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2.
Sci Total Environ ; 714: 136740, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32018962

RESUMO

For both nitrogen and COD removal from biodegradable organic matter (BOM)-containing ammonium wastewater, the simultaneous partial nitritation, anammox, denitrification and COD oxidization (SNADCO) process is a promising solution. In this study, with the stable influent ammonium concentration of 250.0 mg/L (nitrogen loading rate of 0.5 kg/m3/d) and the variation of influent COD/NH4+-N (C/N) ratio from 0.0 to 1.6, the performance of the SNADCO process in a one-stage carrier-packing airlift reactor with continuous mode was investigated for the first time. The results showed that until the C/N ratio of 0.8, both the well nitrogen and COD removal targets could be reached. Mass balance calculations indicated that the average nitrogen removal efficiency (NRE) of 80.9% achieved at the C/N ratio of 0.8 were due to both the anammox and denitrification pathways. Correspondingly, the achieved average COD removal efficiency of 94.6% was attributed to both the denitrification and COD oxidization pathways. Based on the specific sludge activity tests and Fluorescence in Situ Hybridization observation, anammox and denitrification bacteria were mainly distributed in the biofilm sludge, while ammonium oxidizing bacteria and ordinary heterotrophic organisms were mainly in the suspended sludge. At the C/N ratio of 1.6, the washout of suspended sludge became serious while the biofilm sludge was well retained, resulting in inefficient nitritation and a subsequent decrease in NRE. The microbial interaction analysis provided a clear explanation of the performance change of the SNADCO process under different C/N ratios. This research enriches the knowledge of the SNADCO process in BOM-containing ammonium wastewater treatment.

3.
J Affect Disord ; 264: 187-192, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32056749

RESUMO

BACKGROUND: Poor mental health status among both pregnant and postpartum women is commonly reported worldwide. The associations between mental health outcomes and giving birth to the second child since the implementation of China's universal two-child policy have not been identified. METHODS: A large-scale based mental health survey was conducted between March 2017 and December 2018 in Suzhou, China. The survey evaluated the symptoms of anxiety, hypomania, depression and poor sleep quality among both pregnant and postpartum women. RESULTS: A total of 3113 questionnaires were collected, the prevalence of anxiety, hypomanic and depressive symptoms and poor sleep quality in our sample were 3.2% (95%CI: 2.6%-3.9%), 51.7% (95%CI: 49.9%-53.4%), 12.4% (95%CI: 11.3%-13.6%) and 37.8% (95%CI: 36.0%-39.5%), respectively. Logistic regression showed that giving birth to the second child was positively associated with women's age, and was negatively correlated with higher educational level and living in rented housing. Women with the second pregnancy or child were positively associated with anxiety symptoms in the whole sample (OR = 1.75, 95%CI: 1.11-2.75) and among prenatal women (OR = 2.11, 95%CI: 1.16-3.83), while it was inversely correlated with depressive symptoms among postpartum women (OR = 0.63, 95%CI: 0.41-0.99). CONCLUSIONS: Women giving birth a second time were more prone to have anxiety symptoms among the prenatal women and the whole sample, and less likely to have depressive symptoms among the postpartum women. Efficacious measures and interventions are essential to improve maternal mental health.

4.
J Med Internet Res ; 22(2): e16715, 2020 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-32044751

RESUMO

BACKGROUND: People living with HIV (PLWH) have high rates of depressive symptoms. However, only a few effective mental health interventions exist for this vulnerable population. OBJECTIVE: The aim of this study was to assess the efficacy of a WeChat-based intervention, Run4Love, with a randomized controlled trial among 300 people living with HIV and depression (PLWHD) in China. METHODS: We recruited PLWH from the HIV outpatient clinic in South China. Participants were screened based on the Center for Epidemiologic Studies-Depression (CES-D) scale. Those who scored 16 or higher were eligible to participate. A total of 300 eligible patients were enrolled. After obtaining informed consent from the participants, completion of a baseline survey, and collection of participants' hair samples for measuring cortisol, the participants were randomly assigned to an intervention or a control group in a 1:1 ratio. The intervention group received the Run4Love program, delivered via the popular social media app WeChat. Cognitive behavioral stress management courses and weekly reminders of exercise were delivered in a multimedia format. Participants' progress was monitored with timely and tailored feedback. The control group received usual care and a brochure on nutrition for PLWH. Data were collected at 3, 6, and 9 months. The primary outcome was depression, which was measured by a validated instrument. RESULTS: Participants in the intervention and control groups were comparable at baseline; about 91.3% (139/150), 88.3% (132/150), and 86.7% (130/150) participants completed the 3-, 6-, and 9-month follow-ups, respectively. At the 3-month follow-up, a significant reduction in CES-D score was observed in the intervention group (from 23.9 to 17.7 vs from 24.3 to 23.8; mean difference=-5.77, 95% CI -7.82 to -3.71; P<.001; standard effect size d=0.66). The mean changes in CES-D score from baseline to the 6- and 9-month follow-ups between the two groups remained statistically significant. No adverse events were reported. CONCLUSIONS: The WeChat-based mobile health (mHealth) intervention Run4Love significantly reduced depressive symptoms among PLWHD, and the effect was sustained. An app-based mHealth intervention could provide a feasible therapeutic option for many PLWHD in resource-limited settings. Further research is needed to assess generalizability and cost-effectiveness of this intervention. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-IPR-17012606; http://www.chictr.org.cn/showproj.aspx?proj=21019 (Archived by WebCite at https://www.webcitation.org/78Bw2vouF).

5.
Br J Pharmacol ; 2020 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-32037512

RESUMO

BACKGROUND AND PURPOSE: Nonalcoholic fatty liver disease (NAFLD) is a worldwide public health concern with no established pharmacological therapy. Here, we explored the potential pharmacological action of P7C3-A20, a novel aminopropyl carbazole compound with neuroprotective activity, in a high-fat diet (HFD)-induced mouse NAFLD model. EXPERIMENTAL APPROACH: Mice were fed with HFD (42% fat for energy) for 16 weeks to induce NAFLD. P7C3-A20 (20 mg/kg/d) was administrated orally for 2 weeks. Indirect calorimetry, histology analysis, immunoblotting, immunohistochemistry, and biomedical examinations were performed. Gut microbiota were determined using a 16s ribosomal RNA sequencing analysis. KEY RESULTS: P7C3-A20 treatment reduced body weight gain/adiposity, improved insulin resistance, promoted energy expenditure (O2 consumption/CO2 production), inhibited lipid oxidation, suppressed hepatic inflammation (Kupffer cell number and pro-inflammatory factors), decreased necroptosis/apoptosis (receptor-interacting serine-threonine kinase 3 [Ripk3], cleaved caspase-3 and TUNEL), and alleviated liver fibrosis and injury. Mechanically, P7C3-A20 stimulated fibroblast growth factor 21 (FGF21) and FGF1 via activating liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK), which further resulted in a reduced nuclear translocation of CREB regulated transcription coactivator 2 (CRTC2). In AMPKα2 knockout mice, the protection of P7C3-A20 against HFD-induced metabolism abnormities and fat accumulation, as well as the elevation of blood FGF21 and FGF1, were abolished. P7C3-A20 increased the gut microbiota species richness. Moreover, it enhanced the proportions of Akkermansia, Lactobacillus and Prevotellaceae whereas reduced the proportions of Enterobacteriaceae, Escherichia, and Parasutterella. CONCLUSIONS AND IMPLICATIONS: The NAD+ boosting agent P7C3-A20 alleviates NAFLD through stimulating FGF21 and FGF1 in an LKB1/AMPK/CRTC2-dependent manner and shaping gut microbiota.

6.
J Gene Med ; : e3167, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32020700

RESUMO

BACKGROUND: Congenital atrichia (CA) is a rare form of irreversible alopecia with an autosomal recessive mode of inheritance. This form of hair loss is mainly associated with mutations in the human hairless (HR) gene located at chromosome 8p21.3. In atrichia with papular lesions (APL) karatine filled cysts known as papules, is an additional unique feature of the phenotype. The main purpose of our study was to uncover the underlying genetic causes of APL in two consanguineous Kashmiri families. METHODS: In the present study, two consanguineous families of Kashmiri origin with APL displaying AR mode of inheritance were investigated via whole exome and sanger sequencing. RESULTS: A recurrent nonsense (NM_005144: c.2818C>T:p.Arg940*) mutation was detected in exon 13 of human HR gene. CONCLUSION: WES analysis has widely been used in single gene disorders mutations screening both in research and diagnostic laboratories. Sanger sequencing alone for genes like HR becomes expensive and time consuming. Instead it is recommended to screen a patient by WES sequencing and then pay special attention first to known genes of the APL phenotype. This is helpful for intime diagnosis, more efficient and economic. Our results may contribute to prenatal diagnosis, carrier secreening and genetic counseling of families having APL phenotype in Kashmiri poplution.

7.
Cell Commun Signal ; 18(1): 19, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019549

RESUMO

BACKGROUND: Neutrophils form the first line of innate host defense against invading microorganisms. We previously showed that F0F1 ATP synthase (F-ATPase), which is widely known as mitochondrial respiratory chain complex V, is expressed in the plasma membrane of human neutrophils and is involved in regulating cell migration. Whether F-ATPase performs cellular functions through other pathways remains unknown. METHODS: Blue native polyacrylamide gel electrophoresis followed by nano-ESI-LC MS/MS identification and bioinformatic analysis were used to identify protein complexes containing F-ATPase. Then, the identified protein complexes containing F-ATPase were verified by immunoblotting, immunofluorescence colocalization, immunoprecipitation, real-time RT-PCR and agarose gel electrophoresis. Immunoblotting, flow cytometry and a LPS-induced mouse lung injury model were used to assess the effects of the F-ATPase-containing protein complex in vitro and in vivo. RESULTS: We found that the voltage-gated calcium channel (VGCC) α2δ-1 subunit is a binding partner of cell surface F-ATPase in human neutrophils. Further investigation found that the physical connection between the two proteins may exist between the F1 part (α and ß subunits) of F-ATPase and the α2 part of VGCC α2δ-1. Real-time RT-PCR and PCR analyses showed that Cav2.3 (R-type) is the primary type of VGCC expressed in human neutrophils. Research on the F-ATPase/Cav2.3 functional complex indicated that it can regulate extracellular Ca2+ influx, thereby modulating ERK1/2 phosphorylation and reactive oxygen species production, which are typical features of neutrophil activation. In addition, the inhibition of F-ATPase can reduce neutrophil accumulation in the lungs of mice that were intratracheally instilled with lipopolysaccharide, suggesting that the inhibition of F-ATPase may prevent neutrophilic inflammation-induced tissue damage. CONCLUSIONS: In this study, we identified a mechanism by which neutrophil activity is modulated, with simultaneous regulation of neutrophil-mediated pulmonary damage. These results show that surface F-ATPase of neutrophils is a potential innate immune therapeutic target.

8.
ACR Open Rheumatol ; 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913579

RESUMO

OBJECTIVE: Small RNA (sRNA) sequencing has revealed new sRNA classes beyond microRNAs (miRNAs). These sRNAs can regulate genes and act as biomarkers. The aim of this study was to determine if the endogenous plasma sRNA landscape is altered in patients with rheumatoid arthritis (RA) compared with control subjects and to determine its association with disease-related parameters in RA. METHODS: sRNA sequencing was performed on plasma from 165 RA and 90 control subjects who were frequency-matched for age, race, and sex. Endogenous sRNAs, such as miRNAs, isomiRs, sRNAs derived from small nuclear RNAs (snDRs), small nucleolar RNAs (snoDRs), Y RNAs (yDRs), transfer-derived RNAs (tDRs), long noncoding RNAs (lncDRs) as well as miscellaneous sRNAs (miscRNAs), were quantified using Tools for Integrative Genome analysis of Extracellular sRNAs (TIGER). Individual and categories of sRNAs were compared between RA and controls, and significantly altered sRNAs and sRNA categories were correlated with disease activity and general laboratory measures in RA. RESULTS: Patients with RA had more miRNAs (1.42-fold, P = 0.01), more tDRs (1.14-fold, P = 0.04), and fewer yDRs (-1.41-fold, P = 0.009) compared with control subjects. Disease duration was inversely associated with yDRs. Disease-related parameters, such as Disease Activity Score-28 (DAS28), swollen joint count, and inflammatory markers were significantly positively associated with tDRs and miscRNAs, and miR-22-3p and related sequences and isomiRs were most significantly associated with DAS28. CONCLUSION: Endogenous plasma sRNAs are altered in RA compared with control subjects. Although individual miRNAs have been well studied and many are excellent biomarkers in RA, several non-miRNA sRNAs were significantly associated with disease-related parameters as classes and may represent novel biomarkers for RA.

9.
Molecules ; 25(3)2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31979317

RESUMO

A series of novel compounds 6a-h, 8i-1, 10s-v, and 16a-d were synthesized and evaluated, together with the known analogs 11a-f, for their inhibitory activities towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The inhibitory activities of AChE and BChE were evaluated in vitro by Ellman method. The results show that some compounds have good inhibitory activity against AChE and BChE. Among them, compound 8i showed the strongest inhibitory effect on both AChE (eeAChE IC50 = 0.39 µM) and BChE (eqBChE IC50 = 0.28 µM). Enzyme inhibition kinetics and molecular modeling studies have shown that compound 8i bind simultaneously to the peripheral anionic site (PAS) and the catalytic sites (CAS) of AChE and BChE. In addition, the cytotoxicity of compound 8i is lower than that of Tacrine, indicating its potential safety as anti-Alzheimer's disease (anti-AD) agents. In summary, these data suggest that compound 8i is a promising multipotent agent for the treatment of AD.

10.
Bioinformatics ; 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31930398

RESUMO

MOTIVATION: Genome annotation is an important step for all in-depth bioinformatics analysis. It is imperative to augment quantity and diversity of genome-wide annotation data for the latest reference genome to promote its adoption by ongoing and future impactful studies. RESULTS: We developed a python toolkit AnnoGen, which at the first time, allows the annotation of three pragmatic genomic features for the GRCh38 genome in enormous base-wise quantities. The three features are chemical binding Energy, sequence information Entropy, and Homology Score. The Homology Score is an exceptional feature that captures the genome-wide homology through single-base-offset tiling windows of 100 continual nucleotide bases. CONCLUSION: AnnoGen is capable of annotating the proprietary pragmatic features for variable user-interested genomic regions and optionally comparing two parallel sets of genomic regions. AnnoGen is characterized with simple utility modes and succinct HTML report of informative statistical tables and plots. AVAILABILITY: https://github.com/shengqh/annogen. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

11.
Chin Med J (Engl) ; 133(1): 41-48, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31923103

RESUMO

BACKGROUND: The purpose of this study was to analyze cases of AO31-A2 intertrochanteric fractures (ITFs) and to identify the relationship between the loss of the posteromedial support and implant failure. METHODS: Three hundred ninety-four patients who underwent operative treatment for ITF from January 2003 to December 2017 were enrolled. Focusing on posteromedial support, the A2 ITFs were divided into two groups, namely, those with (Group A, n = 153) or without (Group B, n = 241) posteromedial support post-operatively, and the failure rates were compared. Based on the final outcomes (failed or not), we allocated all of the patients into two groups: failed (Group C, n = 66) and normal (Group D, n = 328). We separately analyzed each dataset to identify the factors that exhibited statistically significant differences between the groups. In addition, a logistic regression was conducted to identify whether the loss of posteromedial support of A2 ITFs was an independent risk factor for fixation failure. The basic factors were age, sex, American Society of Anesthesiologists (ASA) score, side of affected limb, fixation method (intramedullary or extramedullary), time from injury to operation, blood loss, operative time and length of stay. RESULTS: The failure rate of group B (58, 24.07%) was significantly higher than that of group A (8, 5.23%) (χ = 23.814, P < 0.001). Regarding Groups C and D, the comparisons of the fixation method (P = 0.005), operative time (P = 0.001), blood loss (P = 0.002) and length of stay (P = 0.033) showed that the differences were significant. The logistic regression revealed that the loss of posteromedial support was an independent risk factor for implant failure (OR = 5.986, 95% CI: 2.667-13.432) (P < 0.001). CONCLUSIONS: For AO31-A2 ITFs, the loss of posteromedial support was an independent risk factor for fixation failure. Therefore, posteromedial wall reconstruction might be necessary for the effective treatment of A2 fractures that lose posteromedial support.

12.
Sci Rep ; 10(1): 44, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913290

RESUMO

Low miR-96-5p expression is characteristic of many cancers but its role in breast cancer (BCa) remains poorly defined. Here, the role of miR-96-5p in BC development was assessed. We demonstrate that exogenously expressing miR-96-5p inhibits the proliferative, migratory and invasive capacity of BCa cells. Mechanistically, miR-96-5p in BCa cells was found to target and downregulate catenin delta 1 (CTNND1) leading to decreased ß-catenin expression, a loss of WNT11 signaling, reduced cyclin D1 levels and lower MMP7 expression. Exogenously expressing CTNND1 alleviated these effects. In summary, we are the first to reveal that miR-96-5p inhibits the proliferative, invasive and migratory phenotypes of BCa cells the targeting of CTNND1 and subsequent Wnt/ß-catenin signaling. These data highlight miR-96-5p as a novel target for BC treatment.

13.
Injury ; 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31987607

RESUMO

INTRODUCTION: To introduce a classification for medial wall fragments in pertrochanteric femur fractures and investigate potential preoperative predictors of implant failure following fixation. MATERIAL AND METHODS: Medical records of 324 adult patients receiving routine operative treatment using intramedullary devices for pertrochanteric femur fractures with medial wall fragments between August 2008 and May 2018 were retrospectively analyzed. Potential predictors including age, gender, body mass index, comorbidities, AO/OTA classification of fractures were noted. The medial wall fractures were categorized into three types: 1) Type I: avulsion of the lesser trochanter; fracture line does not exceed the base of the lesser trochanter; 2) Type II: fragment involving the posterior cortex near the base of the lesser trochanter; fracture line does not reach the midline of the posterior wall; 3) Type III: fragment involving the large posterior cortex; fracture line reaches or exceeds the midline of the posterior wall. RESULTS: The 8 (2.5%) implant failures comprised 1 in 186 Type I fractures, 1 in 76 Type II fractures and 6 in 62 Type III fractures. The failure rates of each fracture type were 0.5% in Type I, 1.3% in Type II and significantly increased to 9.7% in Type III (odds ratio [OR], 19.821; 95% confidence interval [CI], 2.337-168.135; p=0.001). CONCLUSIONS: Type III fractures had a significantly increased failure rate. It is important for orthopedists to identify Type III fractures presurgically, reduction of the medial wall fragment and fixation should be considered during surgery using intramedullary nails.

14.
Orthop Surg ; 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31958886

RESUMO

OBJECTIVE: To assess the therapeutic effect of a novel tension band using 3.0 mm cannulated screw combined with a titanium cable and specific shims comparatively with patellotibial tubercle cerclage in comminuted fractures of the inferior pole of the patella. METHODS: The retrospective study from March 2012 to July 2017 was conducted in Peking University Third Hospital and comprised 63 patients with comminuted fractures of the inferior pole of the patella: 41 treated with new tension band using 3.0 mm cannulated screw combined with a titanium cable and specific shims (new tension band group) and 22 with patellotibial tubercle cerclage (tubercle cerclage group). Gender, age, AO/OTA fracture type, injury mechanism, inter-fragmentary gap, and follow-up time of patients were recorded. Two groups were compared regarding: operation time, blood loss, partial weight-bearing time, fracture-healed time, Bostman score and knee mobility at 12-month follow-up, and postoperative complications. Continuous and categorical parameters were analyzed by Mann-Whitney U test and the chi-squared test, respectively. Fisher's exact test was used for small data subsets. RESULTS: Between the two groups, no statistically significant difference was found in mean age, gender, AO/OTA fracture type, injury mechanism, mean inter-fragmentary gap, or mean follow-up time (P > 0.05). The mean operation time of new tension band group was significantly longer than that of tubercle cerclage group (76.4 min vs 64.2 min, P = 0.006), while there was no significant difference in blood loss. After surgery, new tension band group had a significantly earlier mean partial weight-bearing time (5.2 weeks vs 7.4 weeks, P < 0.001) and fracture-healed time (9.6 weeks vs 11.6 weeks, P < 0.001). At 12-month follow-up, patients of new tension band group had a significantly higher mean Bostman score (28.5 vs 25.8, P < 0.001) and knee mobility (126.7 vs 117.3, P < 0.001). Ten complications related with internal fixation were found in tubercle cerclage group including two cases of loose internal fixation, two cases of cerclage breakage, and six cases of low patella position who undertook secondary operation. No complications were found in new tension band group (0 in 41 vs 10 in 22, P < 0.001). CONCLUSION: Patients with comminuted fractures of the inferior pole of the patella treated with a novel tension band experienced a longer operation time, but earlier partial-weight-bearing and fracture-healed time, better clinical outcomes at 12-month follow-up, and less complications. It should be considered an alternative therapy for the treatment of distal pole patellar fractures.

15.
J Med Chem ; 63(3): 1233-1244, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-31939669

RESUMO

Human hand, foot, and mouth disease (HFMD) is a serious public health threat with high infection rates in children and infants who reside in Asia and the Pacific regions, and no effective drugs are currently available. Enterovirus 71 (EV71) and coxsackievirus A16 are the major etiological pathogens. Based on an essential hydrophobic pocket on the viral capsid protein VP1, we designed and synthesized a series of small molecular weight compounds as inhibitors of EV71. A potential drug candidate named NLD-22 exhibited excellent antiviral activity (with an EC50 of 5.056 nM and a 100% protection rate for mice at a dose of 20 mg/kg) and low toxicity. NLD-22 had a favorable pharmacokinetic profile. High-resolution cryo-electron microscopy structural analysis confirmed NLD-22 bound to the hydrophobic pocket in VP1 to block viral infection. In general, NLD-22 was indicated to be a promising potential drug candidate for the treatment of HFMD.

16.
ACS Appl Mater Interfaces ; 12(6): 7833-7839, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31961648

RESUMO

Recently, neuromorphic devices have been receiving increasing interest in the field of artificial intelligence (AI). Realization of fundamental synaptic plasticities on hard-ware devices would endow new intensions for neuromorphic devices. Spike-rate-dependent plasticity (SRDP) is one of the most important synaptic learning mechanisms in brain cognitive behaviors. It is thus interesting to mimic the SRDP behaviors on solid-state neuromorphic devices. In the present work, nanogranular phosphorus silicate glass (PSG)-based proton conductive electrolyte-gated oxide neuromorphic transistors have been proposed. The oxide neuromorphic transistors have good transistor performances and frequency-dependent synaptic plasticity behavior. Moreover, the neuromorphic transistor exhibits SRDP activities. Interestingly, by introducing priming synaptic stimuli, the modulation of threshold frequency value distinguishing synaptic potentiation from synaptic depression is realized for the first time on an electrolyte-gated neuromorphic transistor. Such a mechanism can be well understood with interfacial proton gating effects of the nanogranular PSG-based electrolyte. Furthermore, the effects of SRDP learning rules on pattern learning and memory behaviors have been conceptually demonstrated. The proposed neuromorphic transistors have potential applications in neuromorphic engineering.

17.
Mol Med Rep ; 21(3): 1043-1050, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31922239

RESUMO

Oxidative stress is a pathophysiological condition resulting in neurotoxicity, which is possibly associated with neurodegenerative disorders. In this study, the antioxidative effects of the antioxidant astaxanthin (AXT) in combination with huperzine A (HupA), which is used as a cholinesterase inhibitor for the treatment of Alzheimer's disease, were investigated. PC12 cells were treated with either tert­butyl hydroperoxide (TBHP), or with the toxic version of ß­amyloid, Aß25­35, to induce oxidative stress and neurotoxicity. Cell viability, morphology, lactate dehydrogenase (LDH) release, intracellular accumulation of reactive oxygen species (ROS), superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were determined, while neuroprotection was also monitored using an MTT assay. It was found that combining AXT with HupA significantly increased the viability of PC12 cells, prevented membrane damage (as measured by LDH release), attenuated intracellular ROS formation, increased SOD activity and decreased the level of MDA after TBHP exposure when compared to these drugs administered alone. Pretreatment with HupA and AXT decreased toxic damage produced by Aß25­35. These data indicated that combining an antioxidant with a cholinesterase inhibitor increases the degree of neuroprotection; with future investigation this could be a potential therapy used to decrease neurotoxicity in the brain.

18.
Cancer Cell ; 37(2): 183-199.e5, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31978326

RESUMO

We developed neratinib-resistant HER2-mutant cancer cells by gradual dose escalation. RNA sequencing identified TORC1 signaling as an actionable mechanism of drug resistance. Primary and acquired neratinib resistance in HER2-mutant breast cancer patient-derived xenografts (PDXs) was also associated with TORC1 hyperactivity. Genetic suppression of RAPTOR or RHEB ablated P-S6 and restored sensitivity to the tyrosine kinase inhibitor. The combination of the TORC1 inhibitor everolimus and neratinib potently arrested the growth of neratinib-resistant xenografts and organoids established from neratinib-resistant PDXs. RNA and whole-exome sequencing revealed RAS-mediated TORC1 activation in a subset of neratinib-resistant models. DNA sequencing of HER2-mutant tumors clinically refractory to neratinib, as well as circulating tumor DNA profiling of patients who progressed on neratinib, showed enrichment of genomic alterations that converge to activate the mTOR pathway.

19.
J Cell Mol Med ; 2020 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-31957212

RESUMO

Polymyxin B has been re-applied to the clinic as the final choice for the treatment of multidrug-resistant gram-negative pathogenic infections, but the use of polymyxin B has been re-assessed because of the emergence and spread of the plasmid-mediated mcr-1 gene. The purpose of this study was to search for an MCR inhibitor synergistically acting with polymyxin to treat the infection caused by this pathogen. In this study, we used the broth microdilution checkerboard method to evaluate the synergistic effect of isoalantolactone (IAL) and polymyxin B on mcr-1-positive Enterobacteriaceae. Growth curve analysis, time-killing assays and a combined disc test were used to further verify the efficacy of the combined drug. Colonization of the thigh muscle in mice, survival experiments and lung tissue section observations was used to determine the effect of synergy in vivo after Klebsiella pneumoniae and Escherichia coli infection. We screened a natural compound, IAL, which can enhance the sensitivity of polymyxin B to mcr-1-positive Enterobacteriaceae. The results showed that the combined use of polymyxin B and IAL has a synergistic effect on mcr-1-positive Enterobacteriaceae, such as K pneumoniae and E coli, not only in vitro but also in vivo. Our results indicate that IAL is a natural compound with broad application prospects that can prolong the service life of polymyxin B and make outstanding contributions to the treatment of gram-negative Enterobacteriaceae infections resistant to polymyxin B.

20.
PLoS One ; 15(1): e0228456, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31999769

RESUMO

The combination of a fluorescent reporter and enzymatic reporter provides a flexible and versatile way for the study of diverse biological processes, such as the detection of transcription and translation. Thus, there is an urgent need to develop this novel bifunctional reporter system. This study reports the design, construction, and validation of a new dicistronic mCherry-lacZα reporter system by artificial lac operon and pbr operon models in lacZM15-producing E. coli. It allows two reporter genes to be co-transcribed into a dicistronic mRNA strand, followed by coupled expression of mCherry and lacZα. In artificial lac operons, expression of the downstream lacZα was demonstrated to be positively related to expression of the upstream ORF. In artificial pbr operons, compared with the insertion of downstream full-length lacZ, the insertion of downstream lacZα exerted a slight effect on the response from the upstream mCherry. Furthermore, the downstream lacZα reporter showed stronger response to Pb(II) than the downstream full-length lacZ. Importantly, the response sensitivity of downstream lacZα was still higher than that of upstream mCherry in a dual RFP-lacZα reporter construct. The highly efficient expression profile of the reporter lacZα peptide makes it a preferred downstream reporter in polycistronic constructs. This novel bifunctional reporter system offers a robust tool for biological studies.

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