WO2024061250A1 - Biomarqueur de diagnostic pour la dépression et utilisation associée - Google Patents

Biomarqueur de diagnostic pour la dépression et utilisation associée Download PDF

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Publication number
WO2024061250A1
WO2024061250A1 PCT/CN2023/119893 CN2023119893W WO2024061250A1 WO 2024061250 A1 WO2024061250 A1 WO 2024061250A1 CN 2023119893 W CN2023119893 W CN 2023119893W WO 2024061250 A1 WO2024061250 A1 WO 2024061250A1
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WO
WIPO (PCT)
Prior art keywords
depression
tmap
mice
serum
detection kit
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Application number
PCT/CN2023/119893
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English (en)
Chinese (zh)
Inventor
朱书
胡冀
Original Assignee
合肥瀚微生物科技有限公司
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Application filed by 合肥瀚微生物科技有限公司 filed Critical 合肥瀚微生物科技有限公司
Publication of WO2024061250A1 publication Critical patent/WO2024061250A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers

Definitions

  • the present invention relates to the field of disease diagnosis, and in particular to a biomarker related to the pathogenesis of depression and its application.
  • MDD Depression
  • MMD Depression
  • It is now the most common mental illness, with continuous and long-term low mood as the main clinical feature. It is the most important type of mental illness in modern people. Clinically, it can be seen that people are depressed and unhappy in reality, and their mood has been low and depressed for a long time. From being unhappy at the beginning to being distraught at the end, they have low self-esteem, pain, pessimism, and world-weariness. They feel that they are torturing themselves in despair every day of their lives. , negativity, avoidance, and finally even suicidal tendencies and behaviors. The patient suffers from somatization symptoms. Chest tightness and shortness of breath.
  • Depression is a common disabling disease with high incidence in the world and has a significant impact on patients' physical and mental health. Depression can impair patients' ability to work and study, seriously affect their quality of life, and may lead to suicide.
  • a 2017 meta-analysis on the Global Burden of Disease Study noted that depression has affected approximately 300 million people and is one of the leading causes of disability and disease burden around the world.
  • the diagnosis of depression should mainly be based on medical history, clinical symptoms, disease course, physical examination and laboratory tests. The diagnosis of typical cases is generally not difficult.
  • the internationally accepted diagnostic standards generally include ICD-10 and DSM-IV.
  • ICD-10 is mainly used, which refers to the first episode of depression and recurrent depression, excluding bipolar depression. Patients often have typical symptoms such as depressed mood, loss of interest and pleasure, low energy, or feelings of fatigue. Other common symptoms are (1) reduced ability to focus and pay attention; (2) reduced self-esteem; (3) thoughts of guilt and worthlessness (even in mild attacks); (4) pessimistic view of the future ; (5) Ideas or behaviors of self-harm or suicide; (6) Sleep disorders; (7) Decreased appetite.
  • the main purpose of the present invention is to provide a biomarker related to depression, which can effectively solve the problems in the background technology.
  • compound 4-TMAP represented by formula (I) as or preparing a biomarker for depression diagnosis.
  • the structure of said compound 4-TMAP is: (I).
  • the present invention provides a detection kit, which contains compound 4-TMAP and necessary diluent; preferably, the 4-TMAP and diluent can be configured to (3-10) ng/mL
  • the concentration is preferably 4-8 ng/mL, more preferably 5 ng/mL; the preferred diluent includes water.
  • the present invention provides an early warning system for depression.
  • the early warning system includes the detection kit and analysis tools.
  • the analysis tools include high performance liquid chromatography (HPLC) or high performance liquid chromatography-mass spectrometry. (HPLC-MS).
  • the present invention provides a method for diagnosing depression, which comprises the step of determining the 4-TMAP content in the serum or feces of a human or animal to be tested; preferably, a prompt or warning is given when the 4-TMAP content is ⁇ 5 ng/mL.
  • the present invention has the following beneficial effects:
  • the present invention discovers for the first time the statistical difference in the relative content of 4-TMAP in the feces and serum of healthy people and patients with depression, and determines the use of 4-TMAP as a biomarker for the diagnosis of depression.
  • the method of the present invention can be used for early screening of patients with depression or potential depression patients conveniently and quickly, and the risk of depression can be found, which is conducive to early detection and early treatment, and prevents the deterioration of the condition of potential depression patients.
  • Figure 1 Relative content of 4-TMAP in serum samples of patients with depression (MDD) and healthy people (HC);
  • Figure 2 Relative content of 4-TMAP in fecal samples of patients with depression (MDD) and healthy people (HC);
  • Figure 3 Relative content of 4-TMAP in serum samples of normal food group and amino acid food group in AFD-induced mouse depression model
  • Figure 4 Relative content of 4-TMAP in fecal samples of normal food group and amino acid food group in AFD-induced mouse depression model
  • Figure 5 Relative content of 4-TMAP in serum samples of normal mice and CRS depressed mice in the CRS-induced mouse depression model
  • Figure 6 Relative content of 4-TMAP in fecal samples of normal mice and CRS depressed mice in CRS-induced mouse depression model
  • Figure 7 Relative content of 4-TMAP in serum samples of normal mice and Cort-depressed mice in the Cort-induced mouse depression model
  • Figure 8 Relative content of 4-TMAP in fecal samples of normal mice and Cort-depressed mice in the Cort-induced mouse depression model
  • Figure 9 Distribution of 4-TMAP in intestinal and whole brain samples of normal mice, AFD, CRS, and Cort-induced mouse depression models.
  • Example 1 4-TMAP can be used as a clinical diagnostic marker for depression
  • Preparation of standard material solution Take the standard material mother solution, add water to prepare standard material solutions with concentrations of 1ng/mL, 2ng/mL, 5ng/mL, 10ng/mL, 20ng/mL, 50ng/mL, and 100ng/mL respectively, and cross 0.22 ⁇ m Filter membrane, HPLC-MS/MS analysis.
  • ESI positive ion mode analysis
  • scanning mode multiple reaction monitoring (MRM)
  • drying gas nitrogen 10.0L/min
  • heating gas air 10.0L/min
  • collision gas argon 270kPa
  • atomizing gas 3.0L /min
  • interface temperature 200°C
  • DL tube temperature 280°C
  • dwell time 150ms
  • heating module temperature 300°C
  • delay time 3ms
  • interface voltage 1.0KV
  • Liquid quality instrument model Shimadzu LC-MS-MS-8050
  • Example 2 4-TMAP is significantly reduced in AFD-induced mouse depression model
  • mice Six 2-day-old SPF grade C57/B6j male mice (purchased from Jicui Yaokang) were randomly divided into 2 groups, one was the normal food group (NCD, 3 mice), and the other was the amino acid food group (AFD, 3 mice). 3), each group was assigned 1 nursing female mouse, and the female mice ate the corresponding food and then suckled the mice. After four weeks of continuous feeding, the female rats were separated, and the amino acid food group was replaced with normal food. Their depression status was monitored through forced swimming, tail suspension, and sugar water preference experiments.
  • the serum, feces, whole brain and intestinal tissues of NCD and AFD mice were taken respectively, and the levels of 4-TMAP were detected by HPLC-MS.
  • Detection method of whole brain and intestines Extract fresh whole brains and intestines from mice, quickly freeze them in liquid nitrogen, freeze sections, 10um, and use imaging mass spectrometry to detect the distribution of 4-TMAP.
  • Example 3 4-TMAP is significantly reduced in the CRS-induced mouse depression model
  • mice Six 6-8 week old SPF grade C57/B6j male mice (purchased from Jicui Yaokang) were randomly divided into 2 groups, one group was normal mice group (3 mice), and the other group was CRS mice (3 mice). Only). After adapting to the environment, starting from day 0, the CRS mouse group received chronic, unpredictable mild stimulation for 21 days, simulating the chronic low-intensity stress that humans receive in daily life. Every day, mice were treated with one stimulus from day and night, in random order and without repetition, so that the mice could not predict the appearance of the stimulus. After 21 days of continuous modeling, the success of depression modeling was confirmed through forced swimming, tail suspension, and sugar water preference experiments (significant differences from normal mice).
  • the serum, feces, whole brain and intestinal tissues of NCD and CRS mice were taken respectively, and the levels of 4-TMAP were measured by HPLC-MS.
  • Detection method of whole brain and intestines Extract fresh whole brains and intestines from mice, quickly freeze them in liquid nitrogen, freeze sections, 10um, and use imaging mass spectrometry to detect the distribution of 4-TMAP.
  • Example 4 4-TMAP is significantly reduced in Cort-induced mouse depression model
  • mice Six 6-8 week old SPF grade C57/B6j male mice (purchased from Jicui Pharmaceutical) were randomly divided into two groups, one group was a normal mouse group (3 mice) and the other group was a Cort group (3 mice). After adapting to the environment, from day 0, the drinking water of the Cort mouse group (MCE, HY-B1618) was a corticosterone solution with a final concentration of 25 ⁇ g/mL (pH 7.0-7.4), and the normal mouse group received ordinary drinking water, which was changed every 2 days, and the model was established for 21 days. After the model was established, the forced swimming, tail suspension, and sugar water preference tests were used to confirm the success of the model (there was a significant difference from normal mice)
  • the serum, feces, whole brain and intestinal tissues of NCD and Cort mice were taken respectively, and the levels of 4TMAP were detected by HPLC-MS.
  • Detection method of whole brain and intestines Extract fresh whole brains and intestines from mice, quickly freeze them in liquid nitrogen, freeze sections, 10um, and use imaging mass spectrometry to detect the distribution of 4-TMAP.
  • Imaging mass spectrometry results are shown in Figure 9. 4-TMAP was significantly reduced in intestinal and whole brain samples of AFD, CRS, and Cort-induced mouse depression models.

Abstract

L'invention concerne l'utilisation d'un composé 4-TMAP en tant que biomarqueur de diagnostic pour la dépression. Il a été découvert dans la présente invention que la différence de 4-TMAP dans le sérum ou les fèces entre les patients atteints de dépression et une population saine est statistiquement significative. Au moyen de l'analyse de la teneur relative en 4-TMAP dans le sérum ou les selles d'un patient à tester, il est possible d'indiquer facilement si le patient souffre d'une dépression, ou d'indiquer un risque potentiel de dépression. Le procédé de détection de la présente invention est simple et pratique, il convient aux examens physiques et au dépistage à grande échelle, il favorise la détection et le traitement précoces et a de vastes perspectives commerciales.
PCT/CN2023/119893 2022-09-23 2023-09-20 Biomarqueur de diagnostic pour la dépression et utilisation associée WO2024061250A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202211165755.8 2022-09-23
CN202211165755.8A CN117805249A (zh) 2022-09-23 2022-09-23 一种抑郁症诊断的生物标记物及其应用

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WO2024061250A1 true WO2024061250A1 (fr) 2024-03-28

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Citations (8)

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US20030147818A1 (en) * 2001-11-15 2003-08-07 Claude Dubief Preparation of polysaccharide betainate type compounds, compounds obtained, their use and compositions comprising them
CN101678120A (zh) * 2006-12-05 2010-03-24 纽罗吉斯克斯公司 前药及其制备和使用方法
US20120197539A1 (en) * 2009-10-09 2012-08-02 Carolyn Slupsky Methods for diagnosis, treatment and monitoring of patient health using metabolomics
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WO2021130267A1 (fr) * 2019-12-23 2021-07-01 Albert-Ludwigs-Universität Freiburg Méthodes associées au microbiote intestinal destinées au traitement de la démence et du déclin cognitif dépendant de l'âge
EP3879272A1 (fr) * 2020-03-09 2021-09-15 Albert-Ludwigs-Universität Freiburg Procédés associés au microbiote intestinal pour le traitement de la démence et du déclin des facultés cognitives liées au vieillissement
US20210353611A1 (en) * 2018-09-20 2021-11-18 Yeda Research And Development Co. Ltd. Methods of treating amyotrophic lateral sclerosis
US20220233611A1 (en) * 2019-05-07 2022-07-28 The Regents Of The University Of California Compositions and methods for promoting healthy neural development in an unborn baby

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030147818A1 (en) * 2001-11-15 2003-08-07 Claude Dubief Preparation of polysaccharide betainate type compounds, compounds obtained, their use and compositions comprising them
CN101678120A (zh) * 2006-12-05 2010-03-24 纽罗吉斯克斯公司 前药及其制备和使用方法
US20120197539A1 (en) * 2009-10-09 2012-08-02 Carolyn Slupsky Methods for diagnosis, treatment and monitoring of patient health using metabolomics
WO2018150077A1 (fr) * 2017-02-16 2018-08-23 Afekta Technologies Oy Biomarqueurs de la bétaïne pour l'état nutritionnel, le régime nutritionnel, le métabolisme endogène ou le risque de maladies cardiovasculaires ou métaboliques
US20210353611A1 (en) * 2018-09-20 2021-11-18 Yeda Research And Development Co. Ltd. Methods of treating amyotrophic lateral sclerosis
US20220233611A1 (en) * 2019-05-07 2022-07-28 The Regents Of The University Of California Compositions and methods for promoting healthy neural development in an unborn baby
WO2021130267A1 (fr) * 2019-12-23 2021-07-01 Albert-Ludwigs-Universität Freiburg Méthodes associées au microbiote intestinal destinées au traitement de la démence et du déclin cognitif dépendant de l'âge
EP3879272A1 (fr) * 2020-03-09 2021-09-15 Albert-Ludwigs-Universität Freiburg Procédés associés au microbiote intestinal pour le traitement de la démence et du déclin des facultés cognitives liées au vieillissement

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