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1.
J Cell Physiol ; 2021 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-33393109

RESUMO

Our understanding of signaling pathways regulating the cell fate of human embryonic stem cells (hESCs) is limited. Calcineurin-NFAT signaling is associated with a wide range of biological processes and diseases. However, its role in controlling hESC fate remains unclear. Here, we report that calcineurin A gamma and the NFATc3/SRPX2 axis control the expression of lineage and epithelial-mesenchymal transition (EMT) markers in hESCs. Knockdown of PPP3CC, the gene encoding calcineurin A gamma, or NFATC3, downregulates certain markers both at the self-renewal state and during differentiation of hESCs. Furthermore, NFATc3 interacts with c-JUN and regulates the expression of SRPX2, the gene encoding a secreted glycoprotein known as a ligand of uPAR. We show that SRPX2 is a downstream target of NFATc3. Both SRPX2 and uPAR participate in controlling expression of lineage and EMT markers. Importantly, SRPX2 knockdown diminishes the upregulation of multiple lineage and EMT markers induced by co-overexpression of NFATc3 and c-JUN in hESCs. Together, this study uncovers a previously unknown role of calcineurin A gamma and the NFATc3/SRPX2 axis in modulating the fate determination of hESCs.

2.
PLoS One ; 16(1): e0244978, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33406133

RESUMO

The location-based services can provide users with the requested location information. But users also need to disclose their current location to the location-based service provider. Therefore, how to protect user's location privacy is a major concern. In this paper, we propose a heterogeneous deniable authenticated encryption scheme called HDAE for location-based services. The proposed scheme permits a sender in a public key infrastructure environment to transmit a message to a receiver in an identity-based environment. Our design utilizes a hybrid encryption method combing the tag-key encapsulation mechanism (tag-KEM) and the data encapsulation mechanism (DEM), which is well adopted for location-based services applications. We give how to design an HDAE scheme utilizing a heterogeneous deniable authenticated tag-KEM (HDATK) and a DEM. We also construct an HDATK scheme and provide security proof in the random oracle model. Comprehensive analysis shows that our scheme is efficient and secure. In addition, we give an application of the HDAE to a location-based services system.

3.
Mol Neurobiol ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33411247

RESUMO

Somatostatin (SST) and its analogues like octreotide (OCT) have analgesic effect on a variety of pain through peripheral SST receptors (SSTRs). However, the precise molecular mechanisms have not yet been fully elucidated. This research aimed to identify possible antinociceptive mechanisms, showing functional links of the SSTR2 and acid-sensing ion channels (ASICs). Herein, we reported that OCT inhibited the electrophysiological activity of ASICs in rat dorsal root ganglia (DRG) neurons. OCT concentration-dependently decreased the peak amplitude of acid-evoked inward currents, which were mediated by ASICs. OCT shifted concentration-response curve to protons downwards, with a decrease of 36.53 ± 5.28% in the maximal current response to pH 4.5 in the presence of OCT. OCT inhibited ASIC-mediated currents through SSTR2, since the inhibition was blocked by Cyn 154806, a specific SSTR2 antagonist. The OCT inhibition of ASIC-mediated currents was mimicked by H-89, a membrane-permeable inhibitor of PKA, and reversed by internal treatment of an adenylyl cyclase activator forskolin or 8-Br-cAMP. OCT also decreased the number of action potentials induced by acid stimuli through SSTR2. Finally, peripheral administration of 20 µM OCT, but not 2 µM OCT, significantly relieved nociceptive responses to intraplantar injection of acetic acid in rats. This occurred through local activation of SSTR2 in the injected hindpaw and was reversed following co-application of Cyn 154806. Our results indicate that activation SSTR2 by OCT can inhibit the activity of ASICs via an intracellular cAMP and PKA signaling pathway in rat DRG neurons. These observations demonstrate a cross-talk between ASICs and SSTR2 in peripheral sensory neurons, which was a novel peripheral analgesic mechanism of SST and its analogues.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33403738

RESUMO

AIM: To investigate the safety and feasibility of taking low-concentration carbohydrate solution at 2 h before induction of anesthesia for gestational diabetes mellitus (GDM) patients. METHODS: GDM patients undergoing cesarean section were randomly assigned to experimental group (n = 43) and control group (n = 42). Two hours before induction of anesthesia, participants in experimental group orally received 300 mL low-concentration carbohydrate solution, while those in control group received equivalent warm water. Blood glucose and serum insulin were measured at 2 h before induction of anesthesia, right before induction of anesthesia, and the morning of postoperative day 1. Neonatal blood glucose level was monitored at birth. Maternal gastrointestinal function and well-being were assessed perioperatively. RESULTS: The levels of blood glucose and serum insulin right before induction of anesthesia in the experimental group were significantly higher than those in the control group. There were four cases with hypoglycemia in the experimental group and 19 cases in the control group right before induction of anesthesia (9.3% vs 45.2%, p < 0.001). The incidence of neonatal hypoglycemia was 2.3% in the experimental group and 7.1% in the control group with no significance. Hunger score of the participants between the two groups right before induction of anesthesia was significantly different. No aspiration, nausea, and vomiting occurred in both groups before, during, and after surgery. No significant difference was found in the time to the first flatus and abdominal distension between the two groups. CONCLUSION: Taking low-concentration carbohydrate solution is safe and feasible for patients with GDM undergoing elective cesarean section.

5.
Acta Pharmacol Sin ; 42(1): 77-87, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32555441

RESUMO

Reducing immunosuppressant-related complications using conventional drugs is an efficient therapeutic strategy. L-carnitine (LC) has been shown to protect against various types of renal injury. In this study, we investigated the renoprotective effects of LC in a rat model of chronic tacrolimus (TAC) nephropathy. SD rats were injected with TAC (1.5 mg · kg-1 · d-1, sc) for 4 weeks. Renoprotective effects of LC were assessed in terms of renal function, histopathology, oxidative stress, expression of inflammatory and fibrotic cytokines, programmed cell death (pyroptosis, apoptosis, and autophagy), mitochondrial function, and PI3K/AKT/PTEN signaling. Chronic TAC nephropathy was characterized by severe renal dysfunction and typical histological features of chronic nephropathy. At a molecular level, TAC markedly increased the expression of inflammatory and fibrotic cytokines in the kidney, induced oxidative stress, and led to mitochondrial dysfunction and programmed cell death through activation of PI3K/AKT and inhibition of PTEN. Coadministration of LC (200 mg · kg-1 · d-1, ip) caused a prominent improvement in renal function and ameliorated histological changes of kidneys in TAC-treated rats. Furthermore, LC exerted anti-inflammatory and antioxidant effects, prevented mitochondrial dysfunction, and modulated the expression of a series of apoptosis- and autophagy-controlling genes to promote cell survival. Human kidney proximal tubular epithelial cells (HK-2 cells) were treated with TAC (50 µg/mL) in vitro, which induced production of intracellular reactive oxygen species and expression of an array of genes controlling programmed cell death (pyroptosis, apoptosis, and autophagy) through interfering with PI3K/AKT/PTEN signaling. The harmful responses of HK-2 cells to TAC were significantly attenuated by cotreatment with LC and the PI3K inhibitor LY294002 (25 µM). In conclusion, LC treatment protects against chronic TAC nephropathy through interfering the PI3K/AKT/PTEN signaling.

6.
Cell Signal ; 78: 109877, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33296740

RESUMO

Tooth and bone are independent tissues with a close relationship. Both are composed of a highly calcified outer structure and soft inner tissue, and both are constantly under mechanical stress. In particular, the alveolar bone and tooth constitute an occlusion system and suffer from masticatory and occlusal force. Thus, mechanotransduction is a key process in many developmental, physiological and pathological processes in tooth and bone. Mechanosensitive ion channels such as Piezo1 and Piezo2 are important participants in mechanotransduction, but their functions in tooth and bone are poorly understood. This review summarizes our current understanding of mechanosensitive ion channels and their roles in tooth and bone tissues. Research in these areas may shed new light on the regulation of tooth and bone tissues and potential treatments for diseases affecting these tissues.

7.
Ying Yong Sheng Tai Xue Bao ; 31(9): 2977-2984, 2020 Sep 15.
Artigo em Chinês | MEDLINE | ID: mdl-33345498

RESUMO

Stellera chamaejasme is one of most common poisonous plant species in degraded grasslands of China. S. chamaejasme could dominate the community in some severely degraded grasslands, which is a serious threat to the sustainable development of animal husbandry in natural grasslands. In this study, S. chamaejasme population was divided into 10 age classes according to the number of branches. We investigated the age structure of S. chamaejasme population and population dynamic indices, and quantified the survival status of S. chamaejasme population by compiling a static life table, drawing a survival curve, conducting survival analysis. The age structure of S. chamaejasme population in the study area was growth type. The number of individuals in Ⅰ age class was sufficient but with relatively low survival rate. The population structure of S. chamaejasme was fitted the growing type. The development process of population was fluctuating. The number of individuals would drop sharply in Ⅱ and Ⅷ, indicating that these two age classes were the bottleneck period in the development of S. chamaejasme population. The survival curves of S. chamaejasme population was the Deevey-Ⅱ type. The results of survival analysis showed that the population had a sharp decrease in the early stage and was stable in the later stage, which was because the value of fx and λx of S. chamaejasme in Ⅰ or Ⅱ age class were the highest. In conclusion, sufficient young individuals (Ⅰ) was the basis for the expansion of S. chamaejasme population in the degraded typical steppe. The low transformation rate of young individuals to adults might be one of the reasons explaining why S. chamaejasme population could not expand rapidly in the early stage of grassland degradation. Therefore, it was suggested to intervene early when the number of S. chamaejasme was limited.


Assuntos
Thymelaeaceae , Animais , China , Humanos
8.
Expert Opin Drug Saf ; : 1-14, 2020 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-33356646

RESUMO

Introduction: Given their importance in cellular processes and association with numerous diseases, protein kinases have emerged as promising targets for drugs. The FDA has approved greater than fifty small molecule kinase inhibitors (SMKIs) since 2001. Nevertheless, severe hepatotoxicity and related fatal cases have grown as a potential challenge in the advancement of these drugs, and the identification and diagnosis of drug-induced liver injury (DILI) are thorny problems for clinicians. Areas covered: This article summarizes the progression and analyzes the significant features in the study of SMKI hepatotoxicity, including clinical observations and investigations of the underlying mechanisms. Expert opinion: The understanding of SMKI-associated hepatotoxicity relies on the development of preclinical models and improvement of clinical assessment. With a full understanding of the role of inflammation in DILI and the mediating role of cytokines in inflammation, cytokines are promising candidates as sensitive and specific biomarkers for DILI. The emergence of three-dimensional spheroid models demonstrates potential use in providing clinically relevant data and predicting hepatotoxicity of SMKIs.

9.
Nurs Open ; 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-33377613

RESUMO

AIM: To assess the effectiveness of decision aids in the treatment, prevention and screening of breast cancer patients. DESIGN: A systematic review and meta-analysis. METHODS: The review protocol was registered in the CRD Prospero database(CRD42020173028). A literature search was carried out in five databases: PubMed, Cochrane, EMBASE, Scopus and Web of science data in January 2020. We used The Cochrane risk bias assessment tool to evaluate the literature quality of included trials and the Review Manager 5.2 software to analyse data. RESULTS: We included 22 studies. Compared with the conventional methods, decision aids reduced treatment decision conflicts and had no significant effect on screening decision conflicts (WMD=-2.25, 95% CI = - 2.64,-1.87, p < .0001; WMD=-1.37, 95% CI = - 3.57,0.83, p = .22). Three were no statistical differences in participants' anxiety, decision regret, knowledge, informed choice and decision-making satisfaction between the two groups.

11.
Nat Commun ; 11(1): 6266, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33293512

RESUMO

Grain weight (GW) is one of the component traits of wheat yield. Existing reports have shown that multiple phytohormones are involved in the regulation of GW in different crops. However, the potential role of jasmonic acid (JA) remains unclear. Here, we report that triticale grain weight 1 (tgw1) mutant, with marked reductions in both GW and JA content, is caused by a premature stop mutation in keto-acyl thiolase 2B (KAT-2B) involved in ß-oxidation during JA synthesis. KAT-2B overexpression increases GW in wild type and boosts yield. Additionally, KAT-2B compliments the grain defect in tgw1 and rescues the lethal phenotype of the Arabidopsis kat2 mutant in a sucrose-free medium. Despite the suppression of JA synthesis in tgw1 mutant, ABA synthesis is upregulated, which is accompanied by enhanced expression of SAG3 and reduction of chlorophyll content in leaves. Together, these results demonstrate a role of the JA synthetic gene KAT-2B in controlling GW and its potential application value for wheat improvement.


Assuntos
Acetil-CoA C-Aciltransferase/metabolismo , Ciclopentanos/metabolismo , Grão Comestível/fisiologia , Oxilipinas/metabolismo , Proteínas de Plantas/metabolismo , Triticum/fisiologia , Ácido Abscísico/metabolismo , Acetil-CoA C-Aciltransferase/genética , Acetil-CoA C-Aciltransferase/isolamento & purificação , Clorofila/metabolismo , Clonagem Molecular , Códon sem Sentido , Folhas de Planta/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/isolamento & purificação , Plantas Geneticamente Modificadas , Locos de Características Quantitativas , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo
12.
Autophagy ; : 1-17, 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33315519

RESUMO

Liver dysfunction is an outstanding dose-limiting toxicity of gefitinib, an EGFR (epidermal growth factor receptor)-tyrosine kinase inhibitor (TKI), in the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). We aimed to elucidate the mechanisms underlying gefitinib-induced hepatotoxicity, and provide potentially effective intervention strategy. We discovered that gefitinib could sequentially activate macroautophagy/autophagy and apoptosis in hepatocytes. The inhibition of autophagy alleviated gefitinib-induced apoptosis, whereas the suppression of apoptosis failed to lessen gefitinib-induced autophagy. Moreover, liver-specific Atg7 +/- heterozygous mice showed less severe liver injury than vehicle, suggesting that autophagy is involved in the gefitinib-promoted hepatotoxicity. Mechanistically, gefitinib selectively degrades the important anti-apoptosis factor COX6A1 (cytochrome c oxidase subunit 6A1) in the autophagy-lysosome pathway. The gefitinib-induced COX6A1 reduction impairs mitochondrial respiratory chain complex IV (RCC IV) function, which in turn activates apoptosis, hence causing liver injury. Notably, this autophagy-promoted apoptosis is dependent on PLK1 (polo like kinase 1). Both AAV8-mediated Plk1 knockdown and PLK1 inhibitor BI-2536 could mitigate the gefitinib-induced hepatotoxicity in vivo by abrogating the autophagic degradation of the COX6A1 protein. In addition, PLK1 inhibition could not compromise the anti-cancer activity of gefitinib. In conclusion, our findings reveal the gefitinib-hepatotoxicity pathway, wherein autophagy promotes apoptosis through COX6A1 degradation, and highlight pharmacological inhibition of PLK1 as an attractive therapeutic approach toward improving the safety of gefitinib-based cancer therapy. Abbreviations: 3-MA: 3-methyladenine; AAV8: adeno-associated virus serotype 8; ATG5: autophagy related 5; ATG7: autophagy related 7; B2M: beta-2-microglobulin; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CHX: cycloheximide; COX6A1: cytochrome c oxidase subunit 6A1; c-PARP: cleaved poly(ADP-ribose) polymerase; CQ: chloroquine; GOT1/AST: glutamic-oxaloacetic transaminase 1, soluble; GPT/ALT: glutamic pyruvic transaminase, soluble; HBSS: Hanks´ balanced salt solution; H&E: hematoxylin and eosin; MAP1LC3/LC3: microtubule associated proteins 1 light chain 3; PLK1: polo like kinase 1; RCC IV: respiratory chain complex IV; ROS: reactive oxygen species; TUBB8: tubulin beta 8 class VIII.

13.
Nat Commun ; 11(1): 6131, 2020 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-33257677

RESUMO

After a dorsal root crush injury, centrally-projecting sensory axons fail to regenerate across the dorsal root entry zone (DREZ) to extend into the spinal cord. We find that chemogenetic activation of adult dorsal root ganglion (DRG) neurons improves axon growth on an in vitro model of the inhibitory environment after injury. Moreover, repeated bouts of daily chemogenetic activation of adult DRG neurons for 12 weeks post-crush in vivo enhances axon regeneration across a chondroitinase-digested DREZ into spinal gray matter, where the regenerating axons form functional synapses and mediate behavioral recovery in a sensorimotor task. Neuronal activation-mediated axon extension is dependent upon changes in the status of tubulin post-translational modifications indicative of highly dynamic microtubules (as opposed to stable microtubules) within the distal axon, illuminating a novel mechanism underlying stimulation-mediated axon growth. We have identified an effective combinatory strategy to promote functionally-relevant axon regeneration of adult neurons into the CNS after injury.


Assuntos
Axônios/fisiologia , Lesões por Esmagamento/metabolismo , Microtúbulos/fisiologia , Regeneração Nervosa/fisiologia , Neurônios/fisiologia , Raízes Nervosas Espinhais/fisiologia , Animais , Clozapina/análogos & derivados , Clozapina/farmacologia , Lesões por Esmagamento/patologia , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/lesões , Gânglios Espinais/fisiologia , Ratos , Ratos Wistar , Medula Espinal , Raízes Nervosas Espinhais/patologia
14.
Front Hum Neurosci ; 14: 568399, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33304251

RESUMO

Hormonal changes across the menstrual cycle have been shown to influence reward-related motivation and impulsive behaviors. Here, with the aim of examining the neural mechanisms underlying cognitive control of impulsivity, we compared event-related monetary delay discounting task behavior and concurrent functional magnetic resonance imaging (fMRI) revealed brain activity as well as resting state (rs)-fMRI activity, between women in the mid-luteal phase (LP) and women in the late follicular phase (FP). The behavioral data were analyzed and related to neural activation data. In the delay discounting task, women in the late FP were more responsive to short-term rewards (i.e., showed a greater discount rate) than women in the mid-LP, while also showing greater activity in the dorsal striatum (DS). Discount rate (transformed k) correlated with functional connectivity between the DS and dorsal lateral prefrontal cortex (dlPFC), consistent with previous findings indicating that DS-dlPFC circuitry may regulate impulsivity. Our rs-fMRI data further showed that the right dlPFC was significantly more active in the mid-LP than in late FP, and this effect was sensitive to absolute and relative estradiol levels during the mid-LP. DS-dlPFC functional connectivity magnitude correlated negatively with psychometric impulsivity scores during the late FP, consistent with our behavioral data and further indicating that relative estradiol levels may play an important role in augmenting cognitive control. These findings provide new insight into the treatment of conditions characterized by hyper-impulsivity, such as obsessive compulsive disorder, Parkinson disease, and attention deficit hyperactivity disorder. In conclusion, our results suggest that cyclical gonadal hormones affect cognitive control of impulsive behavior in a periodic manner, possibility via DS-dlPFC circuitry.

15.
PeerJ ; 8: e10374, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33282557

RESUMO

Background: Periosteum plays critical roles in de novo bone formation and fracture repair. Wnt16 has been regarded as a key regulator in periosteum bone formation. However, the role of Wnt16 in periosteum derived cells (PDCs) osteogenic differentiation remains unclear. The study goal is to uncover whether and how Wnt16 acts on the osteogenesis of PDCs. Methods: We detected the variation of Wnt16 mRNA expression in PDCs, which were isolated from mouse femur and identified by flow cytometry, cultured in osteogenic medium for 14 days, then knocked down and over-expressed Wnt16 in PDCs to analysis its effects in osteogenesis. Further, we seeded PDCs (Wnt16 over-expressed/vector) in ß-tricalcium phosphate cubes, and transplanted this complex into a critical size calvarial defect. Lastly, we used immunofluorescence, Topflash and NFAT luciferase reporter assay to study the possible downstream signaling pathway of Wnt16. Results: Wnt16 mRNA expression showed an increasing trend in PDCs under osteogenic induction for 14 days. Wnt16 shRNA reduced mRNA expression of Runx2, collage type I (Col-1) and osteocalcin (OCN) after 7 days of osteogenic induction, as well as alizarin red staining intensity after 21days. Wnt16 also increased the mRNA expression of Runx2 and OCN and the protein production of Runx2 and Col-1 after 2 days of osteogenic stimulation. In the orthotopic transplantation assay, more bone volume, trabecula number and less trabecula space were found in Wnt16 over-expressed group. Besides, in the newly formed tissue Brdu positive area was smaller and Col-1 was larger in Wnt16 over-expressed group compared to the control group. Finally, Wnt16 upregulated CTNNB1/ß-catenin expression and its nuclear translocation in PDCs, also increased Topflash reporter luciferase activity. By contrast, Wnt16 failed to increase NFAT reporter luciferase activity. Conclusion: Together, Wnt16 plays a positive role in regulating PDCs osteogenesis, and Wnt16 may have a potential use in improving bone regeneration.

16.
Clin Transl Gastroenterol ; 11(11): e00262, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33259161

RESUMO

OBJECTIVES: To establish and verify a simple noninvasive model based on the left gastric vein (LGV) to predict the grade of esophageal varices (EV) and high-risk EV (HEV), to facilitate clinical follow-up and timely treatment. METHODS: We enrolled 320 patients with B-viral cirrhosis. All patients underwent endoscopy, laboratory tests, liver and spleen stiffness (SS), and ultrasonography. HEV were analyzed using the χ test/t test and logistic regression in the univariate and multivariate analyses, respectively. EV grades were analyzed using the variance/rank-sum test and logistic regression. A prediction model was derived from the multivariate predictors. RESULTS: In the training set, multivariate analysis showed that the independent factors of different EV grades were SS, LGV diameter, and platelet count (PLT). We developed the LGV diameter-SS to PLT ratio index (LSPI) and LGV diameter/PLT models without SS. The area under the receiver operating characteristic curve of the LSPI for diagnosis of small EV, medium EV, large EV, and HEV was 0.897, 0.899, 0.853, and 0.954, respectively, and that of the LGV/PLT was 0.882, 0.890, 0.837, and 0.942, respectively. For the diagnosis of HEV, the negative predictive value was 94.07% when LSPI < 19.8 and the positive predictive value was 91.49% when LSPI > 23.0. The negative predictive value was 95.92% when LGV/PLT < 5.15, and the positive predictive value was 86.27% when LGV/PLT > 7.40. The predicted values showed similar accuracy in the validation set. DISCUSSION: Under appropriate conditions, the LSPI was an accurate method to detect the grade of EV and HEV. Alternatively, the LGV/PLT may also be useful in diagnosing the varices when condition limited.

17.
J Nat Prod ; 83(12): 3545-3553, 2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33216556

RESUMO

Eleven metabolites, six echinosporins (1-6), four dibenzoyls (7-10), and an aromatic compound (11), were isolated from the fermentation broth of lichen-associated Amycolatopsis hippodromi. The structures of the new compounds (1-5, 8-11) were elucidated by comprehensive spectroscopic analysis including data from experimental and calculated ECD spectra. Amycolasporins A-C (1-3) demonstrated antibacterial activities against Bacillus subtilis, Staphylococcus aureus, and Escherichia coli with MIC values of 25 or 100 µg/mL. Amycolasporin C (3) and the known dibenzoyl (7) attenuated the production of NO due to the suppression of the expression of nitric oxide synthase (iNOS) in LPS-induced RAW 264.7 cells in a dose-dependent manner.

18.
Strahlenther Onkol ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33231712

RESUMO

PURPOSE: Proliferating cell nuclear antigen-associated factor (PAF) is involved in cancer cell growth and associated with cell death induced by ultraviolet (UV) radiation. However, the contribution of PAF to radiotherapy sensitivity in non-small cell lung cancer (NSCLC) is unknown. The aim of this study was to investigate the relationship between PAF expression and radiotherapy response in NSCLC. METHODS: Associations between PAF expression and patient survival outcomes were evaluated using publicly available online gene expression datasets. RNA interference was performed to knockdown PAF expression in the NSCLC cells. The effects of PAF knockdown on cell proliferation, migration, apoptosis, DNA damage, and activation of MEK/ERK and Wnt/ß-catenin signaling pathways following X­ray irradiation were evaluated in vitro. RESULTS: PAF was found to be overexpressed in lung cancer tissues compared with normal samples, and elevated PAF expression was significantly correlated with inferior patient survival. In vitro, knockdown of PAF inhibited cell proliferation, cell apoptosis, and migration induced by X­ray irradiation. Moreover, X­ray-induced intracellular DNA strand damage was more obvious following PAF knockdown. Additionally, PAF knockdown inhibited activation of the MEK/ERK and Wnt/ß-catenin signaling pathways in X­ray-irradiated A549 cells. CONCLUSION: These data demonstrate that reduced expression of PAF enhances radiosensitivity in NSCLC cells. Mechanistically, inhibition of the MEK/ERK and Wnt/ß-catenin signaling pathways caused by PAF interference may lead to impaired cell function and enhance sensitivity to X­rays. Targeting PAF may therefore serve as a potential therapeutic strategy to increase the efficiency of radiotherapy in NSCLC patients, ultimately improving patient survival.

19.
Cell Microbiol ; : e13294, 2020 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-33222390

RESUMO

Gametogenesis, the formation of gametes from gametocytes, an essential step for malaria parasite transmission, is targeted by transmission-blocking drugs and vaccines. We identified a conserved protein (PBANKA_0305900) in Plasmodium berghei, which encodes a protein of 22 kDa (thus named Pb22) and is expressed in both asexual stages and gametocytes. Its homologues are present in all Plasmodium species and its closely related, Hepatocystis, but not in other apicomplexans. Pb22 protein was localised in the cytosols of schizonts, as well as male and female gametocytes. During gamete-to-ookinete development, Pb22 became localised on the plasma membranes of gametes and ookinetes. Compared to the wild-type (WT) parasites, P. berghei with pb22 knockout (KO) showed a significant reduction in exflagellation (~89%) of male gametocytes and ookinete number (~97%) during in vitro ookinete culture. Mosquito feeding assays showed that ookinete and oocyst formation of the pb22-KO line in mosquito midguts was almost completely abolished. These defects were rescued in parasites where pb22 was restored. Cross-fertilisation experiments with parasite lines defective in either male or female gametes confirmed that the defects in the pb22-KO line were restricted to the male gametes, whereas female gametes in the pb22-KO line were fertile at the WT level. Detailed analysis of male gametogenesis showed that 30% of the male gametocytes in the pb22-KO line failed to assemble the axonemes, whereas ~48.9% of the male gametocytes formed flagella but failed to egress from the host erythrocyte. To explore its transmission-blocking potential, recombinant Pb22 (rPb22) was expressed and used to immunise mice. in vitro assays showed that the rPb22-antisera significantly inhibited exflagellation by ~64.8% and ookinete formation by ~93.4%. Mosquitoes after feeding on rPb22-immunised mice also showed significant decreases in infection prevalence (83.3-93.3%) and oocyst density (93.5-99.6%). Further studies of the Pb22 orthologues in human malaria parasites are warranted.

20.
J Agric Food Chem ; 68(47): 13863-13870, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33166457

RESUMO

Ethyl lactate is an important flavor substance in baijiu, and it is also one of the common raw materials in the production of flavors and spices. In this study, we first established the ethyl lactate biosynthesis pathway in Saccharomyces cerevisiae α(L) by introducing propionyl coenzyme A transferase (Pct) and alcohol acyltransferase (AAT), and the results showed that strain α(L)-CP-Ae produced the most ethyl lactate 239.53 ± 5.45 mg/L. Subsequently, the copy number of the Pctcp gene and AeAT9 gene was increased, and the modified strain α(L)-tCP-tAe produced 346.39 ± 3.99 mg/L ethyl lactate. Finally, the porin gene (por2) and the mitochondrial pyruvate carrier gene (MPC2) were knocked to impede mitochondrial transport of pyruvate, and the final modified strain α(L)-tCP-tAeΔpor2 produced ethyl lactate 420.48 ± 6.03 mg/L.

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