WNT ligands in non-small cell lung cancer: from pathogenesis to clinical practice.

Non-small cell lung cancer (NSCLC) is the malignant tumor with the highest morbidity and leading cause of death worldwide, whereas its pathogenesis has not been fully elucidated. Although mutations in some crucial genes in WNT pathways such as ß-catenin and APC are not common in NSCLC, the abnormal signal transduction of WNT pathways is still closely related to the occurrence and progression of NSCLC. WNT ligands (WNTs) are a class of secreted glycoproteins that activate WNT pathways through binding to their receptors and play important regulatory roles in embryonic development, cell differentiation, and tissue regeneration. Therefore, the abnormal expression or dysfunction of WNTs undoubtedly affects WNT pathways and thus participates in the pathogenesis of diseases. There are 19 members of human WNTs, WNT1, WNT2, WNT2b, WNT3, WNT3a, WNT4, WNT5a, WNT5b, WNT6, WNT7a, WNT7b, WNT8a, WNT8b, WNT9a, WNT9b, WNT10a, WNT10b, WNT11 and WNT16. The expression levels of WNTs, binding receptors, and activated WNT pathways are diverse in different tissue types, which endows the complexity of WNT pathways and multifarious biological effects. Although abundant studies have reported the role of WNTs in the pathogenesis of NSCLC, it still needs further study as therapeutic targets for lung cancer. This review will systematically summarize current research on human WNTs in NSCLC, from molecular pathogenesis to potential clinical practice.

Health-Related Quality of Life and Its Related Factors in Survivors of Stroke in Rural China: A Large-Scale Cross-Sectional Study.

Background: Stroke is a major health threat and the leading cause of mortality and disability in China. The aims of this study were to identify the possible influencing factors of health-related quality of life (HRQoL) and its domain-specific contents in stroke patients in rural areas in China. Methods: A total of 1,709 stroke patients aged 36-79 years from the baseline data of Henan Rural Cohort study (n = 39,259) were included in the cross-sectional study. The Chinese version of the European Quality of Life Five Dimension (including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) Five Level Scale (EQ-5D-5L) and visual analog scale (VAS) were used to evaluate HRQoL in stroke patients. Tobit regression models, generalized linear models and binary logistic regression models were constructed to determine potential influencing factors of the EQ-5D utility index, as well as influencing factors of each domain and VAS score. Results: The mean utility index and VAS scores of stroke patients were 0.885 (SD, 0.204), and 68.39 (SD, 17.31), respectively. Pain/discomfort (PD, 35.2%) and mobility (MO, 30.4%) were the most frequently reported issues. Regression models revealed that illiterate; a low monthly income; low physical activity intensity; and diabetes, anxiety, depression, or poor sleep quality were significantly associated with lower utility index and VAS scores among stroke patients. In addition, patients with stroke who were older, female, drinking, smoking, and consuming a high-fat diet, had a higher BMI, and lived with a stroke for a longer time, were also significantly associated with different dimensions of the EQ-5D. Conclusion: Patients with stroke in rural areas in China had a low HRQoL. Factors associated with the EQ-5D utility index as well as each domain and VAS score, need to be considered by health providers in rural areas. Patients with stroke in rural areas need to be included in national basic public medical services and managed systematically by medical institutions.

Design, synthesis and evaluation of 3-phenoxypyrazine-2-carboxamide derivatives as potent TGR5 agonists.

TGR5 is emerging as an important and promising target for the treatment of non-alcoholic steatohepatitis, type 2 diabetes mellitus (T2DM), and obesity. A series of novel 3-phenoxypyrazine-2-carboxamide derivatives were designed, synthesized and evaluated in vitro and in vivo. The most potent compounds 18g and 18k exhibited excellent hTGR5 agonist activity, which was superior to those of the reference drug INT-777. In addition, compound 18k could significantly reduce blood glucose levels in C57 BL/6 mice and stimulate GLP-1 secretion in NCI-H716 cells and C57 BL/6 mice.

Health-related quality of life and its related factors in coronary heart disease patients: results from the Henan Rural Cohort study.

The aims were to identify the possible influencing factors of health-related quality of life (HRQoL) and its domain-specific scores in patients with coronary heart disease (CHD). A total of 1247 patients with CHD from the Henan Rural Cohort Study (n = 39,259) were included in this study. The Chinese version of the European Quality of Life Five Dimension Five level scale (EQ-5D-5L) and Visual Analogue Scale (VAS) were used to evaluate HRQoL in patients with CHD. Tobit regression, generalized linear models and binary logistic regression were applied to determine the potential factors influencing the EQ-5D utility, as well as each domain, and the VAS. CHD patients had lower per capita monthly actual income, and higher rates of diabetes mellitus, stroke, anxiety and poor sleep quality, which significantly decreased EQ-5D index and VAS scores. In addition, sex, older age, education, not having a spouse, ever drinking alcohol, a high-fat diet, physical activity, hypertension and depression affected the various domain-specific EQ-5D scores in CHD patients. CHD patients in rural areas have a lower HRQoL. Factors associated with the EQ-5D index, including each domain, and the VAS need attention. CHD patients in rural areas need to be managed systematically.

Benefits finding among Chinese family caregivers of stroke survivors: a qualitative descriptive study.

OBJECTIVES: The caregiving experience includes both caregiver burdens and benefits finding. However, the benefits obtained by family caregivers of stroke survivors in Chinese community dwellings are unknown. The objective of this study was to explore the benefits experienced by family caregivers of stroke survivors in Chinese community dwellings. DESIGN: A qualitative descriptive design was used, fulfilling the consolidated criteria for the Standards for Reporting Qualitative Research reporting guidelines. Semi-structured interviews were conducted with 20 family caregivers of stroke survivors. The interviews were audiotaped, transcribed and analysed. Thematic analysis was performed to analyse the interview transcripts. SETTING AND PARTICIPANTS: Home interviews were conducted with family caregivers of stroke survivors in two communities in Zhengzhou, China. RESULTS: The family caregivers of stroke survivors experienced various benefits from caregiving. There were both internal benefits (increases in knowledge and skills, the development of positive attitudes, and the development of a sense of worthiness and achievement) and external benefits (family growth and gains in social support), which interact to create a healthy lifestyle. CONCLUSION: Our findings provide a comprehensive perspective in understanding the benefits perceived by family caregivers of stroke survivors. This study provides insights into interventions focused on identifying benefits finding in six domains that may help reduce negative emotions and promote the mental health of caregivers.

Creating a Caregiver Benefit Finding Scale of Family Caregivers of Stroke Survivors: Development and Psychometric Evaluation.

In recent years, increased attention has been paid to the benefit finding of family caregivers due to the important role they play. Although some instruments measure benefit finding of caregivers, they do not comprehensively address it in terms specific to the family caregivers of stroke survivors, who require long-term, consistent care. This study is the first effort to develop a comprehensive Caregiver Benefit Finding Scale for the family caregivers of stroke survivors in a Chinese cultural setting. First, 50 items were extracted from a systematic literature review, and a semi-structured interview was conducted with 20 stroke family caregivers to develop the preliminary version of the scale (Version 1). Second, Delphi procedures with 20 experts were used to revise the first version and create Version 2 (37 items). Another six experts were recruited for content validation. Item content validity index (I-CVI) values ranged from 0.83 to 1.00, and the value of the scale CVI was 0.97. Third, 309 family caregivers completed the Version 2 questionnaire and the Chinese version of the Positive Aspects of Caregiving. Two weeks later, 35 family caregivers once again completed the questionnaires. An exploratory factor analysis produced four components (personal growth, health promotion, family growth, and self-sublimation) and 26 items for Version 3 (the cumulative proportion variance was 74.14%). Subsequently, 311 family caregivers completed Version 3. A confirmatory factor analysis confirmed the structure. The goodness of fit index (GFI) = 0.921, adjusted GFI = 0.901, normal fit index = 0.951, incremental fit index = 0.990, comparative FI = 0.990, and the root mean square error of approximation = 0.02 were within the acceptable range. Criterion-related validity was equal to 0.803. The model-based internal consistency index was 0.845 and the values of the Cronbach'α coefficient of the four dimensions were 0.885-0.953. The split-half reliability was 0.92, and the test-retest reliability was 0.994. These findings provide preliminary evidence of the validity and reliability of the Caregiver Benefit Finding Scale. The scale can help researchers and clinicians to achieve a more comprehensive understanding of stroke family caregivers' positive experience. This understanding is necessary for future efforts to address issues in benefit finding by targeting the underlying mechanism and intervention.

Novel cyclometalated Ru(II) complexes containing isoquinoline ligands: Synthesis, characterization, cellular uptake and in vitro cytotoxicity.

Two novel cyclometalated Ru(II) complexes containing isoquinoline ligand, [Ru(bpy)2(1-Ph-IQ)](PF6), (bpy = 2,2'-bipyridine; 1-Ph-IQ = 1-phenylisoquinoline; RuIQ-1) and [Ru(phen)2(1-Ph-IQ)](PF6) (phen = 1,10-phenanthroline; RuIQ-2) were found to show high cytotoxic activity against NCI-H460, A549, HeLa and MCF-7 cell lines. Notably, both of them exhibited IC50 values that were an order of magnitude lower than those of clinical cisplatin and two structurally similar Ru(II)-isoquinoline complexes [Ru(bpy)2(1-Py-IQ)](PF6)2 (Ru3) and [Ru(phen)2(1-Py-IQ)](PF6)2 (Ru4) (1-Py-IQ = 1-pyridine-2-yl). The cellular uptake and intracellular localization displayed that the two cyclometalated Ru(II) complexes entered NCI-H460 cancer cells dominantly via endocytosis pathway, and preferentially distributed in the nucleus. Further investigations on the apoptosis-inducing mechanisms of RuIQ-1 and RuIQ-2 revealed that the two complexes could cause S, G2/M double-cycle arrest by regulating cell cycle related proteins. The two complexes also could reduce the mitochondrial membrane potential (MMP), promote the generation of intracellular ROS and trigger DNA damage, and then lead to apoptosis-mediated cell death. More importantly, RuIQ-2 exhibits low toxicity both towards normal HBE cells in vitro and zebrafish embryos in vivo. Accordingly, the developed complexes hold great potential to be developed as novel therapeutics for effective and low-toxic cancer treatment.

Progress, opportunity, and perspective on exosome isolation - efforts for efficient exosome-based theranostics.

Exosomes are small extracellular vesicles with diameters of 30-150 nm. In both physiological and pathological conditions, nearly all types of cells can release exosomes, which play important roles in cell communication and epigenetic regulation by transporting crucial protein and genetic materials such as miRNA, mRNA, and DNA. Consequently, exosome-based disease diagnosis and therapeutic methods have been intensively investigated. However, as in any natural science field, the in-depth investigation of exosomes relies heavily on technological advances. Historically, the two main technical hindrances that have restricted the basic and applied researches of exosomes include, first, how to simplify the extraction and improve the yield of exosomes and, second, how to effectively distinguish exosomes from other extracellular vesicles, especially functional microvesicles. Over the past few decades, although a standardized exosome isolation method has still not become available, a number of techniques have been established through exploration of the biochemical and physicochemical features of exosomes. In this work, by comprehensively analyzing the progresses in exosome separation strategies, we provide a panoramic view of current exosome isolation techniques, providing perspectives toward the development of novel approaches for high-efficient exosome isolation from various types of biological matrices. In addition, from the perspective of exosome-based diagnosis and therapeutics, we emphasize the issue of quantitative exosome and microvesicle separation.

Effect of Irbesartan on Oxidative Stress and Serum Inflammatory Factors in Renal Tissues of Type 2 Diabetic Rats.

OBJECTIVE: To determine the effect of irbesartan on the activity of oxidative stress parameters of glutathione (GSH), superoxide enzyme (SOD) and malondialdehyde (MDA), and concentration of serum inflammatory factors of macrophage chemokine-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor alpha (TNF-∝) in the renal tissue of type 2 diabetic rats. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: The First People's Hospital of Ningyang County, Shandong Province, China, from April 2017 to March 2018. METHODOLOGY: Thirty healthy male Sprague Dawley rats were randomly divided into a normal control group, a diabetic model group, and an irbesartan treatment group, 10 in each group. Rat models of type 2 diabetes were prepared by highsugar high-fat diet with low-dose streptozotocin injection. Changes in blood glucose and lipids, serum GSH, SOD, MDA, MCP-1, ICAM-1, and TNF-∝ levels were determined. RESULTS: Levels of FBG, TC, TG and LDL, activity of GSH, SOD and MDA, and levels of serum MCP-1, ICAM-1 and TNF-∝ among three groups were statistically significant (all p < 0.001). Compared with the diabetic model group, FBG, TC, TG and LDL levels, MDA activity, MCP-1, ICAM-1 and TNF-∝ levels all decreased in rats of the irbesartan treatment group (all p <0.001), and both GSH and SOD activity increased (both p<0.001). CONCLUSION: Irbesartan can improve blood glucose and lipid levels in type 2 diabetic rats, and reduce renal damage by improving oxidative stress and inhibiting the release of inflammatory cytokines.

Normobaric oxygen inhibits AQP4 and NHE1 expression in experimental focal ischemic stroke.

The aim of the present study was to determine the effect of 60% normobaric oxygen (NBO) on neurological function, brain edema and the expression of hypoxia­inducible factor­1α (HIF­1α), aquaporin 4 (AQP4) and Na+/H+ exchanger 1 (NHE1) in a rat model of cerebral ischemia­reperfusion injury. Male Sprague­Dawley rats underwent transient focal cerebral ischemia via right middle cerebral artery occlusion (MCAO) for 120 min followed by 48 h of reperfusion. The rats were exposed to NBO at 60 and 100% or no treatment during reperfusion for 48 h. Neurological impairment score (NIS) was evaluated prior to the sacrifice of all rats. Hematoxylin­eosin staining was performed after 48 h of reperfusion with NBO treatment. The infarct volume and brain water content (BWC) were determined to assess brain ischemic injury at 24 and 48 h. The levels of HIF­1α, AQP4 and NHE1 expression in brain tissue samples were determined by western blotting and reverse transcription­quantitative polymerase chain reaction analysis. During reperfusion, the protein and mRNA expression of HIF­1α, AQP4 and NHE1 increased over time (up to 48 h). Exposure to 60 and 100% NBO during reperfusion following MCAO improved NIS, and alleviated BWC and infarct volume after 24 and 48 h, with further improvements in the 100% NBO group, compared with 60%. Additionally, the molecular mechanisms involved in the effects of NBO may be associated with reduced AQP4 and NHE1 expression and increased HIF­1α expression. However, 60% NBO therapy during reperfusion following an acute ischemic stroke did not achieve the same effects as 100% NBO. Further experimental studies should be performed to elucidate the mechanism and beneficial effects of 60% NBO, as it is more cost­effective to use, compared with 100% NBO.

Andrographolide protects against cigarette smoke-induced lung inflammation through activation of heme oxygenase-1.

This study was conducted to check whether andrographolide, a bioactive molecule isolated from Andrographis paniculata, could protect against cigarette smoke (CS)-induced lung injury through activation of heme oxygenase-1 (HO-1). Pretreatment with andrographolide (1 mg/kg body weight) markedly attenuated lung inflammation in CS-exposed mice, coupled with reduced numbers of total cells, neutrophils, and macrophages in bronchial alveolar lavage fluid (BALF) and decreased production of cytokine/chemokine into BALF. Furthermore, andrographolide pretreatment increased the expression and activation of HO-1 in the lung of CS-exposed animals. Notably, these histological and biochemical changes induced by andrographolide were blocked by prior administration of zinc protoporphyrin IX (ZnPP; 20 mg/kg body weight), a potent heme oxygenase inhibitor. Moreover, andrographolide-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) was attenuated by ZnPP treatment in CS-exposed animals. Our data collectively demonstrate that andrographolide confers protection against CS-induced lung inflammation, partially through activation of HO-1 and STAT3.