ABSTRACT
Aristolochic acid (AA) exposure is a severe public health concern worldwide. AAs damage the kidney with an inevitable acute phase that is similar to acute kidney injury (AKI). Gasdermin E (GSDME) is abundant in the kidney; thus; it-mediated pyroptosis might be essential in connecting cell death and inflammation and promoting AAs-AKI. However, the role and exact mechanism of pyroptosis in AAs-AKI have not been investigated. In this study, aristolochic acid I (AAI) was used to establish AKI models. The expression and translocation results showed GSDME-mediated pyroptosis in AAI-AKI. Knocking down GSDME attenuated AAI-induced cell death and transcription of proinflammatory cytokines. Mechanistic research inhibiting caspase (casp) 3, casp 8, and casp 9 with specific chemical antagonists demonstrated that GSDME was activated by cleaved casp 3. Furthermore, the kinase activity of upstream receptor-interacting protein kinase 1 (RIPK1) was significantly elevated, and inhibiting RIPK1 with specific inhibitors markedly improved AAI-induced cell damage. In addition, the level of autophagy was obviously increased. Pretreatment with a specific autophagic inhibitor (3-methyladenine) or knockdown of autophagic genes (Atg5 or Atg7) evidently reduced the activity of RIPK1 and downstream apoptosis and pyroptosis, thus attenuating AA-induced cell injury, which suggested that RIPK1 was a novel link conferring autophagic promotion of pyroptosis. These findings reveal GSDME-mediated pyroptosis for the first time in AAI-induced AKI, propose its novel role in the transcription of cytokines, and demonstrate that autophagy promotes pyroptosis via the RIPK1-dependent apoptotic pathway. This study promotes the understanding of the toxic effects and exact mechanisms of AAs. This will contribute to evaluating the environmental risk of AA exposure and might provide potential therapeutic targets for AA-AKI.
ABSTRACT
BACKGROUND: Sepsis-associated acute kidney injury (S-AKI) is a critical illness and is often associated with high morbidity and mortality rates. The soluble urokinase-type plasminogen activator receptor (suPAR) is an important immune mediator and is involved in kidney injury. However, its diagnostic value in S-AKI patients remains unclear. Therefore, we assessed the early predictive value of suPAR for S-AKI patients. METHODS: We prospectively enrolled adult patients, immediately after fulfilling the sepsis-3 criteria. Plasma suPAR levels at 0-, 12-, 24-, and 48-h post-sepsis diagnosis were measured. S-AKI development was the primary outcome. S-AKI risk factors were analyzed using logistic regression, and the value of plasma suPAR for early S-AKI diagnosis was assessed using receiver operating characteristic (ROC) curves. RESULTS: Of 179 sepsis patients, 63 (35.2%) developed AKI during hospitalization. At 12-, 24-, and 48-h post-sepsis diagnosis, plasma suPAR levels were significantly higher in patients with S-AKI than in patients without S-AKI (p < 0.05). The plasma suPAR had the highest area under the ROC curve of 0.700 (95% confidence interval (CI), 0.621-0.779) at 24-h post-sepsis diagnosis, at which the best discrimination ability for S-AKI was achieved with suPAR of ≥6.31 ng/mL (sensitivity 61.9% and specificity 71.6%). Logistic regression analysis showed that suPAR at 24-h post-sepsis diagnosis remained an independent S-AKI risk factor after adjusting for mechanical ventilation, blood urea nitrogen, and pH. CONCLUSIONS: The findings suggest that plasma suPAR may be a potential biomarker for early S-AKI diagnosis.
Subject(s)
Acute Kidney Injury , Sepsis , Adult , Humans , Receptors, Urokinase Plasminogen Activator , Sepsis/complications , Sepsis/diagnosis , Biomarkers , Acute Kidney Injury/diagnosis , Acute Kidney Injury/etiology , Critical Illness , ROC Curve , PrognosisABSTRACT
Macrophages play an important role in the pathogenesis of systemic lupus erythematosus-associated diffuse alveolar hemorrhage (DAH). The immunomodulation of macrophage responses might be a potential approach for the prevention and treatment of DAH. Erythropoietin (EPO) could regulate macrophage bioactivities by binding to the EPO receptor expressing on macrophages. This study assessed the effects of EPO on DAH protection using an immune-mediated DAH murine model with macrophages as the major contributor. A DAH murine model was established in female C57BL/6 mice by an i.p. injection of pristane. We found that EPO administration alleviates DAH by reducing pulmonary macrophages recruitment and promoting phenotype switch toward M2 macrophages in vivo. EPO drove macrophages to the anti-inflammatory phenotype in the primary murine bone marrow-derived macrophages and macrophages cell line RAW 264.7 with LPS, IFN-γ, and IL-4 in vitro. Moreover, EPO treatment increases the expression of EPOR and decreases the expression of miR-494-3p, resulting in increased phosphorylation of JAK2 and STAT3. In conclusion, EPO can be a potential therapeutic agent in DAH by reducing cell apoptosis and regulating macrophage polarization through the EPOR/JAK2/STAT3 axis. Further studies are also needed to validate the direct target of miR-494-3p in regulating JAK2/STAT3 signaling transduction.
Subject(s)
Erythropoietin/metabolism , Hemorrhage/immunology , Lung Diseases/immunology , Macrophages, Alveolar/immunology , Pulmonary Alveoli/pathology , Animals , Cell Differentiation , Disease Models, Animal , Female , Humans , Janus Kinase 2/metabolism , Mice , Mice, Inbred C57BL , RAW 264.7 Cells , Receptors, Erythropoietin/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction , TerpenesABSTRACT
Millions of human deaths occur annually due to chronic kidney disease, caused by diabetic kidney disease (DKD). Despite having effective drugs controlling the hyperglycemia and high blood pressure, the incidence of DKD is increasing, which indicates the need for the development of novel therapies to control DKD. In this article, we discussed the recent advancements in the basic innate immune mechanisms in renal tissues triggered under the diabetes environment, leading to the pathogenesis and progression of DKD. We also summarized the currently available innate immune molecules-targeting therapies tested against DKD in clinical and preclinical settings, and highlighted additional drug targets that could potentially be employed for the treatment of DKD. The improved understanding of the disease pathogenesis may open avenues for the development of novel therapies to rein in DKD, which consequently, can reduce morbidity and mortality in humans in the future.
Subject(s)
Diabetic Nephropathies/immunology , Diabetic Nephropathies/pathology , Immunity, Innate , Animals , Diabetic Nephropathies/physiopathology , Diabetic Nephropathies/therapy , Humans , Immunity, Innate/drug effects , Immunity, Innate/immunology , Molecular Targeted Therapy/trendsABSTRACT
Cobalt is a transition element that abundantly exists in the environment. Besides direct hypoxia stress, cobalt ions indirectly induce hypoxia-reoxygenation injury (HRI), the main cause of acute kidney injury (AKI), a life-threatening clinical syndrome characterized by the necrosis of the proximal tubular epithelial cells (PTECs) and inflammation. Pyroptosis, a type of inflammatory programmed cell death, might play an essential role in HRI-AKI. However, whether pyroptosis is involved in cobalt chloride (CoCl2)-induced HRI-AKI remains unknown. Autophagy is a cellular biological process maintaining cell homeostasis that is involved in cell damage in AKI, yet the underlying regulatory mechanism of autophagy on pyroptosis has not been fully understood. In this study, the in vitro and in vivo models of CoCl2-induced HRI-AKI were established with HK-2 cell line and C57BL/6J mouse. Pyroptosis-related markers were detected with western blotting and immunofluorescence assays, and results showed that gasdermin E (GSDME)-mediated pyroptosis was involved in the cell damage in HRI-AKI. Specific chemical inhibitors of caspase 3, caspase 8, and caspase 9 significantly inhibited GSDME-mediated pyroptosis, verifying that GSDME-mediated pyroptosis was induced via the activation of caspase 3/8/9. The western blotting and immunofluorescence assays were adopted to detect the accumulation of the autophagosomes, and results suggested that HRI increased the autophagic level. The effects of autophagy on apoptosis and pyroptosis were evaluated using lentivirus transfection assays to knock down autophagy-specific genes atg5 and fip200, and results demonstrated that autophagy induced GSDME-mediated pyroptosis via apoptotic pathways in HRI-AKI. Our results revealed the involvement of GSDME-mediated pyroptosis in CoCl2-induced HRI-AKI and promoted the understanding of the regulatory mechanism of GSDME cleavage. Our study might provide a potential therapeutic target for HRI-AKI, and will be helpful for the risk evaluation of cobalt exposure.
Subject(s)
Acute Kidney Injury , Pyroptosis , Acute Kidney Injury/chemically induced , Animals , Apoptosis , Autophagy , Caspase 3/metabolism , Cobalt/toxicity , Humans , Hypoxia , Mice , Mice, Inbred C57BL , Pore Forming Cytotoxic ProteinsABSTRACT
Although targeted therapy for renal cell carcinoma (RCC) has achieved good therapeutic effects in clinic, a considerable number of patients develop drug resistance over time. So, there is still an urgent need to develop new drugs for RCC treatment. As LSD1 is considered as a promising drug target in diverse cancers, including RCC, we tried to find new LSD1 inhibitor using drug repurposing strategy from a compound library, and fenoldopam, an FDA-approved drug, was identified as a potent LSD1 inhibitor with IC50 = 0.8974 µM in a reversible manner. Molecular docking predicted that fenoldopam occupied the FAD cavity of LSD1, forming hydrogen bonds with surrounding residues. Moreover, fenoldopam inactivated LSD1 and performed antiproliferative activity against ACHN cells and promoted cells apoptosis in vitro. Taken together, fenoldopam was identified as a novel LSD1 inhibitor firstly, and may serve as a new skeleton for RCC therapy.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Renal Cell/drug therapy , Enzyme Inhibitors/pharmacology , Histone Demethylases/antagonists & inhibitors , Kidney Neoplasms/drug therapy , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Repositioning , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Histone Demethylases/metabolism , Humans , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Molecular Structure , Structure-Activity RelationshipABSTRACT
Phototherapy, which mainly includes photothermal treatment (PTT) and photodynamic treatment (PDT), is a photo-initiated, noninvasive and effective approach for cancer treatment. The high accumulation of photosensitizers (PSs) in a targeted tumor is still a major challenge for efficient light conversion, to generate reactive oxygen species (ROS) and local hyperthermia. In this study, a simple and efficient hyaluronic acid (HA)-modified nanoplatform (HA-TiO2@MWCNTs) with high tumor-targeting ability, excellent phototherapy efficiency, low light-associated side effects and good water solubility was developed. It could be an effective carrier to load hematoporphyrin monomethyl ether (HMME), owing to the tubular conjugate structure. Apart from this, the as-prepared TiO2@MWCNTs nanocomposites could also be used as PSs for tumor PTT and PDT. Those results in vitro and in vivo showed that the anti-tumor effect of this system-mediated PTT/PDT were significantly better than those of single treatment manner. In addition, this drug delivery system could realize high ratio of drug loading, sustained drug release, prolonged circulation in vivo and active targeted accumulation in tumor. These results suggest that HA-TiO2@MWCNTs/HMME has high potential for tumor synergistic phototherapy as a smart theranostic nanoplatform.
Subject(s)
Hematoporphyrins/pharmacology , Nanocomposites/chemistry , Photochemotherapy/methods , Photosensitizing Agents/pharmacology , Sarcoma 180/drug therapy , Titanium/pharmacokinetics , Animals , Drug Compounding , Drug Delivery Systems/methods , Drug Liberation , Female , Hematoporphyrins/blood , Hematoporphyrins/pharmacokinetics , Humans , Hyperthermia, Induced/methods , Injections, Subcutaneous , Lasers , MCF-7 Cells , Mice , Mice, Inbred BALB C , Molecular Targeted Therapy/methods , Nanocomposites/ultrastructure , Nanotubes, Carbon/chemistry , Nanotubes, Carbon/ultrastructure , Photosensitizing Agents/blood , Photosensitizing Agents/pharmacokinetics , Reactive Oxygen Species/agonists , Reactive Oxygen Species/metabolism , Sarcoma 180/metabolism , Sarcoma 180/pathology , Theranostic Nanomedicine/methods , Titanium/bloodABSTRACT
Background and Objectives: The ability of a quality of life (QoL) to guide balloon pulmonary angioplasty (BPA) among patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) has not been fully investigated. This study explored the relationship between QoL scores and hemodynamics in CTEPH patients after BPA and examined whether QoL could be applied as a treatment endpoint. Materials and Methods: This cohort study included patients with inoperable CTEPH who had undergone at least four sessions of BPA. The patients' demographic and clinical data as well as hemodynamic parameters and scores from the RAND 36-item short-form QoL questionnaire were recorded and compared before and after BPA. Results: After BPA treatments, clinical characteristics, hemodynamic parameters, as well as QoL score improved significantly. A physical component summary (PCS) score of 35 or 46 can be used as the cutoff value for predicting better World Health Organization functional classification (WHO FC). Patients who had a higher PCS would have longer 6-min walk distance (6MWD), lower pulmonary vascular resistance (PVR), and better cardiac output (CO) both before and after BPA. However, 19 patients (55.9%) with a higher PCS score after BPA did not achieve the goal of mean pulmonary arterial pressure (mPAP) ≤30 mmHg. During the follow-up period, a significant reduction of PVR was observed, but the PCS score improved a little. Conclusions: QoL is a useful tool for assessing the exercise endurance of patients with inoperable CTEPH treated with BPA, but is insufficient to serve as a treatment endpoint for BPA.
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Disulfidptosis, a novel form of regulated cell death, occurs due to the aberrant accumulation of intracellular cystine and other disulfides. Moreover, targeting disulfidptosis could identify promising approaches for cancer treatment. Long non-coding RNAs (lncRNAs) are known to be critically implicated in clear cell renal cell carcinoma (ccRCC) development. Currently, the involvement of disulfidptosis-related lncRNAs in ccRCC is yet to be elucidated. This study primarily dealt with identifying and validating a disulfidptosis-related lncRNAs-based signature for predicting the prognosis and immune landscape of individuals with ccRCC. Clinical and RNA sequencing data of ccRCC samples were accessed from The Cancer Genome Atlas (TCGA) database. Pearson correlation analysis was conducted for the identification of the disulfidptosis-related lncRNAs. Additionally, univariate Cox regression analysis, Least Absolute Shrinkage and Selection Operator Cox regression, and stepwise multivariate Cox analysis were executed to develop a novel risk prognostic model. The prognosis-predictive capacity of the model was then assessed using an integrated method. Variation in biological function was noted using GO, KEGG, and GSEA. Additionally, immune cell infiltration, the tumor mutational burden (TMB), and tumor immune dysfunction and exclusion (TIDE) scores were calculated to investigate differences in the immune landscape. Finally, the expression of hub disulfidptosis-related lncRNAs was validated using qPCR. We established a novel signature comprised of eight lncRNAs that were associated with disulfidptosis (SPINT1-AS1, AL121944.1, AC131009.3, AC104088.3, AL035071.1, LINC00886, AL035587.2, and AC007743.1). Kaplan-Meier and receiver operating characteristic curves demonstrated the acceptable predictive potency of the model. The nomogram and C-index confirmed the strong correlation between the risk signature and clinical decision-making. Furthermore, immune cell infiltration analysis and ssGSEA revealed significantly different immune statuses among risk groups. TMB analysis revealed the link between the high-risk group and high TMB. It is worth noting that the cumulative effect of the patients belonging to the high-risk group and having elevated TMB led to decreased patient survival times. The high-risk group depicted greater TIDE scores in contrast with the low-risk group, indicating greater potential for immune escape. Finally, qPCR validated the hub disulfidptosis-related lncRNAs in cell lines. The established novel signature holds potential regarding the prognosis prediction of individuals with ccRCC as well as predicting their responses to immunotherapy.
Subject(s)
Carcinoma, Renal Cell , Carcinoma , Kidney Neoplasms , RNA, Long Noncoding , Humans , Carcinoma, Renal Cell/genetics , Prognosis , RNA, Long Noncoding/genetics , Kidney Neoplasms/geneticsABSTRACT
Background and Objective: The prevalence of venous thrombus embolism (VTE) in patients with chronic obstructive pulmonary disease (COPD) is higher than in patients without COPD. Owing to the similarity of clinical symptoms between PE and acute exacerbation COPD (AECOPD), PE is likely to be overlooked or underdiagnosed in patients with AECOPD. The aim of the study was to investigate the prevalence, risk factor, clinical characteristics, and prognostic impact of VTE in patients with AECOPD. Methods: This multicenter, prospective, cohort study was conducted in 11 research centers of China. Data on the baseline characteristics, VTE-related risk factors, clinical symptoms, laboratory examination results, computed tomography pulmonary angiography (CTPA) and lower limb venous ultrasound of AECOPD patients were collected. Patients were followed up for 1 year. Results: A total of 1580 AECOPD patients were included in the study. The mean (SD) age was 70.4 (9.9) years and 195 (26%) patients were women. The prevalence of VTE was 24.5% (387/1580) and PE was 16.8% (266/1580). VTE patients were older; had higher BMI; and longer course of COPD than non-VTE patients. The history of VTE, cor pulmonale, less purulent sputum, increased respiratory rate, higher D-dimer, and higher NT-proBNP/BNP were independently associated with VTE in hospitalized patients with AECOPD. The mortality at 1-year was higher in patients with VTE than patients without VTE (12.9% vs 4.5%, p<0.01). There was no significant difference in the prognosis of patients with PE in segmental or subsegmental arteries and in main pulmonary arteries or lobar arteries (P>0.05). Conclusion: VTE is common in COPD patients and is associated with poor prognosis. Patients with PE at different locations had poorer prognosis than patients without PE. It is necessary to perform active screening strategy for VTE in AECOPD patients with risk factors.
Subject(s)
Embolism , Pulmonary Disease, Chronic Obstructive , Thrombosis , Humans , Female , Aged , Male , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/epidemiology , Prevalence , Cohort Studies , Prospective StudiesABSTRACT
Background: The Padua Prediction Score (PPS) recommended by the guidelines lacks effective external validation in a Chinese cohort. This study sought to assess the accuracy of the PPS to predict venous thromboembolism (VTE) risk in medical inpatients with acute respiratory conditions. Methods: This consecutive cohort study included 1,574 inpatients from January to August 2019. The occurrence rate of VTE in patients classified at high-risk and low-risk groups according to PPS and Caprini risk assessment model (RAM) was compared. The discriminatory capability of the RAMs was evaluated in all the patients and the subgroup without pharmacological prophylaxis. Reclassification parameters were also used to assess the clinical utility. Results: 170 (10.8%) patients were objectively confirmed as having VTE during hospitalization. The incidence rate of VTE in low-risk patients was 6.3% by PPS, which was significantly higher than that by Caprini RAM (2.6%, p < 0.001). The area under the curve (AUC) for PPS and Caprini RAM was 0.714 (95%CI, 0.672-0.756) and 0.760 (95%CI, 0.724-0.797), respectively (p = 0.003). The AUC of Caprini RAM was larger than PPS even in subgroups without pharmacological prophylaxis (0.774 vs 0.709, p = 0.002). Compared with Caprini RAM, the net reclassification index was estimated at 0.037 (p = 0.436), and integrated discrimination improvement was 0.015 (p = 0.495) by PPS. Conclusions: According to our cohort study, PPS may not be appropriate to predict VTE risk in hospitalized patients with acute respiratory conditions. An accurate, widely applicable, validated RAM needs to be further constructed in Chinese medical inpatients.
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Aim: This study aimed to investigate the relationship between a new metric-metabolic score for insulin resistance (METS-IR)-and estimated glomerular filtration rate (eGFR) among Japanese participants who underwent health check-ups. Methods: We conducted a cross-sectional study that involved participants in a medical health screening program, which was conducted at the Medical Health Check-up Center in Japan. This retrospective study examined the relationship between METS-IR and eGFR among 881 individuals that joined the program between March 1, 2004, and December 31, 2012. Covariates consisted of serum laboratory tests and lifestyle questionnaires. Multivariate linear regression analysis was used to explore the association between METS-IR and eGFR. In addition, subgroup and interaction analyses were done based on age, sex, body mass index (BMI), alcohol use, smoking status, and hyperuricemia. Results: A total of 881 individuals participated in this study. High METS-IR was highly linked with reduced eGFR (adjusted ß = -5.04, 95% confidence interval (CI): -7.65 to -2.43), while METS-IR was utilized as a categorical variable inside the multiple regression analysis. A decrease in eGFR of 2.54 units was reported for every 10-unit rise in METS-IR (adjusted ß = -2.54, 95% CI: -4.04 to -1.05, P-value = 0.001). Stratified analysis suggested no marked interaction between METS-IR and eGFR across age, sex, BMI, and alcohol consumption groups. However, there was an indication of interaction between METS-IR level, smoking status (P-value = 0.001), and uric level (P-value = 0.011) on eGFR decrease. Conclusions: METS-IR is remarkably associated with eGFR among the participants who underwent health check-ups in Gifu, Japan. Although more studies are required to prove it, METS-IR could be applied as a monitoring index for early screening, primary prevention, and diagnostic and treatment management strategies for chronic kidney disease.
Subject(s)
Insulin Resistance , Metabolic Syndrome , Humans , Glomerular Filtration Rate , Retrospective Studies , Cross-Sectional Studies , Japan/epidemiologyABSTRACT
ABSTRACT: The aim of the study was to investigate the influence of intrarenal RAS on the decrease of renal function in patients undergoing cardiac surgery with cardiopulmonary bypass. This observational study investigated the activation of intrarenal RAS in 24 patients with AKI after cardiac surgery with cardiopulmonary bypass. The activation of intrarenal RAS was determined by urinary angiotensinogen (uAGT), which was measured at 12âhours before surgery, 0 and12âhours after surgery. The results were compared with those of 21 patients without AKI after cardiac surgery with cardiopulmonary bypass. Clinical and laboratory data were collected. Compared with baseline, all patients with cardiac surgery had activation of intrarenal RAS at 0 and 12âhours after surgery. The activation of intrarenal RAS was found significantly higher at both 0 and 12âhours after surgery in AKI group versus non AKI group (6.18â±â1.93âng/mL vs 3.49â±â1.71âng/mL, 16.38â±â7.50âng/mL vs 6.04â±â2.59âng/mL, respectively). There was a positive correlation between the activation of RAS at 0âhour after surgery and the decrease of renal function at 48âhours after surgery (râ=â0.654, Pâ=â.001). These findings suggest that uAGT might be a suitable biomarker for prediction of the occurrence and severity of AKI after cardiac surgery. Inhibition of intrarenal RAS activation might be one the path of future treatment for this type of disease.
Subject(s)
Cardiac Surgical Procedures , Renin-Angiotensin System , Biomarkers/metabolism , Cardiac Surgical Procedures/adverse effects , Cardiopulmonary Bypass/adverse effects , Humans , KidneyABSTRACT
Clear cell renal cell carcinoma (ccRCC) is one of the most frequent pathological subtypes of kidney cancer, accounting for ~70-75%, and the major cause of mortality is metastatic disease. The difference in gene expression profiles between primary ccRCC tumors and metastatic tumors has not been determined. Thus, we report integrated genomic and transcriptomic analysis for identifying differentially expressed genes (DEGs) between primary and metastatic ccRCC tumors to understand the molecular mechanisms underlying the development of metastases. The microarray datasets GSE105261 and GSE85258 were obtained from the Gene Expression Omnibus (GEO) database, and the R package limma was used for DEG analyses. In summary, the results described herein provide important molecular evidence that metastatic ccRCC tumors are different from primary tumors. Enrichment analysis indicated that the DEGs were mainly enriched in ECM-receptor interaction, platelet activation, protein digestion, absorption, focal adhesion, and the PI3K-Akt signaling pathway. Moreover, we found that DEGs associated with a higher level of tumor immune infiltrates and tumor mutation burden were more susceptible to poor prognosis of ccRCC. Specifically, our study indicates that seven core genes, namely the collagen family (COL1A2, COL1A1, COL6A3, and COL5A1), DCN, FBLN1, and POSTN, were significantly upregulated in metastatic tumors compared with those in primary tumors and, thus, potentially offer insight into novel therapeutic and early diagnostic biomarkers of ccRCC.
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Netrin-1, an axon guidance factor, and its receptor UNC5B play important roles in axonal development and angiogenesis. This study examined netrin-1 and UNC5B expression in kidneys with diabetic kidney disease (DKD) and investigated their roles in angiogenesis. Netrin-1 and UNC5B were upregulated in streptozotocininduced DKD Wistar rats, and their expression was compared with that in healthy controls. However, exogenous netrin-1 in UNC5B-depleted human renal glomerular endothelial cells (HRGECs) inhibited cell migration and tubulogenesis. This effect was likely associated with SRC pathway deactivation. Netrin-1 treatment also eliminated the pro-angiogenic effects of exogenous VEGF-165 on UNC5B-silenced HRGECs. These results indicate that UNC5B antagonizes netrin-1 and that UNC5B upregulation contributes partly to enhancing angiogenesis in DKD. Therefore, introducing exogenous netrin-1 and depleting endogenous UNC5B are potential strategies for reducing the incidence of early angiogenesis and mitigating kidney injury in DKD.
Subject(s)
Diabetic Nephropathies/metabolism , Neovascularization, Pathologic/metabolism , Netrin Receptors/metabolism , Netrin-1/pharmacokinetics , Vascular Endothelial Growth Factor A/metabolism , Adult , Aged , Animals , Cell Movement/drug effects , Diabetic Nephropathies/pathology , Disease Models, Animal , Endothelium, Vascular/metabolism , Female , Humans , Male , Middle Aged , Netrin Receptors/genetics , Netrin-1/metabolism , Rats , Rats, Wistar , Up-Regulation/drug effectsABSTRACT
Artesunate (AS) is an iron-dependent drug, which has been used extensively as anti-malarial drugs worldwide with no obvious side effects. Recently, studies have shown that AS also possess profound cytotoxicity against tumor cells. However, simultaneous delivery of hydrophobic AS and Fe(2+) into tumor cells remains a major challenge. Herein, we report a new kind of active-targeting preparations which could not only specially target to tumor cells but also synchronously transfer AS and irons into tumor tissue. In this study, hyaluronic acid (HA) was grafted onto fullerene to get a water-soluble biomaterial (HA-C60) with excellent biocompatibility, and then combined with transferrin (Tf) to obtain a multi-functional drug delivery system (HA-C60-Tf) with significant tumor-targeting efficacy and powerful photodynamic therapy capacity. Finally, AS was adsorbed on HA-C60-Tf with a high loading efficacy of 162.4% (weight ratio of AS: HA-C60-Tf). Compared with free AS, remarkably enhanced antitumor efficacy of AS-loaded HA-C60-Tf nanoparticles was realized both in a cultured MCF-7 cells in vitro and in a tumor-bearing murine model in vivo, due to increased intracellular accumulation of AS in tumor and activated mechanism by co-delivery of Tf and AS analogs. Furthermore, with laser irradiation in vivo, the relative tumor volume (V/V0) of HA-C60-Tf/AS declined by half, from 1.72 ± 0.12 to 0.84 ± 0.07, suggesting a new way with multi-mechanism for tumor treatment was developed.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Delivery Systems , Fullerenes/chemistry , Iron/metabolism , Nanoparticles/chemistry , Transferrin/metabolism , Animals , Antineoplastic Agents/pharmacokinetics , Apoptosis/drug effects , Artemisinins/pharmacokinetics , Artemisinins/pharmacology , Artesunate , Drug Synergism , Endocytosis/drug effects , Female , Humans , Hyaluronic Acid/chemistry , Intracellular Space/metabolism , MCF-7 Cells , Mice, Inbred BALB C , Nanoparticles/ultrastructure , Reactive Oxygen Species/metabolism , Tissue Distribution/drug effects , Transferrin/pharmacokineticsABSTRACT
Artemisinin (ART) is a kind of drug with an endoperoxide bridge which tends to react with Fe(2+) to generate radicals for killing cancer cells. However, simultaneous delivery of hydrophobic ART and Fe(2+) ions into cancer cells remains a major challenge. In this study, a multi-functional tumor-targeting drug delivery system employing hyaluronic acid-derivatized multi-walled carbon nanotubes (HA-MWCNTs) as drug carriers, transferrin (Tf) as targeting ligand and ART as a model drug for cancer treatment was constructed. This delivery system (HA-MWCNTs/Tf@ART) not only retained optical property of MWCNTs and cytotoxicity of ART but also demonstrated synergistic anti-tumor effect using ART and Tf. Compared with free ART, remarkably enhanced anti-tumor efficacy of this drug vehicle was realized both in cultured MCF-7 cells in vitro and in a tumor-bearing murine model in vivo, due to increased intracellular accumulation of ART and co-delivery of Tf and ART analogs. HA-MWCNTs/Tf@ART with laser irradiation demonstrated the highest inhibition effect compared to the other groups. This result may provide a new way of using promising natural drugs for cancer therapy.
Subject(s)
Artemisinins/administration & dosage , Artemisinins/pharmacology , Drug Carriers/administration & dosage , Drug Carriers/chemistry , Nanoparticles/administration & dosage , Nanotubes, Carbon/chemistry , Transferrin/pharmacokinetics , Animals , Apoptosis/drug effects , Artemisinins/chemistry , Artemisinins/pharmacokinetics , Cell Cycle/drug effects , DNA Fragmentation/drug effects , Drug Carriers/chemical synthesis , Drug Carriers/pharmacokinetics , Drug Synergism , Humans , Hyaluronic Acid/chemistry , Hyaluronic Acid/pharmacokinetics , Hyaluronic Acid/pharmacology , MCF-7 Cells , Mice , Nanoparticles/chemistry , Reactive Oxygen Species/metabolism , Transferrin/administration & dosage , Xenograft Model Antitumor AssaysABSTRACT
As one of the most frequently used chemotherapeutic drugs, doxorubicin (DOX) is accompanied by low accumulation in tumors and severe dose-limiting side effects with systemic administration, which limits its therapeutic index. In this work, a novel and injectable in situ photo-sensitive inorganic/organic hybrid hydrogel as a localized drug-delivery system was examined. It explored poly(ethylene glycol) double acrylates (PEGDA) as a polymeric matrix, DOX as a model drug, a TiO2@MWCNT nanocomposite as the photoinitiator and photosensitizer-photothermal agent for tumor therapy possessing a multi-mechanism using a single NIR laser. Briefly, a PEGDA solution containing DOX and TiO2@MWCNTs was injected into a tumor and rapidly gelled in vivo via a photo-crosslinking action triggered by a NIR laser. DOX release from the DOX/TiO2@MWCNTs/PEGDA hydrogel was sustained and long-lasting, over 10 days, indicating that the PEGDA gel acted as a drug depot. Simultaneously, a NIR laser light was adopted which can be absorbed and converted into reactive oxygen species (ROS) or local hyperthermia by TiO2@MWCNTs, leading to tumor cell death. This DOX/TiO2@MWCNTs/PEGDA hydrogel exhibited remarkable anti-proliferative activities against MCF-7 cancer cells in vitro. Experiments in vivo showed that a single intratumoral injection of this hydrogel with 808 nm laser irradiation was the most effective among all DOX formulations in the tumor-bearing mice models. There was a relatively small DOX distribution in normal tissues and much lower systemic toxicity than the control group (DOX-only). In general, it is believed that the novel photo-sensitive hybrid hydrogel system prepared in this study can afford high drug-loading, sustained and stable drug release, as well as repeated phototherapy of the tumor with the administration of a single dose.
ABSTRACT
OBJECTIVE: A multifunctional tumor-targeting drug delivery system employing single-walled carbon nanotubes (SWCNT) as drug carriers, AS1411 as targeting ligand and doxorubicine (DOX) as a model chemotherapy drug was constructed. METHODS: Firstly, SWCNT were modified with F68 (4.0 mg/ml) by ultrasonic dispersing technology due to the action of hydrophobic force and Van der Waals force, endowing SWCNT water dispersions and biocompatibility. Meanwhile, DOX could be easily absorbed on the surface of SWCNT by the π-π stacking, electrostatic adsorption and hydrophobic interactions. Finally, AS1411 was attached to the surface of DOX-SWCNT by the π-π stacking and electrostatic adsorption to obtain a tumor-targeting delivery system. Cellular uptake, anti-tumor effect in vitro and in vivo, cell cycle and apoptosis and biodistribution of AS1411-DOX-SWCNT were investigated, compared with the DOX solution. CONCLUSION: This AS1411-mediated DOX-loaded SWCNT (AS1411-DOX-SWCNT) delivery system not only retained both optical properties of SWCNT and cytotoxicity of DOX but also could accumulate in tumors, which facilitated combination of chemotherapy and photothermal therapy. AS1411-DOX-SWCNT could effectively promote DOX cellular uptake and then increase intracellular accumulation as a targeting delivery system. AS1411-DOX-SWCNT by NIR laser excited could trigger S phase arrest and the late stage apoptotic on PC3 cancer cells. The investigation in vivo further confirmed that this system possessed higher tumor targeting capacity and antitumor efficacy than DOX, especially with NIR laser irradiation.