TFF3 promotes clonogenic survival of colorectal cancer cells through upregulation of EP4 via activation of STAT3.

Background: While growing evidence indicates the importance of TFF3 in cancer, the molecular mechanism of its action in cancer remains largely unknown. Clonogenic survival is a key ability for tumor cells, which is interpreted as a trait of cancer cells with tumor-initiating capabilities. We investigated the effect and the underlying mechanisms of TFF3 on the clonogenic survival of colorectal cancer (CRC) cells. Methods: Expression of TFF3 in CRC tissues and matched paracancerous tissues was determined by western blotting. Colony formation assays were performed to evaluate the clonogenic survival ability of CRC cells. PTGER4 mRNA expression was detected by quantitative polymerase chain reaction. PTGER4 promoter activity was determined by luciferase reporter assay. STAT3 nuclear localization was investigated using immunofluorescence staining. Expression of TFF3 and EP4 in CRC tissues was determined by immunohistochemistry. Results: TFF3 knockout led to decreased clonogenic survival of CRC cells, while overexpression of TFF3 resulted in the opposite effect. EP4 was found to be upregulated by TFF3 at both the mRNA and protein level. Moreover, EP4 antagonist abrogated TFF3-mediated clonogenic survival of CRC cells. PGE2 and EP4 agonist could restore the effect of TFF3 knockout on the clonogenic survival of CRC cells. Furthermore, TFF3 promoted STAT3 activation and nuclear localization. Activated STAT3 bound to PTGER4 promoter, the gene encoding for EP4, and facilitated PTGER4 transcription. Conclusions: TFF3 promotes clonogenic survival of CRC cells via upregulating EP4 expression.

The association between air pollution and the daily hospital visits for atrial fibrillation recorded by ECG: a cross-sectional study.

BACKGROUND: The relationship between air pollution and atrial fibrillation (AF) recorded by electrocardiograph (ECG) has not yet been illustrated which worsens AF precaution and treatment. This research evaluated the association between air pollution and daily hospital visits for AF with ECG records. METHODS: The study enrolled 4933 male and 5392 female patients whose ECG reports indicated AF from 2015 to 2018 in our hospital. Such data were then matched with meteorological data, including air pollutant concentrations, collected by local weather stations. A case-crossover study was performed to assess the relationship between air pollutants and daily hospital visits for AF recorded by ECG and to investigate its lag effect. RESULTS: Our analysis revealed statistically significant associations between AF occurrence and demographic data, including age and gender. This effect was stronger in female (k = 0.02635, p < 0.01) and in patients over 65 y (k = 0.04732, p < 0.01). We also observed a hysteretic effect that when exposed to higher nitrogen dioxide(NO2), counting AF cases recorded by ECG may elevate at lag 0 with a maximum odds ratio(OR) of 1.038 (95% CI 1.014-1.063), on the contrary, O3 reduced the risk of daily visits for AF and its maximum OR was at lag 2, and the OR value was 0.9869 (95% CI 0.9791-0.9948). Other air pollutants such as PM2.5, PM10, and SO2 showed no clear relationship with the recorded AF. CONCLUSION: The associations between air pollution and AF recorded with ECG were preliminarily discovered. Short-term exposure to NO2 was significantly associated with daily hospital visits for AF management.

Immune-enhancing activity of polysaccharides and flavonoids derived from Phellinus igniarius YASH1.

Introduction: Phellinus igniarius (P. igniarius) (Sanghuang) is a widely used traditional Chinese medicine fungus, and its natural products have great potential for clinical application in immune enhancement. This study aimed to explore the immune-enhancing activity and underlying mechanisms of the polysaccharides and flavonoids derived from Phellinus igniarius (P. igniarius) and to provide a theoretical and experimental basis for the development of novel drugs. Methods: Wild P. igniarius YASH1 from the Loess Plateau in Yan'an region was collected, and polysaccharides and total flavonoids were extracted, isolated and identified from mycelium and sporophore. In vitro antioxidant activity was detected through the scavenging activity of hydroxyl radicals and total antioxidant capacity. Cell Counting Kit-8 and trypan blue detection kit were used to detect the effect of extract polysaccharides and flavonoids on the proliferation and phagocytosis ability of immune cells. To assess the effect of the drugs on cytokine secretion by immune cells and immune recovery in immunocompromised mice, the expression of interleukin (IL)-2, IL-6, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α were examined at the cellular and animal levels. The species composition, abundance of gut microbiota and the altered content of short-chain fatty acids in the feces were analyzed to elucidate the possible mechanisms of drugs by 16S ribosomal RNA (rRNA) amplifiers sequencing and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Both polysaccharides and flavonoids derived from mycelium or sporophore had antioxidant activity and may stimulate the expression and secretion of IL-2, IL-6, and IFN-γ in immune cells while inhibiting TNF-α expression and secretion and increasing IL-2, IL-6, and IFN- γ expression levels in mice. Furthermore, polysaccharides and flavonoids from mycelium and sporophore showed different effects on the metabolic response of intestinal short-chain fatty acids (SCFAs) in mice, and the use of these drugs remarkably changed the species composition and abundance of intestinal flora in mice. Discussion: Polysaccharides and flavonoids from P. igniarius YASH1 mycelium and sporophore have in vitro antioxidant activity, and they affect the promotion of cell proliferation, stimulation of IL-2, IL-6, and IFN-γ secretion, and inhibition of TNF-α expression in immune cells. Polysaccharides and flavonoids from P. igniarius YASH1 may enhance immunity in immunocompromised mice and remarkably affect the intestinal flora and content of SCFAs.

Venlafaxine antagonizes the noradrenaline-promoted colon cancer progression by inhibiting the norepinephrine transporter.

Epidemiological studies have demonstrated that the use of antidepressants is associated with a decreased risk of colorectal cancer (CRC); however, the mechanisms behind this association are yet unknown. Adrenergic system contributes to the stress-related tumor progression, with norepinephrine (NE) mainly secreted from adrenergic nerve fibers. Norepinephrine serotonin reuptake inhibitors are successfully used antidepressants. This study demonstrates that a widely used antidepressant venlafaxine (VEN) antagonizes NE-promoted colon cancer in vivo and in vitro. Bioinformatic analysis suggested that NE transporter (NET, SLC6A2), a target of VEN, was closely associated with the prognosis of clinical patients with CRC. In addition, the knockdown of NET antagonized the effect of NE. The NET-protein phosphatase 2 scaffold subunit alpha/phosphorylated Akt/vascular endothelial growth factor pathway partially mediates the antagonizing effect of VEN on NE's actions in colon cancer cells. These were also confirmed by in vivo experiments. Our findings revealed for the first time that, in addition to its primary function as a transporter, NET also promotes NE-enhanced colon cancer cell proliferation, tumor angiogenesis, and tumor growth. This provides direct experimental and mechanistic evidence for the use of antidepressant VEN in the treatment of CRC and a therapeutic potential for repurposing existing drugs as an anti-cancer approach to improve the prognosis of patients with CRC.

Whole-genome metagenomic analysis of the oral microbiota in patients with obstructive sleep apnea.

PURPOSE: The oral microbiota is closely associated with systemic health, but few studies have investigated the oral microbiota in patients with obstructive sleep apnea (OSA). This study aimed to identify the variation of oral microbiota among patients with severe OSA, and the change of oral microbiota after treatment with continuous positive airway pressure (CPAP). METHODS: Participants were enrolled in the study from November 2020 to August 2021. Sleep parameters using full nocturnal polysomnography (PSG) were collected on healthy controls, patients with severe OSA, and patients with severe OSA after CPAP treatment for 3 months. Oral samples were also collected by rubbing disposable medical sterile swabs on the buccal mucosa. Routine blood tests and biochemical indicators were measured using the fully automated biochemical analyzer. Oral microbial composition of oral samples were determined using whole-genome metagenomic analysis in all participants. Correlations were analyzed between the oral microbiota and blood lipids. RESULTS: Study enrollment included 14 participants, 7 healthy controls and 7 patients with severe OSA. At the species level, the relative abundances of Prevotella, Alloprevotella, Bacteroides, Veillonella_tobetsuensis, Candidatus saccharimonas, and Leptotrichia in the groups with severe OSA were significantly lower than those in the healthy controls (P both < 0.05). The abundances of Capnocytophaga, Veillonella, Bacillus_anthracis, Eikenella, and Kingella were significantly higher whereas the abundances of Gordonia and Streptococcus were significantly lower in the group with severe OSA compared to the severe OSA-CPAP group (P < 0.05 for both). According to the Kyoto Encyclopedia of Genes and Genomes (KEGG), 4 pathways changed in the group with severe OSA compared with healthy controls (P both < 0.05). Pathways related to Novobiocin biosynthesis, 2-Oxocarboxylic acid metabolism, and Histidine metabolism were enriched in the patients with severe OSA. Nine pathways showed significant differences with regard to the relative abundances of phenylalanine metabolism; alanine, aspartate, and glutamate metabolism; one carbon pool by folate; monobactam biosynthesis; 2-oxocarboxylic acid metabolism; arginine biosynthesis and vitamin B6 metabolism; novobiocin biosynthesis; and arginine and proline metabolism, which were significantly higher in the group with severe OSA compared to the severe OSA-CPAP group (P both < 0.05). The Spearman correlation analysis between blood lipid parameters and oral microbiota components showed that negative correlations were observed between total cholesterol and Streptomyces (r = - 0.893, P = 0.007), and high-density lipoprotein cholesterol (HDL-C) and Gordonia (r = - 0.821, P = 0.023); positive correlations were observed between HDL-C and Candidatus saccharimonas (r = 0.929, P = 0.003), and low-density lipoprotein cholesterol (LDL-C) and Capnocytophaga (r = 0.893, P = 0.007). CONCLUSION: There was an apparent discrepancy of the oral microbiota and metabolic pathways between the group with severe OSA and controls, and CPAP significantly changed oral microbial abundance and metabolic pathways in patients with severe OSA. Correlation analysis showed that these oral bacteria were strongly correlated with the blood lipids level.

Ribosomal protein RPL5 regulates colon cancer cell proliferation and migration through MAPK/ERK signaling pathway.

BACKGROUND: Abnormal expression of ribosomal proteins has an important regulatory effect on the progression of cancer. RPL5 is involved in the progression of various malignancies, however, the role of RPL5 in colon cancer remains is still unclear. METHODS: Data from TCGA and GTEx databases were used to analyze the RPL5 expression in pan-cancer. The expression level of RPL5 in clinical colon cancer tissue samples and human colon cancer cell lines was detected by western blotting; siRNA targeting RPL5 was designed, and its interference efficiency was verified by western blotting and RT-qPCR; CCK8 assay, clone formation assay, cell cycle assay, and cell scratch assay were used to observe the effect of RPL5 on colon cancer cell proliferation and migration; the changes of proteins related to MAPK/ERK signaling pathway were also detected using western blotting. RESULTS: The expression level of RPL5 in colon cancer tissues and cell lines was significantly higher than that in adjacent tissues and NCM460 cells, respectively, and its expression level was higher in HCT116 cells and RKO cells. Knockdown of RPL5 significantly inhibited the proliferation and migration of HCT16 and RKO cells, and arrested the cell cycle in G0/G1 phase. Mechanistic studies revealed that the expression of p-MEK1/2, p-ERK, c-Myc were down-regulated, and the expression of FOXO3 was up-regulated after down-regulation of RPL5, ERK activator (TBHQ) could partially reverse the above-mentioned effects caused by siRPL5. Moreover, TBHQ could partially reverse the inhibitory effect of siRPL5 on the proliferation and migration of colon cancer cells. Collectively, RPL5 promoted colon cell proliferation and migration, at least in part, by activating the MAPK/ERK signaling pathway. CONCLUSION: RPL5 promoted colon cell proliferation and migration, at least in part, by activating the MAPK/ERK signaling pathway, which may serve as a novel therapeutic target for cancers in which MAPK/ERK signaling is a dominant feature.

Sleep, short-term memory, and mood states of volunteers with increasing altitude.

Purpose: This study sought to identify the changes and potential association between sleep characteristics and short-term memory, and mood states among volunteers at different altitudes and times. Method: A total of 26 healthy volunteers were recruited from the PLA General Hospital, and we conducted a longitudinal prospective survey for over 1 year from November 2019 to April 2021. First, we collected demographic data, sleep parameters by overnight polysomnography (PSG), short-term memory by digit span test, and mood states by completing a questionnaire with a brief profile of mood states among participants in the plain (53 m). Then, we continuously followed them up to collect data in the 3rd month at an altitude of 1,650 m (on the 3rd month of the 1-year survey period), the 3rd month at an altitude of 4,000 m (on the 6th month of the 1-year survey period), and the 9th month at an altitude of 4,000 m (on the 12th month of the 1-year survey period). Multiple linear regression analysis was used to construct models between sleep parameters and short-term memory, and mood states. Results: The prevalence of sleep apnea syndrome (SAS) significantly increased with rising elevation (P < 0.01). The apnea-hypopnea index (AHI), the mean apnea time (MAT), the longest apnea time (LAT), and the duration of time with SaO2 < 90% (TSA90) were increased (P < 0.05), and the mean pulse oxygen saturation (MSpO2), the lowest pulse oxygen saturation (LSpO2), and heart rate were significantly decreased with increasing altitude (P < 0.05). Digit span scores were decreased with increasing altitude (P < 0.001). A negative mood was more severe and a positive mood increasingly faded with rising elevation (P < 0.001). Additionally, linear correlation analysis showed that higher AHI, LAT, and MAT were strongly associated with a greater decline in short-term memory (in the 3rd and 9th month at an altitude of 4,000 m, respectively: r s = -0.897, -0.901; r s = -0.691, -0.749; r s = -0.732, -0.794, P < 0.001), and also were strongly associated with more severe negative mood (in the 3rd month at altitudes of 1,650 m and 4,000 m, respectively: r s = 0.655, 0.715, 0.724; r s = 0.771, 0.638, 0.737, P < 0.000625). Multiple linear regression pointed out that AHI was a significant predictor of negative mood among people at different altitudes (in the 3rd month at an altitude of 1,650 m: TMD = 33.161 + 6.495*AHI; in the 3rd month at an altitude of 4,000 m: TMD = 74.247 + 1.589*AHI, P < 0.05). Conclusion: SAS developed easily in high altitudes, most often in CSA (central sleep apnea, CSA). The sleep, short-term memory, and negative mood were significantly more damaged with elevation in volunteers. Sleep parameters were closely associated with short-term memory and mood states in volunteers at high altitudes; the higher the sleep parameters (AHI, LAT, and MAT) scores, the more significant the mood disorders and the more obvious impairment of short-term memory. AHI was a critical predictor of the negative mood of volunteers at different altitudes. This study provides evidence that could help with the prevention and control of sleep disorder, cognitive disorder, and negative mood among populations with high altitudes.

Associations between abdominal obesity and the risk of stroke in Chinese older patients with obstructive sleep apnea: Is there an obesity paradox?

Background and purpose: Abdominal obesity (AO) is a well-known independent risk factor for stroke in the general population although it remains unclear in the case of the elderly, especially in Chinese older patients with obstructive sleep apnea (OSA), considering the obesity paradox. This study aimed to investigate the association between AO and stroke among Chinese older patients with OSA. Methods: Data were collected from January 2015 to October 2017, and 1,290 older patients (age 60-96 years) with OSA (apnea-hypopnea index ≥ 5 events/h on polysomnography) were consecutively enrolled from sleep centers at six hospitals, evaluated for AO defined as waist circumference (WC) using the standardized criteria for the Chinese population, and followed up prospectively for a median period of 42 months. Logistic regression and Cox regression analyses were used to determine the cross-sectional and longitudinal associations between AO and stroke risk in these participants and different groups of the severity of OSA. Results: Participants with AO had a higher prevalence of stroke at baseline. A higher incidence of stroke during a median follow-up period of 42 months in participants with AO than in participants without AO (12.4% vs. 6.8% and 8.3% vs. 2.4%, respectively; both P < 0.05) was predicted. Cross-sectional analysis revealed an association between AO and stroke (odds ratio [OR]1.96, 95% confidence interval [CI] 1.31-2.91), which was stronger among participants with moderate OSA only (OR 2.16, 95%CI 1.05-4.43). Cox regression analysis showed that, compared to participants without AO, participants with AO had a higher cumulative incidence of stroke (hazard ratio [HR] 2.16, 95% CI 1.12-4.04) during a median follow-up of 42 months, and this association was observed in patients with severe OSA only (HR 3.67, 95% CI 1.41-9.87) but not for individuals with mild OSA (HR = 1.84, 95% CI 0.43-6.23) and moderate OSA (HR = 1.98, 95% CI 0.73-6.45). Conclusion: The risk of stroke is associated with AO among Chinese older patients who have OSA, both at baseline and during follow-up, and the strength of the association varied by OSA severity. Active surveillance for early detection of AO could facilitate the implementation of stroke-preventive interventions in the Chinese older OSA population.

Patients with comorbid coronary artery disease and hypertension: a cross-sectional study with data from the NHANES.

Background: Hypertension (HTN) and coronary artery disease (CAD), two common cardiovascular diseases, are often comorbid and interacted. The patients with comorbid CAD and HTN have worse outcomes and prognosis, however, the prevalence remains unclear. In the cross-sectional study, we aimed to explore the prevalence and influence factors of patients with comorbid CAD and HTN in the USA. Methods: Adult patients with comorbid CAD and HTN derived from the National Health and Nutrition Examination Survey (NHANES) database in the 1999-2000 and 2017-2018 cycles were included. Demographic data, physical examination results, laboratory data, and questionnaire data were collected and compared in the two cycles. Subgroup analyses were performed between the elder (≥65 years of age) and middle-young (18-65 years of age) populations. Results: The age-adjusted prevalence of patients with comorbid CAD and HTN increased from 4.22% [1999-2000] to 5.40% [2017-2018] (P=0.006) and the age decreased from 71 [63-79] to 69 [61-77] years (P=0.008). The HTN control rate, the low-density lipoprotein cholesterol (LDL-C) control rate, systolic blood pressure (SBP), and the levels of blood lipids, as well as the use of angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), ß-blockers and statins improved in the 2017-2018 cycle as compared with the 1999-2000 (all P<0.05). On the other hand, the proportions complicated with diabetes mellitus (DM), obesity and chronic kidney disease (CKD), as well as the levels of serum glucose, glycohemoglobin and creatinine increased from the 1999-2000 to 2017-2018 (all P<0.01). Subgroup analyses revealed that the prevalence of middle-young patients with comorbid CAD and HTN increased more than their elder counterparts, while diastolic blood pressure (DBP), pulse, blood lipids and oral medication rates were inferior to the latter. Conclusions: The recent prevalence of patients with comorbid CAD and HTN increased than 20 years ago, mainly caused by more morbid middle-young population. For another, the control of blood pressure (BP) and lipids were favorably affected by increased use of statins, ACEIs/ARBs and ß-blockers in these patients. Nevertheless, there is still much room for strengthening medication utilization and intervention of risk factors in future.

[Lipopolysaccharide induces inflammation and up-regulates the expression of methyltransferase-like 3 (METTL3) and METTL14 in human and mouse intestinal epithelial cells].

Objective To investigate the changes of N6-methyladenosine (m6A) modification in the inflammatory status of HIEC-6 human intestinal epithelial cells and MODE-K mouse intestinal epithelial cells. Methods HIEC-6 cells and MODE-K cells were induced by different concentrations of lipopolysaccharide (LPS), interleukin-1ß (IL-1ß), IL-6 and tumor necrosis factor alpha (TNF-α) for 10 hours or the same concentration of LPS, IL-1ß, IL-6 and TNF-α for 0, 3, 6, 12, 24 hours, respectively. The mRNA expression levels of pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α were detected by real-time quantitative PCR. The mRNA and protein expression levels of m6A modification-related molecules methyltransferase-like 3 (METTL3), METTL14, METTL16, Wilm's tumor 1-associated protein (WTAP), alkylation repair homolog protein 5 (ALKBH5), fat-mass and obesity-associated protein (FTO), YTH domain-containing 1 (YTHDC1), YTHDC2 were detected through real-time quantitative PCR and Western blot, respectively. Results The mRNA expression levels of IL-1ß, IL-6 and TNF-α were increased and the mRNA and protein expression levels of METTL3 and METTL14 were simultaneously up-regulated in time-dependent and concentration-dependent LPS-induced model in HIEC-6 cells and MODE-K cells. Conclusion LPS can induce inflammation and up-regulate the expression of METTL3 and METTL14 in intestinal epithelial cells.

Analysis of volatile organic compounds and metabolites of three cultivars of asparagus (Asparagus officinalis L.) using E-nose, GC-IMS, and LC-MS/MS.

Asparagus (A. officinalis L.) is a perennial herb of the genus Asparagus that is rich in nutrients. This study aimed to distinguish three cultivars of asparagus (Paladin, Grace, and Jinggang red) based on their volatile organic compounds (VOCs) and metabolic profiles. VOCs in the three cultivars were separated and identified using electronic nose (E-nose) and gas chromatography-ion mobility spectrometry (GC-IMS). Differences in metabolites among the three cultivars were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). E-nose and GC-IMS showed that the VOCs in asparagus differed significantly among the three groups. E-nose result showed that purple asparagus (Jinggang red) was connected to a stronger earthy odor; green asparagus (Paladin and Grace) were shown characteristic dill flavor. Moreover, 50 VOCs were detected by using GC-IMS. Ketones and alcohols were most abundant in Paladin; methyl benzoate and dimethyl sulfide were most abundance in Grace; aldehydes and acids were most abundance in Jinggang red. Moreover, 130 and 71 different metabolites were detected in the positive and negative modes among three cultivars, such as quercetin and rutin. Functional analysis revealed that these metabolites were involved in beta-alanine metabolism and ATP-binding cassette (ABC) transporters. In summary, E-nose combined with GC-IMS and LC-MS/MS methods has good application prospects in evaluating and identifying VOCs and metabolites of different cultivars of asparagus. The identified VOCs and metabolites can provide guidelines for the development of functional asparagus products.

Prevalence and factors associated with atrial fibrillation in older patients with obstructive sleep apnea.

PURPOSE: This study sought to identify the prevalence and factors associated with atrial fibrillation (AF) in older patients with obstructive sleep apnea (OSA) in China.  METHODS: This was an explorative cross-sectional study. Between January 2015 and October 2017, we continuously recruited 1285 older patients with OSA who underwent overnight polysomnography from sleep centers of multiple hospitals. They were assessed using 12-lead ECG or 24-h dynamic ECG, and their baseline demographics, clinical characteristics, sleep parameters, and medical history were determined. Multivariate binary logistic regression analysis was used to investigate the factors related to AF in these older patients with OSA. RESULTS: The clinician classified 122 (9.5%) patients as having AF. The prevalence of AF significantly increased with age (P < 0.05) but did not significantly differ between the mild, moderate, and severe OSA groups. Additionally, the prevalence of paroxysmal AF was 7.2% among the overall study population, and it increased with OSA severity or advanced age (P < 0.05). Persistent AF was noted in 2.3% participants, and the prevalence also increased with age. The logistic regression analysis showed that age (OR = 1.054, 95%CI: 1.027-1.018, P < 0.001), history of drinking (OR = 1.752, 95%CI: 1.070-2.867, P < 0.05), chronic heart disease (OR = 1.778, 95%CI: 1.156-2.736, P < 0.01), diabetes mellitus (OR = 1.792, 95%CI: 1.183-2.713, P < 0.01), and reduced diastolic function (OR = 2.373, 95%CI = 1.298-4.337, P < 0.01) were relevant to AF among participants with OSA. CONCLUSION: The prevalence of AF is significantly common in older patients with OSA. Age, history of drinking, chronic heart disease, diabetes mellitus, and reduced diastolic function are independently related to AF in these patients.

Impact of obstructive sleep apnea complicated with type 2 diabetes on long-term cardiovascular risks and all-cause mortality in elderly patients.

BACKGROUND: The prognostic significance of obstructive sleep apnea (OSA) in elderly patients with type 2 diabetes is unclear. The aim of this study was to determine the risk of cardiovascular disease (CVD) and mortality in elderly patients with OSA complicated with type 2 diabetes compared to patients with OSA without type 2 diabetes. METHODS: From January 2015 to October 2017, 1113 eligible elderly patients with OSA, no history of cardiovascular, ≥60 years of age, and complete follow-up records were enrolled in this consecutive multicentre prospective cohort study. All patients had completed polysomnography (PSG) examinations. An apnoea-hypopnoea index of ≥5 events per hour recorded by polysomnography was defined as the diagnostic criterion for OSA. We collected baseline demographics, clinical characteristics, sleep parameters and follow-up outcomes. The primary aim of this study was to identify the risk of incident major adverse cardiovascular events (MACE). Secondary outcomes were all-cause mortality, components of MACE and a composite of all events. Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate whether type 2 diabetes was associated with incident events. RESULTS: A total of 266 (23.9%) patients had OSA complicated with type 2 diabetes. MACE occurred in 97 patients during the median 42-month follow-up. Kaplan-Meier survival curves indicated a significant relationship between type 2 diabetes and MACE (log-rank P = 0.003). Multivariable Cox regression analysis showed that type 2 diabetes increased the risk of MACE (HR = 1.64, 95% CI:1.08-2.47, P = 0.019), hospitalisation for unstable angina (HR = 2.11, 95% CI:1.23-3.64, P = 0.007) and a composite of all events in elderly patients with OSA (HR = 1.70, 95% CI:1.17-2.49, P = 0.007). However, there were no significant differences in the incidence of cardiovascular death, all-cause mortality, MI and hospitalisation for heart failure between patients with and without diabetes (P > 0.05). The subgroup analysis demonstrated that females (AHR = 2.46, 95% CI:1.17-5.19, P = 0.018), ≥ 70 years (AHR = 1.95, 95% CI:1.08-3.52, P = 0.027), overweight and obese (AHR = 2.04, 95% CI:1.29-3.33, P = 0.002) with mild OSA (AHR = 2.42, 95% CI: 1.03-5.71, P = 0.044) were at a higher risk for MACE by diabetes. CONCLUSION: OSA and type 2 diabetes are interrelated and synergistic with MACE, hospitalisation for unstable angina and a composite of all events development. Overweight and obese females, ≥ 70 years with mild OSA combined with type 2 diabetes presented a significantly high MACE risk.

Association Cystatin C and Risk of Stroke in Elderly Patients With Obstructive Sleep Apnea: A Prospective Cohort Study.

Background: Few prospective cohort studies have assessed the relationship between Cystatin C (Cys-C) and risk of stroke in elderly patients with obstructive sleep apnea (OSA). The study sought to examine the association between baseline serum Cys-C and long-term risk of stroke among elderly OSA patients. Methods: A total of 932 patients with OSA, no history of stroke, ≥60 years of age, and complete serum Cys-C records were included in this study. All patients had completed polysomnography (PSG). OSA was defined as an apnea-hypopnea index (AHI) of ≥5 events per hour. Participants were categorized into four groups according to baseline serum Cys-C concentration, split into quartiles. Multivariate Cox regression were used to evaluate the association between Cys-C and the incidence of new-onset stroke. Results: Stroke occurred in 61 patients during the median 42-month follow-up period. The cumulative incidence rate of stroke was 6.5%, which included 54 patients with ischemic stroke and 7 patients with hemorrhagic stroke. The cumulative incidence of stroke was higher among patients with baseline serum Cys-C concentration of ≥1.15 mg/L when compared with other groups (P Log-rank < 0.001). After adjusting for potential confounding factors in the Cox regression model, patients with a serum Cys-C concentration of ≥1.15 mg/L had a 2.16-fold higher risk of developing stroke compared with patients with serum Cys-C ≤ 0.81 mg/L (HR, 2.16, 95%CI, 1.09-6.60; P = 0.017). Additionally, there was a higher risk in those of age ≥70 years (HR, 3.23, 95%CI, 1.05-9.24; P = 0.010). The receiver-operating characteristic curves showed that the capability of Cys-C to identify elderly patients with OSA who had a long-time risk of stroke was moderate (AUC = 0.731, 95% CI: 0.683-0.779, P = 0.001). Conclusion: Increased Cys-C concentration was identified as a risk factor in the incidence of stroke in elderly patients with OSA, independent of gender, BMI, hypertension and other risk factors. Additionally, it conferred a higher risk in patients of age ≥70 years.

Association of Metabolic Syndrome With Long-Term Cardiovascular Risks and All-Cause Mortality in Elderly Patients With Obstructive Sleep Apnea.

BACKGROUND: Evidence suggests that an increased risk of major adverse cardiac events (MACE) and all-cause mortality is associated with obstructive sleep apnea (OSA), particularly in the elderly. Metabolic syndrome (MetS) increases cardiovascular risk in the general population; however, less is known about its influence in patients with OSA. We aimed to assess whether MetS affected the risk of MACE and all-cause mortality in elderly patients with OSA. METHODS: From January 2015 to October 2017, 1,157 patients with OSA, aged ≥60 years, no myocardial infarction (MI), and hospitalization for unstable angina or heart failure were enrolled at baseline and were followed up prospectively. OSA is defined as an apnea-hypopnea index of ≥5 events per hour, as recorded by polysomnography. Patients were classified on the basis of the presence of MetS, according to the definition of the National Cholesterol Education Program (NCEP). Incidence rates were expressed as cumulative incidence. Cox proportional hazards analysis was used to estimate the risk of all events. The primary outcomes were MACE, which included cardiovascular death, MI, and hospitalization for unstable angina or heart failure. Secondary outcomes were all-cause mortality, components of MACE, and a composite of all events. RESULTS: MetS was present in 703 out of 1,157 (60.8%) elderly patients with OSA. During the median follow-up of 42 months, 119 (10.3%) patients experienced MACE. MetS conferred a cumulative incidence of MACE in elderly patients with OSA (log-rank, P < 0.001). In addition, there was a trend for MACE incidence risk to gradually increase in individuals with ≥3 MetS components (P = 0.045). Multivariate analysis showed that MetS was associated with an incidence risk for MACE [adjusted hazard ratio (aHR), 1.86; 95% confidence interval (CI), 1.17-2.96; P = 0.009], a composite of all events (aHR, 1.54; 95% CI, 1.03-2.32; P = 0.036), and hospitalization for unstable angina (aHR, 2.01; 95% CI, 1.04-3.90; P = 0.039). No significant differences in the risk of all-cause mortality and other components of MACE between patients with and without MetS (P > 0.05). Subgroup analysis demonstrated that males (aHR, 2.23; 95% CI, 1.28-3.91, P = 0.05), individuals aged <70 years (aHR, 2.36; 95% CI, 1.27-4.39, P = 0.006), overweight and obese individuals (aHR, 2.32; 95% CI, 1.34-4.01, P = 0.003), and those with moderate-severe OSA (aHR, 1.81;95% CI: 1.05-3.12, P = 0.032) and concomitant MetS were at a higher risk for MACE. CONCLUSION: MetS is common in elderly patients with OSA in the absence of MI, hospitalization for unstable angina or heart failure. Further, it confers an independent, increased risk of MACE, a composite of all events, and hospitalization for unstable angina. Overweight and obese males, aged <70 years with moderate-severe OSA combined with MetS presented a significantly higher MACE risk.

THAP11 Functions as a Tumor Suppressor in Gastric Cancer through Regulating c-Myc Signaling Pathways.

We aim to investigate the role of THAP11 (thanatos-associated protein11) in gastric cancer and its regulation mechanisms. THAP11 expression was analyzed in 51 pairs of GC tissues and the corresponding paracancerous tissues by qRT-PCR and Western blot. After THAP11 was overexpressed or knocked-down, cell proliferation, cell cycle, and apoptosis were detected in MKN-45 cells. We found that THAP11 was significantly downregulated in GC tissues and GC cell lines. Functionally, THAP11 overexpression markedly inhibited cell growth, induced G1/G0 cell-cycle arrest, and promoted cell apoptosis of MKN-45 cells, while silencing of THAP11 led to increased cell growth, increased DNA synthesis, and inhibited apoptosis. In addition, THAP11 negatively regulated the expression of c-Myc, decreased cyclinD1 protein, and increased p27 and p21 protein levels. We also found cell growth suppression induced by THAP11 was rescued by c-Myc overexpression, further confirming that THAP11 suppresses gastric cancer cell growth via the c-Myc pathway. THAP11 acts as a cell growth suppressor and exerts its role possibly through negatively regulating c-Myc pathway in gastric cancer.

Nei Endonuclease VIII-Like1 (NEIL1) Inhibits Apoptosis of Human Colorectal Cancer Cells.

The study is aimed at investigating the role of Nei endonuclease VIII-like1 (NEIL1) in the pathogenesis of colorectal cancer (CRC). The human CRC (HCT116 and SW480) cells were subjected to the siRNA silencing and recombinant plasmid overexpression of NEIL1. Transfection of siNEIL1 significantly inhibited the cell growth. It also increased the Bax expression levels, while it decreased the Bcl-2 expression levels in human CRC cells, leading the Bax/Bcl-2 balance toward apoptosis. Moreover, the apoptosis was promoted through the caspase-9 signaling pathway. One the other hand, high expression of NEIL1 promoted the cell viability and reduced the apoptosis, inducing the balance of Bax/Bcl-2 in the human colon cancer cells to be antiapoptotic. In addition, the caspase-9 signaling pathway inhibited apoptosis, contrary to the results obtained by downregulating NEIL1 expression. Furthermore, NEIL1 was negatively regulated by miR-7-5p, indicating that miR-7-5p inhibited the NEIL1 expression after transcription. Overexpression of miR-7-5p reversed the effects of NEIL1 on these CRC cells. In conclusion, NEIL1 promotes the proliferation of CRC cells, which is regulated negatively by miR-7-5p. These findings suggest that NEIL1 is a potential therapeutic target for CRC.

Norepinephrine-CREB1-miR-373 axis promotes progression of colon cancer.

The adrenergic system contributes to the stress-induced onset and progression of cancer. Adrenergic fibers are the primary source of norepinephrine (NE). The underlying mechanisms involved in NE-induced colon cancer remain to be understood. In this study, we describe the function and regulatory network of NE in the progression of colon cancer. We demonstrate that NE-induced phosphorylation of cAMP response element-binding protein 1 (CREB1) promotes proliferation, migration, and invasion of human colon cancer cells. The downstream effector of NE, CREB1, bound to the promoter of miR-373 and transcriptionally activated its expression. miR-373 expression was shown to be necessary for NE-induced cell proliferation, invasion, and tumor growth. We confirmed that proliferation and invasion of colon cancer cells are regulated in vitro and in vivo by miR-373 through targeting of the tumor suppressors TIMP2 and APC. Our data suggest that NE promotes colon cancer cell proliferation and metastasis by activating the CREB1-miR-373 axis. The study of this novel signaling axis may provide mechanistic insights into the neural regulation of colon cancer and help in the design of future clinical studies on stress biology in colorectal cancer.

Norepinephrine transporter promotes the invasion of human colon cancer cells.

Epidemiological studies suggested the use of antidepressants to be associated with decreased risk of colorectal cancer (CRC). However, the underlying mechanism through which this decreased risk occurs remains elusive. The norepinephrine transporter (NET) is a target of antidepressants that maintains noradrenergic transmission homeostasis; however, little is known about its function in human CRC cells. The present study, using public datasets and immunohistochemistry approaches, revealed that NET was highly expressed in human CRC tissues with metastasis and in human colon cancer cells. Furthermore, knockdown of NET inhibited the invasive capability of human colon cancer cells. Additionally, epithelial (E)-cadherin expression was increased and Notch1 signaling was inhibited in NET-depleted colon cancer cells. These findings suggest that NET is highly expressed in human colon cancer, which is associated with the invasion of human colon cancer cells by influencing cell-cell adhesion through the Notch1-E-cadherin pathway. Thus, the present study revealed a novel function for NET and its downstream effectors in colon cancer cells, which will be valuable for future studies in a clinical setting.