[Banxia Xiexin Decoction inhibiting colitis-associated colorectal cancer infected with Fusobacterium nucleatum by regulating Wnt/ß-catenin pathway].

This paper investigates the intervention effect and mechanism of Banxia Xiexin Decoction(BXD) on colitis-associated colorectal cancer(CAC) infected with Fusobacterium nucleatum(Fn). C57BL/6 mice were randomly divided into a control group, Fn group, CAC group [azoxymethane(AOM)/dextran sulfate sodium salt(DSS)](AOM/DSS), model group, and BXD group. Except for the control and AOM/DSS groups, the mice in the other groups were orally administered with Fn suspension twice a week. The AOM/DSS group, model group, and BXD group were also injected with a single dose of 10 mg·kg~(-1) AOM combined with three cycles of 2.5% DSS taken intragastrically. The BXD group received oral administration of BXD starting from the second cycle until the end of the experiment. The general condition and weight changes of the mice were monitored during the experiment, and the disease activity index(DAI) was calculated. At the end of the experiment, the colon length and weight of the mice in each group were compared. Hematoxylin-eosin(HE) staining was used to observe the pathological changes in the colon tissue. Enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of interleukin(IL)-2, IL-4, and IL-6 inflammatory factors in the serum. Immunohistochemistry(IHC) was used to detect the expression of Ki67, E-cadherin, and ß-catenin in the colon tissue. Western blot was used to detect the protein content of Wnt3a, ß-catenin, E-cadherin, annexin A1, cyclin D1, and glycogen synthase kinase-3ß(GSK-3ß) in the colon tissue. The results showed that compared with the control group, the Fn group had no significant lesions. The mice in the AOM/DSS group and model group had decreased body weight, increased DAI scores, significantly increased colon weight, and significantly shortened colon length, with more significant lesions in the model group. At the same time, the colon histology of the model group showed more severe adenomas, inflammatory infiltration, and cellular dysplasia. The levels of IL-4 and IL-6 in the serum were significantly increased, while the IL-2 content was significantly decreased. The IHC results showed low expression of E-cadherin and high expression of Ki67 and ß-catenin in the model group, with a decreased protein content of E-cadherin and GSK-3ß and an increased protein content of Wnt3a, ß-catenin, annexin A1, and cyclin D1. After intervention with BXD, the body weight of the mice increased; the DAI score decreased; the colon length increased, and the tumor decreased. The histopathology showed reduced tumor proliferation and reduced inflammatory infiltration. The levels of IL-6 and IL-4 in the serum were significantly decreased, while the IL-2 content was increased. Meanwhile, the expression of E-cadherin was upregulated, and that of Ki67 and ß-catenin was downregulated. The protein content of E-cadherin and GSK-3ß increased, while that of Wnt3a, ß-catenin, annexin A1, and cyclin D1 decreased. In conclusion, BXD can inhibit CAC infected with Fn, and its potential mechanism may be related to the inhibition of Fn binding to E-cadherin, the decrease in annexin A1 protein level, and the regulation of the Wnt/ß-catenin pathway.

[Tongxie Yaofang regulates tumor-associated macrophage polarization in colorectal cancer under chronic stress].

This study aims to investigate the intervention effect and mechanism of Tongxie Yaofang in regulating tumor-associated macrophage polarization on colorectal cancer under chronic stress. BALB/C mice were randomized into blank, control, model, mifepristone, and low-, medium-, and high-dose Tongxie Yaofang groups. The other groups except the blank and model groups were subjected to chronic restraint stress and subcutaneous implantation of colon cancer cells for the modeling of colon cancer under stress. Du-ring this period, the body mass and tumor size of each group of mice were recorded. The degree of depression in mice was assessed by behavioral changes. Enzyme-linked immunosorbent assay was employed to determine the levels of cortisol(CORT), 5-hydroxytryptamine(5-HT), norepinephrine(NE), M1-associated inflammatory cytokines [interleukin(IL)-1ß, IL-12, and tumor necrosis factor(TNF)-α], and M2-associated inflammatory cytokines(IL-4 and IL-10) in the serum. The tumor growth of mice in each group was regularly monitored by in vivo imaging. The histopathological changes of tumors in each group of mice were observed by hematoxylin-eosin staining. The proportions of CD86 and CD206 in the tumor tissue were detected by flow cytometry and immunofluorescence staining. Western blot was employed to determine the protein levels of Janus kinase(JAK)1, JAK2, JAK3, signal transducer and activator of transcription(STAT)3, and STAT6 in the tumor tissue. The results showed that chronic stress increased the immobility time of mice, elevated the serum levels of CORT, IL-4, and IL-10, lowered the levels of 5-HT, NE, IL-1ß, IL-12, and TNF-α, and promoted the growth of subcutaneous tumors. The tumor cells in the tumor tissue grew actively, with obvious atypia and up-regulated protein levels of CD206, JAK1, JAK2, JAK3, STAT3, and STAT6, and down-regulated protein level of CD86. The treatment with Tongxie Yaofang shortened the immobility time of mice, lowered the serum levels of CORT, IL-4, and IL-10, elevated the serum levels of 5-HT, NE, IL-1ß, IL-12, and TNF-α, and inhibited the growth of subcutaneous tumors in mice. Moreover, the treatment caused different degrees of necrosis in the tumor tissues, down-regulated the protein levels of CD206, JAK1, JAK2, JAK3, STAT3, and STAT6, and up-regulated the protein level of CD86. In summary, Tongxie Yaofang can promote the transformation of M2 macrophages to M1 macrophages and change the tumor microenvironment under chronic stress to inhibit the development of colorectal cancer, which may be related to the JAK/STAT signaling pathway.

Causal relationship association of cheese intake with gestational hypertension and diabetes result from a Mendelian randomization study.

BACKGROUND: The evidence from observational studies has been inconclusive on the causal relationship between cheese intake and gestational hypertension or diabetes. AIM: To determine whether cheese consumption was causally related to hypertension and diabetes during pregnancy. METHODS: This was a two-sample Mendelian randomized (MR) study. Summary-level genetic data for cheese intake was exposure and corresponding outcome data for gestational hypertension and gestational diabetes were extracted from the IEU OpenGWAS database. MR analysis was conducted using inverse variance weighting. For sensitivity analyses, MR-Egger regression, weighted median, weighted mode, and leave-one-out methods were conducted. A fixed-effect model was used to meta-analyze two sample MR estimates. The traits of gestational hypertension were pregnancy hypertension (123579 individuals) and oedema, proteinuria and hypertensive disorders in pregnancy, childbirth and the puerperium (123579 individuals), and traits of gestational diabetes were gestational diabetes (123579 individuals) and diabetes mellitus in pregnancy (116363 individuals), respectively. RESULTS: Cheese intake per standard deviation increase has causally reduced the risks of gestational hypertension [odds ratio (OR) = 0.60, 95% confidence interval (CI): 0.47-0.76, P < 0.001] and gestational diabetes (OR = 0.41, 95%CI: 0.30-0.55, P < 0.001) in inverse variance weighted analysis. Sensitivity analysis showed no heterogeneity (all P > 0.05) nor horizontal pleiotropy (all P > 0.05) in the relationship between cheese intake and gestational hypertension, but heterogeneity presented (all P < 0.05) in relation to gestational diabetes in the two-sample MR analysis. CONCLUSION: Cheese intake was inversely associated with gestational hypertension and gestational diabetes in MR analysis, suggesting that cheese consumption may be beneficial in preventing hypertension and diabetes during pregnancy.

Association of apolipoprotein B with all-cause and cardiovascular mortality among adults: Results from the National Health and Nutrition Examination Surveys.

BACKGROUND: Apolipoprotein B (apoB) is a crucial component that directly reflects the number of atherogenic lipoprotein particles and is closely related to atherosclerosis. However, there was an inconsistency among previous studies in its relationship with mortality. Using nationally representative data, we aimed to investigate the association of apoB with cardiovascular and all-cause mortality. METHODS: We retrospectively included participants from the National Health and Nutrition Examination Survey (2007-2014), and mortality was ascertained through December 31, 2015. Hazard ratios (HRs) with 95% confidence intervals (CIs) of apoB in quartiles (Q1-Q4) for mortality risk were calculated using multivariable-adjusted Cox proportional hazards models, and restricted cubic spline regressions were performed to test dose relationships. RESULTS: We enrolled 10,375 participants with a mean age of 46.3 years, of which 47.88% were men. During a mean follow-up time of 69.2 months, 533 (5.14%) and 91 (0.88%) deaths were due to all causes and cardiovascular disease, respectively. After adjusting for confounders, per SD, increment of apoB was associated with an elevated risk of cardiovascular mortality (HR, 1.13; 95% CI, 1.03-1.24). The risk of all-cause mortality was significantly reduced in the third quartile (Q3) of apoB (HR, 0.71; 95% CI, 0.56-0.91) compared with the reference quartile (Q1). Moreover, spline analyses showed that the relationship of apoB with all-cause mortality was U-shaped, and the threshold value was 108 mg/dL. CONCLUSIONS: ApoB was linearly associated with increased risk of cardiovascular mortality and non-linearly associated with all-cause mortality in a U-shaped manner, independently of other cardiovascular risk factors.

Prevention and treatment of traumatic brain injury-related delirium: a systematic review.

BACKGROUND: Our systematic review examines the effectiveness and safety of non-pharmacologic and pharmacologic interventions in preventing or treating traumatic brain injury (TBI)-related delirium in acute care. METHODS: We searched four electronic databases (MEDLINE, EMBASE, CENTRAL/CDSR, and PsycINFO) to identify randomized controlled trials (RCTs), quasi-experimental, and observational studies. Eligible studies included adults with TBI, at least one comparator group, delirium as an outcome and took place in acute care. Two reviewers independently completed all study screening, data abstraction, and risk of bias assessment using the Cochrane risk of bias 2 tool for RCTs or risk of bias in non-randomized studies-of interventions tool for observational studies. We implemented the PROGRESS-Plus framework to describe social determinants of health (SDoH) reporting. RESULTS: We identified 20,022 citations, reviewed 301 in full text, and included eight studies in the descriptive synthesis. The mean age of study participants ranged from 32 to 62 years. 12.5% of included studies reported SDoH. Included studies had moderate-to-high risk of bias. Studies compared reorientation programs and an intervention bundle to usual care, but these interventions were not better than usual care in treating TBI-related delirium. Individual studies found that rosuvastatin and aripiprazole were more efficacious than placebo, and dexmedetomidine was more efficacious than propofol and haloperidol for preventing TBI-related delirium. No studies reported safety as the primary outcome. CONCLUSIONS: We identified efficacious pharmacologic interventions for preventing TBI-related delirium, but these studies were at moderate-to-high risk of bias, which limits our confidence in these findings. Future studies should incorporate safety outcomes, and a diverse study population, including older adults.

Correlation of Great Chinese Famine Exposure During Early Life to Prevalence of Kidney Stone in Adulthood.

Background: The Great Chinese Famine, as the famine of 1959-1961 was often known. Famine exposure during early life was proven to be associated with some kidney diseases but has not been studied with kidney stone. We aimed to investigate the relationship between exposure to the Great Chinese Famine in early life and the incidence of kidney stone in adulthood. Methods: From 1 January 2017 to 31 December 2018, a total of 19,658 eligible adults were recruited in a cross-sectional survey who were born between 1 October 1952 and 30 September 1964 in Guangdong, China. Participants were separated into kidney stone and none-kidney stone groups based on kidney stone status. According to birth data, participants were divided into non-exposed, fetal-exposed, early-, mid-, and late-childhood-exposed groups. Multivariate logistic regression, subgroup analysis and interaction test were used to estimate the odds ratios (ORs) and confidence intervals (CIs) between famine exposure and kidney stone. Results: In total, 19,658 (12,246 female, mean age 59.31 ± 3.68 years) subjects were enrolled, and 3219 (16.38%) participants with kidney stone. The prevalence of kidney in none-, fetal-, early-, mid-, and late-childhood-exposed groups were 645 (14.9%), 437 (15.9%), 676 (16.3%), 743 (17.0%), and 718 (17.6%), respectively (P<0.001). When compared with the unexposed group, the fully adjusted ORs for kidney stone from fetal-exposed, early-, mid- to late-childhood-exposed groups were 1.37 (95% CI: 1.13, 1.68, P=0.002), 1.98 (95% CI: 1.45, 2.72, P<0.001), 2.94 (95% CI: 1.96, 4.42, P<0.001), and 3.48 (95% CI: 2.11, 5.72, P<0.001), respectively (P for trend<0.001). Subgroup analyses revealed no interactions between the famine effect on kidney stones and body mass index, gender, smoking status, history of diabetes or hypertension (all P for interaction >0.05). Conclusion: This study found that exposure to the Great Chinese Famine during early life was independently associated with the increased incidence of kidney stone in adulthood.

Periplocin inhibits hepatocellular carcinoma progression and reduces the recruitment of MDSCs through AKT/NF-κB pathway.

AIMS: We aimed to evaluate the effect of periplocin on inhibiting hepatocellular carcinoma (HCC) and further determine its mechanisms. MAIN METHODS: Cytotoxic activity of periplocin against HCC cells was tested by CCK-8 and colony formation assays. The antitumor effects of periplocin were evaluated in human HCC SK-HEP-1 xenograft and murine HCC Hepa 1-6 allograft mouse models. Flow cytometry was used to measure cell cycle distribution, apopotosis, and the number of myeloid-derived suppressor cells (MDSCs). Hoechst 33258 dye was applied to observe the nuclear morphology. Network pharmacology was performed to predict possible signaling pathways. Drug affinity responsive target stability assay (DARTS) was used to evaluate AKT binding of periplocin. Western blotting, immunohistochemistry, and immunofluorescence were used to examine the protein expression levels. KEY FINDING: Periplocin inhibited cell viability with IC50 values from 50 nM to 300 nM in human HCC cells. Periplocin disrupted cell cycle distribution and promoted cell apoptosis. Moreover, AKT was predicted as the target of periplocin by network pharmacology, which was confirmed by that AKT/NF-κB signaling was inhibited in periplocin-treated HCC cells. Periplocin also inhibited the expression of CXCL1 and CXCL3, leading to decreased accumulation of MDSCs in HCC tumors. SIGNIFICANCE: These findings reveal the function of periplocin in inhibiting HCC progression by G2/M arrest, apoptosis and suppression of MDSCs accumulation through blockade of the AKT/NF-κB pathway. Our study further suggests that periplocin has the potential to be developed as an effective therapeutic agent for HCC.

The association of lead exposure with blood pressure and hypertension: a mediation analyses of estimated glomerular filtration rate.

The link between lead and blood pressure was debatable, and whether it was mediated by renal function was unknown. The purpose was to investigate the relationship between blood lead concentrations and blood pressure and hypertension, as well as the mediating role of estimated glomerular filtration rate (eGFR) in this relationship. Participants aged 18 were recruited from the National Health and Nutrition Examination Survey (1999-2014) and provided with lead and blood pressure data. Multivariate linear and logistic regression, stratification, interaction tests, and a restricted cubic spline curve were used to assess the association of blood lead with systolic/diastolic blood pressure (SBP/DBP) and hypertension, and mediation effect analysis was used to investigate the role of eGFR in this relationship. A total of 20,073 subjects were enrolled, and among them, 9837 (49.01%) were male and 7800 (38.86%) were hypertensive patients. Multivariate linear and logistic regression analysis showed that blood lead levels were significantly associated with SBP (ß = 3.14, 95%CI: 2.03, 4.25; P < 0.001), DBP (ß = 3.50, 95%CI: 2.69, 4.30; P < 0.001), and hypertension (OR = 1.29, 95%CI: 1.09, 1.52; P = 0.0026). In comparison to the lowest blood lead quartile, the highest lead group was significantly associated with SBP (= 2.55, 95%CI: 1.66, 3.44; P = 0.0001), DBP (= 2.60, 95%CI: 1.95, 3.24; P = 0.0001), and hypertension (OR = 1.26, 95%CI: 1.10, 1.45; P = 0.0007). Mediation analysis showed that the proportion of blood lead mediated for SBP, DBP, and hypertension was 3.56% (95%CI: 0.42%, 7.96%; P = 0.0320), 6.21% (95%CI: 4.02%, 9.32%; P < 0.0001), and 17.39% (95%CI: 9.34%, 42.71%; P < 0.0001), respectively. Adjusted restricted cubic spline curves presented a non-linear correlation of blood lead levels with DBP (P-non-linearity < 0.001), linear with SBP (P-non-linearity = 0.203), and hypertension (P-non-linearity = 0.763). Our findings demonstrated that blood lead levels were non-linear with DBP, but linear with SBP and hypertension, and this relationship was mediated by eGFR.

Diagnostic accuracy of eHealth literacy measurement tools in older adults: a systematic review.

BACKGROUND: In Canada, virtual health care rapidly expanded during the COVID-19 pandemic. There is substantial variability between older adults in terms of digital literacy skills, which precludes equitable participation of some older adults in virtual care. Little is known about how to measure older adults' electronic health (eHealth) literacy, which could help healthcare providers to support older adults in accessing virtual care. Our study objective was to examine the diagnostic accuracy of eHealth literacy tools in older adults. METHODS: We completed a systematic review examining the validity of eHealth literacy tools compared to a reference standard or another tool. We searched MEDLINE, EMBASE, CENTRAL/CDSR, PsycINFO and grey literature for articles published from inception until January 13, 2021. We included studies where the mean population age was at least 60 years old. Two reviewers independently completed article screening, data abstraction, and risk of bias assessment using the Quality Assessment for Diagnostic Accuracy Studies-2 tool. We implemented the PROGRESS-Plus framework to describe the reporting of social determinants of health. RESULTS: We identified 14,940 citations and included two studies. Included studies described three methods for assessing eHealth literacy: computer simulation, eHealth Literacy Scale (eHEALS), and Transactional Model of eHealth Literacy (TMeHL). eHEALS correlated moderately with participants' computer simulation performance (r = 0.34) and TMeHL correlated moderately to highly with eHEALS (r = 0.47-0.66). Using the PROGRESS-Plus framework, we identified shortcomings in the reporting of study participants' social determinants of health, including social capital and time-dependent relationships. CONCLUSIONS: We found two tools to support clinicians in identifying older adults' eHealth literacy. However, given the shortcomings highlighted in the validation of eHealth literacy tools in older adults, future primary research describing the diagnostic accuracy of tools for measuring eHealth literacy in this population and how social determinants of health impact the assessment of eHealth literacy is needed to strengthen tool implementation in clinical practice. PROTOCOL REGISTRATION: We registered our systematic review of the literature a priori with PROSPERO (CRD42021238365).

Expression Profiles and Functional Analysis of Plasma Exosomal Circular RNAs in Acute Myocardial Infarction.

Acute myocardial infarction (AMI) is a common cardiovascular disease with high rates of morbidity and mortality globally. The dysregulation of circular RNAs (circRNAs) has been shown to be closely related to various pathological aspects of AMI. However, the function of exosomal circRNAs in AMI has yet to be investigated. The purpose of this study was to investigate the expression profiles of plasma exosomal circRNAs in AMI and explore their potential functionality. The expression profiles of plasma exosomal circRNAs in patients with AMI, stable coronary heart atherosclerotic disease (CAD), and healthy controls were obtained from a GEO expression dataset (GSE159657). We also analyzed bioinformatics functionality, potential pathways, and interaction networks related to the microRNAs associated with the differentially expressed circRNAs. A total of 253 exosomal circRNAs (184 up- and 69 down-regulated) and 182 exosomal circRNAs (94 up- and 88 down-regulated) were identified as being differentially expressed between the control group and the AMI and CAD patients, respectively. Compared with the CAD group, 231 different exosomal circRNAs (177 up- and 54 down-regulated) were identified in the AMI group. Functional analysis suggested that the parental genes of exosomal has_circ_0061776 were significantly enriched in the biological process of lysine degradation. Pathway interaction network analysis further indicated that exosomal has_circ_0061776 was associated with has-miR-133a, has-miR-214, has-miR-423, and has-miR-217 and may play a role in the pathogenesis of AMI through the MAPK signaling pathway. This study identified the differential expression and functionality of exosomal circRNAs in AMI and provided further understanding of the potential pathogenesis of an exosomal circRNA-related competing endogenous RNA (ceRNA) network in AMI.

Association between famine exposure in early life and risk of hospitalization for heart failure in adulthood.

Background: Few studies have reported the association of early life exposure to famine with the risk of heart failure. The current study aimed to investigate whether exposure to famine in early life is associated with a higher risk of hospitalization for heart failure in adulthood. Methods: We used data from participants included in the sub-cohort of the China Patient-centered Evaluative Assessment of Cardiac Events Million Persons Project in Guangdong Province. Specific years of birth were used to define the famine-exposed group (born during the famine of 1959-1962), the pre-famine group (born before the famine [1954-1957], and the post-famine group (born after the famine [1964-1967]). Multivariable-adjusted generalized linear models were used to examine the associations of early life famine exposure with the risk of hospitalization for heart failure. Results: A total of 36,212 participants were enrolled in this analysis with a median age of 57.4 years and 37.5% of them were men. Compared with the post-famine group, famine births and pre-famine births were associated with increased risk of heart failure (OR: 1.96 [1.56-2.48] and OR: 1.62 [1.07-2.47], respectively). When compared with the age-balanced non-exposed group, the famine-exposed group was also significantly associated with increased risk of heart failure (OR: 1.32 [1.11-1.57]). The associations were stronger in participants with better economic status and in participants with hypertension, diabetes, and dyslipidemia (P for interaction < 0.05). Conclusion: Early life exposure to the Chinese famine is associated with an elevated risk of hospitalization for heart failure in adulthood.

The Relationship Between Famine Exposure During Early Life and Left Ventricular Hypertrophy in Adulthood.

Background: Although the evidence was still limited, some studies suggested that childhood malnutrition might affect cardiac function and structure in adulthood. To address the knowledge gap, this study investigated if the Great Chinese Famine exposure during early life had affected left ventricular hypertrophy (LVH). Methods: This research was a cross-sectional study. It included participants who had cardiac ultrasound assessments and were born in Guangdong, China, from 1 October 1952 to 30 September 1964. They were classified according to their exposure period to famine, namely, no exposure, fetal-, early-, mid-, and late childhood. Multivariate logistic regression and subgroup analysis have been conducted to determine the odds ratio (OR) and confidence intervals (CIs) between famine exposure and LVH. Results: This research included 2,543 participants, 1,612 women, their mean age was 59.07 ± 3.65 years, and 704 participants had LVH. LVH prevalence was 122 (23.6%), 87 (25.1%), 133 (27.3%), 184 (29.2%), and 178 (31.7%), in non-, fetal-, early-, mid-, and late-childhood exposed groups, respectively (p = 0.031), while in the non-exposed group, the ORs for developing carotid plaque as a result of fetal, early-, mid- to late-childhood exposure were 1.08 (95% CI: 0.76, 1.59, p = 0.619), 1.24 (95% CI: 1.03, 1.79, p = 0.031), 1.49 (95% CI: 1.10, 2.01, p = 0.009), and 1.64 (95% CI: 1.25, 2.18, p = 0.001), respectively (p for trend = 0.003). There was no interactive effect between gender, obesity, or hypertension history with how the famine influenced LVH, as the subgroups analyses demonstrated (all p for interaction > 0.05). Conclusion: This research has demonstrated the potential relationship between Great Chinese Famine exposure during childhood and LVH in adults.

The relationship between famine exposure during early life and ascending aorta dilatation in adults.

The relationship between exposure to famine in early life and the risk of ascending aorta dilatation (AAD) in adulthood is still unclear; therefore, we aimed to examine the association in the Chinese population. We investigated the data of 2598 adults who were born between 1952 and 1964 in Guangdong, China. All enrolled subjects were categorised into five groups: not exposed to famine, exposed during fetal period, and exposed during early, mid or late childhood. AAD was assessed by cardiac ultrasound. Multivariate logistic regression and interaction tests were performed to estimate the OR and CI on the association between famine exposure and AAD. There were 2598 (943 male, mean age 58·3 ± 3·68 years) participants were enrolled, and 270 (10·4 %) subjects with AAD. We found that famine exposure (OR = 2·266, 95 % CI 1·477, 3·477, P = 0·013) was associated with elevated AAD after adjusting for multiple confounders. In addition, compared with the non-exposed group, the adjusted OR for famine exposure during fetal period, early, mid or late childhood were 1·374 (95 % CI 0·794, 2·364, P = 0·251), 1·976 (95 % CI 1·243, 3·181, P = 0·004), 1·929 (95 % CI 1·237, 3·058, P = 0·004) and 2·227 (95 % CI 1·433, 3·524, P < 0·001), respectively. Subgroup analysis showed that the effect of famine exposure on the association with AAD was more pronounced in female, current smokers, people with BMI ≥ 24 kg/m2 and hypertensive patients. We observed that exposure to famine during early life was linked to AAD in adulthood.

Diverging targets mediate the pathological roleof miR-199a-5p and miR-199a-3p by promoting cardiac hypertrophy and fibrosis.

MicroRNA-199a-5p (miR-199a-5p) and -3p are enriched in the myocardium, but it is unknown whether miR-199a-5p and -3p are co-expressed in cardiac remodeling and what roles they have in cardiac hypertrophy and fibrosis. We show that miR-199a-5p and -3p are co-upregulated in the mouse and human myocardium with cardiac remodeling and in Ang-II-treated neonatal mouse ventricular cardiomyocytes (NMVCs) and cardiac fibroblasts (CFs). miR-199a-5p and -3p could aggravate cardiac hypertrophy and fibrosis in vivo and in vitro. PPAR gamma coactivator 1 alpha (Ppargc1a) and sirtuin 1 (Sirt1) were identified as target genes to mediate miR-199a-5p in promoting both cardiac hypertrophy and fibrosis. However, miR-199a-3p aggravated cardiac hypertrophy and fibrosis through targeting RB transcriptional corepressor 1 (Rb1) and Smad1, respectively. Serum response factor and nuclear factor κB p65 participated in the upregulation of miR-199a-5p and -3p in Ang-II-treated NMVCs and mouse CFs, and could be conversely elevated by miR-199a-5p and -3p. Together, Ppargc1a and Sirt1, Rb1 and Smad1 mediated the pathological effect of miR-199a-5p and -3p by promoting cardiac hypertrophy and fibrosis, respectively. This study suggests a possible new strategy for cardiac remodeling therapy by inhibiting miR-199a-5p and -3p.

LncRNA OTUD6B-AS1 promotes paclitaxel resistance in triple negative breast cancer by regulation of miR-26a-5p/MTDH pathway-mediated autophagy and genomic instability.

Genomic instability (GIN) is pivotal in regulating tumor drug resistance, which blocked the treatment of triple negative breast cancer (TNBC). Although recent studies implied that non-coding RNA (ncRNA)-mediated autophagy abolishment promoted tumorigenesis by up-regulation of GIN, autophagy was known as a risk factor in tumor drug resistance. However, previous study also pointed that up-regulation of autophagy promoted GIN. Therefore, the relationship between autophagy and GIN is not clear, and more work is needed. And, if an ncRNA is identified to be a co-regulator of autophagy and GIN, it will be a potential therapy target of chemotherapy resistance in TNBC. In our study, we recognized both autophagy-GIN-associated microRNA (mi-26a-5p) by big data analysis, which was prognosis-correlated in breast cancer. Next, we identified the up-stream regulators (long non-coding RNA, lncRNA) and down-stream targets of miR-26a-5p by bioinformatics analysis (online public databases). Finally, we established lncRNA OTUD6B-AS1/miR-26a-5p/MTDH signaling pathway, and verified their functions by cytological, molecular biological and zoological experiments. In general, our study found (1) miR-26a-5p was a protective factor of breast cancer, while OTUD6B-AS1 and MTDH were risk factors; (2) OTUD6B-AS1 was the up-stream regulator of miR-26a-5p verified by luciferase; (3) up-regulation of miR-26a-5p and down-regulation of MTDH promoted cellular cytotoxicity of paclitaxel (PTX) in vitro and in vivo. (4) down-regulation of miR-26a-5p, overexpression of MTDH and OTUD6B-AS1 promoted autophagy and DNA damage; (5) up-regulation of OTUD6B-AS1 and MTDH inhibited DNA damage response (DDR) by inhibiting the phosphorylated activation of RAD51, ATR and ATM.

Relationship Between Change in Serum Uric Acid and Ischemic Stroke in Chinese Hypertensive Patients.

Background: Limited studies focused on the association between serum uric acid (SUA) change with ischemic stroke, and their results remain controversial. The present study aimed to investigate the relationship between change in SUA with ischemic stroke among hypertensive patients. Method: This was a retrospective cohort study. We recruited adult hypertensive patients who had two consecutive measurements of SUA levels from 2013 to 2014 and reported no history of stroke. Change in SUA was assessed as SUA concentration measured in 2014 minus SUA concentration in 2013. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The Kaplan-Meier analysis and log-rank test were performed to quantify the difference in cumulative event rate. Additionally, subgroup analysis and interaction tests were conducted to investigate heterogeneity. Results: A total of 4,628 hypertensive patients were included, and 93 cases of ischemic stroke occurred during the mean follow-up time of 3.14 years. Participants were categorized into three groups according to their SUA change tertiles [low (SUA decrease substantially): <-32.6 µmol/L; middle (SUA stable): ≥-32.6 µmol/L, <40.2 µmol/L; high (SUA increase substantially): ≥40.2 µmol/L]. In the fully adjusted model, setting the SUA stable group as reference, participants in the SUA increase substantially group had a significantly elevated risk of ischemic stroke [HR (95% CI), 1.76 (1.01, 3.06), P = 0.0451], but for the SUA decrease substantially group, the hazard effect was insignificant [HR (95% CI), 1.31 (0.75, 2.28), P = 0.3353]. Age played an interactive role in the relationship between SUA change and ischemic stroke. Younger participants (age < 65 years) tended to have a higher risk of ischemic stroke when SUA increase substantially. Conclusion: SUA increase substantially was significantly correlated with an elevated risk of ischemic stroke among patients with hypertension.

Association of Circulating, Inflammatory-Response Exosomal mRNAs With Acute Myocardial Infarction.

Background: Although many cardiovascular disease studies have focused on the microRNAs of circulating exosomes, the profile and the potential clinical diagnostic value of plasma exosomal long RNAs (exoLRs) are unknown for acute myocardial infarction (AMI). Methods: In this study, the exoLR profile of 10 AMI patients, eight stable coronary artery disease (CAD) patients, and 10 healthy individuals was assessed by RNA sequencing. Bioinformatic approaches were used to investigate the characteristics and potential clinical value of exoLRs. Results: Exosomal mRNAs comprised the majority of total exoLRs. Immune cell types analyzed by CIBERSORT showed that neutrophils and monocytes were significantly enriched in AMI patients, consistent with clinical baseline values. Biological process enrichment analysis and co-expression network analysis demonstrated neutrophil activation processes to be enriched in AMI patients. Furthermore, two exosomal mRNAs, ALPL and CXCR2, were identified as AMI biomarkers that may be useful for evaluation of the acute inflammatory response mediated by neutrophils. Conclusions: ExoLRs were assessed in AMI patients and found to be associated with the acute inflammatory response mediated by neutrophils. Exosomal mRNAs, ALPL and CXCR2, were identified as potentially useful biomarkers for the study of AMI.

A U-Shaped Relationship Between Selenium Concentrations and All-Cause or Cardiovascular Mortality in Patients With Hypertension.

Background: Given the antioxidant activity of selenium, it has been reported benefits for blood pressure control and hypertension prevention, but few studies have investigated the association between serum selenium with mortality in hypertensive population. Methods: All participants with hypertension aged ≥18 years at baseline were recruited from the National Health and Nutritional Examination Surveys (NHANES) 2003-2004, and followed for mortality through December 31, 2015. Subjects were categorized by quartiles of serum selenium (Q1: ≤124 µg/L, Q2: 125-135 µg/L, Q3: 136-147 µg/L, Q4: ≥148 µg/L). Multivariate Cox regression were implemented to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Restricted cubic spline analysis and two-piecewise linear regression were used to evaluate the relationship of serum selenium with mortality. Survival curves were used to depict cause-specific mortalities. Results: A total of 929 participants (52.53% were male) were eligible for the current study with the average age of 63.10 ± 12.59 years. There were 307 deaths occurred including 56 cardiovascular death events during the mean follow-up time of 121.05 ± 40.85 months. A U-shaped association was observed between serum selenium and all-cause or cardiovascular mortality. In fully adjusted model, comparisons among quartiles revealed that risks of all-cause [HR (95%CI), 0.57 (0.39-0.81)] and cardiovascular death [HR (95%CI), 0.33 (0.13-0.86)] were lower in Q3. The nadir mortality of all-cause and cardiovascular was occurred at the serum selenium level of 136 µg/L and 130 µg/L, respectively. Conclusion: Serum selenium concentration showed a U-shaped association with all-cause and cardiovascular mortality.

The Potential Immunomodulatory Properties of Levornidazole Contribute to Improvement in Experimental Ulcerative Colitis.

The use of an antibiotic with immunomodulatory properties could be fascinating in treating multifactorial inflammatory conditions such as ulcerative colitis (UC). We report our investigations into the immunomodulatory properties of levornidazole, the S-enantiomer of ornidazole, which displayed a tremendous therapeutic potential in UC induced by dextran sodium sulfate (DSS). Levornidazole administration to DSS-colitic mice attenuated the intestinal inflammatory process, with an efficacy better than that shown by 5-amino salicylic acid. This was evidenced by decreased disease activity index, ameliorated macroscopic and microscopic colon damages, and reduced expression of inflammatory cytokines. Additionally, levornidazole displayed anti-inflammatory activity through Caveolin-1-dependent reducing IL-1ß and IL-18 secretion by macrophages contributing to its improvement of the intestinal inflammation, as confirmed in vitro and in vivo. In conclusion, these results pointed out that the immunomodulatory effects of levornidazole played a vital role in ameliorating the intestinal inflammatory process, which would be crucial for the translation of its use into clinical settings.

The U-Shaped Association of Non-High-Density Lipoprotein Cholesterol Levels With All-Cause and Cardiovascular Mortality Among Patients With Hypertension.

Background: Non-high-density lipoprotein cholesterol (non-HDL-C) is a valuable indicator in routine blood lipid tests, but the associations of non-HDL-C with mortality in hypertensive population still remain uncertain. Methods: In the National Health and Nutrition Examination Surveys from 1999 to 2014, participants having hypertension were included and grouped by non-HDL-C levels (<130, 130-159, 160-189, 190-219, and ≥220 mg/dl). Multivariate Cox regression was conducted for calculation of hazard ratios (HR) and 95% confidence interval (CI). To reveal the relationship between non-HDL-C and mortality, Kaplan-Meier survival curves, restricted cubic spline, linear regression, and subgroup analysis were also applied. Results: A total of 12,169 participants (47.52% males, mean age 57.27 ± 15.79 years) were included. During average follow-up of 92.5 months, 1,946 (15.99%) all-cause deaths and 422 (3.47%) cardiovascular deaths occurred. After adjusting for confounders, the association of non-HDL-C with mortality was detected as U-shaped. Threshold values were observed at 158 mg/dl for all-cause mortality and 190 mg/dl as to cardiovascular mortality. Below the threshold, every 10 mg/dl increment in non-HDL-C attributed to relatively low all-cause mortality significantly (HR = 0.94, 95% CI: 0.92-0.96). Above the threshold, non-HDL-C has significant positive associations with both all-cause (HR = 1.03, 95% CI: 1.01-1.05) and cardiovascular mortality (HR = 1.09, 95% CI: 1.05-1.14). For subgroups analysis, similar results were found among participants age <65 years old, non-white population, those were not taking lipid-lowering drugs, and subjects with body mass index (BMI) ≥25 kg/m2. Conclusion: The U-shaped association was detected between non-HDL-C and mortality among hypertensive population.