Clinical influencing factors affecting pulmonary hypertension in hemodialysis patients

Background: The fluid status and rate of blood flow through the arteriovenous fistula (AVF) are two important factors affecting hemodynamic in hemodialysis patients; however, their effects on pulmonary hypertension have rarely been studied. Hence, we aimed to evaluate the effects of these factors in hemodialysis patients with pulmonary hypertension. Methods: This single-center cross-sectional survey included 219 maintenance hemodialysis patients (139 [63.5%] male). The prevalence of pulmonary hypertension was 13.6% (30 of 219). Pulmonary artery pressure was measured by echocardiography, fluid status was measured objectively using bioimpedance spectroscopy, and blood flow rate in the AVF (Qa) was determined using Doppler ultrasound. Results: The overall mean overhydration before hemodialysis was 1.5 L (range, 0.6-2.8 L). The mean overhydration in patients with and without pulmonary hypertension was 3.6 L (range, 2.3-4.6 L) and 1.4 L (range, 0.6-2.4 L), respectively (p < 0.001). The overall mean Qa was 780 mL/min (range, 570-1,015.5 mL/min). The mean Qa of patients with and without pulmonary hypertension was 672 mL/min (range, 505.7-982.2 mL/min) and 790 mL/min (range, 591-1,026 mL/min), respectively (p = 0.27). Overhydration (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.08-1.97; p = 0.01), N-terminal prohormone of brain natriuretic peptide (NT-proBNP; OR, 1.36; 95% CI, 1.09-1.71; p = 0.007), and left atrial diameter (OR, 1.14; 95% CI, 1.01-1.28; p = 0.03) were risk factors. Conclusion: Pulmonary hypertension is strongly associated with overhydration, NT-proBNP, and left atrial diameter in hemodialysis patients.

Why subclinical involvement is prescribed the same high dose as gross tumor volume: A study on high-dose clinical target volume in intensity-modulated radiotherapy plan of nasopharyngeal carcinoma.

BACKGROUND: Most nasopharyngeal carcinoma (NPC) protocols define primary gross tumor volume (GTVnx) plus a range from 2 to 5 mm as the high-dose clinical target volume (hd-CTV). However, in China, hd-CTV is defined as GTVnx plus 0 mm. METHODS: A total of 40 patients with newly diagnosed nonmetastatic NPC (T1-T4 ten cases each) treated with IMRT were consecutively enrolled. Real and virtual treatment plans were designed according to the definitions of hd-CTV recommended by China and Radiation Therapy Oncology Group (RTOG), respectively. RESULTS: The hd-CTV in China was significantly smaller than that of RTOG. Exposure doses to 5 mm subclinical involvement and OARs as well as NTCP in the China treatment plan were significantly lower than those of RTOG. CONCLUSION: It could be recommended to divide the hd-CTV into GTV and subclinical target volume and to prescribe different doses for the GTV and subclinical involvement in the IMRT plan of NPC.

Glycyrrhizic Acid Inhibits Core Fucosylation Modification Modulated EMT and Attenuates Bleomycin-Induced Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal and incurable chronic interstitial lung disease with an unknown etiology. Recent evidence suggests that epithelial-mesenchymal transition (EMT) is one of the possible factors in the pathogenesis of pulmonary fibrosis. Glycyrrhizic acid (GA) is a natural active ingredient extracted from the root of the traditional Chinese herb licorice, which has been shown in previous studies to have the effect of alleviating lung injury. In this study, our objective was to investigate whether GA could ameliorate pulmonary fibrosis by altering EMT, as well as the therapeutic potential of changing core fucosylation (CF) to target EMT-related pathways. First, we verified that GA partially reverses EMT in a rat model of bleomycin-induced lung interstitial fibrosis, alleviating pulmonary fibrosis, and implying that GA has antifibrotic potential. Next, we discovered that GA attenuated lung interstitial fibrosis by reducing CF modifications to some extent. Interestingly, we found that GA therapy reduced the expression of phosphorylated Smad2/3 (p-Smad2/3) and ß-catenin in the EMT pathway and that GA inhibited the modification of TGF-ßR and WNT receptor proteins by CF, suggesting that GA may interfere with the EMT process by modulating TGF-ßR, WNT core fucosylation modifications to attenuate pulmonary fibrosis. In conclusion, these findings indicate that GA could be a potential therapeutic agent for IPF, and further support the idea that targeting CF alterations could be a novel technique for the treatment of diseases involving EMT.

Survival outcomes, hematologic complications and growth impairment after sequential chemoradiotherapy in intracranial NGGCTs: a retrospective study.

PURPOSE: This study aimed to evaluate the clinical features, prognostic factors, and survival outcomes for patients with intracranial nongerminomatous germ cell tumors (NGGCTs), with a particular focus on treatment toxicity for long-term survivors. METHODS: Intracranial NGGCTs treated with platinum-based chemotherapy and craniospinal irradiation (CSI) in our institution were retrospectively analyzed. Hematological complications following sequential chemoradiotherapy as well as height and weight in childhood survivors were evaluated. Plasma growth hormone (GH) concentrations prior to and after radiotherapy were obtained for the comparisons. RESULTS: A total of 111 intracranial NGGCTs were included. The 3­year overall survival (OS) and event-free survival (EFS) rates were 83.5% ± 3.9% and 71.0% ± 4.8%, respectively. A combined treatment modality consisting of ≥ 4 cycles of platinum-based chemotherapy and CSI was associated with an improved OS (P = 0.003) and EFS (P < 0.001). Thrombocytopenia of any grade occurred in 35.4% (34/96) of patients, and the threshold age for an increased risk of thrombocytopenia was 14 years (area under the curve AUC = 0.752, P < 0.0001) as derived from receiver operating characteristic (ROC) analysis. Growth impediment was found in 8 of 56 (14%) patients. The age for receiving radiotherapy was found to inversely correlate with height development, revealing a cut-off age of 11.5 years for risking growth impairment (AUC = 0.806, P = 0.004). Consistently, a significant decline in plasma growth hormone after radiotherapy was observed in patients ≤ 11.5 years (P < 0.01) but not patients > 11.5 years. (P > 0.05). CONCLUSION: Our study suggested that a combined treatment modality with at least four cycles of chemotherapy and CSI was safe and effective for patients with intracranial NGGCTs. Radiotherapy should be used with caution for patients < 11.5 years due to growth impairment.

Prognostic Value of E2F Transcription Factor Expression in Pancreatic Adenocarcinoma.

BACKGROUND Pancreatic adenocarcinoma (PAAD) is one of the deadliest types of cancer. In the early stages, patients often have atypical symptoms, making diagnosis difficult. The prognosis of diagnosed patients is very poor and treating PAAD is challenging. Therefore, determining reliable risk factors related to PAAD development is critical for improving patient prognosis. E2F family transcription factors (TFs) are essential regulators of DNA synthesis and cell cycle progression in eukaryotic cells, and they have been identified as prognostic biomarkers associated with multiple cancer types. However, further research is necessary to establish the prognostic relevance of these TFs in PAAD patients. MATERIAL AND METHODS We assessed PAAD patient transcriptional and outcome data using the TIMER, ONCOMINE, STRING, GEPIA, cBioPortal, Kaplan-Meier Plotter, GSCALite, and starBase databases. RESULTS PAAD tumor tissues exhibited increased expression of E2F1/3/5/7/8 relative to that in normal tissues, while the expression of E2F2/3/6/8 was associated with a more advanced tumor stage. Survival analyses indicated that PAAD patients expressing higher levels of E2F1/2/3/7/8 exhibited shorter overall survival (OS) and disease-free survival (DFS) than patients expressing lower levels of these TFs. In addition, E2F4 and E2F6 overexpression was associated with poorer DFS and OS, respectively. We also found that the expression of E2Fs was significantly correlated with immune infiltrates, including CD8+ T cells, CD4+ T cells, B cells, dendritic cells, neutrophils, and macrophages. CONCLUSIONS Our study may provide new insights into the optimal choice of immunotherapy and promising novel targets for therapeutic intervention in PAAD patients.

Absolute quantification of 2-hydroxyglutarate on tissue by matrix-assisted laser desorption/ionization mass spectrometry imaging for rapid and precise identification of isocitrate dehydrogenase mutations in human glioma.

Isocitrate dehydrogenase (IDH) gene mutations are important predictive molecular markers to guide surgical strategy in brain cancer therapy. Herein, we presented a method using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) for absolute quantification of 2-hydroxyglutarate (2-HG) on tissues to identify IDH mutations and evaluate tumor residue. This analytical method was tested among 34 glioma patients and validated with gold standard clinical technologies. The cut-off value of 2-HG was set as 0.81 pmol/µg to identify IDH mutant (IDHmt) gliomas with 100% specificity and sensitivity. In addition, 2-HG levels and tumor cell density (TCD) showed positive correlation in IDHmt gliomas by this spatial method. This MALDI MSI-based absolute quantification method has great potentiality for incorporating into surgical workflow in the future.

Individualized Nomogram for Predicting Survival in Patients with Brain Metastases After Stereotactic Radiosurgery Utilizing Driver Gene Mutations and Volumetric Surrogates.

It is well-known that genomic mutational analysis plays a significant role in patients with NSCLC for personalized treatment. Given the increasing use of stereotactic radiosurgery (SRS) for brain metastases (BM), there is an emerging need for more precise assessment of survival outcomes after SRS. Patients with BM and treated by SRS were eligible in this study. The primary endpoint was overall survival (OS). Cox regression models were used to identify independent prognostic factors. A survival predictive nomogram was developed and evaluated by Concordance-index (C-index), area under the curve (AUC), and calibration curve. From January 2016 to December 2019, a total of 356 BM patients were eligible. The median OS was 17.7 months [95% confidence interval (CI) 15.5-19.9] and the actual OS at 1- and 2-years measured 63.2 and 37.6%, respectively. A nomogram for OS was developed by incorporating four independent prognostic factors: Karnofsky Performance Score, cumulative tumor volume, gene mutation status, and serum lactate dehydrogenase. The nomogram was validated in a separate cohort and demonstrated good calibration and good discriminative ability (C-index = 0.780, AUC = 0.784). The prognostic accuracy of the nomogram (0.792) was considerably enhanced when compared with classical prognostic indices, including the Graded Prognostic Assessment (0.708), recursive partitioning analysis (0.587), and the SRS (0.536). Kaplan-Meier curves showed significant differences in OS among the stratified low-, median- and high-risk groups (P < 0.001). In conclusion, we developed and validated an individualized prognostic nomogram by integrating physiological, volumetric, clinical chemistry, and molecular biological surrogates. Although this nomogram should be validated by independent external study, it has a potential to facilitate more precise risk-stratifications to guide personalized treatment for BM.

YBX1 mediates autophagy by targeting p110ß and decreasing the sensitivity to cisplatin in NSCLC.

Y-box binding protein 1 (YBX1) is involved in the development of multiple types of tumors. However, the relationship between YBX1 and autophagy in non-small cell lung cancer (NSCLC) remains unclear. In this study, we analyzed the expression and clinical significance of YBX1 and markers of autophagy (LC3I/II) in NSCLC and examined their roles in regulating sensitivity to cisplatin in NSCLC. The retrospective analysis of patients with NSCLC indicated that YBX1 was positively correlated with autophagy. Increased levels of YBX1 or autophagy also observed in NSCLC cells compared with those in 16HBE cells. Compared to the controls, the knockdown of YBX1 expression suppressed autophagy, increased drug sensitivity and promoted apoptosis in response to cisplatin in NSCLC cells by targeting the p110ß promoter and inhibiting p110ß/Vps34/beclin1 signaling pathways. We also demonstrated in an in vivo study that the overexpressed YBX1 effectively increased NSCLC growth and progression and decreased the sensitivity to cisplatin by inducing autophagy in a xenograft tumor model, and these effects were concomitant with the increasing of p110ß and beclin1 expression. Collectively, these results show that YBX1 plays an essential role in autophagy in NSCLC.

α1,6-Fucosyltransferase (FUT8) regulates the cancer-promoting capacity of cancer-associated fibroblasts (CAFs) by modifying EGFR core fucosylation (CF) in non-small cell lung cancer (NSCLC).

Cancer-associated fibroblasts (CAFs) are the main cancer-promoting component in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). α1,6-Fucosyltransferase (FUT8), the key enzyme catalyzing core α1,6-fucosylation (CF), plays a promoting role in multiple malignancies. In the current study, we investigated the function of FUT8 in CAFs and elucidated the mechanism through which FUT8 regulates the cancer-promoting capacity of CAFs in NSCLC. A bioinformatics analysis was performed to reveal the relationship between FUT8 and CAFs. Resected specimens from NSCLC patients were analyzed to assess the expression of FUT8 in CAFs. Primary CAFs and normal lung fibroblasts (NLFs) were extracted from NSCLC patient specimens and were co-cultured with NSCLC cell lines in a novel 3D-printed non-contact co-culture device. An In vivo CAF/NSCLC co-injection tumorigenesis assay was performed using nude mice to study the function of FUT8/CF in TME formation. The current study revealed that FUT8-mediated CF in CAFs plays a positive role in the cancer-promoting capacity of these cells. FUT8 overexpression was observed in CAFs isolated from some lung adenocarcinoma cases. Further investigation showed that FUT8/CF in CAFs promoted the formation of an invasive and malignant TME in vivo and in vitro, and the resulting NSCLC cells exhibited faster proliferation and increased invasiveness. EGFR signaling exerts a catalytic effect on the cancer-promoting capacity of CAFs and is regulated by the CF modification of the EGFR protein.

MicroRNA-30e inhibits proliferation and invasion of non-small cell lung cancer via targeting SOX9.

Previous studies have reported that microRNA-30e (miR-30e) is dysregulated in multiple human cancers. However, the expression, functions and molecular mechanism of miR-30e in NSCLC remain unknown. In this study, we found that miR-30e was expressed at a low level in NSCLC tissues and cell lines. In NSCLC cell lines, enforced expression of miR-30e could inhibit cell proliferation and invasion in vitro. In addition, miR-30e negatively regulated SOX9 expression through directly binding to the 3'UTR of SOX9, and an inverse correlation was found between miR-30e and SOX9 mRNA expression in NSCLC tissues. Moreover, knockdown of SOX9 led to decreased proliferation and invasion of NSCLC cells. Taken together, miR-30e acts as a tumor suppressor in NSCLC, and inhibits cell proliferation and invasion possibly by directly targeting SOX9. These findings might provide novel therapeutic targets for NSCLC.

Functional role of RBM10 in lung adenocarcinoma proliferation.

Lung cancer is one of the most common causes of morbidity and mortality among malignant tumors worldwide. The poor prognosis of patients with lung adenocarcinomas is primarily due to its strong ability to invade and metastasize. Recent research has indicated that RNA­binding protein 10 (RBM10) is mutated in lung adenocarcinoma, and is closely associated with tumor proliferation and apoptosis; however, the precise role of RBM10 in lung adenocarcinoma remains unclear. Our preliminary experiments (unpublished data) revealed that RBM10 expression was upregulated in lung adenocarcinoma cell lines and tissues. In this study, we first detected the protein expression level of RBM10 in lung adenocarcinoma cells and tissues, and we then examined the effects of RBM10 overexpression and downregulation (via small interfering RNA) on the proliferation and apoptosis of stable lung adenocarcinoma cells, along with its possible mechanisms of action. We also used clinical samples of lung adenocarcinomas to verify our results. We found that RBM10 protein was overexpressed in lung adenocarcinoma cells and tissues, and it reduced p53 expression (as detected by immunofluorescence assay and western blot analysis) in A549 cells and inhibited apoptosis (as shown by flow cytometric assay). RBM10 also promoted cell growth and proliferation in vitro and increased cell migration in a cell wound scratch assay. Furthermore, we found that RBM10 activated key proliferative signaling pathways [such as the epidermal growth factor receptor (EGFR), mitogen­activated protein kinase (MAPK) and phosphoinositide 3­kinase (PI3K)­AKT pathways] and inhibited apoptotic pathways. In addition, we demonstrated that a high expression of RBM10 protein in patient tissue samples was associated with a shorter overall survival time and a poor prognosis. On the whole, the findings of this study indicate that RBM10 may function as an oncogene in lung cancer, and may thus prove to be a novel therapeutic target for the prophylaxis and treatment of lung adenocarcinomas.

BPTF cooperates with p50 NF-κB to promote COX-2 expression and tumor cell growth in lung cancer.

Cyclooxygenase-2 (COX-2) is overexpressed in most human cancers, but its precise regulatory mechanism in cancer cells remains unclear. The aims of this study are to discover and identify the new regulatory factors which bind to the COX-2 promoter and regulate COX-2 expression and cancer cell growth, and to elucidate the mechanisms of action of these factors in lung cancer. In this study, the COX-2 promoter-binding protein BPTF (bromodomain PHD finger transcription factor) was detected, identified and verified by biotin-streptavidin-agarose pulldown, mass spectrum analysis and chromatin immunoprecipitation (ChIP) in lung cancer cells, respectively. The expressions of COX-2 and BPTF in lung cancer cell lines, mouse tumor tissues and human clinical samples were detected by RT-PCR, Western blot and immunohistochemistry assays. The interaction of BPTF with NF-kB was analyzed by immunoprecipitation and confocal immunofluorescence assays. We discovered and identified BPTF as a new COX-2 promoter-binding protein in human lung cancer cells. Knockdown of BPTF inhibited COX-2 promoter activity and COX-2 expression in lung cancer cells in vitro and in vivo. We also found that BPTF functioned as a transcriptional regulator through its interaction with the p50 subunit of NF-kB. Knockdown of BPTF abrogated the binding of p50 to the COX-2 promoter, while the inhibition of p50 activity abolished the decreased trend of COX-2 expression and lung cancer cell proliferation caused by BPTF silencing. Moreover, we showed that the expressions of BPTF and COX-2 in tumor tissues of lung cancer patients were positively correlated, and high co-expression of BPTF and COX-2 predicted poor prognosis in lung cancer patients. Collectively, our results indicated that BPTF cooperated with p50 NF-κB to regulate COX-2 expression and lung cancer growth, suggesting that the BPTF/p50/COX-2 axis could be a potential therapeutic target for lung cancer.

p38 MAPK is Crucial for Wnt1- and LiCl-Induced Epithelial Mesenchymal Transition.

Idiopathic pulmonary fibrosis (IPF) is characterized by myofibroblast foci in lung parenchyma. Myofibroblasts are thought to originate from epithelial-to-mesenchymal transition (EMT). Wnt1 and lithium chloride (LiCl) induce EMT in alveolar epithelial cells (AECs), but the mechanisms are unclear. AECs were treated with Wnt1 and LiCl, respectively; morphological change and molecular changes of EMT, including E-cadherin, fibronectin, and vimentin, were observed. SB203580 was administrated to test the role of p38 МАРК signaling in EMT. Then AECs were treated with siRNAs targeting p38 МАРК to further test the effects of p38 МАРК, and the role was further confirmed by re-expression of p38 МАРК. At last P-catenin siRNA was used to test the role of ß-catenin in the EMT process and relationship of ß-catenin and p38 МАРК was concluded. Exposure of AECs to Wnt1 and LiCl resulted in upregulation of vimentin and fibronectin with subsequent downregulation of E-cadherin. Wnt1 and LiCl stimulated the p38 МАРК signaling pathways. Perturbing the p38 МАРК pathway either by SB203580 or through p38 МАРК siRNA blocked EMT and inhibited fibronetin synthesis, which were reversed by transfection of p38 МАРК expression plasmid. ß-catenin siRNA attenuated the EMT process and decreased p38 МАРК phosphorylation, indicating that ß-catenin is involved in the EMTrelated changes through regulation of p38 МАРК phosphorylation. These findings suggest that p38 МАРК participates in the pathogenesis of EMT through Wnt pathway and that p38 МАРК may be a novel target for IPF therapy.

Inhibiting core fucosylation attenuates glucose-induced peritoneal fibrosis in rats.

Ultrafiltration failure is a major complication of long-term peritoneal dialysis, resulting in dialysis failure. Peritoneal fibrosis induced by continuous exposure to high glucose dialysate is the major contributor of ultrafiltration failure, for which there is no effective treatment. Overactivation of several signaling pathways, including transforming growth factor-ß1 (TGF-ß1) and platelet-derived growth factor (PDGF) pathways, contribute to the development of peritoneal fibrosis. Therefore, simultaneously blocking multiple signaling pathways might be a potential novel method of treating peritoneal fibrosis. Previously, we showed that core fucosylation, an important posttranslational modification of the TGF-ß1 receptors, can regulate the activation of TGF-ß1 signaling in renal interstitial fibrosis. However, it remains unclear whether core fucosylation affects the progression of peritoneal fibrosis. Herein, we show that core fucosylation was enriched in the peritoneal membrane of rats accompanied by peritoneal fibrosis induced by a high glucose dialysate. Blocking core fucosylation dramatically attenuated peritoneal fibrosis in the rat model achieved by simultaneously inactivating the TGF-ß1 and PDGF signaling pathways. Next the protective effects of blocking core fucosylation and imatinib (a selective PDGF receptor inhibitor) on peritoneal fibrosis were compared and found to exhibit a greater inhibitory effect over imatinib alone, suggesting that blocking activation of multiple signaling pathways may have superior inhibitory effects on the development of peritoneal fibrosis. Thus, core fucosylation is essential for the development of peritoneal fibrosis by regulating the activation of multiple signaling pathways. This may be a potential novel target for drug development to treat peritoneal fibrosis.

Novel Mechanism of the Pericyte-Myofibroblast Transition in Renal Interstitial Fibrosis: Core Fucosylation Regulation.

Pericytes have been identified as a major source of myofibroblasts in renal interstitial fibrosis (RIF). The overactivation of several signaling pathways, mainly the TGF-ß and PDGF pathways, initiates the pericyte-myofibroblast transition during RIF. Key receptors in these two pathways have been shown to be modified by fucosyltransferase 8 (FUT8), the enzyme that catalyzes core fucosylation. This study postulated that core fucosylation might play an important role in regulating the pericyte transition in RIF. The data showed that core fucosylation increased with the extent of RIF in patients with IgA nephropathy (IgAN). Similarly, core fucosylation of pericytes increased in both a unilateral ureteral occlusion (UUO) mouse model and an in vitro model of pericyte transition. Inhibition of core fucosylation by adenoviral-mediated FUT8 shRNA in vivo and FUT8 siRNA in vitro significantly reduced pericyte transition and RIF. In addition, the activation of both the TGF-ß/Smad and PDGF/ERK pathways was blocked by core fucosylation inhibition. In conclusion, core fucosylation may regulate the pericyte transition in RIF by modifying both the TGF-ß/Smad and PDGF/ERK pathways. Glycosylation might be a novel "hub" target to prevent RIF.

Mechanisms of pulmonary fibrosis induced by core fucosylation in pericytes.

Pulmonary fibrosis is a common outcome of a variety of pulmonary interstitial diseases, and myofibroblasts are the main culprit for this process. Recent studies have found that pericytes are one of the major sources of myofibroblasts; the transformation of which involves a complex process of activation of TGF-ß/Smad2/3 and PDGFß/Erk signaling pathways. We have reported that the transforming growth factor-ß receptor and platelet-derived growth factor-ß receptor (TGF-ßR I and PDGFßR, respectively) are modified by glycosylation. Thus, we hope to regulate the above-mentioned signal pathways through core fucosylation (CF) catalyzed by α-1,6-fucosyltransferase (FUT8). Previous work has confirmed that TGF-ß1 can induce the transformation of pericytes into myofibroblasts, while FUT8siRNA can inhibit such transformation. In the present study, we used an adenovirus packaging FUT8 shRNA to infect a bleomycin-induced pulmonary fibrosis mouse model and determined the effect of CF on pulmonary fibrosis by analyzing the mechanism of CF-mediated pericyte transformation. Our findings may shed new light on the mechanism of pulmonary interstitial fibrosis and provide a novel therapeutic target for clinical applications.

Development of a Functional Glomerulus at the Organ Level on a Chip to Mimic Hypertensive Nephropathy.

Glomerular hypertension is an important factor exacerbating glomerular diseases to end-stage renal diseases because, ultimately, it results in glomerular sclerosis (especially in hypertensive and diabetic nephropathy). The precise mechanism of glomerular sclerosis caused by glomerular hypertension is unclear, due partly to the absence of suitable in vitro or in vivo models capable of mimicking and regulating the complex mechanical forces and/or organ-level disease processes. We developed a "glomerulus-on-a-chip" (GC) microfluidic device. This device reconstitutes the glomerulus with organ-level glomerular functions to create a disease model-on-a chip that mimics hypertensive nephropathy in humans. It comprises two channels lined by closely opposed layers of glomerular endothelial cells and podocytes that experience fluid flow of physiological conditions to mimic the glomerular microenvironment in vivo. Our results revealed that glomerular mechanical forces have a crucial role in cellular cytoskeletal rearrangement as well as the damage to cells and their junctions that leads to increased glomerular leakage observed in hypertensive nephropathy. Results also showed that the GC could readily and flexibly meet the demands of a renal-disease model. The GC could provide drug screening and toxicology testing, and create potential new personalized and accurate therapeutic platforms for glomerular disease.

Predominant diffuse ground glass opacity in both lung fields: A case of sarcoidosis with atypical CT findings.

Sarcoidosis can cause fatal diffuse lung fibrosis in the end stage, so its early diagnosis and treatment can prevent the progression of fibrosis. Predominant ground glass opacity on high-resolution CT (HRCT) scans is a rare presentation of sarcoidosis. We report the case of a patient who presented with very few symptoms and signs of sarcoidosis; HRCT revealed large-scale ground glass opacity and minor lymphadenopathy. Bronchoalveolar lavage fluid contained turbid liquid. Sarcoidosis could be confirmed only based on pathological examination of the resected tissue. The patient was administrated prednisone at 40 mg/d orally with tapering of the dose. Lung HRCT scans taken 6 months after the prednisone treatment showed ablation of the ground glass opacity. This case report sheds light on an atypical HRCT presentation of sarcoidosis; the findings here will be useful for the early diagnosis of sarcoidosis and prevention of fatal complications.

Salidroside protects against bleomycin-induced pulmonary fibrosis: activation of Nrf2-antioxidant signaling, and inhibition of NF-κB and TGF-ß1/Smad-2/-3 pathways.

Pulmonary fibrosis (PF) can severely disrupt lung function, leading to fatal consequences. Salidroside is a principal active ingredient of Rhodiola rosea and has recently been reported to protect against lung injures. The present study was aimed at exploring its therapeutic effects on PF. Lung fibrotic injuries were induced in SD rats by a single intratracheal instillation of 5 mg/kg bleomycin (BLM). Then, these rats were administrated with 50, 100, or 200 mg/kg salidroside for 28 days. BLM-triggered structure distortion, collagen overproduction, excessive inflammatory infiltration, and pro-inflammatory cytokine release, and oxidative stress damages in lung tissues were attenuated by salidroside in a dose-dependent manner. Furthermore, salidroside was noted to inhibit IκBα phosphorylation and nuclear factor kappa B (NF-κB) p65 nuclear accumulation while activating Nrf2-antioxidant signaling in BLM-treated lungs. Downregulation of E-cadherin and upregulation of vimentin, fibronectin, and α-smooth muscle actin (α-SMA) indicated an epithelial-mesenchymal transition (EMT)-like shift in BLM-treated lungs. These changes were suppressed by salidroside. The expression of TGF-ß1 and the phosphorylation of its downstream targets, Smad-2/-3, were enhanced by BLM, but weakened by salidroside. Additionally, salidroside was capable of reversing the recombinant TGF-ß1-induced EMT-like changes in alveolar epithelial cells in vitro. Our study reveals that salidroside's protective effects against fibrotic lung injuries are correlated to its anti-inflammatory, antioxidative, and antifibrotic properties.

Glycyrrhizic acid alleviates bleomycin-induced pulmonary fibrosis in rats.

Idiopathic pulmonary fibrosis is a progressive and lethal form of interstitial lung disease that lacks effective therapies at present. Glycyrrhizic acid (GA), a natural compound extracted from a traditional Chinese herbal medicine Glycyrrhiza glabra, was recently reported to benefit lung injury and liver fibrosis in animal models, yet whether GA has a therapeutic effect on pulmonary fibrosis is unknown. In this study, we investigated the potential therapeutic effect of GA on pulmonary fibrosis in a rat model with bleomycin (BLM)-induced pulmonary fibrosis. The results indicated that GA treatment remarkably ameliorated BLM-induced pulmonary fibrosis and attenuated BLM-induced inflammation, oxidative stress, epithelial-mesenchymal transition, and activation of transforming growth factor-beta signaling pathway in the lungs. Further, we demonstrated that GA treatment inhibited proliferation of 3T6 fibroblast cells, induced cell cycle arrest and promoted apoptosis in vitro, implying that GA-mediated suppression of fibroproliferation may contribute to the anti-fibrotic effect against BLM-induced pulmonary fibrosis. In summary, our study suggests a therapeutic potential of GA in the treatment of pulmonary fibrosis.