Current treatment and novel insights regarding ROS1-targeted therapy in malignant tumors.

BACKGROUND: The proto-oncogene ROS1 encodes an intrinsic type I membrane protein of the tyrosine kinase/insulin receptor family. ROS1 facilitates the progression of various malignancies via self-mutations or rearrangements. Studies on ROS1-directed tyrosine kinase inhibitors have been conducted, and some have been approved by the FDA for clinical use. However, the adverse effects and mechanisms of resistance associated with ROS1 inhibitors remain unknown. In addition, next-generation ROS1 inhibitors, which have the advantage of treating central nervous system metastases and alleviating endogenous drug resistance, are still in the clinical trial stage. METHOD: In this study, we searched relevant articles reporting the mechanism and clinical application of ROS1 in recent years; systematically reviewed the biological mechanisms, diagnostic methods, and research progress on ROS1 inhibitors; and provided perspectives for the future of ROS1-targeted therapy. RESULTS: ROS1 is most expressed in malignant tumours. Only a few ROS1 kinase inhibitors are currently approved for use in NSCLC, the efficacy of other TKIs for NSCLC and other malignancies has not been ascertained. There is no effective standard treatment for adverse events or resistance to ROS1-targeted therapy. Next-generation TKIs appear capable of overcoming resistance and delaying central nervous system metastasis, but with a greater incidence of adverse effects. CONCLUSIONS: Further research on next-generation TKIs regarding the localization of ROS1 and its fusion partners, binding sites for targeted drugs, and coadministration with other drugs is required. The correlation between TKIs and chemotherapy or immunotherapy in clinical practice requires further study.

ARHGAP44-mediated regulation of the p53/C-myc/Cyclin D1 pathway in modulating the malignant biological behavior of osteosarcoma cells.

OBJECTIVE: Osteosarcoma is a rare primary malignant tumor of the bone characterized by poor survival rates, owing to its unclear pathogenesis. Rho GTPase-activating protein 44 (ARHGAP44), which belongs to the Rho GTPase-activating protein family, has promising applications in the targeted therapy of tumors. Therefore, this study aimed to investigate the biological function of ARHGAP44 in osteosarcoma and its possible application as a therapeutic target. METHODS: The expression level of ARHGAP44 in osteosarcoma and its relationship with tumor prognosis were detected using Gene Expression Omnibus database analysis and immunohistochemical staining of clinical specimens. The cell model of ARHGAP44 knockdown was constructed, and the effects of this gene on the malignant biological behavior of osteosarcoma cells were investigated using CCK-8, clone formation, transwell invasion, wound healing, and flow cytometry assays. Western blotting was performed to detect the expression of ARHGAP44, p53, C-myc, and Cyclin D1 in osteosarcoma. RESULTS: Biogenic analysis showed that ARHGAP44 was highly expressed in osteosarcoma. This result was associated with poor tumor prognosis and negatively correlated with the expression of the tumor suppressor gene p53. Immunohistochemistry and western blotting revealed significantly upregulated expression of ARHGAP44 in osteosarcoma tissues. Additionally, Kaplan-Meier analysis of clinical specimens suggested that ARHGAP44 was negatively correlated with tumor prognosis. CCK-8, clone formation, transwell invasion, wound healing, and flow cytometry assays showed that downregulation of ARHGAP44 expression significantly reduced the malignant biological behavior of osteosarcoma cells. Furthermore, western blotting showed that the expression level of p53 in osteosarcoma cells was significantly increased after the downregulation of ARHGAP44 expression, whereas the expression of C-myc and Cyclin D1 was significantly decreased compared with that in the control group. CONCLUSION: ARHGAP44 was highly expressed in osteosarcoma and was negatively correlated with its prognosis. The downregulation of ARHGAP44 expression reduced the malignant biological behavior of osteosarcoma cells. These findings suggest that the downregulation of ARHGAP44 expression inhibits the malignant progression of osteosarcoma by regulating the p53/C-myc/Cyclin D1 pathway, demonstrating the potential of ARHGAP44 as a therapeutic target for osteosarcoma.

The implication of necroptosis-related lncRNAs in orchestrating immune infiltration and predicting therapeutic efficacy in colon adenocarcinoma: an integrated bioinformatic analysis with preliminarily experimental validation.

Background: Necroptosis contributes significantly to colon adenocarcinoma (COAD). We aim to assess the relationship between immunoinfiltration and stemness in COAD patients through the development of a risk score profile using necroptosis-related long noncoding RNAs (NRLs). Methods: Our study was based on gene expression data and relevant clinical information from The Cancer Genome Atlas (TCGA). Necroptosis-related genes (NRGs) were obtained from the Kyoto Encyclopedia of Genes and Genome (KEGG) database. Pearson correlation analysis, Cox regression, and least absolute shrinkage and selection operator (LASSO) regression were used to determine the NRL prognositic signature (NRLPS). NRLs expression was examined using qRT-PCR method. Several algorithms were used to identify relationships between immune cell infiltration and NRLPS risk scores. Further analysis of somatic mutations, tumor stemness index (TSI), and drug sensitivity were also explored. Results: To construct NRLPS, 15 lncRNAs were investigated. Furthermore, NRLPS patients with high-risk subgroups had lower survival rates than that of patients with low-risk subgroups. Using GSEA analysis, NRL was found to be enriched in Notch, Hedgehog and Smoothened pathways. Immune infiltration analysis showed significant differences in CD8+ T cells, dendritic cell DCs, and CD4+ T cells between the two risk groups. In addition, our NRLPS showed a relevance with the regulation of tumor microenvironment, tumor mutation burden (TMB) and stemness. Finally, NRLPS demonstrated potential applications in predicting the efficacy of immunotherapy and chemotherapy in patients with COAD. Conclusion: Based on NRLs, a prognostic model was developed for COAD patients that allows a personalized tailoring immunotherapy and chemotherapy to be tailored.

Exploring the pharmacological and adverse reaction mechanism of a drug by network pharmacology strategy: Using colchicine to treat Behcet syndrome as an example.

Colchicine (COLC) is a natural alkaloid used to treat Behcet syndrome (BS), but its adverse reactions limit its clinical application in treating BS. However, the adverse reaction mechanism of COLC in the treatment of BS remains unclear. Herein, a network pharmacology-based strategy was designed to analyze the pharmacological and adverse reaction mechanism of COLC in treating BS. The biological functions of COLC and BS pathogenesis were analyzed through a series of network construction and analysis. The data above predicted the pharmacological and adverse reaction mechanism of COLC in BS treatment. The pharmacological mechanism of COLC against BS was predicted to control inflammatory responses. Interleukin-8, interleukin-18, integrin alpha-4, integrin beta-2, and tubulin targets are crucial in treating BS. The adverse reactions of COLC in BS treatment were predicted as neurotoxicity and hepatotoxicity. The mechanism of hepatotoxicity may be related to the decrease of cytochrome P450 family 3 subfamily A activity caused by various factors, such as poor hepatic function, the dosage of COLC, and combination with inhibitors. The mechanism of neurotoxicity may be related to the disruption of microtubules in the nervous system by COLC transport across the blood-brain barrier. This study provided basic evidence for the medication safety management of COLC used in treating BS. Moreover, this study demonstrated that it is feasible to analyze the adverse reaction mechanisms of drugs using a network pharmacology strategy, which facilitates systematic drug safety management and evaluation.

PROTACs: Novel tools for improving immunotherapy in cancer.

Posttranslational modifications (PTMs), such as phosphorylation, methylation, ubiquitination, and acetylation, are important in governing protein expression levels. Proteolysis targeting chimeras (PROTACs) are novel structures designed to target a protein of interest (POI) for ubiquitination and degradation, leading to the selective reduction in the expression levels of the POI. PROTACs have exhibited great promise due to their ability to target undruggable proteins, including several transcription factors. Recently, PROTACs have been characterized to improve anticancer immunotherapy via the regulation of specific proteins. In this review, we describe how the PROTACs target several molecules, including HDAC6, IDO1, EGFR, FoxM1, PD-L1, SHP2, HPK1, BCL-xL, BET proteins, NAMPT, and COX-1/2, to regulate immunotherapy in human cancers. PROTACs may provide potential treatment benefits by enhancing immunotherapy in cancer patients.

Targeted therapy for osteosarcoma: a review.

BACKGROUND: Osteosarcoma is a common primary malignant tumour of the bone that usually occurs in children and adolescents. It is characterised by difficult treatment, recurrence and metastasis, and poor prognosis. Currently, the treatment of osteosarcoma is mainly based on surgery and auxiliary chemotherapy. However, for recurrent and some primary osteosarcoma cases, owing to the rapid progression of disease and chemotherapy resistance, the effects of chemotherapy are poor. With the rapid development of tumour-targeted therapy, molecular-targeted therapy for osteosarcoma has shown promise. PURPOSE: In this paper, we review the molecular mechanisms, related targets, and clinical applications of targeted osteosarcoma therapy. In doing this, we provide a summary of recent literature on the characteristics of targeted osteosarcoma therapy, the advantages of its clinical application, and development of targeted therapy in future. We aim to provide new insights into the treatment of osteosarcoma. CONCLUSION: Targeted therapy shows potential in the treatment of osteosarcoma and may offer an important means of precise and personalised treatment in the future, but drug resistance and adverse effects may limit its application.

Current status and future challenges of CAR-T cell therapy for osteosarcoma.

Osteosarcoma, the most common bone malignancy in children and adolescents, poses considerable challenges in terms of prognosis, especially for patients with metastatic or recurrent disease. While surgical intervention and adjuvant chemotherapy have improved survival rates, limitations such as impractical tumor removal or chemotherapy resistance hinder the treatment outcomes. Chimeric antigen receptor (CAR)-T cell therapy, an innovative immunotherapy approach that involves targeting tumor antigens and releasing immune factors, has shown significant advancements in the treatment of hematological malignancies. However, its application in solid tumors, including osteosarcoma, is constrained by factors such as low antigen specificity, limited persistence, and the complex tumor microenvironment. Research on osteosarcoma is ongoing, and some targets have shown promising results in pre-clinical studies. This review summarizes the current status of research on CAR-T cell therapy for osteosarcoma by compiling recent literature. It also proposes future research directions to enhance the treatment of osteosarcoma.

Case report: Resection of a massive primary sacrococcygeal mature teratoma in an adult using 3-dimensional reconstruction and mixed reality technology.

Introduction: Teratomas are rare neoplasms that arise from pluripotent germ cells. Sacrococcygeal teratomas are often diagnosed in infants but are rare in adults; a mature teratoma can contain hair, teeth, bony tissue, and other mature tissue types. Herein, we report for the first time a patient with a teratoma containing intact bones that formed a pseudoarthrosis. Case report: A 49-year-old woman was admitted to hospital after a massive life-long sciatic tumor had begun to grow larger over the past year. A 16 cm × 25 cm solid mass with a clear boundary was palpable in the sacrococcygeal region. Radiography, computed tomography, and magnetic resonance imaging indicated a sacrococcygeal teratoma, although blood alpha-fetoprotein levels were normal. The teratoma was completely excised using 3-dimensional reconstruction mixed reality (MR) technology with no notable complications. Postoperative pathological examination of the excised lesion confirmed a mature teratoma. Interestingly, two intact irregular bones that formed a pseudoarthrosis were isolated; one was 11 cm and the other 6 cm. The patient is currently healthy and has experienced no recurrences. Conclusion: Sacrococcygeal teratomas are rare, especially in adults, and often comprised lots of components, such as fat, bony tissue. However, it's first reported that formation of pseudoarthrosis in this case so far. It is difficult for surgeons to achieve complete excision without complications owing to the complex anatomic structure of the sacrum. The 3-dimensional reconstruction and mixed reality (MR) technology based on computed tomography can provide spatial visualization, which allows surgeons to examine the teratoma at different angles preoperatively. Combining 3-dimensional reconstruction and mixed reality (MR) technology in this case facilitated complete resection and prevented recurrence.

Targeting matrix metalloproteinases by E3 ubiquitin ligases as a way to regulate the tumor microenvironment for cancer therapy.

The tumor microenvironment (TME) plays an important role in neoplastic development. Matrix metalloproteinases (MMPs) are critically involved in tumorigenesis by modulation of the TME and degradation of the extracellular matrix (ECM) in a large variety of malignancies. Evidence has revealed that dysregulated MMPs can lead to ECM damage, the promotion of cell migration and tumor metastasis. The expression and activities of MMPs can be tightly regulated by TIMPs, multiple signaling pathways and noncoding RNAs. MMPs are also finely controlled by E3 ubiquitin ligases. The current review focuses on the molecular mechanism by which MMPs are governed by E3 ubiquitin ligases in carcinogenesis. Due to the essential role of MMPs in oncogenesis, they have been considered the attractive targets for antitumor treatment. Several strategies that target MMPs have been discovered, including the use of small-molecule inhibitors, peptides, inhibitory antibodies, natural compounds with anti-MMP activity, and RNAi therapeutics. However, these molecules have multiple disadvantages, such as poor solubility, severe side-effects and low oral bioavailability. Therefore, it is necessary to discover the novel inhibitors that suppress MMPs for cancer therapy. Here, we discuss the therapeutic potential of targeting E3 ubiquitin ligases to inhibit MMPs. We hope this review will stimulate the discovery of novel therapeutics for the MMP-targeted treatment of a variety of human cancers.

Detection of 13C labeling of glutamate and glutamine in human brain by proton magnetic resonance spectroscopy.

A proton magnetic resonance spectroscopy (MRS) technique was used to measure 13C enrichments of glutamate and glutamine in a 3.5 × 1.8 × 2 cm3 voxel placed in the dorsal anterior cingulate cortex of five healthy participants after oral administration of [U-13C]glucose. Strong pseudo singlets of glutamate and glutamine were induced to enhance the signal strength of glutamate and glutamine. This study demonstrated that 13C labeling of glutamate and glutamine can be measured with the high sensitivity and spatial resolution of 1H MRS using a proton-only MRS technique with standard commercial hardware. Furthermore, it is feasible to measure 13C labeling of glutamate and glutamine in limbic structures, which play major roles in behavioral and emotional responses and whose abnormalities are involved in many neuropsychiatric disorders.

Carbonic anhydrase activity in the frontal lobe of human brain.

Carbonic anhydrase (CA) plays an important role in many biological processes. Recent technological advances have demonstrated the feasibility of measuring CA activity in the occipital lobe of human subjects in vivo. In this work we report, for the first time, in vivo measurement of CA activity in the frontal lobe of human brain, where structural and function abnormalities are strongly associated with symptoms of major psychiatric disorders. Despite the much larger magnetic field distortion in the frontal lobe, the pseudo first-order bicarbonate dehydration rate constant was determined with high precision using in vivo 13 C magnetic resonance magnetization transfer spectroscopy following oral administration of [U-13 C6 ]glucose. Nuclear Overhauser effect pulses were used to increase the signal-to-noise ratio; no proton decoupling was applied. The unidirectional dehydration rate constant of bicarbonate was found to be 0.26 ± 0.07 s-1 , which is not statistically different from the dehydration rate constant in the occipital lobe determined in our previous study, indicating that CA activity in the two brain regions is essentially indistinguishable. These results demonstrate the feasibility of characterizing CA activity in the frontal lobe for future psychiatric studies.

Cerebral phosphoester signals measured by 31P magnetic resonance spectroscopy at 3 and 7 Tesla.

Abnormal cell membrane metabolism is associated with many neuropsychiatric disorders. Free phosphomonoesters and phosphodiesters, which can be detected by in vivo 31P magnetic resonance spectroscopy (MRS), are important cell membrane building blocks. However, the quantification of phosphoesters has been highly controversial even in healthy individuals due to overlapping signals from macromolecule membrane phospholipids (MP). In this study, high signal-to-noise ratio (SNR) cerebral 31P MRS spectra were acquired from healthy volunteers at both 3 and 7 Tesla. Our results indicated that, with minimal spectral interference from MP, the [phosphocreatine (PCr)]/[phosphocholine (PC) + glycerophosphocholine (GPC)] ratio measured at 7 Tesla agreed with its value expected from biochemical constraints. In contrast, the 3 Tesla [PCr]/[PC+GPC] ratio obtained using standard spectral fitting procedures was markedly smaller than the 7 Tesla ratio and than the expected value. The analysis suggests that the commonly used spectral model for MP may fail to capture its complex spectral features at 3 Tesla, and that additional prior knowledge is necessary to reliably quantify the phosphoester signals at low magnetic field strengths when spectral overlapping is significant.

Correction: Investigation of plasma metabolomics and neurotransmitter dysfunction in the process of Alzheimer's disease rat induced by amyloid beta 25-35.

[This corrects the article DOI: 10.1039/C9RA00302A.].

Oxidative phosphorylation in creatine transporter deficiency.

X-linked creatine transporter deficiency (CTD) is one of the three types of cerebral creatine deficiency disorders. CTD arises from pathogenic variants in the X-linked gene SLC6A8. We report the first phosphorus (31 P) MRS study of patients with CTD, where both phosphocreatine and total creatine concentrations were found to be markedly reduced. Despite the diminished role of creatine and phosphocreatine in oxidative phosphorylation in CTD, we found no elevation of lactate or lowered pH, indicating that the brain energy supply still largely relied on oxidative metabolism. Our results suggest that mitochondrial function is a potential therapeutic target for CTD.

Network pharmacology strategy for predicting the correlation of Systemic Scleroderma with Vitamin D deficiency.

The deficiency of Vitamin D (VD) is a common symptom of systemic scleroderma (SSc), but the correlation of VD deficiency and SSc is not completely clear. Therefore, a strategy based on network pharmacology was designed to explore the correlation of VD deficiency and SSc. After a series of network construction and analysis, 5 integrins were predicated as the kernel targets in the correlation of VD deficiency and SSc, including ITGA5, ITGA4, ITGB3, ITGB1 and ITGAV. The crucial pathways in which the kernel targets participated were mainly involved in the function of immune, vascular and internal organ. The regulation modules of crucial pathways were closely related to the biological processes in the pathological of SSc. Taken together, the analysis predicted that the deficiency of VD might affect the pathological of SSc through the mediation of these integrins. Therefore, targeted regulation of these integrins might be an effective therapy against SSc.

Urinary and plasmatic metabolomics strategy to explore the holistic mechanism of lignans in S. chinensis in treating Alzheimer's disease using UPLC-Q-TOF-MS.

Schisandra chinensis (Turcz.) Baill (S. chinensis), a functional food, is used as a tonic and sedative agent in traditional Chinese medicine. Modern pharmacological research has proved that S. chinensis could prevent and treat age-related neurodegenerative diseases. The presence of bioactive lignans in S. chinensis is the main reason for its neuroprotective and cognitive enhancement effects. This study aimed to clarify the mechanism of lignans in S. chinensis in ameliorating learning and memory deficits in Alzheimer's disease (AD) animals. The step-down test and Morris water maze (MWM) test were used to verify the effects of lignans in S. chinensis on learning and memory in AD animals. Then, metabolomics approaches based on ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) were used to clarify the mechanism of lignans in S. chinensis in treating AD. Finally, quantitative analysis of AD-related neurotransmitters in the brain was conducted after treatment with lignans in S. chinensis. In the MWM and step-down tests, lignans in S. chinensis showed a clear ability to ameliorate the impaired learning and memory of AD animals. A total of 31 endogenous metabolites were identified after treatment with lignans in S. chinensis, which were associated with lignans ameliorating learning and memory. These biomarkers were mainly associated with polyunsaturated fatty acid metabolism and amino acid and vitamin metabolism. Moreover, lignans in S. chinensis upregulated the levels of γ-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT), acetylcholine (Ach), norepinephrine (NE) and glycine (Gly) and downregulate the level of aspartic acid (Asp). Lignans in S. chinensis might alleviate the neurotoxic effects of neurological inflammation and oxidative stress, Aß deposition, and tau phosphorylation via the regulation of multiple endogenous metabolic pathways during pathological AD. The research might provide useful support for the further study of pharmacology and new drug development of lignans in S. chinensis.

Systematically Characterize the Anti-Alzheimer's Disease Mechanism of Lignans from S. chinensis based on In-Vivo Ingredient Analysis and Target-Network Pharmacology Strategy by UHPLC⁻Q-TOF-MS.

Lignans from Schisandra chinensis (Turcz.) Baill can ameliorate cognitive impairment in animals with Alzheimer's disease (AD). However, the metabolism of absorbed ingredients and the potential targets of the lignans from S. chinensis in animals with AD have not been systematically investigated. Therefore, for the first time, we performed an in-vivo ingredient analysis and implemented a target-network pharmacology strategy to assess the effects of lignans from S. chinensis in rats with AD. Ten absorbed prototype constituents and 39 metabolites were identified or tentatively characterized in the plasma of dosed rats with AD using ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Based on the results of analysis of the effective constituents in vivo, the potential therapeutic mechanism of the effective constituents in the rats with AD was investigated using a target-network pharmacology approach and independent experimental validation. The results showed that the treatment effects of lignans from S. chinensis on cognitive impairment might involve the regulation of amyloid precursor protein metabolism, neurofibrillary tangles, neurotransmitter metabolism, inflammatory response, and antioxidant system. Overall, we identified the effective components of lignans in S. chinensis that can improve the cognitive impairment induced by AD and proposed potential therapeutic metabolic pathways. The results might serve as the basis for a fundamental strategy to explore effective therapeutic drugs to treat AD.

Investigation of plasma metabolomics and neurotransmitter dysfunction in the process of Alzheimer's disease rat induced by amyloid beta 25-35.

Alzheimer's disease (AD) has become one of the major diseases endangering the health of the elderly. Clarifying the features of each AD animal model is valuable for understanding the onset and progression of diseases and developing potential treatments in the pharmaceutical industry. In this study, we aimed to clarify plasma metabolomics and neurotransmitter dysfunction in the process of AD model rat induced by amyloid beta 25-35 (Aß 25-35). Firstly, Morris Water Maze (MWM) test was used to investigate cognitive impairment in AD rat after 2, 4 and 8 weeks of modelling. Based on this, the effects on levels of AD-related enzymes and eight neurotransmitters were analyzed. And plasma metabolomics analysis based on ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was used to research the metabolic disturbances in the process of AD rat. The results shown the injury on the spatial learning ability of AD rats was gradually aggravated within 4 weeks, reached the maximum at 4 weeks and then was stable until 8 weeks. During 8 weeks of modeling, the levels of enzymes including ß-secretase, γ-secretase, glycogen synthase kinase-3ß (GSK-3ß), acetyl cholinesterase (AchE) and nitric oxide synthase (NOS) were significant increased in the plasma of AD rats. The neurotransmitter dysfunction was mainly involved in γ-aminobutyric acid (GABA), acetyl choline (Ach), glutamic acid (Glu), 5-hydroxytryptamine (5-HT), dopamine (DA) and norepinephrine (NE). 17 endogenous metabolites correlated with AD were successfully detected in the metabolomics analysis. These metabolites were mainly involved in fatty acids, sphingolipids, and sterols metabolisms, vitamin metabolism, and amino acid metabolism. These metabolites might be the potential biomarkers that correctly mark different stages of AD. The study on peripheral plasma indices reflecting the process of AD laid the foundation for understand the pathophysiology of AD and find an effective and radical cure. And the rules of endogenous metabolic disorder in AD rats also have a certain guiding significance for the future study of food-drug interactions at different stages of AD.

Study on Urine Metabolic Profile of Aß25-35-Induced Alzheimer's Disease Using UHPLC-Q-TOF-MS.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, with no effective method for its treatment so far. The pathogenesis of AD has been reported, but the endogenous metabolic profile and disease-related biomarkers are still not clear. To better understand AD, an AD model induced by injecting ß-amyloid 25-35 (Aß 25-35) solution into bilateral hippocampus was developed on Sprague-Dawley rats. After 8 weeks of modeling, the impairment of spatial learning and memory ability in AD rats were assessed by Morris water maze task. Hematoxylin and eosin staining and immunohistochemistry were used to investigate the pathological changes of hippocampus. The neurotransmitter concentrations in the hippocampus were measured using UHPLC-TQ-MS. Urinary metabolomics based on UHPLC-Q-TOF-MS was established to delineate the alterations of endogenous metabolites in AD rats. The results showed that compared with healthy control rats, AD rats suffered from cognitive dysfunction, hippocampus damage, Aß formation and tau phosphorylation at 8 weeks after surgery, suggesting that the Aß25-35-induced AD model was successfully established. In addition, the levels of γ-aminobutyric acid, acetylcholine, glycine, norepinephrine, serotonin, taurine and dopamine decreased and glutamate and aspartic acid increased in hippocampal tissue of AD rats. 45 altered metabolites mainly involved in 8 metabolic pathways were identified as the endogenous biomarkers of AD. According to the analysis of the biological significance of metabolic profiles, the pathogenesis of AD was mainly due to gut microbiome dysbiosis, inhibition of energy metabolism, oxidative stress injury and loss of neuronal protective substances.