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1.
MedComm (2020) ; 5(6): e547, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38764726

RESUMO

Cancer is a disease with molecular heterogeneity that is closely related to gene mutations and epigenetic changes. The principal histological subtype of lung cancer is non-small cell lung cancer (NSCLC). Long noncoding RNA (lncRNA) is a kind of RNA that is without protein coding function, playing a critical role in the progression of cancer. In this research, the regulatory mechanisms of lncRNA phosphorylase kinase regulatory subunit alpha 1 antisense RNA 1 (PHKA1-AS1) in the progression of NSCLC were explored. The increased level of N6-methyladenosine (m6A) modification in NSCLC caused the high expression of PHKA1-AS1. Subsequently, high-expressed PHKA1-AS1 significantly facilitated the proliferation and metastasis of NSCLC cells, and these effects could be reversed upon the inhibition of PHKA1-AS1 expression, both in vivo and in vitro. Additionally, the target protein of PHKA1-AS1 was actinin alpha 4 (ACTN4), which is known as an oncogene. Herein, PHKA1-AS1 could enhance the protein stability of ACTN4 by inhibiting its ubiquitination degradation process, thus exerting the function of ACTN4 in promoting the progress of NSCLC. In conclusion, this research provided a theoretical basis for further exploring the potential mechanism of NSCLC metastasis and searching novel biomarkers related to the pathogenesis and progression of NSCLC.

2.
World J Clin Cases ; 12(8): 1454-1460, 2024 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-38576808

RESUMO

BACKGROUND: A rare autosomal recessive genetic disorder, 3M syndrome, is characterized by severe intrauterine and postnatal growth retardation. Children with 3M syndrome typically exhibit short stature, facial deformities, long tubular bones, and high vertebral bodies but generally lack mental abnormalities or other organ damage. Pathogenic genes associated with 3M syndrome include CUL7, OBSL1 and CCDC8. The clinical and molecular characteristics of patient with 3M syndrome are unique and serve as important diagnostic indicators. CASE SUMMARY: In this case, the patient displayed square shoulders, scoliosis, long slender tubular bones, and normal neurological development. Notably, the patient did not exhibit the typical dysmorphic facial features, relative macrocephaly, or growth retardation commonly observed in individuals with 3M syndrome. Whole exon sequencing revealed a novel heterozygous c.56681+1G>C (Splice-3) variant and a previously reported nonsense heterozygous c.3341G>A (p.Trp1114Ter) variant of OBSL1. Therefore, it is important to note that the clinical features of 3M syndrome may not always be observable, and genetic confirmation is often required. Additionally, the identification of the c.5683+1G>C variant in OBSL1 is noteworthy because it has not been previously reported in public databases. CONCLUSION: Our study identified a new variant (c.5683+1G>C) of OBSL1 that contributes to expanding the molecular profile of 3M syndrome.

3.
Thorac Cancer ; 14(32): 3202-3207, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37718475

RESUMO

BACKGROUND: To explore the altered functional connectivity (FC) of the nucleus tractus solitarii (NTS) in patients with chronic cough after lung surgery using resting-state functional magnetic resonance imaging (rs-fMRI), and the association between abnormal FC and clinical scale scores. METHODS: A total of 22 patients with chronic cough after lung surgery and 22 healthy controls were included. Visual analog scale (VAS), Mandarin Chinese version of the Leicester Cough Questionnaire (LCQ-MC), and Hamilton anxiety rating scale (HAMA) scores were assessed, and rs-fMRI data were collected. The FC analysis was performed using the NTS as the seed point, and FC values with all voxels in the whole brain were calculated. A two-sample t-test was used to compare FC differences between the two groups. The FC values of brain regions with differences were extracted and correlated with clinical scale scores. RESULTS: In comparison to healthy controls, FC values in the NTS and anterior cingulate cortex(ACC) were reduced in patients with chronic cough after lung surgery (GRF correction, p-voxel < 0.005, p-cluster < 0.05) which were positively correlated with LCQ-MC scores (r = 0.534, p = 0.011), but with VAS (r = -0.500, p = 0.018), HAMA (r = -0.713, p < 0.001) scores were negatively correlated. CONCLUSIONS: Reduced FC of the NTS with ACC may be associated with cough hypersensitivity and may contribute to anxiety in patients with chronic cough after lung surgery.


Assuntos
Tosse , Núcleo Solitário , Humanos , Tosse/diagnóstico por imagem , Tosse/etiologia , Imageamento por Ressonância Magnética/métodos , Pulmão/diagnóstico por imagem
4.
J Thorac Dis ; 15(4): 1848-1860, 2023 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-37197543

RESUMO

Background: Acupuncture has achieved good results in the treatment of cough, asthma, chronic obstructive pulmonary disease (COPD) and other lung diseases, but the mechanism associated with acupuncture in the treatment of chronic cough induced by lung surgery is unknown. We investigated whether acupuncture therapy could improve the symptoms of chronic cough after lung surgery through cyclic-AMp dependent protein kinase A (PKA)/cyclic-AMp dependent protein kinase C (PKC) regulation of the transient receptor potential vanilloid-1 (TRPV1) signaling pathway. Methods: The guinea pigs were divided into 5 groups: the Sham operation Group (Sham), the Model Group (Model), the Electroacupuncture + Model Group (EA + M), the H89 + Model Group (H89 + M) and the Go6983 + Model Group (Go6983 + M). The effect of treatment was determined by measuring cough symptoms (number of coughs/cough incubation period) as the outcome criterion. The levels of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and blood were determined by enzyme-linked immunosorbent assays (ELISA). Lung tissue was stained with hematoxylin and eosin (H&E). The expression of p-PKA, p-PKC and p-TRPV1 proteins was measured by Western blotting. The mRNA levels of TRPV1, Substance P (SP), calcitonin gene-related peptide (CGRP) and neurokinin-1R (NK1R) were measured by real-time polymerase chain reaction (RT-PCR). Results: Acupuncture significantly reduced the cough frequency and prolonged the cough latency of chronic cough in guinea pigs after lung surgery. In addition, acupuncture reduced the damage to lung tissue. The levels of inflammatory cytokines decreased in all treatment groups, the expression levels of p-PKA, p-PKC and p-TRPV1 were significantly inhibited and the mRNA levels of TRPV1, SP, CGRP and NK1R decreased significantly after acupuncture treatment. Conclusions: Acupuncture therapy ameliorated chronic cough in guinea pigs after lung surgery by regulating the TRPV1 signaling pathway via PKA/PKC. Our results showed that acupuncture may be an effective treatment of chronic cough after lung surgery, and also clarified the potential mechanism, which provides a theoretical basis for the clinical treatment of patients with chronic cough after lung surgery.

5.
Thorac Cancer ; 14(15): 1383-1391, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37037492

RESUMO

BACKGROUND: To investigate the correlation between the fibrinogen combined with neutrophil-to-lymphocyte ratio (F-NLR) and the clinicopathologic features of non-small cell lung cancer (NSCLC) patients who underwent radical resection. METHODS: This study reviewed the medical records of 289 patients with NSCLC who underwent radical resection. The patients were stratified into three groups based on F-NLR as follows: patients with low NLR and fibrinogen were group A, patients with high NLR or fibrinogen were group B, and patients with high NLR and fibrinogen were group C. Receiver operating characteristic curve and Youden index were used to determine the cutoff value of the NLR and fibrinogen. Survival curves were described by Kaplan-Meier method and compared by log-rank test. The univariate and multivariate analyses were performed with the Cox proportional hazard model to identify the prognostic factors. RESULTS: A value of 3.19 was taken as the optimal cutoff value of NLR in this study. A value of 309 was used as the optimal cutoff value of fibrinogen. Cox multivariate analysis showed that tumor, nodes, metastasis (TNM) stage and F-NLR were independent prognostic factors affecting the survival rate of patients. The first-, third-, and fifth-year survival rates in group A were 99.2%, 96.6%, and 95.0%, respectively. The first-, third-, and fifth-year survival rates in group B were 98.4%, 76.6%, and 63.2%, respectively. The first-, third-, and fifth-year survival rates in group C were 91.3%, 41.1%, and 22.8%, respectively. F-NLR was significantly correlated with overall survival in patients with NSCLC (p < 0.001). CONCLUSIONS: The F-NLR level is markedly related to the prognosis of patients with NSCLC undergoing radical surgery. Therefore, closer attention should be given to patients with NSCLC with a high F-NLR before surgery to provide postoperative adjuvant therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neutrófilos/patologia , Prognóstico , Fibrinogênio , Neoplasias Pulmonares/patologia , Linfócitos/patologia , Estudos Retrospectivos
6.
J Clin Neurophysiol ; 40(4): 355-363, 2023 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34817444

RESUMO

PURPOSE: Evaluate the value of bilateral final/baseline threshold level changes of lower cranial nerve MEPs in postoperative swallowing function deterioration prediction. METHODS: Bilateral lower cranial nerve motor-evoked potentials (MEPs) were recorded in 51 patients who underwent treatment for skull base and brainstem tumors. Corkscrew-like electrodes were positione 2 cm below C3/C4 and Cz. The MEPs were recorded from different muscle groups, including the posterior pharyngeal wall muscle, tongue muscle, genioglossus muscle, and cricothyroid muscle through paired needle electrodes. Swallowing function was assessed clinically using the Mann Assessment of Swallowing Ability score before and after the procedure at 7 days, 1 month, and 3 months. RESULTS: Bilateral final/baseline threshold level increases in lower cranial nerve MEPs under the dual monitoring were significantly correlated with postoperative swallowing function deterioration ( r = 0.660 at 7 days, r = 0.735 at 1 month, and r = 0.717 at 3 months; p < 0.05). Bilateral final/baseline threshold level changes of more than 20% were recorded in 23 of the 51 patients, with 21 patients experiencing swallowing function deterioration postoperatively. The other 28 patients had bilateral threshold level changes of less than 20%, with 26 patients maintaining or improving their swallowing function, and 12 of those patients presented transient deterioration of swallowing function in the early postoperative period. CONCLUSIONS: Dual monitoring of lower cranial nerves and their different muscle groups MEPs was a safe and effective way to predict postoperative swallowing function. An increase in bilateral final/baseline threshold level change of more than 20% was predictive of permanent swallowing deterioration, especially in patients with poor swallowing function preoperatively.


Assuntos
Deglutição , Base do Crânio , Humanos , Base do Crânio/cirurgia , Potencial Evocado Motor/fisiologia , Nervos Cranianos , Tronco Encefálico
7.
Nutrients ; 14(19)2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36235813

RESUMO

Research has connected Parkinson's disease (PD) with impaired intestinal barrier. The activation of G-protein-coupled receptor 109A (GPR109A) protects the intestinal barrier by inhibiting the NF-κB signaling pathway. Sodium butyrate (NaB), which is a GPR109A ligand, may have anti-PD effects. The current study's objective is to demonstrate that NaB or monomethyl fumarate (MMF, an agonist of the GPR109A) can treat PD mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) via repairing the intestinal barrier. Male C57BL/6J mice were divided into four groups randomly: control, MPTP + vehicle, MPTP + NaB, and MPTP + MMF. Modeling mice received MPTP (20 mg/kg/day, i.p.) for a week, while control mice received sterile PBS. Then, four groups each received two weeks of sterile PBS (10 mL/kg/day, i.g.), sterile PBS (10 mL/kg/day, i.g.), NaB (600 mg/kg/day, i.g.), or MMF (100 mg/kg/day, i.g.). We assessed the expression of tight junction (TJ) proteins (occludin and claudin-1), GPR109A, and p65 in the colon, performed microscopic examination via HE staining, quantified markers of intestinal permeability and proinflammatory cytokines in serum, and evaluated motor symptoms and pathological changes in the substantia nigra (SN) or striatum. According to our results, MPTP-induced defected motor function, decreased dopamine and 5-hydroxytryptamine levels in the striatum, decreased tyrosine hydroxylase-positive neurons and increased activated microglia in the SN, and systemic inflammation were ameliorated by NaB or MMF treatment. Additionally, the ruined intestinal barrier was also rebuilt and NF-κB was suppressed after the treatment, with higher levels of TJ proteins, GPR109A, and decreased intestinal permeability. These results show that NaB or MMF can remedy motor symptoms and pathological alterations in PD mice by restoring the intestinal barrier with activated GPR109A. We demonstrate the potential for repairing the compromised intestinal barrier and activating GPR109A as promising treatments for PD.


Assuntos
Fármacos Neuroprotetores , Doença de Parkinson , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Ácido Butírico/farmacologia , Claudina-1 , Citocinas , Modelos Animais de Doenças , Dopamina/metabolismo , Fumaratos , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B , Fármacos Neuroprotetores/farmacologia , Ocludina , Receptores Acoplados a Proteínas G , Serotonina , Tirosina 3-Mono-Oxigenase
8.
Am J Alzheimers Dis Other Demen ; 37: 15333175221115247, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35833655

RESUMO

The AD7c-NTP is a promising biomarker for AD diagnosis. However, the exact urinary AD7c-NTP concentration to differentiate AD from the mild cognitive impairment (MCI) remains inconclusive. We enrolled 98 and 90 clinical defined AD and MCI patients, respectively, and access their cognition impairment with Neuropsychiatric Inventory (NPI) and Mental State Examination (MMSE) along with their urinary AD7c-NTP. We demonstrated that urinary AD7c-NTP level in sequence from high to low was AD, MCI, and healthy groups (P < .01), and the AD7c-NTP was positively and negatively correlated with the NPI and MMSE scores, respectively. Additionally, AD7c-NTP well-matched NPI subscale scores, including agitation, depression, and apathy (P < .05). Importantly, the optimal cut-off AD7c-NTP level to distinguish the AD and MCI was .94 ng/mL (sensitivity 85.71% & specificity 73.91%). Conclusively, urinary AD7c-NTP could be used for cognition impairment evaluation and differentiated diagnosis of AD and MCI.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Proteínas do Tecido Nervoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Doença de Alzheimer/urina , Cognição , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/urina , Humanos , Proteínas do Tecido Nervoso/urina , Testes Neuropsicológicos
9.
J Colloid Interface Sci ; 619: 42-50, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35367924

RESUMO

Metal sulfides have attracted much attentions as anode materials for lithium-ion batteries (LIBs) because of the high theoretical capacity. However, the poor electronic conductivity and large volume variation usually give rise to the rapid capacity decay and undesirable rate performance, severely hampering their practical application. Herein, a gradient selenium-doped hollow sandwich structured zinc sulfide/carbon (ZnS/C) composite (Se-HSZC) is designed and fabricated as long life-span and stable anode material for LIBs. The gradient Se-doping enhances the interfacial charge transfer in Se-HSZC, while the unique double carbon shell sandwich structure further greatly reduces the volume expansion and ensures the electron fast transportation. Consequently, the Se-HSZC anode presents outstanding rate capability (654 mAh g-1 at 2 A g-1) with remarkable reversible capacity (567 mAh g-1 after 1500 cycles at 4 A g-1) for the half battery. In particular, a reversible capacity of 457 mAh g-1 at 0.5 A g-1 is achieved after 50 cycles for the full battery with LiNi0.6Co0.2Mn0.2O2 as cathode. This work offers a promising design route of novel metal sulfides nanostructures for high performance LIBs.

10.
Zhongguo Zhong Yao Za Zhi ; 46(21): 5693-5700, 2021 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-34951223

RESUMO

To investigate the potential molecular markers and drug-compound-target mechanism of Mahuang Shengma Decoction(MHSM) in the intervention of acute lung injury(ALI) by network pharmacology and experimental verification. Databases such as TCMSP, TCMIO, and STITCH were used to predict the possible targets of MHSM components and OMIM and Gene Cards were employed to obtain ALI targets. The common differentially expressed genes(DEGs) were therefore obtained. The network diagram of DEGs of MHSM intervention in ALI was constructed by Cytoscape 3. 8. 0, followed by Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses of target genes. The ALI model was induced by abdominal injection of lipopolysaccharide(LPS) in mice. Bronchoalveolar lavage fluid(BALF) was collected for the detection of inflammatory factors. Pathological sectioning and RT-PCR experiments were performed to verify the therapeutic efficacy of MHSM on ALI. A total of 494 common targets of MHSM and ALI were obtained. Among the top 20 key active compounds of MHSM, 14 from Ephedrae Herba were found to be reacted with pivotal genes of ALI [such as tumor necrosis factor(TNF), tumor protein 53(TP53), interleukin 6(IL6), Toll-like receptor 4(TLR4), and nuclear factor-κB(NF-κB)/p65(RELA)], causing an uncontrolled inflammatory response with activated cascade amplification. Pathway analysis revealed that the mechanism of MHSM in the treatment of ALI mainly involved AGE-RAGE, cancer pathways, PI3 K-AKT signaling pathway, and NF-κB signaling pathway. The findings demonstrated that MHSM could dwindle the content of s RAGE, IL-6, and TNF-α in the BALF of ALI mice, relieve the infiltration of inflammatory cells in the lungs, inhibit alveolar wall thickening, reduce the acute inflammation-induced pulmonary congestion and hemorrhage, and counteract transcriptional activities of Ager-RAGE and NF-κB p65. MHSM could also synergically act on the target DEGs of ALI and alleviate pulmonary pathological injury and inflammatory response, which might be achieved by inhibiting the expression of the key gene Ager-RAGE in RAGE/NF-κB signaling pathway and downstream signal NF-κB p65.


Assuntos
Lesão Pulmonar Aguda , Medicamentos de Ervas Chinesas/farmacologia , NF-kappa B , Receptor para Produtos Finais de Glicação Avançada , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/genética , Animais , Lipopolissacarídeos , Pulmão/metabolismo , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Farmacologia em Rede , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais
11.
Thorac Cancer ; 11(3): 612-618, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31967724

RESUMO

BACKGROUND: The aim of this study was to evaluate the effect of uniportal and three-portal VATS in lung cancer patients on the postoperative short-term quality of life (QOL). METHODS: A single-center, prospective, nonrandomized study was performed on patients who underwent uniportal or three-portal video-assisted thoracoscopic surgery (VATS) lobectomy and systemic mediastinal lymph node dissection. QOL was measured before surgery at baseline and at one, two, four, and eight weeks after the operation. The measured data of normal distribution were indicated by the mean ± standard deviation, the independent sample t-test was used among the groups, and the χ2 test was used to compare the counting. Non-normal distribution of the measurement data was carried out using the Mann-Whitney test. RESULTS: Preoperative functional areas, symptom areas and overall health scores were similar in the two groups. The physical, role, emotional and social functions and overall health status of the uniportal group were significantly higher than those of the three-portal group in postoperative time. The score of symptom field was higher in one week after operation, the score of two, four and eight weeks decreased gradually, but it was still above the preoperative level, and the fatigue and pain of the uniportal group were significantly lower than that of the three-portal group. CONCLUSION: The advantages of uniportal VATS include a shorter hospital stay, more rapid recovery and superior cosmetic results compared to three-portal VATS. Additionally, uniportal VATS is superior to three-portal thoracoscopic surgery in terms of the immediate postoperative short-term QOL.


Assuntos
Adenocarcinoma de Pulmão/cirurgia , Carcinoma de Células Escamosas/cirurgia , Neoplasias Pulmonares/cirurgia , Excisão de Linfonodo/métodos , Pneumonectomia/métodos , Qualidade de Vida , Cirurgia Torácica Vídeoassistida/métodos , Adenocarcinoma de Pulmão/patologia , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
12.
Thorac Cancer ; 11(1): 156-165, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31777195

RESUMO

BACKGROUND: To investigate the regulatory mechanism behind miR-34a-altered Axl levels in non-small-cell lung cancer (NSCLC) with gefitinib-acquired resistance. METHODS: The expression of miR-34a, Axl, Gas6 and related downstream signaling proteins in the EGFR mutant NSCLC cell lines were determined by qRT-PCR and Western blot; PC9-Gef-miR-34a and HCC827-Gef-miR-34a cells were established by transfecting the parent cells with a miR-34a overexpressing virus, then the expression of Axl, Gas6 and the downstream channel-related proteins were also compared in PC9-Gef-miR-34a and HCC827-Gef-miR-34a and drug-resistant strains. The survival rate of the cells were measured by CCK8 assay. A luciferase reporter detected whether Axl was the target of miR-34a. Finally, a tumor-bearing nude mouse model was established to verify the relationship between the expression of miR-34a, Axl and Gas6 mRNA in vivo. RESULTS: The expression levels of Axl mRNA and protein, Gas6 mRNA and protein, and related downstream proteins in PC9-Gef and HCC827-Gef cell lines were higher than those in PC9 and HCC827 parental cell lines, while the expression of miR-34a was lower than it was in the parental cell lines (P < 0.05). The expression of Axl mRNA and protein, Gas6 mRNA and protein, and related downstream signaling proteins in PC9-Gef and HCC827-Gef cell lines was higher than the expression in PC9-Gef-miR-34a and HCC827-Gef-miR-34a cells, which overexpressed miR-34a (P < 0.05). CONCLUSION: The miR-34a regulation of Axl plays an important role in NSCLC-acquired gefitinib resistance, and their expression is inversely correlated, which suggests that they can be used as prognostic markers or potential therapeutic targets for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Gefitinibe/farmacologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/tratamento farmacológico , MicroRNAs/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Receptor Tirosina Quinase Axl
13.
J Pharmacol Exp Ther ; 372(2): 193-204, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31776208

RESUMO

Synthetic high-density lipoprotein (sHDL) nanoparticles composed of apolipoprotein A-I mimetic peptide and phospholipids have been shown to reduce atherosclerosis in animal models. Cholesterol is mobilized from atheroma macrophages by sHDL into the blood compartment and delivered to the liver for elimination. Historically, sHDL drug discovery efforts were focused on optimizing peptide sequences for interaction with cholesterol cellular transporters rather than understanding how both sHDL components, peptide and lipid, influence its pharmacokinetic and pharmacodynamic profiles. We designed two sets of sHDL having either identical phospholipid but variable peptide sequences with different plasma stability or identical peptide and phospholipids with variable fatty acid chain length and saturation. We found that sHDL prepared with proteolytically stable 22A-P peptide had 2-fold longer circulation half-time relative to the less stable 22A peptide. Yet, longer half-life did not translate into any improvement in cholesterol mobilization. In contrast, sHDL with variable phospholipid compositions showed significant differences in phospholipid PK, with distearoyl phosphatidylcholine-based sHDL demonstrating the longest half-life of 6.0 hours relative to 1.0 hour for palmitoyl-oleoyl phosphatidylcholine-based sHDL. This increase in half-life corresponded to an approx. 6.5-fold increase in the area under the curve for the mobilized cholesterol. Therefore, the phospholipid component in sHDL plays a major role in cholesterol mobilization in vivo and should not be overlooked in the design of future sHDL. SIGNIFICANCE STATEMENT: The phospholipid composition in sHDL plays a critical role in determining half-life and cholesterol mobilization in vivo.


Assuntos
Apolipoproteína A-I/química , Lipoproteínas HDL/farmacocinética , Nanopartículas/química , Peptídeos/química , Peptídeos/farmacocinética , Fosfolipídeos/química , Sequência de Aminoácidos , Animais , Aterosclerose/prevenção & controle , Colesterol/química , Colesterol/metabolismo , Sistemas de Liberação de Medicamentos , Estabilidade de Medicamentos , Humanos , Lipoproteínas HDL/administração & dosagem , Lipoproteínas HDL/química , Masculino , Estrutura Molecular , Nanopartículas/administração & dosagem , Peptídeos/administração & dosagem , Placa Aterosclerótica/metabolismo , Ratos Sprague-Dawley , Relação Estrutura-Atividade
14.
BMC Med ; 17(1): 200, 2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31711490

RESUMO

BACKGROUND: Niemann-Pick disease type C is a fatal and progressive neurodegenerative disorder characterized by the accumulation of unesterified cholesterol in late endosomes and lysosomes. We sought to develop new therapeutics for this disorder by harnessing the body's endogenous cholesterol scavenging particle, high-density lipoprotein (HDL). METHODS: Here we design, optimize, and define the mechanism of action of synthetic HDL (sHDL) nanoparticles. RESULTS: We demonstrate a dose-dependent rescue of cholesterol storage that is sensitive to sHDL lipid and peptide composition, enabling the identification of compounds with a range of therapeutic potency. Peripheral administration of sHDL to Npc1 I1061T homozygous mice mobilizes cholesterol, reduces serum bilirubin, reduces liver macrophage size, and corrects body weight deficits. Additionally, a single intraventricular injection into adult Npc1 I1061T brains significantly reduces cholesterol storage in Purkinje neurons. Since endogenous HDL is also a carrier of sphingomyelin, we tested the same sHDL formulation in the sphingomyelin storage disease Niemann-Pick type A. Utilizing stimulated Raman scattering microscopy to detect endogenous unlabeled lipids, we show significant rescue of Niemann-Pick type A lipid storage. CONCLUSIONS: Together, our data establish that sHDL nanoparticles are a potential new therapeutic avenue for Niemann-Pick diseases.


Assuntos
Lipoproteínas HDL/uso terapêutico , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Animais , Colesterol/metabolismo , Relação Dose-Resposta a Droga , Feminino , Lipídeos , Lipoproteínas HDL/síntese química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/uso terapêutico
15.
Angew Chem Int Ed Engl ; 58(49): 17636-17640, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31595601

RESUMO

An aliphatic polyester has been prepared from ethylene oxide and maleic anhydride that undergoes reversible transformation between amorphous (Tg =18 °C) and crystalline (Tm =124 °C) states through cis-trans isomerization of the C=C bonds in the polymer backbone without any change in either the molecular weight or dispersity of the polymer. A similar transformation was also observed in chiral unsaturated polyesters formed from enantiopure terminal epoxides, such as epichlorohydrin, phenyl glycidyl ether, and (2,3-epoxypropyl)benzene. These unsaturated polyesters with 100 % E-configuration in the crystalline state were prepared by quantitative isomerization of their Z-configuration analogues in the presence of a catalytic amount of diethylamine, while in the presence of benzophenone, irradiation with 365 nm UV light resulted in the transformation of about 30 % trans-alkene to cis-maleate form, thereby affording amorphous polyesters.

16.
ANZ J Surg ; 89(9): 1056-1060, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31334598

RESUMO

BACKGROUND: To evaluate the systematic mediastinal lymph node (LN) dissection outcomes and conversion rates of uniportal video-assisted thoracoscopic surgery (UVATS). METHODS: Patients with non-small-cell lung cancer who underwent video-assisted thoracoscopic surgery (VATS) and systematic mediastinal LN dissection between January 2015 and January 2017 were retrospectively reviewed. We categorized the patients into two groups according to the different surgical approaches. Patients' clinical data were collected and compared. The index of estimated benefit from LN dissection was used to evaluate the therapeutic value of LN dissection for each station. RESULTS: A total of 453 patients underwent VATS, including 197 patients in the UVATS group and 256 patients in the triportal VATS (TVATS) group. There were no significant differences in the 1-, 2- and 3-year survival rates of these two groups (P > 0.05). There were no statistically significant differences in the operative time, numbers and stations of LNs, numbers and stations of N2 LNs, conversion rate or postoperative complications. The UVATS group had less intraoperative blood loss, a shorter duration of hospital stay, less chest tube drainage and a shorter duration of chest tube drainage than the TVATS group (P < 0.05). The conversion rates in the UVATS and TVATS groups were 5.1% and 4.3%, respectively, and the difference was not significant. The same degree of LN sampling was achieved in both groups. CONCLUSION: UVATS permits the same degree of LN sampling as TVATS without a difference in the conversion rate.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/cirurgia , Conversão para Cirurgia Aberta/estatística & dados numéricos , Neoplasias Pulmonares/patologia , Excisão de Linfonodo/métodos , Cirurgia Torácica Vídeoassistida/métodos , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Estudos de Casos e Controles , Tubos Torácicos/efeitos adversos , Drenagem/estatística & dados numéricos , Humanos , Tempo de Internação/estatística & dados numéricos , Neoplasias do Mediastino/patologia , Neoplasias do Mediastino/cirurgia , Duração da Cirurgia , Pneumonectomia/métodos , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida , Cirurgia Torácica Vídeoassistida/estatística & dados numéricos , Cirurgia Torácica Vídeoassistida/tendências , Toracotomia/métodos , Toracotomia/estatística & dados numéricos , Fatores de Tempo
17.
Thorac Cancer ; 10(4): 898-903, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30875149

RESUMO

BACKGROUND: In this study, we investigated the relationship between chronic cough and clinicopathological features in postoperative patients with non-small cell lung cancer (NSCLC) and evaluated the effectiveness of acupuncture therapy for the treatment of postoperative chronic cough in patients with NSCLC. METHODS: We retrospectively evaluated 171 patients with NSCLC who received lobectomy at our center between September 2017 and February 2018. The Mandarin Chinese version of the Leicester Cough Questionnaire (LCQ-MC) was used to evaluate the degree of cough in patients. Postoperative cough was assessed by a visual analog scale (VAS). RESULTS: The total LCQ-MC score for the whole group was 19.79 ± 0.53 before surgery and 18.40 ± 0.70 after surgery (p < 0.001). Logistic regression analysis showed that right lung cancer, difficult airway, acute cough and history of COPD were independent predictors of chronic cough. Of the 68 patients diagnosed with chronic cough, 41 received acupuncture therapy (acupuncture therapy group), and 27 received no acupuncture therapy (no therapy group). No significant difference was found between the two groups in terms of their LCQ-MC scores at eight weeks after surgery (p = 0.756). However, the acupuncture therapy group had a significantly higher LCQ-MC score than the no therapy group at 10 weeks after surgery (p = 0.002). CONCLUSIONS: Right lung cancer, difficult airway, acute cough, and history of COPD are independent predictors of chronic cough after surgery. For patients with chronic cough, acupuncture therapy can shorten the recovery time and improve quality of life after surgery.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/cirurgia , Tosse/terapia , Neoplasias Pulmonares/cirurgia , Complicações Pós-Operatórias/terapia , Terapia por Acupuntura , Adulto , Idoso , Tosse/etiologia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Escala Visual Analógica
18.
Thorac Cancer ; 10(4): 988-991, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30883022

RESUMO

BACKGROUND: We investigated preoperative and postoperative TRPV1, bradykinin (BK), and prostaglandin e-2 (PGE2) levels in patients who underwent lung cancer surgery and evaluated the correlations between these levels and the development of acute or chronic cough after surgery. METHODS: We evaluated 60 patients with non-small cell lung cancer who underwent lobectomy at our center between August and October 2018. TRPV1, BK, and PGE2 levels were determined by enzyme-linked immunosorbent assay and postoperative cough was assessed using the visual analog scale (VAS). RESULTS: The postoperative serum TRPV1, BK, and PEG2 levels of the 60 patients were significantly higher than the preoperative levels (P < 0.001). Thirty-five patients (58.3%) were diagnosed with acute cough (VAS ≥ 60 mm), and 25 were diagnosed with non-acute cough (41.7%). Three days after surgery, the serum TRPV1, BK, and PGE2 levels were significantly higher in the acute cough group than in the non-acute cough group (P < 0.001). Twenty-two patients (36.7%) were diagnosed with chronic cough (VAS ≥ 60 mm), and 25 (62.3%) were diagnosed with non-chronic cough. Eight weeks after surgery, the serum TRPV1, BK, and PGE2 levels were significantly higher in the chronic cough group than in the non-chronic cough group (P < 0.05). CONCLUSIONS: The postoperative TRPV1, BK and PGE2 levels were significantly higher than the preoperative levels. The TRPV1 level was also higher in patients with an acute or chronic cough than in patients without. Postoperative acute or chronic cough symptoms can be improved and alleviated by blocking the TRPV1 pathway.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/cirurgia , Tosse/metabolismo , Neoplasias Pulmonares/cirurgia , Complicações Pós-Operatórias/metabolismo , Canais de Cátion TRPV/metabolismo , Regulação para Cima , Idoso , Bradicinina/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Tosse/etnologia , Dinoprostona/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Escala Visual Analógica
19.
J Cell Biochem ; 120(6): 10821-10829, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30672010

RESUMO

Bladder cancer is the most common malignancy with high recurrence. Currently, the long noncoding RNAs (lncRNAs) have been suggested to play vital roles in the pathogenesis of bladder cancer. The present study investigated the role of lncRNA MIR503 host gene (MIR503HG) in the pathogenesis of bladder cancer by using both in vitro and in vivo functional assays. The expression of MIR503HG was downregulated in bladder cancer tissues and cell lines. Low expression of MIR503HG was associated with advanced tumor stage, advanced histological grade, and lymph node metastasis. Ectopic expression of MIR503HG inhibited cell proliferation, cell growth, cell invasion, and migration, and also promoted cell apoptosis and inhibited cell cycle progression in SW780 cells. In parallel, T24 cells were used for loss-of-function studies. Knockdown of MIR503HG promoted the cancer cell proliferation and increased the migration and invasion abilities of T24 cells. In addition, knockdown of MIR503HG reduced the cell apoptotic rate in cancer cells and promoted cell cycle progression. Furthermore, MIR503HG overexpression decreased the epithelial-mesenchymal transition-related mRNA and protein levels of ZEB1, Snail, N-cadherin, and vimentin, with an increase in E-cadherin level. Consistently, knockdown of MIR503HG showed the opposite effects. In vivo xenograft, nude mice results showed that overexpression of MIR503HG suppressed the tumor growth and tumor metastasis. In conclusion, our results identified a novel lncRNA MIR503HG that exhibited significant antiproliferation, antimigration/invasion effects on bladder cancer cells both in vitro and in vivo, which may hold a therapeutic promise to treat bladder cancer.


Assuntos
Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/genética , Neoplasias da Bexiga Urinária/genética , Idoso , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Metástase Linfática , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Carga Tumoral , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Vimentina/genética , Vimentina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
20.
Transl Cancer Res ; 8(3): 887-898, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35116828

RESUMO

BACKGROUND: Tumor recurrence following the surgical resection of lung cancer (LCa) reduces long-term disease-free survival rates. This study aimed to investigate the association of pulmonary venous blood (PVB) circulating tumor cells (CTCs) with the clinicopathological features of patients with early-stage lung adenocarcinoma. METHODS: A total of 120 cases were enrolled, including 24 healthy controls, 36 patients with lung benign tumors, and 60 early-stage lung adenocarcinoma patients. Cells displaying a profile of human chromosome 8 specific sequence (CEP8)+/4',6-diamidino-2-phenylindole (DAPI)+/leukocyte-specific antibodies (CD45)‒ were regarded as CTCs, and counts of ≥2 CTCs per 3.2 mL of PVB were considered positive. The association of CTC counts with clinical parameters were analyzed. RESULTS: The number of CTCs were significantly higher in early-stage lung adenocarcinoma patients compared to benign or normal control group. Moreover, increased CTCs in lung adenocarcinoma was closely associated with tumor invasion, pathological staging and the epidermal growth factor receptor (EGFR) mutations (P<0.05), whereas no significant difference was observed between CTC counts and age, sex, smoking history, pathological cell morphology or immunohistochemical indicators (P>0.05). Univariate and multivariate Cox's proportional hazards regression confirmed that CTC counts were an independent indicator for the prediction of tumor invasion, pathological staging, and EGFR mutations. CONCLUSIONS: Our data suggest that CTC counts correlate with tumor invasion, pathological staging, and EGFR mutations. CTCs therefore represent promising biomarkers for the surveillance of lung adenocarcinoma progression.

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