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Background Increasing evidence suggests an association between pro-inflammatory diets and cognitive function. However, only a few studies based on small sample sizes have explored the association between pro-inflammatory diets and dementia using the dietary inflammatory index (DII). Additionally, the relationship between DII and different subtypes of dementia, such as Alzheimer's dementia and vascular dementia, remains largely unexplored. Given the changes in brain structure already observed in patients with dementia, we also investigated the association between DII and magnetic resonance imaging (MRI) measures of brain structure to provide some hints to elucidate the potential mechanisms between pro-inflammatory diet and cognitive decline. Methods A total of 166,377 UK Biobank participants without dementia at baseline were analyzed. DII calculations were based on the information collected by the 24-h recall questionnaire. Brain structural anatomy and tissue-specific volumes were measured using brain MRI. Cox proportional hazards models, competing risk models, and restricted cubic spline were applied to assess the longitudinal associations. The generalized linear model was used to assess the association between DII and MRI measurements. Results During a median follow-up time of 9.46 years, a total of 1372 participants developed dementia. The incidence of all-cause dementia increased by 4.6% for each additional unit of DII [hazard ratio (HR): 1.046]. Besides, DII displayed a “J-shaped” non-linear association with Alzheimer’s dementia ( P nonlinear  = 0.003). When DII was above 1.30, an increase in DII was significantly associated with an increased risk of Alzheimer’s dementia (HR: 1.391, 95%CI: 1.085–1.784, P  = 0.009). For brain MRI, the total volume of white matter hyperintensities increased with an increase in DII, whereas the volume of gray matter in the hippocampus decreased. Conclusions In this cohort study, higher DII was associated with a higher risk of all-cause dementia and Alzheimer’s dementia. However, our findings suggested that the association with DII and vascular and frontotemporal dementia was not significant.

This study investigated the knowledge, attitudes, and practices (KAP) of caregivers of children with Type 1 diabetes (T1D) using insulin pumps, particularly focusing on skin complications associated with insulin pump therapy. Conducted at a children’s hospital between April and September 2024, the research involved 329 caregivers, most of whom were female. A cross-sectional design was employed, using a structured questionnaire to assess caregivers’ knowledge, attitudes, and practices regarding insulin pump–related skin complications. The findings showed that over a third of the children experienced skin complications related to insulin pump use. The average scores indicated that caregivers generally had limited knowledge but relatively positive attitudes and practices regarding skin management. Structural equation modeling demonstrated that a caregiver’s knowledge significantly influenced their attitudes and practices, with knowledge also indirectly affecting practices through attitudes. The results highlight a gap in caregiver knowledge, emphasizing the importance of educational programs aimed at improving skin care and management strategies. Future efforts should focus on creating and assessing targeted educational interventions to enhance caregiver understanding and management of skin issues, which could lead to better health outcomes for children using insulin pumps.

Background Nuclear acetyl-CoA pools govern histone acetylation that controls synaptic plasticity and contributes to cognitive deterioration in patients with Alzheimer’s disease (AD). Nuclear acetyl-CoA pools are generated partially from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). However, the underlying mechanism of histone acetylation dysregulation in AD remains poorly understood. Methods We detected ACSS2 expression and histone acetylation levels in the brains of AD patients and 5 × FAD mice. When we altered ACSS2 expression by injecting adeno-associated virus into the dorsal hippocampus of 5 × FAD mice and replenished ACSS2 substrate (acetate), we observed changes in cognitive function by Morris water maze. We next performed RNA-seq, ChIP-qPCR, and electrophysiology to study molecular mechanism underlying ACSS2-mediated spatial learning and memory in 5 × FAD mice. Results We reported that ACSS2 expression and histone acetylation (H3K9, H4K12) were reduced in the hippocampus and prefrontal cortex of 5 × FAD mice. Reduced ACSS2 levels were also observed in the temporal cortex of AD patients. 5 × FAD mice exhibited a low enrichment of acetylated histones on the promoters of NMDARs and AMPARs, together with impaired basal and activity-dependent synaptic plasticity, all of which were rescued by ACSS2 upregulation. Moreover, acetate replenishment enhanced ac-H3K9 and ac-H4K12 in 5 × FAD mice, leading to an increase of NMDARs and AMPARs and a restoration of synaptic plasticity and cognitive function in an ACSS2-dependent manner. Conclusion ACSS2 is a key molecular switch of cognitive impairment and that targeting ACSS2 or acetate administration may serve as a novel therapeutic strategy for the treatment of intermediate or advanced AD. Graphical Abstract Nuclear acetyl-CoA pools are generated partly from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). Model depicts that ACSS2 expression is downregulated in the brains of 5×FAD model mice and AD patients. Of note, ACSS2 downregulation mediates a reduction in ionotropic glutamate receptor expression through histone acetylation, which exacerbates synaptic plasticity impairment in AD. These deficits can be rescued by ACSS2 upregulation or acetate supplementation (GTA, an FDA-approved food additive), which may serve as a promising therapeutic strategy for AD treatment.

The proportion of elderly people infected with tuberculosis (TB) is increasing, and misdiagnosis and missed diagnosis are common. This study aimed to explore the diagnostic value of metagenomic next-generation sequencing (mNGS) for pulmonary TB (PTB) and to investigate age-related differences in lung microbial composition, clinical characteristics and imaging findings among PTB patients. We retrospectively recruited 162 suspected PTB patients, and finally 143 patients were used in this analysis. Patients were classified into two groups: adult (18 ≤ age < 60, n  = 66) and elderly (Age ≥ 60, n  = 77). Differences and associations in clinical characteristics, imaging findings, and lung microbiota were analyzed. Compared to adult patients, elderly patients had a higher prevalence of hypertension (31.17% vs. 9.09%, P  = 0.0012), fever (20.78% vs. 4.55%, P  = 0.0044) and chest tightness (24.68% vs. 10.61%, P  = 0.0297), but a lower prevalence of chest pain (7.58% vs. 0%, P  = 0.0139). For TB identification, mNGS had the highest positive rate (100%), followed by T-spot (74.75%), GeneXpert (37.80%) and acid-fast staining (AFS) (7.30%), and all the conventional methods showed slight higher positive rates in the elderly group compared to the adult group ( P  > 0.05). Bilateral lung infection was more common in elderly patients (79.22% vs. 60.61%, P  = 0.0148), with infiltration (32.17%, 46/143), shadows (26.57%, 38/143), nodules (20.28%, 29/143), and bronchiectasis (20.28%, 29/143) being the most common imaging features. The diversity of the lung microbial communities was significantly lower in elderly patients compared to adults ( P  < 0.05). Clinical characteristics, imaging findings, and the top 20 most abundant species in lung microbiota showed significantly positive correlation. This study demonstrates that mNGS has excellent diagnostic value for PTB in both adult and elderly patients. Significant differences in clinical characteristics, imaging, and lung microbial composition were observed between the two groups. Understanding these differences may aid in the diagnosis and treatment of tuberculosis in elderly patients.

Background Hepatic arterial infusion chemotherapy (HAIC) provides sustained high intrahepatic drug exposure with limited systemic toxicity, potentially enhancing antigen release and immune sensitization. This study compared the efficacy and safety of HAIC combined with lenvatinib and PD-1/PD-L1 inhibitors versus systemic chemotherapy-based triple therapy in advanced unresectable intrahepatic cholangiocarcinoma (iCCA). Methods A retrospective analysis of 67 patients with unresectable iCCA treated with HAIC-based triple therapy ( n  = 32) or systemic triple therapy ( n  = 35) was conducted. Clinical efficacy, survival, prognostic factors and safety profiles were evaluated. Baseline imbalances were adjusted using inverse probability of treatment weighting (IPTW). Kaplan–Meier and Cox regression analyses before and after IPTW assessed treatment effects on overall survival (OS) and progression-free survival (PFS). Results HAIC-based triple therapy achieved superior tumor control versus systemic therapy, with higher objective response rate (59.4 vs. 20.0%; P  < 0.001), disease control rate (90.6 vs. 68.6%; P  < 0.001), and tumor shrinkage (+ 6.5 vs. − 1.0 mm; P  = 0.002). Local (93.8 vs. 66.7%; P  = 0.006) and distant (90.3 vs. 72.7%; P  = 0.071) control rates favored HAIC-based triple therapy. After IPTW adjustment, Kaplan–Meier survival analysis showed that HAIC-based triple therapy significantly improved both OS (24.1 vs. 15.5 months; P  = 0.010) and PFS ( P  = 0.020) compared to systemic therapy. In the IPTW-adjusted multivariate Cox regression analysis, HAIC-based triple therapy was associated with a markedly reduced risk of OS (HR [95% CI]: 0.221[0.070–0.693]) and PFS (HR[95% CI]: 0.129[0.028–0.592]). Toxicities were manageable, and immune-related adverse events correlated with reduced progression. Conclusion HAIC-based triple therapy provided superior tumor control, prolonged survival, and preserved hepatic function with acceptable safety in unresectable iCCA.

Abstract Alzheimer’s disease (AD) is the most common cause of dementia and is a growing public health challenge. Neuroinflammation has been proposed as a prominent pathological feature of AD and has traditionally been attributed to the innate immune system. However, emerging evidence highlights the involvement of adaptive immunity, particularly T and B lymphocytes, in the neuroinflammatory processes of AD. It remains unclear how adaptive immune responses, originally intended to protect the body, contribute to chronic inflammation and neuronal dysfunction in AD. Here, we review the roles of adaptive immunity, cellular composition, and niches and their contribution to AD development and progression. Notably, we synthesize the crosstalk between adaptive immunity and the innate immune system of the central nervous system (CNS), which is mainly mediated by glial cells and myeloid cells, and their interrelationships with amyloid-β (Aβ)/Tau pathology. We hypothesized that the alterations observed in innate immunity in AD mirror age-related immune alterations, whereas the dysregulation of adaptive immunity contributes more accurately to disease-specific immune responses. Targeting adaptive immunity in the context of neuroinflammation may provide new insights into potential therapeutic strategies designed to modulate immune responses, thereby facilitating the diagnosis, intervention, and treatment of AD.

To reflect the volatile differences of dried citrus peel as affected by cultivars and drying methods, the volatile compounds of dried citrus peel of two cultivars (Citrus reticulata “Chachi” and Citrus reticulata “Ponkan”), prepared under three drying methods (sun-drying (SD), hot-air-drying (AD), and freeze-drying (FD)), were analyzed by GC-MS, odor activity values (OAVs), and GC-IMS. GC-MS data indicated that SD was favorable to preserve terpenic alcohols (linalool, α-terpineol and terpinene-4-ol), β-cymene, methyl methanthranilate, and monoterpenes; while AD was favorable to preserve aliphatic aldehydes and sesquiterpenes; and SD was more similar with AD in GC-MS analysis of volatile profile (of higher MW) for both cultivars from the PCA outcome. Furthermore, significant difference in volatile isomeric composition of different samples was also clearly demonstrated through extracted ion chromatogram (EIC) by GC-MS analysis. GC-IMS analysis showed the favorability of FD to preserve ketones, phenols, esters, and aromatic aldehydes; and SD was more similar with FD in GC-IMS analysis of volatile profile (of smaller MW) for both cultivars from the PCA outcome. Moreover, the OAVs indicate that 2-methoxy-4-vinylphenol contributed much to the flavor of dried Ponkan peel, while 2-methoxy-4-vinylphenol, methyl methanthranilate, and methyl anthranilate played an important role in the flavor of dried Chachi peel; and the highest OAVs for monoterpenes were observed at SD for both cultivars. Thus, the combination of GC-MS and GC-IMS analyses with PCA in this paper suggested the superiority of SD to preserve volatiles and characteristic aroma in dried citrus peel, and that SD contributed much to the quality of dried Chachi peel.

Cognitive deterioration and memory decline associated with the progression of Alzheimer's disease (AD) primarily results from synaptic failure. However, current understanding of the upstream regulatory mechanisms controlling synaptic plasticity remains limited. Salt-inducible kinase 3 (SIK3) is central to the signal pathway and is involved in neuronal regulation of sleep duration in mice. We speculated that the SIK3 cascade signaling pathway might contribute to the pathogenesis of AD. Thus, the present study employed AD transgenic mouse models, Morris Water Maze, virus-mediated gene transfer, electrophysiology, co-immunoprecipitation, western blotting, quantitative polymerase chain reaction, immunofluorescence, ChIP-qPCR, Golgi-Cox staining and dendritic spine analysis to investigate this connection. Our results revealed that SIK3 mRNA/protein expression was significantly reduced in middle-aged AD transgenic mouse models and AD patients. Conditional deletion of SIK3 gene in dorsal hippocampal neurons of 5×FAD mice further accelerated cognitive deterioration and impaired synaptic plasticity. In hippocampal neuronal cultures, SIK3 formed a complex with HDAC4, directly phosphorylated HDAC4 and regulated its nuclear cytoplasmic shuttle. Overexpression of SIK3 could facilitate the expression of synaptic plasticity-related genes by directly repressing mef2c or involving the recruitment of histone deacetylase to promoter regions of target genes through regulation of p-HDAC4, and vice versa. Moreover, up-regulation of SLP-S, the truncated fragment of SIK3, in dorsal hippocampal neurons, restored the synaptic plasticity and alleviates the cognitive impairment in 5×FAD mice. Collectively, these findings revealed a novel and important role of SIK3-HDAC4 regulation of synaptic plasticity and propose a new target for therapeutic approaches of cognitive deficits associated with AD.

The tumor‐suppressor role of long noncoding RNA (lncRNA) growth arrest‐specific transcript 5 (GAS5) has been proven in various types of cancer. However, the specific function of GAS5 in tumor‐associated macrophages (TAMs) of endometrial cancer (EC) is elusive. Quantitative PCR results showed that GAS5 expression decreased in EC tissues and primary TAMs from EC tumors. Tumor‐associated macrophage infiltration was significantly positively associated with the developmental stage of EC. Direct coculture of GAS5‐overexpressing TAMs and EC cells showed that GAS5 enhanced phagocytosis, antigen presentation, and activation of cytotoxic T cells, and repressed “Don’t eat me” signals between TAMs and EC cells. Tumor formation in immunodeficient mice showed that GAS5‐overexpressing macrophages could repress EC formation in vivo. GAS5 promoted M1 polarization by activating the microRNA‐21– phosphatase and tensin homolog (PTEN)–AKT signaling pathway and directly repressing the nuclear accumulation and phosphorylation of oncogenic yes‐associated protein 1 (YAP1) in TAMs. GAS5 inhibited the development of EC from both innate and adaptive immunity by transforming TAMs from a protumor to an antitumor phenotype. These antitumor effects of GAS5 on TAMs were mediated by the activation of the miR‐21‐PTEN‐AKT pathway and inhibition of YAP1. Long noncoding RNA growth arrest‐specific transcript 5 (GAS5) promotes M1 polarization by activating the microRNA‐21‐PTEN‐AKT signaling pathway and directly repressing the nuclear accumulation and phosphorylation of oncogenic yes‐associated protein 1 (YAP1) in tumor‐associated macrophages (TAMs) of endometrial cancer (EC). The antitumor effects of GAS5 on TAMs brings novel ideas and identifies potential targets of EC.

Small molecule RNAs (microRNAs) are a kind of endogenous, stable, and noncoding RNA molecule that can regulate the expression of target genes such as DJ-1 at the posttranscriptional level. This study aimed to detect the expression of salivary microRNAs and to discover their value as a salivary potential biomarker for Parkinson's disease (PD). Through a case-control study, RT-qPCR technology was used to detect the expression of miR-874 and miR-145-3p in the saliva of 30 PD patients and 30 healthy volunteers. Then we compared the differences in the expression levels of salivary miR-874 and miR-145-3p between the PD group and the control group and analyzed the correlation between the expression of salivary miR-874 and miR-145-3p in terms of age, gender, disease condition, and disease course. We found that salivary miR-874 and miR-145-3p were both positively expressed in the PD group and control group, and their expression in the PD group was higher than that in the control group. The expression of salivary miRNA-874 and miR-145-3p had no clear correlation to age, gender, total RNA concentrations in saliva, the score of UPDRSII, UPDRSIII, olfactory test scale, MMSE, MoCA, Hohn-Yahr stage and disease course. In conclusion, in the PD group and the control group with positive expression, the expression levels of miR-874 and miR-145-3p in the PD group were higher than those in the control group. The detection of miR-874 and miR-145-3p expression in saliva can be used as an auxiliary biomarker for PD.