (SCI) by analyzing the characteristics of electrophysiological signals.

Animals ; Electrodes, Implanted ; Electrophysiological Phenomena ; physiology ; Evoked Potentials, Motor ; physiology ; Male ; Microelectrodes ; Pyramidal Tracts ; physiology ; Rats ; Rats, Sprague-Dawley ; Spinal Cord ; physiology ; Spinal Cord Injuries ; physiopathology