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Fuzheng Huayu recipe (FZHYR) is a Chinese patent medicine for the treatment of fibrosis. The effects of FZHYR on pulmonary fibrosis and macrophage polarization were investigated in vitro. FZHYR inhibited pulmonary inflammation and fibrosis and M2 polarization of macrophages in bleomycin-induced pulmonary fibrosis (BPF) of rat model. Differentially expressed genes were screened by high-throughput mRNA sequencing and GSEA showed that oxidative phosphorylation (OXPHOS) was correlated with BPF. FZHYR inhibited expressions of Ndufa2 and Ndufa6 in lung tissues of BPF rats. These findings suggest that OXPHOS pathway serves as a possible target for pulmonary fibrosis therapy by FZHYR.
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BACKGROUND: Chronic obstructive pulmonary disease (COPD) has a high fatality rate and poses a great threat to human health. Astragaloside IV (AS-IV) is proven to attenuate cigarette smoke (CS)-induced pulmonary inflammation, based on which this research focuses on the mechanism of AS-IV in COPD. METHODS: To evaluate the effects of AS-IV, CD4+ T cells received different concentrations of AS-IV. CD4+ T cell viability, T helper 17 (Th17)/regulatory T (Treg) markers and CXCR4 expressions in CD4+ T cells or spleen/lung tissues were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay, quantitative real-time polymerase chain reaction and Western blot. The proportions of Treg and Th17 cells were assessed by flow cytometry. Enzyme-linked immune sorbent assay was employed to determine cytokine contents in serum and lung tissues. RESULTS: AS-IV with concentration exceeding 40 µM inhibited CD4+ T cell viability. In vitro, AS-IV suppressed the expressions of CXCR4, retinoid-related orphan receptor γt (RORγt), and interleukin (IL)-17A as well as Th17 cells but promoted the expressions of forkhead box p3 (Foxp3) and IL-10 as well as Treg cells, while CXCR4 overexpression reversed the effects of AS-IV. In vivo, AS-IV alleviated COPD, and CS-induced Th17/Treg imbalance in mice and reduced CS-induced down-regulation of IL-10 in serum and lung tissues and Foxp3 and up-regulation of IL-1ß, tumor necrosis factor alpha (TNF-α), IL-6, and IL-17A in serum and lung tissues and RORγt. AS-IV mitigated CS-induced CXCR4 up-regulation. Above effects of AS-IV on mice were offset by CXCR4 overexpression. CONCLUSIONS: AS-IV restores Th17/Treg balance via impeding CXCR4 to ameliorate COPD.
Subject(s)
Pulmonary Disease, Chronic Obstructive , Receptors, CXCR4 , Saponins , T-Lymphocytes, Regulatory , Th17 Cells , Male , Animals , Mice , Mice, Inbred ICR , Receptors, CXCR4/metabolism , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/immunology , Saponins/pharmacology , Triterpenes/pharmacology , Cytokines/metabolism , Spleen/cytology , Lung/cytologyABSTRACT
BACKGROUND: The discovery of a potent photosensitizer with desirable immunogenic cell death (ICD) ability can prominently enhance antitumor immunity in photodynamic therapy (PDT). However, majority of commercially-available photosensitizers suffer from serious aggregation and fail to elicit sufficient ICD. Pyroptosis as a newly identified pattern for potent ICD generation is rarely disclosed in reported photosensitizers. In addition, the photosensitizer with excellent mitochondria-anchored ability evokes prominent mitochondria oxidative stress, and consequently induces ICD. RESULTS: Herein, a novel supramolecular photosensitizer LDH@ZnPc is reported, without complicated preparation, but reveals desirable pyroptosis-triggered ability with mitochondria anchoring feature. LDH@ZnPc is obtained through isolation of ZnPc using positive charged layered double hydroxides (LDH), and excellent mitochondria-anchored ability is achieved. More importantly, LDH@ZnPc-mediated PDT can effectively initiate gasdermin D (GSDMD)-dependent pyroptosis of tumor cells. In vitro and in vivo results verify robust ICD ability and potent tumor inhibition efficacy, and antitumor immunity towards distant tumor inhibition. CONCLUSIONS: This study reveals that LDH@ZnPc can act as an excellent pyroptosis inducer with simultaneous mitochondria anchoring ability for enhancing photodynamic therapy and boosting antitumor immunity.
Subject(s)
Photochemotherapy , Photosensitizing Agents , Photosensitizing Agents/pharmacology , Pyroptosis , MitochondriaABSTRACT
The tumor immune microenvironment (TIME) has been demonstrated to be the main cause of cancer immunotherapy failure in various malignant tumors, due to poor immunogenicity and existence of immunosuppressive factors. Thus, establishing effective treatments for hostile TIME remodeling has considerable potential to enhance immune response rates for durable tumor growth retardation. This study aims to develop a novel nanocomposite, polyethyleneimine-modified dendritic mesoporous silica nanoparticles loaded with microRNA-125a (DMSN-PEI@125a) to synergistically enhance immune response and immunosuppression reversion, ultimately generating a tumoricidal environment. Our results showed that DMSN-PEI@125a exhibited excellent ability in cellular uptake by murine macrophages and the cervical cancer cell line TC-1, repolarization of tumor associated macrophages (TAMs) to M1 type in a synergistic manner, and promotion of TC-1 immunogenic death. Intratumor injection of DMSN-PEI@125a facilitated the release of more damage-related molecular patterns and enhanced the infiltration of natural killer and CD8+ T cells. Meanwhile, repolarized TAMs could function as a helper to promote antitumor immunity, thus inhibiting tumor growth in TC-1 mouse models in a collaborative manner. Collectively, this work highlights the multifunctional roles of DMSN-PEI@125a in generating an inflammatory TIME and provoking antitumor immunity, which may serve as a potential agent for cancer immunotherapy.
Subject(s)
Antineoplastic Agents , Nanocomposites/chemistry , Silicon Dioxide , Tumor Microenvironment , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Female , Immunotherapy , Macrophages/immunology , Macrophages/metabolism , Mice , Mice, Inbred C57BL , MicroRNAs/chemistry , MicroRNAs/pharmacology , Nanoparticle Drug Delivery System , Polyethyleneimine/chemistry , Silicon Dioxide/chemistry , Silicon Dioxide/pharmacology , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunologyABSTRACT
Herein, we found that serum chemokine ligand 14 (CXCL14) was significantly enhanced in patients with idiopathic pulmonary fibrosis (IPF). In our current study, mouse L929 fibroblasts were stimulated with lipopolysaccharide (LPS) (100 ng/mL). Cell proliferation, the levels of matrix metalloproteinase 2 (MMP2) and MMP9, as well as extracellular matrix (ECM) content were assessed to evaluate the fibrogenesis of L929 cells. Proliferating cell nuclear antigen and cell viability were assessed to evaluate cell proliferation. Hydroxyproline (Hyp), collagen I/III, connective tissue growth factor (CTGF), and phosphorylated Smad2/3 (p-Smad2/3) were assessed to evaluate ECM secretion and deposition. α-Smooth muscle actin (α-SMA) was used to measure the occurrence of differentiation from fibroblast toward myofibroblast. Our data suggested that knockdown of CXCL14 prevented LPS-induced fibrogenesis of L929 cells through inhibiting cell proliferation and decreasing the expression of MMP2/9, Hyp, collagen I/III, CTGF, p-Smad2/3, and α-SMA. Notably, upregulation of protein phosphatase magnesium-dependent 1A (PPM1A) was involved in this process. On the contrary, recombinant CXCL14 protein led to an opposite effect. We first suggested that overexpression of PPM1A ameliorated LPS-induced fibrogenesis. Furthermore, we substantiated that knockdown of CXCL14 exerted an antifibrotic effect in IPF in vitro probably via the upregulation of PPM1A. Besides, evidently enhanced CXCL14, yet reduced PPM1A, was found in bleomycin-induced rat pulmonary fibrosis, confirming the roles of CXCL14 and its potential association with PPM1A in IPF in vivo. In conclusion, CXCL14 could be considered as a therapeutic target for preventing fibrogenesis of mouse L929 fibroblasts.
Subject(s)
Chemokines, CXC/metabolism , Fibroblasts/drug effects , Fibroblasts/metabolism , Lipopolysaccharides/toxicity , Myofibroblasts/drug effects , Myofibroblasts/metabolism , Protein Phosphatase 2C/metabolism , Animals , Cell Line , Chemokines, CXC/genetics , Connective Tissue Growth Factor/genetics , Connective Tissue Growth Factor/metabolism , Mice , Protein Phosphatase 2C/geneticsABSTRACT
Tumor-associated macrophages (TAMs) are important immune cells in the tumor microenvironment (TME). The polar plasticity of TAMs makes them important targets for improving the immunosuppressive microenvironment of tumors. The previous study reveals that layered double hydroxides (LDHs) can effectively promote the polarization of TAMs from the anti-inflammatory M2 type to the pro-inflammatory M1 type. However, their mechanisms of action remain unexplored. This study reveals that LDHs composed of different cations exhibit distinct abilities to regulate the polarity of TAMs. Compared to Mg-Fe LDH, Mg-Al LDH has a stronger ability to promote the repolarization of TAMs from M2 to M1 and inhibit the formation of myeloid-derived suppressor cells (MDSCs). In addition, Mg-Al LDH restrains the growth of tumors in vivo and promotes the infiltration of activated immune cells into the TME more effectively. Interestingly, Mg-Al LDH influences the autophagy of TAMs; this negatively correlates with the pro-inflammatory ability of TAMs. Therefore, LDHs exert their polarization ability by inhibiting the autophagy of TAMs, and this mechanism might be related to the ionic composition of LDHs. This study lays the foundation for optimizing the performance of LDH-based immune adjuvants, which display excellent application prospects for tumor immunotherapy.
Subject(s)
Autophagy , Tumor-Associated Macrophages , Adjuvants, Immunologic , Hydroxides/pharmacologyABSTRACT
Purpose: The study aimed to identify potential risk factors for family transmission and to provide precautionary guidelines for the general public during novel Coronavirus disease 2019 (COVID-19) waves. Methods: A retrospective cohort study with numerous COVID-19 patients recruited was conducted in Shanghai. Epidemiological data including transmission details, demographics, vaccination status, symptoms, comorbidities, antigen test, living environment, residential ventilation, disinfection and medical treatment of each participant were collected and risk factors for family transmission were determined. Results: A total of 2,334 COVID-19 patients participated. Compared with non-cohabitation infected patients, cohabitated ones were younger (p = 0.019), more commonly unvaccinated (p = 0.048) or exposed to infections (p < 0.001), and had higher rates of symptoms (p = 0.003) or shared living room (p < 0.001). Risk factors analysis showed that the 2019-nCov antigen positive (OR = 1.86, 95%CI 1.40-2.48, p < 0.001), symptoms development (OR = 1.86, 95%CI 1.34-2.58, p < 0.001), direct contact exposure (OR = 1.47, 95%CI 1.09-1.96, p = 0.010) were independent risk factors for the cohabitant transmission of COVID-19, and a separate room with a separate toilet could reduce the risk of family transmission (OR = 0.62, 95%CI 0.41-0.92, p = 0.018). Conclusion: Patients showing negative 2019-nCov antigen tests, being asymptomatic, living in a separate room with a separate toilet, or actively avoiding direct contact with cohabitants were at low risk of family transmission, and the study recommended that avoiding direct contact and residential disinfection could reduce the risk of all cohabitants within the same house being infected with COVID-19.
Subject(s)
COVID-19 , Humans , COVID-19/epidemiology , Quarantine , Retrospective Studies , China/epidemiology , Risk FactorsABSTRACT
INTRODUCTION: Embryonic stem cells (ESCs) possess great application prospects in biological research and regenerative medicine, so it is important to obtain ESCs with excellent and stable cellular states during in vitro expansion. The feeder layer culture system with the addition of leukemia inhibitory factor (LIF) is currently applied in ESC cultures, but it has a series of disadvantages that could influence the culture efficiency and quality of the ESCs. With the development of nanotechnology, many studies have applied nanomaterials to optimize the stem cell culture system and regulate the fate of stem cells. In this study, we investigated the layer-number-dependent biofunction of graphene oxide (GO) on the pluripotency of ESCs from mice (mESCs). METHODS: Single-layer GO (SGO) and multi-layer GO (MGO) were characterized and their effects on the cytotoxicity and self-renewal of mESCs were detected in vitro. The differentiation potentials of mESCs were identified through the formation of embryoid bodies and teratomas. The regulatory mechanism of GO was verified by blocking the target receptors on the surface of mESCs using antibodies. RESULTS: Both SGO and MGO were biocompatible with mESCs, but only MGO effectively sustained their self-renewal and differentiation potential. In addition, GO influenced the cellular activities of mESCs by regulating the interactions between extracellular matrix proteins and integrins. CONCLUSION: This work demonstrates the layer-number-dependent effects of GO on regulating the cell behavior of mESCs and reveals the extracellular regulatory mechanism of this process.
Subject(s)
Extracellular Matrix/metabolism , Graphite/pharmacology , Integrins/metabolism , Mouse Embryonic Stem Cells/cytology , Mouse Embryonic Stem Cells/metabolism , Animals , Apoptosis/drug effects , Cell Differentiation/drug effects , Cell Self Renewal/drug effects , Cell Survival/drug effects , Extracellular Matrix/drug effects , Extracellular Matrix Proteins/metabolism , Mice , Mouse Embryonic Stem Cells/drug effects , Mouse Embryonic Stem Cells/ultrastructure , Oxidative Stress/drug effectsABSTRACT
Inefficient differentiation and poor engraftment hinder the clinical applications of mesenchymal stem cell (MSC)-based cell therapies in regenerative medicine. Layered double hydroxide (LDH) nanoparticles are sheet-like materials with desirable biocompatibility and anion-exchange properties and have been widely applied as drug and nucleotide carriers in the field of tissue repair. However, few studies have focused on the biological effects of LDH itself. In this study, we demonstrated the novel function of LDH in stimulating osteogenic differentiation of bone marrow-derived MSCs (BMSCs). The expression of osteogenic-related genes, alkaline phosphatase (ALP) activity, and calcium deposits were significantly increased after LDH treatment. Mechanistic analysis performed with RNA sequencing revealed that LDH promoted osteogenesis by targeting the LGR5/ß-catenin axis. LDH also inactivated IKK/NF-κB signaling under LPS-triggered inflamed conditions, suggesting the dual benefits of LDH in enhancing bone regeneration and alleviating the inflammatory response. Furthermore, we utilized LDH as the transport vehicle of the osteoinductive miRNA let-7d to synergistically regulate BMSCs toward the osteoblastic lineage. The LDH/let-7d complex resulted in a better induction of osteogenesis than LDH alone. For cell transplantation, BMSCs were seeded in LDH/let-7d-incorporated fibrin scaffolds, which proved enhanced osteoinduction capability in the subcutaneous ectopic osteogenesis model in nude mice. Taken together, this study provides a novel strategy for effective and synergistic improvement of osteogenesis via LDH-mediated delivery of miRNA let-7d, thus shedding light on the future application of LDH in regenerative medicine.
Subject(s)
Drug Carriers/chemistry , Hydroxides/chemistry , Mesenchymal Stem Cells/drug effects , MicroRNAs/therapeutic use , Nanoparticles/chemistry , Osteogenesis/drug effects , Animals , Cell Differentiation/drug effects , Cells, Cultured , Female , Gene Expression/drug effects , Mice, Nude , MicroRNAs/pharmacology , Rats, Sprague-Dawley , Wnt Signaling Pathway/drug effectsABSTRACT
Visualization technology has become a trend in tumor therapy in recent years. The superior optical properties of graphene quantum dots (GQDs) make them suitable candidates for tumor diagnosis, but their tumor targeting and drug-carrying capacities are still not ideal for treatment. Sulfur-doped graphene quantum dots (SGQDs) with stable fluorescence are prepared in a previous study. A reliable strategy by associating layered double hydroxides (LDHs) and etoposide (VP16) is designed for precise visualization therapy. Trifunctional LDH@SGQD-VP16 integrated nanoprobes can simultaneously achieve targeted aggregation, fluorescence visualization, and chemotherapy. LDH@SGQD-VP16 can accumulate in the tumor microenvironment, owing to pH-sensitive properties and long-term photostability in vivo, which can provide a basis for cancer targeting, real-time imaging, and effect tracking. The enhanced therapeutic and attenuated side effects of VP16 are demonstrated, and the apoptosis caused by LDH@SGQD-VP16 is ≈2.7 times higher than that of VP16 alone, in HGC-27 cells. This work provides a theoretical and experimental basis for LDH@SGQD-VP16 as a potential multifunctional agent for visualization therapy of gastric cancer.
Subject(s)
Graphite , Quantum Dots , Stomach Neoplasms , Etoposide , Humans , Hydroxides , Stomach Neoplasms/drug therapy , Tumor MicroenvironmentABSTRACT
BACKGROUND: Chronic obstructive pulmonary disease (COPD) often coexists with multiple comorbidities which may have a significant impact on acute exacerbations of patients. At present, what kind of comorbidities affects acute exacerbations and how comorbidities lead to poor prognosis are still controversial. The purpose of our study is to determine the impact of comorbidities on COPD exacerbation and establish an acute exacerbation risk assessment system related to comorbidities. METHODS: A total of 742 COPD patients participated in the Shanghai COPD Investigation on Comorbidity Program (SCICP, ChiCTR2000030911). Finally, the baseline information of 415 participants and one-year follow-up data were involved in the analysis. We collected hemogram indices, pulmonary function tests and acute exacerbation of COPD with regular medical follow-up. Q-type cluster analysis was used to determine the clusters of participants. Receiver operating characteristic (ROC) analysis was constructed to assess the ability of indicators in predicting acute exacerbations. RESULTS: Almost 65% of the population we investigated had at least one comorbidity. The distribution and incidence of comorbidities differed between exacerbation group and non-exacerbation group. Three comorbidity clusters were identified: (1) respiratory, metabolic, immune and psychologic disease (non-severe cases); (2) cardiovascular and neoplastic disease (severe cases); (3) less comorbidity. Different sub-phenotypes of COPD patients showed significant distinction in health status. Anxiety (OR=5.936, P=0.001), angina (OR=10.155, P=0.025) and hypertension (OR=3.142, P=0.001) were found to be independent risk factors of exacerbation in a year. The novel risk score containing BODEx and four diseases showed great prognostic value of COPD exacerbation in developing sample. CONCLUSION: Our study detailed the major interaction between comorbidities and exacerbation in COPD. Noteworthily, a novel risk score using comprehensive index - BODEx - and comorbidity parameters can identify patients at high risk of acute exacerbation.
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Background: The COVID-19 pandemic is a significant health threat. Health care worker (HCWs) are at a significant risk of infection which may cause high levels of psychological distress. The aim of this study was to investigate the psychological impact of the COVID-19 on HCWs and factors which were associated with these stresses during the first outbreak in Shanghai. Methods: Between February 9 and 21, 2020, a total of 3,114 frontline HCWs from 26 hospitals in Shanghai completed an online survey. The questionnaire included questions on their sociodemographic characteristics, 15 stress-related questions, and General Health Questionnaire-12 (GHQ-12). Exploratory factor analysis was applied to the 15 stress-related questions which produced four distinct factors for evaluation. Multiple linear regression models were performed to explore the association of personal characteristics with each score of the four factors. Binary logistic analysis was used to explain the association of personal characteristics and these four factors with the GHQ-12. Results: There were 2,691 valid surveys received. The prevalence of emotional distress (defined as GHQ-12 ≥ 12) was noted in 47.7% (95%CI:45.7-49.6%) HCWs. Females (OR = 1.43, 95%CI:1.09-1.86) were more likely to have a psychological distress than males. However, HCWs who work in secondary hospitals (OR = 0.71, 95% CI:0.58-0.87) or had a no contact history (OR = 0.45, 95%CI: 0.35-0.58) were less likely to suffer psychological distress. HCWs who were nurses, married, and had a known contact history were highly likely to have anxiety. HCWs working at tertiary hospitals felt an elevated anxiety regarding the infection, a lack of knowledge, and less protected compared to those who worked at secondary hospitals. Conclusions: Our study shows that the frontline HCWs had a significant psychosocial distress during the COVID-19 outbreak in Shanghai. HCWs felt a lack of knowledge and had feelings of being not protected. It is necessary for hospitals and governments to provide additional trainings and psychological counseling to support the first-line HCWs.
Subject(s)
COVID-19 , Pandemics , China/epidemiology , Cross-Sectional Studies , Disease Outbreaks , Female , Health Personnel , Humans , Male , SARS-CoV-2ABSTRACT
Recent studies indicate that exogenous chemotherapy agents can cross the placenta barrier and cause fetal toxicity, while there exists barely alternative therapy for pregnant cancer patients. Here, we show a robust protective effect of layered double hydroxide (LDH) against etoposide (VP16) induced in vitro mouse embryonic stem cells (mESCs) toxicity and in vivo embryo developmental disorders. The nano-composite system (L-V) abrogated the original VP16 generated mitochondrial mediated mESCs toxicity totally, surprisingly maintained the pluripotency without leukemia inhibitory factor (LIF) and prevented the down-regulation of ectoderm marker expression during spontaneous embryoid bodies differentiation. Fetal growth retardation, the related placenta and skeletal structural abnormalities and long-term toxicity in the offspring were generated when pregnant mice exposed to VP16, while these detrimental effects were abolished when substituted with L-V. The different uterine drug accumulation of VP16 and L-V contributed to partly cause for the functional variation. And further transcriptome analysis confirmed developmental related BMP4-SMAD6 signaling pathway is of crucial importance. Our study revealed the devastating effects of VP16 on embryonic development and the toxicity-relieve method using nano-carrier system, which will provide important guidance for clinical application of LDH as alternative therapeutic system with minimal side effects for pregnant women diagnosed with cancer.
Subject(s)
Antineoplastic Agents , Hydroxides , Pharmaceutical Preparations , Signal Transduction , Animals , Antineoplastic Agents/toxicity , Cell Differentiation , Embryo, Mammalian/drug effects , Etoposide , Female , Humans , Mice , Pregnancy , Signal Transduction/drug effectsABSTRACT
AIMS: To investigate the effect and underlying mechanism of melittin and tripartite motif (TRIM) family in human embryonic lung fibroblast (HELF). MATERIALS AND METHODS: Lentiviral RNA interference vector and lentiviral overexpression vector were constructed and packaged by transfecting 293T cells; the proliferation of HELF was examined using Cell Counting Kit 8; Western blot and qRT-PCR were performed to examine protein and mRNA expression; the interaction with protein phosphatase magnesium-dependent 1A (PPM1A) was examined by Co-immunoprecipitation. KEY FINDINGS: Compared with the control group, the mRNA expression of the TRIM6, TRIM8 and TRIM47 in the IPF group significantly increased. Melittin inhibited the mRNA expression and protein expression levels of TRIM47, the HELF proliferation, the hydroxyproline levels, and the phosphorylation of Smad2/3; the interference of TRIM47 inhibited the protein expression of Vimentin, α-SMA, CTGF, the phosphorylation of Smad2/3 and the synthesis of hydroxyproline; TRIM47 overexpression elevated the phosphorylation of Smad2/3, induced ubiquitination of PPM1A and decreased the expression level of PPM1A, while TRIM47 RNA interference reversed this result. SIGNIFICANCE: Melittin has anti-fibrotic effect in HELF by directly reducing the phosphorylation of Smad2/3 or indirectly reducing the phosphorylation of Smad2/3 by decreasing the expression levels of TRIM47 whose overexpression induces ubiquitination of PPM1A.
Subject(s)
Carrier Proteins/metabolism , Fibroblasts/metabolism , Fibroblasts/pathology , Lung/embryology , Melitten/pharmacology , Neoplasm Proteins/metabolism , Nuclear Proteins/metabolism , Signal Transduction , Actins/metabolism , Carrier Proteins/blood , Cell Proliferation/drug effects , Connective Tissue Growth Factor/genetics , Connective Tissue Growth Factor/metabolism , Fibroblasts/drug effects , Fibrosis , Gene Expression Regulation/drug effects , Humans , Hydroxyproline/metabolism , Neoplasm Proteins/blood , Nuclear Proteins/blood , Phosphorylation/drug effects , Protein Phosphatase 2C/metabolism , RNA Interference , RNA, Messenger/genetics , RNA, Messenger/metabolism , Signal Transduction/drug effects , Smad Proteins/metabolism , Transforming Growth Factor beta/metabolism , Ubiquitination/drug effects , Vimentin/metabolismABSTRACT
Background: Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary and systemic inflammatory processes, and exacerbation of COPD represents a critical moment in the progression of COPD. Several biomarkers of inflammation have been proposed to have a predictive function in acute exacerbation. However, their use is still limited in routine clinical practice. The purpose of our study is to explore the prognostic efficacy of novel inflammatory hemogram indexes in the exacerbation among stable COPD patients. Method: A total of 275 stable COPD patients from the Shanghai COPD Investigation Comorbidity Program were analyzed in our study. Blood examinations, especially ratio indexes like platelet-lymphocyte ratio (PLR), platelet × neutrophil/lymphocyte ratio [systemic immune-inflammation index (SII)], and monocyte × neutrophil/lymphocyte ratio [systemic inflammation response index (SIRI)], lung function test, CT scans, and questionnaires were performed at baseline and routine follow-ups. Clinical characteristics and information of exacerbations were collected every 6 months. The relationship between hemogram indexes and diverse degrees of exacerbation was assessed by logistic regression. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to evaluate the ability of hemogram indexes to predict exacerbation of COPD. Furthermore, the discrimination and accuracy of combined indexes were measured by ROC and calibration curve. Result: There was a significant positive correlation between PLR levels and total exacerbation of COPD patients in a stable stage in a year. Also, the predictive ability of PLR exceeded any other ratio indexes, with an AUC of 0.66. SII and SIRI ranked second only to PLR, with an AUC of 0.64. When combining PLR with other indexes (sex, COPD year, and St. George's Respiratory Questionnaire scores), they were considered as the most suitable panel of index to predict total exacerbation. Based on the result of the ROC curve and calibration curve, the combination shows optimal discrimination and accuracy to predict exacerbation events in COPD patients. Conclusion: The hemogram indexes PLR, SII, and SIRI were associated with COPD exacerbation. Moreover, the prediction capacity of exacerbation was significantly elevated after combining inflammatory hemogram index PLR with other indexes, which will make it a promisingly simple and effective marker to predict exacerbation in patients with stable COPD.
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Background: The outbreak of COVID-19 has led to international concern. We aimed to establish an effective screening strategy in Shanghai, China, to aid early identification of patients with COVID-19. Methods: We did a multicentre, observational cohort study in fever clinics of 25 hospitals in 16 districts of Shanghai. All patients visiting the clinics within the study period were included. A strategy for COVID-19 screening was presented and then suspected cases were monitored and analysed until they were confirmed as cases or excluded. Logistic regression was used to determine the risk factors of COVID-19. Findings: We enrolled patients visiting fever clinics from Jan 17 to Feb 16, 2020. Among 53â617 patients visiting fever clinics, 1004 (1·9%) were considered as suspected cases, with 188 (0·4% of all patients, 18·7% of suspected cases) eventually diagnosed as confirmed cases. 154 patients with missing data were excluded from the analysis. Exposure history (odds ratio [OR] 4·16, 95% CI 2·74-6·33; p<0·0001), fatigue (OR 1·56, 1·01-2·41; p=0·043), white blood cell count less than 4â×â109 per L (OR 2·44, 1·28-4·64; p=0·0066), lymphocyte count less than 0·8â×â109 per L (OR 1·82, 1·00-3·31; p=0·049), ground glass opacity (OR 1·95, 1·32-2·89; p=0·0009), and having both lungs affected (OR 1·54, 1·04-2·28; p=0·032) were independent risk factors for confirmed COVID-19. Interpretation: The screening strategy was effective for confirming or excluding COVID-19 during the spread of this contagious disease. Relevant independent risk factors identified in this study might be helpful for early recognition of the disease. Funding: National Natural Science Foundation of China.
Subject(s)
COVID-19/diagnosis , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , COVID-19/epidemiology , COVID-19/etiology , COVID-19/pathology , Child , Child, Preschool , China/epidemiology , Female , Fever/etiology , Humans , Infant , Infant, Newborn , Leukocyte Count , Lung/pathology , Male , Middle Aged , Multivariate Analysis , Risk Factors , Young AdultABSTRACT
Pulmonary fibrosis (PF) is a heterogeneous pathological process in lung tissues with a considerable mortality rate. Currently, combination therapy represents an effective approach to treat PF. Dexamethasone (Dxs) and berberine (BBR) are widely applied to inhibit the progression of PF. Dxs plus penehyclidine hydrochloride or alfacalcidol have been reported more effective in therapy compared with any single drug treatment. However, whether Dxs plus BBR induces an increased antifibrotic effect remains unknown. The current study aimed to evaluate the therapeutic effect of BBR plus Dxs in bleomycin (BLM)-induced PF. A PF model in rats was established and rats were divided into control, BLM, BBR, Dxs and BBR plus Dxs groups (n=9/group). On days 3, 7 and 14, blood samples were collected from the eyes of the rats (n=6/group). CXC chemokine ligand 14 (CXCL14), collagen I, collagen III, matrix metalloproteinase (MMP)2 and MMP9 serum levels were measured by ELISA. On day 14, all rats were sacrificed. Hematoxylin and eosin analysis, Masson staining and hydroxyproline (Hyp) assessment were performed to observe histopathological changes and collagen deposition. mRNA and protein levels of CXCL14, CXC chemokine receptor 4 (CXCR4), collagen I/III, α-smooth muscle actin (α-SMA), MMP2/9 and phosphorylated-Smad 2/3 in lung tissue were further evaluated. Similar effects in preventing lung damage were observed histopathologically for Dxs and BBR compared with the BLM group. These treatments further reduced levels of Hyp, CXCL14, CXCR4, collagen I/III, MMP2/9, α-SMA and p-Smad 2/3. The combination of Dxs and BBR exhibited increased effectiveness compared with the single treatments. Results further suggested that antifibrotic mechanisms were involved in inhibiting CXCL14 and MMP2/MMP9 expression, and preventing the activation of Smad2/3 and hedgehog signaling pathways. The combined use of Dxs and BBR may represent a potential therapeutic approach for PF.
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The aim of this study was to investigate the expression of FGF2 and FGFR2 in patients with idiopathic pulmonary fibrosis (IPF) and lung cancer (LC) as well as their clinical significance. Reverse transcription-quantitative PCR (RT-qPCR) and western blotting were used to detect FGF2 and FGFR2 expression in LC and adjacent normal tissues of LC patients and lavage fluid of idiopathic pulmonary fibers patients and normal controls (confirmed by bronchoalveolar lavage examination). The expression levels of FGF2 mRNA and protein in the non-small cell LC tissues were significantly higher than those in the adjacent normal tissues (P<0.001). The expression level of FGF2 protein in lavage fluid of patients with IPF was higher than that of the control group (P<0.001). The expression level of FGFR2 mRNA in the non-small cell LC tissues was significantly higher than that in the adjacent normal tissues (P<0.001). The expression level of FGFR2 protein in the non-small cell LC tissues was higher than that in the adjacent normal lung tissues (P<0.001). The expression levels of FGF2 mRNA and FGFR2 mRNA in cancer tissues were not significantly correlated with age, sex and history of smoking (P>0.05), but were significantly correlated with lymph node metastasis, tumor differentiation and TNM staging. FGF2 and FGFR2 proteins were highly expressed in cancer tissues of LC patients and lavage fluid of patients with IPF. The expression of FGF2 mRNA and FGFR2 mRNA was correlated with lymph node metastasis and TNM stage. The high expression levels of FGF2 mRNA and FGFR2 mRNA were associated with tumor metastasis and poor prognosis of LC patients.
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Glioblastoma (GBM) is the most malignant and lethal glioma in human brain tumors and contains self-renewing, tumorigenic glioma stem cells (GSCs) that contribute to tumor initiation, therapeutic resistance and further recurrence. In this study, we combined in vitro cellular efficacy with in vivo antitumor performance to evaluate the outcome of an etoposide (VP16) loaded layered double hydroxide (LDH) nanocomposite (L-V) on human GSCs. The effects on GSC proliferation and apoptosis showed that loading with LDH could significantly sensitize GSCs to VP16 and enhance the GSC elimination. Further qPCR and western blot assays demonstrated that L-V could effectively attenuate GSC related pluripotency gene expression and reduce the cancer stemness. An in vivo GSC xenograft mice model showed that L-V can overcome drug resistance, eradicate GSCs, sharply decrease the stemness and reverse the epithelial-mesenchymal transition (EMT). RNA-seq analysis elucidated that L-V plays a vital role by down-regulating the PI3K/AKt/mTOR expression and activating the Wnt/GSK3ß/ß-catenin signaling pathway, hence leading to GSC stemness loss and greatly enhancing the GSC targeting effect. Taken together, this study demonstrated the outstanding performance of L-V reversing the drug resistance of GSCs, thus providing a novel strategy for clinical translation application of nanomedicine in malignant glioma chemotherapy.
Subject(s)
Drug Carriers/chemistry , Drug Resistance, Neoplasm , Etoposide/administration & dosage , Glioblastoma/drug therapy , Hydroxides/chemistry , Nanoparticles/chemistry , Animals , Brain Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation , Humans , Mice , Neoplastic Stem Cells/drug effects , Phosphatidylinositol 3-Kinases , Xenograft Model Antitumor AssaysABSTRACT
Carbon dots (CDs) hold great promise as a class of fluorophores for bioimaging. Here, we report a simple solvothermal approach to prepare photoluminescent CDs derived from the antineoplastic drug etoposide. The CDs show photoluminescence ranging from 365 to 650 nm when excited at 360 nm. When excited at 405, 488 and 543 nm, strong blue, green and red fluorescence can be detected. Our experiments reveal that the CDs can penetrate into the cells in a short time and remain emissive, even at low temperature. Also, optical signals can be detected from mice after hypodermic or intravenous injection. We demonstrated that the CDs can serve as a low-cytotoxicity biological imaging agent for bioimaging in vitro and in vivo.