5-Hydroxymethylcytosine (5hmC) is an epigenetic DNA modification that is highly abundant in central nervous system. It has been reported that DNA 5hmC dysregulation play a critical role in ...Alzheimer's disease (AD) pathology. Changes in 5hmC signatures can be detected in circulating cell-free DNA (cfDNA), which has shown potential as a non-invasive liquid biopsy material.
However, the genome-wide profiling of 5hmC in cfDNA and its potential for the diagnosis of AD has not been reported to date.
We carried out a case-control study and used a genome-wide chemical capture followed by high-throughput sequencing to detect the genome-wide profiles of 5hmC in human cfDNA and identified differentially hydroxymethylated regions (DhMRs) in late-onset AD patients and the control.
We discovered significant differences of 5hmC enrichment in gene bodies which were linked to multiple AD pathogenesis-associated signaling pathways in AD patients compared with cognitively normal controls, indicating they can be well distinguished from normal controls by DhMRs in cfDNA. Specially, we identified 7 distinct genes (RABEP1, CPNE4, DNAJC15, REEP3, ROR1, CAMK1D, and RBFOX1) with predicting diagnostic potential based on their significant correlations with MMSE and MoCA scores of subjects.
The present results suggest that 5hmC markers derived from plasma cfDNA can served as an effective, minimally invasive biomarkers for clinical auxiliary diagnosis of late-onset AD.
Both epidemiological and preclinical studies have shown the benefits of n-3 polyunsaturated fatty acid (n-3 PUFA) on dementia and cognitive impairment, yet the results of clinical randomized ...controlled trials (RCTs) performed to date are conflicting. The difference in the baseline omega-3 index (O3i) of subjects is a potential cause for this disparity, yet this is usually ignored. The present meta-analysis aimed to evaluate the effect of n-3 polyunsaturated fatty acid (n-3 PUFA) on cognitive function in the elderly and the role of baseline O3i. A systematic literature search was conducted in PubMed, Embase, Cochrane Library, and Web of Science up to June 27th, 2023. The mean changes in the mini-mental state examination (MMSE) score were calculated as weighted mean differences by using a fixed-effects model. Fifteen random controlled trials were included in the meta-analysis. Pooled analysis showed that n-3 PUFA supplementation did not significantly improve the MMSE score (WMD = 0.04, −0.08, 0.16;
Z
= 0.62,
P
= 0.53;
I
2
= 0.00%,
P
(
I
2
) = 0.49). Out of the 15 studies included in the meta-analysis, only 7 reported O3i at baseline and outcome, so only these 7 articles were used for subgroup analysis. Subgroup analysis showed that the MMSE score was significantly improved in the higher baseline O3i subgroup (WMD = 0.553, 0.01, 1.095;
I
2
= 0.00%,
P
(
I
2
) = 0.556) and higher O3i increment subgroup (WMD = 0.525, 0.023, 1.026;
I
2
= 0.00%,
P
(
I
2
) = 0.545). The overall effect demonstrated that n-3 PUFA supplementation exerted no improvement on global cognitive function. However, a higher baseline O3i and higher O3i increment were associated with an improvement in cognitive function in the elderly.
Preclinical studies have shown the benefits of n-3 polyunsaturated fatty acid (n-3 PUFA) on dementia and cognitive impairment, yet the results of clinical randomized controlled trials (RCTs) performed to date are conflicting.
Although the ε4 allele of the apolipoprotein E (ApoE4) gene has been established as a genetic risk factor for many neurodegenerative diseases, including Alzheimer's disease, the mechanism of action ...remains poorly understood. Transient receptor potential vanilloid 1 (TRPV1) was reported to regulate autophagy to protect against foam cell formation in atherosclerosis. Here, we show that ApoE4 leads to lipid metabolism dysregulation in microglia, resulting in enhanced MHC-II-dependent antigen presentation and T-cell activation. Lipid accumulation and inflammatory reactions were accelerated in microglia isolated from TRPV1
; Cx3cr1
-ApoE4 mice. We showed that metabolic boosting by treatment with the TRPV1 agonist capsaicin rescued lipid metabolic impairments in ApoE4 neurons and defects in autophagy caused by disruption of the AKT-mTOR pathway. TRPV1 activation with capsaicin reversed ApoE4-induced microglial immune dysfunction and neuronal autophagy impairment. Capsaicin rescued memory impairment, tau pathology, and neuronal autophagy in ApoE4 mice. Activation of TRPV1 decreased microglial phagocytosis of synapses in ApoE4 mice. TRPV1 gene deficiency exacerbated recognition memory impairment and tau pathology in ApoE4 mice. Our study suggests that TRPV1 regulation of lipid metabolism could be a therapeutic approach to alleviate the consequences of the ApoE4 allele.
Coronavirus causes a disease with high infectivity and pathogenicity, especially SARS in 2003, MERS in 2012, and COVID-2019 currently. The spike proteins of these coronaviruses are critical for host ...cell entry by receptors. Thus, searching for broad-spectrum anti-coronavirus candidates, such as spike protein inhibitors, is vital and desirable due to the mutations in the spike protein. In this study, a combination of computer-aided drug design and biological verification was used to discover active monomers from traditional Chinese medicine. Surface plasmon resonance (SPR) assays and NanoBit assays were used to verify the predicated compounds with their binding activities to spike proteins and inhibitory activities on the SARS-CoV-2 RBD/ACE2 interaction, respectively. Furthermore, an MTT assay was used to evaluate the cell toxicities of active compounds. As a result, glycyrrhizic acid (ZZY-44) was found to be the most efficient and nontoxic broad-spectrum anti-coronavirus molecule in vitro, especially, the significant effect on SARS-CoV-2, which provided a theoretical basis for the study of the pharmacodynamic material basis of traditional Chinese medicine against SARS-CoV-2 and offered a lead compound for further structural modification in order to obtain more effective candidate drugs against SARS-CoV-2.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Autophagy is a major regulator of the ageing process of the central nervous system and neurodegeneration. Autophagy dysfunction has been implicated in the pathogenesis of Alzheimer's disease (AD). ...TRPV1 was reported to regulate autophagy to protect against foam cell formation and reduce the release of inflammatory factors in atherosclerosis. In this study, pharmacological activation of TRPV1 with the TRPV1 agonist capsaicin induced autophagy in a TRPV1-dependent manner in both primary microglia and BV2 cells. TRPV1-mediated autophagy regulated glycolysis and oxidative phosphorylation by controlling the expression of genes required for aerobic glycolysis and mitochondrial respiration in primary microglia. TRPV1 agonist capsaicin decreased amyloid and phosphorylated tau pathology and reversed memory deficits by promoting microglia activation, metabolism, and autophagy in 3xTg mice. These results indicate that TRPV1 was a potential therapeutic target for AD, which suggests that capsaicin should be further assessed as a possible treatment for AD.
Hirudomacin (Hmc) belongs to the Macin family of antimicrobial peptides, which can be used for bactericidal purposes
by cleaving cell membranes. Although the Macin family has broad-spectrum ...antibacterial properties, few studies have been reported on bacterial inhibition by enhancing innate immunity. To further investigate the mechanism of Hmc inhibition, we chose the classical innate immune model organism Caenorhabditis elegans as the study subject. In this investigation, we found that Hmc treatment directly reduced the number of Staphylococcus aureus and Escherichia coli in the intestine of infected wild-type nematodes and infected pmk-1 mutant nematodes. Hmc treatment significantly prolonged the life span of infected wild-type nematodes and increased the expression of antimicrobial effectors (
,
,
,
), and Hmc treatment still significantly increased the expression of antimicrobial effectors (
,
,
) in wild-type nematodes in the absence of bacterial stimulation. In addition, Hmc treatment significantly increased the expression of key genes of the pmk-1/p38 MAPK pathway (
,
,
,
) under both infected and uninfected conditions but failed to increase the life span of infected pmk-1 mutant nematodes as well as the expression of antimicrobial effector genes. Western blot results further demonstrated that Hmc treatment significantly elevated pmk-1 protein expression levels in infected wild-type nematodes. In conclusion, our data suggest that Hmc has both direct bacteriostatic and immunomodulatory effects and may upregulate antimicrobial peptides in response to infection via the pmk-1/p38 MAPK pathway. It has the potential to serve as a new antibacterial agent and immune modulator.
In today's world, bacterial drug resistance is becoming increasingly serious, and natural antibacterial proteins are attracting attention because of advantages such as their diverse and complex antibacterial modes, lack of residue, and harder-to-develop drug resistance. Notably, there are few antibacterial proteins with multiple effects such as direct antibacterial and innate immunity enhancement at the same time. We believe that an ideal antimicrobial agent can be developed only through a more comprehensive and in-depth study of the bacteriostatic mechanism of natural antibacterial proteins. The significance of our study is that based on the known
bacterial inhibition of Hirudomacin (Hmc), we further clarified its mechanism
, which can be subsequently developed as a natural bacterial inhibitor for various applications in medicine, food, farming, and daily chemicals.
Neuroinflammation may induce a phenotype switch to reactive astrogliosis in neurodegenerative disorders. The calcium-activated potassium channel (KCa3.1) is active in the phenotypic switch that ...occurs during astrogliosis in Alzheimer's disease and ischemic stroke. Here, transcriptome sequencing (RNA-Seq), immunohistochemistry, western blotting, pharmacological blockade, and calcium imaging were used to investigate astrocyte KCa3.1 activity in neuroinflammation, Tau accumulation, and insulin signaling deficits in male wild-type C57BL/6 and KCa3.1−/− knockout (KO) mice, and in primary astrocyte cultures. KCa3.1 deficiency in KO mice decreased lipopolysaccharide (LPS)-induced memory deficits, neuronal loss, glial activation, Tau phosphorylation, and insulin signaling deficits in vivo. KCa3.1 expression in astrocytes was associated with LPS-induced upregulation of the Orai1 store-operated Ca2+ channel protein. The KCa3.1 channel was found to regulate store-operated Ca2+ overload through an interaction with Orai1 in LPS-induced reactive astrocytes. The LPS-induced effects on KCa3.1 and Orai1 indirectly promoted astrogliosis-related changes via the PI3K/AKT/GSK3β and NF-κB signaling pathways in vitro. Unbiased evaluation of RNA-Seq results for actively translated RNAs confirmed that substantial astrocyte diversity was associated with KCa3.1 deficiency. Our results suggest that KCa3.1 regulated astrogliosis-mediated neuroinflammation, Tau accumulation, and insulin signaling deficiency via PI3K/AKT/GSK3β and NF-κB signaling pathways, and contributing to neuronal loss and memory deficits in this neuroinflammation mouse model.
•Loss of KCa3.1 expression decreases LPS-induced memory deficiency and neuronal loss and glial activation•KCa3.1 and Orai1 are involved LPS-induced store-operated calcium entry (SOCE) in astrocytes•KCa3.1 and Orai1 are required for LPS-induced reactive astrogliosis and resultant neurotoxicity•RNA-Seq results confirmed that substantial astrocyte diversity was associated with KCa3.1 deficiency
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background The intermediate-conductance Ca.sup.2+-activated K.sup.+ channel KCa3.1 was recently shown to control the phenotype switch of reactive astrogliosis (RA) in Alzheimer's disease (AD). ...Methods KCa3.1 channels expression and cell localization in the brains of AD patients and APP/PS1 mice model were measured by immunoblotting and immunostaining. APP/PS1 mice and KCa3.1.sup.-/-/APP/PS1 mice were subjected to Morris water maze test to evaluate the spatial memory deficits. Glia activation and neuron loss was measured by immunostaining. Fluo-4AM was used to measure cytosolic Ca.sup.2+ level in beta-amyloid (Abeta) induced reactive astrocytes in vitro. Results KCa3.1 expression was markedly associated with endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in both Abeta-stimulated primary astrocytes and brain lysates of AD patients and APP/PS1 AD mice. The KCa3.1 channel was shown to regulate store-operated Ca.sup.2+ entry (SOCE) through an interaction with the Ca.sup.2+ channel Orai1 in primary astrocytes. Gene deletion or pharmacological blockade of KCa3.1 protected against SOCE-induced Ca.sup.2+ overload and ER stress via the protein kinase B (AKT) signaling pathway in astrocytes. Importantly, gene deletion or blockade of KCa3.1 restored AKT/mechanistic target of rapamycin signaling both in vivo and in vitro. Consistent with these in vitro data, expression levels of the ER stress markers 78-kDa glucose-regulated protein and CCAAT/enhancer-binding protein homologous protein, as well as that of the RA marker glial fibrillary acidic protein were increased in APP/PS1 AD mouse model. Elimination of KCa3.1 in KCa3.1.sup.-/-/APP/PS1 mice corrected these abnormal responses. Moreover, glial activation and neuroinflammation were attenuated in the hippocampi of KCa3.1.sup.-/-/APP/PS1 mice, as compared with APP/PS1 mice. In addition, memory deficits and neuronal loss in APP/PS1 mice were reversed in KCa3.1.sup.-/-/APP/PS1 mice. Conclusions Overall, these results suggest that KCa3.1 is involved in the regulation of Ca.sup.2+ homeostasis in astrocytes and attenuation of the UPR and ER stress, thus contributing to memory deficits and neuronal loss. Keywords: Alzheimer's disease, Endoplasmic reticulum stress, Mouse model, Unfolded protein response, KCa3.1
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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