Correlation between the triglyceride-glucose index and arterial stiffness in Japanese individuals with normoglycaemia: a cross-sectional study.

BACKGROUND: The association between the triglyceride-glucose (TyG) index and arterial stiffness in individuals with normoglycaemia remains unclear. We aimed to evaluate the relationship between the TyG index and arterial stiffness in Japanese individuals with normoglycaemia, providing additional evidence for predicting early arterial stiffness. METHODS: This study included 15,453 adults who participated in the NAGALA Physical Examination Project of the Murakami Memorial Hospital in Gifu, Japan, from 2004 to 2015. Data on clinical demographic characteristics and serum biomarker levels were collected. The TyG index was calculated from the logarithmic transformation of fasting triglycerides multiplied by fasting glucose, and arterial stiffness was measured using the estimated pulse wave velocity calculated based on age and mean blood pressure. The association between the TyG index and arterial stiffness was analysed using a logistic regression model. RESULTS: The prevalence of arterial stiffness was 3.2% (500/15,453). After adjusting for all covariates, the TyG index was positively associated with arterial stiffness as a continuous variable (adjusted odds ratio (OR) = 1.86; 95% Confidence Interval = 1.45-2.39; P<0.001). Using the quartile as the cutoff point, a regression analysis was performed for arterial stiffness when the TyG index was converted into a categorical variable. After adjusting for all covariates, the OR showed an upward trend; the trend test was P<0.001. Subgroup analysis revealed a positive association between the TyG index and arterial stiffness in Japanese individuals with normoglycaemia and different characteristics. CONCLUSION: The TyG index in Japanese individuals with normoglycaemia is significantly correlated with arterial stiffness, and the TyG index may be a predictor of early arterial stiffness.

PARP1 modulates METTL3 promoter chromatin accessibility and associated LPAR5 RNA m6A methylation to control cancer cell radiosensitivity.

Chromatin remodeling and N6-methyladenosine (m6A) modification are two critical layers in controlling gene expression and DNA damage signaling in most eukaryotic bioprocesses. Here, we report that poly(ADP-ribose) polymerase 1 (PARP1) controls the chromatin accessibility of METTL3 to regulate its transcription and subsequent m6A methylation of poly(A)+ RNA in response to DNA damage induced by radiation. The transcription factors nuclear factor I-C (NFIC) and TATA binding protein (TBP) are dependent on PARP1 to access the METTL3 promoter to activate METTL3 transcription. Upon irradiation or PARP1 inhibitor treatment, PARP1 disassociated from METTL3 promoter chromatin, which resulted in attenuated accessibility of NFIC and TBP and, consequently, suppressed METTL3 expression and RNA m6A methylation. Lysophosphatidic Acid Receptor 5 (LPAR5) mRNA was identified as a target of METTL3, and m6A methylation was located at A1881. The level of m6A methylation of LPAR5 significantly decreased, along with METTL3 depression, in cells after irradiation or PARP1 inhibition. Mutation of the LPAR5 A1881 locus in its 3' UTR results in loss of m6A methylation and, consequently, decreased stability of LPAR5 mRNA. METTL3-targeted small-molecule inhibitors depress murine xenograft tumor growth and exhibit a synergistic effect with radiotherapy in vivo. These findings advance our comprehensive understanding of PARP-related biological roles, which may have implications for developing valuable therapeutic strategies for PARP1 inhibitors in oncology.

Association between relative muscle strength and hypertension in middle-aged and older Chinese adults.

BACKGROUND: The association between muscle defects and hypertension is well-established. However, the absence of pertinent and uncomplicated clinical indicators presents a challenge. Relative muscle strength (RMS) may offer a viable indicator. This study aimed to explore the association between RMS and hypertension. METHODS: A total of 12,720 individuals aged ≥ 45 years from the 2011 wave of the China Health and Retirement Longitudinal Study (CHARLS) were included. Grip strength was recorded and appendicular skeletal muscle mass (ASM) was estimated using a validated mathematical formula. The RMS was calculated as the ratio of grip strength to ASM. Hypertension was determined based on previous diagnosis, history of hypertension medication use, and current blood pressure. Logistic regression models were employed to investigate the relationship between RMS and hypertension. RESULTS: The prevalence of hypertension was 41.7% (5,307/12,720 patients). RMS was negatively correlated with hypertension with an OR (95% CI) of 0.68 (0.59-0.79) for males, 0.81 (0.73-0.90) for females, and 0.78 (0.72-0.85) for the entire population after adjusting for related covariates including age, education, marital history, smoking history, drinking history, diabetes, hyperlipidemia, and obesity. The trend test showed a linear association among males, females, or the entire population. Stratified analysis showed a consistent negative correlation between RMS and hypertension. CONCLUSIONS: Higher RMS is an independent protective factor against hypertension and efforts to promote RMS may be beneficial for the prevention and management of hypertension.

FAK-targeting PROTAC demonstrates enhanced antitumor activity against KRAS mutant non-small cell lung cancer.

Focal adhesion kinase (FAK) has been established as a promising therapeutic target for KRAS mutant non-small cell lung cancer (NSCLC). However, phase II clinical trials of a FAK inhibitor (Defactinib) have only shown modest antitumor activity. To address this challenge, here we report the use of a FAK-targeting proteolysis targeting chimera (D-PROTAC) to treat KRAS mutant NSCLC. We validated that D-PROTAC could efficiently eliminate FAK protein via the ubiquitin-proteasome pathway in KRAS mutant NSCLC A427 cells, causing over 90% degradation at 800 nM. After comparing both in vitro and in vivo therapeutic efficacies, we demonstrated that D-PRTOAC outperformed Defactinib in inhibiting tumor growth. Specifically, D-PROTAC at 800 nM reduced cell viability, migration, and invasion by ∼80%. Furthermore, a ∼85% suppression of tumor growth was elicited by D-PROTAC when intratumorally administrated at 10 mg/kg in subcutaneous A427-bearing mice. These results thus demonstrate for the first time that PROTACs may serve as promising therapeutic agents for the intractable NSCLC harboring KRAS mutations.

Photoelectrochemical determination of cardiac troponin I based on rod-like g-C3N5@MnO2 heterostructure.

Rod-like graphite carbon nitride@MnO2 (R-g-C3N5@MnO2) heterostructure was prepared by in situ self-anchored growth of MnO2 nanosheet on the surface of R-g-C3N5. The synthesized R-g-C3N5@MnO2 heterostructure as photoactive material exhibited excellent photoelectrochemical (PEC) performance, and the prepared heterostructure-aptamer probe displayed sensitive PEC response to cTnI. Therefore, the PEC method was developed to detect cTnI based on the R-g-C3N5@MnO2 heterostructure. It was found that the linear response to cTnI was in the range 0.001-30 ng/mL under optimized conditions, and the detection limit of the proposed sensor was 0.3 pg/mL. The PEC method displays stable photocurrent response up to 8 cycles and exhibited outstanding selectivity and sensitivity. The PEC method was successfully applied to detect cTnI in serum samples. The recoveries of cTnI detection in serums reach 95.5-104%, and the relative standard deviations range from 3.20 to 4.45%.

Stability, Antioxidant Activity and Intestinal Permeation of Oleuropein Inclusion Complexes with Beta-Cyclodextrin and Hydroxypropyl-Beta-Cyclodextrin.

Compared to beta-cyclodextrins (beta-CD), hydroxypropyl-beta-cyclodextrins (HP-beta-CD) are a more popular material used to prepare inclusion complexes due to their superior solubility and intestinal absorption. In this study, oleuropein (OL) inclusion complexes with beta-CD (beta-CD:OL) and HP-beta-CD (HP-beta-CD:OL) were prepared and the formation of inclusion complexes was validated by IR, PXRD, and DSC. A phase solubility test showed that the lgK (25 °C) and binding energy of beta-CD:OL and HP-beta-CD:OL was 2.32 versus 1.98, and −6.1 versus −24.66 KJ/mol, respectively. Beta-CD:OL exhibited a more powerful effect than HP-beta-CD:OL in protecting OL from degradation upon exposure to light, high temperature and high humidity. Molecular docking, peak intensity of carbonyls in IR, and ferric reducing power revealed that beta-CD:OL formed more hydrogen bonds with the unstable groups of OL. Both inclusion complexes significantly enhanced the solubility, intestinal permeation and antioxidant activity of OL (p < 0.05). Though HP-beta-CD:OL had higher solubility and intestinal absorption over beta-CD:OL, the difference was not significant (p > 0.05). The study implies that lower binding energy is not always associated with the higher stability of a complex. Beta-CD can protect a multiple-hydroxyl compound more efficiently than HP-beta-CD with the intestinal permeation comparable to HP-beta-CD complex.

Optical coherence tomography angiography characteristics and correlated factors with visual acuity in retinal arterial occlusion.

PURPOSE: To reveal the characteristics of vascular changes in retinal arterial occlusion (RAO) using optical coherence tomography angiography (OCTA) and determine the correlated factors with best-corrected visual acuity (BCVA). METHODS: This retrospective study recruited 54 RAO patients and 27 healthy individuals. Ophthalmic examinations including BCVA and OCTA were performed in all the patients and individuals. The OCTA outcomes were analyzed using SPSS software, and the characteristics of vascular changes and BCVA-related factors were summarized. RESULTS: The vessel density in all areas except fovea of both superficial capillary plexus (SCP) and deep capillary plexus (DCP) was significantly reduced in RAO eyes compared with the fellow eyes and normal control eyes (P < 0.05). The vessel density of DCP in all areas except fovea was significantly reduced in the fellow eyes compared with that in the normal control eyes as well (P < 0.05). The retinal thickness in fovea was significantly increased in RAO eyes compared with that in the fellow eyes and normal control eyes (P < 0.05), without any differences in other areas between the RAO eyes and the other two groups (P > 0.05). The retinal thickness in whole area and retinal thickness in fovea were correlated with BCVA, respectively (whole area: r = 0.295, P = 0.030; fovea: r = 0.322, P = 0.018). CONCLUSIONS: OCTA is a fast, noninvasive, and effective examination means for RAO that can display the vascular density and retinal thickness quantitatively and distinctly. RAO patients had reduced vascular density in both eyes and increased foveal retinal thickness in RAO eyes, showing a correlation with BCVA.

Airway epithelial integrin ß4-deficiency exacerbates lipopolysaccharide-induced acute lung injury.

Airway epithelial cells, the first barrier of the respiratory tract, play an indispensable role in innate immunity. Integrin ß4 (ITGB4) is a structural adhesion molecule that is involved in the pathological progression of acute inflammatory diseases and is downregulated in asthmatic patients. Research has shown that endothelial ITGB4 has proinflammatory properties in acute lung injury (ALI). However, the role of epithelial ITGB4 in a murine ALI model is still unknown. This study investigated the role of ITGB4 in lipopolysaccharide (LPS)-induced ALI. We found that ITGB4 in the airway epithelium had remarkably increased after the introduction of LPS in vivo and in vitro. Then, we constructed airway epithelial cell-specific ITGB4 knockout (ITGB4-/- ) mice to study its role in ALI. At a time point of 12 h after the tracheal injection of LPS, ITGB4-/- mice showed increased macrophages (mainly M1-type macrophages) and neutrophil infiltration into the lungs; inflammation-related proteins including interleukin (IL)-6, tumor necrosis factor, and IL-17A were significantly elevated compared to their levels in ITGB4+/+ mice. Furthermore, we investigated the role of ITGB4 in the anti-inflammatory response. Intriguingly, in the ITGB4-/- + LPS group, we found significantly reduced expression of anti-inflammatory factors, including IL-10 messenger RNA (mRNA) and ARG-1 mRNA. We also observed that monocyte chemotactic protein (MCP-1) increased significantly both in vivo and in vitro. Airway epithelium activates macrophages, most likely driven by MCP-1, which we confirmed in the coculture of epithelia and macrophages. These phenomena indicate that ITGB4 in airway epithelial cells plays an important role in the process of inflammation and activation of macrophages in ALI. Overall, these data demonstrated a novel link between airway epithelial ITGB4 and the inflammatory response in LPS-induced ALI.

Development and validation of nomograms to intraoperatively predict metastatic patterns in regional lymph nodes in patients diagnosed with esophageal cancer.

BACKGROUND: An accurate intraoperative prediction of lymph node metastatic risk can help surgeons in choosing precise surgical procedures. We aimed to develop and validate nomograms to intraoperatively predict patterns of regional lymph node (LN) metastasis in patients with esophageal cancer. METHODS: The prediction model was developed in a training cohort consisting of 487 patients diagnosed with esophageal cancer who underwent esophagectomy with complete LN dissection from January 2016 to December 2016. Univariate and multivariable logistic regression were used to identify independent risk factors that were incorporated into a prediction model and used to construct a nomogram. Contrast-enhanced computed tomography reported LN status and was an important comparative factor of clinical usefulness in a validation cohort. Nomogram performance was assessed in terms of calibration, discrimination, and clinical usefulness. An independent validation cohort comprised 206 consecutive patients from January 2017 to December 2017. RESULTS: Univariate analysis and multivariable logistic regression revealed three independent predictors of metastatic regional LNs, three independent predictors of continuous regional LNs, and two independent predictors of skipping regional LNs. Independent predictors were used to build three individualized prediction nomograms. The models showed good calibration and discrimination, with area under the curve (AUC) values of 0.737, 0.738, and 0.707. Application of the nomogram in the validation cohort yielded good calibration and discrimination, with AUC values of 0.728, 0.668, and 0.657. Decision curve analysis demonstrated that the three nomograms were clinically useful in the validation cohort. CONCLUSION: This study presents three nomograms that incorporate clinicopathologic factors, which can be used to facilitate the intraoperative prediction of metastatic regional LN patterns in patients with esophageal cancer.

Recent advances in separation applications of polymerized high internal phase emulsions.

Polymerized high internal phase emulsions as highly porous adsorption materials have received increasing attention and wide applications in separation science in recent years due to their remarkable merits such as highly interconnected porosity, high permeability, good thermal and chemical stability, and tailorable chemistry. In this review, we attempt to introduce some strategies to utilize polymerized high internal phase emulsions for separation science, and highlight the recent advances made in the applications of polymerized high internal phase emulsions for diverse separation of small organic molecules, carbon dioxide, metal ions, proteins, and other interesting targets. Potential challenges and future perspectives for polymerized high internal phase emulsion research in the field of separation science are also speculated at the end of this review.

Respiratory syncytial virus persistent infection causes acquired CFTR dysfunction in human bronchial epithelial cells. / å‘¼å¸é“åˆèƒžç— æ¯’æŒç»­æ„ŸæŸ“å¯¼è‡´äººæ”¯æ°”ç®¡ä¸Šçš®ç»†èƒžå›Šæ€§çº¤ç»´åŒ–ç©¿è†œä¼ å¯¼è°ƒèŠ‚è›‹ç™½åŠŸèƒ½éšœç¢.

OBJECTIVES: Many studies have shown that respiratory syncytial virus persistent infection may be the main cause of chronic respiratory pathology.However, the mechanism is unclear. Cystic fibrosis transmembrane conduction regulator (CFTR) is an apical membrane chloride channel, which is very important for the regulation of epithelial fluid, chloride ion, and bicarbonate transport. CFTR dysfunction will lead to changes in bronchial secretions and impair mucus clearance, which is related to airway inflammation. In our previous study, we observed the down-regulation of CFTR in airway epithelial cells in respiratory syncytial virus (RSV) infected mouse model. In this study, we further investigated the expression and function of CFTR by constructing an airway epithelial cell model of RSV persistent infection. METHODS: 16HBE14o- cells were infected with RSV at 0.01 multiplicity of infection (MOI). The expression of CFTR was detected by real-time RT-PCR, immunofluorescence, and Western blotting. The intracellular chloride concentration was measured by N-(ethoxycarbonylmethyl)-6-methoxyquinolium bromide (MQAE) and the chloride current was measured by whole-cell patch clamp recording. RESULTS: 16HBE14o- cells infected with RSV were survived to successive passages of the third generation (G3), while the expression and function of CFTR was progressively decreased upon RSV infection from the first generation (G1) to G3. Exposure of 16HBE14o- cells to RSV led to the gradual increase of TGF-ß1 as well as phosphorylation of Smad2 following progressive RSV infection. Disruption of TGF-ß1 signaling by SB431542 prevented Smad2 phosphorylation and rescued the expression of CFTR. CONCLUSIONS: RSV infection can lead to defective CFTR function in airway epithelial cells, which may be mediated via activation of TGF-ß1 signaling pathway.

Increased intracellular Cl- concentration by activating FAK promotes airway epithelial BEAS-2B cells proliferation and wound healing.

An increase in intracellular Cl- concentration ([Cl-]i) may be a general response of airway epithelial cells to various stimuli and may participate in some basic cellular functions. However, whether the basic functional activities of cells, such as proliferation and wound healing, are related to Cl- activities remains unclear. This study aimed to investigate the effects and potential mechanisms of [Cl-]i on the proliferation and wound healing ability of airway epithelial BEAS-2B cells. BEAS-2B cells were treated with four Cl- channel inhibitors (T16Ainh-A01, CFTRinh-172, CaCCinh-A01, and IAA-94), and the Cl- fluorescence probe N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide was used. Results showed that all Cl- channel inhibitors could increase [Cl-]i in BEAS-2B cells. The increased [Cl-]i induced by Cl- channel inhibitors or clamping [Cl-]i at high levels enhanced the phosphorylation of focal adhesion kinase (FAK) and subsequently promoted the proliferation and wound healing ability of BEAS-2B cells. By contrast, the FAK inhibitor PF573228 abrogated these effects induced by the increased [Cl-]i. FAK also activated the PI3K/AKT signaling pathway. In conclusion, increased [Cl-]i promotes the proliferation and wound healing ability of BEAS-2B cells by activating FAK to activate the PI3K/AKT signaling pathway. Intracellular Cl- may act as a signaling molecule to regulate the proliferation and wound healing ability of airway epithelial cells.

Epigenetic regulation of TIMP1 expression by 8-oxoguanine DNA glycosylase-1 binding to DNA:RNA hybrid.

8-Oxoguanine DNA glycosylase-1 (OGG1)-initiated base excision repair pathway is primarily responsible for 7, 8-dihydro-8-oxoguanine (8-oxoG) removal from DNA. Recent studies, however, have shown that 8-oxoG in gene regulatory elements may serve as an epigenetic mark, and OGG1 has distinct functions in modulating gene expression. Genome-wide mapping of oxidative stress-induced OGG1 enrichment within introns was documented, but its significance has not yet been fully characterized. Here, we explored whether OGG1 recruited to intron 1 of tissue inhibitor of metalloproteinase-1 (TIMP1) gene and modulated its expression. Using chromatin and DNA:RNA hybrid immunoprecipitation assays, we report recruitment of OGG1 to the DNA:RNA hybrid in intron 1, where it increases nascent RNA but lowers mRNA levels in O3-exposed human airway epithelial cells and mouse lungs. Decrease in TIMP1 expression is alleviated by antioxidant administration, small interfering RNA depletion, or inhibition of OGG1 binding to its genomic substrate. In vitro studies revealed direct interaction between OGG1 and 8-oxoG containing DNA:RNA hybrid, without excision of its substrate. Inhibition of OGG1 binding to DNA:RNA hybrid translated into an increase in TIMP1 expression and a decrease in oxidant-induced lung inflammatory responses as well as airway remodeling. Data documented here reveal a novel molecular link between OGG1 at damaged sites and transcription dynamics that may contribute to oxidative stress-induced cellular and tissue responses.-Pan, L., Wang, H., Luo, J., Zeng, J., Pi, J., Liu, H., Liu, C., Ba, X., Qu, X., Xiang, Y., Boldogh, I., Qin, X. Epigenetic regulation of TIMP1 expression by 8-oxoguanine DNA glycosylase-1 binding to DNA:RNA hybrid.

Effect of the mixture of mulberry leaf powder and KGM flour on promoting calcium absorption and bone mineral density in vivo.

BACKGROUND: In this paper, mulberry leaf powder (MLP) and konjac glucomannan (KGM) flour were used as raw materials, and animal experiments were designed to evaluate the effects of a mixture of MLP and KGM on bone density. The femoral bone microstructure of mice and pathological changes were observed by using micro-computed tomography) and haematoxylin and eosin (HE) staining methods, respectively. A three-point bending test was used to determine the biomechanical properties of the femur. RESULTS: Results indicated that the calcium content of MLP was high, reaching 16 148.5 mg kg-1 , and the total proportion of water-soluble calcium, calcium pectinate, and calcium carbonate accounted for about 60% of the total calcium content. Serum alkaline phosphatase (AKP) activity was significantly lower, and serum calcium content was significantly higher (P < 0.05), in the MLP + KGM group (KM) than in the low-calcium control group, whereas no significant difference (P > 0.05) was found for serum phosphorus content. KM had a longer femur length, a higher bone mineral density (BMD) (P > 0.05), and significantly greater femur diameter, dry weight, index and bone calcium content (P < 0.05). However, these parameters were not significantly different from those of the calcium carbonate control group (P > 0.05). CONCLUSION: The results indicate that the MLP/KGM mixture can reduce the high rate of bone turnover and the corresponding loss of bone mass caused by calcium deficiency and is thus effective in enhancing bone density. © 2019 Society of Chemical Industry.

Genome-wide copy number variation analysis identified ANO1 as a novel oncogene and prognostic biomarker in esophageal squamous cell cancer.

Copy number variations (CNVs) represent one of the most common genomic alterations. This study aimed to evaluate the roles of genes within highly aberrant genome regions in the prognosis of esophageal squamous cell cancer (ESCC). Exome sequencing data from 81 paired ESCC tissues were used to screen aberrant genomic regions. The associations between CNVs and gene expression were evaluated using gene expression data from the same individuals. Then, an RNA expression array profile from 119 ESCC samples was adopted for differential gene expression and prognostic analyses. Two independent ESCC cohorts with 315 subjects were further recruited to validate the prognostic value using immunohistochemistry tests. Finally, we explored the potential mechanism of our identified novel oncogene in ESCC. In total, 2003 genes with CNVs were observed, of which 76 genes showed recurrent CNVs in more than three samples. Among them, 32 genes were aberrantly expressed in ESCC tumor tissues and statistically correlated with CNVs. Strikingly, 4 (CTTN, SHANK2, INPPL1 and ANO1) of the 32 genes were significantly associated with the prognosis of ESCC patients. Patients with a positive expression of ANO1 had a poorer prognosis than ANO1 negative patients (overall survival rate: 42.91% versus 26.22% for ANO1-/+ samples, P < 0.001). Functionally, ANO1 promoted ESCC cell proliferation, migration and invasion by activating transforming growth factor-ß pathway. Knockdown of ANO1 significantly inhibited tumor progression in vitro and in vivo. In conclusion, ANO1 is a novel oncogene in ESCC and may serve as a prognostic biomarker for ESCC.

The role of pretreatment prognostic nutritional index in esophageal cancer: A meta-analysis.

Clinicopathological characteristics and prognosis of esophageal cancer (EC) patients with decreased prognostic nutritional index (PNI) have not been well investigated. So, we conducted this meta-analysis. We performed comprehensive research in PubMed, Embase, and Cochrane databases. The effect size was hazard ratio (HR) with 95% confidence interval (CI) for overall survival (OS) and cancer-specific survival (CSS). The pooled odds ratio (OR) with 95% CI were used to assess the association between PNI and clinicopathological features. A total of 3,425 EC patients were included in the present meta-analysis. Male patients, advanced age, higher tumor stage, and lymph node metastases were associated with reduced PNI level (OR = 1.40, 95% CI: 1.10-1.79; OR = 1.35, 95% CI: 1.10-1.66; OR = 2.37, 95% CI: 1.91-2.94; OR = 1.63, 95% CI: 1.04-2.56). And, the EC patients with decreased PNI held a worse OS and CSS compared with those who carried a higher PNI (HR = 1.29, 95% CI: 1.10-1.50; HR = 2.53, 95% CI: 1.15-5.57). This meta-analysis demonstrated PNI level was associated with tumor stage and lymph nodes metastases and was an independent prognostic factor in EC.

Clinicopathologic analysis of lymph node status in superficial esophageal squamous carcinoma.

BACKGROUND: Endoscopic approaches are gradually considered as a reliable treatment of intramucosal esophageal squamous carcinoma. However, endoscopic resection (ER) is limited by the potential lymph node metastasis (LNM) at various depths of mucosal and submucosal invasion. METHODS: We conducted a retrospective review of 498 patients with pT1 superficial esophageal squamous carcinoma (SESC) who underwent surgical resection from January 2008 to August 2015. Pathological characteristics of tumors including location, size, appearance, differentiation, invasion depth, and nodal status were reviewed, and risk factors were analyzed. RESULTS: LNM was found in 0.0, 2.7, 6.3, 18.2, 15.9, and 34.3 % of the m1, m2, m3, sm1, sm2, and sm3 lesions, respectively. Univariate logistic regression identified the presence of the tumor size > 2 cm (p < 0.05), the presence of the poor tumor differentiation (p < 0.05), and the depth of tumor invasion (p < 0.05) and angiolymphatic invasion (p < 0.05) to be the important risk factors associated with the prevalence of tumor-positive lymph nodes. These findings were confirmed in multivariate logistic regression as independent predictors for LNM. CONCLUSIONS: ER is considered as a reliable treatment of m1 to m2 lesions. Radical surgical resection (SR) is the standard and irreplaceable therapy of sm1 to sm3 lesions. Patients with m3 lesions should undergo ER as the initial procedure for diagnosis. And this treatment is supported only by a successful description of the tumor's characteristics, including (1) only muscularis mucosa invasion and without invasion of the resection margins and (2) without any risk predictors for LNM. Otherwise, SR is recommended.

Sunitinib, a Small-Molecule Kinase Inhibitor, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice.

Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease, characterized by excessive accumulation of fibroblasts, extensive deposition of extracellular matrix, and destruction of alveolar architecture. IPF is associated with an epithelial-dependent fibroblast-activated process, termed the epithelial-to-mesenchymal transition (EMT). However, there is still a lack of strategies to target EMT for the treatment of IPF. Sunitinib, a small-molecule multi-targeted tyrosine kinase inhibitor, targets multiple kinases that may play an important role in developing pulmonary fibrosis. Here, we explored the therapeutic potential of sunitinib using a mouse model of pulmonary fibrosis. Mice received intratracheal instillation of bleomycin (BLM). Then, the mice were intragastrically administrated with sunitinib or normal saline until the end of the experiment. Distinguished destruction of pulmonary architecture, conspicuous proliferation of fibroblasts and extensive deposition of collagen fibers were found in BLM mice. Sunitinib attenuated the pulmonary fibrosis and inhibited the accumulation of fibroblasts in the lung of BLM mice. To investigate if the inhibition of fibroblast accumulation in the lung by sunitinib was associated with EMT, we used human bronchial epithelial cells (HBEs) and W138 human lung fibroblasts. Sunitinib suppressed the degree of EMT induced by TGF-ß, a profibrotic factor, in HBEs and the proliferation of WI38 fibroblasts. Moreover, sunitinib reduced the degree of phosphorylation of serine residues on Smad2/3 that was induced by TGF-ß in HBEs. As EMT and accumulation of fibroblasts are critical for the development of pulmonary fibrosis, targeting multiple pro-fibrosis signaling pathways with sunitinib may be a novel strategy to treat pulmonary fibrosis.

Effect of Ganoderma lucidum spores intervention on glucose and lipid metabolism gene expression profiles in type 2 diabetic rats.

BACKGROUND: The fruiting body of Ganoderma lucidum has been used as a traditional herbal medicine for many years. However, to the date, there is no detailed study for describing the effect of G. lucidum spores on oxidative stress, blood glucose level and lipid compositions in animal models of type 2 diabetic rats, in particular the effect on the gene expression profiles associated with glucose and lipid metabolisms. METHODS: G. lucidum spores powder (GLSP) with a shell-broken rate >99.9 % was used. Adult male Sprague-Dawley rats were randomly divided into three groups (n = 8/group). Group 1: Normal control, normal rats with ordinary feed; Group 2: Model control, diabetic rats with ordinary feed without intervention; Group 3: GLSP, diabetic rats with ordinary feed, an intervention group utilizing GLSP of 1 g per day by oral gavages for 4 consecutive weeks. Type 2 diabetic rats were obtained by streptozocin (STZ) injection. The changes in the levels of glucose, triglycerides, total cholesterol and HDL-cholesterol in blood samples were analyzed after GLSP intervention. Meanwhile, gene expressions associated with the possible molecular mechanism of GLSP regulation were also investigated using a quantitative RT-PCR. RESULTS: The reduction of blood glucose level occurred within the first 2 weeks of GLSP intervention and the lipid synthesis in the diabetic rats of GLSP group was significantly decreased at 4 weeks compared to the model control group. Furthermore, it was also found that GLSP intervention greatly attenuated the level of oxidative stress in the diabetic rats. Quantitative RT-PCR analysis showed up-regulation of lipid metabolism related genes (Acox1, ACC, Insig-1 and Insig-2) and glycogen synthesis related genes (GS2 and GYG1) in GLSP group compared to model control group. Additionally, there were no significant changes in the expression of other genes, such as SREBP-1, Acly, Fas, Fads1, Gpam, Dgat1, PEPCK and G6PC1. CONCLUSION: This study might indicate that GLSP consumption could provide a beneficial effect in terms of lowering the blood glucose levels by promoting glycogen synthesis and inhibiting gluconeogenesis. Meanwhile, GLSP treatment was also associated with the improvement of blood lipid compositions through the regulation of cholesterol homeostasis in the type 2 diabetic rats.

Depletion of NUAK2 blocks the stemness and angiogenesis and facilitates senescence of lung adenocarcinoma cells via enhancing ferroptosis.

BACKGROUND: NUAK family kinase 2 (NUAK2) has been identified as an important mediator for tumor progression in multiple malignancies. Nevertheless, its role in lung adenocarcinoma (LUAD) remains unclear. METHODS: Bioinformatic analysis was performed to assess the expression and prognosis of NUAK2 in patients with LUAD. The NUAK2 expression was measured in multiple LUAD cell lines, and the loss-of-function experiment was conducted. Cell proliferation ability was assessed using CCK-8 and colony formation assays. Spheroid formation, alkaline phosphatase (AP) staining, tube formation and SA-ß-gal staining assays were performed to examine stemness, angiogenesis and senescence. Lipid peroxidase was assessed by TBARS production and lipid ROS. Western blot was used to detect critical proteins. In addition, A549 cells were treated with ferroptosis inhibitor ferrostatin-1 (Fer-1) for a rescue assay. Finally, A549 cells were subcutaneously injected into the right flank of mice to establish LUAD-bearing mouse model, and the tumor weight and size were detected. RESULTS: NUAK2 was upregulated in patients with LUAD and LUAD cell lines. NUAK2 depletion inhibited cell viability, colonies, tumor spheres and decreased Oct4 and Nanog expression, confirming NUAK2 depletion inhibited proliferation and stemness of A549 cells. Meanwhile, NUAK2 depletion blocked angiogenesis via reducing formed tubes and VEGFR1/2 expression, and promoted senescence of A549 cells by elevating SA-ß-gal-positive cells and p16, p21 and p53 expression. Moreover, NUAK2 depletion elevated lipid ROS, TBARS production and Fe2+ level, demonstrating that NUAK2 depletion could trigger ferroptosis in A549 cells. Furthermore, the rescue experiments revealed that the impacts of NUAK2 depletion on malignant behaviors in A549 cells were partly weakened by additional Fer-1 treatment. Finally, in vivo experiments demonstrated that NUAK2 knockdown greatly inhibited tumor growth in LUAD-bearing mice. CONCLUSION: In summary, NUAK2 depletion impeded oncogenic phenotypes of A549 cells partly via triggering ferroptosis, suggesting NUAK2 as a novel target for treating LUAD.