CN114209700A - New application of Salubrinal in preparation of medicines for treating bone marrow mesenchymal stem cell aging - Google Patents
New application of Salubrinal in preparation of medicines for treating bone marrow mesenchymal stem cell aging Download PDFInfo
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- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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Abstract
The invention provides a new application of Salubrinal in preparing a medicine for treating bone marrow mesenchymal stem cell senescence. The method adopts RT-qPCR and Western Blot to detect indexes of endoplasmic reticulum stress related changes, adopts a beta galactosidase staining kit, adopts RT-qPCR, Western Blot and an immunofluorescence technique to detect the change condition of the aging condition of the mesenchymal stem cells after Salubrinal intervention, adopts flow cytometry, RT-qPCR and an immunofluorescence technique to detect the apoptosis condition of the mesenchymal stem cells, and adopts micro-CT, RT-qPCR and ELISA tests to detect the bone state of a mouse. The result shows that the Salubrinal has good effects of resisting the aging of mesenchymal stem cells and resisting the aging osteoporosis, and is a better Senolytic anti-aging drug.
Description
Technical Field
The invention relates to a new application of Salubrinal, in particular to a new application of Salubrinal in preparing a medicine for treating bone marrow mesenchymal stem cell senescence.
Background
Aging is one of the recognized risk factors for many major chronic diseases, such as osteoporosis. Over the past decades, many aging mechanisms have been discovered, with cellular aging being considered the fundamental mechanism of aging. Several characteristics are used to characterize senescent cells, such as apoptosis resistance, cell cycle arrest, and overproducing senescence-associated secretory phenotype (SASP). Cellular senescence can be caused by a variety of stimuli, such as DNA Damage Response (DDR), oncogene induction, and oxidative stress. Understanding the maintenance mechanisms of cellular senescence has helped develop a strategy for the treatment of hyperthermophilic diseases, including Senolytics and Senomorphics, to ameliorate tissue damage, promote repair and regeneration by eliminating senescent cells or their effects.
The concept of Senolytic was first proposed by Kirkland JL et al in 2015 to eliminate senescent cells by drug or small molecule targeted modulation of senescence-associated anti-apoptotic pathways (SCAPs) in senescent cells. This discovery based on the relevant drug mechanisms has prompted the development of combination therapy with dasatinib (D), an FDA-approved tyrosine kinase inhibitor, and quercetin (Q), a flavanol found in many fruits and vegetables. This treatment may reduce the abundance of senescent cells and is further shown to be beneficial in improving age-related pathologies. Driven by these breakthrough studies, several other strategies have been used to develop potential Senolytic therapies, such as inhibition of associated senescence by targeting renal glutaminase (KGA) dependent glutaminolysis.
In the related art, by measuring aging and aging-associated secretory phenotype (SASP) markers in the bone microenvironment of aging mice, relevant experiments have found that cellular aging occurs in a subset of different lineages, such as preosteoblasts, osteoblasts, and osteocytes. Senolytic therapy of D + Q has been found to improve bone fragility in older mice compared to the control group. In addition, in the skull defect model, it was recently found that D + Q therapy also improves the osteogenic potential of bone marrow mesenchymal stem cells in aged mice. However, elimination of senescent cells does not reverse OVX-induced bone loss or alter senescence biomarkers. Therefore, it is of interest to find other complementary strategies in the bone microenvironment that can be used to remove senescent cells.
Given its stress phenotype, senescent cells require a protein quantity control system to meet their demand for large numbers of secretes in the senescent state. In mammalian cells, this process is mainly ensured by activation of the Unfolded Protein Response (UPR) of endoplasmic reticulum stress (ER stress). When the load of unfolded proteins exceeds the capacity of the endoplasmic reticulum, endoplasmic reticulum stress is induced and the unfolded protein response of the endoplasmic reticulum is activated to restore the stable state of the endoplasmic reticulum. Endoplasmic reticulum stress is mainly sensed and regulated by three transmembrane proteins ATF6, PERK and IRE 1. In recent years, there has been increasing evidence for the presence of endoplasmic reticulum stress in cellular senescence. For example, aging melanocytes, induced by replication and oncogenes, display endoplasmic reticulum stress and activation of three UPR pathways. In addition, activation of endoplasmic reticulum stress states, including IRE1 α/XBP1 and PERK/ATF4 branches of UPR, was also found in senescent lymphoma cells. Related studies in recent years have shown that endoplasmic reticulum stress and UPR are ubiquitous in some senescent cells and may play some subtle roles. However, the relationship between cellular senescence and the role of endoplasmic reticulum stress in bone cells is not clear.
Disclosure of Invention
Given that in senescent cells, endoplasmic reticulum stress can be tightly regulated to avoid apoptosis, maintaining the persistence of the endoplasmic reticulum stress state may induce the initiation of an apoptotic program, thereby clearing the senescent cells. Based on these assumptions, the present invention first measured the endoplasmic reticulum stress status in oxidative stress-induced aging bone marrow mesenchymal stem cells in the current study, and then activated and elongated the PERK-eIF2 α pathway by Salubrinal in vitro and in vivo to find whether extending the endoplasmic reticulum stress signal could alleviate cellular aging and improve bone integrity of bone marrow mesenchymal stem cells in aged mice.
Salubrinal has been used to study the effects of stress protection genes and pathways on the development and longevity of organisms. It has also been used to study the therapeutic potential in methamphetamine-induced disruption of the blood brain barrier. The Salubrinal formula is C21H17Cl3N4OS, molecular weight 479.81 formula is as follows:
salubrinal, as an eIF2 alpha dephosphorylation inhibitor, is effective in promoting the sustained activation of the endoplasmic reticulum stress pathway, thereby achieving the expectation of elimination of senescent cells.
Salubrinal is currently under-studied in aging-associated alterations in bone shape, and research on such drugs in related diseases is the focus of the present invention. In view of the above background problems, the present invention provides the use of Salubrinal for the treatment of aging-related osteoporosis.
To demonstrate the novel use of Salubrinal, the present invention was completed by the following experiment:
in vitro experiments, the invention takes the mesenchymal stem cells of ICR mice of 2-3 months age, suspends the cells in a minimal medium alpha-MEM containing 10 percent of fetal calf serum and 1 percent of penicillin/streptomycin after centrifugation, and takes 1.0 multiplied by 106/cm2Was cultured in a cell culture dish for 72 hours. The cell culture medium containing the suspension cells was removed and further analyzed using adherent mesenchymal stem cells. The cells were placed in 12-well plates using 25. mu. M H2O2The cell senescence model was established after 3.5 days of treatment. Osteoblast differentiation days were induced with 10mM beta-phosphoglycerol and 50. mu.g/ml ascorbic acid, to which treatment with Salubrinal (0/10/20/50/100. mu.M) was introduced and changes in the senescence status of the cells were investigated. On the basis, the method utilizes beta galactosidase staining to detect the aging condition of the mesenchymal stem cells, utilizes CCK-8 cell activity to detect cell activity, and utilizes the technologies of RT-qPCR, Wes ter Blot, immunofluorescence and the like to detect various indexes related to aging.
In vivo experiments, 5-month-old mice SAMP6 and SAMR1 were selected for testing. The rapid aging model mouse (SAM) is a series of rapid aging mouse models bred by Japanese scholars through selection of AKR/J line mouse inbreeding, and comprises 14 rapid aging P strains and 4 normal aging strains, wherein the SAMP6 mouse of the P strain is a spontaneous senile osteoporosis model and has the characteristics of low peak bone density, low peak bone mass, reduction of systemic bone mass, destruction of bone tissue microstructure, increase of bone fragility and the like. Two target mice were injected intraperitoneally with Salubrinal (1 mg/kg/day) or saline for 4 weeks, respectively, and then sacrificed. Distal femoral and vertebral microstructural parameters were examined for SAMR1 and SAMP6 mice: bone volume fraction (BV/TV), trabecular thickness (tb.th), trabecular number (tb.n), trabecular resolution (tb.sp), cortical area fraction (ct.ar/tt.ar), average cortical thickness (ct.th). ELISA detection includes CTX, P1NP concentration detection.
Compared with the prior art, the invention has the following beneficial effects:
(1) the Salubrinal can prolong an eIF2 alpha signal channel in the aged mesenchymal stem cells and effectively relieve the cell aging phenotype of the aged mesenchymal stem cells.
(2) Salubrinal promotes apoptosis of senescent mesenchymal stem cells. Salubrinal improves the skeletal microstructure of mice with accelerated aging, osteoblastogenesis/osteoblastogenesis defects.
(3) The Salubrinal has good effects of resisting the aging of mesenchymal stem cells and resisting aging osteoporosis, and is a good Senolytic anti-aging drug.
Drawings
FIG. 1: the PERK pathway is significantly activated in senescent mesenchymal stem cells.
(A)H2O2(25 μ M) treatment of mesenchymal stem cells induced cellular senescence.
(B) And (3) staining by beta galactosidase to detect the mesenchymal stem cells. The scale specification is as follows: 50 μm. Beta galactosidase staining statistics.
(C) Western blot (Western immunoblot) for detection of different doses of H2O2Levels of ATF6 α, IRE1, p-IRE1, XBP1, thapsigargin (TG, 1 μ M)) in mesenchymal stem cells of bone marrow treated for 3.5 days served as positive controls.
(D)H2O2Bone marrow mesenchymal stem cells PERK, p-EIF2 alpha, ATF4, CHOP, GADD34 protein levels after 3.5 days of treatment.
(E-J)H2O23.5 days after treatment (25. mu.M), real-time quantitative PCR measures mRNA expression levels in BMSCs for the endoplasmic reticulum stress markers Perk, Atf4, G-add34, Grp94, Chop, and Atf 6. Data represent SD mean. P<0.05；**P＜0.01；***P＜0.001；****P is less than 0.0001; ns means no statistical difference.
FIG. 2: activation of the eIF2 α signaling pathway with salvrinal significantly reduced the level of senescence in bone marrow mesenchymal stem cells.
(A) By H2O2Bone marrow mesenchymal stem cells were treated (25 μ M) for 3.5 days and then treated with Salubrinal (50 μ M) for 24 hours.
(B) And (3) staining with beta galactosidase to detect the aged mesenchymal stem cells. The scale specification is as follows: 50 μm.
(C) Real-time quantitative PCR detected mRNA levels of Cdkn1 α and Cdkn2 α.
(D) The Western blotting method detects the levels of P16, P21 and P-eIF2 alpha protein.
(E) CCK8 measures cell viability.
(F-H) immunofluorescence assay for H2O2P16(F), P21(G) and (-H2AX (H) positive cells in treated mesenchymal stem cells nuclear DAPI staining (blue) Scale: 50 μm.
(I) And counting the proportion of P16, P21 and gamma-H2 AX positive cells. Data represent SD mean. P < 0.05; p < 0.01; p < 0.001; p < 0.0001; ns means no statistical difference.
FIG. 3: salubrinal promotes apoptosis of aged mesenchymal stem cells.
(A) Bone marrow mesenchymal stem cells are firstly used with H2O2(25. mu.M) for 3.5 days, followed by Salubrinal (50. mu.M) for 24h, followed by apoptosis-related assays.
(B) Annexin V-FITC and PI staining were used to detect apoptotic BMSCs, with the Q4 quadrant being the rate of premature senescence.
(C-E) real-time quantitative PCR analysis of expression of apoptosis marker genes Caspase3, Bim and Bcl 211.
(F) Immunofluorescence analysis detected double-stained cells of P21 (red) and cleared-Caspase 3 (blue). Nuclei were stained with DAPI (blue). Data represent SD mean. P < 0.05; p < 0.01; p < 0.001; p < 0.0001; ns means no statistical difference.
FIG. 4: salubrinal improved the skeletal microstructure of aged SAMP6 mice.
(A) 5-month-old SAMP6 and SAMR1 mice were treated with Salubrinal (1 mg/kg/day) or saline for 4 weeks, respectively, and then subjected to schematic analysis to assess bone integrity.
(B-G) taking bone marrow mesenchymal stem cells of SAMP6 or SAMR1 mouse thighbone and shinbone, and detecting mRNA expression of Cdkn1 alpha, Cdkn2 alpha, Il1 alpha, Il6, Chop and Gadd34 by real-time quantitative PCR.
(H-I) representative micro-CT reconstructed images of distal femur (H) and thoracic vertebrae (I) of SAMP6 and SAMR 1.
(J-P) SAMR1 and SAMP6 mice distal femoral and vertebral body microstructural parameters: bone volume fraction (BV/TV), trabecular thickness (tb.th), trabecular number (tb.n), trabecular resolution (tb.sp), cortical area fraction (ct.ar/tt.ar), average cortical thickness (ct.th).
(Q-R) ELISA was used to detect CTX, P1NP concentrations. Data represent SD mean. P < 0.05; p < 0.01; p < 0.001; p < 0.0001; ns means no statistical difference.
Detailed Description
The features and advantages of the present invention will be further understood from the following detailed description taken in conjunction with the accompanying drawings. The examples provided are merely illustrative of the methods of the present invention and do not limit the remainder of the disclosure in any way. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Salubrinal is a potent selective eIF2 α dephosphorylation inhibitor. Salubrinal acts as a dual specificity phosphatase 2(Dusp2) inhibitor, inhibiting anti-collagen antibody-induced arthritis. Salubrinal has activity against HSV-1 virus and inhibits dephosphorylation of eIF2 α mediated by the HSV-1 protein ICP 34.5.
Example 1: effect of aging of mesenchymal Stem cells on expression of endoplasmic reticulum stress
Alternative H in this example2O2Is an inducer for in vitro aging of bone marrow mesenchymal stem cells, and the change of the endoplasmic reticulum stress related index of the cells is observed on the basis. Aiming at exploring the change of the connection between the two. As shown in FIG. 1A as H2O2(25. mu.M) treatment of mesenchymal Stem cell-induced cellsAnd (5) aging.
The material and the method are as follows:
drugs and reagents: 3% Hydrogen peroxide (H)2O2) (Sigma-Aldrich, St.Louis, MO, USA); antibodies IRE1, p-IRE1 from Novus Biologicals, LLC, Littleton, CO, USA; antibody ATF6 α, XBP-1 was from Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA; the antibodies PERK, eIF2 α, p-eIF2 α, ATF4, CHOP from Cell Signaling Technology, inc., Danvers, MA, USA; antibody GADD34 is from the Prot eintech Group, Rosemont, IL, USA; the related primers are all from Shanghai biological products, Inc.; the beta galactosidase staining kit is from Shanghai Biyuntian science and technology Limited.
The experimental method comprises the following steps:
cell grouping and processing: dividing the mesenchymal stem cells into a control group and H2O2Treatment group (25. mu.M) for 1/3.5/5 day.
Detection indexes are as follows:
after the treatment of each group according to the specified time is finished, beta-lactase staining is carried out to detect the aging state of the cells, and indexes of related changes of endoplasmic reticulum stress are detected by RT-qPCR and Western Blot.
The experimental results are as follows:
as can be seen in the staining results for beta-galactosidase shown in FIG. 1B, H relative to the control group2O2The positive rate of staining after treatment is obviously improved. Among the three pathways for unfolded protein, no significant change in the ATF6 and IRE1 pathways was observed as shown in fig. 1C, while a significant activation state of the PERK pathway was observed as shown in fig. 1D. The qPCR results for the relevant primers also suggest the same trend as shown in FIG. 1 (E-J). These all indicate that changes in endoplasmic reticulum stress are evident in the senescent state of bone marrow mesenchymal stem cells and focus on the PERK pathway. This also suggests the investigatability of alterations in endoplasmic reticulum stress status in aged mesenchymal stem cells.
Example 2: effect of Salubrinal on the aging status of cells by continuous activation of endoplasmic reticulum stress status
This example selects Salubrinal asThe model is established for continuous activation of endoplasmic reticulum stress, and aims at eliminating senescent cells by inducing apoptosis through continuous activation. As shown in FIG. 2A by H2O2Bone marrow mesenchymal stem cells were treated (25 μ M) for 3.5 days and then treated with Salubrinal (50 μ M) for 24 hours.
The material and the method are as follows:
the experiment was divided into a control group and an aging model group (H)2O2) And intervention group (H)2O2+Salubrinal)。
Detection indexes are as follows:
in the embodiment, the change of the aging condition of the mesenchymal stem cells of the bone marrow after the intervention of the Salubrinal is detected by using a kit stained by beta-lactase, RT-qPCR, Western Blot and an immunofluorescence technology.
The experimental results are as follows:
the continuous activation of endoplasmic reticulum stress has obvious reversal effect on the aging state of the aged mesenchymal stem cells.
The invention further researches the influence of Salubrinal on the aging state of the mesenchymal stem cells. SA- β -Gal staining showed a significant 34.8% decrease in the proportion of senescent mesenchymal stem cells following Salubrinal treatment. As shown in fig. 2B. Under the effect of Salubrinal, the mRNA levels of Cdkn1 α and Cdkn2 α in senescent bone marrow mesenchymal stem cells were also inhibited, and further decreased with increasing sal-ubrinal concentration as shown in fig. 2C. Also, protein expression of P16 and P21 was significantly reduced in senescent bone marrow mesenchymal stem cells after salvrinal treatment as shown in fig. 2D. Meanwhile, after Salubrinal treatment, the proliferation activity of the aged mesenchymal stem cells can be effectively relieved by 28.5%. As shown in fig. 2E. Finally, cells positively stained for P16, P21, or γ -H2AX were also significantly reduced in Salubrinal-treated senescent bone marrow mesenchymal stem cells as detected by immunofluorescence analysis (F-I) as shown in fig. 2. The results show that Salubrinal can prolong the eIF2 signal pathway in the aged mesenchymal stem cells and effectively relieve the cell aging phenotype of the aged mesenchymal stem cells.
Example 3: apoptotic Effect of Salubrinal on aging mesenchymal Stem cells
In the embodiment, Salubrinal is used as an apoptosis inducer of the mesenchymal stem cells, an apoptosis model after endoplasmic reticulum stress continuous activation is established, and the Salubrinal is introduced to induce apoptosis of the aged mesenchymal stem cells, so that the aging state is relieved. FIG. 3A shows the pre-application of H to mesenchymal stem cells2O2(25. mu.M) for 3.5 days, followed by Salubrinal (50. mu.M) for 24h, followed by apoptosis-related assays.
The material and the method are as follows:
the experiment was divided into a control group and an aging model group (H)2O2) And intervention group (H)2O2+Salubrinal)。
Detection indexes are as follows: the apoptosis status of the aged mesenchymal stem cells is detected by using flow cytometry, RT-qPCR and immunofluorescence technology.
The experimental results are as follows:
CHOP is a key factor involved in endoplasmic reticulum stress-mediated apoptosis, and apoptosis of mesenchymal stem cells increases significantly after Salubrinal treatment. Thus, the present invention hypothesizes that apoptosis of senescent cells occurs after Salubrinal treatment, ultimately promoting clearance of senescent cells. To demonstrate, the present invention first analyzed total apoptotic cells using PI-annexinV double staining flow cytometry. After Salubrinal treatment, H, as shown in FIG. 3B2O2The induced aging BMSCs show obvious apoptosis trend, and especially the proportion of early apoptosis group is obviously increased by 6.2%. In line with this, the mRNA levels of the apoptotic factors Caspase3 and Bim in senescent mesenchymal stem cells gradually increased with the increase in Salubrinal concentration, while the expression of the anti-apoptotic factor Bcl211 was maintained at a higher level as shown in FIG. 3 (C-E). In addition, immunofluorescence showed that both clear C-caspase 3 and P21 positively stained fewer cells in both control and senescent BMSCs, but increased significantly after salubral treatment as shown in fig. 3F. These results indicate that Salubrinal promotes apoptosis of senescent bone marrow mesenchymal stem cells.
Example 4: map of the effect of Salubrinal intervention on the skeletal status of SAMP6 in senilised mice
In this example, SAMP6 mice were introduced via intraperitoneal injection using salvprinal, and the effect of salvprinal introduction on changes in skeletal status in SAMP6 mice was investigated, aiming to select an anti-aging osteoporosis drug with precise therapy and low toxicity. As shown in fig. 4A, age-old SAMP6 and SAMR1 mice were treated with Salubrinal (1 mg/kg/day) or saline for 4 weeks, respectively, and then subjected to schematic analysis to assess bone integrity.
The material and the method are as follows:
Salubrinal(Tocris Bioscience，Bio-Techne China Co.Ltd.，Shanghai，China)
SAMP6 mice and SAMR1 mice, 3 months of age, were purchased from the department of laboratory zoology, department of medicine, beijing university. All procedures involving animals were performed in the animal facility at the medical school of south of the Yangtze university. The animal protocol was reviewed and approved by the animal protection and ethics committee of south of the Yangtze university (Wuxi, Jiangsu, China).
Animals were randomly divided into four groups on average 8 weeks after quarantine and adaptive feeding: control group (SAMR1, n is 5), salubrin treated control group (SAMR1+ Sal, n is 5), SAMP6 group (SAMP6, n is 5) and salubrin treated SAMP6 group (SAMP6+ Sal, n is 5). SAMP6 mice were drug-treated at five months of age, and SAMR1+ Sal control and SAMP6+ Sal groups were subcutaneously injected daily with Salubrin, administered at a concentration of 1mg/kg, first dissolved in DMSO to 100mg/kg, and then dissolved in saline physiological water to a final concentration. The SAMP6 group and the SAMR1 group were given an equal volume of vehicle (physiological saline). The administration mode is intraperitoneal injection, the injection is performed once a day, and the injection period is 4 weeks.
Detection indexes are as follows:
skeletal status testing of SAMP6 and SAMR1 mice included micro-CT, RT-qPCR, and ELISA assays.
The experimental results are as follows:
to further measure the in vivo effects of Salubrinal on bone microstructure in aged mice, the present invention employs an aging-accelerating mouse model SAMP6, which accelerates bone loss and concomitant osteogenic decline in aging-related mesenchymal stem cells. S-alubrinal treatment significantly reduced the expression of m-RNA from Cdkn1 alpha, Cdkn2 alpha, Il1 alpha and Il6 in bone marrow mesenchymal stem cells from SAMP6 mice, whereas the mRNA levels of Chop and Gadd34 were also up-regulated in bone marrow mesenchymal stem cells from SAMP6 mice, as shown in FIG. 4(F-G), in bone marrow mesenchymal stem cells from SMAR1 mice, as shown in FIG. 4 (B-E). SAMP6 mice had significantly reduced bone volume compared to SMAR1 mice, which could be improved by Salubrinal administration as shown in FIG. 4 (H-I). Furthermore, Salubrinal treatment for 1 month significantly improved the microstructure of the spine and trabecular bone, as compared to the control group, and the improvement of the trabecular bone was similar as shown in fig. 4 (J-N). Dosing also resulted in increased thickness of the femoral cortex in SMAP6 mice as shown in fig. 4 (O-P). Peripheral blood of mice was tested by ELISA for the bone formation marker P1NP and the bone resorption marker CTX. The P1NP level of Salubri-nal treated SAMP6 mice was higher than that of vehicle treated SAMP6 mice, and the CTX level was lower than that of vehicle treated SAMP6 mice, while neither index of the SAMR1 group changed significantly as shown in FIG. 4 (Q-R). The above results suggest that Salubrinal improves the skeletal microstructure of SAMP6 mice, which are deficient in aging, osteoblastogenesis/osteoblastogenesis.
And (4) experimental conclusion:
the results from examples 1-4 show that the PERK-eIF2 α signaling pathway is specifically activated and tightly regulated in aging mesenchymal stem cells, further revealing that Salubrinal is a potential Se-nonlytic drug against the aging of mesenchymal stem cells to improve bone quality in SAMP6 mice. Therefore, the Salubrinal has good effects of resisting the aging of mesenchymal stem cells and resisting the aging osteoporosis, and is a good Senolytic anti-aging drug.
Claims (3)
- Application of Salubrinal in preparation of medicines for treating bone marrow mesenchymal stem cell aging.
- 2. The use of claim 1, wherein said Salubrinal is of the formula C21H17Cl3N4OS, molecular weight 479.81 formula is as follows:
- 3. the use according to claim 1, wherein the medicament for treating the aging of the mesenchymal stem cells is freeze-dried powder or injection.
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| CN115350188A (en) * | 2022-07-25 | 2022-11-18 | 福建医科大学附属第一医院 | Application of small molecular compound Salubrinal in preparation of medicines for treating or improving sarcopenia |
| CN117771265A (en) * | 2024-02-23 | 2024-03-29 | 山东大学 | Small molecular RNA for delaying mesenchymal stem cell aging and application thereof |
| CN117771265B (en) * | 2024-02-23 | 2024-06-11 | 山东大学 | Small molecular RNA for delaying mesenchymal stem cell aging and application thereof |
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| CN111544374A (en) * | 2020-05-13 | 2020-08-18 | 中国人民解放军总医院第四医学中心 | Application of deferoxamine mesylate for injection in treating age-increasing bone loss and bone marrow stem cell senescence |
| CN111568904A (en) * | 2020-05-14 | 2020-08-25 | 张平 | Application of small molecular compound Salubrinal in medicine for treating or preventing osteoporosis and osteopenia diseases |
| CN113308537A (en) * | 2021-06-23 | 2021-08-27 | 徐文停 | Application of serum galectin-1 as bone metabolism marker in osteoporosis diagnosis |
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| CN111544374A (en) * | 2020-05-13 | 2020-08-18 | 中国人民解放军总医院第四医学中心 | Application of deferoxamine mesylate for injection in treating age-increasing bone loss and bone marrow stem cell senescence |
| CN111568904A (en) * | 2020-05-14 | 2020-08-25 | 张平 | Application of small molecular compound Salubrinal in medicine for treating or preventing osteoporosis and osteopenia diseases |
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| CN117771265A (en) * | 2024-02-23 | 2024-03-29 | 山东大学 | Small molecular RNA for delaying mesenchymal stem cell aging and application thereof |
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