Hyperoside protects against oxidative stress-mediated photoreceptor degeneration: therapeutic potentials for photoreceptor degenerative diseases.

BACKGROUND: Photoreceptor degeneration underpinned by oxidative stress-mediated mitochondrial dysfunction and cell death leads to progressive and irreversible vision impairment. Drug treatments that protect against photoreceptor degeneration are currently available in the clinical settings. It has been shown that hyperoside, a flavonol glycoside, protects against neuronal loss in part by suppressing oxidative stress and maintaining the functional integrity of mitochondria. However, whether hyperoside protects against photoreceptor degeneration remains unknown. METHODS: To address the pharmacological potentials of hyperoside against oxidative stress-mediated photoreceptor degeneration on molecular, cellular, structural and functional levels, multiple in vitro and in vivo methodologies were employed in the current study, including live-cell imaging, optical coherence tomography, electroretinography, histological/immunohistochemical examinations, transmission electron microscopy, RNA-sequencing and real-time qPCR. RESULTS: The in vitro results demonstrate that hyperoside suppresses oxidative stress-mediated photoreceptor cell death in part by mitigating mitochondrial dysfunction. The in vivo results reveal that hyperoside protects against photooxidative stress-induced photoreceptor morphological, functional and ultrastructural degeneration. Meanwhile, hyperoside treatment offsets the deleterious impact of photooxidative stress on multiple molecular pathways implicated in the pathogenesis of photoreceptor degeneration. Lastly, hyperoside attenuates photoreceptor degeneration-associated microglial inflammatory activation and reactive Müller cell gliosis. CONCLUSIONS: All things considered, the present study demonstrates for the first time that hyperoside attenuates oxidative stress-induced photoreceptor mitochondrial dysfunction and cell death. The photoreceptor-intrinsic protective effects of hyperoside are corroborated by hyperoside-conferred protection against photooxidative stress-mediated photoreceptor degeneration and perturbation in retinal homeostasis, warranting further evaluation of hyperoside as a photoreceptor protective agent for the treatment of related photoreceptor degenerative diseases.

Comparison of X-ray Radiant Power Absolute Measurement between a Free-Air Ionization Chamber and a Cryogenic Electrical Substitution Radiometer.

Absolute measurement of radiant power in the X-ray region is essential for many applications in astrophysics, spectroscopy, and X-ray diagnostics. Comparison between different measuring methods is an effective way to check their reliability. In the present work, a comparison of X-ray radiant power absolute measurement between a free-air ionization chamber and a cryogenic electrical substitution radiometer was performed at Beijing Synchrotron Radiation Facility. The absolute radiant power obtained by these two methods were mutually compared via a transfer standard detector's spectral responsivity at a photon energy of 10 keV. The result of the comparison showed that the difference was 0.47%. A conclusion was reached that the free-air ionization chamber and the cryogenic electrical substitution radiometer agreed within the combined relative uncertainty of 3.35%.

The Flooring for Injury Prevention (FLIP) Study of compliant flooring for the prevention of fall-related injuries in long-term care: A randomized trial.

BACKGROUND: Fall-related injuries exert an enormous health burden on older adults in long-term care (LTC). Softer landing surfaces, such as those provided by low-stiffness "compliant" flooring, may prevent fall-related injuries by decreasing the forces applied to the body during fall impact. Our primary objective was to assess the clinical effectiveness of compliant flooring at preventing serious fall-related injuries among LTC residents. METHODS AND FINDINGS: The Flooring for Injury Prevention (FLIP) Study was a 4-year, randomized superiority trial in 150 single-occupancy resident rooms at a single Canadian LTC site. In April 2013, resident rooms were block randomized (1:1) to installation of intervention compliant flooring (2.54 cm SmartCells) or rigid control flooring (2.54 cm plywood) covered with identical hospital-grade vinyl. The primary outcome was serious fall-related injury over 4 years that required an emergency department visit or hospital admission and a treatment procedure or diagnostic evaluation in hospital. Secondary outcomes included minor fall-related injury, any fall-related injury, falls, and fracture. Outcomes were ascertained by blinded assessors between September 1, 2013 and August 31, 2017 and analyzed by intention to treat. Adverse outcomes were not assessed. During follow-up, 184 residents occupied 74 intervention rooms, and 173 residents occupied 76 control rooms. Residents were 64.3% female with mean (SD) baseline age 81.7 (9.5) years (range 51.1 to 104.6 years), body mass index 25.9 (7.7) kg/m2, and follow-up 1.64 (1.39) years. 1,907 falls were reported; 23 intervention residents experienced 38 serious injuries (from 29 falls in 22 rooms), while 23 control residents experienced 47 serious injuries (from 34 falls in 23 rooms). Compliant flooring did not affect odds of ≥1 serious fall-related injury (12.5% intervention versus 13.3% control, odds ratio [OR]: 0.98, 95% CI: 0.52 to 1.84, p = 0.950) or ≥2 serious fall-related injuries (5.4% versus 7.5%, OR: 0.74, 95% CI: 0.31 to 1.75, p = 0.500). Compliant flooring did not affect rate of serious fall-related injuries (0.362 versus 0.422 per 1,000 bed nights, rate ratio [RR]: 1.04, 95% CI: 0.45 to 2.39, p = 0.925; 0.038 versus 0.053 per fall, RR: 0.81, 95% CI: 0.38 to 1.71, p = 0.560), rate of falls with ≥1 serious fall-related injury (0.276 versus 0.303 per 1,000 bed nights, RR: 0.97, 95% CI: 0.52 to 1.79, p = 0.920), or time to first serious fall-related injury (0.237 versus 0.257, hazard ratio [HR]: 0.92, 95% CI: 0.52 to 1.62, p = 0.760). Compliant flooring did not affect any secondary outcome in this study. Study limitations included the following: findings were specific to 2.54 cm SmartCells compliant flooring installed in LTC resident rooms, standard fall and injury prevention interventions were in use throughout the study and may have influenced the observed effect of compliant flooring, and challenges with concussion detection in LTC residents may have prevented estimation of the effect of compliant flooring on fall-related concussions. CONCLUSIONS: In contrast to results from previous retrospective and nonrandomized studies, this study found that compliant flooring underneath hospital-grade vinyl was not effective at preventing serious fall-related injuries in LTC. Future studies are needed to identify effective methods for preventing fall-related injuries in LTC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01618786.

Assessment of Cardiac Lead Perforation: Comparison Among Chest Radiography, Transthoracic Echocardiography and Electrocardiography-gated Contrast-enhanced Cardiac CT.

OBJECTIVES: Cardiac lead perforation is a rare but potentially life-threatening event. The purpose of this study was to investigate the diagnostic performances of chest radiography, transthoracic echocardiography (TTE) and electrocardiography (ECG)-gated contrast-enhanced cardiac CT in the assessment of cardiac lead perforation. METHODS: This retrospective study was approved by the ethics review board of Sun Yat-Sen Memorial Hospital at Sun Yat-Sen University (Guangzhou, China), and the need to obtain informed consent was waived. Between May 2010 and Oct 2017, 52 patients were clinically suspected to have a cardiac lead perforation and received chest radiography, TTE and ECG-gated contrast-enhanced cardiac CT. Among them, 13 patients were identified as having cardiac lead perforation. The diagnostic performances of these three modalities were evaluated by receiver-operating characteristic (ROC) curves using a composite reference standard of surgical and electrophysiological results and clinical follow-up. The areas under ROCs (AUROCs) were compared with the McNemar test. RESULTS: The accuracies of chest radiography, TTE and ECG-gated contrast-enhanced cardiac CT imaging for the diagnosis of cardiac lead perforation were 73.1%, 82.7% and 98.1%, respectively. ECG-gated contrast-enhanced cardiac CT had a higher AUROC than chest radiography (p < 0.001) and TTE (p < 0.001). CONCLUSIONS: ECG-gated contrast-enhanced cardiac CT is superior to both chest radiography and TTE imaging for the assessment of cardiac lead perforation. KEY POINTS: • ECG-gated contrast-enhanced cardiac CT has an accuracy of 98.1% in the diagnosis of cardiac lead perforation. • The AUROC of ECG-gated contrast-enhanced cardiac CT is higher than those of chest radiography and TTE imaging. • ECG-gated contrast-enhanced cardiac CT imaging has better diagnostic performance than both chest radiography and TTE imaging for the assessment of cardiac lead perforation.

Direct repression of IGF2 is implicated in the anti-angiogenic function of microRNA-210 in human retinal endothelial cells.

Pathological angiogenesis leads to the development of retinal vasculopathies and causes severe vision impairment. Increased understanding of the mechanisms underlying the angiogenic behavior of retinal endothelial cells helps provide new insights for developing treatment of retinal vasculopathies. Pro-angiogenic function of miR-210 has previously been identified. However, the functional implication of miR-210 in retinal endothelial cells remains unknown. Human retinal microvascular endothelial cells (HRECs) were employed to investigate the impact of miR-210 on the angiogenic capacity of retinal endothelial cells. It was observed that without affecting the viability of HRECs, miR-210 significantly suppressed the migration and capillary-like tube formation in HRECs. Moreover, pro-angiogenic insulin growth factor 2 (IGF2) was newly identified as a direct target of miR-210 in HRECs. MiR-210 decreased the expression of IGF2 at both mRNA and protein levels in HRECs. IGF2-simulated activation of p38 MAPK was attenuated by miR-210 in HRECs. Recombinant IGF2 protein rescued miR-210-induced impairment of tube formation in HRECs. Therefore, in contrast to the previously reported pro-angiogenic function of miR-210, the current work reveals novel anti-angiogenic activity of miR-210 in HRECs. Furthermore, IGF2 is identified for the first time as a direct target of miR-210 in HRECs, adding new mechanistic insights into the expression regulation of pro-angiogenic IGF2 in human retinal endothelial cells. The current work helps increase the understanding of regulatory mechanisms underlying retinal endothelial cell physiology, justifying further evaluation for the therapeutic implications of miR-210/IGF2 interaction in the treatment of related retinal vasculopathies.

Interactive effects of nonylphenol and bisphenol A exposure with oxidative stress on fetal reproductive indices.

Nonylphenol (NP) and/or bisphenol A (BPA) may have reproductive effects. Although the mechanisms of action remain unclear, steroid hormones biosynthesis, hypothalamus pituitary adrenal axis activity, oxidative stress, and crosstalk interaction of NP and BPA mixture and its pathways may play a contributory role. This cross-sectional study examined whether the interactive effects of NP/BPA and oxidative stress biomarkers played a role in reproductive indices (penis length and anogenital distance (AGD)) in 244 mother-fetus pairs. Four biomarkers of oxidative stress, (8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-nitroguanine (8-NO2Gua), 8-iso-prostaglandin F2α (8-isoPF2α), and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)) were simultaneously analyzed using the high-performance liquid chromatography-electrospray ionization tandem mass spectrometry method. No significant associations were found between reproductive indices and NP/BPA or oxidative stress biomarkers. Maternal exposure to a mixture of NP and BPA may enhance 8-OHdG. Interactive effects were found in the high 8-isoPF2α group, and prenatal NP exposure was inversely associated with penis length (ß = -3.68 mm; p = 0.01). Similar results were noted among boys who were born to mothers in the high 8-isoPF2α group, in which BPA was inversely associated with penis length (ß = -4.43 mm; p = 0.005). Our findings suggest important implications for prenatal exposure to oxidative stress, as evidenced by the 8-isoPF2α level. Thus, NP and BPA may interact to shape fetal reproductive tract development, particularly in boys. The interactive effects of NP/BPA, oxidative stress, and reproductive indices should be considered.

Prenatal Nonylphenol and Bisphenol A Exposures and Inflammation Are Determinants of Oxidative/Nitrative Stress: A Taiwanese Cohort Study.

Prenatal exposure to nonylphenol (NP) and/or bisphenol A (BPA) has been reported to be associated with adverse birth outcomes; however, the underlying mechanisms remain unclear. The primary mechanism is endocrine disruption of the binding affinity for the estrogen receptor, but oxidative stress and inflammation might also play a contributory role. We aimed to investigate urinary NP and BPA levels in relation to biomarkers of oxidative/nitrative stress and inflammation and to explore whether changes in oxidative/nitrative stress are a function of prenatal exposure to NP/BPA and inflammation in 241 mother-fetus pairs. Third-trimester urinary biomarkers of oxidative/nitrative stress were simultaneously measured, including products of oxidatively and nitratively damaged DNA (8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-nitroguanine (8-NO2Gua)) as well as products of lipid peroxidation (8-iso-prostaglandin F2α (8-isoPF2α) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)). The antioxidant glutathione peroxidase (GPx) and inflammation biomarkers, including C-reactive protein (CRP) and a panel of cytokines (interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)), were analyzed in maternal and umbilical cord plasma samples. In adjusted models, we observed significant positive associations between NP exposure and 8-OHdG and 8-NO2Gua levels, between BPA and 8-isoPF2α levels, and between maternal CRP levels and HNE-MA levels. Additionally, BPA and TNF-α levels in cord blood were inversely associated with maternal and GPx levels in cord blood as well as maternal TNF-α levels were inversely associated with maternal GPx levels. These results support a role for exposure to NP and BPA and possibly inflammation in increasing oxidative/nitrative stress and decreasing antioxidant activity during pregnancy.

Luteolin-7-diglucuronide attenuates isoproterenol-induced myocardial injury and fibrosis in mice.

Myocardial injury and ensuing fibrotic alterations impair normal heart architecture and cause cardiac dysfunction. Oxidative stress has been recognized as a key player in the pathogenesis of cardiac injury and progression of cardiac dysfunction, and promoting fibrosis. In the current study we investigated whether luteolin-7-diglucuronide (L7DG), a naturally occurring antioxidant found in edible plants, could attenuate isoproterenol (ISO)-induced myocardial injury and fibrosis in mice and the underlying mechanisms. Myocardial injury and fibrosis were induced in mice via injection of ISO (5 mg·kg-1·d-1, ip) for 5 or 10 d. Two treatment regimens (pretreatment and posttreatment) were employed to administer L7DG (5-40 mg·kg-1·d-1, ip) into the mice. After the mice were euthanized, morphological examinations of heart sections revealed that both L7DG pretreatment and posttreatment regimens significantly attenuated ISO-induced myocardial injury and fibrosis. But the pretreatment regimen caused better protection against ISO-induced myocardial fibrosis than the posttreatment regimen. Furthermore, L7DG pretreatment blocked ISO-stimulated expression of the genes (Cyba, Cybb, Ncf1, Ncf4 and Rac2) encoding the enzymatic subunits of NADPH oxidase, which was the primary source of oxidant production in mammalian cells. Moreover, L7DG pretreatment significantly suppressed ISO-stimulated expression of collagen genes Col1a1, Col1a2, Col3a1, and Col12a1 and non-collagen extracellular matrix genes fibrillin-1, elastin, collagen triple helix repeat containing 1 and connective tissue growth factor. In addition, L7DG pretreatment almost reversed ISO-altered expression of microRNAs that were crosstalking with TGFß-mediated fibrosis, including miR-29c-3p, miR-29c-5p, miR-30c-3p, miR-30c-5p and miR-21. The current study demonstrated for the first time that L7DG is pharmacologically effective in protecting the heart against developing ISO-induced injury and fibrosis, justifying further evaluation of L7DG as a cardioprotective agent to treat related cardiovascular diseases.

Celastrol protects mouse retinas from bright light-induced degeneration through inhibition of oxidative stress and inflammation.

BACKGROUND: Photoreceptor death leads to vision impairment in several retinal degenerative disorders. Therapies protecting photoreceptor from degeneration remain to be developed. Anti-inflammation, anti-oxidative stress, and neuroprotective effects of celastrol have been demonstrated in a variety of disease models. The current study aimed to investigate the photoreceptor protective effect of celastrol. METHODS: Bright light-induced retinal degeneration in BALB/c mice was used, and morphological, functional, and molecular changes of retina were evaluated in the absence and presence of celastrol treatment. RESULTS: Significant morphological and functional protection was observed as a result of celastrol treatment in bright light-exposed BALB/c mice. Celastrol treatment resulted in suppression of cell death in photoreceptor cells, alleviation of oxidative stress in the retinal pigment epithelium and photoreceptors, downregulation of retinal expression of proinflammatory genes, and suppression of microglia activation and gliosis in the retina. Additionally, leukostasis was found to be induced in the retinal vasculature in light-exposed BALB/c mice, which was significantly attenuated by celastrol treatment. In vitro, celastrol attenuated all-trans-retinal-induced oxidative stress in cultured APRE19 cells. Moreover, celastrol treatment significantly suppressed lipopolysaccharides-stimulated expression of proinflammatory genes in both APRE19 and RAW264.7 cells. CONCLUSIONS: The results demonstrated for the first time that celastrol prevents against light-induced retinal degeneration through inhibition of retinal oxidative stress and inflammation.

Apocynin attenuates isoproterenol-induced myocardial injury and fibrogenesis.

Oxidative stress is mechanistically implicated in the pathogenesis of myocardial injury and the subsequent fibrogenic tissue remodeling. Therapies targeting oxidative stress in the process of myocardial fibrogenesis are still lacking and thus remain as an active research area in myocardial injury management. The current study evaluated the effects of a NADPH oxidase inhibitor, apocynin, on the production of reactive oxygen species and the development of myocardial fibrogenesis in isoproterenol (ISO)-induced myocardial injury mouse model. The results revealed a remarkable effect of apocynin on attenuating the development of myocardial necrotic lesions, inflammation and fibrogenesis. Additionally, the protective effects of apocynin against myocardial injuries were associated with suppressed expression of an array of genes implicated in inflammatory and fibrogenic responses. Our study thus provided for the first time the histopathological and molecular evidence supporting the therapeutic value of apocynin against the development of myocardial injuries, in particular, myocardial fibrogenesis, which will benefit the mechanism-based drug development targeting oxidative stress in preventing and/or treating related myocardial disorders.

Nonylphenol in pregnant women and their matching fetuses: placental transfer and potential risks of infants.

As the predominant environmental biodegradation product of nonylphenol (NP) ethoxylates and with proven estrogenic effects, NP is formed during the alkylation process of phenols. The purposes of this study were (1) to examine maternal and prenatal exposure to NP in Taiwan, (2) to determine the level of placental protection against NP exposure as well as the level of NP in breast milk, and (3) to assess the potential risk for breastfed newborns exposed to NP through the milk. Thirty pairs of maternal and fetal blood samples, placenta, and breast milk during the 1st and the 3rd months of lactation were collected. External NP exposures of these specimens were then analyzed by using high-performance liquid chromatography coupling with fluorescence detection. Next, the socio-demographics, lifestyle, delivery method, dietary and work history were collected using a questionnaire. In addition, the daily intake of NP from consuming breast milk in the 1st and 3rd months for newborns was studied through deterministic and probabilistic risk assessment methods. The geometric means and geometric standard deviation of NP levels in maternal blood, fetal cord blood, placenta, and breast milk in the 1st and 3rd months were 14.6 (1.7) ng/ml, 18.8 (1.8) ng/ml, 19.8 (1.9) ng/g, 23.5 (3.2) ng/ml, and 57.3 (1.4) ng/ml, respectively. The probabilistic percentiles (50th, 75th, and 95th) of daily intake NP in breast milk were 4.33, 7.79, and 18.39 µg/kg-bw/day in the 1st month, respectively, and were 8.11, 10.78, 16.08 µg/kg-bw/day in the 3rd month, respectively. The probabilistic distributions (5th, 25th, and 50th) of risk for infants aged 1 month old were 0.27, 0.64, and 1.15, respectively, and that for infants aged 3 month old were 0.31, 0.46, and 0.62, respectively. Through repeated exposure from the dietary intake of expectant mothers, fetuses could encounter a high NP exposure level due to transplacental absorption, partitioning between the maternal and fetal compartments. Daily NP intake via breast milk in three month-old babies exceeded the tolerable daily intake (TDI) of 5 µg/kg bw/day indicated a potential risk for Taiwan infants.

Bidirectional regulation of angiogenesis and miR-18a expression by PNS in the mouse model of tumor complicated by myocardial ischemia.

BACKGROUND: Panax Notoginseng Saponins (PNS) is the major class of active constituents of notoginseng, a natural product extensively used as a therapeutic agent in China. Tumor when accompanied by cardiovascular disorders poses a greater challenge for clinical management given the paradoxical involvement of angiogenesis, therefore gaining increased research attention. This study aim to investigate effects of PNS and its activity components in the mouse model of tumor complicated with myocardial ischemia. METHODS: Tumor complexed with myocardial ischemia mouse model was first established, which was followed by histological and immunohistochemistry examination to assess the effect of indicated treatments on tumor, myocardial ischemia and tissue specific angiogenesis. MicroRNA (miRNA) profiling was further carried out to identify potential miRNA regulators that might mechanistically underline the therapeutic effects of PNS in this complex model. RESULTS: PNS and its major activity components Rg1, Rb1 and R1 suppressed tumor growth and simultaneously attenuated myocardial ischemia. PNS treatment led to decreased expression of CD34 and vWF in tumor and increased expression of these vascular markers in heart. PNS treatment resulted in reduced expression of miR-18a in tumor and upregulated expression of miR-18a in heart. CONCLUSIONS: Our data demonstrated for the first time that PNS exerts tissue specific regulatory effects on angiogenesis in part through modulating the expression of miR-18a, which could be responsible for its bidirectional effect on complex disease conditions where paradoxical angiogenesis is implicated. Therefore, our study provides experimental evidence warranting evaluation of PNS and related bioactive component as a rational therapy for complex disease conditions including co-manifestation of cancer and ischemic cardiovascular disease.

Prenatal and childhood neonicotinoid exposure and neurodevelopment: A study in a young Taiwanese cohort.

Neonicotinoid insecticides (NEOs) dominate the global pesticide market because of their low cost and effectiveness. However, epidemiological studies regarding the potential adverse health effects of exposure to NEOs before birth and in early childhood are limited. Therefore, this study investigated the associations between NEO exposure before birth and during early childhood and neurodevelopment. A total of 273 mother-child pairs were enrolled in this study. Mothers provided urine samples in the third trimester and breast milk during the first and third months of lactation. Their children provided urine samples and were evaluated for neurodevelopment by using the Bayley Scales of Infant and Toddler Development, Third Edition at 2-3 years (N = 96) and the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) at 4-6 years (N = 63). The sum of the concentrations of seven NEOs (ΣNEOs) and the relative potency factor of NEOs, based on comparison with imidacloprid (IMIRPF), were used to assess total exposure to NEOs. Multivariate linear regression analyses were conducted to assess the associations between prenatal and childhood exposure to NEOs and neurodevelopment. The results of the analysis revealed that clothianidin (CLO) and thiamethoxam were the most common NEOs to which children in the Taipei metropolitan area were exposed and that exposure concentrations were high in the Taipei metropolitan area. Imidacloprid was the most frequently detected NEO during the postnatal period. Additionally, exposure to NEOs through breast milk was low. Exposure to CLO, ΣNEOs, and IMIRPF in boys aged 4-6 years was negatively correlated with WPPSI-IV Fluid Reasoning Index. The results of this study indicate that exposure during the third trimester to NEOs does not affect neurodevelopment but that childhood exposure to NEOs may, especially for boys. Further studies with larger sample sizes are required to confirm the sex-specific associations between NEO exposure and neurodevelopment.

Prenatal to preschool exposure of nonylphenol and bisphenol A exposure and neurodevelopment in young children.

BACKGROUND: Nonylphenol (NP) and bisphenol A (BPA) are produced in large quantities worldwide as multipurpose agents. However, studies on relations between NP and BPA exposure and childhood neurodevelopment are few, and the results are inconsistent. This study aimed to investigate associations between prenatal and early childhood NP and BPA exposure and neurodevelopment in mother-child pairs. METHODS: Pregnant women at 27-38 weeks' gestation were recruited, as were children 2-3 years of age (n = 94) and 4-6 years of age (n = 56) years. Urine was collected to assess NP and BPA exposure. Bayley Scales of Infant and Toddler Development (3rd edition; Bayley-III), Wechsler Preschool and Primary Scale of Intelligence (4th edition), and the Full Scale Intelligence Quotient (WPPSI-IV-FSIQ) were used to assess the neurodevelopment of the children. RESULTS: The detection rate and concentration of NP and BPA in the urine of children 4-6 years old were higher than in those 2-3 years old. Children were divided into a high concentration group (3rd tertile) and a reference group (1st and 2nd tertiles) based on natural log-transformed urine concentration of NP and BPA. Girls' Bayley-III motor scores in the high concentration group were higher than those of the BPA reference group of urine of mothers (ß = 6.85, 95% confidence interval [CI]: 1.58-12.13). Boys' FSIQ in the higher concentration group were significantly lower than those in children 2-3 years old in the NP reference group (ß = -11.29, 95% CI: -18.62 to -3.96) (all, p < 0.05). CONCLUSIONS: Prenatal and childhood exposure to NP and BPA may have different effects on the neurodevelopment of young children, and there are no consistent effects between boys and girls.

Ginsenoside Rb1 mitigates acute catecholamine surge-induced myocardial injuries in part by suppressing STING-mediated macrophage activation.

Stress cardiomyopathy (SCM) is associated with cardiovascular mortality rates similar to acute coronary syndrome. Myocardial injuries driven by inflammatory mechanisms may in part account for the dismal prognosis of SCM. Currently, no inflammation-targeted therapies are available to mitigate SCM-associated myocardial injuries. In this study, acute catecholamine surge-induced SCM was modeled by stimulating the ovariectomized (OVX) mice with isoproterenol (ISO). The effects of ginsenoside Rb1 (Rb1) on SCM-associated myocardial injuries were assessed in the OVX-ISO compound mice. RAW 264.7 macrophages stimulated with calf thymus DNA (ctDNA) or STING agonist DMXAA were adopted to further understand the anti-inflammatory mechanisms of Rb1. The results show that estrogen deprivation increases the susceptibility to ISO-induced myocardial injuries. Rb1 mitigates myocardial injuries and attenuates cardiomyocyte necrosis as well as myocardial inflammation in the OVX-ISO mice. Bioinformatics analysis suggests that cytosolic DNA-sensing pathway is closely linked with ISO-triggered inflammatory responses and cell death in the heart. In macrophages, Rb1 lowers ctDNA-stimulated production of TNF-α, IL-6, CCL2 and IFN-ß. RNA-seq analyses uncover that Rb1 offsets DNA-stimulated upregulation in multiple inflammatory response pathways and cytosolic DNA-sensing pathway. Furthermore, Rb1 directly mitigates DMXAA-stimulated STING activation and inflammatory responses in macrophages. In conclusion, the work here demonstrates for the first time that Rb1 protects against SCM-associated myocardial injuries in part by counteracting acute ISO stress-triggered cardiomyocyte necrosis and myocardial inflammation. Moreover, by evidencing that Rb1 downregulates cytosolic DNA-sensing machineries in macrophages, our findings warrant further investigation of therapeutic implications of the anti-inflammatory Rb1 in the treatment of SCM.

Study on the relationship between atrial high-rate episode and left atrial strain in patients with cardiac implantable electronic device.

Background: Although atrial high-rate episode (AHRE) and atrial fibrillation (AF) cannot entirely be identical, recent studies suggest AHRE is linked to AF development and shares some characteristics with AF regarding thromboembolism. At present, there is still lack of predictive indicators for AHRE and diagnostic methods and clinical indicators for AHRE in patients without cardiac implantable electronic device (CIED). The aim of this study was thus to explore the relationship between AHRE and left atrial (LA) strain parameters with the goal of identifying high-risk populations of AHRE by LA strain characteristics. Methods: From February 2022 to May 2023, a total of 105 CIED patients were enrolled and divided into two groups based on whether AHRE had occurred: AHRE (-) group (n=65) and AHRE (+) group (n=40). Real-time three-dimensional echocardiography (RT-3DE) technique was used to obtain the LA time-volume curve. The collected dynamic images were analyzed on the Echopac 204 workstation to obtain the parameters of LA. The four-dimensional automatic LA quantitative analysis (4D Auto LAQ) technology was used to analyze the LA strain parameters: LA reservoir longitudinal strain (LASr), LA conduit longitudinal strain (LAScd), LA contraction longitudinal strain (LASct), LA reservoir circumferential strain (LASr-c), LA conduit circumferential strain (LAScd-c), LA contraction circumferential strain (LASct-c). Correlation analysis was carried out using Binary logistic regression analysis. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the diagnostic performance of LASct in AHRE. Results: Body surface area (BSA) [odds ratio (OR) =8.34, 95% confidence interval (CI): 1.32-72.30, P=0.037], LASct (OR =1.20, 95% CI: 1.05-1.39, P=0.013) and LA end-systolic volume (LAESV) (OR =1.02, 95% CI: 1.00-1.04, P=0.023) were the influencing factors of AHRE. Only LASct (OR =1.18, 95% CI: 1.01-1.38, P=0.041) was found to be an independent influencing factor of AHRE. This result remained significant after adjusting for age, sex, hypertension, diabetes, and stroke history. The ROC curve showed that the cut-off for predicting AHRE was LASct =-4.125% with sensitivity of 37.5% and specificity of 87.7%. Conclusions: This cross-sectional study found that decreased LASct (absolute value) is an independent risk factor for the AHRE and has diagnostic efficacy in certain degree for the occurrence of AHRE.

Cinnamic acid mitigates left ventricular hypertrophy and heart failure in part through modulating FTO-dependent N6-methyladenosine RNA modification in cardiomyocytes.

Left ventricular hypertrophy leads to heart failure, a serious medical condition associated with high rates of hospitalization and mortality. Limited success with the existing pharmacological treatments necessitates the development of mechanisms-based new therapies to better control the progression from left ventricular hypertrophy to heart failure. The current work investigated the pharmacological potentials and mechanisms of naturally occurring cinnamic acid in the treatment of left ventricular hypertrophy and heart failure. The in vitro findings reveal that cinnamic acid attenuates the hypertrophic responses and mitochondrial dysfunction in the phenylephrine (PE)-stimulated cardiomyocytes. Furthermore, cinnamic acid offsets PE-induced increases in N6-methyladenosine (m6A) RNA modification and reductions in the expression of the key m6A demethylase FTO in cardiomyocytes. Most importantly, FTO knockdown abrogates anti-hypertrophic and mitochondrial protective effects of cinnamic acid in the PE-stimulated cardiomyocytes. The in vivo results further demonstrate that cinnamic acid mitigates left ventricular hypertrophy, left ventricular systolic dysfunction and ultrastructural impairment of cardiomyocyte mitochondria and myofibrils in the mice subjected to transverse aortic constriction (TAC)-induced pressure overload. Moreover, FTO knockdown abolishes these beneficial effects of cinnamic acid in the TAC mice. In conclusion, the work here demonstrates for the first time that cinnamic acid is effective at mitigating pressure overload-induced left ventricular hypertrophy and heart failure in part by modulating the expression of FTO and the level of FTO-dependent m6A RNA modification in cardiomyocytes. These novel findings warrant further evaluation of cinnamic acid as a pharmacological agent/component to complement the existing treatment of pressure overload-mediated left ventricular hypertrophy and heart failure.

Left bundle branch pacing on mechanical synchrony and myocardial work in bradycardia patients.

Left bundle branch pacing (LBBP) has emerged as a novel physiological pacing method to produce narrower QRS duration, but whether it could restore mechanical synchrony and improve myocardial work still lacks sufficient evidence. Therefore, the goal of this study was to evaluate mechanical synchrony and myocardial work in LBBP. We collected 20 patients with LBBP due to symptomatic bradycardia and another 29 age-matched patients with right ventricular pacing (RVP). For LBBP patients, cardiac electro-mechanical synchrony and myocardial work were measured at baseline and 7 days after implantation and compared with the RVP patients. In the LBBP group, paced QRS duration and mechanical synchrony were not significantly different from baseline(all P > 0.05), but significantly smaller than that in the RVP group (all P<0.05). Meanwhile, global longitudinal strain (GLS) in LBBP was greater than that in the RVP group (17.7 ± 3.5% vs. 14.8 ± 3.1%, P < 0.05). Global myocardial work index and global constructive work were also better than that in the RVP group(all P<0.05). Global work efficiency was 91.9 ± 3.1%, which was greater when compared with RVP (P < 0.05). LBBP provides better cardiac electro-mechanical synchrony and more effective myocardial work than that in RVP, thus improving global heart function.

Application of an angiogenesis-related genes risk model in lung adenocarcinoma prognosis and immunotherapy.

Lung adenocarcinoma (LUAD) is an essential pathological subtype of non-small cell lung cancer and offers a severe problem for worldwide public health. There is mounting proof that angiogenesis is a crucial player in LUAD progression. Consequently, the purpose of this research was to construct a novel LUAD risk assessment model based on genetic markers related to angiogenesis. We accessed The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases for LUAD mRNA sequencing data and clinical information. Based on machine algorithms and bioinformatics, angiogenic gene-related risk scores (RS) were calculated. Patients in the high-risk category had a worse prognosis (p < 0.001) in the discovery TCGA cohort, and the results were confirmed by these three cohorts (validation TCGA cohort, total TCGA cohort, and GSE68465 cohort). Moreover, risk scores for genes involved in angiogenesis were independent risk factors for lung cancer in all four cohorts. The low-risk group was associated with better immune status and lower tumor mutational load. In addition, the somatic mutation study revealed that the low-risk group had a lower mutation frequency than the high-risk group. According to an analysis of tumor stem cell infiltration, HLA expression, and TIDE scores, the low-risk group had higher TIDE scores and HLA expression levels than the high-risk group, and the amount of tumor stem cell infiltration correlated with the risk score. In addition, high-risk groups may benefit from immune checkpoint inhibitors and targeted therapies. In conclusion, we developed an angiogenesis-related gene risk model to predict the prognosis of LUAD patients, which may aid in the classification of patients with LUAD and select medications for LUAD patients.

Circulating MicroRNA-505 May Serve as a Prognostic Biomarker for Hypertension-Associated Endothelial Dysfunction and Inflammation.

Our previous study has reported that the plasma microRNA-505 (miR-505) is elevated in hypertensive patients. However, the pathophysiological significance of miR-505 in hypertension remains to be elucidated. Hypertension is not only a vascular disorder, but also an inflammatory condition. The current study therefore aims to further investigate the pathophysiological implications of miR-505 in hypertension-associated vascular and inflammatory changes. In vivo experiments reveal that the plasma level of miR-505 is elevated in spontaneously hypertensive rats and angiotensin II-infused mice. In addition, miR-505 agomir treatment results in elevated blood pressure, endothelial dysfunction, increased vascular expression of inflammatory genes and renal inflammatory injuries as well as pre-activation of PBMCs in mice. In vitro experiments further demonstrate that miR-505 agomir increases the expression of IL1B and TNFA, whereas miR-505 antagomir attenuates TNF-α-induced upregulation of IL1B and TNFA in endothelial cells, HUVECs. In addition, miR-505 modulates the levels of endothelial activation markers VCAM1 and E-selectin in HUVECs as well as the adhesion of THP-1 monocytes to HUVECs. Lastly, the plasma level of miR-505 is positively correlated with systolic blood pressure and the level of C-reactive protein in human subjects. Our work links for the first time miR-505 to endothelial dysfunction and inflammation under hypertensive conditions, supporting the translational value of miR-505 in prognosticating hypertension-associated endothelial impairment and inflammatory injuries in target organs such as the vessels and kidneys.