Malignancy risk stratification for solitary pulmonary nodule: A clinical practice guideline.

CLINICAL QUESTION: The detection rate of the solitary pulmonary nodule (SPN) is increasing with the popularization of CT scanning. Malignancy risk stratification for SPN is a major clinical difficulty. CURRENT PRACTICE: There have been several guidelines for SPN assessment. Inconsistency of these guidelines makes the clinical application difficult and confusing. RECOMMENDATIONS: In this Rapid Recommendation, solid and subsolid SPNs are recommended to be evaluated respectively. Six factors, namely the combination of age with sex, smoking history, history of malignancy, family history of malignancy, and nodule size, are recommended for malignancy risk stratification for both kinds of SPNs; the border of nodules (spiculation and lobulation) is recommended for evaluating solid SPNs and the density of nodules (pure or mixed ground-glass nodule) is recommended for subsolid nodules. Among them, smoking history and radiologic features (nodule diameter, border, and density) are of relatively higher importance. A scoring system was proposed to assist malignancy risk stratification of SPNs, with a total score ranging from six points to 15 points (if solid) or 17 points (if subsolid). For each SPN, regardless of solid or subsolid in nature, a total score of ≤ 7 points suggested a low risk of being malignant, while 7 to 9 points suggested medium risk, and ≥ 9 points suggested high risk. HOW THIS GUIDELINE WAS CREATED: This rapid recommendation was developed using the MAGIC (Making GRADE the Irresistible Choice) methodological framework. First, a clinical subcommittee identified the topic of recommendation and requested evidence. Then, an independent evidence synthesis subcommittee performed a comprehensive literature review and evaluated the evidence. Finally, based on findings from the systematic review and use of real-world data, the clinical subcommittee formulated recommendations, including the scoring system, through a consensus procedure. THE EVIDENCE: A total of 13857 patients with SPNs were included in the meta-analysis and the association between 12 candidate factors and the risk of SPNs being malignant was studied. Eventually, seven factors were recommended for SPNs evaluation, and a scoring system was proposed. UNDERSTANDING THE RECOMMENDATION: The parameters included are objective. Therefore, this recommendation is feasible in clinical practice. However, there are several uncertainties, such as a lack of further verification. It might be misclassified by the scoring system. Clinicians could choose the most suitable scheme according to the recommendation, along with their own experience in specific situations.

Autophagy inhibition protects from alveolar barrier dysfunction in LPS-induced ALI mice by targeting alveolar epithelial cells.

OBJECTIVE: The aim of this study was to investigate whether autophagy is enhanced in alveolar epithelial cells as well as its role in alveolar barrier function of in lipopolysaccharide (LPS)-induced ALI mice. MATERIALS AND METHODS: Autophagy inhibitors, including 3-methyladenine (3-MA) and chloroquine (CLQ), and LPS were intraperitoneally administered to mice. Histological evaluation and confocal microscopy, Western blot, transmission electron microscopy, and ELISA were performed for analysis. First, the mouse model of ALI was established. Then, autophagy level changes in the mouse lung as well as the effects of autophagy inhibition on indirect ALI and alveolar epithelial barrier function induced by LPS were assessed. Finally, pro-inflammatory factors in BALF from ALI mice after autophagy inhibition by 3-MA or CLQ administration were detected. RESULTS: The experimental animal model of LPS-induced ALI had the expected features. In addition, autophagy in alveolar epithelial cells in ALI mice was enhanced. Furthermore, autophagy in alveolar epithelial cells promoted alveolar epithelial barrier dysfunction in LPS-induced ALI. Finally, autophagy inhibition resulted in reduced LPS-induced lung tissue inflammation. CONCLUSION: These findings suggest that autophagy inhibition protects from alveolar barrier dysfunction in LPS-induced ALI mice by targeting alveolar epithelial cells.

ZNF300 promotes chemoresistance and aggressive behaviour in non-small-cell lung cancer.

OBJECTIVES: Chemoresistance induced by cisplatin has become the major impediment to lung cancer chemotherapy. This study explored the potential chemoresistant genes and underlying mechanisms of chemoresistance in NSCLC. MATERIALS AND METHODS: Gene expression profile was integrated with DNA methylation profile to screen the candidate chemoresistant genes. Bioinformatic analysis and immunohistochemistry were used to analyse the association of a candidate gene with the characteristics of NSCLC patients. Recombinant lentivirus vectors were utilized to overexpress or silence candidate gene. Microarrays and immunoblotting were applied to explore the downstream targets of candidate gene. Xenograft models were established to validate the findings in vitro. RESULTS: An increased ZNF300 expression was detected in three chemoresistant cell lines of NSCLC, and the higher expression of ZNF300 was associated with poor OS of NSCLC patients. Cells with upregulated ZNF300 presented chemoresistance and enhanced aggressive growth compared to cells with downregulated ZNF300. ZNF300 inhibited MAPK/ERK pathways and activated CDK1 through inhibiting WEE1 and MYT1 and modulating MYC/AURKA/BORA/PLK1 axis. ICA and ATRA improved the anti-tumour effect of cisplatin on chemoresistant cells by inducing differentiation. CONCLUSIONS: ZNF300 promotes chemoresistance and aggressive behaviour of NSCLC through regulation of proliferation and differentiation by downregulating MAPK/ERK pathways and regulation of slow-cycling phenotype via activating CDK1 by inhibiting WEE1/MYT1 and modulating MYC/AURKA/BORA/PLK1 axis. Cisplatin, combined with ATRA and ICA, might be beneficial in chemoresistant cases of NSCLC.

Omentin-1 attenuates adipose tissue inflammation via restoration of TXNIP/NLRP3 signaling in high-fat diet-induced obese mice.

Omentin-1 is an adipokine expressed by the adipose tissue and is reduced in obesity. This study was designed to calculate the protective efficiency and mechanism of omentin-1 against inflammation of the adipose tissue in obese mice. A transgenic mouse model with omentin-1 protein overexpression was established by crossing omentin-1 transgenic mice with Fabp4-Cre mice. Obesity was induced in the mice by feeding them a high-fat diet for 10 weeks. Fabp4-Cre-mediated overexpression of omentin-1 significantly increased serum omentin-1 level, serum anti-inflammatory factor levels, and expression of M2-specific mRNAs; inhibited body weight and adipose tissue weight gain; improved glucose tolerance, insulin tolerance, and insulin sensitivity; decreased serum levels of insulin and proinflammatory factors, adipocyte size, and expression of M1-specific mRNAs; suppressed macrophage infiltration; downregulated expression of proinflammatory factors; upregulated expression of anti-inflammatory factors; and inhibited thioredoxin-interacting protein (TXNIP)/NOD-like receptor 3 (NLRP3) signaling in the adipose tissue of obese mice. An NLRP3 inhibitor (20 mg/kg MCC950) exhibited the same effects as overexpression of omentin-1. Pretreatment with omentin-1 inhibited lipopolysaccharide-induced inflammation via TXNIP/NLRP3 signaling in RAW 264.7 macrophages. These findings suggest that omentin-1 suppresses adipose tissue inflammation in obese mice, at least partly, via inhibiting the TXNIP/NLRP3 signaling pathway.

Diabetic Cognitive Dysfunction: From Bench to Clinic.

Type 2 diabetes increases the risk of developing cognitive dysfunction in the elderly in the form of short-term memory and executive function impairment. Genetic and diet-induced models of type 2 diabetes further support this link, displaying deficits in working memory, learning, and memory performance. The risk factors for diabetic cognitive dysfunction include vascular disease, hypoglycaemia, hyperlipidaemia, adiposity, insulin resistance, lifestyle factors, and genetic factors. Using neuronal imaging technologies, diabetic patients with cognitive dysfunction show atrophy of the whole brain, particularly the grey matter, hippocampus and amygdala; increased volume of the ventricular and white matter; brain infarcts; impaired network integrity; abnormal microstructure; and reduced cerebral blood flow and amplitude of low-frequency fluctuations. The pathogenesis of type 2 diabetes with cognitive dysfunction involves hyperglycaemia, macrovascular and microvascular diseases, insulin resistance, inflammation, apoptosis, and disorders of neurotransmitters. Large clinical trials may offer further proof of biomarkers and risk factors for diabetic cognitive dysfunction. Advanced neuronal imaging technologies and novel disease animal models will assist in elucidating the precise pathogenesis and to provide better therapeutic interventions and treatment.

Efficacy of Shenqi Pollen Capsules for High-Altitude Deacclimatization Syndrome via Suppression of the Reoxygenation Injury and Inflammatory Response.

High-altitude deacclimatization syndrome (HADAS) is involved in hypoxia-reoxygenation injury and inflammatory response, induced a series of symptoms, and has emerged as a severe public health issue. Here, we investigated the mechanism as well as potential means to prevent HADAS using Shenqi pollen capsules (SPCs) in subjects with HADAS in a multicenter, double-blinded, randomized, placebo-controlled study. All subjects were at the same high altitude (3650 m) for 4-8 months before returning to lower altitudes. Subjects (n = 288) in 20 clusters were diagnosed with mild or moderate HADAS on the third day of the study. We randomly allocated 20 clusters of subjects (1 : 1) to receive SPCs or a placebo for 7 weeks, and they were then followed up to the 14th week. The primary endpoints were subjects' HADAS scores recorded during the 14 weeks of follow-up. Compared with the placebo, SPC treatment significantly decreased the subjects' HADAS scores and reduced the incidence of symptom persistence. SPC therapy also reduced the serum levels of CK, CK-MB, LDH, IL-17A, TNF-α, and miR-155 and elevated IL-10 and miR-21 levels. We thus demonstrate that SPCs effectively ameliorated HADAS symptoms in these subjects via suppression of the hypoxia-reoxygenation injury and inflammatory response.

Neuropathy and inflammation in diabetic bone marrow.

Diabetes impairs the bone marrow (BM) architecture and function as well as the mobilization of immature cells into the bloodstream and number of potential regenerative cells. Circadian regulation of bone immature cell migration is regulated by ß-adrenergic receptors, which are expressed on haematopoietic stem cells, mesenchymal stem cells, and osteoblasts in the BM. Diabetes is associated with a substantially lower number of sympathetic nerve terminal endings in the BM; thus, diabetic neuropathy plays a critical role in BM dysfunction. Treatment with mesenchymal stem cells, BM mononuclear cells, haematopoietic stem cells, and stromal cells ameliorates the dysfunction of diabetic neuropathy, which occurs, in part, through secreted neurotrophic factors, growth factors, adipokines, and polarizing macrophage M2 cells and inhibiting inflammation. Inflammation may be a therapeutic target for BM stem cells to improve diabetic neuropathy. Given that angiogenic and neurotrophic effects are two major barriers to effective diabetic neuropathy therapy, targeting BM stem cells may provide a novel approach to develop these types of treatments.

The Role of SIRT1 in Autophagy in Lipopolysaccharide-Induced Mouse Type II Alveolar Epithelial Cells.

Silent mating type information regulation 2 homolog-1 (SIRT1) is involved in a wide range of cellular processes because of its role as a deacetylated histone and its association with a variety of transcription factors. SIRT1 has essential roles in autophagy, including in the formation of autophagic vacuoles and the assembly of autophagy-related gene (ATG) protein complexes. The present study focused on the role of SIRT1 in autophagy in lipopolysaccharide (LPS)-induced mouse type II alveolar epithelial cells (AECII). We designed experiments using SIRT1-overexpressing mice and wild-type mice, and AECII were isolated from these two types of mouse for in vitro LPS injury trials. Our results suggest that levels of the autophagy proteins, Beclin1 and LC3B, as well as those of the inflammatory factors, IL-6 and TNF-α, were increased in LPS-induced mouse AECII, and that SIRT1 protected against damage in mice with acute respiratory distress syndrome and in mouse AECII in vitro following LPS treatment. Subsequently, we screened multiple inflammatory, apoptotic, and unclassified genes (including Atg7), which interacted with SIRT1 in LPS-injured mouse AECII, as assessed by mRNA microarray analysis. These results demonstrate that LPS can reduce the levels of SIRT1 and ATG7 in vivo and in vitro and indicate that SIRT1 is involved in autophagy through regulation of ATG7 in AECII in response to LPS.

RAB26-dependent autophagy protects adherens junctional integrity in acute lung injury.

Microvascular barrier dysfunction is the central pathophysiological feature of acute lung injury (ALI). RAB26 is a newly identified small GTPase involved in the regulation of endothelial cell (EC) permeability. However, the mechanism behind this protection has not been clearly elucidated. Here we found that RAB26 promoted the integrity of adherens junctions (AJs) in a macroautophagy/autophagy-dependent manner in ALI. RAB26 is frequently downregulated in mouse lungs after LPS treatment. Mice lacking Rab26 exhibited phosphorylated SRC expression and increased CDH5/VE-cadherin phosphorylation, leading to AJ destruction. rab26-null mice showed further aggravation of the effects of endotoxin insult on lung vascular permeability and water content. Depletion of RAB26 resulted in upregulation of phosphorylated SRC, enhancement of CDH5 phosphorylation, and aggravation of CDH5 internalization, thereby weakening AJ integrity and endothelial barrier function in human pulmonary microvascular endothelial cells (HPMECs). RAB26 overexpression caused active interaction between SRC and the autophagy marker LC3-II and promoted degradation of phosphorylated SRC. Furthermore, RAB26 was involved in a direct and activation-dependent manner in autophagy induction through interaction with ATG16L1 in its GTP-bound form. These findings demonstrate that RAB26 exerts a protective effect on endothelial cell (EC) permeability, which is in part dependent on autophagic targeting of active SRC, and the resultant CDH5 dephosphorylation maintains AJ stabilization. Thus, RAB26-mediated autophagic targeting of phosphorylated SRC can maintain barrier integrity when flux through the RAB26-SRC pathway is protected. These findings suggest that activation of RAB26-SRC signaling provides a new therapeutic opportunity to prevent vascular leakage in ALI. ABBREVIATIONS: AJs: adherens junctions; ALI: acute lung injury; ARDS: acute respiratory distress syndrome; ATG5: autophagy related 5; ATG12: autophagy related 12; ATG 16L1: autophagy related 16 like; 1 BALF: bronchoalveolar lavage fluidCQ: chloroquine; Ctrl: control; EC: endothelial cell; GFP: green fluorescent protein; HA-tagged; RAB26WT: HA-tagged wild-type; RAB26  HA-tagged; RAB26QL: HA-tagged; RAB26Q123LHA-tagged; RAB26NI: HA-tagged; RAB26N177IHPMECs: human pulmonary microvascular endothelial cells; H&E: hematoxylin & eosin; IgG: immunoglobulin; GIF: immunofluorescence; IP: immunoprecipitationi;. p.: intraperitoneal; LPS: lipopolysaccharide; PBS: phosphate-buffered salinesi; RNA: small interfering;RNASQSTM1/p62, sequestosome; 1TBS: Tris-buffered saline; VEGF: vascular endothelial growth factor; WB: western blot; WT: wild-type.

ATG101 Single-Stranded Antisense RNA-Loaded Triangular DNA Nanoparticles Control Human Pulmonary Endothelial Growth via Regulation of Cell Macroautophagy.

Autophagy plays a key role in pulmonary vascular remodeling via regulation of apoptosis and hyperproliferation of pulmonary arterial endothelial cells, which are the subject of increased attention. Autophagy-related 101 (ATG101) is an essential gene for the initiation of autophagy. Although the structure of ATG101 has been well-characterized, its exact biological function in autophagy is still unknown. In this study, an ATG101 single-stranded antisense RNA-loaded DNA triangular nanoparticle (ssATG101-TNP) is constructed to knock down the ATG101 gene expression. ssATG101-TNP can be effectively transfected into human pulmonary arterial endothelial cells (HPAECs) in time- and dose-dependent manners. Knockdown of ATG101 promotes cell apoptosis as well as inhibits cell autophagy and proliferation with hypoxic stimulation. Additionally, the hedgehog/Gli signal pathway is involved in ATG101-mediated macroautophagy and HPAEC proliferation. This study found that ATG101, an important member of the autophagy gene family, can regulate cell macroautophagy, apoptosis, and growth in HPAECs. ssATG101-TNP is demonstrated to be a nontoxic, highly efficient, gene-delivery vehicle for HPAECs. These findings also suggest that ATG101 might be a potential therapeutic target in diseases involving endothelial injury.

Trigonelline Inhibits Inflammation and Protects ß Cells to Prevent Fetal Growth Restriction during Pregnancy in a Mouse Model of Diabetes.

BACKGROUND: As an active component from traditional Chinese medicine, trigonelline has a protective effect on diabetes. This study evaluated the protective effects of trigonelline on diabetic mice during pregnancy. METHODS: Diabetes was induced in female mice by intraperitoneal injection for continuous 5-day of 40 mg/kg/day streptozotocin. Female mice were divided into 4 groups after they were allowed to mate with normal male mice: nondiabetic, nondiabetic treated with trigonelline (70 mg/kg) for 18 days, diabetic, and diabetic treated with trigonelline (70 mg/kg). RESULTS: Diabetic pregnant mice had significantly higher levels of blood glucose, serum total cholesterol, triglyceride, insulin, and leptin but lower serum omentin-1 level and insulin sensitivity index than the nondiabetic ones. Trigonelline improved the hyperglycemia, dyslipidemia, insulin resistance, and adipocytokine of diabetic pregnant mice. Diabetic pregnant mice had significantly reduced fetus numbers, fetal weight, and fetal/placental ratio, which were reversed by trigonelline. Trigonelline prevented the increase in proinflammatory cytokines and reduced interleukin-10 level in placenta of diabetic pregnant mice. Trigonelline increased ß-cell replication and the decreased ß-cell mass, and decreased the ß-cell apoptosis of diabetic pregnant mice. CONCLUSION: These findings suggest that trigonelline protects diabetic pregnancy partly by suppressing inflammation, regulating the secretion of adipocytokines, increasing ß-cell mass, replication, and decreasing ß-cell apoptosis.

Regulation on Toll-like Receptor 4 and Cell Barrier Function by Rab26 siRNA-loaded DNA Nanovector in Pulmonary Microvascular Endothelial Cells.

The small GTPase Rab26 is involved in multiple processes, such as vesicle-mediated secretion and autophagy. However, the mechanisms and functions of Rab26 in the human pulmonary microvascular endothelial cells (HPMVECs) are not clear. In this study, we thoroughly investigated the role and novel mechanism of Rab26 in permeability and apoptosis of HPMVECs using a self-assembled Rab26 siRNA loaded DNA Y-motif nanoparticle (siRab26-DYM) and Rab26 adenovirus. We found that siRab26-DYM could be efficiently transfected into HPMVECs in a time- and dose-dependent manner. Importantly, the siRab26-DYM nanovector markedly aggravated the LPS-induced apoptosis and hyper-permeability of HPMVECs by promoting the nuclear translocation of Foxo1, and subsequent activation of Toll-like receptor 4 (TLR4) signal pathway. Overexpression of Rab26 by Rab26 adenoviruses partially inactivated LPS-induced TLR4 signaling pathway, suppressed the cell apoptosis and attenuated the hyperpermeability of HPMVECs. These results suggest that the permeability and apoptosis of HPMVECs can be modulated by manipulating Rab26 derived TLR4 signaling pathway, and that Rab26 can be potential therapeutic target for the treatment of vascular diseases related to endothelial barrier functions.

Assessment of the cancer risk factors of solitary pulmonary nodules.

There are no large samples or exact prediction models for assessing the cancer risk factors of solitary pulmonary nodules (SPNs) in the Chinese population. We retrospectively analyzed the clinical and imaging data of patients with SPNs who underwent computer tomography guided needle biopsy in our hospital from Jan 1st of 2011 to March 30th of 2016. These patients were divided into a development data set and a validation data set. These groups included 1078 and 344 patients, respectively. A prediction model was developed from the development data set and was validated with the validation data set using logistic regression. The predictors of cancer in our model included female gender, age, pack-years of smoking, a previous history of malignancy, nodule size, lobulated and spiculated edges, lobulation alone and spiculation alone. The Area Under the Curves, sensitivity and specificity of our model in the development and validation data sets were significantly higher than those of the Mayo model and VA model (p < 0.001). We established the largest sampling risk prediction model of SPNs in a Chinese cohort. This model is particularly applicable to SPNs > 8 mm in size. SPNs in female patients, as well as SPNs featuring a combination of lobulated and spiculated edges or lobulated edges alone, should be evaluated carefully due to the probability that they are malignant.

Macrophage migration inhibitory factor triggers vascular smooth muscle cell dedifferentiation by a p68-serum response factor axis.

AIMS: Macrophage migration inhibitory factor (MIF) is an important proinflammatory mediator linked to arterial diseases. Although its inflammatory property such as macrophage recruitment is known for contributing to vascular pathogenesis, the direct effects of MIF on homeostasis and biological function of vascular smooth muscle cell (VSMC) that are crucial for development of arterial abnormalities, are poorly understood. METHODS AND RESULTS: We show that MIF is able to directly induce VSMC dedifferentiation, a pathophysiological process fundamental for progression of various arterial diseases. Mechanistically, MIF suppresses p68 protein, a crucial regulator of cell growth and organ differentiation, via activation of JNK and p38 MAPKs. siRNA targeting of p68 facilitated dedifferentiation state in VSMCs, whereas p68 overexpression blocked MIF-elicited transition. In addition, MIF decreased the expression of serum response factor (SRF) that governs VSMC differentiation marker genes transcription, through repression of p68 protein. Furthermore, we showed a previously uncharacterized molecular interaction between p68 and SRF by co-immunoprecipitation assay. p68 attenuated MIF-elicited suppression of SRF recruitment to VSMC-specific promoter. Finally, anti-MIF treatment could reverse VSMC dedifferentiation, preserve vascular function, and inhibit remodelling due to vascular injury. CONCLUSIONS: Our results demonstrate a novel mechanism for the regulation of VSMC differentiation by MIF involving p68 and SRF. Strategy for targeting of MIF could inhibit aberrant transition of VSMC in cardiovascular pathogenesis, and may be of therapeutic benefit in phenotype-related arterial remodelling.

Tumor angiogenesis of SCLC inhibited by decreased expression of FMOD via downregulating angiogenic factors of endothelial cells.

Fibromodulin (FMOD), an ECM small leucine-rich proteoglycan (SLRP), was reported to promote angiogenesis not only during wound healing, but also in optical and cutaneous angiogenesis-dependent diseases. However, whether it plays important roles in tumor angiogenesis remains unclear. To explore the role of FMOD in tumor angiogenesis of human small cell lung cancer (SCLC), initially the study analyzed the relationship of FMOD expression in cancer tissues of SCLC with clinical characteristics. The analysis revealed that the positive FMOD expression was significantly associated with extensive stage of SCLC and higher vascular density. In mouse models, xenograft tumors developed with FMOD-silenced H446 cells (H446-shFMOD) exhibited slowed growth rate, decreased microvessel density, and reduced blood perfusion related to that of controls (H446-shCON). Additionally, compared with that of controls, the decreased secretion of FMOD in conditioned medium (CM) from H446-shFMOD inhibited proliferation, migration, and invasion of human umbilical vessel endothelial cells (HUVECs). Moreover, the decreased secretion of FMOD downregulated the expression of VEGF, TGF-ß1, FGF-2, and PDGF-B in HUVECs. The findings strongly suggested that the autocrine FMOD of cancer cells may promote tumor angiogenesis of SCLC by upregulating the expression of angiogenic factors that act in concert to facilitate the angiogenic phenotype of endothelial cells as a proangiogenic factor. Therefore, silencing FMOD may be a potentially clinical therapy for repressing tumor angiogenesis.

The breast cancer susceptibility-related polymorphisms at the TOX3/LOC643714 locus associated with lung cancer risk in a Han Chinese population.

It has been well established that besides environmental factors, genetic factors are also associated with lung cancer risk. However, to date, the prior identified genetic variants and loci only explain a small fraction of the familial risk of lung cancer. Hence it is vital to investigate the remaining missing heritability to understand the development and process of lung cancer. In the study, to test our hypothesis that the previously identified breast cancer risk-associated genetic polymorphisms at the TOX3/LOC643714 locus might contribute to lung cancer risk, 16 SNPs at the TOX3/LOC643714 locus were evaluated in a Han Chinese population based on a case-control study. Pearson's chi-square test or Fisher's exact test revealed that rs9933638, rs12443621, and rs3104746 were significantly associated with lung cancer risk (P < 0.001, P < 0.001, and P = 0.005, respectively). Logistic regression analyses displayed that lung cancer risk of individuals with rs9933638(GG+GA) were 1.89 times higher than that of rs9933638AA carriers (OR = 1.893, 95% CI = 1.308-2.741, P = 0.001). Similar findings were manifested for rs12443621 (OR = 1.824, 95% CI = 1.272-2.616, P = 0.001, rs12443621(GG+GA) carriers vs. rs12443621AA carriers) and rs3104746 (OR = 1.665, 95% CI = 1.243-2.230, P = 0.001, rs3104746TT carriers vs. rs3104746(TA+AA) carriers). The study discovered for the first time that three SNPs (rs9933638, rs12443621, and rs3104746) at the TOX3/LOC643714 locus contributed to lung cancer risk, providing new evidences that lung cancer and breast cancer are linked at the molecular and genetic level to a certain extent.

Neuroprotective effect of berberine is mediated by MAPK signaling pathway in experimental diabetic neuropathy in rats.

The mechanisms leading to diabetic neuropathy are complex. As an active component in several traditional Chinese medicines, berberine has a beneficial effect in the treatment of diabetes with hyperlipidemia. This study evaluated the protective effects of berberine on diabetic neuropathy induced by streptozotocin and a high-carbohydrate/high-fat diet in rats. Diabetic neuropathy was induced in rats by intraperitoneal injection of 35 mg/kg streptozotocin and a high-carbohydrate/high-fat diet. Two weeks after diabetes induction, rats were treated with berberine (100 mg/kg) and rosiglitazone (4 mg/kg) for 24 weeks. Rats were studied using evoked potentials, the Morris water maze, transmission electron microscopy, real-time PCR, and Western blotting. Blood glucose, glycated hemoglobin, lipid profile, body weight, evoked potentials, and memory were altered in diabetic rats, as was the hippocampal expression of neuritin mRNA, p38 mitogen-activated protein kinase mRNA, c-Jun N-terminal kinase (JNK) mRNA, extracellular signal-regulated kinase mRNA and the phospho-proteins of p38, JNK, and extracellular signal-regulated kinase. In diabetic rats, berberine decreased body weight and the blood levels of glucose, glycated hemoglobin, triglyceride, and total cholesterol, improved memory and affected evoked potential by decreasing latency. Berberine decreased the mRNA expression of neuritin, p38, and JNK and the protein expression of neuritin, p-p38, and p-JNK. Slight micropathological changes were observed in the hippocampus of berberine-treated diabetic rats. These findings suggest that berberine has a beneficial effect against diabetic neuropathy by improving micropathology and increasing neuritin expression via the mitogen-activated protein kinase signaling pathway.

Effectiveness of problem-based learning in Chinese pharmacy education: a meta-analysis.

BACKGROUND: This review provides a critical overview of problem-based learning (PBL) practices in Chinese pharmacy education. PBL has yet to be widely applied in pharmaceutical education in China. The results of those studies that have been conducted are published in Chinese and thus may not be easily accessible to international researchers. Therefore, this meta-analysis was carried out to review the effectiveness of PBL. METHODS: Databases were searched for studies in accordance with the inclusion criteria. Two reviewers independently performed the study identification and data extraction. A meta-analysis was conducted using Revman 5.3 software. RESULTS: Sixteen randomized controlled trials were included. The meta-analysis revealed that PBL had a positive association with higher theoretical scores (SMD = 1.17, 95% CI [0.77, 11.57], P < 0.00001). The questionnaire results show that PBL methods are superior to conventional teaching methods in improving students' learning interest, independent analysis skills, scope of knowledge, self-study, team spirit, and oral expression. CONCLUSIONS: This meta-analysis indicates that PBL pedagogy is superior to traditional lecture-based teaching in Chinese pharmacy education. PBL methods could be an optional, supplementary method of pharmaceutical teaching in China. However, Chinese pharmacy colleges and universities should revise PBL curricula according to their own needs, which would maximize the effectiveness of PBL.

Silencing of Paralemmin-3 Protects Mice from lipopolysaccharide-induced acute lung injury.

Excessive inflammatory response induced by lipopolysaccharide (LPS) plays a critical role in the development of acute lung injury (ALI). Paralemmin-3 (PALM3) is a novel protein that can modulate LPS-stimulated inflammatory responses in alveolar epithelial A549 cells. However, it remains unclear whether it is involved in the progression of ALI in vivo. Therefore, we studied the role of PALM3 in the pathogenesis of ALI induced by LPS. ALI was induced by LPS peritoneal injection in C57BL/6J mice. Lentivirus-mediated small interfering RNA (siRNA) targeting the mouse PALM3 gene and a negative control siRNA were intranasally administered to the mice. We found that the expression of PALM3 was up-regulated in the lung tissues obtained from the mouse model of LPS-induced ALI. The LPS-evoked inflammatory response (neutrophils and the concentrations of proinflammatory cytokines [IL-6, IL-1ß, TNF-α, MIP-2] in the bronchoalveolar lavage fluid [BALF]), histologic lung injury (lung injury score), permeability of the alveolar capillary barrier (lung wet/dry weight ratio and BALF protein concentration) and mortality rates were attenuated in the PALM3 siRNA-treated mice. These results indicate that PALM3 contributes to the development of ALI in mice challenged with LPS. Inhibiting PALM3 through the intranasal application of specific siRNA protected against LPS-induced ALI.

Ezrin Regulating the Cytoskeleton Remodeling is Required for Hypoxia-Induced Myofibroblast Proliferation and Migration.

BACKGROUND: Hypoxia pulmonary arterial hypertension (HPAH) is a disease of the small vessels characterized by sustained vasoconstriction, thickening of arterial walls, vascular remodeling, and progressive increase in pulmonary vascular resistance, thus leading to right heart failure and finally death. Recent evidence demonstrated that massive pulmonary artery smooth muscle-like cells (PASMLCs) accumulating in the intima might also be developed from the differentiation of pulmonary myofibroblast (PMF) of tunica media. And PMF appeared the phenomenon of the cytoskeleton remodeling. So, it would be important in the clarification of the pivotal factors controlling this cytoskeleton structure change. METHODS: PMFs were cultured from the normal rats and then divided into three groups and incubated by normal or hypoxic conditions respectively. mRNA level was evaluated by real-time reverse transcription polymerase chain reaction, and protein expression was detected by western blot. Cell proliferation was determined by the MTT and thymidine incorporation assay. RESULTS: Here, we report that the hypoxia increased the expression levels of ezrin mRNA and protein in PMFs, which might explain that the expression of cytoskeletal proteins (destrin, a1-actin, and a1-tubulin) in PMFs was significantly induced by hypoxia. After inhibiting ezrin in PMFs by siRNA transfection, we found the over-expression of cytoskeletal proteins induced by hypoxia was significantly suppressed at all time-points. Additionally, we found that hypoxia or over-expression of ezrin through adenovirus-mediated ezrin gene transfection significantly increases the proliferation and migration of PMFs, and which could be inverted by the transfection of siRNA. CONCLUSION: These findings suggest that ezrin regulating of aberrant dysregulation of cytoskeletal proteins may be the major cause of PMFs' proliferation and migration under the condition of hypoxia and may, therefore, play a fundamental role in the accumulation of PASMLCs of HPAH.