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1.
Chemosphere ; 239: 124796, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31520972

RESUMO

In July 2013, a fatal train derailment led to an explosion and fire in the town of Lac-Mégantic (LM), Quebec, and the crude oil contamination of regional surface water, soil, and sediment in the adjacent Lake Mégantic. This study investigated the degradation potential of the spilled crude oil by using the sediments from the incident site as the source of microorganisms. Two light crude oils (LM source oil and Alberta Sweet Mixed Blend (ASMB)) were tested at 22 °C for 4 weeks and 4 °C for 8 weeks, respectively. The post-incubation biological and chemical information of the samples were analysed. There was no marked difference in degradation efficacy and biological activities for both the LM and ASMB oils, although the biodegradation potential differed between the two incubations. Higher temperature favoured the growth of microorganisms, thus for the degradation of all petroleum hydrocarbons, except for some conservative biomarkers. The degradation of both oils followed the order of resolved components > total saturated hydrocarbons (TSH) > unresolved complex mixture (UCM) >total aromatic hydrocarbons (TAH). Normal alkanes were generally degraded more significantly than branched ones, and polycyclic aromatic hydrocarbons (PAHs). Degradation of polycyclic aromatic hydrocarbons (PAHs) and their alkylated congeners (APAHs) for both incubations generally decreased as the number of aromatic rings, and the degree of alkylation increased. This study showed that the LM sediments can biodegrade the petroleum hydrocarbons efficaciously if appropriate ambient temperatures are generated to favour the growth of autochthonous microorganisms.

2.
Methods Mol Biol ; 2043: 265-273, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31463919

RESUMO

Cell surface proteolysis controls numerous biological processes including cell-cell attachment and the communication between cells. The membrane-tethered families of matrix metalloproteinases (MT-MMPs) and disintegrin metalloproteinases (ADAMs) are major enzymes involved in the cleavage of molecules at the cell surface, and their activity is finely regulated by their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). The biological function of a metalloproteinase closely depends on the subset of substrates that it cleaves. Similarly, molecular processes that are regulated by a specific TIMP strictly depend on its unique inhibitory profile.Herein, we describe a mass spectrometry-based method for the quantitative analysis of protein abundance in conditioned media of cultured cells that is particularly suited for substrate identification of membrane-tethered metalloproteinases and for the identification of membrane proteins whose cleavage is regulated by TIMPs. This unbiased proteomic method represents a valuable tool to investigate biological functions of metalloproteinases and TIMPs at the "omic" level.

3.
Nat Chem ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792388

RESUMO

Topological transitions between considerably different phases typically require harsh conditions to collectively break chemical bonds and overcome the stress caused to the original structure by altering its correlated bond environment. In this work we present a case system that can achieve rapid rearrangement of the whole lattice of a metal-organic framework through a domino alteration of the bond connectivity under mild conditions. The system transforms from a disordered metal-organic framework with low porosity to a highly porous and crystalline isomer within 40 s following activation (solvent exchange and desolvation), resulting in a substantial increase in surface area from 725 to 2,749 m2 g-1. Spectroscopic measurements show that this counter-intuitive lattice rearrangement involves a metastable intermediate that results from solvent removal on coordinatively unsaturated metal sites. This disordered-crystalline switch between two topological distinct metal-organic frameworks is shown to be reversible over four cycles through activation and reimmersion in polar solvents.

4.
Int J Colorectal Dis ; 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31786652

RESUMO

OBJECTIVE: To develop a predicting model for tumor resistance to neoadjuvant chemoradiotherapy (NCRT) in locally advanced rectal cancer (LARC) by using pre-treatment apparent diffusion coefficient (ADC) image-derived radiomics features. METHOD: A total of 89 patients with LARC were randomly assigned into training (N = 66) and testing cohorts (N = 23) at the ratio of 3:1. Radiomics features were derived from manually determined tumor region of pre-treatment ADC images. Random forest algorithm was used to determine the most relevant features and then to construct a predicting model for identifying resistant tumor. Stability and diagnostic performance of the random forest model was evaluated with the testing cohort. RESULTS: The top 10 most relevant features (entropymean, inverse variance, energymean, small area emphasis, ADCmin, ADCmean, sdGa02, small gradient emphasis, age, and size) were determined from clinical characteristics and 133 radiomics features. In the prediction of resistant tumor of the testing cohort, the random forest model constructed based on these most relevant features achieved an area under the receiver operating characteristic curve of 0.83, with the highest accuracy of 91.3%, a sensitivity of 88.9%, and a specificity of 92.8%. CONCLUSION: The random forest classifier based on radiomics features derived from pre-treatment ADC images have the potential to predict tumor resistance to NCRT in patients with LARC, and the use of predicting model may facilitate individualized management of rectal cancer.

5.
Bioorg Chem ; : 103469, 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31787345

RESUMO

Obovatol, a novel lignan isolated from the leaf and stem bark of Magnolia obovata Thunb exhibits many important biological activities. To discover natural-product-based potential fungicides with novel structural skeletons, a series of Mannich base derivatives were prepared by the C-4-aminomethylated modification of obovatol and all synthesized compounds were evaluated for antifungal activities in vitro against several phytopathogenic fungi using the spore germination method and the mycelium growth rate method. Furthermore, their structures were also characterized by 1H NMR, 13C NMR, and HR-MS, and compound 2k was further analyzed by single-crystal X-ray diffraction. Among all of the derivatives, compounds 2b (IC50 = 28.68 µg/mL) and 2g (IC50 = 16.90 µg/mL) demonstrated greater inhibition of Botrytis cinerea spore germination than two positive controls, hymexazol and difenoconazole. Compounds 2c, 2f, and 2g displayed potent mycelial growth inhibition of B. cinerea with an average inhibition rate (AIR) of >90% at a concentration of 100 µg/mL. Additionally, the structure-activity relationships (SARs) suggested that the introduction of a diethylamino, pyrrolyl, 1-methyl-piperazinyl or 1-ethyl-piperazinyl groups on the C-4 position of obovatol may be more likely to yield potential antifungal compounds than the introduction of 4-phenyl-piperazinyl or 4-phenyl-piperidinyl groups.

6.
J Crit Care ; 56: 12-17, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31785505

RESUMO

PURPOSE: This study investigated the feasibility and efficacy of continuous noninvasive ventilation (NIV) support with 100% oxygen using a specially designed face mask, for reducing desaturation during fiberoptic bronchoscopy (FOB)-guided intubation in critically ill patients with respiratory failure. MATERIALS AND METHODS: This was a single-center prospective randomized study. All patients undergoing FOB-guided nasal tracheal intubation were randomized to bag-valve-mask ventilation or NIV for preoxygenation followed by intubation. The NIV group were intubated through a sealed hole in a specially designed face mask during continuous NIV support with 100% oxygen. Control patients were intubated with removal of the mask and no ventilatory support. RESULTS: We enrolled 106 patients, including 53 in each group. Pulse oxygen saturation (SpO2) after preoxygenation (99% (96%-100%) vs. 96% (90%-99%), p = .001) and minimum SpO2 during intubation (95% (87%-100%) vs. 83% (74%-91%), p < .01) were both significantly higher in the NIV compared with the control group. Severe hypoxemic events (SpO2 < 80%) occurred less frequently in the NIV group than in controls (7.4% vs. 37.7%, respectively; p < .01). CONCLUSIONS: Continuous NIV support during FOB-guided nasal intubation can prevent severe desaturation during intubation in critically ill patients with respiratory failure. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02462668. Registered on 25 May 2015, https://www.clinicaltrials.gov/ct2/results?term=NCT02462668.

7.
J Clin Pathol ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796635

RESUMO

AIM: Tissue microarray (TMA) is a powerful and effective tool for in situ tissue analysis. However, manual TMA construction methods showed varied qualities. This study aimed to raise a standardised TMA preparation technique that can be easily operated and is economical. METHODS: A sampling needle was used to punch the tissue rods from the donor block and holes in the recipient block. To indicate the dots' positions and ensure vertical punching, a novel auxiliary device made using commercial three-dimensional printing technology was attached. The TMA block was made up of tissue rods and a recipient block. RESULTS: A 77-rod (7×11) TMA block was constructed. The rows and columns were fixed in straight lines. There was no specimen loss during the process of embedding. CONCLUSIONS: An alternative method for the construction of TMA blocks that met the basic requirement of many laboratories and can be effortlessly performed was presented.

8.
Sleep Med Rev ; 50: 101235, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31801100

RESUMO

Disruption of the sleep-wake cycle is a risk factor and a prodromal indicator of delirium. Melatonergic agents may thus play a role in the prevention of delirium. Based upon literature search on eight databases, this systemic review and frequentist model network meta-analysis (NMA) aimed to determine the efficacy and tolerability of melatonergic agents in delirium prevention. Six randomized controlled trials (RCTs) were included with a total of 913 adult participants (mean age = 78.8, mean female proportion = 59.4%) investigating the preventive effects of melatonergic agents in patients with high risks of developing delirium. The outcomes of NMA demonstrated significant preventive effects with 5 mg/day of melatonin [Odds Ratio (OR) = 0.21, 95% Confidence Intervals (CIs): 0.07 to 0.64], melatonin (0.5 mg/d) [OR = 0.16 (95% CIs: 0.03 to 0.75)], and ramelteon (8 mg/d) [OR = 0.28 (95% CIs: 0.12 to 0.65)] against placebo groups. According to the surface under the cumulative ranking curve (SUCRA), 0.5 mg/d of melatonin was associated with the best preventive effect. Our findings provided the rationale for recommending low-dose melatonergic agents for delirium prevention in the practice guidelines.

9.
J Neuroinflammation ; 16(1): 202, 2019 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-31679515

RESUMO

BACKGROUND: The thymus plays an essential role in the pathogenesis of myasthenia gravis (MG). In patients with MG, natural regulatory T cells (nTreg), a subpopulation of T cells that maintain tolerance to self-antigens, are severely impaired in the thymuses. In our previous study, upregulated nTreg cells were observed in the thymuses of rats in experimental autoimmune myasthenia gravis after treatment with exosomes derived from statin-modified dendritic cells (statin-Dex). METHODS: We evaluated the effects of exosomes on surface co-stimulation markers and Aire expression of different kinds of thymic stromal cells, including cTEC, mTEC, and tDCs, in EAMG rats. The isolated exosomes were examined by western blot and DLS. Immunofluorescence was used to track the exosomes in the thymus. Flow cytometry and western blot were used to analyze the expression of co-stimulatory molecules and Aire in vivo and in vitro. RESULTS: We confirmed the effects of statin-Dex in inducing Foxp3+ nTreg cells and found that both statin-Dex and DMSO-Dex could upregulate CD40 but only statin-Dex increased Aire expression in thymic stromal cells in vivo. Furthermore, we found that the role of statin-Dex and DMSO-Dex in the induction of Foxp3+ nTreg cells was dependent on epithelial cells in vitro. CONCLUSIONS: We demonstrated that statin-Dex increased expression of Aire in the thymus, which may further promote the Foxp3 expression in the thymus. These findings may provide a new strategy for the treatment of myasthenia gravis.

10.
Stress ; : 1-7, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31672079

RESUMO

Exposure to chronic stress can influence nociception and further induce hyperalgesia. Whether stress modulation of pain in female animals occurs in an estrous cycle-specific manner is still unclear. We profiled the changes in nociception (thermal, mechanical, formalin-evoked acute and inflammatory pain) of female Sprague-Dawley rats after treatment with chronic unpredictable mild stress (CUMS) and investigated whether these changes occur in an estrous cycle-dependent manner. The results showed that CUMS female rats exhibited a lower mechanical withdrawal threshold in proestrus and estrus, a longer formalin-evoked licking time in metestrus and diestrus, but no changes in the latency time on the tail-flick test. The present study findings suggest that chronic stress induces mechanical and formalin-evoked acute hyperalgesia of female rats in an estrous cycle-dependent manner.SUMMARYOur studies showed that chronic stress increased nociceptive sensitivity of female rats. Furthermore females had different stress-induced pain responses in different estrous phases: mechanical hyperalgesia in proestrus and estrus, formalin-evoked acute hyperalgesia in metestrus and diestrus.

11.
BMC Plant Biol ; 19(1): 469, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31690290

RESUMO

BACKGROUND: Soybean (Glycine max (L.)) is one the most important oil-yielding cash crops. However, the soybean production has been seriously restricted by salinization. It is therefore crucial to identify salt tolerance-related genes and reveal molecular mechanisms underlying salt tolerance in soybean crops. A better understanding of how plants resist salt stress provides insights in improving existing soybean varieties as well as cultivating novel salt tolerant varieties. In this study, the biological function of GmNHX1, a NHX-like gene, and the molecular basis underlying GmNHX1-mediated salt stress resistance have been revealed. RESULTS: We found that the transcription level of GmNHX1 was up-regulated under salt stress condition in soybean, reaching its peak at 24 h after salt treatment. By employing the virus-induced gene silencing technique (VIGS), we also found that soybean plants became more susceptible to salt stress after silencing GmNHX1 than wild-type and more silenced plants wilted than wild-type under salt treatment. Furthermore, Arabidopsis thaliana expressing GmNHX1 grew taller and generated more rosette leaves under salt stress condition compared to wild-type. Exogenous expression of GmNHX1 resulted in an increase of Na+ transportation to leaves along with a reduction of Na+ absorption in roots, and the consequent maintenance of a high K+/Na+ ratio under salt stress condition. GmNHX1-GFP-transformed onion bulb endothelium cells showed fluorescent pattern in which GFP fluorescence signals enriched in vacuolar membranes. Using the non-invasive micro-test technique (NMT), we found that the Na+ efflux rate of both wild-type and transformed plants after salt treatment were significantly higher than that of before salt treatment. Additionally, the Na+ efflux rate of transformed plants after salt treatment were significantly higher than that of wild-type. Meanwhile, the transcription levels of three osmotic stress-related genes, SKOR, SOS1 and AKT1 were all up-regulated in GmNHX1-expressing plants under salt stress condition. CONCLUSION: Vacuolar membrane-localized GmNHX1 enhances plant salt tolerance through maintaining a high K+/Na+ ratio along with inducing the expression of SKOR, SOS1 and AKT1. Our findings provide molecular insights on the roles of GmNHX1 and similar sodium/hydrogen exchangers in regulating salt tolerance.

12.
Transl Psychiatry ; 9(1): 280, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699965

RESUMO

Although the robust antidepressant effects of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine in patients with treatment-resistant depression are beyond doubt, the precise molecular and cellular mechanisms underlying its antidepressant effects remain unknown. NMDAR inhibition and the subsequent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation are suggested to play a role in the antidepressant effects of ketamine. Although (R)-ketamine is a less potent NMDAR antagonist than (S)-ketamine, (R)-ketamine has shown more marked and longer-lasting antidepressant-like effects than (S)-ketamine in several animal models of depression. Furthermore, non-ketamine NMDAR antagonists do not exhibit robust ketamine-like antidepressant effects in patients with depression. These findings suggest that mechanisms other than NMDAR inhibition play a key role in the antidepressant effects of ketamine. Duman's group demonstrated that the activation of mammalian target of rapamycin complex 1 (mTORC1) in the medial prefrontal cortex is reportedly involved in the antidepressant effects of ketamine. However, we reported that mTORC1 serves a role in the antidepressant effects of (S)-ketamine, but not of (R)-ketamine, and that extracellular signal-regulated kinase possibly underlie the antidepressant effects of (R)-ketamine. Several lines of evidence have demonstrated that brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), are crucial in the antidepressant effects of ketamine and its two enantiomers, (R)-ketamine and (S)-ketamine, in rodents. In addition, (2R,6R)-hydroxynormetamine [a metabolite of (R)-ketamine] and (S)-norketamine [a metabolite of (S)-ketamine] have been shown to exhibit antidepressant-like effects on rodents through the BDNF-TrkB cascade. In this review, we discuss recent findings on the molecular and cellular mechanisms underlying the antidepressant effects of enantiomers of ketamine and its metabolites. It may be time to reconsider the hypothesis of NMDAR inhibition and the subsequent AMPAR activation in the antidepressant effects of ketamine.

13.
Org Lett ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31710501

RESUMO

A direct and convenient approach for the coupling of propargylic substrates with diphenylphosphine oxide in the presence of Tf2O and 2,6-lutidine has been developed. The method provides a general approach for the construction of attractive allenylphosphoryl skeletons with high atom and step economy under metal free conditions.

14.
J Affect Disord ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31744738

RESUMO

OBJECTIVE: To examine prospective associations of clinically relevant depressive symptoms with cognitive functions and rates of cognitive decline among Chinese adults aged 45 years and older. METHODS: Data was from the China Health and Retirement Longitudinal Study (CHARLS) with a follow-up of 4 years. Based on the Chinese version of 10-item Center for Epidemiologic Studies Depression Scale (CESD-10), clinically relevant depressive symptoms were defined with a CESD-10 score≥10 points. Cognitive functions were measured in three domains: episodic memory, mental status and global cognition. Linear mixed models were used to assess the associations between clinically relevant depressive symptoms and cognitive functions. RESULTS: A total of 7335 participants (50.10% men; mean age: 57.47) were included in analyses. Participants with clinically relevant depressive symptoms showed poorer episodic memory (ß=-0.35; 95% CI:-0.41, -0.29), mental status (ß=-0.48; 95% CI: -0.57, -0.39), and global cognition (ß=-0.82; 95% CI: -0.94, -0.70) during the follow-up. Compared with counterparts, rates of decline in episodic memory, mental status, and global cognition increased by 0.04 (ß=0.04; 95% CI: 0.02, 0.06), 0.06 (ß=0.06; 95% CI: 0.02, 0.09) and 0.11 (ß=0.11; 95% CI: 0.06, 0.15) units per year in participants with clinically relevant depressive symptoms. LIMITATIONS: A major limitation is that clinically relevant depressive symptoms were assessed by a screening tool and the follow-up was short. CONCLUSION: More severe clinically relevant depressive symptoms were associated with poorer cognitive functions and moderately faster cognitive decline in episodic memory, mental status and global cognition in middle-aged and elderly Chinese adults.

15.
Int J Infect Dis ; 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31740407

RESUMO

OBJECTIVES: We assessed the economic burden of AIDS-defining illnesses (ADIs), which was further stratified by adherence to antiretroviral therapy (ART). METHODS AND MATERIALS: A nationwide longitudinal cohort of 18,234 incident cases with HIV followed for 11 years was utilized. Adherence to ART was measured by medication possession ratio (MPR). Generalized estimating equations modeling was used to estimate the cost impact of ADIs. RESULTS: Having opportunistic infections increased the annual cost by 9% (varicella-zoster virus infection) to 98% (cytomegalovirus disease), while the annual costs increased by 26% (Kaposi's sarcoma) to 95% (non-Hodgkin's lymphoma) in the year when AIDS-related cancer occurred. ADIs occurred more frequently in the years with low adherence for ART compared to the high-adherence years (e.g., 0.1 ≤ MPR<0.8 vs. MPR ≥ 0.8, event rate of cytomegalovirus disease 4.03% vs. 0.51%). The annual baseline costs in the years with MPR < 0.1, 0.1 ≤ MPR<0.8, and MPR ≥ 0.8 were $250, $4,752, and $8,990 (in 2018 USD), respectively. The economic impact of ADIs in the years with low adherence (MPR < 0.1) was larger than that in the high-adherence years (MPR ≥ 0.8) (e.g., MPR < 0.1 vs. MPR ≥ 0.8, annual cost increased by 244% vs. 9% when candidiasis occurred). CONCLUSIONS: Adherence to ART may increase the baseline medical costs but mitigate the incidence and economic burden of ADIs.

16.
J Cosmet Dermatol ; 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31697031

RESUMO

BACKGROUND/OBJECTIVES: Sjogren - Larsson syndrome (SLS) is a rare autosomal recessive disease of the mutation ALDH3A2 that identifies a part of fatty acids for fatty aldehyde dehydrogenase: NAD-oxidoreductase enzyme complex. This study aimed to access variant ALDH3A2 gene coded for FALDH and products regulating pathogenic melanogenesis owing to increased oxidative stress and reactive oxygen species resulting in DNA harm in SLS. By turning them into fatty acids, FALDH avoids the accumulation of toxic fatty aldehydes. The mutation results in the accumulation of aldehyde-modified lipids or fatty alcohols that may interfere with skin and brain function. METHODS: In Nov 2018, we performed a literature search in PubMed for clinical studies, clinical trials, case reports, controlled trials, randomized controlled trials, and systemic reviews. The search terms we used were "SJOGREN-LARSSON SYNDROME" AND "HYPERMELANNOSIS" OR "FALDH" (from 1985). The search resulted in 1,289 articles, out of these 95 articles met our inclusion exclusion criteria. Our inclusion criteria included relevant original articles relevant, critical systemic reviews, and crucial referenced articles, ex-clusion criteria included duplicates and articles not published in English language. RESULTS: Toxicity of long-chain aldehydes to FALDH-deficient cells owing to accumulation under the profound epidermis layer improves oxidative stress in the cell resulting in keratinocyte hyperproliferation. CONCLUSION: While it continues to be determined whether accumulated fatty alcohol and fatty aldehydes obtained from ether glycerolipids and sphingolipids improve the susceptibility of melanocytes and their element accountable for skin hyperpigmentation to biological colour.

17.
Electrophoresis ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31667875

RESUMO

We report a microfluidic paper based analytical device implementing ion concentration polarization (ICP) for rapid pre-concentration of Escherichia coli in water. The fabricated device consists of a paper channel with a Nafion® membrane and in-built micro wire electrodes to supply electric voltage to induce the ICP effect. E. coli cells were stained with SYTO 9 and fluorescence was used as a sensing method. The device achieved high concentration factor up to 2 × 105 within minutes. The effect of total ion concentration, on ICP and fluorescence intensity was studied. The reported device and method are suitable and effective for detection of E. coli during ballast water quality monitoring, coastal water quality monitoring where high salinity water is present.

18.
Biol Trace Elem Res ; 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31707638

RESUMO

Abnormal hepatic iron metabolism is detrimental to health. The objective of this study was to detect repeated restraint stress on liver iron metabolism in rats. Twenty-four male rats aged 7 weeks were randomly divided into 2 groups: control group (Con) and repeated restraint stress group (RS). Rats were subjected to 6 h of daily restraint stress for 14 consecutive days in the repeated restraint stress group. The results showed that repeated restraint stress exposure decreased growth performance including impaired final weight (P = 0.07), reducing average daily gain (P = 0.01), and average daily feed intake (P = 0.00) during the 14-day experimental period. Repeated restraint stress exposure did not affect hemoglobin content and plasma iron parameters except downregulated unsaturated iron-binding capacity (P = 0.04). Repeated restraint stress exposure inhibited liver development (P = 0.03) and induced liver iron accumulation (P = 0.05). In addition, repeated restraint stress downregulated the expression of transferrin (TF) and transferrin receptor 2 (TFR2) at the mRNA level (P < 0.01), but upregulated at the protein level (P = 0.03 for TF; P = 0.00 for TFR2). These results indicated that repeated restraint stress induces hepatic iron accumulation, which is closely related to higher expression of hepatic TFR2 protein in rats.

19.
Exp Cell Res ; : 111737, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31759058

RESUMO

The presence of elevated T lymphocytic microparticles (TLMPs) during respiratory illness is associated with airway and lung inflammation and epithelial injuries. Although inflammasome and IL-1ß signaling are crucial in airway inflammation, little was known about their regulatory mechanism. We hypothesized that TLMPs trigger inflammasome activation and IL-1ß production in bronchial and alveolar epithelial cells to induce airway and lung inflammation. In this study, TLMPs induced IL-1ß and IL-18 secretion through NLRP3 inflammasome activation and upregulated TLR4 mRNA and protein expression in alveolar (A549) and human airway epithelial (16HBE) cells. Pretreatment with CLI-095, a specific inhibitor of TLR4 signaling, dramatically diminished the TLMP-induced release of IL-1ß and IL-18 by inhibiting the formation of NLRP3/ASC/pro-caspase-1 inflammasome in a dose-dependent manner. The TLMP-induced autophagy inhibition in epithelial cells was dependent on the PI3K/Akt signaling pathway, which significantly increased NLRP3 expression and enhanced TLMP-induced inflammation. TLR4, IL-1ß, and IL-18 proteins harbored in TLMPs were nonessential for the pro-inflammatory effect. In conclusion, TLMPs induce bronchial and alveolar epithelial cell secretion of IL-1ß and IL-18 cytokines by activating the TLR4 and PI3K/Akt signaling pathways and inhibiting autophagy. These effects lead to NLRP3 inflammasome formation and accumulation. TLMPs may be regarded as deleterious markers of airway and lung damage in respiratory diseases.

20.
Int J Mol Sci ; 20(23)2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31779098

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis and atherogenesis. However, there are only limited rodent models, with a functional low-density lipoprotein receptor (LDLR) pathway and cholesteryl ester transfer protein (CETP) to evaluate the drug candidates targeting the PCSK9/LDLR pathway, that are translatable to humans. Here, by using our recently generated LDLR heterozygote (Ldlr+/-) hamster model with functional LDLR pathway and CETP function, we seek to evaluate the effect of a PCSK9 antibody, evolocumab, on dyslipidemia and atherosclerosis compared with ezetimibe, an effective inhibitor of cholesterol absorption, as a positive therapeutic control. We show that the plasma levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were significantly increased in Ldlr+/- hamsters fed a high-fat high-cholesterol (HFHC) diet; therefore, areas of atherosclerotic lesion in the aorta were obviously increased and positively correlated with plasma LDL-C and TC. Circulating free PCSK9 was downregulated by the HFHC diet and was undetectable in the evolocumab treated group, as expected. Most importantly, either evolocumab or ezetimibe treatment prevented HFHC diet-induced hyperlipidemia and subsequent atherosclerotic plaque formation. The results indicate that Ldlr+/- hamsters fed an HFHC diet represent an ideal rodent model to evaluate drug candidates that affect LDLR pathways.

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