Diabetes and aortic dissection: unraveling the role of 3-hydroxybutyrate through mendelian randomization.

BACKGROUND: In observational and experimental studies, diabetes has been reported as a protective factor for aortic dissection. 3-Hydroxybutyrate, a key constituent of ketone bodies, has been found to favor improvements in cardiovascular disease. However, whether the protective effect of diabetes on aortic dissection is mediated by 3-hydroxybutyrate is unclear. We aimed to investigate the causal effects of diabetes on the risk of aortic dissection and the mediating role of 3-hydroxybutyrate in them through two-step Mendelian randomization. MATERIALS AND METHODS: We performed a two-step Mendelian randomization to investigate the causal connections between diabetes, 3-hydroxybutyrate, and aortic dissection and calculate the mediating effect of 3-hydroxybutyrate. Publicly accessible data for Type 1 diabetes, Type 2 diabetes, dissection of aorta and 3-hydroxybutyrate were obtained from genome-wide association studies. The association between Type 1 diabetes and dissection of aorta, the association between Type 2 diabetes and dissection of aorta, and mediation effect of 3-hydroxybutyrate were carried out separately. RESULTS: The IVW method showed that Type 1 diabetes was negatively associated with the risk of aortic dissection (OR 0.912, 95% CI 0.836-0.995), The weighted median, simple mode and weighted mode method showed consistent results. The mediated proportion of 3-hydroxybutyrate on the relationship between Type 1 diabetes and dissection of aorta was 24.80% (95% CI 5.12-44.47%). The IVW method showed that Type 2 diabetes was negatively associated with the risk of aortic dissection (OR 0.763, 95% CI 0.607-0.960), The weighted median, simple mode and weighted mode method showed consistent results. 3-Hydroxybutyrate does not have causal mediation effect on the relationship between Type 2 diabetes and dissection of aorta. CONCLUSION: Mendelian randomization study revealed diabetes as a protective factor for dissection of aorta. The protective effect of type 1 diabetes on aortic dissection was partially mediated by 3-hydroxybutyrate, but type 2 diabetes was not 3-hydroxybutyrate mediated.

Precise large-fragment deletions in mammalian cells and mice generated by dCas9-controlled CRISPR/Cas3.

Currently, the Cas9 and Cas12a systems are widely used for genome editing, but their ability to precisely generate large chromosome fragment deletions is limited. Type I-E CRISPR mediates broad and unidirectional DNA degradation, but controlling the size of Cas3-mediated DNA deletions has proven elusive thus far. Here, we demonstrate that the endonuclease deactivation of Cas9 (dCas9) can precisely control Cas3-mediated large-fragment deletions in mammalian cells. In addition, we report the elimination of the Y chromosome and precise retention of the Sry gene in mice using CRISPR/Cas3 and dCas9-controlled CRISPR/Cas3, respectively. In conclusion, dCas9-controlled CRISPR/Cas3-mediated precise large-fragment deletion provides an approach for establishing animal models by chromosome elimination. This method also holds promise as a potential therapeutic strategy for treating fragment mutations or human aneuploidy diseases that involve additional chromosomes.

Programmable RNA 5-methylcytosine (m5C) modification of cellular RNAs by dCasRx conjugated methyltransferase and demethylase.

5-Methylcytosine (m5C), an abundant RNA modification, plays a crucial role in regulating RNA fate and gene expression. While recent progress has been made in understanding the biological roles of m5C, the inability to introduce m5C at specific sites within transcripts has hindered efforts to elucidate direct links between specific m5C and phenotypic outcomes. Here, we developed a CRISPR-Cas13d-based tool, named reengineered m5C modification system (termed 'RCMS'), for targeted m5C methylation and demethylation in specific transcripts. The RCMS editors consist of a nuclear-localized dCasRx conjugated to either a methyltransferase, NSUN2/NSUN6, or a demethylase, the catalytic domain of mouse Tet2 (ten-eleven translocation 2), enabling the manipulation of methylation events at precise m5C sites. We demonstrate that the RCMS editors can direct site-specific m5C incorporation and demethylation. Furthermore, we confirm their effectiveness in modulating m5C levels within transfer RNAs and their ability to induce changes in transcript abundance and cell proliferation through m5C-mediated mechanisms. These findings collectively establish RCMS editors as a focused epitranscriptome engineering tool, facilitating the identification of individual m5C alterations and their consequential effects.

Targeted mutagenesis in mice via an engineered AsCas12f1 system.

SpCas9 and AsCas12a are widely utilized as genome editing tools in human cells, but their applications are largely limited by their bulky size. Recently, AsCas12f1 protein, with a small size (422 amino acids), has been demonstrated to be capable of cleaving double-stranded DNA protospacer adjacent motif (PAM). However, low editing efficiency and large differences in activity against different genomic loci have been a limitation in its application. Here, we show that engineered AsCas12f1 sgRNA has significantly improved the editing efficiency in human cells and mouse embryos. Moreover, we successfully generated three stable mouse mutant disease models using the engineered CRISPR-AsCas12f1 system in this study. Collectively, our work uncovers the engineered AsCas12f1 system expands mini CRISPR toolbox, providing a remarkable promise for therapeutic applications.

Sensorineural hearing loss induced by gefitinib: A CARE-compliant case report and literature reviews.

RATIONALE: Gefitinib is a potent and selective orally active growth factor receptor (EGFR)-tyrosine kinase inhibitor that is commonly used to treat advanced non-small cell lung cancer patients with activating EGFR mutations. Hearing impairment with gefitinib was sparsely reported. In this report, we describe a case of sensorineural deafness associated with the administration of gefitinib, with a Naranjo score of 7. PATIENT CONCERNS: An 81-year-old female was diagnosed with lung adenocarcinoma with bone metastasis and an EGFR-activating mutation. The patient was prescribed gefitinib tablets at a daily dose of 250 mg for lung adenocarcinoma treatment. However, the patient experienced moderate to severe bilateral sensorineural deafness, primarily in her right ear, after taking gefitinib. Following the cessation of gefitinib administration, the patient exhibited partial restoration of auditory function. Upon resuming the medication, she experienced a worsening of deafness. DIAGNOSES: The otoscopic audiogram and hearing test indicated moderate to severe bilateral sensorineural deafness. INTERVENTIONS: The otolaryngologist recommended bilateral hearing aids to enhance hearing function. OUTCOMES: Throughout our follow-up period, the patient did not receive a hearing aid implant. LESSONS: This article first reported the ototoxicity caused by gefitinib. While rare, our report highlights that gefitinib-induced sensorineural deafness is possible and its mechanisms are still unclear. This adverse reaction should be monitored closely during clinical application of gefitinib to improve patient outcomes.

Anemia and frailty in the aging population: implications of dietary fiber intake (findings of the US NHANES from 2007-2018).

BACKGROUND: Frailty has long been seen as an indicator of reduced physical functions in the elderly, which may be caused by a variety of chronic illnesses or cancerous tumors. Dietary fiber was connected with anemia and frailty, whereas it was uncertain if dietary fiber consumption modifies the impact of anemia on frailty in elderly adults. METHODS: We performed a secondary analysis using older adults aged 60 years and over from the National Health and Nutrition Examination Survey (NHANES) 2007-2018 cycles. Dietary fiber intake was estimated using two 24-h dietary recalls. Participants were dichotomized as frail or non-frail based on a modified Fried physical frailty phenotype from previous NHANES studies. The weighted logistic regression was used to estimate the odds ratio (OR) and confidence interval (CI) for the associations between hemoglobin levels and frailty at high- and low-dietary fiber intake levels. RESULTS: A total of 9644 older adults were included in this study, and the weighted sample was 56,403,031, of whom 3,569,186 (6.3%) were deemed to be frail, and the remainder were deemed to be non-frail. Among the low dietary fiber intake group, higher hemoglobin was significantly associated with a lower risk of frailty (OR = 0.79, 95% CI: 0.71-0.87), and anemia was associated with an almost threefold elevated risk of frailty (OR = 3.24, 95% CI:1.98-5.29) in the fully adjusted model. However, this phenomenon was not observed in groups with high dietary fiber intake. In addition, L-shaped dose response relationship was found in the high dietary fiber intake group (P overall association < 0.001; P non-linear association = 0.076). Whereas the dose response relationship was not significant in the high dietary fiber intake group (P overall association 0.752; P non-linear association = 0.734). CONCLUSIONS: Frailty was positively associated with the severity of anemia in older adults with low, but not high, dietary fiber intake. Adequate fiber intake may be an innovative dietary strategy to reduce frailty in older adults.

Mortality from all-cause and cause-specific in the elderly: Joint implications of anemia and frailty.

BACKGROUND: Anemia is prevalent among older adults, and it contributes to the incidence of frailty. In turn, the frail elderly may be deficient in nutrients, including iron, vitamin B-12, and folate, that can be materials for human blood, as a result of their limited nutrient intake, resulting in anemia. Both anemia and frailty are associated with an increased risk of mortality in elderly adults. However, the combined influence of anemia and frailty on mortality is unclear. METHODS: Data obtained from NHANES 2007-2014 were analyzed in this study. Frailty status was determined using a modified Fried Phenotype, and anemia was defined according to the criteria set by the World Health Organization. Public-use Linked Mortality files until December 31, 2019 were available. The weighted Cox proportional hazard regression models were used to estimate separate effects and joint effects of frailty and anemia on all-cause and cause-specific mortality. RESULTS: This study analyzed 6,406 participants aged 60 years or older. Over a 13-year follow-up period, considering participants with no anemia and no frailty as reference, participants with both anemia and frailty had nearly fourfold the all-cause (HR (95% CI): 4.03 (2.95,5.52)), more than four-time the cardiovascular (HR (95% CI): 4.24(2.46,7.32)) mortality risk, and above five-time the non-CVD/non-cancer (HR (95% CI): 5.17 (3.58,7.46)) mortality risk. CONCLUSIONS: The study indicated that older adults who exhibit low levels of hemoglobin and frailty are at the greatest risk for all-cause, cardiovascular, cancer, and non-cancer/non-cardiovascular mortality, with the exception of cancer mortality, which was only increased by anemia.

A strategy for Cas13 miniaturization based on the structure and AlphaFold.

The small size of the Cas nuclease fused with various effector domains enables a broad range of function. Although there are several ways of reducing the size of the Cas nuclease complex, no efficient or generalizable method has been demonstrated to achieve protein miniaturization. In this study, we establish an Interaction, Dynamics and Conservation (IDC) strategy for protein miniaturization and generate five compact variants of Cas13 with full RNA binding and cleavage activity comparable the wild-type enzymes based on a combination of IDC strategy and AlphaFold2. In addition, we construct an RNA base editor, mini-Vx, and a single AAV (adeno-associated virus) carrying a mini-RfxCas13d and crRNA expression cassette, which individually shows efficient conversion rate and RNA-knockdown activity. In summary, these findings highlight a feasible strategy for generating downsized CRISPR/Cas13 systems based on structure predicted by AlphaFold2, enabling targeted degradation of RNAs and RNA editing for basic research and therapeutic applications.

Sustained delivery of osteogenic growth peptide through injectable photoinitiated composite hydrogel for osteogenesis.

One of the most challenging clinical issues continues to be the effective bone regeneration and rebuilding following bone abnormalities. Although osteogenic growth peptide (OGP) has been proven to be effective in promoting osteoblast activity, its clinical application is constrained by abrupt release and easily degradation. We developed a GelMA/HAMA dual network hydrogel loaded with OGP based on a combination of physical chain entanglement and chemical cross-linking effects to produce an efficient long-term sustained release of OGP. The hydrogel polymers were quickly molded under ultraviolet (UV) light and had the suitable physical characteristics, porosity structure and biocompatibility. Significantly, the GelMA/HAMA-OGP hydrogel could promote cell proliferation, adhesion, increase osteogenic-related gene and protein expression in vitro. In conclusion, the OGP sustained-release system based on GelMA/HAMA dual network hydrogel offers a fresh perspective on bone regeneration therapy.

Surface Modification and Functionalities for Titanium Dental Implants.

Dental implants have become the mainstream strategy for oral restoration, and implant materials are the most important research hot spot in this field. So far, Ti implants dominate all kinds of implants. The surface properties of the Ti implant play decisive roles in osseointegration and antibacterial performance. Surface modifications can significantly change the surface micro/nanotopography and composition of Ti implants, which will effectively improve their hydrophilicity, mechanical properties, osseointegration performance, antibacterial performance, etc. These optimizations will thus improve implant success and service life. In this paper, the latest surface modification techniques of Ti dental implants are systematically and comprehensively reviewed. The various biomedical functionalities of surface modifications are discussed in-depth. Finally, a profound comment on the challenges and opportunities of this frontier is proposed, and the most promising directions for the future were explored.

Safety, Pharmacokinetics, and Pharmacodynamics of Midazolam Gel After Rectal Administration in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVES: Midazolam rectal gel is a novel rectal formulation that may be a promising and potential alternative to oral administration for pediatric sedation. The objective of this study was to evaluate the safety, pharmacokinetics, pharmacodynamics, and absolute bioavailability of midazolam rectal gel in healthy Chinese subjects. METHODS: An open-label, single-dose, randomized, two-period, two-treatment, crossover clinical study was conducted in 22 healthy subjects (16 males and six females), each receiving 2.5 mg intravenous midazolam in one period and 5 mg midazolam rectal gel in another period (the dosages here were calculated as active midazolam). Safety, pharmacokinetic, and pharmacodynamic assessments were conducted throughout the study. RESULTS: All of the subjects completed both treatment periods. The formulation of rectal gel was well tolerated, with no serious adverse events occurring. After a single rectal dose of 5 mg midazolam rectal gel, it was absorbed rapidly with a median value of time to peak concentration (Tmax) of 1.00 h, and mean values of the peak concentration (Cmax) and area under the concentration-time curve (AUC0-t) of 37.2 ng/mL and 137 h·ng/mL, respectively. The absolute bioavailability of rectal gel was 59.7%. The rectal gel exhibited a relatively delayed onset but a more stable sedative effect and a longer duration when compared with intravenous midazolam. CONCLUSION: Midazolam rectal gel may be a feasible alternative with a high level of acceptance in pediatric sedation and enhanced bioavailability compared to an oral formulation. The modeling results may help to disclose out the exposure-response relationship of midazolam rectal gel and support the design of an escalating-doses study and pediatric extrapolation study. CLINICAL TRIAL REGISTRATION: The study was registered at http://www.chinadrugtrials.org.cn (No. CTR20192350).

A Responsive Feeding Questionnaire Based on Self-Determination Theory for Caregivers of Chinese Toddlers.

OBJECTIVE: To develop and test the psychometric properties of a responsive feeding questionnaire (RFQ) on the basis of Self-Determination Theory for caregivers of toddlers aged 12-24 months in China. DESIGN: Item generation, preliminary evaluation items, refinement questionnaire, and psychometric properties testing. SETTING: Toddlers' caregivers from Shandong Province, China, were surveyed online between June 2021 and February 2022 (n = 616). MAIN OUTCOME MEASURE: Content, face, and construct validity and reliability of the RFQ. ANALYSIS: Content validity was performed on the basis of expert panel feedback and cognitive interviews among caregivers. Construct validity was evaluated using principal component analysis with varimax rotation. Test-retest reliability was conducted with a sample of 105 caregivers. RESULTS: Over 3 phases of testing, a new instrument was developed to measure responsive feeding in toddler caregivers. The instrument was reliable, with an internal consistency of 0.87 and an intraclass correlation of 0.92. The principal component analysis identified a 3-factor solution (autonomy support, positive involvement, appropriate response) aligning with a theoretical framework from Self-Determination Theory. The final version of the instrument included 23 items. CONCLUSIONS AND IMPLICATIONS: The 23-item RFQ has been validated in a Chinese population. Future research needs to validate this instrument in other countries and with children of different ages.

Suppressing high mobility group box-1 release alleviates morphine tolerance via the adenosine 5'-monophosphate-activated protein kinase/heme oxygenase-1 pathway.

Opioids, such as morphine, are the most potent drugs used to treat pain. Long-term use results in high tolerance to morphine. High mobility group box-1 (HMGB1) has been shown to participate in neuropathic or inflammatory pain, but its role in morphine tolerance is unclear. In this study, we established rat and mouse models of morphine tolerance by intrathecal injection of morphine for 7 consecutive days. We found that morphine induced rat spinal cord neurons to release a large amount of HMGB1. HMGB1 regulated nuclear factor κB p65 phosphorylation and interleukin-1ß production by increasing Toll-like receptor 4 receptor expression in microglia, thereby inducing morphine tolerance. Glycyrrhizin, an HMGB1 inhibitor, markedly attenuated chronic morphine tolerance in the mouse model. Finally, compound C (adenosine 5'-monophosphate-activated protein kinase inhibitor) and zinc protoporphyrin (heme oxygenase-1 inhibitor) alleviated the morphine-induced release of HMGB1 and reduced nuclear factor κB p65 phosphorylation and interleukin-1ß production in a mouse model of morphine tolerance and an SH-SY5Y cell model of morphine tolerance, and alleviated morphine tolerance in the mouse model. These findings suggest that morphine induces HMGB1 release via the adenosine 5'-monophosphate-activated protein kinase/heme oxygenase-1 signaling pathway, and that inhibiting this signaling pathway can effectively reduce morphine tolerance.

Mesenchymal Stem Cell-Derived Exosomes Enhance 3D-Printed Scaffold Functions and Promote Alveolar Bone Defect Repair by Enhancing Angiogenesis.

The reconstruction of severe alveolar bone defects remains a complex and challenging field for clinicians. Three-dimensional-printed scaffolds can adapt precisely to the complicated shape of the bone defects, which is an alternative solution to bone tissue engineering. Our previous study constructed an innovative low-temperature 3D-printed silk fibroin/collagen I/nano-hydroxyapatite (SF/COL-I/nHA) composite scaffold with a stable structure and remarkable biocompatibility. However, the clinical translation of most scaffolds is limited by insufficient angiogenesis and osteogenesis. In this study, we investigated the effects of human umbilical cord mesenchymal-stem-cell-derived exosomes (hUCMSC-Exos) on bone regeneration, especially from the perspective of inducing angiogenesis. HUCMSC-Exos were isolated and characterized. In vitro, the effect of hUCMSC-Exos on the proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) was examined. Moreover, the loading and release of hUCMSC-Exos on 3D-printed SF/COL-I/nHA scaffolds were evaluated. In vivo, hUCMSC-Exos and 3D-printed SF/COL-I/nHA scaffolds were implanted into alveolar bone defects, and bone regeneration and angiogenesis were investigated by micro-CT, HE staining, Masson staining, and immunohistochemical analysis. The results showed that hUCMSC-Exos stimulated HUVEC proliferation, migration, and tube formation in vitro, and the effect increased with increasing exosome concentrations. In vivo, the combination of hUCMSC-Exos and 3D-printed SF/COL-I/nHA scaffolds promoted alveolar bone defect repair by enhancing angiogenesis and osteogenesis. We constructed an elaborate cell-free bone-tissue-engineering system by combining hUCMSC-Exos with 3D-printed SF/COL-I/nHA scaffolds, potentially providing new ideas for treating alveolar bone defects.

Silk Fibroin/Collagen/Hydroxyapatite Scaffolds Obtained by 3D Printing Technology and Loaded with Recombinant Human Erythropoietin in the Reconstruction of Alveolar Bone Defects.

The fast osteogenesis of the large alveolar fossa and the maintenance of the height of the alveolar ridge after tooth extraction have always been a clinical challenge. Therefore, this work describes the creation of innovative silk fibroin/collagen/hydroxyapatite (SCH) biological scaffolds by 3D printing technology, which are loaded with recombinant human erythropoietin (rh-EPO) for the reconstruction of bone defects. Low-temperature 3D printing can maintain the biological activity of silk fibroin and collagen. The SCH scaffolds showed the ideal water absorption and porosity, being a sustained-release carrier of rh-EPO. The optimized scaffolds had ideal mechanical properties in vitro, and MC3T3-E1 cells could easily adhere and proliferate on it. In vivo experiments in rabbits demonstrated that the composite scaffolds gradually degraded and promoted the accumulation and proliferation of osteoblasts and the formation of collagen fibers, significantly promoting the reconstruction of mandibular defects. In this study, a novel composite biological scaffold was prepared using 3D printing technology, and the scaffold was innovatively combined with the multifunctional growth factor rh-EPO. This provides a new optimized composite material for the reconstruction of irregular mandible defects, and this biomaterial is promising for clinical reconstruction of alveolar bone defects.

Social Infrastructure and Street Networks as Critical Infrastructure for Aging Friendly Community Design: Mediating the Effect of Physical Activity.

Establishing an age-friendly environment at the community level is essential for promoting healthy aging. This study focused on the relationship between older adults and the community environment through their levels of satisfaction within it. We measured their physical activity (PA) in the community environment and three variables of community-level satisfaction: community environment (SCE), community social infrastructure (SSI), and community street networks (SSN). We analyzed 108 older adult participants in Suzhou using mediation analysis and multiple linear regression to investigate the relationship between physical activity and the community environment. The results of the mediation effect model showed that SCE, SSI, and SSN all affected the physical functions of older adults via the total amount of physical activity (TPA); SSI and SSN affected older adults' physical functions by affecting the total duration of moderate-intensity physical activity (MPA) and vigorous-intensity physical activity (VPA). In addition, SSI and SSN are related to the types of community facilities, street space quality, and accessibility. Our study provides valuable insights into optimizing aging-friendly neighborhoods through moderate-to-vigorous-intensity PAs at both the facility and street space levels.

A causal association of ANKRD37 with human hippocampal volume.

Human hippocampal volume has been separately associated with single nucleotide polymorphisms (SNPs), DNA methylation and gene expression, but their causal relationships remain largely unknown. Here, we aimed at identifying the causal relationships of SNPs, DNA methylation, and gene expression that are associated with hippocampal volume by integrating cross-omics analyses with genome editing, overexpression and causality inference. Based on structural neuroimaging data and blood-derived genome, transcriptome and methylome data, we prioritized a possibly causal association across multiple molecular phenotypes: rs1053218 mutation leads to cg26741686 hypermethylation, thus leads to overactivation of the associated ANKRD37 gene expression in blood, a gene involving hypoxia, which may result in the reduction of human hippocampal volume. The possibly causal relationships from rs1053218 to cg26741686 methylation to ANKRD37 expression obtained from peripheral blood were replicated in human hippocampal tissue. To confirm causality, we performed CRISPR-based genome and epigenome-editing of rs1053218 homologous alleles and cg26741686 methylation in mouse neural stem cell differentiation models, and overexpressed ANKRD37 in mouse hippocampus. These in-vitro and in-vivo experiments confirmed that rs1053218 mutation caused cg26741686 hypermethylation and ANKRD37 overexpression, and cg26741686 hypermethylation favored ANKRD37 overexpression, and ANKRD37 overexpression reduced hippocampal volume. The pairwise relationships of rs1053218 with hippocampal volume, rs1053218 with cg26741686 methylation, cg26741686 methylation with ANKRD37 expression, and ANKRD37 expression with hippocampal volume could be replicated in an independent healthy young (n = 443) dataset and observed in elderly people (n = 194), and were more significant in patients with late-onset Alzheimer's disease (n = 76). This study revealed a novel causal molecular association mechanism of ANKRD37 with human hippocampal volume, which may facilitate the design of prevention and treatment strategies for hippocampal impairment.

ß-sheets in serum protein are independent risk factors for coronary lesions besides LDL-C in coronary heart disease patients.

Background: Coronary heart disease (CHD) patients with standard low-density lipoprotein cholesterol (LDL-C) remain at risk of cardiovascular events, making it critical to explore new targets to reduce the residual risk. The relationship between ß-sheet conformation and CHD is gaining attention. This study was designed to compare the coronary lesions in CHD patients with varying LDL-C and evaluate whether serum ß-sheets are associated with coronary damage. Methods: Two hundred and one patients diagnosed with stable CHD were recruited and divided into four groups according to LDL-C. Baseline information, coronary lesion-related indicators, and peripheral blood samples were collected. Serum ß-sheet content was determined by thioflavin T fluorescence. Results: The baseline information was comparable in CHD patients with different LDL-C. No difference was found in indicators relevant to coronary lesions among groups. The content of ß-sheet was negatively correlated with LDL-C. Multiple linear regression revealed that serum ß-sheet was positively correlated with coronary lesion when risk factors such as age, smoking, and LDL-C were controlled. Conclusions: This is the first study that reports the serum ß-sheet levels of CHD patients being gradually increased with decreasing LDL-C when coronary lesions were comparable. Serum ß-sheet might exacerbate the coronary lesions in CHD patients independent of known risk factors such as LDL-C.

Dimethyl Fumarate is a Potential Therapeutic Option for Alzheimer's Disease.

BACKGROUND: Dimethyl fumarate (DMF) has been approved for clinical treatment of multiple sclerosis based on its antioxidant and anti-inflammatory effects by activating the Nrf2 pathway. Since both oxidative stress and inflammation are involved in Alzheimer's disease (AD), DMF is a potential therapeutic option for AD. OBJECTIVE: This study aims to test the therapeutic effects of DMF on AD model mice and to reveal its underlying molecular mechanisms. METHODS: Cell viability assay and in vitro immunofluorescence imaging were used to evaluate the antioxidant effect of DMF on embryonic mouse hippocampal neurons. Behavioral test and brain magnetic resonance imaging were used to assess the therapeutic effects of DMF on spatial learning and memory as well as hippocampal volume in AD model mice with and without Nrf2 knockdown. Western blotting was used to analyze the expression of antioxidant enzymes and molecules associated with AD-related pathological pathways. RESULTS: DMF inhibits reactive oxygen species overproduction and protects neurons without Nrf2 knockdown from death. DMF reduces amyloid-ß induced memory impairment and hippocampal atrophy in AD model mice rather than in Nrf2 knockdown AD mice. DMF delays the progression of AD by activating the Nrf2 pathway to enhance the expression of downstream antioxidant enzymes and inhibits lipid peroxidation, apoptosis, inflammation, mitochondrial dysfunction and amyloid-ß deposition. CONCLUSION: These results indicate that DMF is a potential therapeutic option for AD through its antioxidant, anti-inflammatory, anti-apoptotic, and other anti-AD effects by activating the Nrf2 pathway.

Emergence agitation after intraoperative neurolytic celiac plexus block with alcohol: a case report.

BACKGROUND: Emergence agitation after general anesthesia may cause several undesirable events in the clinic during patient anesthesia recovery, and acute alcohol intoxication, while rare in surgery, is one of the risk factors. CASE PRESENTATION: A 66-year-old male patient was found to have pancreatic tail neoplasm upon computed tomography (CT) examination. The surgeon planned to resect the pancreatic tail under general anesthesia. However, the surgeon found extensive tumor metastasis in the abdominal cavity, and thus performed a neurolytic celiac plexus block (NCPB) with 40 ml 95% ethyl alcohol and finished the surgery in approximately 1 h. Twenty minutes later, the patient was extubated and developed significant emergence agitation in the postoperative care unit, characterized by restlessness, uncontrollable movements, confusion and disorientation. The patient was flushed and febrile with an alcohol smell in his breath and was unable to follow commands. Patient symptoms were suspected to be due to acute alcohol intoxication. Thus, the patient was given 40 mg of propofol intravenously. Following treatment, the patient recovered with less confusion and disorientation after approximately 10 min. After treatment with propofol twice more, he regained consciousness, was calm and cooperative, had no pain, and could obey instructions approximately 1 h and 40 min following the last treatment. Following this treatment, the patient was transferred to the inpatient ward and felt well. CONCLUSIONS: It is paramount to correctly identify the underlying cause of emergence agitation in order to successfully manage patient symptoms, since treatment plans vary between different etiological causes. Emergence agitation may be due to acute alcohol intoxication after intraoperative use of alcohol.