Direct generation of a 635 nm red random laser based on praseodymium (Pr)-doped ZBLAN fiber.

Visible random fiber lasers have garnered significant attention due to their unique emission properties and potential applications in various fields. We first, to the best of our knowledge, demonstrated a compact all-fiber structure, red wavelength, and random fiber laser (RFL) based on a double-clad Pr-doped ZBLAN fiber. The simple half-open cavity consists of a high-reflectivity fiber pigtail mirror and the Pr-doped ZBLAN fiber. The Pr-doped ZBLAN fiber not only served as a gain medium but also offered random backward scattering. We investigated the effects of different lengths on output power and slope efficiency of the RFL. For 21 m Pr-doped fiber, the RFL emitted a maximum output power of 208.50 mW with a slope efficiency of 11.09%. For 15 m Pr-doped fiber, the maximum power decreased to 120.18 mW with the slope efficiency of 7.27%. We are also numerically simulating the output power versus the pump power at different fiber lengths based on power steady-state light propagation equations. This novel RFL has the potential for broad applications in fields such as display technology, spectroscopy, biomedical imaging, and optical sensing due to its unique properties and simple all-fiber structure.

Global Epidemiology and Geographic Variations of Pediatric-Onset Inflammatory Bowel Disease: A Comprehensive Analysis of the Global Burden of Disease Study 1990 to 2019.

BACKGROUND: An increasing incidence of pediatric-onset inflammatory bowel disease (PIBD) has been reported in many countries. However, the global burden and distribution of this disease remain less understood. We aimed to examine the global epidemiology and trends of PIBD from 1990 to 2019. METHODS: Data from the 2019 Global Burden of Disease Study, covering 204 countries, were analyzed. We assessed key measures like incidence, prevalence, mortality, and disability-adjusted life years (DALYs) using linear regression to calculate annual percentage changes and assess trends. RESULTS: Between 1990 and 2019, the PIBD incidence rate increased and the DALY rate and mortality rate declined. The incidence rate was notably elevated in the high Socio-demographic Index (SDI) quintile, reaching 6.3 per 100 000 person-years, corresponding to 13 914 new cases in 2019. Incidence and prevalence of PIBD positively correlated with the SDI, while higher death and DALY burdens were observed in lower-SDI countries. In 2019, the top 5 countries with the highest PIBD incidence rates were Canada (19.9 per 100 000 population), Denmark (12.4 per 100 000 population), Hungary (8.5 per 100 000 population), Austria (8.1 per 100 000 population), and the United States (7.4 per 100 000 population). Several countries experienced significant increases in incidence rates from 1990 to 2019, led by Taiwan (annual percent change 4.2%), followed by China (2.8%), Japan (2.1%), Australia (1.8%), and Hungary (1.6%). DISCUSSION: PIBD incidence has significantly increased since 1990. High-SDI countries face higher incidence, while lower-SDI countries experience higher mortality and DALY burdens. The study underscores the need for ongoing monitoring and research to address this emerging public health issue.

This study analyzed global pediatric-onset inflammatory bowel disease trends from 1990 to 2019. Findings show an increased incidence, especially in high Socio-demographic Index countries, highlighting a growing public health concern and the need for continued monitoring and investigation.

An investigation into the potential association between nutrition and Alzheimer's disease.

Background: Malnutrition is the most common nutritional issue in Alzheimer's disease (AD) patients, but there is still a lack of a comprehensive evaluation of the nutritional status in AD patients. This study aimed to determine the potential association of various nutritional indices with AD at different stages. Methods: Subjects, including individuals with normal cognition (NC) and patients diagnosed with AD, were consecutively enrolled in this cross-sectional study. Demographics, body composition, dietary patterns, nutritional assessment scales and nutrition-related laboratory variables were collected. Binary logistics regression analyses and receiver operating characteristic (ROC) curves were used to indicate the association between nutrition-related variables and AD at different stages. Results: Totals of 266 subjects, including 73 subjects with NC, 72 subjects with mild cognitive impairment due to AD (AD-MCI) and 121 subjects with dementia due to AD (AD-D) were included. There was no significant difference in dietary patterns, including Mediterranean diet and Mediterranean-DASH diet intervention for neurodegenerative delay (MIND) diet between the three groups. Lower BMI value, smaller hip and calf circumferences, lower Mini Nutritional Assessment (MNA) and Geriatric Nutritional Risk Index (GNRI) scores, and lower levels of total protein, albumin, globulin, and apolipoprotein A1 were associated with AD (all p < 0.05). Total protein and albumin levels had the greatest ability to distinguish AD from non-AD (AUC 0.80, 95% CI 0.74-0.84, p < 0.001), increased by combining calf circumference, MNA score and albumin level (AUC 0.83, 95% CI 0.77-0.88, p < 0.001). Albumin level had the greatest ability to distinguish NC from AD-MCI (AUC 0.75, 95% CI 0.67-0.82, p < 0.001), and MNA score greatest ability to distinguish AD-MCI from AD-D (AUC 0.72, 95% CI 0.65-0.78, p < 0.001). Conclusion: Nutritional status of AD patients is significantly compromised compared with normal controls, and tends to be worsened with AD progresses. Early identification and intervention of individuals with nutritional risk or malnutrition may be significantly beneficial for reducing the risk, development, and progression of AD.

Missense mutation of angiotensin converting enzyme gene in an Alzheimer's disease patient: a case report.

Alzheimer's disease (AD) is the most common type of cognitive impairment in the elderly. In this report, we presented a case of a 52-year-old woman with rapid disease progression within 6 months. She was diagnosed with mild dementia according to the clinical symptoms and neuropsychological assessment results. Based on the results of neuropathological proteins in cerebrospinal fluid, cranial magnetic resonance imaging, and positron emission tomography/computed tomography, the patient showed the presence of ß amyloid deposition, pathologic tau along with neurodegeneration [A+T+(N+)], indicative of AD. Whole exome sequencing revealed a heterozygous C-to-T missense mutation of nucleotide 3,755 (c.3755C > T) in exon 25 of the angiotensin converting enzyme (ACE) gene on chromosome 17q23 (rs762056936).

Methane-dependent complete denitrification by a single Methylomirabilis bacterium.

Methane-dependent nitrate and nitrite removal in anoxic environments is thought to rely on syntrophy between ANME-2d archaea and bacteria in the genus 'Candidatus Methylomirabilis'. Here we enriched and purified a single Methylomirabilis from paddy soil fed with nitrate and methane, which is capable of coupling methane oxidation to nitrate reduction via nitrite to dinitrogen independently. Isotope labelling showed that this bacterium we name 'Ca. Methylomirabilis sinica' stoichiometrically performed methane-dependent complete nitrate reduction to dinitrogen gas. Multi-omics analyses collectively demonstrated that 'M. sinica' actively expressed a well-established pathway for this process, especially including nitrate reductase Nap. Furthermore, 'M. sinica' exhibited a higher nitrate affinity than most denitrifiers, implying its competitive fitness under oligotrophic nitrogen-limited conditions. Our findings revise the paradigm of methane-dependent denitrification performed by two organisms, and the widespread presence of 'M. sinica' in public databases suggests that the coupling of methane oxidation and complete denitrification in single cells substantially contributes to global methane and nitrogen budgets.

Association between nutritional status and gait performance in Alzheimer's disease.

AIMS: This study aimed to comprehensively explore the nutrition and gait of AD patients at different stages and the relationship between them. METHODS: A total of 85 AD patients were consecutively enrolled in this cross-sectional study and divided into the mild cognitive impairment (MCI) due to AD (AD-MCI) and the dementia due to AD (AD-D) groups. Demographic information, nutritional status, and gait performance were compared between the two groups, and the correlation between nutritional status and gait performance was subsequently analyzed by Pearson and Spearman correlation analyses. RESULTS: The AD-D group had lower scores on Mini-Nutritional Assessment (MNA) and MNAm scales, lower levels of urea nitrogen, folic acid, and vitamin B12 in blood, and higher homocysteine level than those in the AD-MCI group (all p < 0.05). The AD-D group had slower step speed, shorter step length, and shorter stride length than those in the AD-MCI group (all p < 0.05). AD patients with decreased scores of MNA and MNAm scales, and declined levels of urea nitrogen and vitamin B12 in blood had reduced gait speed and gait cadence, and prolonged step length time and stride length time, whereas homocysteine showed the almost opposite results (all p < 0.05). In the AD-MCI group, the score of scale was negatively correlated with the coefficient of variation (CV) of stride length, and the folic acid level was negatively correlated with the CV of stride length and cadence (all p < 0.05). CONCLUSIONS: AD patients at the dementia stage had worse nutritional status and gait performance than those at the MCI stage, which was associated with worse global cognition and activities of daily living. Poorer nutritional status was associated with higher gait variability in patients at the MCI stage and with poorer gait performance in patients at the dementia stage. Early identification and intervention of patients with nutritional risk or malnutrition may improve gait performance, thus reducing the risk of falling and cognitive decline, as well as the mortality.

The roles of apolipoprotein E ε4 on neuropathology and neuroinflammation in patients with Alzheimer's disease.

AIMS: To explore the roles of apolipoprotein E (APOE) ε4 on the neuropathology and neuroinflammation in Alzheimer's disease (AD) patients. METHODS: AD patients were divided into the APOE ε4 carrier and the APOE ε4 non-carrier groups according to APOE genotype. Demographic information, cognitive function, the levels of neuropathological proteins and neuroinflammatory factors in cerebrospinal fluid (CSF) were compared between the two groups, and their correlations were subsequently analyzed. RESULTS: ß amyloid protein (Aß)1-42 level from the APOE ε4 carrier group was significantly lower than that from the non-carrier group (p = 0.023), which was associated with worse cognitive function. The nitric oxide (NO) level was significantly elevated in the APOE ε4 carrier group compared to the non-carrier group (p = 0.016), which was significantly and positively correlated with the Trail Making Test (TMT)-A-time (r = 0.21, p = 0.026) and TMT-B-time (r = 0.38, p < 0.01). CONCLUSION: APOE ε4 is associated with poorer cognition, particularly the early symptoms of memory, language, and attention. APOE ε4 is associated with lower Aß1-42 level, and the more numbers of APOE ε4 are carried, the lower level of Aß1-42 is measured. APOE ε4 is associated with elevated NO level, which is linked to the impaired attention and executive function.

Clinical features and neurobiochemical mechanisms of olfactory dysfunction in patients with Parkinson disease.

This study aimed to investigate clinical features, influencing factors and neurobiochemical mechanisms of olfactory dysfunction (OD) in Parkinson disease (PD). Total 39 patients were divided into the PD with OD (PD-OD) and PD with no OD (PD-nOD) groups according to overall olfactory function, including threshold, discrimination and identification, assessed by Sniffin' Sticks test. Motor function and non-motor symptoms were rated by multiple scales. Dopamine, acetylcholine, norepinephrine and 5-hydroxytryptamine levels in cerebrospinal fluid (CSF) were measured. We found that the PD-OD group showed significantly lower score of Montreal Cognitive Assessment Scale, higher scores of rapid eye movement sleep behavior disorder (RBD) Screening Questionnaire and Epworth Sleepiness Scale than the PD-nOD group (p < 0.05). RBD Screening Questionnaire score was independently associated with the scores of overall olfactory function and discrimination (p < 0.05). Dopamine and acetylcholine levels in CSF from the PD-OD group was significantly lower than that from the PD-nOD group (p < 0.05). Dopamine and acetylcholine levels in CSF were significantly and positively correlated with the scores of overall olfactory function, threshold, discrimination and identification in PD patients (p < 0.05). RBD Screening Questionnaire score was significantly and negatively correlated with acetylcholine level in CSF in PD patients with poor olfactory detection (p < 0.05). This investigation reveals that PD-OD is associated with cognitive impairment, probable RBD and excessive daytime sleepiness. PD-OD is correlated with the decreased levels of dopamine and acetylcholine in CSF. RBD is an independent influencing factor of overall olfactory function and discrimination, and the decreased acetylcholine level in CSF may be the common neurobiochemical basis of RBD and OD in PD patients.

Electron Donor-Acceptor Complex Enabled Radical Cyclization of α-Diazodifluoroethyl Sulfonium Salt with Unactivated Alkynes.

An α-diazodifluoroethane sulfonium reagent was developed in this study to undergo [3 + 2] radical cyclization with unactivated alkynes to give the corresponding 3-difluoromethyl pyrazoles under blue light irradiation conditions. The key to the success of this transformation lies in the formation of an electron donor-acceptor (EDA) complex between an electron-deficient α-diazo sulfonium salt and an electron-rich triaryl amine. This study circumvents a major substrate scope limitation in polar cycloaddition reactions of existent diazodifluoroethane reagents.

Role of nerve growth factor on cognitive impairment in patients with Alzheimer's disease carrying apolipoprotein E ε4.

AIMS: To investigate the roles of neurotrophic factors on cognition in patients with Alzheimer's disease (AD) carrying Apolipoprotein E (APOE) ε4. METHODS: Totals of 173 patients with AD were divided into APOE ε4 carrier and non-carrier groups, and their demographics, cognition, and neurotrophic factors in cerebrospinal fluid (CSF) were compared. Multiple linear regression analyses were performed to assess correlations among APOE ε4, neurotrophic factors and cognition. Mediation analyses were conducted to assess the sequential associations among APOE ε4, nerve growth factor (NGF), and cognition. RESULTS: Global cognition and multiple domains were impaired in the APOE ε4 carrier group (all p < 0.05). NGF level in the APOE ε4 carrier group was lower than that in the non-carrier group (p = 0.016). NGF level showed significant correlations with both global and multiple domains cognitions. Specifically, NGF mediated the association between APOE ε4 and Animal Fluency Test score (ß, -0.45; 95% CI [-0.96, -0.07]; p < 0.001) and Trail Making Test-A (time) (ß, 0.15; 95% CI [0.01, 0.33]; p < 0.001). CONCLUSION: APOE ε4 is associated with cognitive impairment, and those carrying APOE ε4 have decreased NGF level in CSF. Declined NGF level is correlated with compromised cognition. NGF mediates APOE ε4-associated cognitive impairment.

Nationwide in-hospital mortality and morbidity analysis of COVID-19 in advanced chronic kidney disease, dialysis and kidney transplant recipients.

Background: Patients with advanced chronic kidney disease (CKD), end-stage kidney disease (ESKD), and kidney transplants (KT) are at an elevated risk for COVID-19 infection, hospitalization, and mortality. A comprehensive comparison of morbidity and mortality between these populations with kidney disease and individuals without any kidney disease is lacking. Methods: We analysed the 2020 Nationwide Inpatient Sample (NIS) database for non-elective adult COVID-19 hospitalizations, categorizing patients into advanced CKD, ESKD, KT, and kidney disease-free cohorts. Our analysis included a description of the distribution of comorbidities across the entire spectrum of CKD, ESKD, and KT. Additionally, we investigated in-hospital mortality, morbidity, and resource utilization, adjusting for potential confounders through multivariable regression models. Results: The study included 1,018,915 adults hospitalized for COVID-19 in 2020. The incidence of advanced CKD, ESKD, and KT in this cohort was 5.8%, 3.8%, and 0.4%, respectively. Patients with advanced CKD, ESKD, and KT exhibited higher multimorbidity burdens, with 90.3%, 91.0%, and 75.2% of patients in each group having a Charlson comorbidity index (CCI) equal to or greater than 3. The all-cause in-hospital mortality ranged from 9.3% in kidney disease-free patients to 20.6% in advanced CKD, 19.4% in ESKD, and 12.4% in KT patients. After adjusting for potential confounders at both the patient and hospital levels, CKD stages 3-5; ESKD; and KT were found to be associated with increased odds of mortality, with adjusted odds ratios (aOR) of 1.34, 1.80, 2.66, 1.97, and 1.69, respectively. Conclusion: Patients hospitalized for COVID-19 with advanced CKD, ESKD, or KT demonstrated a higher burden of comorbidities and increased mortality rates compared to those without kidney disease. After adjusting for confounders, CKD stages 3-5; ESKD; and KT were identified as independent risk factors for in-hospital mortality, illustrating a dose-response relationship between the odds of mortality and adverse outcomes as CKD progressed from stages 3 to 5. Our study highlights the necessity for enhanced management of comorbidities, targeted interventions, and vigorous vaccination efforts to mitigate the risk of adverse outcomes in the vulnerable populations of patients with CKD, ESKD, and KT.

COVID-19 Vaccine Antibody Response in a Single-Center Urban Hemodialysis Unit.

BACKGROUND: The longitudinal response to the COVID-19 vaccines among patients on hemodialysis with and without prior SARS-CoV-2 infection has not been well characterized. METHODS: To guide vaccination strategies in patients on hemodialysis, it is critical to characterize the longevity and efficacy of the vaccine; therefore, we conducted a prospective single-center monthly antibody surveillance study between March 2021 and March 2022 to investigate the dynamic humoral response to a series of COVID-19 mRNA vaccines in patients on hemodialysis with and without prior SARS-CoV-2 infection. Monthly quantitative antibody testing was performed using the Beckman Coulter Access SARS-CoV-2 IgG Antibody Test©, which detects IgG antibodies targeting the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. RESULTS: This cohort of 30 participants (mean age: 61 ± 3 years) predominantly self-identified as African American (97%) and male (53%). Eight participants (27%) had recovered from COVID-19 (recovered) before the vaccine initiation. All participants received two vaccine doses, and 86.6% received a 6-month booster dose. Among patients naïve to COVID-19, the antibody positivity rate (APR) was 55% post-first-dose, 91% post-second-dose, 50% pre-booster at 6 months, 100% post-booster, and 89% at 6 months post-booster. Recovered patients sustained a consistent 100% APR throughout the year. The naïve patients demonstrated lower peak antibody levels post-second-dose than the recovered patients (17.9 ± 3.2 vs. 44.7 ± 5.6, p < 0.001). The peak antibody levels post-booster showed no significant difference between both groups (27.1 ± 3.9 vs. 37.9 ± 8.2, p = 0.20). Two naïve patients contracted COVID-19 during the follow-up period. CONCLUSIONS: The patients naïve to COVID-19 exhibited an attenuated and foreshortened antibody response following two doses of the mRNA vaccines compared with the recovered patients, who maintained 100% APR before the booster dose. The 6-month booster dose counteracted declining immunity and stimulated antibody responses in the naïve patients, even in previously non-responsive patients. This observation implies that different booster vaccination strategies might be required for COVID-19-naïve and -recovered patients. Post-vaccination antibody testing may serve as a valuable tool for guiding vaccination strategies.

Concentration-dependent mechanisms of fluoranthene uptake by ryegrass.

Fluoranthene (Flu) uptake by plants is affected by plant growth and environmental concentration. Although plant growth processes, including substance synthesis and antioxidant enzyme activities, have been reported to regulate Flu uptake, their contributions have been poorly evaluated. Moreover, the effect of Flu concentration is little known. Here, low concentrations (0, 1, 5, and 10 mg/L) and high concentrations (20, 30, and 40 mg/L) of Flu were set to compare the changes in Flu uptake by ryegrass (Lolium multiflorum Lam.). Indices of plant growth (biomass, root length, root area, root tip number, and photosynthesis and transpiration rates), substance synthesis (indole acetic acid [IAA] content), and antioxidant enzyme activities (superoxide dismutase [SOD], peroxidase [POD], and catalase [CAT]) were recorded to unravel the mechanism of Flu uptake. Findings suggested that the Langmuir model fitted Flu uptake by ryegrass well. Flu absorption capacity in the root was stronger than that that in the leaf. Flu bioconcentration and translocation factors increased then reduced with the increase in Flu concentration and reached the maximum value under 5 mg/L Flu treatment. Plant growth and IAA content had the same pattern as before bioconcentration factor (BCF). SOD and POD activities increased then decreased with Flu concentration and reached their highest levels under 30 and 20 mg/L Flu treatments, respectively, whereas CAT activity decreased continuously and reached its lowest level under 40 mg/L Flu treatment. Variance partitioning analysis indicated that IAA content had the greatest significant effect on Flu uptake under low-concentration Flu treatments, whereas antioxidant enzyme activities had the greatest significant effect on Flu uptake under high-concentration Flu treatments. Revealing the concentration-dependent mechanisms of Flu uptake could provide a basis for regulating pollutant accumulation in plants.

Antioxidant Carboxymethyl Chitosan Carbon Dots with Calcium Doping Achieve Ultra-Low Calcium Concentration for Iron-Induced Osteoporosis Treatment by Effectively Enhancing Calcium Bioavailability in Zebrafish.

Iron overloads osteoporosis mainly occurs to postmenopausal women and people requiring repeated blood transfusions. Iron overload increases the activity of osteoclasts and decreases the activity of osteoblasts, leading to the occurrence of osteoporosis. Conventional treatment options include calcium supplements and iron chelators. However, simple calcium supplementation is not effective, and it does not have a good therapeutic effect. Oxidative stress is one of the triggers for osteoporosis. Therefore, the study focuses on the antioxidant aspect of osteoporosis treatment. The present work revealed that antioxidant carboxymethyl chitosan-based carbon dots (AOCDs) can effectively treat iron overload osteoporosis. More interestingly, the functional modification of AOCDs by doping calcium gluconate (AOCDs:Ca) is superior to the use of any single component. AOCDs:Ca have the dual function of antioxidant and calcium supplement. AOCDs:Ca effectively improve the bioavailability of calcium and achieve ultra-low concentration calcium supplement for the treatment of iron-induced osteoporosis in zebrafish.

Alzheimer's disease with sleep insufficiency: a cross-sectional study on correlations among clinical characteristics, orexin, its receptors, and the blood-brain barrier.

Previous studies have shown that reduced sleep duration, sleep fragmentation, and decreased sleep quality in patients with Alzheimer's disease are related to dysfunction in orexin signaling. At the same time, blood-brain barrier disruption is considered an early biomarker of Alzheimer's disease. However, currently no report has examined how changes in orexin signaling relate to changes in the blood-brain barrier of patients who have Alzheimer's disease with sleep insufficiency. This cross-sectional study included 50 patients with Alzheimer's disease who received treatment in 2019 at Beijing Tiantan Hospital. Patients were divided into two groups: those with insufficient sleep (sleep duration ≤ 6 hours, n = 19, age 61.58 ± 8.54 years, 10 men) and those with normal sleep durations (sleep duration > 6 hours, n = 31, age 63.19 ± 10.09 years, 18 men). Demographic variables were collected to evaluate cognitive function, neuropsychiatric symptoms, and activities of daily living. The levels of orexin, its receptor proteins, and several blood-brain barrier factors were measured in cerebrospinal fluid. Sleep insufficiency was associated with impaired overall cognitive function that spanned multiple cognitive domains. Furthermore, levels of orexin and its receptors were upregulated in the cerebrospinal fluid, and the blood-brain barrier was destroyed. Both these events precipitated each other and accelerated the progression of Alzheimer's disease. These findings describe the clinical characteristics and potential mechanism underlying Alzheimer's disease accompanied by sleep deprivation. Inhibiting the upregulation of elements within the orexin system or preventing the breakdown of the blood-brain barrier could thus be targets for treating Alzheimer's disease.

Lead Exposure Causes Spinal Curvature during Embryonic Development in Zebrafish.

Lead (Pb) is an important raw material for modern industrial production, they enter the aquatic environment in several ways and cause serious harm to aquatic ecosystems. Lead ions (Pb2+) are highly toxic and can accumulate continuously in organisms. In addition to causing biological deaths, it can also cause neurological damage in vertebrates. Our experiment found that Pb2+ caused decreased survival, delayed hatching, decreased frequency of voluntary movements at 24 hpf, increased heart rate at 48 hpf and increased malformation rate in zebrafish embryos. Among them, the morphology of spinal malformations varied, with 0.4 mg/L Pb2+ causing a dorsal bending of the spine of 72 hpf zebrafish and a ventral bending in 120 hpf zebrafish. It was detected that spinal malformations were mainly caused by Pb2+-induced endoplasmic reticulum stress and apoptosis. The genetic changes in somatic segment development which disrupted developmental polarity as well as osteogenesis, resulting in uneven myotomal development. In contrast, calcium ions can rescue the series of responses induced by lead exposure and reduce the occurrence of spinal curvature. This article proposes new findings of lead pollution toxicity in zebrafish.

H2O2/DEM-Promoted Maft Promoter Demethylation Drives Nrf2/ARE Activation in Zebrafish.

The Nrf2/ARE signaling pathway is a cell survival response pathway in response to environmental stresses. The Nrf2/ARE signaling pathway can be activated by stimulating cysteine residues at different positions in the Keap1. However, the epigenetic mechanisms of the Nrf2/ARE pathway under different stimuli are still poorly understood. In this study, we found that both hydrogen peroxide (H2O2) and Diethyl Maleate (DEM) activated the Nrf2/ARE signaling pathway at 120 hpf in zebrafish. H2O2 regulated the demethylation of the maft promoter by inhibiting the expression of methyltransferase. This promotes the mRNA expression of the Nrf2 binding factor maft, thereby promoting the downstream antioxidant genes. The methylation of the Nrf2/ARE signaling pathway was not significantly regulated by DEM. However, under oxidative stress, the methyltransferase inhibitors (decitabine and azacitidine) demethylated the promoter region of maft. It activated the expression of the maft, further improving the Nrf2/ARE signal pathway. At last, antioxidant target genes were activated. It was shown that H2O2 and DEM cooperated with methyltransferase inhibitors, providing an important reference for the treatment of oxidative stress-related diseases and breaking new ground for the study of the mechanism of methyltransferase inhibitors in the process of tumor chemotherapy.

The Influence of 24-h Ambulatory Blood Pressure on Cognitive Function and Neuropathological Biomarker in Patients With Alzheimer's Disease.

Purpose: This study aimed to investigate the influence of 24-h ambulatory blood pressure (BP) on cognitive function and neuropathological biomarkers in patients with Alzheimer's disease (AD) at the stages of mild cognitive impairment (MCI) and dementia. Methods: The patients with AD were divided into the MCI (AD-MCI) group and the dementia (AD-D) group. Notably, 24-h BP variables, including BP level, coefficient of variation (CV) of BP, and pulse pressure, were collected and compared between the two groups. The correlations between 24-h BP variables and the scores of cognitive domains were analyzed. The independent influencing factors of cognitive domains of patients with AD were investigated. The levels of neuropathological biomarkers of AD, including ß amyloid (Aß)1-42, phosphorylated tau (P-tau), and total tau (T-tau), in cerebrospinal fluid (CSF) were measured and compared between the two groups, and the correlations between 24-h BP variables and the levels of neuropathological biomarkers of AD were analyzed. Results: Daytime CV of systolic BP (SBP) was significantly increased in the AD-D group compared to that in the AD-MCI group. The 24-h and daytime CV of SBP and ambulatory pulse pressure were significantly and negatively correlated with memory score. The average 24-h and average daytime SBP level and CV of SBP, daytime CV of diastolic BP (DBP), and 24-h, daytime, and night-time ambulatory pulse pressure were significantly and negatively correlated with language score. The average 24-h SBP level, daytime CV of SBP, and 24-h, daytime, and night-time ambulatory pulse pressure were significantly and negatively correlated with attention score. Further analysis indicated that daytime CV of SBP as well as age and course of disease were the independent influencing factors of language. Age was also the independent influencing factor of memory and attention of patients with AD. T-tau level in CSF in the AD-D group was significantly higher than that in the AD-MCI group, but the levels of Aß1-42, P-tau, and T-tau in CSF were not correlated with 24-h ambulatory BP variables. Conclusion: Daytime CV of SBP was the independent influencing factor of language in patients with AD. The AD-D patients had significantly severe neurodegeneration than AD-MCI patients, which was, however, not through the influence of 24-h ambulatory BP variables on neuropathological biomarkers of AD.

Clinical Features and Potential Mechanisms Relating Neuropathological Biomarkers and Blood-Brain Barrier in Patients With Alzheimer's Disease and Hearing Loss.

Background: The aim of this study was to explore clinical features and potential mechanisms relating neuropathological biomarkers and blood-brain barrier (BBB) in Alzheimer's disease (AD) and hearing loss (HL). Materials and Methods: A total of 65 patients with AD were recruited and auditory function was assessed by threshold of pure tone audiometry (PTA). Patients were divided into AD with HL (AD-HL) and AD with no HL (AD-nHL) groups based on the standard of World Health Organization. Clinical symptoms were assessed by multiple rating scales. The levels of neuropathological biomarkers of ß amyloid1-42 (Aß1-42) and multiple phosphorylated tau (P-tau), and BBB factors of matrix metalloproteinases (MMPs), receptor of advanced glycation end products, glial fibrillary acidic protein, and low-density lipoprotein receptor related protein 1 were measured. Results: (1) Compared with AD-nHL group, AD-HL group had significantly impaired overall cognitive function and cognitive domains of memory, language, attention, execution, and activities of daily living (ADL) reflected by the scores of rating scales (P < 0.05). PTA threshold was significantly correlated with the impairments of overall cognitive function and cognitive domains of memory and language, and ADL in patients with AD (P < 0.05). (2) P-tau (S199) level was significantly increased in CSF from AD-HL group (P < 0.05), and was significantly and positively correlated with PTA threshold in patients with AD. (3) MMP-3 level was significantly elevated in CSF from AD-HL group (P < 0.05), and was significantly and positively correlated with PTA threshold in patients with AD (P < 0.05). (4) In AD-HL group, P-tau (S199) level was significantly and positively correlated with the levels of MMP-2 and MMP-3 in CSF (P < 0.05). Conclusion: AD-HL patients have severely compromised overall cognitive function, multiple cognitive domains, and ADL. The potential mechanisms of AD-HL involve elevations of AD neuropathological biomarker of P-tau (S199) and BBB factor of MMP-3, and close correlations between P-tau (S199) and MMP-2/MMP-3 in CSF. Findings from this investigation highly suggest significance of early evaluation of HL for delaying AD progression, and indicate new directions of drug development by inhibiting neuropathological biomarkers of AD and protecting BBB.

Nitric Oxide-Releasing Platforms for Treating Cardiovascular Disease.

Cardiovascular disease (CVD) is the first leading cause of death globally. Nitric oxide (NO) is an important signaling molecule that mediates diverse processes in the cardiovascular system, thereby providing a fundamental basis for NO-based therapy of CVD. At present, numerous prodrugs have been developed to release NO in vivo. However, the clinical application of these prodrugs still faces many problems, including the low payloads, burst release, and non-controlled delivery. To address these, various biomaterial-based platforms have been developed as the carriers to deliver NO to the targeted tissues in a controlled and sustained manner. This review aims to summarize recent developments of various therapeutic platforms, engineered to release NO for the treatment of CVD. In addition, two potential strategies to improve the effectiveness of existing NO therapy are also discussed, including the combination of NO-releasing platforms and either hydrogen sulfide-based therapy or stem cell therapy. Hopefully, some NO-releasing platforms may provide important therapeutic benefits for CVD.