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1.
Future Sci OA ; 10(1): FSO926, 2024.
Article in English | MEDLINE | ID: mdl-38827800

ABSTRACT

Aim: This population-based analysis aimed to explore the associations among marital status, prognosis and treatment of stage I non-small-cell lung cancer. Materials & methods: The propensity score matching (PSM), logistic regression and Cox proportional hazards model were used in this study. Results: A total of 13,937 patients were included. After PSM, 10579 patients were co-insured. The married were more likely to receive surgical treatment compared with the unmarried patients (OR: 1.841, p < 0.001), and patients who underwent surgery also tended to have better survival (HR: 0.293, p < 0.001). Conclusion: Compared with unmarried patients, a married group with stage I NSCLC had timely treatment and more satisfactory survival. This study highlights the importance of prompt help and care for unmarried patients.

2.
Org Lett ; 26(22): 4672-4677, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38787765

ABSTRACT

Picrachinentins A-F (1-6, respectively), six novel cyclopeptide alkaloid-type burpitides (CPABs), were isolated and fully elucidated from the EtOH extract of the stems and leaves of Picrasma chinensis. Structurally, compounds 1-6 have a 14-membered paracyclophane ring system that was closed through an ether bond between the ß-hydroxy amino acid and tyrosine and modified with a 4,5-methylenedioxybenzoyloxy (MDBz, 3 and 5) or hexanoyl (Hexa, 1, 2, 4, and 6) group at the N-terminus. Interestingly, this is the first report on the isolation and characterization of CPABs from plants of the Simaroubaceae family. In addition, all compounds showed a neuroprotective effect against H2O2-damaged SH-SY5Y cells. Compound 1 was further investigated for its neuroprotective activities using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease animal model, and it dramatically improved MPTP-impaired motor behavioral performance. Biochemical analysis revealed compound 1 restored the tyrosine hydroxylase expression in the striatum of the MPTP-damaged mouse brain, which demonstrates its protective effect on dopaminergic neurons.


Subject(s)
Alkaloids , Neuroprotective Agents , Peptides, Cyclic , Picrasma , Neuroprotective Agents/pharmacology , Neuroprotective Agents/chemistry , Neuroprotective Agents/isolation & purification , Animals , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Peptides, Cyclic/isolation & purification , Mice , Picrasma/chemistry , Alkaloids/pharmacology , Alkaloids/chemistry , Alkaloids/isolation & purification , Molecular Structure , Humans , Hydrogen Peroxide/pharmacology , Hydrogen Peroxide/antagonists & inhibitors , Plant Leaves/chemistry , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology
3.
Fitoterapia ; 175: 105908, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38479621

ABSTRACT

Three undescribed sesquiterpenes, designed as pichinenoid A-C (1-3), along with nine known ones (4-12) were isolated from the stems and leaves of Picrasma chinensis. The new isolates including their absolute configurations were elucidated based on extensive spectroscopic methods, single crystal X-ray diffraction, and electronic circular dichroism (ECD) experiments, as well as comparison with literature data. Structurally, compounds 1 and 2 are descending sesquiterpenes, while pichinenoid C (3) is a rare sesquiterpene bearing a 2-methylenebut-3-enoic acid moiety at the C-6 side chain. All the isolated compounds were tested for their neuroprotective effects against the H2O2-induced damage on human neuroblastoma SH-SY5Y cells, and most of them showed moderate neuroprotective activity. Especially, compounds 1, 3-5, and 7 showed a potent neuroprotective effect at 25 or 50 µM. Moreover, the neuroprotective effects of compounds 1 and 4 were tested on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model. Results of western blot and immunofluorescence indicated that compound 4 significantly counteract the toxicity of MPTP, and reversed the expression of tyrosine hydroxylase (TH) in substantia nigra (SN) and striatum (ST) of the mouse brain. Interestingly, western blot data suggested compound 4 also enhanced B-cell lymphoma-2 (Bcl-2) and heme oxygenase 1 (HO-1) expressions in the brain tissues from MPTP damaged mouse.


Subject(s)
Neuroprotective Agents , Picrasma , Plant Leaves , Plant Stems , Sesquiterpenes , Animals , Neuroprotective Agents/pharmacology , Neuroprotective Agents/isolation & purification , Sesquiterpenes/pharmacology , Sesquiterpenes/isolation & purification , Mice , Humans , Cell Line, Tumor , Molecular Structure , Picrasma/chemistry , Plant Stems/chemistry , Plant Leaves/chemistry , Male , Heme Oxygenase-1/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , China , Phytochemicals/pharmacology , Phytochemicals/isolation & purification , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Mice, Inbred C57BL
4.
Phytochemistry ; 218: 113932, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38056516

ABSTRACT

Twenty-six clerodane diterpenoids have been isolated from T. sagittata, a plant species of traditional Chinese medicine Radix Tinosporae, also named as "Jin Guo Lan". Among them, there are eight previously undescribed clerodane diterpenoids (tinotanoids A-H: 1-8), and 18 known diterpenoids (9-26). The absolute configurations of compounds 1, 2, 5, 8, 13, 17 and 20 were determined by single-crystal X-ray diffraction. Compound 1 is the first example of rotameric clerodane diterpenoid with a γ-lactone ring which is constructed between C-11 and C-17; meanwhile, compounds 3 and 4 are two pairs of inseparable epimers. Compounds 2, 12 and 17 demonstrated excellent inhibitory activity on NO production against LPS-stimulated BV-2 cells with IC50 values of 9.56 ± 0.69, 9.11 ± 0.53 and 11.12 ± 0.70 µM, respectively. These activities were significantly higher than that of the positive control minocycline (IC50 = 23.57 ± 0.92 µM). Moreover, compounds 2, 12 and 17 dramatically reduced the LPS-induced upregulation of iNOS and COX-2 expression. Compounds 2 and 12 significantly inhibited the levels of pro-inflammatory cytokines TNF-α, IL-1ß and IL-6 that were increased by LPS stimulation.


Subject(s)
Diterpenes, Clerodane , Menispermaceae , Tinospora , Diterpenes, Clerodane/pharmacology , Diterpenes, Clerodane/chemistry , Tinospora/chemistry , Lipopolysaccharides/pharmacology , Plant Roots/chemistry , Molecular Structure
5.
Bioorg Chem ; 140: 106812, 2023 11.
Article in English | MEDLINE | ID: mdl-37651894

ABSTRACT

A total of 17 structurally diverse clerodane diterpenoids, including ten undescribed clerodane diterpenoids (tinopanoids K-T, 1-10) and seven known compounds (11-17), were isolated from the vines and leaves of Tinospora crispa. Compound 3 has not only bear the dominant substituents of γ-hydroxy-α, ß-unsaturated-γ-lactone with anti-inflammatory activity, but also a ternary epoxy structure at C-3/C-4. The planar structures and relative configurations of the clerodane diterpenoids were elucidated by spectroscopic data interpretation. The absolute configurations of compounds 1, 4, 8 and 13 were determined by single-crystal X-ray crystallographic, while that of compound 3 was determined using computed ECD data and single crystal X-ray diffraction of related p-bromobenzoate ester (3a). Subsequently, all compounds were evaluated for their inhibitory effect on nitric oxide (NO) production of LPS-activated BV-2 cells, and compounds 3 and 8 exhibited better NO inhibitory potency, with IC50 values of 5.6 and 13.8 µM than the positive control minocycline (Mino, IC50 = 22.9 µM). The corresponding results of western blot analysis and qRT-PCR revealed that compound 3 can significantly inhibit the inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) protein expressions, mRNA levels of pro-inflammatory cytokins of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6) and interleukin 1ß (IL-1ß). The underlying mechanism by which compound 3 exerted anti-neuroinflammatory effects was investigated by western blot and immunofluorescence assay, which suggested compound 3 inhibited LPS induced neuroinflammation via the suppression of toll-like receptor 4 (TLR4) dependent Signal Transducer and Activator of Transcription 3 (Stat3) and mitogen-activated protein kinase (MAPK) signaling pathways, and the activation of Heme Oxygenase-1 (HO-1) mediated signals.


Subject(s)
Diterpenes, Clerodane , Tinospora , Diterpenes, Clerodane/pharmacology , Lipopolysaccharides/pharmacology , Anti-Inflammatory Agents/pharmacology , Blotting, Western
6.
Carbohydr Res ; 532: 108918, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37586142

ABSTRACT

A triazolylsialoside-human serum albumin conjugate was prepared as a multivalent hemagglutinin and neuraminidase inhibitor using a di-(N-succinimidyl) adipate strategy. Matrix-Assisted Laser Desorption/Ionization-Time of Flight-Mass Spectrometry (MALDI-TOF-MS) indicated that five tetravalent sialyl galactosides were grafted onto the protein backbone resulting in an eicosavalent triazolylsialoside-protein complex. Compared with monomeric sialic acid, molecular interaction studies showed that the synthetic pseudo-glycoprotein bound tightly not only to hemagglutinin (HA)/neuraminidase (NA) but also to mutated drug-resistant NA on the surface of the influenza virus with a dissociation constant (KD) in the 1 µM range, attributed to the cluster effect. Moreover, this glycoconjugate exhibited potent antiviral activity against a broad spectrum of virus strains and showed no cytotoxicity towards Human Umbilical Vein Endothelial Cells (HUVECs) and Madin-Darby canine kidney (MDCK) cells at high concentrations. Further mechanistic studies demonstrated this multivalent sialyl conjugate showed strong capture and trapping of influenza virions, thus disrupting the ability of the influenza virus to infect host cells. This research lays the experimental foundation for the development of new antiviral agents based on multivalent sialic acid-protein conjugates.


Subject(s)
Influenza, Human , Animals , Dogs , Humans , Antiviral Agents/chemistry , Endothelial Cells/metabolism , Hemagglutinin Glycoproteins, Influenza Virus/metabolism , Hemagglutinins/metabolism , Madin Darby Canine Kidney Cells , N-Acetylneuraminic Acid/metabolism , Neuraminidase/metabolism , Serum Albumin, Human , Viral Proteins/antagonists & inhibitors , Viral Proteins/chemistry , Viral Proteins/metabolism , Virion/metabolism
7.
Inorg Chem ; 62(31): 12565-12572, 2023 Aug 07.
Article in English | MEDLINE | ID: mdl-37498665

ABSTRACT

Photocatalytic reduction of excess CO2 in the atmosphere to value-added chemicals by visible light can be an effective solution to fuel shortage and global warming. Considering these issues, we designed and successfully synthesized a trinuclear Re(I)-coordinated organic cage (Re-C4R) as the supramolecular photocatalyst. Photophysical, electrochemical properties, and photocatalytic performance comparison of Re-C4R and its mononuclear analogue Re-bpy are discussed in detail. Notably, the covalent linkage of three Re(I) subunits in Re-C4R leads to TONCO = 691 (per Re(I) site in 4 h) more than three times as much as TONCO = 208 of Re-bpy. Compared to Re-bpy, higher current enhancement in the control CV experiments under CO2 was observed for Re-C4R. CO2 adsorption process can be promoted because of the cryptand structure and multiple amine groups of Re-C4R. Moreover, decay lifetimes of Re-C4R are shorter than those of Re-bpy in the ultrafast transient absorption (TA) and photoluminescence (PL) decay spectra, indicating that the trinuclear cryptate structure of Re-C4R could facilitate electron transfer efficiency during CO2 reduction.

8.
Discov Med ; 35(176): 321-331, 2023 06.
Article in English | MEDLINE | ID: mdl-37272099

ABSTRACT

OBJECTIVE: Anti-angiogenic therapy has proven effective in non-small-cell lung cancer (NSCLC) patients. The purpose of this study was to evaluate the efficacy of programmed cell death protein 1 (PD-1) inhibitors combined with anti-angiogenic therapy in patients with driver gene mutation negative NSCLC and brain metastases (BMs). METHODS: A retrospective analysis was performed on NSCLC BMs in patients without driver gene mutations who received PD-1 inhibitors. Two groups, receiving either PD-1 inhibitor monotherapy or PD-1 inhibitor plus anti-angiogenesis therapy, were identified. The primary endpoints were overall survival (OS) and intracranial progression-free survival (iPFS). The secondary endpoints were safety, intracranial objective response rate (iORR) and intracranial disease control rate (iDCR). RESULTS: 113 NSCLC patients were included, 51 (45.1%) in the PD-1 inhibitor monotherapy group and 62 (54.9%) in the PD-1 inhibitor plus anti-angiogenesis therapy group. The median follow-up time was 26.2 months. OS was higher in the combination therapy cohort than in the monotherapy cohort (OS: 21.4 vs. 11.8 months; p = 0.004), with no significant difference in iPFS (p = 0.088). Moreover, the PD-1 inhibitor + anti-angiogenic therapeutic regimen exhibited the preferred iDCR (p = 0.005) but not the iORR (p = 0.121). There was no significant difference in the incidence of grade 3-4 adverse events between the two groups. In multivariate Cox regression analysis, PD-1 inhibitor therapy combined with anti-angiogenic treatment (p = 0.003) was an independent prognostic indicator of OS. CONCLUSIONS: Combining PD-1 inhibitor therapy with anti-angiogenic treatment significantly improves the OS of driver gene mutation negative NSCLC patients with BMs.


Subject(s)
Brain Neoplasms , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Immune Checkpoint Inhibitors , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Retrospective Studies , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Mutation
9.
J Am Chem Soc ; 144(19): 8778-8788, 2022 05 18.
Article in English | MEDLINE | ID: mdl-35507479

ABSTRACT

Supramolecular cage chemistry is of lasting interest because, as artificial blueprints of natural enzymes, the self-assembled cage structures not only provide substrate-hosting biomimetic environments but also can integrate active sites in the confined nanospaces for function synergism. Herein, we demonstrate a vertex-directed organic-clip chelation assembly strategy to construct a metal-organic cage Fe4L68+ (MOC-63) incorporating 12 imidazole proton donor-acceptor motifs and four redox-active Fe centers in an octahedral coordination nanospace. Different from regular supramolecular cages assembled with coordination metal vertices, MOC-63 comprises six ditopic organic-clip ligands as vertices and four tris-chelating Fe(N∩N)3 moieties as faces, thus improving its acid, base, and redox robustness by virtue of cage-stabilized dynamics in solution. Improved dehydrogenation catalysis of 1,2,3,4-tetrahydroquinoline derivatives is accomplished by MOC-63 owing to a supramolecular cage effect that synergizes multiple Fe centers and radical species to expedite intermediate conversion of the multistep reactions in a cage-confined nanospace. The acid-base buffering imidazole motifs play a vital role in modulating the total charge state to resist pH variation and tune the solubility among varied solvents, thereby enhancing reaction acceleration in acidic conditions and rendering a facile recycling catalytic process.


Subject(s)
Imidazoles , Metals , Catalysis , Imidazoles/chemistry , Ligands , Oxidation-Reduction , Solvents
10.
Aust N Z J Psychiatry ; 56(3): 292-300, 2022 Mar.
Article in English | MEDLINE | ID: mdl-33985351

ABSTRACT

OBJECTIVE: Cognitive impairment is prevalent in schizophrenia. Macrophage migration inhibitory factor which is released into the circulation under stress or inflammation, is associated with cognition and also plays an important role in immunity. However, no study has investigated the relationship between macrophage migration inhibitory factor and cognitive function in first-episode schizophrenia patients at baseline or after treatment. This study investigated the pre- and post-risperidone treatment correlations between serum macrophage migration inhibitory factor levels and cognitive function in first-episode schizophrenia patients. METHODS: A total of 83 first-episode schizophrenia patients who received risperidone monotherapy and 57 healthy controls - matched for sex, age, smoking status, education (years), marital status and waist-to-hip ratio - were included. Macrophage migration inhibitory factor levels were measured before and 10 weeks after treatment in the patient group and at baseline in the controls. Pre- and post-treatment cognitive functions in patients were assessed using the MATRICS Consensus Cognitive Battery. RESULTS: At baseline, macrophage migration inhibitory factor levels were significantly higher in first-episode schizophrenia patients than those in healthy controls (p < 0.01) and decreased in patients after 10 weeks of risperidone treatment compared with baseline (p < 0.05). The MATRICS Consensus Cognitive Battery total score and the sub-scores for the Trail Making Test, Symbol Coding, Letter Number Sequence, Maze and Brief Visuospatial Memory Test-Revised improved significantly after risperidone treatment. After controlling for age, sex, education, waist-to-hip ratio and smoking status, partial correlation analysis showed a positive correlation between baseline macrophage migration inhibitory factor levels and patients' baseline MATRICS Consensus Cognitive Battery verbal memory scores (r = 0.29, p = 0.01). Macrophage migration inhibitory factor changes correlated negatively with verbal memory changes (r = -0.26, p = 0.04). Multiple linear regression analysis identified a definite correlation between the changes in word memory test score and macrophage migration inhibitory factor level (ß = -0.09, p = 0.04). CONCLUSION: Macrophage migration inhibitory factor may be involved in the process of cognitive impairment in first-episode schizophrenia and repair mechanisms following risperidone treatment.


Subject(s)
Cognition Disorders , Cognitive Dysfunction , Macrophage Migration-Inhibitory Factors , Schizophrenia , Biomarkers , Cognition , Cognitive Dysfunction/etiology , Humans , Neuropsychological Tests , Schizophrenia/complications , Schizophrenia/drug therapy
11.
Carbohydr Res ; 495: 108088, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32807356

ABSTRACT

We report the preparation of multivalent amide-sialoside-decorated human serum albumin (HSA) and bovine serum albumin (BSA) as mimics of natural mucin and bioshields against influenza virus infection. Free sialic acid with an amine on C-2 was covalently attached to the protein scaffolds using di-(N-succinimidyl) adipate. Dynamic light scattering (DLS) showed that the synthetic neomucins were able to act as bioshields and aggregate the influenza virion particles. The dissociation constants (KD) of the interactions between the prepared glycoconjugates and three different viral strains were measured by isothermal titration calorimetry (ITC) indicating the multivalent presentation of sialyl ligands on the HSA and BSA backbones can dramatically enhance the adsorbent capability compared to the corresponding monomeric sialoside. Hemagglutinin inhibition (HAI) and neuraminidase inhibition (NAI) assays showed that the glycoconjugates acted as moderate HA and NA inhibitors, thus impeding viral infection. Moreover, the different binding affinities of the glycoproteins to HA and NA proteins from different influenza viruses demonstrated the importance of HA/NA balance in viral replication and evolution. These findings provide a foundation for the development of antiviral drugs and viral adsorbent materials based on mimicking the structure of mucin.


Subject(s)
Antiviral Agents/pharmacology , Glycerol/pharmacology , Influenza, Human/prevention & control , Mucins/metabolism , Orthomyxoviridae/drug effects , Stearates/pharmacology , Amides/chemistry , Amides/pharmacology , Animals , Antiviral Agents/chemistry , Cattle , Drug Combinations , Glycerol/chemistry , Hemagglutinin Glycoproteins, Influenza Virus/metabolism , Humans , Molecular Structure , Mucins/chemistry , Neuraminidase/antagonists & inhibitors , Neuraminidase/metabolism , Serum Albumin, Bovine/metabolism , Serum Albumin, Human/metabolism , Sialic Acids/chemistry , Sialic Acids/pharmacology , Stearates/chemistry
12.
Eur J Med Chem ; 199: 112357, 2020 Aug 01.
Article in English | MEDLINE | ID: mdl-32428793

ABSTRACT

We describe the preparation of thiosialoside-modified poly (methyl vinyl ether-alt-maleic anhydride) as second-generation polymeric conjugates for the inhibition of influenza virus infection. These synthetic glycopolymers show significantly enhanced neuraminidase inhibitory and antiviral activity in enzyme and cellular levels, respectively. The polyvalent thiosialosides also exhibit comparable inhibitory activity to the first-line anti-influenza drugs Zanamivir® and Oseltamivir® against the PR8 influenza virus strain in virus growth inhibition assays, which may be attributed to multivalent binding to neuraminidase on the virion particles, leading to the virion aggregation and further inhibiting the attaching/fusion and releasing steps in the influenza virus life-cycle. These findings suggest that attaching monomeric sialoside with neuraminidase inhibitory activity to a polymeric scaffold will synergistically disturb both the early and late stages of influenza virus infection, and provides a basis for the development of efficacious anti-viral agents against both wild-type and drug-resistant mutant strains.


Subject(s)
Antiviral Agents/pharmacology , Influenza A virus/drug effects , Orthomyxoviridae Infections/drug therapy , Polymers/pharmacology , Sialic Acids/pharmacology , Thioglycosides/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cells, Cultured , Dogs , Dose-Response Relationship, Drug , Madin Darby Canine Kidney Cells/drug effects , Madin Darby Canine Kidney Cells/virology , Microbial Sensitivity Tests , Molecular Structure , Polymers/chemical synthesis , Polymers/chemistry , Sialic Acids/chemical synthesis , Sialic Acids/chemistry , Structure-Activity Relationship , Thioglycosides/chemical synthesis , Thioglycosides/chemistry
13.
Gastroenterology ; 158(6): 1713-1727, 2020 05.
Article in English | MEDLINE | ID: mdl-31972238

ABSTRACT

BACKGROUND AND AIMS: The relationship between serum cholesterol level and development of hepatocellular carcinoma (HCC) remains unclear. We investigated the effects of serum cholesterol level on development of liver tumors in mice. METHODS: We performed studies with C57BL/6J mice, mice with disruption of the low-density lipoprotein receptor gene (Ldlr-/-mice), and mice with conditional deletion of nature killer (NK) cells (NKdele mice). Some C57BL/6J and NKdele mice were given injections of diethylinitrosamine to induce liver tumor formation. Mice were placed on a normal diet (ND) or high-cholesterol diet (HCD) to induce high serum levels of cholesterol. We also studied mice with homozygous disruption of ApoE (ApoE-/- mice), which spontaneously develop high serum cholesterol. C57BL/6J and NKdele mice on the ND or HCD were implanted with Hep1-6 (mouse hepatoma) cells and growth of xenograft tumors and lung metastases were monitored. Blood samples were collected from mice and analyzed by biochemistry and flow cytometry; liver and tumor tissues were collected and analyzed by histology, immunohistochemistry, and RNA-sequencing analysis. NK cells were isolated from mice and analyzed for cholesterol content, lipid raft formation, immune signaling, and changes in functions. We obtained matched tumor tissues and blood samples from 30 patients with HCC and blood samples from 40 healthy volunteers; levels of cholesterol and cytotoxicity of NK cells were measured. RESULTS: C57BL/6J mice on HCD and ApoE-/- mice with high serum levels of cholesterol developed fewer and smaller liver tumors and lung metastases after diethylinitrosamine injection or implantation of Hep1-6 cells than mice on ND. Liver tumors from HCD-fed mice and ApoE-/- mice had increased numbers of NK cells compared to tumors from ND-fed mice. NKdele mice or mice with antibody-based depletion for NK cells showed similar tumor number and size in ND and HCD groups after diethylinitrosamine injection or implantation of Hep1-6 cells. NK cells isolated from C57BL/6J mice fed with HCD had increased expression of NK cell-activating receptors (natural cytotoxicity triggering receptor 1 and natural killer group 2, member D), markers of effector function (granzyme B and perforin), and cytokines and chemokines compared with NK cells from mice on ND; these NK cells also had enhanced cytotoxic activity against mouse hepatoma cells, accumulated cholesterol, increased lipid raft formation, and immune signaling activation. NK cells isolated from HCD-fed Ldlr-/- mice did not have increased cholesterol content or cytotoxic activity against mouse hepatoma cells compared with ND-fed Ldlr-/- mice. Serum levels of cholesterol correlated with number and activity of NK cells isolated from human HCCs. CONCLUSIONS: Mice with increased serum levels of cholesterol due to an HCD or genetic disruption of ApoE develop fewer and smaller tumors after injection of hepatoma cells or a chemical carcinogen. We found cholesterol to accumulate in NK cells and activate their effector functions against hepatoma cells. Strategies to increase cholesterol uptake by NK cells can be developed for treatment of HCC.


Subject(s)
Carcinoma, Hepatocellular/immunology , Cholesterol/blood , Killer Cells, Natural/immunology , Liver Neoplasms/immunology , Lung Neoplasms/immunology , Animals , Carcinoma, Hepatocellular/blood , Carcinoma, Hepatocellular/chemically induced , Carcinoma, Hepatocellular/secondary , Cell Line, Tumor/transplantation , Cholesterol/metabolism , Diet, Atherogenic , Diethylnitrosamine/toxicity , Disease Models, Animal , Female , Humans , Killer Cells, Natural/metabolism , Liver Neoplasms/blood , Liver Neoplasms/chemically induced , Liver Neoplasms/pathology , Lung Neoplasms/blood , Lung Neoplasms/secondary , Male , Mice , Mice, Knockout, ApoE , Receptors, LDL/genetics
14.
Int J Antimicrob Agents ; 55(1): 105806, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31533074

ABSTRACT

OBJECTIVES: To characterize the colistin-resistant bacterial population in the gut and assess diversity of mcr-1 transmission within a single individual. METHODS: Large numbers of isolates (>100 colonies/chicken cecum sample) were collected from nine randomly selected mcr-1-positive chickens in China and used for comprehensive microbiological, molecular and comparative genomics analyses. RESULTS: Of 1273 colonies, 968 were mcr-1 positive (962 Escherichia coli, two Escherichia fergusonii, two Klebsiella pneumoniae and two Klebsiella quasipneumoniae). One to six colistin-resistant species and three to 10 E. coli pulsed-field gel electrophoresis (PFGE) clusters could be identified from each sample. Whole-genome sequencing (WGS) analysis of the representative E. coli strains revealed three to nine sequence types observed in a single chicken host. The mcr-1 genes are located in either chromosomes or plasmids of different types, including IncI2 (n=30), IncHI2 (n=14), IncX4 (n=4), p0111(n=2) and IncHI1(n=1). Strikingly, in single cecum samples, one to five Inc type plasmids harbouring mcr-1 could be identified. Great diversity was also observed for the same IncI2 plasmid within a single chicken host. In addition, up to eight genetic contexts of the mcr-1 gene occurred within a single chicken. CONCLUSIONS: There is extensive heterogeneity and flexibility of mcr-1 transmission in chicken gut due to bacterial species differences, distant clonal relatedness of isolates, many types and variations of mcr-positive plasmids, and the flexible genetic context of the mcr-1 gene. These compelling findings indicate that the gut is a 'melting pot' for active horizontal transfer of the mcr-1 gene.


Subject(s)
Chickens/microbiology , Enterobacteriaceae Infections/microbiology , Enterobacteriaceae/enzymology , Escherichia coli Infections/microbiology , Escherichia coli Proteins/genetics , Escherichia coli/enzymology , Poultry Diseases/microbiology , Animals , Anti-Bacterial Agents/pharmacology , Cecum/microbiology , China/epidemiology , Colistin/pharmacology , Drug Resistance, Bacterial/genetics , Electrophoresis, Gel, Pulsed-Field/veterinary , Enterobacteriaceae/drug effects , Enterobacteriaceae/genetics , Enterobacteriaceae Infections/epidemiology , Escherichia coli/drug effects , Escherichia coli/genetics , Escherichia coli Infections/epidemiology , Gene Transfer, Horizontal , Microbial Sensitivity Tests/veterinary , Plasmids/genetics , Poultry Diseases/epidemiology , Whole Genome Sequencing/veterinary
15.
Med. clín (Ed. impr.) ; 153(12): 454-459, dic. 2019. graf, tab
Article in English | IBECS | ID: ibc-188455

ABSTRACT

Objective: Birth month and climate affect lifetime disease risk, while the underlying mechanisms remain largely elusive. It is vital to investigate the risks of coronary artery disease (CAD) and its complications in patients born in different months. Methods: A total of 12,263 patient medical records were reviewed from the BioBank of First Affiliated Hospital of Xinxiang Medical University, with 4729 records from patients with CAD (CAD group) and 7534 records from control patients without CAD (control group). Two groups of patients were matched by the propensity score matched method. Birth months were compared between two groups of patients. The relationships between birth month and the numbers of CAD and its complications were also investigated. Interestingly, we also explore the relationship between the birth seasons and the numbers of CAD and its complications. Results: Compared to control, CAD group had greater CAD risks for patients born in November (OR 1.390, 95% CI 1.090-1.772), December (OR 1.358, 95% CI 1.067-1.730), and February (OR 1.332, 95% CI 1.043-1.700) compared to those born in May. Compared to patients born in December, patients born in January to March and May to September had greater risk of heart failure (P<0.05). There was no difference in the incidence of myocardial infarction, conduction block, and atrial fibrillation across birth months (P>0.05). In terms of birth season, patients born in winter have greater CAD risk than those born in spring (OR 1.247, 95% CI 1.075-1.447). And there was no difference in the incidence of CAD complications across with birth seasons (P>0.05). Conclusions: There was a correlation between birth month and CAD. People born in November, December, and February had greater CAD risk, and people born in winter had greater CAD risk. Among CAD patients, those born in January to March and May to September had the greater risk of heart failure


Objetivo: El mes de nacimiento y el clima están relacionados con el riesgo de padecer una enfermedad crónica, aunque siguen desconociéndose en gran medida los mecanismos subyacentes. Resulta fundamental investigar los riesgos de padecer una arteriopatía coronaria (AC) y sus complicaciones en pacientes nacidos en distintos meses. Métodos: Se revisaron un total de 12.263 historias clínicas de pacientes extraídas del Biobanco del primer hospital afiliado de la Universidad Médica de Xinxiang, de las cuales 4.729 correspondían a pacientes con una AC (grupo con AC) y 7.534 correspondían a pacientes control sin una AC (grupo comparativo). Se emparejaron a 2 grupos de pacientes siguiendo el método de pareamiento por puntaje de propensión, y se compararon los meses de nacimiento de los pacientes de ambos grupos. También se investigó la relación existente entre el mes de nacimiento y el número de casos de AC y sus complicaciones. Resulta interesante destacar que también exploramos la relación existente entre las estaciones de nacimiento y el número de casos de AC y sus complicaciones. Resultados: En comparación con los pacientes del grupo comparativo, los pacientes del grupo con AC nacidos en noviembre (razón de posibilidades odds ratio [OR]: 1,390; intervalo de confianza [IC] del 95%: 1,090-1,772), diciembre (OR: 1,358; IC 95%: 1,067-1,730) y febrero (OR: 1,332; IC 95%: 1,043-1,700) presentaban un mayor riesgo de padecer una AC en comparación con los nacidos en mayo. En comparación con los pacientes nacidos en diciembre, los pacientes nacidos entre enero y marzo, y entre mayo y septiembre, presentaron un mayor riesgo de padecer una insuficiencia cardíaca (P<0,05). No se observaron diferencias en la incidencia de infarto de miocardio, bloqueo de la conducción y fibrilación auricular entre los distintos meses de nacimiento (P>0,05). En cuanto a la temporada de nacimiento, los pacientes nacidos en invierno presentaron un mayor riesgo de desarrollar una AC que los nacidos en primavera (OR: 1,247; IC 95%: 1,075-1,447). No se observaron diferencias en la incidencia de complicaciones de la AC entre las distintas temporadas de nacimiento (P>0,05). Conclusiones: Se observó una correlación entre el mes de nacimiento y la AC. Tanto las personas nacidas en los meses de noviembre, diciembre y febrero, como las nacidas en la temporada de invierno presentaron un mayor riesgo de padecer una AC. Entre los pacientes con AC, los nacidos entre enero y marzo, y entre mayo y septiembre, presentaron un mayor riesgo de padecer una insuficiencia cardíaca


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Coronary Artery Disease/complications , Propensity Score , Risk Factors , Climate , Odds Ratio , Confidence Intervals , Heart Failure/epidemiology , Myocardial Infarction/epidemiology , Atrial Fibrillation/epidemiology , Correlation of Data
16.
Med Clin (Barc) ; 153(12): 454-459, 2019 12 27.
Article in English, Spanish | MEDLINE | ID: mdl-31122721

ABSTRACT

OBJECTIVE: Birth month and climate affect lifetime disease risk, while the underlying mechanisms remain largely elusive. It is vital to investigate the risks of coronary artery disease (CAD) and its complications in patients born in different months. METHODS: A total of 12,263 patient medical records were reviewed from the BioBank of First Affiliated Hospital of Xinxiang Medical University, with 4729 records from patients with CAD (CAD group) and 7534 records from control patients without CAD (control group). Two groups of patients were matched by the propensity score matched method. Birth months were compared between two groups of patients. The relationships between birth month and the numbers of CAD and its complications were also investigated. Interestingly, we also explore the relationship between the birth seasons and the numbers of CAD and its complications. RESULTS: Compared to control, CAD group had greater CAD risks for patients born in November (OR 1.390, 95% CI 1.090-1.772), December (OR 1.358, 95% CI 1.067-1.730), and February (OR 1.332, 95% CI 1.043-1.700) compared to those born in May. Compared to patients born in December, patients born in January to March and May to September had greater risk of heart failure (P<0.05). There was no difference in the incidence of myocardial infarction, conduction block, and atrial fibrillation across birth months (P>0.05). In terms of birth season, patients born in winter have greater CAD risk than those born in spring (OR 1.247, 95% CI 1.075-1.447). And there was no difference in the incidence of CAD complications across with birth seasons (P>0.05). CONCLUSIONS: There was a correlation between birth month and CAD. People born in November, December, and February had greater CAD risk, and people born in winter had greater CAD risk. Among CAD patients, those born in January to March and May to September had the greater risk of heart failure.


Subject(s)
Coronary Artery Disease/complications , Coronary Artery Disease/epidemiology , Parturition , Seasons , Aged , Female , Humans , Male , Middle Aged , Propensity Score , Retrospective Studies , Risk Assessment
17.
Sci Rep ; 6: 38511, 2016 12 05.
Article in English | MEDLINE | ID: mdl-27917926

ABSTRACT

Since initial identification in China, the widespread geographical occurrence of plasmid-mediated colistin resistance gene mcr-1 in Enterobacteriaceae has been of great concern. In this study, a total of 22 Salmonella enterica were resistant to colistin, while only five isolates which belonged to ST34 Salmonella enterica serovar Typhimurium (S. Typhimurium) were mcr-1 positive. Four of them shared nearly identical PFGE type, although they were from different host species and diverse geographical locations. All the mcr-1-positive S. Typhimurium exhibited multi-resistant phenotypes including ampicillin, streptomycin, gentamicin, florfenicol, nalidixic acid, tetracycline, trimethoprim-sulfamethox, in addition to colistin. The oqxAB and aac(6')-Ib-cr genes were present alone or in combination in four (80.0%) and five (100%) isolates, respectively. The mcr-1 gene was located on a transferable IncI2 plasmid in the four genetically related strains. In the other one strain, mcr-1 was located on an approximately 190 kb IncHI2 plasmid. In conclusion, we report five mcr-1-positive S. Typhimurium/ST34 isolates. Both clonal expansion and horizontal transmission of IncI2-type plasmids were involved in the spread of the mcr-1 gene in Salmonella enterica from food-producing animals in China. There is a great need to monitor the potential dissemination of the mcr-1 gene.


Subject(s)
Drug Resistance, Multiple, Bacterial/genetics , Genes, Bacterial , Plasmids/metabolism , Salmonella Infections, Animal/microbiology , Salmonella typhimurium/genetics , Salmonella typhimurium/isolation & purification , Animals , Base Sequence , Clone Cells , Colistin , Electrophoresis, Gel, Pulsed-Field , Microbial Sensitivity Tests , Molecular Typing
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