1.Brain injury biomarkers and applications in neurological diseases.
Han ZHANG ; Jing WANG ; Yang QU ; Yi YANG ; Zhen-Ni GUO
Chinese Medical Journal 2025;138(1):5-14
Neurological diseases are a major health concern, and brain injury is a typical pathological process in various neurological disorders. Different biomarkers in the blood or the cerebrospinal fluid are associated with specific physiological and pathological processes. They are vital in identifying, diagnosing, and treating brain injuries. In this review, we described biomarkers for neuronal cell body injury (neuron-specific enolase, ubiquitin C-terminal hydrolase-L1, αII-spectrin), axonal injury (neurofilament proteins, tau), astrocyte injury (S100β, glial fibrillary acidic protein), demyelination (myelin basic protein), autoantibodies, and other emerging biomarkers (extracellular vesicles, microRNAs). We aimed to summarize the applications of these biomarkers and their related interests and limits in the diagnosis and prognosis for neurological diseases, including traumatic brain injury, status epilepticus, stroke, Alzheimer's disease, and infection. In addition, a reasonable outlook for brain injury biomarkers as ideal detection tools for neurological diseases is presented.
Humans
;
Biomarkers/cerebrospinal fluid*
;
Nervous System Diseases/diagnosis*
;
Brain Injuries/metabolism*
;
Phosphopyruvate Hydratase/cerebrospinal fluid*
;
Glial Fibrillary Acidic Protein/blood*
;
S100 Calcium Binding Protein beta Subunit/blood*
;
tau Proteins/cerebrospinal fluid*
;
Ubiquitin Thiolesterase/blood*
;
Myelin Basic Protein/cerebrospinal fluid*
;
Neurofilament Proteins/blood*
;
MicroRNAs/blood*
;
Brain Injuries, Traumatic/metabolism*
2.Mechanism of Compound Ziyin Granules in improving postmenopausal osteoporosis by modulating Wnt/β-catenin pathway.
Wen-Jing LIU ; Fan XIE ; Piao-Piao WANG ; Yu-Ting SUN ; Wen-Yan LI
China Journal of Chinese Materia Medica 2025;50(16):4659-4667
This study investigates the therapeutic effect and underlying mechanism of Compound Ziyin Granules(CZYG) on postmenopausal osteoporosis(PMOP) induced by bilateral ovariectomy in rats. Six-month-old female SD rats were randomly divided into sham-operated(sham) group, ovariectomy(OVX) model group, high-, medium-, and low-dose CZYG groups, and alendronate sodium(AS) group. After 30 days of model establishment, treatment was administered by gavage once daily for 8 weeks, followed by sample collection. Enzyme-linked immunosorbent assay(ELISA) was used to measure serum levels of calcium ions, alkaline phosphatase(AKP), estrogen(E_2), osteoprotegerin(OPG), osteocalcin(BGP), tartrate-resistant acid phosphatase(TRAP), and type Ⅰ procollagen N-terminal propeptide(PINP). Hematoxylin-eosin(HE) staining was used to observe the histopathological changes in the femurs of rats, while micro-computed tomography(micro-CT) was used to analyze the microstructure of the distal femur. Western blot analysis was performed to measure the expression levels of bone metabolism-related proteins, including wingless-type MMTV integration site family member 2(Wnt2), β-catenin, low-density lipoprotein receptor-related protein 5(LRP5), glycogen synthase kinase-3β(GSK-3β). The mRNA expression levels of Wnt2, β-catenin, LRP5, GSK-3β, p-GSK-3β were determined by quantitative real-time PCR(qRT-PCR). Thirty days after bilateral ovariectomy, compared to the sham group, the OVX group showed significant increases in body weight and significant decreases in uterine coefficient. After 8 weeks of treatment, compared to the OVX group, CZYG(medium and high doses) and AS reduced body weight, with high-dose CZYG and AS significantly increasing the uterine coefficient. Serum levels of AKP and TRAP were significantly elevated, while levels of calcium, E_2, BGP, and OPG were significantly decreased in the OVX group. Compared to the OVX group, CZYG and AS significantly reduced serum levels of AKP and TRAP, while high-dose CZYG and AS notably increased the levels of E_2, BGP, OPG, and PINP. Micro-CT and HE staining results indicated that CZYG(medium and high doses) and AS significantly increased bone tissue volume, trabecular number, bone mineral density, and improved the microstructure of the femur. Compared to the OVX group, high-dose CZYG and AS significantly upregulated the protein and mRNA expression levels of Wnt2, β-catenin, and LRP5, and downregulated the phosphorylation level of p-GSK-3β. These results suggest that CZYG can improve PMOP by promoting estrogen secretion, improving bone metabolism indicators, increasing trabecular number and bone mineral density. Its mechanism may be related to the regulation of the Wnt/β-catenin signaling pathway.
Animals
;
Female
;
Rats, Sprague-Dawley
;
Osteoporosis, Postmenopausal/genetics*
;
Rats
;
Wnt Signaling Pathway/drug effects*
;
Humans
;
Drugs, Chinese Herbal/administration & dosage*
;
beta Catenin/genetics*
;
Osteoprotegerin/metabolism*
;
Ovariectomy
;
Calcium/blood*
;
Bone Density/drug effects*
3.Role of antibiotic eluting absorbable calcium sulfate in phaseⅠrevision treatment of periprosthetic knee infection.
Xiao-Bo CHEN ; Shuai-Lei LI ; Ai-Bin LIU ; Hao CHAI ; Yong-Qiang SUN
China Journal of Orthopaedics and Traumatology 2025;38(6):580-586
OBJECTIVE:
To explore the role of antibiotic-eluting absorbable calcium sulfate in treating periprosthetic infection after one-stage revision of knee arthroplasty.
METHODS:
A retrospective analysis was performed on 36 patients(36 knees)who underwent phaseⅠrevision for periprosthesis infection after total knee arthroplasty from January 2018 to March 2022. All patients were underwent knee cavity puncture before operation and had positive results of aseptic body fluid culture, 21 patients received revision combined with antibiotic loaded calcium sulfate at stageⅠ(calcium sulfate group) during operation, and 15 patients underwent renovation at stageⅠ(revision group). There were 9 males and 12 females in calcium sulfate group, aged from 54 to 76 years old with an average of(67.6±6.2) years old. There were 15 patients in revision group, including 4 males and 11 females, aged from 60 to 75 years old with average of (69.6±4.1) years old. The levels of serum C-reactive protein (CRP), interleukin-6 (IL-6) at 7, 14, 30 and 90 days after operation were compared between two groups, and the rate of end-infection control at follow-up were compared. The systemic antibiotic application time, hospital stay and postoperative complications were observed between two groups.
RESULTS:
Calcium sulfate group were followed up for 12 to 29 months with an average of(18.9±4.2) months, and the infection control rate was 90.5%;while revision group were followed up 18 to 29 months with average of (21.6±3.7) months, and the infection control rate was 86.7% (13/15). There were no significant differences in follow-up time and infection control rate between two groups(P>0.05). Postoperative levels of CRP and IL-6 at 7, 14 and 30 days in calcium sulfate group were (32.79±11.48), (15.50±6.52), (9.36±3.32) mg·L-1 and (17.31±6.15) pg·ml-1, respectively;which were lower than those in revision group (40.65±11.32), (30.15±10.57), (18.97±5.86) mg·L-1 and (25.54±6.73) pg·ml-1, had statistical differences(P<0.05). There were no significant differences in IL-6 levels at 7 and 14 days after operation and CRP levels at 90 days after operation between two groups (P>0.05). The hospitalization time and systemic antibiotic application time in calcium sulfate group were (18.4±2.2) and (63.5±21.4) d, respectively;which were better than those in revision group (20.5±2.4) and (82.7±16.9) d, and had statistical differences(P<0.05). No significant wound complications and hypercalcemia were observed in calcium sulfate group.
CONCLUSION
Antibiotic eluted absorbable calcium sulfate could be used to treat periprosthetic knee infection, significantly reducing CRP levels in the early postoperative period, shortening hospital stay and systemic antibiotic application time, but it does not significantly improve the control rate of revision infection at stageⅠ.
Humans
;
Male
;
Female
;
Aged
;
Prosthesis-Related Infections/surgery*
;
Middle Aged
;
Calcium Sulfate/administration & dosage*
;
Arthroplasty, Replacement, Knee/adverse effects*
;
Retrospective Studies
;
Anti-Bacterial Agents/therapeutic use*
;
Interleukin-6/blood*
;
C-Reactive Protein/metabolism*
;
Reoperation
;
Knee Prosthesis/adverse effects*
4.Acute dual therapeutic effects of the BKCa channel opener LDD175 on erectile dysfunction and lower urinary tract symptoms in chronic pelvic ischemia: a preliminary study.
Jiwoong YU ; Mee Ree CHAE ; Deok Hyun HAN ; Su Jeong KANG ; Jimin SHIN ; Hyun Hwan SUNG
Asian Journal of Andrology 2025;27(6):714-722
Recent studies have revealed a significant relationship between erectile dysfunction (ED) and lower urinary tract symptoms (LUTS), both of which commonly affect middle-aged and older men. These conditions share underlying causes, particularly endothelial dysfunction, atherosclerosis, and chronic pelvic ischemia (CPI). This study investigated the therapeutic potential of LDD175, a large-conductance Ca 2+ -activated K + channel (BKCa channel) opener, in simultaneously treating both conditions using a CPI animal model of male Sprague Dawley rats. Our study investigated the induction of CPI through surgical endothelial damage combined with a high-cholesterol diet. We assessed erectile and voiding functions by measuring intracavernosal pressure (ICP) and intraurethral pressure (IUP), respectively, after nerve stimulation. We performed histological examinations of vascular changes and western blot analyses of cavernous and prostate tissues to understand the underlying mechanisms. This study evaluated the effectiveness of LDD175 compared to standard treatments, such as sildenafil for ED and tamsulosin for LUTS. Therefore, the CPI model successfully demonstrated ED and LUTS symptoms with decreased ICP and increased IUP. Analysis revealed elevated levels of hypoxia-inducible factor-1α, transforming growth factor-β1 and β2 in cavernous tissue, and increased α1A-adrenoceptor expression in prostate tissue. LDD175 administration showed promising results, with dose-dependent improvements in ICP and IUP, and therapeutic effects comparable to those of established treatments. Our findings suggest a novel therapeutic approach that can simultaneously address ED and LUTS, opening new possibilities for clinical application in the treatment of these interconnected conditions.
Male
;
Animals
;
Erectile Dysfunction/etiology*
;
Rats, Sprague-Dawley
;
Lower Urinary Tract Symptoms/etiology*
;
Ischemia/drug therapy*
;
Rats
;
Tamsulosin
;
Hypoxia-Inducible Factor 1, alpha Subunit/drug effects*
;
Sildenafil Citrate/therapeutic use*
;
Penis/blood supply*
;
Disease Models, Animal
;
Transforming Growth Factor beta1/metabolism*
;
Pelvis/blood supply*
;
Prostate/metabolism*
;
Sulfonamides/therapeutic use*
;
Large-Conductance Calcium-Activated Potassium Channels/agonists*
5.Correlation between bone mineral density and bone metabolic markers in preschool children and the influencing factors for bone mineral density.
Luopa NI ; Ailipati TAILAITI ; Kereman PAERHATI ; Min-Nan WANG ; Yan GUO ; Zumureti YIMIN ; Gulijianati ABULAKEMU ; Rena MAIMAITI
Chinese Journal of Contemporary Pediatrics 2025;27(8):989-993
OBJECTIVES:
To investigate the correlation between bone mineral density (BMD) and bone metabolic markers in preschool children and the influencing factors for BMD, and to provide a clinical basis for promoting bone health in children.
METHODS:
A retrospective analysis was performed for the data of 127 preschool children who underwent physical examination in the Department of Child Health Care of the First Affiliated Hospital of Xinjiang Medical University, from June to December 2024. BMD and bone metabolic markers were measured, and physical examination was performed. A multiple linear regression analysis was used to investigate the effect of general information on BMD Z-score in preschool children. Spearman's rank correlation test was used to investigate the correlation of BMD Z-score with 25-hydroxyvitamin D (25-OHD), serum bone Gla protein (BGP), and parathyroid hormone (PTH).
RESULTS:
BMD Z-score significantly differed by ethnicity, weight category, and height category (all P<0.05). The multiple linear regression analysis indicated that weight and height significantly influenced BMD Z-score (P<0.05), whereas sex, age, ethnicity, and parental education level did not (P>0.05). In children, BMD Z-score was positively correlated with 25-OHD level (rs=0.260, P<0.001) and BGP level (rs=0.075, P=0.025) and was negatively correlated with PTH level (rs=-0.043, P=0.032).
CONCLUSIONS
Weight, height, 25-OHD, BGP, and PTH are influencing factors for BMD in preschool children. In clinical practice, combined measurement of bone metabolic markers may provide a scientific basis for early identification of children with abnormal BMD and prevention of osteoporosis and osteomalacia.
Humans
;
Bone Density
;
Child, Preschool
;
Female
;
Male
;
Retrospective Studies
;
Vitamin D/blood*
;
Parathyroid Hormone/blood*
;
Biomarkers/blood*
;
Osteocalcin/blood*
;
Bone and Bones/metabolism*
;
Calcium-Binding Proteins/blood*
;
Linear Models
;
Matrix Gla Protein
;
Extracellular Matrix Proteins/blood*
;
Body Weight
;
Infant
6.Clinical Characteristics and Prognosis of Patients with Non-Hodgkin Lymphoma Complicated by Hypercalcemia.
Ying LIN ; Rong-Dong ZHANG ; Zeng-Hua LIN ; Xin-Yu XU ; Ren-Li CHEN
Journal of Experimental Hematology 2025;33(4):1029-1035
OBJECTIVE:
To analyze the clinical characteristics, treatment effect and prognosis of patients with non-Hodgkin lymphoma (NHL) complicated by hypercalcemia.
METHODS:
The clinical features, treatment and prognosis of 47 patients with NHL complicated by hypercalcemia in Ningde Municipal Hospital of Ningde Normal University and Affiliated Hospital of Nantong University from January 2018 to January 2023 were retrospectively analyzed.
RESULTS:
Among the 47 lymphoma patients, 33 cases were T-cell NHL, 14 cases were B-cell NHL. The median serum calcium level of the 47 patients was 3.10 (2.77-4.86) mmol/L, with 27 cases (57.4%) experiencing mild hypercalcemia (2.75-3.00 mmol/L), 8 cases (17.0%) experiencing moderate hypercalcemia (3.00-3.50 mmol/L), and 12 cases (25.5%) experiencing severe hypercalcemia (>3.50 mmol/L). All 47 patients were treated with hydration, alkalization, diuresis, etc. 32 cases (68.1%) received combination chemotherapy, 21 cases (44.7%) received salmon calcitonin treatment, and 3 cases were treated with denosumab in 5 patients with renal insufficiency. After treatment, 38 patients' serum calcium gradually returned to normal, with a median recovery time of 6 (1-18) days, while 9 patients still failed to recover their serum calcium after treatment and all died within 1 month. 32 patients undergoing combination chemotherapy were evaluated for efficacy after 2-4 courses of chemotherapy. Among them, 8 cases (25.0%) achieved complete response (CR), 11 cases (34.4%) achieved partial response (PR), 7 cases (21.9%) showed stable disease (SD), and 6 cases (18.8%) showed progressive disease (PD). The median follow-up time was 10 months. There were 13 cases of disease progression after combination chemotherapy and a total of 28 deaths. The survival time ranged from 0.8 to 23.7 months, and the median progression time was 4.9 months. Multivariate Cox regression analysis showed that the T-cell NHL, blood calcium >3.5 mmol/L, and no decrease in blood calcium after treatment were independent risk factors for the OS, and the T-cell NHL was independent risk factors for the PFS.
CONCLUSION
NHL complicated by hypercalcemia has a poor prognosis, and hypercalcemia can be used as one of the indicators reflecting the tumor burden. Patients with NHL complicated by hypercalcemia should be given more clinical attention and treated actively.
Humans
;
Hypercalcemia/complications*
;
Lymphoma, Non-Hodgkin/diagnosis*
;
Prognosis
;
Retrospective Studies
;
Female
;
Male
;
Middle Aged
;
Adult
;
Aged
;
Calcium/blood*
7.Therapeutic effect of concentrated growth factors combined with self-curing calcium phosphate cement on periodontal intrabony defects: Clinical and radiographic evaluation.
Xinying WANG ; Xueyuan CHENG ; Yong ZHANG ; Fei LI ; Jinyu DUAN ; Jing QIAO
Journal of Peking University(Health Sciences) 2025;57(1):42-50
OBJECTIVE:
To clarify the role of concentrated growth factors (CGF) in the treatment of periodontal cement defects using calcium phosphate cement (CPC) with self-curing properties.
METHODS:
Thirty-six intrabony defects were randomly divided into two groups. The experimental group received CGF+CPC treatment (n=18), while the control group received CPC treatment alone (n=18). The probing depth, clinical attachment loss, and hard tissue filling as measured by cone beam CT (CBCT) were evaluated at baseline and 1 year postoperatively in both groups, and the levels of major growth factors in CGF and serum were compared [platelet-derived growth factor-BB (PDGF-BB), transforming growth factor-β1 (TGF-β1), insulin-like growth factor-1 (IGF-1), and vascular endothelial growth factor (VEGF)].
RESULTS:
At baseline, there were no statistically significant differences in probing depth, clinical attachment loss and CBCT measurements between the two groups (P>0.05). At 1 year postoperatively, significant improvements were observed in parameters mentioned above in both groups (P < 0.05). The CGF+CPC group seemed more effective compared with the CPC group in reduction of probing depth [(4.5±1.3) mm vs. (3.2±1.1) mm] and clinical attachment gain [(3.8±0.9) mm vs. (2.0±0.5) mm, P < 0.05]. Compared with the group treated with CPC alone, the hard tissue filling degree shown by CBCT in the CGF+CPC group was significantly increased [the reduction of the depth of the intrabony defects was (3.9±1.2) mm vs. (2.1±0.7) mm, respectively, P < 0.01]. At 1 year post-operatively, the volume of the intrabony defects shown by CBCT in the CGF+CPC group was reduced by (0.031 8±0.004 1) mL, which was significantly more than that in the CPC group [(0.019 7±0.001 2) mL, P < 0.05]. In addition, the concentration of the main growth factors (PDGF-BB, TGF-β1, IGF-1, and VEGF) in CGF were higher than those in serum (P < 0.001).
CONCLUSION
After 1 year of follow-up, the results of the present study indicated that CGF could significantly improve the clinical and radiological effects of CPC on the treatment of periodontal intrabony defects.
Humans
;
Calcium Phosphates/therapeutic use*
;
Male
;
Female
;
Bone Cements/therapeutic use*
;
Middle Aged
;
Cone-Beam Computed Tomography
;
Alveolar Bone Loss/therapy*
;
Becaplermin
;
Adult
;
Insulin-Like Growth Factor I
;
Intercellular Signaling Peptides and Proteins/therapeutic use*
;
Proto-Oncogene Proteins c-sis/blood*
;
Transforming Growth Factor beta1/blood*
;
Vascular Endothelial Growth Factor A/blood*
8.Vascular Protection of Neferine on Attenuating Angiotensin II-Induced Blood Pressure Elevation by Integrated Network Pharmacology Analysis and RNA-Sequencing Approach.
A-Ling SHEN ; Xiu-Li ZHANG ; Zhi GUO ; Mei-Zhu WU ; Ying CHENG ; Da-Wei LIAN ; Chang-Geng FU ; Jun PENG ; Min YU ; Ke-Ji CHEN
Chinese journal of integrative medicine 2025;31(8):694-706
OBJECTIVE:
To explore the functional roles and underlying mechanisms of neferine in the context of angiotensin II (Ang II)-induced hypertension and vascular dysfunction.
METHODS:
Male mice were infused with Ang II to induce hypertension and randomly divided into treatment groups receiving neferine or a control vehicle based on baseline blood pressure using a random number table method. The hypertensive mouse model was constructed by infusing Ang II via a micro-osmotic pump (500 ng/kg per minute), and neferine (0.1, 1, or 10 mg/kg), valsartan (10 mg/kg), or double distilled water was administered intragastrically once daily for 6 weeks. A non-invasive blood pressure system, ultrasound, and hematoxylin and eosin staining were performed to assess blood pressure and vascular changes. RNA sequencing and network pharmacology were employed to identify differentially expressed transcripts (DETs) and pathways. Vascular ring tension assay was used to test vascular function. A7R5 cells were incubated with neferine for 24 h and then treated with Ang II to record the real-time Ca2+ concentration by confocal microscope. Immunohistochemistry (IHC) and Western blot were used to evaluate vasorelaxation, calcium, and the extracellular signal-regulated kinase (ERK)1/2 pathway.
RESULTS:
Neferine treatment effectively mitigated the elevation in blood pressure, pulse wave velocity, aortic thickening in the abdominal aorta of Ang II-infused mice (P<0.05). RNA sequencing and network pharmacology analysis identified 355 DETs that were significantly reversed by neferine treatment, along with 25 potential target genes, which were further enriched in multiple pathways and biological processes, such as ERK1 and ERK2 cascade regulation, calcium pathway, and vascular smooth muscle contraction. Further investigation revealed that neferine treatment enhanced vasorelaxation and reduced Ca2+-dependent contraction of abdominal aortic rings, independent of endothelium function (P<0.05). The underlying mechanisms were mediated, at least in part, via suppression of receptor-operated channels, store-operated channels, or voltage-operated calcium channels. Neferine pre-treatment demonstrated a reduction in intracellular Ca2+ release in Ang II stimulated A7R5 cells. IHC staining and Western blot confirmed that neferine treatment effectively attenuated the upregulation of p-ERK1/2 both in vivo and in vitro, which was similar with treatment of ERK1/2 inhibitor PD98059 (P<0.05).
CONCLUSIONS
Neferine remarkably alleviates Ang II-induced elevation of blood pressure, vascular dysfunction, and pathological changes in the abdominal aorta. This beneficial effect is mediated by the modulation of multiple pathways, including calcium and ERK1/2 pathways.
Animals
;
Angiotensin II
;
Male
;
Benzylisoquinolines/therapeutic use*
;
Network Pharmacology
;
Blood Pressure/drug effects*
;
Sequence Analysis, RNA
;
Mice
;
Hypertension/chemically induced*
;
Mice, Inbred C57BL
;
Calcium/metabolism*
9.Changes in circulating levels of calcium and bone metabolism biochemical markers in patients receiving denosumab treatment.
Yuancheng CHEN ; Wen WU ; Ling XU ; Haiou DENG ; Ruixue WANG ; Qianwen HUANG ; Liping XUAN ; Xueying CHEN ; Ximei ZHI
Journal of Southern Medical University 2025;45(4):760-764
OBJECTIVES:
To investigate the changes in blood levels of calcium and bone metabolism biochemical markers in patients with primary osteoporosis receiving treatment with denosumab.
METHODS:
Seventy-three patients with primary osteoporosis treated in our Department between December, 2021 and December 2023 were enrolled. All the patients were treated with calcium supplements, vitamin D and calcitriol in addition to regular denosumab treatment every 6 months. Blood calcium, parathyroid hormone (PTH), osteocalcin (OC), type I procollagen amino-terminal propeptide (PINP), and type I collagen carboxy-terminal telopeptide β special sequence (β‑CTX) data before and at 3, 6, 9, and 12 months after the first treatment were collected from each patient.
RESULTS:
Three months after the first denosumab treatment, the bone turnover markers (BTMs) OC, PINP, and β-CTX were significantly decreased compared to their baseline levels by 39.5% (P<0.001), 56.2% (P<0.001), and 81.8% (P<0.001), respectively. At 6, 9, and 12 months of treatment, OC, PINP, and β-CTX remained significantly lower than their baseline levels (P<0.001). Blood calcium level was decreased (P<0.05) and PTH level increased (P<0.05) significantly in these patients at months of denosumab treatment, but their levels were comparable to the baseline levels at 6, 9, and 12 months of the treatment (P>0.05).
CONCLUSIONS
Denosumab can suppress BTMs and has a good therapeutic effect in patients with primary osteoporosis, but reduction of blood calcium and elevation of PTH levels can occur during the first 3 months in spite of calcium supplementation. Blood calcium and PTH levels can recover the baseline levels as the treatment extended, suggesting the importance of monitoring blood calcium and PTH levels during denosumab treatment.
Humans
;
Denosumab/therapeutic use*
;
Calcium/blood*
;
Parathyroid Hormone/blood*
;
Biomarkers/blood*
;
Osteoporosis/blood*
;
Osteocalcin/blood*
;
Procollagen/blood*
;
Female
;
Collagen Type I/blood*
;
Peptide Fragments/blood*
;
Bone Density Conservation Agents/therapeutic use*
;
Bone and Bones/metabolism*
;
Male
;
Middle Aged
;
Vitamin D
;
Peptides/blood*
;
Aged
10.Mechanism of human embryonic stem cell-derived mesenchymal stem cells on alleviating brain injury after cardiopulmonary resuscitation in swine with cardiac arrest.
Feng GE ; Jiefeng XU ; Jinjiang ZHU ; Guangli CAO ; Xuguang WANG ; Meiya ZHOU ; Tiejiang CHEN ; Mao ZHANG
Chinese Critical Care Medicine 2025;37(2):133-139
OBJECTIVE:
To investigate the mechanism of human embryonic stem cell-derived mesenchymal stem cells (hESC-MSC) in alleviating brain injury after resuscitation in swine with cardiac arrest (CA).
METHODS:
Twenty-nine healthy male large white swine were randomly divided into Sham group (n = 9), cardiopulmonary resuscitation (CPR) group (n = 10) and hESC-MSC group (n = 10). The Sham group only completed animal preparation. In CPR group and hESC-MSC group, the swine model of CA-CPR was established by inducing ventricular fibrillation for 10 minutes with electrical stimulation and CPR for 6 minutes. At 5 minutes after successful resuscitation, hESC-MSC 2.5×106/kg was injected via intravenous micropump within 1 hour in hESC-MSC group. Venous blood samples were collected before resuscitation and at 4, 8, 24, 48 and 72 hours of resuscitation. The levels of neuron specific enolase (NSE) and S100B protein (S100B) were detected by enzyme linked immunosorbent assay (ELISA). At 24, 48 and 72 hours of resuscitation, neurological deficit score (NDS) and cerebral performance category (CPC) were used to evaluate the neurological function of the animals. Three animals from each group were randomly selected and euthanized at 24, 48, and 72 hours of resuscitation, and the hippocampus tissues were quickly obtained. Immunofluorescence staining was used to detect the distribution of hESC-MSC in hippocampus. Immunohistochemical staining was used to detect the activation of astrocytes and microglia and the survival of neurons in the hippocampus. The degree of apoptosis was detected by TdT-mediated dUTP nick end labeling (TUNEL).
RESULTS:
The serum NSE and S100B levels of brain injury markers in CPR group and hESC-MSC group were significantly higher than those in Sham group at 24 hours of resuscitation, and then gradually increased. The levels of NSE and S100B in serum at each time of resuscitation in hESC-MSC group were significantly lower than those in CPR group [NSE (μg/L): 20.69±3.62 vs. 28.95±3.48 at 4 hours, 27.04±5.56 vs. 48.59±9.22 at 72 hours; S100B (μg/L): 2.29±0.39 vs. 3.60±0.73 at 4 hours, 2.38±0.15 vs. 3.92±0.50 at 72 hours, all P < 0.05]. In terms of neurological function, compared with the Sham group, the NDS score and CPC score in the CPR group and hESC-MSC group increased significantly at 24 hours of resuscitation, and then gradually decreased. The NDS and CPC scores of hESC-MSC group were significantly lower than those of CPR group at 24 hours of resuscitation (NDS: 111.67±20.21 vs. 170.00±21.79, CPC: 2.33±0.29 vs. 3.00±0.00, both P < 0.05). The expression of hESC-MSC positive markers CD73, CD90 and CD105 in the hippocampus of hESC-MSC group at 24, 48 and 72 hours of resuscitation was observed under fluorescence microscope, indicating that hESC-MSC could homing to the damaged hippocampus. In addition, compared with Sham group, the proportion of astrocytes, microglia and apoptotic index in hippocampus of CPR group were significantly increased, and the proportion of neurons was significantly decreased at 24, 48 and 72 hours of resuscitation. Compared with CPR group, the proportion of astrocytes, microglia and apoptotic index in hippocampus of hESC-MSC group decreased and the proportion of neurons increased significantly at 24 hours of resuscitation [proportion of astrocytes: (14.33±1.00)% vs. (30.78±2.69)%, proportion of microglia: (12.00±0.88)% vs. (27.89±5.68)%, apoptotic index: (12.89±3.86)% vs. (52.33±7.77)%, proportion of neurons: (39.44±3.72)% vs. (28.33±1.53)%, all P < 0.05].
CONCLUSIONS
Application of hESC-MSC at the early stage of resuscitation can reduce the brain injury and neurological dysfunction after resuscitation in swine with CA. The mechanism may be related to the inhibition of immune cell activation, reduction of cell apoptosis and promotion of neuronal survival.
Animals
;
Heart Arrest/therapy*
;
Cardiopulmonary Resuscitation
;
Swine
;
Humans
;
Male
;
Human Embryonic Stem Cells/cytology*
;
Mesenchymal Stem Cell Transplantation
;
Mesenchymal Stem Cells/cytology*
;
Phosphopyruvate Hydratase/blood*
;
Brain Injuries/therapy*
;
S100 Calcium Binding Protein beta Subunit
;
Apoptosis
;
Disease Models, Animal

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