Associations of dichlorophenols, trichlorophenols, and ortho-phenylphenol with the risk and prognosis of diabetes and prediabetes: A population-based study.

2,4-dichlorophenol (2,4-DCP), 2,5-DCP, 2,4,5-trichlorophenol (2,4,5-TCP), 2,4,6-TCP, and ortho-phenylphenol (OPP) are widely present in the environment. However, their associations with risk and prognosis of diabetes and prediabetes remains unclear. We investigated the associations of these five phenols with the risk of diabetes and prediabetes, and with all-cause and cardiovascular disease (CVD) mortality, in adults with diabetes or prediabetes (n=6419). Information on diabetes and prediabetes indicators, and mortality data was collected from the National Health and Nutrition Examination Survey. Logistic and Cox regression models were used to explore the associations of the five phenols with risk and prognosis of diabetes and prediabetes. Participants in the highest urinary 2,4-DCP and 2,5-DCP tertiles had higher odds of diabetes [adjusted odds ratio (aOR), 1.34, 95 % confidence interval (CI): 1.10, 1.62; aOR, 1.29, 95 % CI: 1.07, 1.56, respectively] than those in the lowest tertiles. Participants with urinary OPP concentrations above the limit of detection (LOD), but below median had an aOR of 1.25 (95 % CI: 1.08, 1.46) for prediabetes compared to those with concentrations below the LOD. In adults with diabetes, the highest 2,4-DCP and 2,5-DCP tertiles were associated with all-cause mortality [adjusted hazard ratio (aHR), 1.49; 95 % CI: 1.08, 2.06; aHR, 1.49; 95 % CI: 1.08, 2.05, respectively] and CVD mortality (aHR, 2.58; 95 % CI: 1.33, 4.97; aHR, 1.96; 95 % CI: 1.06, 3.60, respectively) compared with the lowest tertiles. Compared with 2,4,5-TCP concentrations below the LOD, those above median were associated with all-cause mortality (aHR: 1.75; 95 % CI: 1.24, 2.48) and CVD mortality (aHR: 2.34; 95 % CI: 1.19, 4.63) in adults with prediabetes. Furthermore, the associations between these phenols and mortality were strengthened in some subgroups. Environmental exposure to 2,4-DCP, 2,5-DCP, 2,4,5-TCP, and OPP increases the risk or adverse prognosis of diabetes or prediabetes in adults in the US. Further studies are required to confirm these findings.

Network-based identification and mechanism exploration of active ingredients against Alzheimer's disease via targeting endoplasmic reticulum stress from traditional chinese medicine.

Alzheimer's disease is a neurodegenerative disease that leads to dementia and poses a serious threat to the health of the elderly. Traditional Chinese medicine (TCM) presents as a promising novel therapeutic therapy for preventing and treating dementia. Studies have shown that natural products derived from kidney-tonifying herbs can effectively inhibit AD. Furthermore, endoplasmic reticulum (ER) stress is a critical factor in the pathology of AD. Regulation of ER stress is a crucial approach to prevent and treat AD. Thus, in this study, we first collected kidney-tonifying herbs, integrated chemical ingredients from multiple TCM databases, and constructed a comprehensive drug-target network. Subsequently, we employed the endophenotype network (network proximity) method to identify potential active ingredients in kidney-tonifying herbs that prevented AD via regulating ER stress. By combining the predicted outcomes, we discovered that 32 natural products could ameliorate AD pathology via regulating ER stress. After a comprehensive evaluation of the multi-network model and systematic pharmacological analyses, we further selected several promising compounds for in vitro testing in the APP-SH-SY5Y cell model. Experimental results showed that echinacoside and danthron were able to effectively reduce ER stress-mediated neuronal apoptosis by inhibiting the expression levels of BIP, p-PERK, ATF6, and CHOP in APP-SH-SY5Y cells. Overall, this study utilized the endophenotype network to preliminarily decipher the effective material basis and potential molecular mechanism of kidney-tonifying Chinese medicine for prevention and treatment of AD.

Assessing the Global, Regional, and National Impact of High Body Mass Index on Alzheimer's Disease and Other Dementias Between 1990 and 2019.

BACKGROUND: Obesity significantly increases Alzheimer's disease (AD) and dementia risk. Understanding the link between a high body mass index (BMI) and these conditions is crucial for effective management and prevention. OBJECTIVE: We aimed to estimate the burden of AD and other dementias attributed to high BMI from 1990 to 2019 based on sex, age, and socio-demographic indicators (SDI) at global, regional, and national levels. METHODS: We collected data on deaths, disability-adjusted life years (DALYs), age-standardized mortality rates (ASMR), and age-standardized DALY rates (ASDR) from the 2019 Global Burden of Disease study for AD and dementia attributed to high BMI. We explored the correlation between SDI levels and ASDR. RESULTS: In 2019, there were 198,476.2 deaths (95% UI: 32,695.4-593,366.4) and 3,159,912.4 DALYs (848,330.5-8,042,531) attributed to high BMI. Numbers of deaths, DALYs, ASMR, and ASDR increased since 1990. Females had higher deaths, ASMR, and ASDR than males. Mortality and DALYs rates increased with age. ASMR and ASDR increased across five SDI levels, with the highest rise in Low-middle SDI. High-income North America had the most deaths [30,993.9 (5,101.7-89,912.9)], while North Africa and the Middle East had the highest ASMR [4.61 (0.79-13.64)] and ASDR [72.56 (20.98-181.16)] in 2019. CONCLUSIONS: The burden of AD and other dementias attributed to high BMI increased since 1990 globally and is still heaviest in developed regions. Females accounted predominantly for the burden than males. Timely measures are needed to against high BMI.

Protein-centric omics analysis reveals circulating complements linked to non-viral liver diseases as potential therapeutic targets.

BACKGROUND/AIMS: To evaluate the causal correlation between complement components and non-viral liver diseases and their potential use as druggable targets. METHODS: We conducted Mendelian randomization (MR) to assess the causal role of circulating complements in the risk of non-viral liver diseases. A complement-centric protein interaction network was constructed to explore biological functions and identify potential therapeutic options. RESULTS: In the MR analysis, genetically predicted levels of complement C1q C chain (C1QC) were positively associated with the risk of autoimmune hepatitis (odds ratio 1.125, 95% confidence interval 1.018-1.244), while complement factor H-related protein 5 (CFHR5) was positively associated with the risk of primary sclerosing cholangitis (PSC;1.193, 1.048- 1.357). On the other hand, CFHR1 (0.621, 0.497-0.776) and CFHR2 (0.824, 0.703-0.965) were inversely associated with the risk of alcohol-related cirrhosis. There were also significant inverse associations between C8 gamma chain (C8G) and PSC (0.832, 0.707-0.979), as well as the risk of metabolic dysfunction-associated steatotic liver disease (1.167, 1.036-1.314). Additionally, C1S (0.111, 0.018-0.672), C7 (1.631, 1.190-2.236), and CFHR2 (1.279, 1.059-1.546) were significantly associated with the risk of hepatocellular carcinoma. Proteins from the complement regulatory networks and various liver diseaserelated proteins share common biological processes. Furthermore, potential therapeutic drugs for various liver diseases were identified through drug repurposing based on the complement regulatory network. CONCLUSION: Our study suggests that certain complement components, including C1S, C1QC, CFHR1, CFHR2, CFHR5, C7, and C8G, might play a role in non-viral liver diseases and could be potential targets for drug development.

Inflammatory microenvironment in gastric premalignant lesions: implication and application.

Gastric precancerous lesions (GPL) are a major health concern worldwide due to their potential to progress to gastric cancer (GC). Understanding the mechanism underlying the transformation from GPL to GC can provide a fresh insight for the early detection of GC. Although chronic inflammation is prevalent in the GPL, how the inflammatory microenvironment monitored the progression of GPL-to-GC are still elusive. Inflammation has been recognized as a key player in the progression of GPL. This review aims to provide an overview of the inflammatory microenvironment in GPL and its implications for disease progression and potential therapeutic applications. We discuss the involvement of inflammation in the progression of GPL, highlighting Helicobacter pylori (H. pylori) as a mediator for inflammatory microenvironment and a key driver to GC progression. We explore the role of immune cells in mediating the progression of GPL, and focus on the regulation of inflammatory molecules in this disease. Furthermore, we discuss the potential of targeting inflammatory pathways for GPL. There are currently no specific drugs for GPL treatment, but traditional Chinese Medicine (TCM) and natural antioxidants, known as antioxidant and anti-inflammatory properties, exhibit promising effects in suppressing or reversing the progression of GPL. Finally, the challenges and future perspectives in the field are proposed. Overall, this review highlights the central role of the inflammatory microenvironment in the progression of GPL, paving the way for innovative therapeutic approaches in the future.

Alkali-Driven Photoinduced N-Dealkylation of Aryl Tertiary Amines and Amides.

By extending the photoinduced oxidative mechanism of aryl tertiary amines proposed earlier to an alkaline environment based on the prediction of quantum mechanics computations and the validation of meticulous experiments, we discovered a photoinduced oxidative N-dealkylation method for both aryl tertiary amines and amides. The dealkylation was achieved in an alkaline environment under mild conditions accompanied by excellent functional group tolerance.

Corrigendum: Systems pharmacology approach to investigate the mechanism of Kai-Xin-San in Alzheimer's disease.

[This corrects the article DOI: 10.3389/fphar.2020.00381.].

Identification of immune-associated signatures and potential therapeutic targets for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) comprises a heterogeneous group of diseases with diverse aetiologies. It is characterized by increased pulmonary arterial pressure and right ventricular (RV) failure without specific drugs for treatment. Emerging evidence suggests that inflammation and autoimmune disorders are common features across all PAH phenotypes. This provides a novel idea to explore the characteristics of immunological disorders in PAH and identify immune-related genes or biomarkers for specific anti-remodelling regimens. In this study, we integrated three gene expression profiles and performed Gene Ontology (GO) and KEGG pathway analysis. CIBERSORT was utilized to estimate the abundance of tissue-infiltrating immune cells in PAH. The PPI network and machine learning were constructed to identify immune-related hub genes and then evaluate the relationship between hub genes and differential immune cells using ImmucellAI. Additionally, we implemented molecular docking to screen potential small-molecule compounds based on the obtained genes. Our findings demonstrated the density and distribution of infiltrating CD4 T cells in PAH and identified four immune-related genes (ROCK2, ATHL1, HSP90AA1 and ACTR2) as potential targets. We also listed 20 promising molecules, including TDI01953, pemetrexed acid and radotinib, for PAH treatment. These results provide a promising avenue for further research into immunological disorders in PAH and potential novel therapeutic targets.

Wogonin inhibits oxidative stress and vascular calcification via modulation of heme oxygenase-1.

Vascular calcification (VC) is highly prevalent and increases the morbidity and mortality of cardiovascular diseases. However, the underlying mechanism remains unclear and there is no effective treatment so far. Interestingly, using systems pharmacology approach, we have predicted that Wogonin (Wog) exhibited potential activity against VC. Then we validated the effect of Wog on VC using human and rat vascular smooth muscle cells (VSMCs), rat arterial rings and vitamin D3-overloaded mouse models. Our results showed that Wog dose-dependently inhibited calcification of VSMCs and rat arterial rings. Consistently, alizarin red staining and calcium content assay confirmed that Wog inhibited aortic calcification in vitamin D3-overloaded mice. Moreover, by constructing the protein regulating network of Wog in suppressing VC, we found heme oxygenase-1 (HMOX-1) was regulated by Wog. Additionally, pathway enrichment analysis revealed that inhibition of reactive oxygen species (ROS) pathway participated in the inhibitory role of Wog in VC and HMOX-1 was also involved in this process. Notably, our study revealed that Wog treatment promoted HMOX-1 expression, and reduced ROS levels in VSMCs. Interestingly, both inhibition of HMOX-1 by ZnPP9 and knockdown of HMOX-1 by siRNA independently eliminated the inhibitory effect of Wog on VC. Finally, administration of Wog suppressed aortic calcification in vitamin D3-overloaded mice and this effect was counteracted by ZnPP9,suggesting the crucial role of HMOX-1 in the inhibitory effect of Wog on VC. Collectively, this study combines systems pharmacology-based strategy and experiments to identify the therapeutic potential of Wog for VC via upregulating HMOX-1 and reducing oxidative stress.

Multifunctional Gomisin B enhances cognitive function in APP/PS1 transgenic mice by regulating Aß clearance and neuronal apoptosis.

This study aimed to investigate the potential effects of Gomisin B, a natural compound known for its inhibition of CYP3A4, on cognitive dysfunction in APP/PS1 transgenic mice with Alzheimer's disease (AD). Additionally, the study explored the combined effects of Gomisin B and Osthole (OST). The research involved male wild-type (WT) mice and 7-month-old APP/PS1 transgenic AD mice. The assessment of behavioral changes included the use of the open field test (OFT) and the Morris water maze (MWM). OST levels in brain tissue were quantified using LC-MS/MS, while levels of oxidative stress were measured through an assay kit. Neuronal apoptosis was studied using Nissl staining, RT-qPCR, and immunofluorescence. Amyloid plaque clearance was assessed using thioflavine-S (Th-S) staining, RT-qPCR, and ELISA. The results of the study revealed that Gomisin B led to a significant improvement in cognitive dysfunction in APP/PS1 mice. Moreover, the simultaneous administration of OST and Gomisin B demonstrated enhanced therapeutic effects. These effects were attributed to the inhibition of ß-site APP-Cleaving Enzyme 1 (BACE1) and oxidative stress by Gomisin B, along with its anti-apoptotic properties. The combined use of OST and Gomisin B exhibited a synergistic impact, resulting in more pronounced anti-oxidant and anti-apoptotic effects. In summary, this study pioneers the exploration of Gomisin B's multifunctional anti-AD properties in APP/PS1 mice. The findings provide a solid groundwork for the development of anti-Alzheimer's drugs based on natural active ingredients.

Modulating endoplasmic reticulum stress in APP/PS1 mice by Gomisin B and Osthole in Bushen-Yizhi formula: Synergistic effects and therapeutic implications for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder with no effective cure. Targeting endoplasmic reticulum (ER) stress pathway may offer a novel approach to ameliorate cognitive deficits in AD. Bushen-Yizhi formula (BSYZ), a traditional Chinese medicine (TCM) prescription, has shown potential benefits for AD. To facilitate the development of new therapeutic agents for AD, it is important to identify the active components and the underlying mechanisms of BSYZ against AD. PURPOSE: The aim of this study was to systematically screen the active components of BSYZ that could improve learning and memory impairment in AD by modulating ER stress pathway. METHODS: A drug-target (D-T) network was constructed to analyze the herbal components of BSYZ. Network proximity method was used to identify the potential anti-AD components that targeted ER stress and evaluate their synergistic effects. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and the literature evidence were considered to select promising candidates for further validation. The selected components were tested in vitro using an AD cell model (APPswe-SH-SY5Y). In vivo anti-AD effects of the components were assessed in APP/PS1 double-transgenic mice. RESULTS: 58 potential anti-AD components targeting ER stress were detected by network proximity analysis, and 13 out of them were selected based on ADMET properties and literature evidence. In vitro experiments confirmed that 5 components, namely gomisin B, ß-Carotene, imperatorin, chrysophanol, and osthole (OST), exhibited anti-AD effects on the APPswe-SH-SY5Y model. Moreover, network proximity analysis suggested that OST and Gomisin B might have synergistic effects on modulating ER stress. In vivo experiments demonstrated that OST, Gomisin B, OST+Gomisin B, and BSYZ all improved learning and memory function in APP/PS1 mice. Gomisin B and OST also restored cellular morphology and tissue structure in APP/PS1 mice. Thioflavine-S (Th-S) staining revealed that they reduced amyloid plaque deposition in the brain tissue of AD model mice. The qPCR results indicated that BSYZ, OST, and Gomisin B differentially regulated IRE1α, PERK, EIF2α, DDIT3, and Caspase 12 expression levels, while the OST and Gomisin B co-administration group showed better efficacy. This trend was further confirmed by immunofluorescence experiments. CONCLUSION: This study identified the active components of BSYZ that could ameliorate learning and memory impairment in AD by targeting ER stress pathway. OST and Gomisin B exhibited synergistic effects on modulating ER stress and reducing amyloid plaque deposition in vivo. Overall, our study elucidated the molecular mechanisms of BSYZ and its active components in attenuating AD symptoms which suggested the therapeutic potential of TCM for AD.

Covalent Modification of Proteins by Osthole Reactive Metabolites using Proteomic Approaches.

BACKGROUND: Osthole (OST) is a bioactive natural coumarin derived from the plant Cnidium monnieri (L.) Cusson fruit (She Chuang Zi), which has various pharmacological and biological activities. OST contains an α,ß- unsaturated lactone, which is an electrophilic group that tends to be metabolized into reactive metabolites (RMs). Then, RMs are able to covalently modify nucleophilic amino acid (AA) residues of target proteins. However, few researchers considered the contribution of the covalent modification induced by OST or its metabolites. OBJECTIVE: This study aims to investigate the metabolic profile and the metabolites-protein modification of OST. METHODS: The metabolites of OST were qualitatively identified using UHPLC-Q-TOF-MS. The RMs modification patterns and potentially modified AA residues were confirmed by UHPLC-Q-TOF-MS using rat liver microsomes (RLMs) and model AAs. Finally, the modified peptides derived from high-abundance microsomal peptides were separated via nano-LC-Orbitrap-MS, and then RM-modified proteins were identified using a proteome discoverer. RESULTS: In the presence of RLMs, OST could rapidly be metabolized within 1 h and hardly identified at 4 h. We detected 10 OST metabolites, 13 OST metabolites-NAC (N-acetyl cysteine) adducts, 3 NAL (N-acetyl lysine) adducts, and 11 GSH (glutathione) adducts. Furthermore, 16 RM-modified protein targets were identified, many of which are included in the essential biological processes of OST's anti-Alzheimer's disease (AD) and anti-tumor. CONCLUSION: This study provides a novel perspective on the molecular mechanism of OST's pharmacological activities, as well as identifies potential targets for further development and application of OST and other Natural products (NPs).

Systems pharmacology-based mechanism exploration of Acanthopanax senticosusin for Alzheimer's disease using UPLC-Q-TOF-MS, network analysis, and experimental validation.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease, characterized by progressive cognitive dysfunction and memory loss. However, the disease-modifying treatments for AD are still lacking. Traditional Chinese herbs, have shown their potentials as novel treatments for complex diseases, such as AD. PURPOSE: This study was aimed at investigating the mechanism of action (MOA) of Acanthopanax senticosusin (AS) for treatment of AD. METHODS: In this study, we firstly identified the chemical constituents in Acanthopanax senticosusin (AS) utilizing ultra-high performance liquid chromatography coupled with Q-TOF-mass spectrometry (UPLC-Q-TOF-MS), and next built the drug-target network of these compounds. We also performed the systems pharmacology-based analysis to preliminary explore the MOA of AS against AD. Moreover, we applied the network proximity approach to identify the potential anti-AD components in AS. Finally, experimental validations, including animal behavior test, ELISA and TUNEL staining, were conducted to verify our systems pharmacology-based analysis. RESULTS: 60 chemical constituents in AS were identified via the UPLC-Q-TOF-MS approach. The systems pharmacology-based analysis indicated that AS might exert its therapeutic effects on AD via acetylcholinesterase and apoptosis signaling pathway. To explore the material basis of AS against AD, we further identified 15 potential anti-AD components in AS. Consistently, in vivo experiments demonstrated that AS could protect cholinergic nervous system damage and decrease neuronal apoptosis caused by scopolamine. CONCLUSION: Overall, this study applied systems pharmacology approach, UPLC-Q-TOF-MS, network analysis, and experimental validation to decipher the potential molecular mechanism of AS against AD.

Systems pharmacology dissection of pharmacological mechanisms of Xiaochaihu decoction against human coronavirus.

BACKGROUND: Although coronavirus disease 2019 (COVID-19) pandemic is still rage worldwide, there are still very limited treatments for human coronaviruses (HCoVs) infections. Xiaochahu decoction (XCHD), which is one of the traditional Chinese medicine (TCM) prescriptions in Qingfeipaidu decoction (QFPDD), is widely used for COVID-19 treatment in China and able to relieve the symptoms of fever, fatigue, anorexia, and sore throat. To explore the role and mechanisms of XCHD against HCoVs, we presented an integrated systems pharmacology framework in this study. METHODS: We constructed a global herb-compound-target (H-C-T) network of XCHD against HCoVs. Multi-level systems pharmacology analyses were conducted to highlight the key XCHD-regulated proteins, and reveal multiple HCoVs relevant biological functions affected by XCHD. We further utilized network-based prediction, drug-likeness analysis, combining with literature investigations to uncover the key ani-HCoV constituents in XCHD, whose effects on anit-HCoV-229E virus were validated using cytopathic effect (CPE) assay. Finally, we proposed potential molecular mechanisms of these compounds against HCoVs via subnetwork analysis. RESULTS: Based on the systems pharmacology framework, we identified 161 XCHD-derived compounds interacting with 37 HCoV-associated proteins. An integrated pathway analysis revealed that the mechanism of XCHD against HCoVs is related to TLR signaling pathway, RIG-I-like receptor signaling pathway, cytoplasmic DNA sensing pathway, and IL-6/STAT3 pro-inflammatory signaling pathway. Five compounds from XCHD, including betulinic acid, chrysin, isoliquiritigenin, schisandrin B, and (20R)-Ginsenoside Rh1 exerted inhibitory activity against HCoV-229E virus in Huh7 cells using in vitro CPE assay. CONCLUSION: Our work presented a comprehensive systems pharmacology approach to identify the effective molecules and explore the molecular mechanism of XCHD against HCoVs.

Bushen-Yizhi formula ameliorates mitochondrial dysfunction and oxidative stress via AMPK/Sirt1 signaling pathway in D-gal-induced aging rats.

BACKGROUND: As a major risk factor for neurodegenerative diseases, aging has become a heavy health care burden worldwide. Age-related decline in mitochondrial function and oxidative stress is strongly associated with neurodegeneration. The previous study demonstrated that Bushen-Yizhi formula (BSYZ), a traditional Chinese medicine formula, is effective in reducing neurodegeneration. METHODS: This study is the first to investigate the effect of BSYZ on D-gal-induced learning memory in rats. Secondly, the potential metabolic mechanism of BSYZ was explored by 1H-NMR metabolomics analysis. Then based on the comparison of differential metabolites implied that BSYZ ameliorated mitochondrial dysfunction through choline metabolic pathway in D-gal-treated rats. Finally, pharmacological validation was conducted to explore the effects of BSYZ on D-gal-induced oxidative stress, neuroinflammation, and neuronal apoptosis. RESULTS: Our data showed that BSYZ increased aspartate and betaine levels, while decreasing choline levels. Furthermore, BSYZ also increased the proteins level of CHDH and BHMT to regulate choline metabolic pathway. Meanwhile, BSYZ alleviated mitochondrial damage and oxidative stress, including enhanced ATP production and the ratio of NAD+/NADH, reduced the level of MDA, enhanced GSH and SOD activity, upregulated the expressions of p-AMPK, SIRT1 proteins. In addition, BSYZ downregulated the levels of inflammatory cytokines, such as TNF-α, IL-1ß and IL-6, as well as suppressed Bcl-2 proteins family dependent apoptosis. CONCLUSION: BSYZ treatment effectively rescues neurobehavioral impairment by improving mitochondrial dysfunction, oxidative stress, neuroinflammation and neuroapoptosis via AMPK/SIRT1 pathway in D-gal-induced aging.

Network Proximity-based computational pipeline identifies drug candidates for different pathological stages of Alzheimer's disease.

Despite the massive investment in Alzheimer's disease (AD), there are still no disease-modifying treatments (DMTs) for AD. One major reason is attributed to the limitation of clinical "one-size-fits-all" approach, since the same AD treatment solely based on clinical diagnosis was unlikely to achieve good clinical efficacy. In recent years, computational approaches based on multiomics data have provided an unprecedented opportunity for drug discovery since they can substantially lower the costs and boost the efficiency. In this study, we intended to identify potential drug candidates for different pathological stages of AD by computationally repurposing Food and Drug Administration (FDA) approved drugs. First, we assembled gene expression data from three different AD pathological stages, which include mild cognitive impairment (MCI) and early and late stages of AD (EAD, LAD). We next quantified the network distances between drug target networks and AD modules by utilizing a network proximity approach, and identified 193 candidates that possessed significant associations with AD. After searching for previous literature evidence, 63 out of 193 (32.6%) predicted drugs were demonstrated to exert therapeutic effects on AD. We further explored the novel mechanism of action (MOA) for these drug candidates by determining the specific brain cells they might function on based on AD patient single cell transcriptomic data. Additionally, we selected several promising candidates that could cross the blood brain barrier together with confirmed neuroprotective effects, and subsequently determined the antioxidative activity of these compounds. Experimental results showed that azathioprine decreased the reactive oxygen species (ROS) and malondialdehyde (MDA) levels and improved the superoxide dismutase (SOD) activity in APP-SH-SY5Y cells. Finally, we deciphered the potential MOA of azathioprine against AD via network analysis and validated several apoptosis-related proteins (Caspase 3, Cleaved Caspase 3, Bax, Bcl2) through western blotting. In summary, this study presented an effective computational strategy utilizing omics data for AD drug repurposing, which provides a new perspective for drug discovery and development.