Microwave Ablation versus Surgical Resection for US-detected Multifocal T1N0M0 Papillary Thyroid Carcinoma: A 10-Center Study.

Background Microwave ablation (MWA) is currently under preliminary investigation for the treatment of multifocal papillary thyroid carcinoma (PTC) and has shown promising treatment efficacy. Compared with surgical resection (SR), MWA is minimally invasive and could preserve thyroid function. However, a comparative analysis between MWA and SR is warranted to draw definitive conclusions. Purpose To compare MWA and SR for preoperative US-detected T1N0M0 multifocal PTC in terms of overall and 1-, 3-, and 5-year progression-free survival rates and complication rates. Materials and Methods In this retrospective study, 775 patients with preoperative US-detected T1N0M0 multifocal PTC treated with MWA or SR across 10 centers between May 2015 and December 2021 were included. Propensity score matching (PSM) was performed for patients in the MWA and SR groups, followed by comparisons between the two groups. The primary outcomes were overall and 1-, 3-, and 5-year progression-free survival (PFS) rates and complication rates. Results After PSM, 229 patients (median age, 44 years [IQR 36.5-50.5 years]; 179 female) in the MWA group and 453 patients (median age, 45 years [IQR 37-53 years]; 367 female) in the SR group were observed for a median of 20 months (range, 12-74 months) and 26 months (range, 12-64 months), respectively. MWA resulted in less blood loss, shorter incision length, and shorter procedure and hospitalization durations (all P < .001). There was no evidence of differences in overall and 1-, 3-, or 5-year PFS rates (all P > .05) between MWA and SR (5-year rate, 77.2% vs 83.1%; P = .36) groups. Permanent hoarseness (2.2%, P = .05) and hypoparathyroidism (4.0%, P = .005) were encountered only in the SR group. Conclusion There was no evidence of a significant difference in PFS rates between MWA and SR for US-detected multifocal T1N0M0 PTC, and MWA resulted in fewer complications. Therefore, MWA is a feasible option for selected patients with multifocal T1N0M0 PTC. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Georgiades in this issue.

Clinical characteristics and effects of inhaled corticosteroid in patients with post-COVID-19 chronic cough during the Omicron variant outbreak.

BACKGROUND: Chronic cough is a common symptom in patients post the coronavirus disease 2019 (COVID-19). In this study, we aimed to investigate the efficacy of inhaled corticosteroids (ICS) and the clinical characteristics of patients with post-COVID-19 chronic cough during the Omicron era. METHODS: An ambispective, longitudinal cohort study was conducted that included patients with post-COVID-19 who attended the respiratory clinic at our hospital between January 1, 2023, and March 31, 2023 with a complaint of persistent cough lasting more than 8 weeks. At 30 and 60 days after the first clinic visit for post-COVID-19 chronic cough, enrolled patients were prospectively followed up. We compared the changes in symptoms and pulmonary function between patients receiving ICS treatment (ICS group) and those not receiving ICS treatment (NICS group) at the two visits. RESULTS: A total of 104 patients with post-COVID-19 chronic cough were enrolled in this study (ICS group, n = 51; NICS group, n = 53). The most common symptoms accompanying post-COVID-19 chronic cough were sputum (58.7%, 61/104) and dyspnea (48.1%, 50/104). Seventy-one (82.6%, 71/86) patients had airway hyperresponsiveness, and 49 patients (47.1%, 49/104) were newly diagnosed with asthma. Most patients (95.2%, 99/104) exhibited improvement at 60 days after the first visit. The pulmonary function parameters of the patients in the ICS group were significantly improved compared to the baseline values (P < 0.05), and the improvement in the FEV1/FVC was significantly greater than that in the NICS group (P = 0.003) after 60 days. CONCLUSIONS: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may contribute to the pathogenesis of asthma, which could be the underlying cause of persistent cough post-COVID-19 infection. Post-COVID-19 chronic cough during the Omicron era was often accompanied by sputum, dyspnea, and airway hyperresponsiveness. ICS treatment did not have a significant impact on symptom management of post-COVID-19 chronic cough; however, it can improve impaired lung function in in these individuals.

Discovery of Fusarium pseudograminearum Causing Crown Rot of Winter Wheat in Xinjiang Uygur Autonomous Region, China.

Fusarium pseudograminearum is an important plant pathogen that invades many crops (Zhang et al. 2018). Since it was first discovered in Australia in 1951, F. pseudograminearum has been reported in many countries and regions and caused huge economic losses (Burgess et al. 2001). In 2012, crown rot of wheat caused by F. pseudograminearum was discovered for the first time in Henan Province, China (Li et al. 2012). Wheat (Triticum aestivum L.) is one of the most important food crops in Xinjiang Uygur Autonomous Region (XUAR), with 1.07 million hectares cultivated in 2020. In June 2023, a survey of crown rot disease was carried out in winter wheat cv. Xindong 20 in Hotan area, XUAR, China (80.148907°E, 37.051474°N). About 5% of wheat plants showed symptoms of crown rot such as browning of the stem base and white head. The disease was observed in 85% of wheat fields. In order to identify the pathogens, 36 pieces of diseased stem basal tissue, 0.5 cm in length, were collected and sterilized with 75% alcohol for 30s and 5% NaOCl solution for 2 min, then rinsed three times with sterile water and placed on potato dextrose agar (PDA) medium at 25°C. A total of 27 isolates with consistent morphological characteristics were obtained using single-spore technique (Leslie and Summerell. 2006), and the isolation rate was 75%. The isolates grew rapidly on PDA, produced large numbers of fluffy white hyphae, and pink pigment accumulated in the medium. The isolates were grown on 2% mung bean flour medium and identified by morphological and molecular methods. Macroconidia were abundant, relatively slender, curved to almost straight, commonly two to seven septate, and averaged 22 to 72 × 1.8 to 4.9 µm. Microconidia were not observed. The morphological characters are consistent with Fusarium (Aoki and O'Donnell. 1999). Two isolates (LP-1 and LP-3) were selected for molecular identification. Primers EF1/EF2 (5'-ATGGGTAAGGARGACAAGAC-3'/5'-GGARGTACCAGTSATCATG-3') were used to amplify a portion of the EF-1α gene (O'Donnell et al. 1998). The two 696 bp PCR products were sequenced and submitted to GenBank. The EF-1α gene sequences (GenBank Accession No: PP062794 and PP062795) shared 99.9% identity (695/696) with published F.pseudograminearum sequences (e.g., OP105187, OP105184, OP105179, OP105173). The identification was further confirmed by F. pseudograminearum species-specific PCR primers Fp1-1/Fp1-2 (Aoki and O'Donnell. 1999). The expected PCR products of 518 bp were produced only in F. pseudograminearum. Pathogenicity tests of LP-1 and LP-3 isolates were performed on 7-day-old seedlings of winter wheat cv. Xindong 20 using the drip inoculation method with a 10-µl of a 106 macroconidia ml-1 suspension near the stem base (Xu et al. 2017). The experiment was repeated five times in a 20 to 25°C greenhouse. Control seedlings were treated with sterile water. After 4 weeks, wheat seedling death and crown browning occurred in the inoculated plants with over 90% incidence. No symptoms were observed in the control plants. The pathogen was reisolated from the inoculated plants by the method described above and identified by morphological and PCR amplification using F. pseudograminearum species-specific primers Fp1-1/Fp1-2. No F. pseudograminearum was isolated from the control plants, fulfilling Koch's postulates. To our knowledge, this is the first report of F. pseudograminearum causing crown rot of winter wheat in XUAR of China. Since F. pseudograminearum can cause great damage to wheat, one of the most important food crops in China, necessary measures should be taken to prevent the spread of F. pseudograminearum to other regions.

Tom70-regulated mitochondrial biogenesis via TFAM improves hypoxia-induced dysfunction of pulmonary vascular endothelial cells and alleviates hypoxic pulmonary hypertension.

BACKGROUND: Hypoxic pulmonary hypertension (HPH) is a common type of pulmonary hypertension and characterized by pulmonary vascular remodeling and constriction. A large number of studies have shown that pulmonary vascular endothelial cells (PVECs) dysfunction plays an important role in the initiation and development stages of HPH, but the mechanism of PVECs dysfunction after hypoxia remains unclear. In this study, we explored the exact mechanism of PVECs dysfunction after hypoxia. METHODS: In vitro, we used primary cultured PVECs hypoxia model to mimic HPH injury. We detected the expressions of mitochondrial biogenesis markers, mitochondrial transcription factor A (TFAM) level inside mitochondria, mitochondrial quantity and function, and the components expressions of translocase of outer mitochondrial membrane (TOM) at 24 h after hypoxia. To explore the effects of Tom70 on mitochondrial biogenesis and functions of PVECs after hypoxia, Tom70 overexpression adenovirus was constructed, and the expressions of mitochondrial biogenesis markers, TFAM level inside mitochondria, mitochondrial quantity and function, and the functions of PVECs were detected. And in vivo, we used cre-dependent overexpression adenovirus of Tom70 in the Cdh5-CreERT2 mouse model of HPH to verify the role of upregulating PVECs Tom70 in improving HPH. RESULTS: Hypoxia obviously increased the expressions of mitochondrial biogenesis markers for PGC-1α, NRF-1 and TFAM, but reduced the content of TFAM in mitochondria and the quantity and functions of mitochondria. In addition, only Tom70 expression among the TOM components was significantly decreased after hypoxia, and up-regulation of Tom70 significantly increased the content of TFAM in mitochondria of PVECs by transporting TFAM into mitochondria after hypoxia, enhanced the quantity and functions of mitochondria, improved the functions of PVECs, and ultimately alleviated HPH. CONCLUSION: The findings of present study demonstrated that hypoxia induced the decreased expression of Tom70 in PVECs, reduced the mitochondrial biogenesis-associated TFAM protein transporting into mitochondria, inhibited mitochondrial biogenesis, caused PVECs injury, and prompted the formation of HPH. However, up-regulation of Tom70 abolished the hypoxia-induced injurious effects on PVECs and alleviated HPH.

PDK1 upregulates PINK1-mediated pulmonary endothelial cell mitophagy during hypoxia-induced pulmonary vascular remodeling.

BACKGROUND: Hypoxic pulmonary hypertension (HPH) is a complication of lung diseases with pulmonary vascular remodeling, although the underlying molecular mechanisms have not been fully elucidated. This study investigated the underlying molecular events by using a rat HPH model and primary pulmonary microvascular endothelial cells (PMVECs). METHODS AND RESULTS: This study first established a rat HPH model and cultured PMVECs for transmission electron microscopic analysis and manipulation of 3-phosphoinositide-dependent protein kinase 1 (PDK1) or phosphatase and tensin homolog-induced kinase 1 (PINK1) expression in vitro. After that, the cell viability was assessed and the expression of different proteins was assayed using cell viability and western blot assays, respectively. Reactive oxygen species production, apoptosis, NLR family pyrin domain containing 3 (NLRP3) expression, and the levels of interleukin (IL)-1ß, IL-6, and IL-8 were also assessed, while the interaction of PDK1 and PINK1 was determined using co-immunoprecipitation/western blot assays. Hypoxia induced mitophagy in the PMVECs and upregulated PINK1/Parkin expression, whereas knockdown of PINK1 expression under hypoxic conditions inhibited cell proliferation but induced endothelial cell apoptosis in vitro, decreased reactive oxygen species production and NLRP3 expression, and reduced the levels of inflammatory factors in PMVECs. However, hypoxia induced PDK1 expression, whereas knockdown of PDK1 downregulated PINK1 expression. Furthermore, treatment of the model rats with the PDK1 inhibitor dichloroacetate (DCA) was able to decrease PINK1 expression. In addition, the PDK1 and PINK1 proteins could interact with each other in the mitochondria of PMVECs to regulate the cell viability. CONCLUSIONS: This study revealed that PDK1 induced PMVEC proliferation but inhibited their apoptosis to participate in pulmonary vascular remodeling, ultimately leading to HPH through regulation of PINK1-mediated mitophagy signaling. Therefore, PINK1 is a novel therapeutic target for the control of HPH.

Association between thyroid hormones and diabetic kidney disease in Chinese adults.

OBJECTIVE: We aimed to explore the association between thyroid hormones and different stages of diabetic kidney disease (DKD) in Chinese adults. METHODS: This is a retrospective study involving 2,832 participants. DKD was diagnosed and classified according to the Kidney Disease: Improving Global Outcomes (KDIGO) categories. Effect sizes are expressed as odds ratio (OR) with 95% confidence interval (CI). RESULTS: After propensity score matching (PSM) on age, gender, hypertension, hemoglobin A1c(HbA1c), total cholesterol (TC), serum triglyceride (TG) and duration of diabetes, per 0.2 pg/mL increment in serum free triiodothyronine (FT3) was significantly associated with 13%, 22% and 37% reduced risk of moderate-risk (OR, 95% CI, P: 0.87, 0.70-0.87, < 0.001), high-risk (0.78, 0.70-0.87, < 0.001) and very-high-risk (0.63, 0.55-0.72, < 0.001) DKD stages relative to the low-risk DKD stage, respectively. After PSM analyses, serum FT4 and TSH showed no statistical significance in risk estimates for all DKD stages. To facilitate clinical application, a nomogram prediction model was established for the moderate-risk, high-risk and very-high-risk DKD stages, with decent accuracy. CONCLUSION: Our results indicate that high concentrations of serum FT3 were associated with the significantly reduced risk of having moderate-risk to very-high-risk DKD stages.

Multifunctional antibacterial bioactive nanoglass hydrogel for normal and MRSA infected wound repair.

Large-scale skin damage brings potential risk to patients, such as imbalance of skin homeostasis, inflammation, fluid loss and bacterial infection. Moreover, multidrug resistant bacteria (MDRB) infection is still a great challenge for skin damage repair. Herein, we developed an injectable self-healing bioactive nanoglass hydrogel (FABA) with robust antibacterial and anti-inflammatory ability for normal and Methicillin-resistant Staphylococcus aureus (MRSA) infected skin wound repair. FABA hydrogel was fabricated facilely by the self-crosslinking of F127-CHO (FA) and alendronate sodium (AL)-decorated Si-Ca-Cu nanoglass (BA). FABA hydrogel could significantly inhibit the growth of Staphylococcus aureus, Escherichia coli and MRSA in vitro, while showing good cytocompatibility and hemocompatibility. In addition, FABA hydrogel could inhibit the expression of proinflammatory factor TNF-α and enhance the expression of anti-inflammatory factor IL-4/ IL-10. Based on its versatility, FABA hydrogel could complete wound closure efficiently (75% at day 3 for normal wound, 70% at day 3 for MRSA wound), which was almost 3 times higher than control wound, which was related with the decrease of inflammatory factor in early wound. This work suggested that FABA hydrogel could be a promising dressing for acute and MRSA-infected wound repair.

[Influencing Factors and Prediction Model of Performance of Needle Visualization in Fine Needle Aspiration of Thyroid Nodules].

Objective To investigate the influencing factors and establish a model predicting the performance of needle visualization in fine-needle aspiration (FNA) of thyroid nodules. Methods This study prospectively included 175 patients who underwent FNA of thyroid nodules in the Department of Ultrasound in China-Japan Friendship Hospital and compared the display of the needle tips in the examination of 199 thyroid nodules before and after the application of needle visualization.We recorded the location,the positional relationship with thyroid capsule,ultrasonic characteristics,and the distribution of the soft tissue strip structure at the puncture site of the nodules with unclear needle tips display before using needle visualization.Furthermore,according to the thyroid imaging reporting and data system proposed by the American College of Radiology,we graded the risk of the nodules.Lasso-Logistic regression was employed to screen out the factors influencing the performance of needle visualization and establish a nomogram for prediction. Results The needle tips were not clearly displayed in the examination of 135 (67.8%) and 53 (26.6%) nodules before and after the application of needle visualization,respectively,which showed a significant difference (P<0.001).Based on the positional relationship between the nodule and capsule,anteroposterior/transverse diameter (A/T) ratio,blood supply,and the distribution of subcutaneous strip structure at the puncture site,a nomogram was established to predict the probability of unclear display of the needle tips after application of needle visualization.The C-index of the prediction model was 0.75 (95%CI=0.67-0.84) and the area under the receiver operating characteristic curve was 0.72.The calibration curve confirmed the appreciable reliability of the prediction model,with the C-index of 0.70 in internal validation. Conclusions Needle visualization can improve the display of the needle tip in ultrasound-guided FNA of thyroid nodules.The nomogram established based on ultrasound features such as the positional relationship between the nodule and capsule,A/T ratio,blood supply,and the distribution of subcutaneous strip structure at the puncture site can predict whether needle visualization is suitable for the examination of nodules.

Microwave Ablation versus Surgical Resection for Solitary T1N0M0 Papillary Thyroid Carcinoma.

Background Microwave ablation (MWA) has attracted interest as a minimally invasive treatment for papillary thyroid carcinoma (PTC). However, comparisons between MWA and surgical resection (SR) in the management of T1N0M0 PTC are rare. Purpose To compare the technical effectiveness, disease progression, and complications of MWA and SR for solitary T1N0M0 PTC. Materials and Methods This retrospective study was conducted in a single center. A total of 1029 patients with T1N0M0 PTC treated with either MWA or SR from January 2015 to May 2021 were studied and divided into two groups according to treatment modality. Propensity score matching and inverse probability of treatment weighting were used to control for confounding factors. Disease progression was analyzed in T1N0M0 PTCs as well as T1a and T1b subgroups by using Kaplan-Meier curves and Cox proportional hazards regression models. Results A total of 404 patients (mean age, 43 years ± 12 [SD]; 289 women; 337 with T1a PTC) underwent MWA, and 625 (mean age, 46 years ± 12; 495 women; 521 with T1a PTC) underwent SR. During the follow-up (median, 25 months; IQR, 7-61 months), there was no evidence of differences regarding disease progression in T1N0M0 (4.0% vs 4.0%; P = .97), T1a (3.4% vs 3.8%; P = .89), or T1b PTCs (6.8% vs 5.0%; P = .72). Compared with SR, MWA resulted in less blood loss (2 mL vs 10 mL) and a shorter procedure time (23 minutes vs 72 minutes) (both P < .001). The rate of major complications was 5.4% (19 of 350 patients) in the MWA group and 6.3% (22 of 350 patients) in the SR group (P = .75). Permanent hoarseness only occurred in the SR group (1.7%; P = .03). Conclusion For T1a and T1b solitary T1N0M0 papillary thyroid carcinomas, there was no evidence of differences regarding disease progression and major complications between microwave ablation and surgical resection. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by vanSonnenberg and Simeone in this issue.

miR-188-3p-targeted regulation of ATG7 affects cell autophagy in patients with nonobstructive azoospermia.

BACKGROUND: Nonobstructive azoospermia (NOA) is one of the most difficult forms of male infertility to treat, and its pathogenesis is still unclear. miRNAs can regulate autophagy by affecting their target gene expression. Our previous study found that miR-188-3p expression in NOA patients was low. There are potential binding sites between the autophagy gene ATG7 and miR-188-3p. This study aimed to verify the binding site between miR-188-3p and ATG7 and whether miR-188-3p affects autophagy and participates in NOA by regulating ATG7 to influence the autophagy marker genes LC3 and Beclin-1. METHODS: Testicular tissue from 16 NOA patients and 16 patients with normal spermatogenesis and 5 cases in each group of pathological sections were collected. High-throughput sequencing was performed to detect mRNA expression differences. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, immunohistochemical staining and immunofluorescence were used to detect protein localization and expression. Autophagosome changes were detected by electron microscopy. The targeting relationship between miR-188-3p and ATG7 was confirmed by a luciferase assay. RESULTS: ATG7 protein was localized in the cytoplasm of spermatogenic cells at all levels, and the ATG7 gene (p = 0.019) and protein (p = 0.000) were more highly expressed in the NOA group. ATG7 expression after overexpression/inhibition of miR-188-3p was significantly lower (p = 0.029)/higher (p = 0.021) than in the control group. After overexpression of miR-188-3p, the ATG7 3'UTR-WT luciferase activity was impeded (p = 0.004), while the ATG7 3'UTR-MUT luciferase activity showed no significant difference (p = 0.46). LC3 (p = 0.023) and Beclin-1 (p = 0.041) expression in the NOA group was significantly higher. LC3 and Beclin-1 gene expression after miR-188-3p overexpression/inhibition was significantly lower (p = 0.010 and 0.024, respectively) and higher (p = 0.024 and 0.049, respectively). LC3 punctate aggregation in the cytoplasm decreased after overexpression of miR-188-3p, while the LC3 punctate aggregation in the miR-188-3p inhibitor group was higher. The number of autophagosomes in the miR-188-3p mimic group was lower than the number of autophagosomes in the mimic NC group. CONCLUSIONS: LC3 and Beclin-1 were more highly expressed in NOA testes and negatively correlated with the expression of miR-188-3p, suggesting that miR-188-3p may be involved in the process of autophagy in NOA. miR-188-3p may regulate its target gene ATG7 to participate in autophagy anDual luciferase experiment d affect the development of NOA.

piNET: a versatile web platform for downstream analysis and visualization of proteomics data.

Rapid progress in proteomics and large-scale profiling of biological systems at the protein level necessitates the continued development of efficient computational tools for the analysis and interpretation of proteomics data. Here, we present the piNET server that facilitates integrated annotation, analysis and visualization of quantitative proteomics data, with emphasis on PTM networks and integration with the LINCS library of chemical and genetic perturbation signatures in order to provide further mechanistic and functional insights. The primary input for the server consists of a set of peptides or proteins, optionally with PTM sites, and their corresponding abundance values. Several interconnected workflows can be used to generate: (i) interactive graphs and tables providing comprehensive annotation and mapping between peptides and proteins with PTM sites; (ii) high resolution and interactive visualization for enzyme-substrate networks, including kinases and their phospho-peptide targets; (iii) mapping and visualization of LINCS signature connectivity for chemical inhibitors or genetic knockdown of enzymes upstream of their target PTM sites. piNET has been built using a modular Spring-Boot JAVA platform as a fast, versatile and easy to use tool. The Apache Lucene indexing is used for fast mapping of peptides into UniProt entries for the human, mouse and other commonly used model organism proteomes. PTM-centric network analyses combine PhosphoSitePlus, iPTMnet and SIGNOR databases of validated enzyme-substrate relationships, for kinase networks augmented by DeepPhos predictions and sequence-based mapping of PhosphoSitePlus consensus motifs. Concordant LINCS signatures are mapped using iLINCS. For each workflow, a RESTful API counterpart can be used to generate the results programmatically in the json format. The server is available at http://pinet-server.org, and it is free and open to all users without login requirement.

A New Case of Hb Headington (HBB: c.217A>C) Due to a New DNA Transversion, Found in a Patient with Type 2 Diabetes Mellitus.

We here report a novel case of Hb Headington [ß72(E16)Ser→Arg, HBB: c.217A>C, p.Ser73Arg], in a 68-year-old woman with type 2 diabetes mellitus (T2DM). Glycosylated hemoglobin (Hb) was measured by capillary electrophoresis (CE). The spectrum showed abnormal peaks between the A0 and A2 peaks. DNA sequencing demonstrated a mutation on the HBB gene, which predicted a substitution of serine to arginine at position 73 in the ß-globin chain. Moreover, this amino acid substitution occurs at the same position as Hb Headington [ß72(E16)Ser→Arg, HBB: c.219T>A, p.Ser73Arg], which showed increased oxygen affinity.

Predicting mechanism of action of cellular perturbations with pathway activity signatures.

MOTIVATION: Misregulation of signaling pathway activity is etiologic for many human diseases, and modulating activity of signaling pathways is often the preferred therapeutic strategy. Understanding the mechanism of action (MOA) of bioactive chemicals in terms of targeted signaling pathways is the essential first step in evaluating their therapeutic potential. Changes in signaling pathway activity are often not reflected in changes in expression of pathway genes which makes MOA inferences from transcriptional signatures (TSeses) a difficult problem. RESULTS: We developed a new computational method for implicating pathway targets of bioactive chemicals and other cellular perturbations by integrated analysis of pathway network topology, the Library of Integrated Network-based Cellular Signature TSes of genetic perturbations of pathway genes and the TS of the perturbation. Our methodology accurately predicts signaling pathways targeted by the perturbation when current pathway analysis approaches utilizing only the TS of the perturbation fail. AVAILABILITY AND IMPLEMENTATION: Open source R package paslincs is available at https://github.com/uc-bd2k/paslincs. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The alveolar epithelial cells are involved in pulmonary vascular remodeling and constriction of hypoxic pulmonary hypertension.

BACKGROUND: Hypoxic pulmonary hypertension (HPH) is a common type of pulmonary hypertension and characterized by pulmonary vascular remodeling and constriction. Alveolar epithelial cells (AECs) primarily sense alveolar hypoxia, but the role of AECs in HPH remains unclear. In this study, we explored whether AECs are involved in pulmonary vascular remodeling and constriction. METHODS: In the constructed rat HPH model, hemodynamic and morphological characteristics were measured. By treating AECs with hypoxia, we further detected the levels of superoxide dismutase 2 (SOD2), catalase (CAT), reactive oxygen species (ROS) and hydrogen peroxide (H2O2), respectively. To detect the effects of AECs on pulmonary vascular remodeling and constriction, AECs and pulmonary artery smooth cells (PASMCs) were co-cultured under hypoxia, and PASMCs and isolated pulmonary artery (PA) were treated with AECs hypoxic culture medium. In addition, to explore the mechanism of AECs on pulmonary vascular remodeling and constriction, ROS inhibitor N-acetylcysteine (NAC) was used. RESULTS: Hypoxia caused pulmonary vascular remodeling and increased pulmonary artery pressure, but had little effect on non-pulmonary vessels in vivo. Meanwhile, in vitro, hypoxia promoted the imbalance of SOD2 and CAT in AECs, leading to increased ROS and hydrogen peroxide (H2O2) production in the AECs culture medium. In addition, AECs caused the proliferation of co-cultured PASMCs under hypoxia, and the hypoxic culture medium of AECs enhanced the constriction of isolated PA. However, treatment with ROS inhibitor NAC effectively alleviated the above effects. CONCLUSION: The findings of present study demonstrated that AECs were involved in pulmonary vascular remodeling and constriction under hypoxia by paracrine H2O2 into the pulmonary vascular microenvironment.

Flavonoid derivatives synthesis and anti-diabetic activities.

In high fat diet-induced obese mice, the flavonoid derivative of tiliroside, Fla-CN, has antihyperglycemic effects, can improve insulin sensitivity, ameliorate metabolic lipid disorders, and benefits certain disorders characterized by insulin resistance. Fla-CN is a novel lead compound to discovery anti-diabetic and anti-obesity drugs. The present study reported the optimization of Fla-CN to obtain a new derivative, 10b, which has improved glucose consumption at the nanomolar level (EC50 = 0.3 nM) in insulin resistant (IR) HepG2 cells. 10b also increased the glycogen content and glucose uptake, and concurrently inhibited gluconeogenesis in HepG2 cells. Western blotting showed that 10b markedly enhanced the phosphorylation of AMPK (AMP-activated protein kinase) and AS160 (protein kinase B substrate of 160 kDa) and reduced the levels of the gluconeogenesis key enzymes PEPCK (phosphoenolpyruvate carboxykinase) and G6P (glucose 6-phosphatase) in HepG2 cells. The potential molecular mechanism of 10b may be activation of the AMPK/AS160 and AMPK/PEPCK/G6P pathways. We concluded that 10b might be a valuable candidate to discover anti-diabetic drugs.

Data Portal for the Library of Integrated Network-based Cellular Signatures (LINCS) program: integrated access to diverse large-scale cellular perturbation response data.

The Library of Integrated Network-based Cellular Signatures (LINCS) program is a national consortium funded by the NIH to generate a diverse and extensive reference library of cell-based perturbation-response signatures, along with novel data analytics tools to improve our understanding of human diseases at the systems level. In contrast to other large-scale data generation efforts, LINCS Data and Signature Generation Centers (DSGCs) employ a wide range of assay technologies cataloging diverse cellular responses. Integration of, and unified access to LINCS data has therefore been particularly challenging. The Big Data to Knowledge (BD2K) LINCS Data Coordination and Integration Center (DCIC) has developed data standards specifications, data processing pipelines, and a suite of end-user software tools to integrate and annotate LINCS-generated data, to make LINCS signatures searchable and usable for different types of users. Here, we describe the LINCS Data Portal (LDP) (http://lincsportal.ccs.miami.edu/), a unified web interface to access datasets generated by the LINCS DSGCs, and its underlying database, LINCS Data Registry (LDR). LINCS data served on the LDP contains extensive metadata and curated annotations. We highlight the features of the LDP user interface that is designed to enable search, browsing, exploration, download and analysis of LINCS data and related curated content.

Inhibition of microRNA-124a attenuates non-alcoholic fatty liver disease through upregulation of adipose triglyceride lipase and the effect of liraglutide intervention.

AIM: Glucagon-like peptide-1 receptor agonists (GLP-1Ras) have been reported to prevent non-alcoholic fatty liver disease (NAFLD), but the potential mechanisms are still debated. MicroRNAs (miRNAs) play a prominent role in the field of metabolic disorders, including NAFLD. Our study was designed to further evaluate the effect of GLP-1Ra liraglutide on NAFLD in terms of miRNAs. METHODS: MicroRNA expression was evaluated by clustering analysis of microRNA arrays in high fat diet-fed mice. The luciferase reporter assay was carried out to validate the cross-talk between adipose triglyceride lipase (ATGL) and miR-124a. MicroRNA-124a mimics and inhibitor plasmids were transfected to study the role of miR-124a in palmitate-treated normal human liver cell line (HL-7702). Liraglutide treatment was used to observe the effect of GLP-1Ra on the miR-124a/ATGL pathway. RESULTS: Expression of ATGL decreased and miR-124a expression increased in hepatosteatosis in vivo and in vitro. Mechanistically, miR-124a interacted with the 3'-untranslated region of ATGL mRNA and induced its degradation. MicroRNA-124a overexpression antagonized the effect of liraglutide on NAFLD by inhibiting ATGL expression, whereas miR-124a knockdown led to elevated ATGL and sirtuin 1 (Sirt1) expression, and subsequently decreased lipid accumulation and inflammation in cells. CONCLUSIONS: MicroRNA-124a overexpression contributes to the progression of NAFLD through reduction of ATGL expression, whereas miR-124a knockdown can reverse this trend, suggesting that miR-124a and its downstream target ATGL can be novel therapeutic targets of NAFLD. We reveal a novel mechanism by which liraglutide attenuates NAFLD by the miR-124a/ATGL/Sirt1 pathway.

SKA3 promotes cell proliferation and migration in cervical cancer by activating the PI3K/Akt signaling pathway.

BACKGROUND: Cervical cancer (CC) is one of the most common cancers among females worldwide. Spindle and kinetochore-associated complex subunit 3 (SKA3), located on chromosome 13q, was identified as a novel gene involved in promoting malignant transformation in cancers. However, the function and underlying mechanisms of SKA3 in CC remain unknown. Using the Oncomine database, we found that expression of SKA3 mRNA is higher in CC tissues than in normal tissues and is linked with poor prognosis. METHODS: In our study, immunohistochemistry showed increased expression of SKA3 in CC tissues. The effect of SKA3 on cell proliferation and migration was evaluated by CCK8, clone formation, Transwell and wound-healing assays in HeLa and SiHa cells with stable SKA3 overexpression and knockdown. In addition, we established a xenograft tumor model in vivo. RESULTS: SKA3 overexpression promoted cell proliferation and migration and accelerated tumor growth. We further identified that SKA3 is involved in regulating cell cycle progression and the PI3K/Akt signaling pathway via RNA-sequencing (RNA-Seq) and gene set enrichment analyses. Western blotting results revealed that SKA3 overexpression increased levels of p-Akt, cyclin E2, CDK2, cyclin D1, CDK4, E2F1 and p-Rb in HeLa cells. Additionally, the use of an Akt inhibitor (GSK690693) significantly reversed the cell proliferation capacity induced by SKA3 overexpression in HeLa cells. CONCLUSIONS: We suggest that SKA3 overexpression contributes to CC cell growth and migration by promoting cell cycle progression and activating the PI3K-Akt signaling pathway, which may provide potential novel therapeutic targets for CC treatment.

PGC-1α-Mediated Mitochondrial Biogenesis is Involved in Cannabinoid Receptor 2 Agonist AM1241-Induced Microglial Phenotype Amelioration.

Cannabinoid type 2 receptor (CB2R) agonist AM1241 induces anti-inflammation by ameliorating microglial phenotypes, the mechanism, however, is still unknown. Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is a transcription protein which can regulate mitochondrial biogenesis, and the aim of this study is to investigate whether PGC-1α is involved in AM1241-induced anti-inflammation in N9 microglial cells. We used 10 ng/ml lipopolysaccharide (LPS) plus 10 U/ml interferon γ (IFNγ) to activate microglia into classic activated phenotype (M1 phenotype), and found that co-administration of 10 µM AM1241 increased the expressions of mitochondria biogenesis-associated proteins, including nuclear respiratory factor 1 (NRF-1), mitochondrial transcription factor A (TFAM) and COX IV, and up-regulated the biomarker levels of microglial M2 phenotype, including arginase 1 (Arg-1) and brain-derived neurotrophic factor (BDNF), and down-regulated biomarker levels of M1 phenotype, including inducible nitric oxide synthase (iNOS) and tumor necrosis factor α (TNF-α), compared to the cells treated with LPS plus IFNγ only (P < 0.05). By using PGC-1α-siRNA, however, we found that down-regulation of PGC-1α significantly reversed the AM1241-induced effects above (P < 0.05). According to the results in this study, we found that PGC-1α may mediate CB2R agonist AM1241-induced anti-inflammation in N9 microglial cells, and the mechanism might be associated with the enhancement of mitochondria biogenesis.

Automatic regulation of NF-κB by pHSP70/IκBαm to prevent acute lung injury in mice.

Controlling target gene expression is a vital step in the procedure of gene therapy upon acute lung injury (ALI). Excessive activation of nuclear factor-kappa B (NF-κB) has been the key point of the inflammation overwhelming process in onset of ALI. We designed and tested a variety of plasmid named pHSP70/IκBαm which conditionally carries a mutant inhibitor of kappa B (IκB) transgene to regulate the activity of NF-κB signaling pathway in its response to an inflammatory stimulus that causes acute lung injury. Results recorded along our experiments showed that pHSP70/IκBαm was able to control mutant IκB expression in RAW264.7 cells with reference to the level of inflammatory response induced by LPS, thereby inhibiting NF-κB activation and downstream inflammatory cytokine expression. Vivo experiments revealed that construction naming pHSP70/IκBαm reduced LPS-induced lung injury and the secretion of inflammatory factors from lungs, hearts, and livers of sample mice in a LPS dose-dependent manner. In conclusion, the promoter heat shocking protein 70(HSP70) regulatory sequence of the construction was shown to drive mutant IκB expression so that its levels were positively associated with the dose of LPS used to induce acute lung injury. NF-κB activation and the downstream expression of inflammatory factors were therefore down-regulated in along an efficient path and ameliorating the damage as a consequence of LPS-induced acute lung injury.