Paraoxonase 1 (PON1) enzyme has antioxidative properties and is present in mammalian blood and several other body fluids. In blood, PON1 is usually integrated into the high-density lipoprotein (HDL) cholesterol. PON1 is a highly versatile enzyme displaying diverse functions such as arylesterase, lactonase, and paraoxonase, among others. PON1 activities are usually investigated with artificial substrates, for example, dihydrocoumarin and thiobutyl butyrolactone for lactonase activity. The PON1 enzyme activities measured with different substrates tend to be falsely assumed as being equivalent in the literature, although there are poor or weak correlations among the PON1 enzyme activities with different substrates. In addition, and despite our knowledge of the factors influencing PON1 paraoxonase and arylesterase activities, there is little knowledge of PON1 lactonase activity variations and attendant mechanisms. This is important considering further that the lactonase activity is the native activity of PON1. We report here a multi-omics analysis of PON1 lactonase activity. The influence of genetic variations, particularly of single nucleotide polymorphisms and epigenetic, proteomic, and lipidomic variations on PON1 lactonase activity are reviewed. In addition, the influence of various environmental, clinical, and demographic variables on PON1 lactonase activity is discussed. Finally, we examine the associations between PON1 lactonase activity and health states and common complex diseases such as atherosclerosis, dementias, obesity, and diabetes. To the best of our knowledge, this is the first multi-omics analysis of PON1 lactonase activity with an eye to future applications in basic life sciences and translational medicine and the nuances of critically interpreting PON1 function with lactones as substrates.

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A Multi-Omics Analysis of PON1 Lactonase Activity in Relation to Human Health and Disease.

Background LINC-DUBR may be a potential therapeutic target in ovarian cancer (OC). The purpose of this research was to explore the impact of miR-107 on the tumorigenicity of OC and its underlying molecular mechanisms. Methods RT-qPCR was adopted to measure the expression of LINC-DUBR and miR-107 in ovarian cancer tissues and cells. CCK-8 assays and transwell chamber assays were conducted to evaluate the impacts of LINC-DUBR and miR-107 on the proliferation and invasion of human ovarian cancer cells (SKOV3). In addition, we determined the relationship between LINC-DUBR, miR-107, and SMAC using TargetScan and luciferase reporter assay. The protein expression of SMAC was determined by western blot. Results Compared with normal tissues and cells, LINC-DUBR was downregulated and miR-107 was highly expressed in ovarian cancer tissues and cell lines. Overexpression of LINC-DUBR inhibited the cell proliferation and invasive ability in OC cells SKOV3. The luciferase reporter assay proved overexpression of LINC-DUBR repressed cells proliferation and invasion via binding to miR-107 in ovarian cancer. In addition, we found that SMAC was downregulated directly by miR-107 in ovarian cancer. miR-107 mimic significantly increased cell proliferation and invasiveness of SKOV3, while overexpressed SMAC eliminated this effect. Furthermore, miR-107 could regulate the XIAP/caspase-3 signaling pathway in ovarian cancer by targeting SMAC. Conclusion LINC-DUBR suppressed malignant progression of ovarian cancer by downregulating miR-107 to induce SMAC expression and involving in the XIAP/caspase-3 signaling pathway.

LINC-DUBR Suppresses Malignant Progression of Ovarian Cancer by Downregulating miR-107 to Induce SMAC Expression

Background The Jiedu-Yizhi formula (JDYZF) is a Chinese herbal prescription used to treat Alzheimer's disease (AD). It was previously confirmed that JDYZF can inhibit the expression of pyroptosis-related proteins in the hippocampus of AD rats and inhibit gut inflammation in AD rats. Therefore, it is hypothesized that JDYZF has a regulatory effect on the gut microbiota. Methods In this study, an AD rat model was prepared by bilateral hippocampal injection of Aβ25-35 and AD rats received high, medium, and low doses of JDYZF orally for 8 weeks. The body weights of the AD rats were observed to assess the effect of JDYZF. The 16S rRNA sequencing technique was used to study the regulation of the gut microbiota by JDYZF in AD rats. Immunohistochemical staining was used to observe the expression levels of Caspase-1 and Caspase-11 in the hippocampus. Results JDYZF reduced body weight in AD rats, and this effect may be related to JDYZF regulating body-weight-related gut microbes. The 16S rRNA analysis showed that JDYZF increased the diversity of the gut microbiota in AD rats. At the phylum level, JDYZF increased the abundances of Bacteroidota and Actinobacteriota and decreased the abundances of Firmicutes, Campilobacterota, and Desulfobacterota. At the genus level, the abundances of Lactobacillus, Prevotella, Bacteroides, Christensenellaceae_R-7_group, Rikenellaceae_RC9_gut_group, and Blautia were increased and the abundances of Lachnospiraceae-NK4A136-group, Anaerobiospirillum, Turicibacter, Oscillibacter, Desulfovibrio, Helicobacter, and Intestinimonas were decreased. At the species level, the abundances of Lactobacillus johnsonii, Lactobacillus reuteri, and Lactobacillus faecis were increased and the abundances of Helicobacter rodentium and Ruminococcus_sp_N15.MGS-57 were decreased. Immunohistochemistry showed that JDYZF reduced the levels of Caspase-1- and Caspase-11-positive staining. Conclusion JDYZF has a regulatory effect on the gut microbiota of AD rats, which may represent the basis for the anti-inflammatory effect of JDYZF.

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Jiedu-Yizhi Formula Alleviates Neuroinflammation in AD Rats by Modulating the Gut Microbiota

Background Beta-amyloid (Aβ) peptide is a widely recognized pathological marker of Alzheimer's disease (AD). Salidroside and Hedysari Radix polysaccharide (HRP) were extracted from Chinese herb medicine Rhodiola rosea L and Hedysarum polybotrys Hand-Mazz, respectively. The neuroprotective effects and mechanisms of the combination of salidroside and Hedysari Radix polysaccharide (CSH) against Aβ25–35 induced neurotoxicity remain unclear. Objective This study aims to investigate the neuroprotective effects and pharmacological mechanisms of CSH on Aβ25–35-induced HT22 cells. Materials and Methods HT22 cells were pretreated with various concentrations of salidroside or HRP for 24 h, followed by exposed to 20 μm Aβ25–35 in the presence of salidroside or RHP for another 24 h. In a CSH protective assay, HT22 cells were pretreated with 40 μm salidroside and 20 μg/mL HRP for 24 h. The cell viability assay, cell morphology observation, determination of mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and cell apoptosis rate were performed. The mRNA expression of protein kinase C-beta (PKCβ), Bax, and Bcl-2 were measured by qRT-PCR. The protein expression levels of cleaved caspase-3, Cyt-C, PKCβ, phospho-ERK1/2, Bax, and Bcl-2 were measured by Western blot. Results CSH treatment increased cell viability, MMP, and decreased ROS generation in Aβ25–35-induced HT22 cells. PKCβ and Bcl-2 mRNA expression were elevated by CSH while Bax was decreased. CSH increased the protein expression levels of PKCβ, Bcl-2, and phospho-ERK1/2, and decreased those of Bax, Cyt-C, and cleaved caspase-3. Conclusions CSH treatment have protective effects against Aβ25–35-induced cytotoxicity through decreasing ROS levels, increasing MMP, inhibiting early apoptosis, and regulating PKC/ERK pathway in HT22 cells. CSH may be a potential therapeutic agent for treating or preventing neurodegenerative diseases.

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The Combination of Salidroside and Hedysari Radix Polysaccharide Inhibits Mitochondrial Damage and Apoptosis via the PKC/ERK Pathway

Background Non-coding RNAs (ncRNA) are a kind of RNA that does not encode protein, which play an important role in Alzheimer’s disease (AD). However, there is a lack of bibliometric analysis and visualization analysis of the research related to AD and ncRNAs. Materials and methods Literature related to AD and ncRNAs in the last decade were searched through the Web of Science Core Collection (WOSCC). The relevant information from all the searched articles was collected. The bibliometric visualization website, CiteSpace, and VOSviewer were used for visualization analysis of countries/regions, institutions, authors, and keywords. Results In total, 1,613 kinds of literature were published in the field. Literature in this field were published in 494 journals. The Journal of Alzheimer’s Disease was the most popular journal. China, Louisiana State University System, and Lukiw WJ were the countries/regions, institutions, and authors with the highest scientific productivity, respectively. The research hotspots in this field focused on the role and mechanism of ncRNAs, especially microRNAs, in AD. The level of research was mainly based on basic research, focusing on animal and cellular levels, and related to proteomics. “Circular RNAs,” “regulation of neuroinflammation,” and “tau protein” were the future research directions. Conclusion Taken together, the field of AD and ncRNAs is developing well. The research hotspots and frontiers in this field can provide a reference for researchers to choose their research direction.

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Bibliometric analysis of research on Alzheimer’s disease and non-coding RNAs: Opportunities and challenges

Jiedu-Yizhi formula (JDYZF) is prescribed for the treatment of Alzheimer's disease (AD) and was created by Jixue Ren, a master of traditional Chinese medicine, based on the “marrow deficiency and toxin damage” theory. In our clinic, this formula has been used for the treatment of AD for many years and has achieved good results. However, the mechanism by which JDYZF improves cognitive impairment has not been determined. In this study, we confirmed that orally administered JDYZF reversed the cognitive deficits in an Aβ25–35-induced rat model, increased the number of neurons in the hippocampal CA1 area, improved their structure, decreased the deposition of β-amyloid (Aβ), reduced the expression of proteins related to the NLRP3/Caspase-1/GSDMD and LPS/Caspase-11/GSDMD pyroptosis pathways, and reduced the levels of interleukin 1β (IL-1β) and IL-18, thereby inhibiting the inflammatory response. In addition, JDYZF exerted no hepatotoxicity in rats. In short, these results provide scientific support for the clinical use of JDYZF to improve the cognitive function of patients with AD.

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Jiedu-Yizhi Formula Improves Cognitive Impairment in an Aβ25–35-Induced Rat Model of Alzheimer's Disease by Inhibiting Pyroptosis

Coronary atherosclerosis affects human health all over the world. PON1 was found to be associated with coronary atherosclerosis but the specific mechanism is still unclear. Non-coding RNA plays an important role in many diseases. In recent years, studies have focused on non-coding RNA in coronary atherosclerosis. In this study, we investigated the effect of non-coding RNA Linc-OIP5 on PON1 expression. Results showed that in the serum of patients with coronary atherosclerosis, there was lower PON1 activity and PON1 level, the same trend in Linc-OIP5, and the opposite trend in miR-616 expression. Through further cell experiments, with up-regulation or down-regulation of Linc-OIP5 and miR-616, we found that Linc-OIP5 positively regulated the expression of PON1 gene and its protein level, while miR-616 negatively regulated the expression of PON1 gene and protein. Through further functional experiments, we also found that the levels of superoxide dismutase (SOD) and nitric oxide (NO) related to oxidative stress also had corresponding changes. Further dual luciferase reporter assay demonstrated that Linc-OIP5 regulated PON1 expression as a ceRNA of miR-616. Thus Linc-OIP5 working as a ceRNA of miR-616 apparently promotes PON1 expression in HUEVC cells and Linc-OIP5 and miR-616 may be an ideal target for the treatment of coronary atherosclerosis in the future.

Linc-OIP5 working as a ceRNA of miR-616 promotes PON1 expression in HUEVC cells.

Objective The objective of this study was to explore the neuroprotective mechanism of JDYZF in treating AD from the perspective of inflammation and intestinal microflora. Methods A total of 24 APP/PS1 mice were randomly divided into four groups: model (n = 6), JDYZF low-dose (n = 6), JDYZF high-dose (n = 6), and positive drug (n = 6), six C57 mice were used as the control group. The body weights and diets of all mice were examined daily. After 8 weeks of administration, the learning and memory of mice were evaluated by the Morris water maze test. The histopathological changes of hippocampus, liver and kidney in mice were observed by HE staining after being euthanized. The expression of p-tau in hippocampus tissue was detected by immunohistochemistry. After that, 16S rDNA sequencing was used to investigate the relationship between JDYZF and intestinal microbiota. Finally, a comparison of TLR4, p65, p-p65, iκB, p-iκB, and IL-1β protein expression in the hippocampus tissue of mice in each group was measured by Western blot. Results The results showed that APP/PS1 mice taking JDYZF orally were generally in good condition. Compared with the control group, JDYZF significantly improved learning and memory ability in ethology. Histology showed that JDYZF improved the hippocampal structure of mice and inhibited the deposition of p-tau. JDYZF treatment could regulate the gut microbiota of APP/PS1 mice by increasing the richness of Lachnospiraceae, Ruminococcaceae, and Actinobacteria and reducing that of Alistipes and Muribaculaceae. It also significantly inhibited the activation of the TLR4/NF-κB signaling pathway in the brain. In addition, no obvious toxic reactions were found in the liver and kidney of APP/PS1 mice after taking JDYZF for 8 weeks. Conclusion The findings revealed that JDYZF improved cognitive ability and alleviated the TLR4/NF-κB signaling pathway in APP/PS1 mice, and the modulating the gut microbiota presented here may help illuminate its activation mechanism.

https://www.dovepress.com/getfile.php?fileID=86558

Jiedu Yizhi Formula Improves Cognitive Function by Regulating the Gut Dysbiosis and TLR4/NF-κB Signaling Pathway

Alzheimer’s disease (AD) seriously endangers the health and life of elderly individuals worldwide. However, despite all scientific efforts, at the moment there are no effective clinical treatment options for AD. In this work, the effect of the class I histone deacetylase inhibitor (HDACI) BG45 on synapse-related proteins was investigated in primary neurons from APP/PS1 transgenic mice. The results showed that BG45 can upregulate the expression of synaptotagmin-1 (SYT-1) and neurofilament light chain (NF-L) in primary neurons. In vivo, the APPswe/PS1dE9 (APP/PS1) transgenic mice were treated with BG45 (30 mg/kg) daily for 12 days. Behavioral testing of BG45-treated APP/PS1 mice showed improvements in learning and memory. BG45 can alleviate damage to the dendritic spine and reduce the deposition of Aβ. Similar to the in vitro results, synapse-related proteins in the prefrontal cortex were increased after BG45 treatment. Proteomic analysis results highlighted the differences in the biological processes of energy metabolism and calmodulin regulation in APP/PS1 mice with or without BG45 treatment. Further verification demonstrated that the effect of BG45 on synapses and learning and memory may involve the CaMKII/ITPKA/Ca2+ pathway. These results suggest that class I HDACI BG45 might be a promising drug for the early clinical treatment of AD.

https://www.mdpi.com/1424-8247/15/12/1481/pdf?version=1669810508

Jiale Wang

Papers

Jiedu-Yizhi Formula Improves Cognitive Impairment in an Aβ25–35-Induced Rat Model of Alzheimer's Disease by Inhibiting Pyroptosis

Jiedu-Yizhi Formula Alleviates Neuroinflammation in AD Rats by Modulating the Gut Microbiota

Linc-OIP5 working as a ceRNA of miR-616 promotes PON1 expression in HUEVC cells.

Jiedu Yizhi Formula Improves Cognitive Function by Regulating the Gut Dysbiosis and TLR4/NF-κB Signaling Pathway

A Class I HDAC Inhibitor BG45 Alleviates Cognitive Impairment through the CaMKII/ITPKA/Ca2+ Signaling Pathway