Assessing causality between different risk factors and pulmonary embolism: A Mendelian randomization study.

Objectives: Mendelian randomization (MR) was used to estimate the causal relationship between body mass index (BMI), ever smoked, heart failure, alcohol intake frequency, inflammatory bowel disease (IBD), and pulmonary embolism (PE). This study aimed to investigate whether there is a causal relationship between BMI, the presence of smoking, heart failure, frequency of alcohol intake, IBD, and PE. Methods: Pooled data on PE from a published GWAS meta-analysis involving approximately 461,164 participants of European ancestry were selected. A publicly available pooled dataset of BMI (461,460), ever smokers (461,066), heart failure (977,323), IBD (75,000), and frequency of alcohol intake (462,346) was used from another independent GWAS. MR was performed using established analysis methods, including Wald ratios, inverse variance weighted (IVW), weighted median (WM), and MR-Egger. Also, the final expansion was validated with multivariate MR. Results: In the IVW model, genetically elevated BMI was causally associated with PE [OR = 1.002, 95% CI (1.001, 1004), P = 0.039]. Cochran's Q test was used to detect heterogeneity in the MR-Egger analysis (P = 0.576). Therefore, the effect of gene-level heterogeneity was not considered. In the MR analysis of other risk factors, we observed genes for ever smoking [IVW OR = 1.004, 95% CI (0.997, 1.012)], heart failure [IVW OR = 0.999, 95% CI (0.996, 1.001)], IBD [IVW OR = 1.000, 95% CI (0.999, 1.001)], and frequency of alcohol intake [IVW OR = 1.002, 95% CI (1.000, 1.004)] were not causally associated with PE. Analysis using multivariate MR expansion showed no causal effect of BMI on PE considering the effect of height as well as weight (P = 0.926). Conclusion: In European populations, a causal relationship exists between BMI and PE: increased BMI leads to PE. In contrast, ever smoking, heart failure, frequency of alcohol intake, and IBD are not directly associated with PE. There was no causal effect of BMI with PE in multivariate Mendelian randomized analysis.

Qualitative descriptive study during the COVID-19 pandemic on the needs of informal caregivers of Chinese minors who underwent craniopharyngioma surgery.

PURPOSE: To determine the needs of informal caregivers during the long-term health management of minors who have undergone craniopharyngioma surgery. Design and methodology This is a qualitative and descriptive research study. Purposive sampling was used to select participants, and semi-structured interviews were conducted to explore the needs of 21 informal caregivers for postoperative minors. Due to the COVID-19 pandemic, the respondents were provided with the options of online video call or offline one-on-one interviews. Following this, a content analysis method was conducted. RESULTS: Four themes and 14 sub-themes were extracted from the results of the study, including needs for relieving psychological stress (including psychological pressure on both minors and on caregivers); requirement for on-campus assistance (physical activity, eliminating verbal violence in schools, special education needs for child, healthcare services provided by school hospitals); demands for medical help (acquiring medical knowledge, need for medication management, convenience and reliable access to medical services, need for technological development, expectations of multidisciplinary cooperation, the necessity of health review reminders); and the desire for financial aid (charity platform assistance, inclination of government policy). CONCLUSIONS: In China, informal caregivers of young patients with onset craniopharyngioma require both the multidisciplinary cooperation of medical institutions and the multi-departmental cooperation of society. Information and medical technology advancements may benefit families with young patients. Improving community hospitals' medical services and encouraging the practical use of online medical treatment and prescriptions are both necessary in the context of COVID-19. PRACTICE IMPLICATIONS: By identifying the needs of informal caregivers, medical professionals are able to develop care plans and interventions aimed at reducing the burden of care for minors who have undergone craniopharyngioma surgery.

The metaplastic effects of cordycepin in hippocampal CA1 area of rats.

Metaplasticity is referred to adjustment in the requirements for induction of synaptic plasticity based on the prior history of activity. Synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), has been considered to be the neural processes underlying learning and memory. Previous observations that cordycepin (an adenosine derivative) improved learning and memory seemed to be contradictory to the findings that cordycepin inhibited LTP. Therefore, we speculated that the conflicting reports of cordycepin might be related to metaplasticity. In the current study, population spike (PS) in hippocampal CA1 area of rats was recorded by using electrophysiological method in vivo. The results showed that cordycepin reduced PS amplitude in hippocampal CA1 with a concentration-dependent relationship, and high frequency stimulation (HFS) failed to induce LTP when cordycepin was intrahippocampally administrated but improved LTP magnitude when cordycepin was pre-treated. Cordycepin increased LTD induced by activating N-Methyl-D-aspartate (NMDA) receptors and subsequently facilitated LTP induced by HFS. Furthermore, we found that 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), an adenosine A1 receptors antagonist, could block the roles of cordycepin on LTD and LTP. Collectively, cordycepin was able to modulate metaplasticity in hippocampal CA1 area of rats through adenosine A1 receptors. These findings would be helpful to reconcile the conflicting reports in the literatures and provided new insights into the mechanisms underlying cognitive function promotions with cordycepin treatment.

Aloe emodin inhibits telomerase activity in breast cancer cells: transcriptional and enzymological mechanism.

BACKGROUND: Telomerase plays an essential role in cancer cell proliferation. In this study, we investigated inhibition mechanism of aloe emodin (AE) on three different types of breast cancer cell lines, MDA-MB-453, MDA-MB-231 and MCF-7. METHODS: The cells were treated with different concentrations of AE. Relative length of telomere and human telomerase reverse-transcriptase (hTERT) mRNA level was analyzed by quantitative PCR (qPCR). Protein level was assayed by Western blot. Sodium bisulfite methylation sequencing was performed to assess the methylation status of gene promoter. Enzymology kinetics was applied to reveal the interaction between AE and telomerase. Ultraviolet-visible titration and fluorescence resonance energy transfer (FRET) melting experiment were carried out to study the interaction between AE and telomeric DNA. RESULTS: Continuous AE exposure of these cells for 48 h results in shortening of telomeres and inhibition of telomerase. The transcription of hTERT was repressed by activation of E2F1 and inactivation of c-myc proteins. Significant demethylation of CpG islands in hTERT gene promoter was observed in MDA-MB-453 and MCF-7 cells. AE competed with dNTP for occupation of the enzyme active site. AE was a telomeric G-quadruplex structure stabilizer as indicated by titration test and FRET experiments. CONCLUSIONS: AE was a competitive inhibitor of telomerase and a G-quadruplex structure stabilizer. AE decreased the transcription of hTERT gene in the three breast cancer cell lines via up-regulation E2F1 and down-regulation c-myc expressions. The suppressed transcription was also related to the demethylation of the gene promoter.

Wnt/ß-catenin signaling as a useful therapeutic target in hepatoblastoma.

Hepatoblastoma is a malignant tumor in the liver of children that generally occurs at the age of 2-3 years. There have been ample evidence from the preclinical as well as clinical studies suggesting the activation of Wnt/ß-catenin signaling in hepatoblastoma, which is mainly attributed to the somatic mutations in the exon 3 of ß-catenin gene. There is increased translocation of ß-catenin protein from the cell surface to cytoplasm and nucleus and intracellular accumulation is directly linked to the severity of the cancer. Accordingly, the alterations in ß-catenin and its target genes may be used as markers in the diagnosis and prognosis of pediatric live tumors. Furthermore, scientists have reported the therapeutic usefulness of inhibition of Wnt/ß-catenin signaling in hepatoblastoma and this inhibition of signaling has been done using different methods including short interfering RNA (siRNA), miRNA and pharmacological agents. Wnt/ß-catenin works in association with other signaling pathways to induce the development of hepatoblastoma including Yes-associated protein (YAP)1 (YAP-1), mammalian target of rapamycin (mTOR) 1 (mTOR-1), SLC38A1, glypican 3 (GPC3), nuclear factor κ-light-chain-enhancer of activated B cells (NF-kB), epidermal growth factor receptor, ERK1/2, tumor necrosis factor-α (TNF-α), regenerating islet-derived 1 and 3 α (REG1A and 3A), substance P (SP)/neurokinin-1 receptor and PARP-1. The present review describes the key role of Wnt/ß-catenin signaling in the development of hepatoblastoma. Moreover, the role of other signaling pathways in hepatoblastoma in association with Wnt/ß-catenin has also been described.

Cordycepin improves behavioral-LTP and dendritic structure in hippocampal CA1 area of rats.

Cordycepin, an adenosine analog, has been reported to improve cognitive function, but which seems to be inconsistent with the reports showing that cordycepin inhibited long-term potentiation (LTP). Behavioral-LTP is usually used to study long-term synaptic plasticity induced by learning tasks in freely moving animals. In order to investigate simultaneously the effects of cordycepin on LTP and behavior in rats, we applied the model of behavioral-LTP induced by Y-maze learning task through recording population spikes in hippocampal CA1 region. Golgi staining and Sholl analysis were employed to assess the morphological structure of dendrites in pyramidal cells of hippocampal CA1 area, and western blotting was used to examine the level of adenosine A1 receptors and A2A receptors (A2AR). We found that cordycepin significantly improved behavioral-LTP magnitude, accompanied by increases in the total length of dendrites, the number of intersections and spine density but did not affect Y-maze learning task. Furthermore, cordycepin obviously reduced A2AR level without altering adenosine A1 receptors level; and the agonist of A2AR (CGS 21680) rather than antagonist (SCH 58261) could reverse the potentiation of behavioral-LTP induced by cordycepin. These results suggested that cordycepin improved behavioral-LTP and morphological structure of dendrite in hippocampal CA1 but did not contribute to the improvement of learning and memory. And cordycepin improved behavioral-LTP may be through reducing the level of A2AR in hippocampus. Collectively, the effects of cordycepin on cognitive function and LTP were complex and involved multiple mechanisms.

Peroxidase from jackfruit: Purification, characterization and thermal inactivation.

Peroxidase (POD) from jackfruit bulb was purified using ammonium sulfate precipitation, hydrophobic interaction and gel filtration columns. The POD was a dimer with a molecular weight of 104kDa. The Km and Vmax values for guaiacol, gallic acid and o­phenylenediamine (OPD) were estimated. OPD was the most suitable substrate. The enzyme showed its maximum activity at pH5.5 and 55-60°C. The activation energy (Ea) of heat inactivation was estimated to be 206.40kJ/mol. The enthalpy, free energy and entropy values for the thermal inactivation were also determined. The POD activity was enhanced by K+, Zn2+, Ba2+, citric acid, malic acid, benzoic acid and EDTA·Na2, but inhibited by Cu2+, Ca2+, glutathione, cysteine and ascorbic acid. Chemical modification indicated a histidine residue was located in the enzyme active site. The POD activity in fruit extracts significantly decreased when heated at 80°C and 90°C. The ferric-reducing antioxidant power, ABTS radical scavenging activity and total phenolics decreased with increasing heating temperature and time.

Cordycepin decreases activity of hippocampal CA1 pyramidal neuron through membrane hyperpolarization.

Cordycepin (3'-deoxyadenosine) is the main functional component of Cordycepins militaris, a renowned traditional Chinese medicine, which has been shown to possess anti-tumor, anti-inflammatory, anti-diabetic and neuro-protective effects. However, the effect of cordycepin on the central nervous system (CNS) remains unclear. In this study, the effects of cordycepin on neuronal activity were investigated on the CA1 pyramidal neurons in rat hippocampal brain slices using a whole-cell patch clamp technique. Our results revealed that cordycepin significantly decreased the frequency of both the spontaneous and evoked action potential (AP) firing. While AP spike width, the amplitude of fast after hyperpolarization (fAHP), and membrane input resistance were not altered by cordycepin, the neuronal membrane potential was hyperpolarized by cordycepin. Collectively, these results demonstrate that cordycepin reduces neuronal activity by inducing membrane hyperpolarization, indicating that cordycepin may be a potential therapeutic strategy for ischemic and other excitotoxic disorders.

[Effects of exercise therapy at the intensity of anaerobic threshold for exercise tolerance in patients with chronic stable coronary artery disease].

OBJECTIVE: To investigate the effects of exercise therapy at the intensity of anaerobic threshold (AT) for exercise tolerance in patients with chronic stable coronary artery disease. METHODS: Forty-three patients with chronic stable coronary artery disease (3 patients after coronary arterial bypass graft (CABG) surgery, 22 patients with old myocardial infarction and 18 unstable angina pectoris undergoing successful percutaneous coronary intervention (PCI) finished twice cardiopulmonary exercise test (CPET) and followed their rehabilitation program for 3 months. Thirty-two patients finished their aerobic exercise therapy based on their individual anaerobic thresholds while 11 patients had no exercise therapy. RESULTS: The heart rate at AT intensity (97 ± 9/min) was lower than their traditional minimal target heart rate (112 ± 7/min) and lower than heart rate (115 ± 11/min) at ischemic threshold post-CPET. The O(2) consumption (10.7 ± 2.4 to 12.6 ± 2.9 ml×min(-1)×kg(-1)) (P = 0.04) and workload (37 ± 18 to 47 ± 13 J/s) (P = 0.04) at AT level and the O(2) consumption (15.3 ± 3.1 to 20.6 ± 4.2 ml×min(-1)×kg(-1), P = 0.02) and workload(68 ± 12 and 87 ± 14 J/s, P = 0.01) at peak level markedly increased after 3 months in the exercise group. And the O(2) consumption (15.3 ± 2.9 to 16.2 ± 3.1 ml×min(-1)×kg(-1)) and workload (65 ± 13 to 73 ± 16 J/s) at peak level mild increased after 3 months in the non-exercise group, but their O(2) consumption (11.0 ± 2.7 to 11.3 ± 2.8 ml×min(-1)×kg(-1)) and workload (38 ± 11 to 37 ± 9 J/s) at AT level had no obvious change. CONCLUSION: AT exercise intensity was lower than ischemic threshold post-CPET. Exercise therapy at the intensity of anaerobic threshold can improve oxygen capacity and exercise tolerance.