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Abstract Background Limited research has analyzed the association between diastolic blood pressure (DBP) and survival after pediatric cardiopulmonary resuscitation (CPR). This study aimed to explore the association between post-resuscitation diastolic blood pressure and survival in pediatric patients who underwent CPR. Method This retrospective single-center study included pediatric patients admitted to the pediatric intensive care unit of Asan Medical Center between January 2016 to November 2022. Patients undergoing extracorporeal CPR and those with unavailable data were excluded. The primary endpoint was survival to ICU discharge. Results A total of 106 patients were included, with 67 (63.2%) achieving survival to ICU discharge. Multivariate logistic regression analysis identified DBP within 1 h after ROSC as the sole significant variable (p = 0.002, aOR, 1.043; 95% CI, 1.016–1.070). Additionally, DBP within 1 h demonstrated an area under the ROC curve of 0.7 (0.592–0.809) for survival to ICU discharge, along with mean blood pressure within the same timeframe. Conclusion Our study highlights the importance of DBP within 1-hour post-ROSC as a significant prognostic factor for survival to ICU discharge. However, further validation through further prospective large-scale studies is warranted to confirm the appropriate post-resuscitation DBP of pediatric patients.

Purpose This study was performed to analyze clinical features and use of renal replacement therapy (RRT) for children who visit the pediatric emergency department with benign acute childhood myositis (BACM) or rhabdomyolysis. Methods We retrospectively reviewed medical records of 289 children who visited the emergency department with BACM or rhabdomyolysis from January 2013 through December 2022. Clinical features, laboratory and microbiological findings, and outcomes were compared between children with the two diagnoses. Subsequently, multivariable logistic regressions were performed to identify factors associated with applying RRT. Results Of the 289 children, a total of 212 were analyzed, including 93 with BACM and 119 with rhabdomyolysis. Influenza (70 of the 145 children [48.3%]) was the most common cause, followed by exercise (36 of 212 [17.0%]). Compared with the children with BACM, those with rhabdomyolysis showed significantly higher frequencies of being boys and hematuria, and higher concentrations of hemoglobin, creatinine, creatine kinase, and myoglobin. Continuous venovenous hemofiltration, a modality of RRT, was applied to 8 children (6.7%) with rhabdomyolysis, of whom 1 died. Creatine kinase was independently associated with the application of RRT (adjusted odds ratio, 1.06; 95% confidence interval, 1.00-1.12; P = 0.036). Conclusion Rhabdomyolysis in children who require RRT may be associated with a higher concentration of creatine kinase.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by the deposition of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. The accumulation of these aggregated proteins causes memory and synaptic dysfunction, neuroinflammation, and oxidative stress. This research study is significant as it aims to assess the neuroprotective properties of vitamin E (VE) analog Trolox in an Aβ1 − 42-induced AD mouse model. Aβ1 − 42 5μL/5min/mouse was injected intracerebroventricularly (i.c.v.) into wild-type adult mice brain to induce AD-like neurotoxicity. For biochemical analysis, Western blotting and confocal microscopy were performed. Remarkably, intraperitoneal (i.p.) treatment of Trolox (30 mg/kg/mouse for 2 weeks) reduced the AD pathology by reducing the expression of Aβ, phosphorylated tau (p-tau), and β-site amyloid precursor protein cleaving enzyme1 (BACE1) in both cortex and hippocampus regions of mice brain. Furthermore, Trolox-treatment decreased neuroinflammation by inhibiting Toll-like receptor 4 (TLR4), phosphorylated nuclear factor-κB (pNF-κB) and interleukin-1β (IL-1β), and other inflammatory biomarkers of glial cells [ionized calcium-binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP)]. Moreover, Trolox reduced oxidative stress by enhancing the expression of nuclear factor erythroid-related factor 2 (NRF2) and heme oxygenase 1 (HO1). Similarly, Trolox-induced synaptic markers, including synaptosomal associated protein 23 (SNAP23), synaptophysin (SYN), and post-synaptic density protein 95 (PSD-95), and memory functions in AD mice. Our findings could provide a useful and novel strategy for investigating new medications to treat AD-associated neurodegenerative diseases.

Abstract Lung cancer is the second most frequently diagnosed cancer and the leading cause of cancer-related mortality worldwide. Tumour ecosystems feature diverse immune cell types. Myeloid cells, in particular, are prevalent and have a well-established role in promoting the disease. In our study, we profile approximately 900,000 cells from 25 treatment-naive patients with adenocarcinoma and squamous-cell carcinoma by single-cell and spatial transcriptomics. We note an inverse relationship between anti-inflammatory macrophages and NK cells/T cells, and with reduced NK cell cytotoxicity within the tumour. While we observe a similar cell type composition in both adenocarcinoma and squamous-cell carcinoma, we detect significant differences in the co-expression of various immune checkpoint inhibitors. Moreover, we reveal evidence of a transcriptional “reprogramming” of macrophages in tumours, shifting them towards cholesterol export and adopting a foetal-like transcriptional signature which promotes iron efflux. Our multi-omic resource offers a high-resolution molecular map of tumour-associated macrophages, enhancing our understanding of their role within the tumour microenvironment.

Abstract Acute pancreatitis (AP) is an acute inflammatory disorder that is common, costly, and is increasing in incidence worldwide with over 300,000 hospitalizations occurring yearly in the United States alone. As its course and outcomes vary widely, a critical knowledge gap in the field has been a lack of accurate prognostic tools to forecast AP patients’ outcomes. Despite several published studies in the last three decades, the predictive performance of published prognostic models has been found to be suboptimal. Recently, non-regression machine learning models (ML) have garnered intense interest in medicine for their potential for better predictive performance. Each year, an increasing number of AP models are being published. However, their methodologic quality relating to transparent reporting and risk of bias in study design has never been systematically appraised. Therefore, through collaboration between a group of clinicians and data scientists with appropriate content expertise, we will perform a systematic review of papers published between January 2021 and December 2023 containing artificial intelligence prognostic models in AP. To systematically assess these studies, the authors will leverage the CHARMS checklist, PROBAST tool for risk of bias assessment, and the most current version of the TRIPOD-AI. (Research Registry ( http://www.reviewregistry1727 .).

Alzheimer's disease is the most common and costly chronic progressive neurodegenerative disorder, with the highest global public health impact. However, diagnosing this neurodegenerative disorder is challenging and often relies on traditional clinical diagnostics techniques applied after symptoms appear, which are complex, costly, time-consuming, and potentially intrusive methods. This hinders the development of effective tools for Point-of-Care applications. To address these limitations, researchers have been developing several biosensing techniques utilizing biosensors, which have excellent selectivity and sensitivity for detecting Alzheimer's disease biomarkers at an early stage more efficiently and promptly. This comprehensive study focuses on promising biomarkers for Alzheimer's disease detection in various bio-fluids, as well as the accompanying obstacles and advantages. Furthermore, we provide a comprehensive review of current biosensing techniques, focusing on electrochemical and optical biosensors, which are well-known for their exceptional sensitivity and selectivity in detecting Alzheimer's disease biomarkers. These biosensors facilitate the early diagnosis of Alzheimer's disease in point-of-care testing, thereby enhancing point-of-care applications for Alzheimer's disease. We also explore bioelectronic tongues and bioelectronic noses as innovative, non-invasive tools for detecting biomarkers in Alzheimer's disease, which further facilitates point-of-care applications for Alzheimer's disease.

Intense neuroinflammation contributes to neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. Lipopolysaccharides (LPSs) are an integral part of the cell wall of Gram-negative bacteria that act as pathogen-associated molecular patterns (PAMPs) and potentially activate the central nervous system’s (CNS) immune system. Microglial cells are the local macrophages of the CNS and have the potential to induce and control neuroinflammation. This study aims to evaluate the anti-inflammatory and antioxidant effect of kojic acid against the toxic effects of LPSs, such as neuroinflammation-induced neurodegeneration and cognitive decline. The C57BL/6N mice were subjected to LPS injection for 2 weeks on alternate days (each mouse received 0.25 mg/kg/i.p. for a total of seven doses), and kojic acid was administered orally for 3 weeks consecutively (50 mg/kg/mouse, p. o). Bacterial endotoxins, or LPSs, are directly attached to TLR4 surface receptors of microglia and astrocytes and alter the cellular metabolism of immune cells. Intraperitoneal injection of LPS triggers the toll-like receptor 4 (TLR4), phospho-nuclear factor kappa B (p-NFκB), and phospho-c-Jun n-terminal kinase (p-JNK) protein expressions in the LPS-treated group, but these expression levels were significantly downregulated in the LPS + KA-treated mice brains. Prolong neuroinflammation leads to the generation of reactive oxygen species (ROS) followed by a decrease in nuclear factor erythroid-2-related factor 2 (Nrf2) and the enzyme hemeoxygenase 1 (HO-1) expression in LPS-subjected mouse brains. Interestingly, the levels of both Nrf-2 and HO-1 increased in the LPS + KA-treated mice group. In addition, kojic acid inhibited LPS-induced TNF-α and IL-1β production in mouse brains. These results indicated that kojic acid may suppress LPS-induced neuroinflammation and oxidative stress in male wild-type mice brains (in both the cortex and the hippocampus) by regulating the TLR4/NF-κB signaling pathway.

Neuroinflammation includes the activation of immune glial cells in the central nervous system, release pro-inflammatory cytokines, which disrupt normal neural function and contribute to various neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis, and stroke. AD is characterized by various factors including amyloidogenesis, synaptic dysfunction, memory impairment and neuroinflammation. Lipopolysaccharide (LPS) constitutes a vital element of membrane of the gram-negative bacterial cell, triggering vigorous neuroinflammation and facilitating neurodegeneration. Lupeol, a naturally occurring pentacyclic triterpene, has demonstrated several pharmacological properties, notably its anti-inflammatory activity. In this study, we evaluated the anti-inflammatory and anti-Alzheimer activity of lupeol in lipopolysaccharide (LPS)-injected mice model. LPS (250ug/kg) was administered intraperitoneally to C57BL/6 N male mice for 1 week to induce neuroinflammation and cognitive impairment. For biochemical analysis, acetylcholinesterase (AChE) assay, western blotting and confocal microscopy were performed. AChE, western blot and immunofluorescence results showed that lupeol treatment (50 mg/kg) along with LPS administration significantly inhibited the LPS-induced activation of neuroinflammatory mediators and cytokines like nuclear factor (NF-κB), tumor necrosis factor (TNF-α), cyclooxygenase (COX-2) and interleukin (IL-1β). Furthermore, we found that LPS-induced systemic inflammation lead to Alzheimer’s symptoms as LPS treatment enhances level of amyloid beta (Aβ), amyloid precursor protein (APP), Beta-site APP cleaving enzyme (BACE-1) and hyperphosphorylated Tau (p-Tau). Lupeol treatment reversed the LPS-induced elevated level of Aβ, APP, BACE-1 and p-Tau in the hippocampus, showing anti-Alzheimer’s properties. It is also determined that lupeol prevented LPS-induced synaptic dysfunction via enhanced expression of pre-and post-synaptic markers like SNAP-23, synaptophysin and PSD-95. Overall, our study shows that lupeol prevents memory impairment and synaptic dysfunction via inhibition of neuroinflammatory processes. Hence, we suggest that lupeol might be a useful therapeutic agent in prevention of neuroinflammation-induced neurological disorders like AD.

Purpose We aimed to investigate changes in visiting patterns after the lifting of mask mandates in a single pediatric emergency medical center in Seoul, Korea. Methods This retrospective study was based on the data of patients’ (≤ 18 years) visits to the emergency department (ED) of the center from January 1, 2022 through June 30, 2023. Clinical characteristics, Korean Triage and Acuity Scale (KTAS) level, ED outcomes, and length of stay were compared between before (March 20-June 30, 2022) and after (March 20-June 30, 2023) the lifting of mask mandates. The comparisons were iterated in the patients with infectious disease. Results During the study period, a total of 18,654 children visited the ED. After the lifting of mask mandates, ED visits increased from 7,146 to 11,508 (61.0%; 95% confidence interval, 59.5-62.6; P < 0.001). The increase was more prominent in the age of 2-5 years (82.9%), infectious diseases (175.3%), KTAS level 3 (127.7%), and length of stay shorter than 3 hours (78.8%-92.6%). The number of patients per hour increased by 151.2% for 5 patients or more and over 3,000% for 10 or more. Median length of stay decreased (2.3 hours [interquartile range, 1.2-4.1] to 1.9 hours [1.1-3.5]; P < 0.001). The patients with infectious disease (n = 7,139) showed similar patterns of increase in the age of 2-5 years, KTAS level 3, and length of stay shorter than 3 hours, with an additional increase in the age of 6-18 years. Conclusion After the lifting of mask mandates, pediatric visits increased by 61%, with the highest increase in children with mild infectious diseases on weekends and at night, and the proportion of more than 10 visits per hour significantly increased. We need urgent and realistic support measures from health authorities.

Alzheimer’s disease (AD) is the most predominant cause of dementia, considered a progressive decline in cognitive function that ultimately leads to death. AD has posed a substantial challenge in the records of medical science over the past century, representing a predominant etiology of dementia with a high prevalence rate. Neuroinflammation is a common characteristic of various central nervous system (CNS) pathologies like AD, primarily mediated by specialized brain immune and inflammatory cells, such as astrocytes and microglia. The present study aims to elucidate the potential mechanism of physcion that mitigates LPS-induced gliosis and assesses oxidative stress in mice. Physcion reduced the reactivity of Iba-1- and GFAP-positive cells and decreased the level of inflammatory cytokines like TNF-α and IL-1β. Physcion also reversed the effect of LPS-induced oxidative stress by upregulating the expression of Nrf2 and HO-1. Moreover, physcion treatment reversed LPS-induced synaptic disorder by increasing the level of presynaptic protein SNAP-23 and postsynaptic protein PSD-95. Our findings may provide a contemporary theoretical framework for clinical investigations aimed at examining the pathogenic mechanisms and therapeutic approaches for neuroinflammation and AD.

The facet joint contributes to lumbar spine stability as it supports the weight of body along with the intervertebral discs. However, most studies on the causes of degenerative lumbar diseases focus on the intervertebral discs and often overlook the facet joints. This study aimed to investigate the impact of facet joint degeneration on the degenerative changes and diseases of the lumbar spine. A finite element model of the lumbar spine (L1–S1) was fabricated and validated to study the biomechanical characteristics of the facet joints. To simulate degeneration of the facet joint, the model was divided into four grades based on the number of degenerative segments (L4–L5 or L4–S1) and the contact condition between the facet joint surfaces. Finite element analysis was performed on four spine motions: flexion, extension, lateral bending, and axial torsion, by applying a pure moment to the upper surface of L1. Important parameters that could be used to confirm the effect of facet joint degeneration on the lumbar spine were calculated, including the range of motion (ROM) of the lumbar segments, maximum von Mises stress on the intervertebral discs, and reaction force at the facet joint. Facet joint degeneration affected the biomechanical characteristics of the lumbar spine depending on the movements of the spine. When analyzed by dividing it into degenerative onset and onset-adjacent segments, lumbar ROM and the maximum von Mises stress of the intervertebral discs decreased as the degree of degeneration increased in the degenerative onset segments. The reaction force at the facet joint decreased with flexion and increased with lateral bending and axial torsion. In contrast, lumbar ROM of the onset-adjacent segments remained almost unchanged despite severe degeneration of the facet joint, and the maximum von Mises stress of the intervertebral discs increased with flexion and extension but decreased with lateral bending and axial torsion. Additionally, the facet joint reaction force increased with extension, lateral bending, and axial rotation. This analysis, which combined the ROM of the lumbar segment, maximum von Mises stress on the intervertebral disc, and facet joint reaction force, confirmed the biomechanical changes in the lumbar spine due to the degeneration of isolated facet joints under the load of spinal motion. In the degenerative onset segment, spinal instability decreased, whereas in the onset-adjacent segment, a greater load was applied than in the intact state. When conducting biomechanical studies on the lumbar spine, considering facet joint degeneration is important since it can lead to degenerative spinal diseases, including adjacent segment diseases.

Portosystemic shunt is a rare congenital vascular anomaly. The shunt is hard to clinically suspect because its symptoms develop insidiously and affect various systems at different time points. We report a case of an 11-year-old girl who presented with brain abscess and hypoxemia without respiratory distress. No abnormality related to the hypoxemia, such as intracardiac shunt, was found on the initial chest radiograph and echocardiogram. However, computed tomography showed a portosystemic shunt. An intrapulmonary shunt was demonstrated by bubble contrast echocardiography, indicating a grade 2 hepatopulmonary syndrome, a complication of portosystemic shunt. This case describes the diagnostic process of an unusual case presenting neurological abnormalities and hypoxemia without respiratory distress. Portosystemic shunt with hepatopulmonary syndrome should be considered in the differential diagnosis of unexplained hypoxemia.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that comprises amyloid-beta protein (Aβ) as a main component of neuritic plaques. Its deposition is considered a trigger for AD pathogenesis, progression, and the clinical symptoms of cognitive impairment. Some distinct pathological features of AD include phosphorylation of tau protein, oxidative stress, and mitochondrial dysfunction. These pathological consequences tend to produce reactive oxygen species (ROS), resulting in the dysregulation of various signaling pathways of neuroinflammation and neurodegeneration. The relationship between the Aβ cascade and oxidative stress in AD pathogenesis is like a “chicken and egg” story, with the etiology of the disease regarding these two factors remaining a question of “which comes first.” However, in this review, we have tried our best to clarify the interconnection between these two mechanisms and to show the precise cause-and-effect relationship. Based on the above hallmarks of AD, several therapeutic strategies using natural antioxidants, monoclonal antibodies, and vaccines are employed as anti-Aβ therapy to decrease ROS, Aβ burden, chronic neuroinflammation, and synaptic failure. These natural antioxidants and immunotherapeutics have demonstrated significant neuroprotective effects and symptomatic relief in various in vitro and in vivo models, as well as in clinical trials for AD. However, none of them have received final approval to enter the drug market for mitigating AD. In this review, we extensively elaborate on the pitfalls, assurances, and important crosstalk between oxidative stress and Aβ concerning current anti-Aβ therapy. Additionally, we discuss future strategies for the development of more Aβ-targeted approaches and the optimization of AD treatment and mitigation.

Abstract Background Parkinson’s disease (PD) is the second most frequent age-related neurodegenerative disorder and is characterized by the loss of dopaminergic neurons. Both environmental and genetic aspects are involved in the pathogenesis of PD. Osmotin is a structural and functional homolog of adiponectin, which regulates the phosphorylation of 5′ adenosine monophosphate-activated protein kinase (AMPK) via adiponectin receptor 1 (AdipoR1), thus attenuating PD-associated pathology. Therefore, the current study investigated the neuroprotective effects of osmotin using in vitro and in vivo models of PD. Methods The study used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced and neuron-specific enolase promoter human alpha-synuclein (NSE-hαSyn) transgenic mouse models and 1-methyl-4-phenylpyridinium (MPP+)- or alpha-synuclein A53T-treated cell models. MPTP was injected at a dose of 30 mg/kg/day for five days, and osmotin was injected twice a week at a dose of 15 mg/kg for five weeks. We performed behavioral tests and analyzed the biochemical and molecular changes in the substantia nigra pars compacta (SNpc) and the striatum. Results Based on our study, osmotin mitigated MPTP- and α-synuclein-induced motor dysfunction by upregulating the nuclear receptor-related 1 protein (Nurr1) transcription factor and its downstream markers tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2). From a pathological perspective, osmotin ameliorated neuronal cell death and neuroinflammation by regulating the mitogen-activated protein kinase (MAPK) signaling pathway. Additionally, osmotin alleviated the accumulation of α-synuclein by promoting the AMPK/mammalian target of rapamycin (mTOR) autophagy signaling pathway. Finally, in nonmotor symptoms of PD, such as cognitive deficits, osmotin restored synaptic deficits, thereby improving cognitive impairment in MPTP- and α-synuclein-induced mice. Conclusions Therefore, our findings indicated that osmotin significantly rescued MPTP/α-synuclein-mediated PD neuropathology. Altogether, these results suggest that osmotin has potential neuroprotective effects in PD neuropathology and may provide opportunities to develop novel therapeutic interventions for the treatment of PD.

Background and Aims: Biliary atresia is a rare and devastating bile duct disease that occurs during the neonatal period. Timely identification and prompt surgical intervention is critical for improving the outcome. The aim of the study was to develop a new machine learning–based prediction model for the detection of biliary atresia. Methods: Neonates aged

Abstract Observations of comorbidity in heart diseases, including cardiac dysfunction (CD) are increasing, including and cognitive impairment, such as Alzheimer’s disease and dementia (AD/D). This comorbidity might be due to a pleiotropic effect of genetic variants shared between CD and AD/D. Here, we validated comorbidity of CD and AD/D based on diagnostic records from millions of patients in Korea and the University of California, San Francisco Medical Center (odds ratio 11.5 [8.5–15.5, 95% Confidence Interval (CI)]). By integrating a comprehensive human disease–SNP association database (VARIMED, VARiants Informing MEDicine) and whole-exome sequencing of 50 brains from individuals with and without Alzheimer's disease (AD), we identified missense variants in coding regions including APOB, a known risk factor for CD and AD/D, which potentially have a pleiotropic role in both diseases. Of the identified variants, site-directed mutation of ADIPOQ (268 G > A; Gly90Ser) in neurons produced abnormal aggregation of tau proteins (p = 0.02), suggesting a functional impact for AD/D. The association of CD and ADIPOQ variants was confirmed based on domain deletion in cardiac cells. Using the UK Biobank including data from over 500000 individuals, we examined a pleiotropic effect of the ADIPOQ variant by comparing CD- and AD/D-associated phenotypic evidence, including cardiac hypertrophy and cognitive degeneration. These results indicate that convergence of health care records and genetic evidences may help to dissect the molecular underpinnings of heart disease and associated cognitive impairment, and could potentially serve a prognostic function. Validation of disease–disease associations through health care records and genomic evidence can determine whether health conditions share risk factors based on pleiotropy.

Parkinson’s disease (PD) is a chronic neurodegenerative disease that affects the central nervous system, specifically the motor system. It is mainly caused by the loss of dopamine due to the accumulation of α-synuclein (α-syn) protein in the striatum and substantia nigra pars compacta (SNpc). Previous studies have reported that immunization may be a potential preventive strategy for neurodegenerative diseases such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). Therefore, the aim of the study was to design an α-syn specific epitope vaccine and investigate its effect in PD-related pathophysiology using an α-syn-induced mouse model. We used an in silico model to identify and design a non-toxic α-syn-based peptide epitope vaccine and, to overcome poor immunogenicity, the vaccine was coupled with immunogenic carrier proteins, i.e., ovalbumin (OVA) and keyhole limpet haemocyanin (KLH). Our results showed that vaccinated PD mouse models, especially with vaccines with carrier proteins, improved in motor functions compared with the non-vaccinated PD model. Additionally, the vaccinated groups showed increased immunoglobulin G (IgG) levels in the spleen and plasma as well as decreased interleukin-10 (IL-10) levels in the plasma. Furthermore, vaccinated groups, especially OVA and KLH groups, showed decrease in α-syn levels and increased dopamine-related markers, i.e., tyrosine hydroxylase (TH), vesicle monoamine transporter 2 (VMAT2), and dopamine transporter (DAT), and autophagy activities in the striatum and SNpc. Lastly, our data showed decreased neuroinflammation by reducing the activation of microglia and astrocytes and pro-inflammatory cytokines in the immunized groups, especially with OVA and KLH carrier proteins. Overall, these results suggest that vaccination, especially with immunogenic carrier proteins, is effective in reducing the accumulation of α-syn aggregates in the brain and ameliorate PD-related pathophysiology. Hence, further development of this approach might have a potential role in preventing the development of PD.

Purpose The lifestyle changes during the coronavirus disease 2019 pandemic possibly affected mental health among the pediatric population. We aimed to analyze changes in psychiatric emergency-related visits to the emergency department (ED). Methods We reviewed cases of pediatric patients (≤ 18 years) who visited the ED of a tertiary hospital with psychiatric emergency as a chief complaint from March 2019 through February 2021. The study period was dichotomized by March 2020, starting point of social distancing, into the pandemic and control periods. Clinical data were collected and compared between the 2 periods. Results A total of 246 cases with a mean age of 15.2 years were included. The overall visits to the ED decreased to 43.8% whereas the proportion of psychiatric emergency-related visits increased during the pandemic period, compared to the control period (0.5% vs. 1.0%; P < 0.001). The cases with suicidality, including ideation and attempt, increased in both number and proportion during the pandemic period (51 [38.9%] vs. 63 [54.8%]; P = 0.013). Conclusion Pediatric psychiatric emergency-related visits, particularly suicidality, proportionally increased during the pandemic. This finding may be useful to prepare psychiatric resources in EDs.

We report a case of inguinal hernia that contained the entire uterus and both adnexa, presenting with an irreducible soft mass in the left groin and asymmetric labia majora, in a 2-month-old, full-term girl who visited the emergency department. Ultrasonography was performed immediately, and urgent surgical repair was performed without complications. Although inguinal hernia is a common surgical disease, it is rare that the hernia contains the uterus with its adnexa, and presents as a mass of the labia majora. Unlike the bowel herniation, the entity can be complicated by strangulation of the ovary, leading to infertility. To preserve fertility, rapid and accurate diagnosis using ultrasonography should be considered in an infant with an irreducible inguinal mass and asymmetric labia majora.

Button battery ingestion requires emergency endoscopic removal since severe complications, such as esophageal perforation, can develop within 4 hours of the ingestion. Given that guardians do not witness the children’s foreign body ingestion 40% of the time, physicians can only guess what was swallowed based on plain radiography. We report a case of a 45-month-old-boy who visited the emergency department after swallowing an unknown foreign body and whose radiographs showed “circle-within-a-circle appearance” on the anteroposterior view and “step-off appearance” on the lateral view, suggesting button battery ingestion. We conducted emergency endoscopic removal, and found stacked coins mimicking a button battery on the radiographs. The coins were pushed into the stomach and came out through defecation 3 weeks later without further complications. Distinguishing between stacked coins and a button battery through radiography may help avoid unnecessary emergency endoscopy.

Oxidative stress plays an important role in cognitive dysfunctions and is seen in neurodegeneration and Alzheimer’s disease (AD). It has been reported that the polyphenolic compound caffeic acid possesses strong neuroprotective and antioxidant effects. The current study was conducted to investigate the therapeutic potential of caffeic acid against amyloid beta (Aβ1–42)-induced oxidative stress and memory impairments. Aβ1–42 (5 μL/5 min/mouse) was administered intracerebroventricularly (ICV) into wild-type adult mice to induce AD-like pathological changes. Caffeic acid was administered orally at 50 mg/kg/day for two weeks to AD mice. Y-maze and Morris water maze (MWM) behavior tests were conducted to assess memory and cognitive abilities. Western blot and immunofluorescence analyses were used for the biochemical analyses. The behavioral results indicated that caffeic acid administration improved spatial learning, memory, and cognitive abilities in AD mice. Reactive oxygen species (ROS) and lipid peroxidation (LPO) assays were performed and showed that the levels of ROS and LPO were markedly reduced in the caffeic acid-treated mice, as compared to Aβ-induced AD mice brains. Moreover, the expression of nuclear factor erythroid 2–related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were regulated with the administration of caffeic acid, compared to the Aβ-injected mice. Next, we checked the expression of ionized calcium-binding adaptor molecule 1 (Iba-1), glial fibrillary acidic proteins (GFAP), and other inflammatory markers in the experimental mice, which suggested enhanced expression of these markers in AD mice brains, and were reduced with caffeic acid treatment. Furthermore, caffeic acid enhanced synaptic markers in the AD mice model. Additionally, caffeic acid treatment also decreased Aβ and BACE-1 expression in the Aβ-induced AD mice model.

Abstract Background Noonan syndrome (NS) is a developmental disorder caused by mutations of Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2). Although NS patients have diverse neurological manifestations, the mechanisms underlying the involvement of SHP2 mutations in neurological dysfunction remain elusive. Methods Induced pluripotent stem cells generated from dermal fibroblasts of three NS-patients (NS-iPSCs) differentiated to the neural cells by using two different culture systems, 2D- and 3D-cultured systems in vitro. Results Here we represent that SHP2 mutations cause aberrant neural development. The NS-iPSCs exhibited impaired development of EBs in which BMP and TGF-β signalings were activated. Defective early neuroectodermal development of NS-iPSCs recovered by inhibition of both signalings and further differentiated into NPCs. Intriguingly, neural cells developed from NS-NPCs exhibited abundancy of the glial cells, neurites of neuronal cells, and low electrophysiological property. Those aberrant phenotypes were also detected in NS-cerebral organoids. SHP2 inhibition in the NS-NPCs and NS-cerebral organoids ameliorated those anomalies such as biased glial differentiation and low neural activity. Conclusion Our findings demonstrate that SHP2 mutations contribute to precocious gliogenesis in NS-iPSCs during neural development in vitro.

The use of virtual reality as a safety training technology is gaining attention in the construction industry. While current studies focus mainly on the development of VR-based safety training programs, studies focusing on improving its effectiveness is still lacking. Thus, this study aims to understand the psychological process of training transfer and determine the factors that affect VR safety training effectiveness. The study analysed survey data from 248 construction workers who finished construction safety training using VR using PLS-SEM. The results show that the telepresence experienced through the VR and the risk perception of the trainees regarding occupational accidents significantly affect their satisfaction with VR safety training, which affected its effectiveness. Considering that the use of VR in the construction safety training context is still in its early stages, the results of our study, which comprehensively analyses both the technological and psychological aspects of VR safety training, could provide meaningful implications to VR training content developers. Furthermore, the theoretical approach of our study could be implemented in future studies focusing on the topic of training effectiveness.

O-cyclic phytosphingosine-1-phosphate (cPS1P) is a novel and chemically synthesized sphingosine metabolite derived from phytosphingosine-1-phosphate (S1P). This study was undertaken to unveil the potential neuroprotective effects of cPS1P on two different mouse models of Parkinson’s disease (PD). The study used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and neuron specific enolase promoter human alpha-synuclein (NSE-hαSyn) Korl transgenic mice. MPTP was injected for five consecutive days and cPS1P was injected for alternate days for six weeks intraperitoneally. We performed behavioral tests and analyzed the immunohistochemistry and immunofluorescence staining in the substantia nigra pars compacta (SNpc) and the striatum. The behavior tests showed a significant reduction in the motor functions in the PD models, which was reversed with the administration of cPS1P. In addition, both PD-models showed reduced expression of the sphingosine-1-phosphate receptor 1 (S1PR1), and α-Syn which was restored with cPS1P treatment. In addition, administration of cPS1P restored dopamine-related proteins such as tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2), and dopamine transporter (DAT). Lastly, neuroinflammatory related markers such as glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter protein-1 (Iba-1), c-Jun N-terminal kinases (JNK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), tumor necrosis factor-alpha (TNF-α), and interleukin 1 beta (IL-1β) were all reduced after cPS1P administration. The overall findings supported the notion that cPS1P protects against dopamine depletion, neuroinflammation, and PD-associated symptoms.

Cadmium (Cd) is an environmental contaminant, which is a potential risk factor in the progression of aging-associated neurodegenerative diseases. Herein, we have assessed the effects of chronic administration of Cd on cellular oxidative stress and its associated Alzheimer’s disease (AD) pathologies in animal models. Two groups of mice were used, one group administered with saline and the other with Cd (1 mg/kg/day; intraperitoneally) for 3 months. After behavioral studies, molecular/biochemical (Immunoblotting, ELISAs, ROS, LPO, and GSH assays) and morphological analyses were performed. We observed an exacerbation of memory and synaptic deficits in chronic Cd-injected mice. Subacute and chronic Cd escalated reactive oxygen species (ROS), suppressed the master antioxidant enzymes, e.g., nuclear factor-erythroid 2-related factor 2 and heme oxygenase-1, and evoked the stress kinase phospho-c-Jun N-terminal kinase 1 signaling pathways, which may escalate AD pathologies possibly associated with amyloidogenic processes. These findings suggest the regulation of oxidative stress/ROS and its associated amyloid beta pathologies for targeting the Cd-exacerbated AD pathogenesis. In addition, these preclinical animal studies represent a paradigm for epidemiological studies of the human population exposed to chronic and subacute administration of Cd, suggesting avoiding environmental contaminants.

The role of brain somatic mutations in neurodegenerative diseases such as Alzheimer’s disease (AD) is not well understood. Here the authors carry out high-depth exome sequencing ~500× on brain tissue from patients with AD and controls, and identify mutations in a number of genes that are known to contribute to phosphorylation and aggregation of tau, including PIN1.

Tyrosine-protein kinase (Syk) plays a potential role in neuroinflammation and adaptive immune responses in several neurodegenerative conditions. Seeing the significant role of Syk in the pathophysiology of neurodegeneration, several pharmacological inhibitors have been developed. One of the known inhibitors of Syk is BAY61-3606, which has shown efficacies in Alzheimer’s disease (AD) through regulating amyloid production. However, little is known about its efficacies in neuroinflammation and neurodegeneration. Our finding showed that Syk expression was up-regulated by lipopolysaccharide (LPS)-dependent manner, and BAY61-3606 significantly suppressed the activated microglia (ionized calcium-binding adaptor molecule 1 [Iba-1]) and the inflammatory cytokines (tumor necrosis factor-alpha [TNF-α], interleukin 1-beta [IL-1β], IL-6) and other inflammatory mediators (nuclear factor kappa B [NF-κB], cyclooxygenase-2 [Cox-2], and inducible nitric axide synthase [iNOS]) in the lipopolysaccharide (LPS)-treated in vivo and in vitro models. Moreover, BAY61-3606 significantly reduced microglia-mediated neuronal cell death by regulating the expression of Cytochrome C and Bim (B-cell lymphoma 2 [BCL-2] interacting mediator of cell death) in the LPS-treated mice brain and HT22 cells. Furthermore, the expression of synaptic markers, synaptosomal-associated protein, 25 kDa (SNAP25), synaptophysin (Syp), and postsynaptic density protein-95 (PSD95) in LPS-challenged mice showed that BAY61-3606 significantly recovered the synaptic markers. Finally, we have analyzed the effects of BAY61-3606 against memory and cognitive dysfunctions in the LPS injected mice. The Y-maze test and Passive avoidance test suggested that BAY61-3606 significantly protected against LPS-induced cognitive and memory dysfunctions. The current findings not only highlight the mechanisms of Syk in the pathophysiology of neuro-inflammation, but also support the therapeutic efficacy of BAY61-3606 in the management of neurodegeneration.

Background: The best strategy for implant selection in midshaft clavicular fractures (MCF) remains controversial. The present study aims to determine the optimal strategy for implant selection by comparing plate and Titanium Elastic Nail (TEN) with respect to outcomes and related complications and analyze the results based on fracture patterns. Methods: A total of 97 patients with MCF who underwent plate (48 patients) or TEN (49 patients) fixation were retrospectively reviewed. Both groups were divided into three subgroups by fracture type using the AO Foundation/Orthopaedic Trauma Association classification: simple fracture (type A), wedge fracture (type B), and multi-fragmentary fracture (type C). The observed outcome measures were bone union rate, related complications, functional scores, and patient satisfaction score. These outcomes were analyzed based on the fracture classification. Results: Both groups demonstrated excellent union rates (p = 0.495) and similar functional scores (p > 0.05). Visual analog scale (VAS) for satisfaction was better in TEN than plate fixation (p < 0.001). In type A and B subgroups, there were no significant difference in functional scores between plate and TEN fixation (p > 0.05). In type C subgroup, however, both VAS for pain and DASH score in TEN fixation were significantly worse than in plate fixation at 2 and 6 weeks postoperatively (p < 0.05). The incidences of clavicle shortening and skin irritation are higher especially in type C subgroup of TEN fixation (p < 0.05). Conclusion: Patient satisfaction of TEN fixation was higher than that of plate fixation, but TEN fixation had a higher incidence of early postoperative pain and migration in type C fractures. Therefore, type A and B fractures can successfully be treated with plate or TEN fixation, but type C fractures should be treated with plate fixation.

Biological repair of cartilage lesions remains a significant clinical challenge. A wide variety of methods involving mesenchymal stem cells (MSCs) have been introduced. Because of the limitation of the results, most of the treatment methods have not yet been approved by the Food and Drug Administration (FDA). However, bone marrow aspirate concentrate (BMAC) and human umbilical cord blood derived mesenchymal stem cells (hUCB-MSCs) implantation were approved by Korea FDA. The aim of this study was to evaluate clinical and magnetic resonance imaging (MRI) outcomes after two different types of MSCs implantation in knee osteoarthritis. Fifty-two patients (52 knees) who underwent cartilage repair surgery using the BMAC (25 knees) and hUCB-MSCs (27 knees) were retrospectively evaluated for 2 years after surgery. Clinical outcomes were evaluated according to the score of visual analogue scale (VAS), the International Knee Documentation Committee (IKDC) subjective, and the Knee Injury and Osteoarthritis Outcome Score (KOOS). Cartilage repair was assessed according to the modified Magnetic Resonance Observation of Cartilage Repair Tissue (M-MOCART) score and the International Cartilage Repair Society (ICRS) cartilage repair scoring system. At 2-year follow-up, clinical outcomes including VAS, IKDC, and KOOS significantly improved ( P < 0.05) in both groups; however, there were no differences between two groups. There was no significant difference in M-MOCART [1-year ( P = 0.261), 2-year ( P = 0.351)] and ICRS repair score ( P = 0.655) between two groups. Both groups showed satisfactory clinical and MRI outcomes. Implantation of MSCs from BMAC or hUCB-MSCs is safe and effective for repairing cartilage lesion. However, large cases and a well-controlled prospective design with long-term follow-up studies are needed.

Objectives: Acute kidney injury (AKI) is a rare but serious complication after hip fractures. The aim of this study was to evaluate the incidence and the risk factors of postoperative AKI after hip fractures. Methods: From January 2011 to December 2016, 550 patients who underwent surgery of hip fractures at our institution were retrospectively reviewed. AKI was defined and classified by AKI Network (AKIN) Classification/Staging System. The incidence, mortality, and risk factors of postoperative AKI were investigated. Receiver operating characteristic curve analysis was conducted to evaluate the ability of markers in predicting AKI. Results: The incidence of postoperative AKI was 4.4% (25 cases). The mean onset of postoperative AKI was 8.0 ± 5.3 days and recovered after 7.0 ± 4.2 days after the occurrence of AKI. Of 25 patients with AKI, 6 patients (24.0%) died within 1 year after surgery. The independent risk factors for postoperative AKI are the estimated blood loss (EBL) (odds ratio (OR) 1.64; 95% confidence interval (CI) 1.33–2.58; p < 0.01) and postoperative level of albumin (OR 1.77; 95% CI 1.52–2.74; p < 0.01). The cutoff value of the serum albumin was

Age-related decline in mitochondrial function and oxidative stress plays a critical role in neurodegeneration. Lactate dehydrogenase-B (LDHB) is a glycolytic enzyme that catalyzes the conversion of lactate, an important brain energy substrate, into pyruvate. It has been reported that the LDHB pattern changes in the brain during ageing. Yet very little is known about the effect of LDHB deficiency on brain pathology. Here, we have used Ldhb knockout (Ldhb−/−) mice to test the hypothesis that LDHB deficiency plays an important role in oxidative stress-mediated neuroinflammation and neurodegeneration. LDHB knockout (Ldhb−/−) mice were generated by the ablation of the Ldhb gene using the Cre/loxP-recombination system in the C57BL/6 genetic background. The Ldhb−/− mice were treated with either osmotin (15 μg/g of the body; intraperitoneally) or vehicle twice a week for 5-weeks. After behavior assessments, the mice were sacrificed, and the cortical and hippocampal brain regions were analyzed through biochemical and morphological analysis. Ldhb−/− mice displayed enhanced reactive oxygen species (ROS) and lipid peroxidation (LPO) production, and they revealed depleted stores of cellular ATP, GSH:GSSG enzyme ratio, and downregulated expression of Nrf2 and HO-1 proteins, when compared to WT littermates. Importantly, the Ldhb−/− mice showed upregulated expression of apoptosis mediators (Bax, Cytochrome C, and caspase-3), and revealed impaired p-AMPK/SIRT1/PGC-1alpha signaling. Moreover, LDHB deficiency-induced gliosis increased the production of inflammatory mediators (TNF-α, Nf-ĸB, and NOS2), and revealed cognitive deficits. Treatment with osmotin, an adipoR1 natural agonist, significantly increased cellular ATP production by increasing mitochondrial function and attenuated oxidative stress, neuroinflammation, and neuronal apoptosis, probably, by upregulating p-AMPK/SIRT1/PGC-1alpha signaling in Ldhb−/− mice. In brief, LDHB deficiency may lead to brain oxidative stress-mediated progression of neurodegeneration via regulating p-AMPK/SIRT1/PGC-1alpha signaling, while osmotin could improve mitochondrial functions, abrogate oxidative stress and alleviate neuroinflammation and neurodegeneration in adult Ldhb−/− mice.

Abstract Background To date, several trials have reported the use of mesenchymal stem cell (MSC) implantation for osteonecrosis of the femoral head (ONFH). However, the clinical outcomes have not been conclusive. This study compared the clinical and radiological results of bone marrow mesenchymal stem cell (BMMSC) implantation with traditional simple core decompression (CD) using a matched pair case–control design. Methods We retrospectively reviewed 100 patients with ONFH (106 hips) who had been treated by CD alone (50 patients, 53 hips) and CD + BMMSC implantation (50 patients, 53 hips) between February 2004 and October 2014. We assessed the total hip replacement arthroplasty (THA) conversion rate and ARCO (Association Research Circulation Osseous) stage progression. Survivor rate analysis was performed using the Kaplan–Meier method, and an additional THA was defined as the primary endpoints. Results The mean follow-up period was 4.28 years. There was a difference in the THA conversion rate between the CD (49%) and CD + BMMSC groups (28.3%) (p = 0.028). ARCO stage progression was noted in 20 of 53 hips (37.7%) in the CD group and 19 of 53 hips (35.8%) in the CD + BMMSC group. Among collapsed cases (ARCO stages III and IV), there was no difference in clinical failure rate between the two groups. Conversely, in the pre-collapse cases (ARCO stages I and II), only 6 of 30 hips (20%) progressed to clinical failure in the CD + BMMSC group, whereas 15 of 30 hips (50%) progressed to clinical failure in the CD group (p = 0.014). Kaplan–Meier survival analysis showed a significant difference in the time to failure between the two groups up to 10-year follow-up (log-rank test p = 0.031). There was no significant difference in terms of age (p = 0.87) and gender (p = 0.51) when comparing THA conversion rates between groups. No complication was noted. Conclusions These results suggest that implantation of MSCs into the femoral head at an early stage of ONFH lowers the THA conversion rate. However, ARCO stage progression is not affected by this treatment. Trial registration Retrospectively registered

Background: The purpose of this study was to evaluate clinical and radiological outcomes and to analyze the histological findings of repaired cartilage in patients more than 50 years old with underwent fibrin–matrix autologous chondrocyte implantation (ACI). Methods: From January 2013 to February 2014, a prospective study was conducted on 16 patients (16 knees) who underwent fibrin–matrix ACI for International Cartilage Repair Society grade 3 or 4 chondral lesions of the knee. The major lesion was in the medial femoral condyle in all patients. The mean age of the patients was 58.1 ± 6.2 (range 51–66) years, and the minimum follow-up period was 2 years. All patients had clinical and radiological evaluations at 3 months, 6 months, 1 year, and 2 years after surgery. Twelve patients had second-look arthroscopies at 1 year after surgery, and implanted chondral biopsies were performed in 11 of these 12 patients for histological analysis. Results: Functional disability assessment scales for the knee significantly improved after fibrin–matrix ACI ( p < 0.05). The visual analog scale score significantly decreased from 6.7 ± 1.2 to 2.0 ± 1.8 ( p < 0.001). The mean modified magnetic resonance observation of cartilage repair tissue score was 83.8 ± 17.3 at 1 year after surgery and 74.0 ± 19.2 at 2 years after surgery. Repair of the tissue with hyaline cartilage was confirmed histologically. Conclusions: Satisfactory clinical and radiological outcomes were obtained from gel-type fibrin–matrix ACI technique in older patients with a cartilage defect of the knee. Histological analysis confirmed that the new repaired tissue with hyaline cartilage filled the cartilage defect area. Therefore, fibrin–matrix ACI is believed to be an applicable treatment for older patients with chondral lesions of the knee. Level of evidence: Level IV.

Coronavirus disease 2019 (COVID-19) changed the epidemiology of various diseases. The present study retrospectively investigates the epidemiologic and clinical changes in pediatric intussusception for ages ≤ 7 years before (February 2019–January 2020) and after (February 2020–January 2021) the COVID-19 outbreak in a single pediatric emergency department of a university-affiliated tertiary hospital. The incidence of communicable diseases—defined as infectious diseases with the potential for human-to-human transmission via all methods, non-communicable diseases, and intussusception were decreased following the COVID-19 outbreak (15,932 to 3880 (24.4%), 12,994 to 8050 (62.0%), and 87 to 27 (31.0%), respectively). The incidence of intussusception correlated significantly with the change in incidence of communicable diseases (Poisson log-linear regression, odds ratio = 2.15, 95% CI = 1.08–4.26, and p = 0.029). Compared with the pre-pandemic period, patients of the pandemic period showed higher proportions of pathologic leading point (PLP) and hospitalization (14.8% vs. 2.3% and 18.5% vs. 4.6%, respectively), lower base excesses (−4.8 mmol/L vs. −3.6 mmol/L), and higher lactate concentrations (1.7 mmol/L vs. 1.5 mmol/L). The incidence of pediatric intussusception decreased after the COVID-19 pandemic. This reduced incidence may be related to the reduced incidence of communicable diseases. However, the proportions of more severe diseases and PLPs were higher after the COVID-19 pandemic.

Disruptions in brain energy metabolism, oxidative damage, and neuroinflammation are commonly seen in traumatic brain injury (TBI). Microglial activation is the hallmark of neuroinflammation. After brain injury, microglia also act as a double-edged sword with distinctive phenotypic changes. Therefore, therapeutic applications to potentiate microglia towards pro-inflammatory response following brain injury have become the focus of attention in recent years. Here, in the current study, we investigated the hypothesis that 17β-estradiol could rescue the mouse brain against apoptotic cell death and neurodegeneration by suppressing deleterious proinflammatory response probably by abrogating metabolic stress and oxidative damage after brain injury. Male C57BL/6N mice were used to establish a cortical stab wound injury (SWI) model. Immediately after brain injury, the mice were treated with 17β-estradiol (10 mg/kg, once every day via i.p. injection) for one week. Immunoblotting and immunohistochemical analysis was performed to examine the cortical and hippocampal brain regions. For the evaluation of reactive oxygen species (ROS), reduced glutathione (GSH), and oxidized glutathione (GSSG), we used specific kits. Our findings revealed that 17β-estradiol treatment significantly alleviated SWI-induced energy dyshomeostasis and oxidative stress by increasing the activity of phospho-AMPK (Thr172) and by regulating the expression of an antioxidant gene (Nrf2) and cytoprotective enzymes (HO-1 and GSH) to mitigate ROS. Importantly, 17β-estradiol treatment downregulated gliosis and proinflammatory markers (iNOS and CD64) while significantly augmenting an anti-inflammatory response as evidenced by the robust expression of TGF-β and IGF-1 after brain injury. The treatment with 17β-estradiol also reduced inflammatory mediators (Tnf-α, IL-1β, and COX-2) in the injured mouse. Moreover, 17β-estradiol administration rescued p53-associated apoptotic cell death in the SWI model by regulating the expression of Bcl-2 family proteins (Bax and Bcl-2) and caspase-3 activation. Finally, SWI + 17β-estradiol-treated mice illustrated reduced brain lesion volume and enhanced neurotrophic effect and the expression of synaptic proteins. These findings suggest that 17β-estradiol is an effective therapy against the brain secondary injury-induced pathological cascade following trauma, although further studies may be conducted to explore the exact mechanisms.

An amendment to this paper has been published and can be accessed via the original article.

The human gut is a safe environment for several microbes that are symbiotic and important for the wellbeing of human health. However, studies on gut microbiota in different animals have suggested that changes in the composition and structure of these microbes may promote gut inflammation by releasing inflammatory cytokines and lipopolysaccharides, gut-wall leakage, and may affect systemic inflammatory and immune mechanisms that are important for the normal functioning of the body. There are many factors that aid in the gut’s dysbiosis and neuroinflammation, including high stress levels, lack of sleep, fatty and processed foods, and the prolonged use of antibiotics. These neurotoxic mechanisms of dysbiosis may increase susceptibility to Alzheimer’s disease (AD) and other neurodegenerative conditions. Therefore, studies have recently been conducted to tackle AD-like conditions by specifically targeting gut microbes that need further elucidation. It was suggested that gut dyshomeostasis may be regulated by using available options, including the use of flavonoids such as anthocyanins, and restriction of the use of high-fatty-acid-containing food. In this review, we summarize the gut microbiota, factors promoting it, and possible therapeutic interventions especially focused on the therapeutic potential of natural dietary polyflavonoid anthocyanins. Our study strongly suggests that gut dysbiosis and systemic inflammation are critically involved in the development of neurodegenerative disorders, and the natural intake of these flavonoids may provide new therapeutic opportunities for preclinical or clinical studies.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by the deposition of amyloid beta (Ab) plaques and neurofibrillary tangles (NFTs) in the brain. The accumulation of these aggregated proteins causes memory and synaptic dysfunction, neuroinflammation, and oxidative stress. This research study is significant as it aims to assess the neuroprotective properties of vitamin E (VE) analog Trolox in an Ab1-42-induced AD mouse model. Ab1-42 5µL/5min/mouse was injected intracerebroventricularly (i.c.v.) into wild-type adult mice brain to induce AD-like neurotoxicity. For biochemical analysis, Western blotting and confocal microscopy were performed. Remarkably, intraperitoneal (i.p.) treatment of Trolox (30 mg/kg/mouse for 2 weeks) reduced the AD pathology by reducing the expression of Ab, phosphorylated tau (p-tau), and b-site amyloid precursor protein cleaving enzyme1 (BACE1) in both cortex and hippocampus regions of mice brain. Furthermore, Trolox-treatment decreased neuroinflammation by inhibiting Toll-like receptor 4 (TLR4), phosphorylated nuclear factor-kB (pNF-kB) and interleukin-1b (IL-1b), and other inflammatory biomarkers of glial cells [ionized calcium-binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP)]. Moreover, Trolox reduced oxidative stress by enhancing the expression of nuclear factor erythroid-related factor 2 (NRF2) and heme oxygenase 1 (HO1). Similarly, Trolox-induced synaptic markers, including synaptosomal associated protein 23 (SNAP23), synaptophysin (SYN), and post-synaptic density protein 95 (PSD-95), and memory functions in AD mice. Our findings could provide a useful and novel strategy for investigating new medications to treat AD-associated neurodegenerative diseases. [ABSTRACT FROM AUTHOR]