BACKGROUND Osteoporosis(OP)has become a major public health problem worldwide.Most OP treatments are based on the inhibition of bone resorption,and it is necessary to identify additional treatments aimed at enhancing ...BACKGROUND Osteoporosis(OP)has become a major public health problem worldwide.Most OP treatments are based on the inhibition of bone resorption,and it is necessary to identify additional treatments aimed at enhancing osteogenesis.In the bone marrow(BM)niche,bone mesenchymal stem cells(BMSCs)are exposed to a hypoxic environment.Recently,a few studies have demonstrated that hypoxiainducible factor 2alpha(HIF-2α)is involved in BMSC osteogenic differentiation,but the molecular mechanism involved has not been determined.AIM To investigate the effect of HIF-2αon the osteogenic and adipogenic differentiation of BMSCs and the hematopoietic function of hematopoietic stem cells(HSCs)in the BM niche on the progression of OP.METHODS Mice with BMSC-specific HIF-2αknockout(Prx1-Cre;Hif-2αfl/fl mice)were used for in vivo experiments.Bone quantification was performed on mice of two genotypes with three interventions:Bilateral ovariectomy,semilethal irradiation,and dexamethasone treatment.Moreover,the hematopoietic function of HSCs in the BM niche was compared between the two mouse genotypes.In vitro,the HIF-2αagonist roxadustat and the HIF-2αinhibitor PT2399 were used to investigate the function of HIF-2αin BMSC osteogenic and adipogenic differentiation.Finally,we investigated the effect of HIF-2αon BMSCs via treatment with the mechanistic target of rapamycin(mTOR)agonist MHY1485 and the mTOR inhibitor rapamycin.RESULTS The quantitative index determined by microcomputed tomography indicated that the femoral bone density of Prx1-Cre;Hif-2αfl/fl mice was lower than that of Hif-2αfl/fl mice under the three intervention conditions.In vitro,Hif-2αfl/fl mouse BMSCs were cultured and treated with the HIF-2αagonist roxadustat,and after 7 d of BMSC adipogenic differentiation,the oil red O staining intensity and mRNA expression levels of adipogenesis-related genes in BMSCs treated with roxadustat were decreased;in addition,after 14 d of osteogenic differentiation,BMSCs treated with roxadustat exhibited increased expression of osteogenesis-related genes.The opposite effects were shown for mouse BMSCs treated with the HIF-2αinhibitor PT2399.The mTOR inhibitor rapamycin was used to confirm that HIF-2αregulated BMSC osteogenic and adipogenic differentiation by inhibiting the mTOR pathway.Consequently,there was no significant difference in the hematopoietic function of HSCs between Prx1-Cre;Hif-2αfl/fl and Hif-2αfl/fl mice.CONCLUSION Our study showed that inhibition of HIF-2αdecreases bone mass by inhibiting the osteogenic differentiation and increasing the adipogenic differentiation of BMSCs through inhibition of mTOR signaling in the BM niche.展开更多
Hypoxia-inducible factor 1(HIF1)has a crucial function in the regulation of oxygen levels in mammalian cells,especially under hypoxic conditions.Its importance in cardiovascular diseases,particularly in cardiac ischem...Hypoxia-inducible factor 1(HIF1)has a crucial function in the regulation of oxygen levels in mammalian cells,especially under hypoxic conditions.Its importance in cardiovascular diseases,particularly in cardiac ischemia,is because of its ability to alleviate cardiac dysfunction.The oxygen-responsive subunit,HIF1α,plays a crucial role in this process,as it has been shown to have cardioprotective effects in myocardial infarction through regulating the expression of genes affecting cellular survival,angiogenesis,and metabolism.Furthermore,HIF1αexpression induced reperfusion in the ischemic skeletal muscle,and hypoxic skin wounds in diabetic animal models showed reduced HIF1αexpression.Increased expression of HIF1αhas been shown to reduce apoptosis and oxidative stress in cardiomyocytes during acute myocardial infarction.Genetic variations in HIF1αhave also been found to correlate with altered responses to ischemic cardiovascular disease.In addition,a link has been established between the circadian rhythm and hypoxic molecular signaling pathways,with HIF1αfunctioning as an oxygen sensor and circadian genes such as period circadian regulator 2 responding to changes in light.This editorial analyzes the relationship between HIF1αand the circadian rhythm and highlights its significance in myocardial adaptation to hypoxia.Understanding the changes in molecular signaling pathways associated with diseases,specifically cardiovascular diseases,provides the opportunity for innovative therapeutic interventions,especially in low-oxygen environments such as myocardial infarction.展开更多
BACKGROUND In China,the prevalence of type 2 diabetes mellitus(T2DM)among diabetic patients is estimated to be between 90%-95%.Additionally,China is among the 22 countries burdened by a high number of tuberculosis cas...BACKGROUND In China,the prevalence of type 2 diabetes mellitus(T2DM)among diabetic patients is estimated to be between 90%-95%.Additionally,China is among the 22 countries burdened by a high number of tuberculosis cases,with approximately 4.5 million individuals affected by active tuberculosis.Notably,T2DM poses a significant risk factor for the development of tuberculosis,as evidenced by the increased incidence of T2DM coexisting with pulmonary tuberculosis(T2DMPTB),which has risen from 19.3%to 24.1%.It is evident that these two diseases are intricately interconnected and mutually reinforcing in nature.AIM To elucidate the clinical features of individuals diagnosed with both T2DM and tuberculosis(T2DM-PTB),as well as to investigate the potential risk factors associated with active tuberculosis in patients with T2DM.METHODS T2DM-PTB patients who visited our hospital between January 2020 and January 2023 were selected as the observation group,Simple DM patients presenting to our hospital in the same period were the control group,Controls and case groups were matched 1:2 according to the principle of the same sex,age difference(±3)years and disease duration difference(±5)years,patients were investigated for general demographic characteristics,diabetes-related characteristics,body immune status,lifestyle and behavioral habits,univariate and multivariate analysis of the data using conditional logistic regression,calculate the odds ratio(OR)values and 95%CI of OR values.RESULTS A total of 315 study subjects were included in this study,including 105 subjects in the observation group and 210 subjects in the control group.Comparison of the results of both anthropometric and biochemical measures showed that the constitution index,systolic blood pressure,diastolic blood pressure and lymphocyte count were significantly lower in the case group,while fasting blood glucose and high-density lipoprotein cholesterol levels were significantly higher than those in the control group.The results of univariate analysis showed that poor glucose control,hypoproteinemia,lymphopenia,TB contact history,high infection,smoking and alcohol consumption were positively associated with PTB in T2DM patients;married,history of hypertension,treatment of oral hypoglycemic drugs plus insulin,overweight,obesity and regular exercise were negatively associated with PTB in T2DM patients.Results of multivariate stepwise regression analysis found lymphopenia(OR=17.75,95%CI:3.40-92.74),smoking(OR=12.25,95%CI:2.53-59.37),history of TB contact(OR=6.56,95%CI:1.23-35.03)and poor glycemic control(OR=3.37,95%CI:1.11-10.25)was associated with an increased risk of developing PTB in patients with T2DM,While being overweight(OR=0.23,95%CI:0.08-0.72)and obesity(OR=0.11,95%CI:0.02-0.72)was associated with a reduced risk of developing PTB in patients with T2DM.CONCLUSION T2DM-PTB patients are prone to worse glycemic control,higher infection frequency,and a higher proportion of people smoking,drinking alcohol,and lack of exercise.Lymphopenia,smoking,history of TB exposure,poor glycemic control were independent risk factors for T2DM-PTB,and overweight and obesity were associated with reduced risk of concurrent PTB in patients with T2DM.展开更多
In Africa, the prevalence of diabetes is escalating and remains a concern due to the numerous complications it causes. Vascular damage associated with diabetes leads to a prothrombotic state observed in diabetic indiv...In Africa, the prevalence of diabetes is escalating and remains a concern due to the numerous complications it causes. Vascular damage associated with diabetes leads to a prothrombotic state observed in diabetic individuals. Diabetes is a complex and multifactorial disease involving genetic components. With the aim of preventing complications and contributing to an efficient management of diabetes, we investigated genes likely to lead to a risk of thrombosis, in particular the C677T of MTHFR, G20210A of prothrombin, and R506Q of factor V Leiden in type 2 diabetics in Abidjan receiving ambulatory care. A descriptive cross-sectional study was carried out on consenting type 2 diabetic patients. Mutation detection was carried out using the PCR-RFLP method employing restriction enzymes. Hemostasis tests (fibrinogen, D-dimers, fibrin monomers, and von Willebrand factor) were performed using citrate tubes on the Stage? Star Max automated system. Plasminogen activator inhibitor was assayed by ELISA method, and biochemical parameters were determined using the COBAS C311. The study population consisted of 45 diabetic patients, 51.1% of whom presented vascular complications, mainly neuropathy. Disturbances in hemostasis parameters were observed, with 15.5% of patients showing an increase in fibrin monomers. Mutation analysis revealed an absence of factor V mutation (factor V Leiden) and of G20210A mutation of the prothrombin gene. However, 15.6% of subjects had a heterozygous C677T mutation of MTHFR, with 57% of them being anemic. The exploration of biological and genetic factors associated with thrombotic risk is of significant interest in the optimal management of African type 2 diabetics.展开更多
Self-efficacy plays an important role in the management of type 2 diabetes mellitus (T2DM) patients, and it runs through the whole process of diabetes treatment, which is conducive to controlling and delaying the occu...Self-efficacy plays an important role in the management of type 2 diabetes mellitus (T2DM) patients, and it runs through the whole process of diabetes treatment, which is conducive to controlling and delaying the occurrence and development of complications, as well as improving the quality of life of patients. This paper mainly describes the concept of self-efficacy, the current situation of self-efficacy of diabetic patients at home and abroad, the functional aspects and their influencing factors, so as to take relevant measures on how to improve self-efficacy. It aims to provide a theoretical basis for the development of self-efficacy interventions for patients with type 2 diabetes mellitus.展开更多
Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance.Human epidermal growth factor receptor 2(HER2)is one of the most important ...Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance.Human epidermal growth factor receptor 2(HER2)is one of the most important targets in targeted therapy for gastric cancer.Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer.The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified.However,monoclonal antibodies,due to their large molecular weight,inability to penetrate the blood-brain barrier,and drug resistance,lead to decreased therapeutic efficacy,so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer.Small-molecule tyrosine kinase inhibitors,such as lapatinib and pyrrotinib,have the advantages of small molecular weight,penetrating the blood-brain barrier and high oral bioavailability,and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future.Antibo-drug conjugate,such as T-DM1 and T-DXd,can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing,and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab.Therefore,after more detailed stratification of gastric cancer patients,various gastric cancer drugs targeting HER2 are expected to play a more significant role.展开更多
BACKGROUND Human epidermal growth factor receptor-2(HER-2)plays a vital role in tumor cell proliferation and metastasis.However,the prognosis of HER2-positive gastric cancer is poor.Inetetamab,a novel anti-HER2 target...BACKGROUND Human epidermal growth factor receptor-2(HER-2)plays a vital role in tumor cell proliferation and metastasis.However,the prognosis of HER2-positive gastric cancer is poor.Inetetamab,a novel anti-HER2 targeting drug independently developed in China,exhibits more potent antibody-dependent cell-mediated cytotoxicity than trastuzumab,which is administered as the first-line treatment for HER2-positive gastric cancer in combination with chemotherapy.In this case,the efficacy and safety of inetetamab combined with tegafur was investigated as a second-line treatment for HER2-positive gastric cancer.CASE SUMMARY A 52-year-old male patient with HER2-positive gastric cancer presented with abdominal distension,poor appetite,and fatigue two years after receiving six cycles of oxaliplatin combined with tegafur as first-line treatment after surgery,followed by tegafur monotherapy for six months.The patient was diagnosed with postoperative recurrence of gastric adenocarcinoma.He received 17 cycles of a combination of inetetamab,an innovative domestically developed anti-HER2 monoclonal antibody,and tegafur chemotherapy as the second-line treatment(inetetamab 200 mg on day 1,every 3 wk combined with tegafur twice daily on days 1–14,every 3 wk).Evaluation of the efficacy of the second-line treatment revealed that the patient achieved a stable condition and progression-free survival of 17 months.He tolerated the treatment well without exhibiting any grade 3-4 adverse events.CONCLUSION Inetetamab combined with chemotherapy for the treatment of metastatic HER2-positive gastric cancer demonstrates significant survival benefits and acceptable safety.展开更多
BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly fatal disease with limited effective treatment especially after first-line chemotherapy.The human epidermal growth factor receptor 2(HER-2)immunohistochemis...BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly fatal disease with limited effective treatment especially after first-line chemotherapy.The human epidermal growth factor receptor 2(HER-2)immunohistochemistry(IHC)positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC.CASE SUMMARY We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn’t have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment.A novel combination therapy PRaG 3.0 of RC48(HER2-antibody-drug conjugate),radio-therapy,PD-1 inhibitor,granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month.She had not developed any grade 2 or above treatment-related adverse events at any point.Percentage of peripheral CD8^(+) Temra and CD4^(+) Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy.CONCLUSION PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.展开更多
This paper takes college students as research subjects to investigate the factors affecting L2 Reading ability and their regulation strategies through scale surveys.The findings are as follows:(1)Linguistic factors ha...This paper takes college students as research subjects to investigate the factors affecting L2 Reading ability and their regulation strategies through scale surveys.The findings are as follows:(1)Linguistic factors have significant impacts on L2 Reading ability,and the influence of non-linguistic factors,such as non-intellectual factors and cultural background knowledge,is also important;and(2)flexible use of reading regulation strategies according to the learning conditions(such as the information extraction strategy,the metacognitive reading regulation strategy,and the interactive reading strategy)can effectively improve learners’L2 Reading ability.The findings of this study have important theoretical and practical value for improving L2 learners’Reading ability.展开更多
BACKGROUND Although treatment options for gastric cancer(GC)continue to advance,the overall prognosis for patients with GC remains poor.At present,the predictors of treatment efficacy remain controversial except for h...BACKGROUND Although treatment options for gastric cancer(GC)continue to advance,the overall prognosis for patients with GC remains poor.At present,the predictors of treatment efficacy remain controversial except for high microsatellite instability.AIM To develop methods to identify groups of patients with GC who would benefit the most from receiving the combination of a programmed cell death protein 1(PD-1)inhibitor and chemotherapy.METHODS We acquired data from 63 patients with human epidermal growth factor receptor 2(HER2)-negative GC with a histological diagnosis of GC at the Cancer Hospital,Chinese Academy of Medical Sciences between November 2020 and October 2022.All of the patients screened received a PD-1 inhibitor combined with chemotherapy as the first-line treatment.RESULTS As of July 1,2023,the objective response rate was 61.9%,and the disease control rate was 96.8%.The median progression-free survival(mPFS)for all patients was 6.3 months.The median overall survival was not achieved.Survival analysis showed that patients with a combined positive score(CPS)≥1 exhibited an extended trend in progression-free survival(PFS)when compared to patients with a CPS of 0 after receiving a PD-1 inhibitor combined with oxaliplatin and tegafur as the first-line treatment.PFS exhibited a trend for prolongation as the expression level of HER2 increased.Based on PFS,we divided patients into two groups:A treatment group with excellent efficacy and a treatment group with poor efficacy.The mPFS of the excellent efficacy group was 8 months,with a mPFS of 9.1 months after excluding a cohort of patients who received interrupted therapy due to surgery.The mPFS was 4.5 months in patients in the group with poor efficacy who did not receive surgery.Using good/poor efficacy as the endpoint of our study,univariate analysis revealed that both CPS score(P=0.004)and HER2 expression level(P=0.015)were both factors that exerted significant influence on the efficacy of treatment the combination of a PD-1 inhibitor and chemotherapy in patients with advanced GC(AGC).Finally,multivariate analysis confirmed that CPS score was a significant influencing factor.CONCLUSION CPS score and HER2 expression both impacted the efficacy of immunotherapy combined with chemotherapy in AGC patients who were non-positive for HER2.展开更多
BACKGROUND The hypoxic environment during bone healing is important in regulating the differentiation of periosteal stem cells(PSCs)into osteoblasts or chondrocytes;however,the underlying mechanisms remain unclear.AIM...BACKGROUND The hypoxic environment during bone healing is important in regulating the differentiation of periosteal stem cells(PSCs)into osteoblasts or chondrocytes;however,the underlying mechanisms remain unclear.AIM To determine the effect of hypoxia on PSCs,and the expression of microRNA-584-5p(miR-584-5p)and RUNX family transcription factor 2(RUNX2)in PSCs was modulated to explore the impact of the miR-584-5p/RUNX2 axis on hypoxiainduced osteogenic differentiation of PSCs.METHODS In this study,we isolated primary mouse PSCs and stimulated them with hypoxia,and the characteristics and functional genes related to PSC osteogenic differentiation were assessed.Constructs expressing miR-584-5p and RUNX2 were established to determine PSC osteogenic differentiation.RESULTS Hypoxic stimulation induced PSC osteogenic differentiation and significantly increased calcified nodules,intracellular calcium ion levels,and alkaline phosphatase(ALP)activity in PSCs.Osteogenic differentiation-related factors such as RUNX2,bone morphogenetic protein 2,hypoxia-inducible factor 1-alpha,and ALP were upregulated;in contrast,miR-584-5p was downregulated in these cells.Furthermore,upregulation of miR-584-5p significantly inhibited RUNX2 expression and hypoxia-induced PSC osteogenic differentiation.RUNX2 was the target gene of miR-584-5p,antagonizing miR-584-5p inhibition in hypoxia-induced PSC osteogenic differentiation.CONCLUSION Our study showed that the interaction of miR-584-5p and RUNX2 could mediate PSC osteogenic differentiation induced by hypoxia.展开更多
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 (FGF23) by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures...Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 (FGF23) by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la (HIF-la) in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.展开更多
Brachial plexus avulsion often results in massive motor neuron death and severe functional deficits of target muscles. However, no satisfactory treatment is currently available. Hypoxia-inducible factor 1α is a criti...Brachial plexus avulsion often results in massive motor neuron death and severe functional deficits of target muscles. However, no satisfactory treatment is currently available. Hypoxia-inducible factor 1α is a critical molecule targeting several genes associated with ischemia-hypoxia damage and angiogenesis. In this study, a rat model of brachial plexus avulsion-reimplantation was established, in which C5–7 ventral nerve roots were avulsed and only the C6 root reimplanted. Different implants were immediately injected using a microsyringe into the avulsion-reimplantation site of the C6 root post-brachial plexus avulsion. Rats were randomly divided into five groups: phosphate-buffered saline, negative control of lentivirus, hypoxia-inducible factor 1α(hypoxia-inducible factor 1α overexpression lentivirus), gel(pluronic F-127 hydrogel), and gel + hypoxia-inducible factor 1α(pluronic F-127 hydrogel + hypoxia-inducible factor 1α overexpression lentivirus). The Terzis grooming test was performed to assess recovery of motor function. Scores were higher in the hypoxia-inducible factor 1α and gel +hypoxia-inducible factor 1α groups(in particular the gel + hypoxia-inducible factor 1α group) compared with the phosphate-buffered saline group. Electrophysiology, fluorogold retrograde tracing, and immunofluorescent staining were further performed to investigate neural pathway reconstruction and changes of neurons, motor endplates, and angiogenesis. Compared with the phosphate-buffered saline group, action potential latency of musculocutaneous nerves was markedly shortened in the hypoxia-inducible factor 1α and gel + hypoxia-inducible factor1α groups. Meanwhile, the number of fluorogold-positive cells and ChAT-positive neurons, neovascular area(labeled by CD31 around av ulsed sites in ipsilateral spinal cord segments), and the number of motor endplates in biceps brachii(identified by α-bungarotoxin) were all visibly increased, as well as the morphology of motor endplate in biceps brachil was clear in the hypoxia-inducible factor 1α and gel + hypoxia-inducible factor 1α groups. Taken together, delivery of hypoxia-inducible factor 1α overexpression lentiviral vectors mediated by pluronic F-127 effectively promotes spinal root regeneration and functional recovery post-brachial plexus avulsion. All animal procedures were approved by the Institutional Animal Care and Use Committee of Guangdong Medical University, China.展开更多
BACKGROUND As human placenta-derived mesenchymal stem cells(hP-MSCs)exist in a physiologically hypoxic microenvironment,various studies have focused on the influence of hypoxia.However,the underlying mechanisms remain...BACKGROUND As human placenta-derived mesenchymal stem cells(hP-MSCs)exist in a physiologically hypoxic microenvironment,various studies have focused on the influence of hypoxia.However,the underlying mechanisms remain to be further explored.AIM The aim was to reveal the possible mechanisms by which hypoxia enhances the proliferation of hP-MSCs.METHODS A hypoxic cell incubator(2.5%O2)was used to mimic a hypoxic microenvironment.Cell counting kit-8 and 5-ethynyl-20-deoxyuridine incorporation assays were used to assay the proliferation of hP-MSCs.The cell cycle was profiled by flow cytometry.Transcriptome profiling of hP-MSCs under hypoxia was performed by RNA sequencing.CD99 mRNA expression was assayed by reverse transcription-polymerase chain reaction.Small interfering RNA-mediated hypoxia-inducible factor 1α(HIF-1α)or CD99 knockdown of hP-MSCs,luciferase reporter assays,and the ERK1/2 signaling inhibitor PD98059 were used in the mechanistic analysis.Protein expression was assayed by western blotting;immunofluorescence assays were conducted to evaluate changes in expression levels.RESULTS Hypoxia enhanced hP-MSC proliferation,increased the expression of cyclin E1,cyclin-dependent kinase 2,and cyclin A2,and decreased the expression of p21.Under hypoxia,CD99 expression was increased by HIF-1α.CD99-specific small interfering RNA or the ERK1/2 signaling inhibitor PD98059 abrogated the hypoxia-induced increase in cell proliferation.CONCLUSION Hypoxia promoted hP-MSCs proliferation in a manner dependent on CD99 regulation of the MAPK/ERK signaling pathway in vitro.展开更多
基金Supported by Basic and Applied Basic Research Foundation of Guangdong Province,No.2020A1515010123 and No.2021A1515010695Special Fund Project for Science and Technology Innovation Strategy of Guangdong Province,No.2019A030317011.
文摘BACKGROUND Osteoporosis(OP)has become a major public health problem worldwide.Most OP treatments are based on the inhibition of bone resorption,and it is necessary to identify additional treatments aimed at enhancing osteogenesis.In the bone marrow(BM)niche,bone mesenchymal stem cells(BMSCs)are exposed to a hypoxic environment.Recently,a few studies have demonstrated that hypoxiainducible factor 2alpha(HIF-2α)is involved in BMSC osteogenic differentiation,but the molecular mechanism involved has not been determined.AIM To investigate the effect of HIF-2αon the osteogenic and adipogenic differentiation of BMSCs and the hematopoietic function of hematopoietic stem cells(HSCs)in the BM niche on the progression of OP.METHODS Mice with BMSC-specific HIF-2αknockout(Prx1-Cre;Hif-2αfl/fl mice)were used for in vivo experiments.Bone quantification was performed on mice of two genotypes with three interventions:Bilateral ovariectomy,semilethal irradiation,and dexamethasone treatment.Moreover,the hematopoietic function of HSCs in the BM niche was compared between the two mouse genotypes.In vitro,the HIF-2αagonist roxadustat and the HIF-2αinhibitor PT2399 were used to investigate the function of HIF-2αin BMSC osteogenic and adipogenic differentiation.Finally,we investigated the effect of HIF-2αon BMSCs via treatment with the mechanistic target of rapamycin(mTOR)agonist MHY1485 and the mTOR inhibitor rapamycin.RESULTS The quantitative index determined by microcomputed tomography indicated that the femoral bone density of Prx1-Cre;Hif-2αfl/fl mice was lower than that of Hif-2αfl/fl mice under the three intervention conditions.In vitro,Hif-2αfl/fl mouse BMSCs were cultured and treated with the HIF-2αagonist roxadustat,and after 7 d of BMSC adipogenic differentiation,the oil red O staining intensity and mRNA expression levels of adipogenesis-related genes in BMSCs treated with roxadustat were decreased;in addition,after 14 d of osteogenic differentiation,BMSCs treated with roxadustat exhibited increased expression of osteogenesis-related genes.The opposite effects were shown for mouse BMSCs treated with the HIF-2αinhibitor PT2399.The mTOR inhibitor rapamycin was used to confirm that HIF-2αregulated BMSC osteogenic and adipogenic differentiation by inhibiting the mTOR pathway.Consequently,there was no significant difference in the hematopoietic function of HSCs between Prx1-Cre;Hif-2αfl/fl and Hif-2αfl/fl mice.CONCLUSION Our study showed that inhibition of HIF-2αdecreases bone mass by inhibiting the osteogenic differentiation and increasing the adipogenic differentiation of BMSCs through inhibition of mTOR signaling in the BM niche.
基金Supported by Croatian Ministry of Science and Education,Josip Juraj Strossmayer University of Osijek,Faculty of Dental Medicine and Health,Osijek,Croatia,No.IP7-FDMZ-2023West-Siberian Science and Education Center,Government of Tyumen District,Decree of 20.11.2020,No.928-rpMinistry of Science and Higher Education,No.FMEN 2022-0009.
文摘Hypoxia-inducible factor 1(HIF1)has a crucial function in the regulation of oxygen levels in mammalian cells,especially under hypoxic conditions.Its importance in cardiovascular diseases,particularly in cardiac ischemia,is because of its ability to alleviate cardiac dysfunction.The oxygen-responsive subunit,HIF1α,plays a crucial role in this process,as it has been shown to have cardioprotective effects in myocardial infarction through regulating the expression of genes affecting cellular survival,angiogenesis,and metabolism.Furthermore,HIF1αexpression induced reperfusion in the ischemic skeletal muscle,and hypoxic skin wounds in diabetic animal models showed reduced HIF1αexpression.Increased expression of HIF1αhas been shown to reduce apoptosis and oxidative stress in cardiomyocytes during acute myocardial infarction.Genetic variations in HIF1αhave also been found to correlate with altered responses to ischemic cardiovascular disease.In addition,a link has been established between the circadian rhythm and hypoxic molecular signaling pathways,with HIF1αfunctioning as an oxygen sensor and circadian genes such as period circadian regulator 2 responding to changes in light.This editorial analyzes the relationship between HIF1αand the circadian rhythm and highlights its significance in myocardial adaptation to hypoxia.Understanding the changes in molecular signaling pathways associated with diseases,specifically cardiovascular diseases,provides the opportunity for innovative therapeutic interventions,especially in low-oxygen environments such as myocardial infarction.
文摘BACKGROUND In China,the prevalence of type 2 diabetes mellitus(T2DM)among diabetic patients is estimated to be between 90%-95%.Additionally,China is among the 22 countries burdened by a high number of tuberculosis cases,with approximately 4.5 million individuals affected by active tuberculosis.Notably,T2DM poses a significant risk factor for the development of tuberculosis,as evidenced by the increased incidence of T2DM coexisting with pulmonary tuberculosis(T2DMPTB),which has risen from 19.3%to 24.1%.It is evident that these two diseases are intricately interconnected and mutually reinforcing in nature.AIM To elucidate the clinical features of individuals diagnosed with both T2DM and tuberculosis(T2DM-PTB),as well as to investigate the potential risk factors associated with active tuberculosis in patients with T2DM.METHODS T2DM-PTB patients who visited our hospital between January 2020 and January 2023 were selected as the observation group,Simple DM patients presenting to our hospital in the same period were the control group,Controls and case groups were matched 1:2 according to the principle of the same sex,age difference(±3)years and disease duration difference(±5)years,patients were investigated for general demographic characteristics,diabetes-related characteristics,body immune status,lifestyle and behavioral habits,univariate and multivariate analysis of the data using conditional logistic regression,calculate the odds ratio(OR)values and 95%CI of OR values.RESULTS A total of 315 study subjects were included in this study,including 105 subjects in the observation group and 210 subjects in the control group.Comparison of the results of both anthropometric and biochemical measures showed that the constitution index,systolic blood pressure,diastolic blood pressure and lymphocyte count were significantly lower in the case group,while fasting blood glucose and high-density lipoprotein cholesterol levels were significantly higher than those in the control group.The results of univariate analysis showed that poor glucose control,hypoproteinemia,lymphopenia,TB contact history,high infection,smoking and alcohol consumption were positively associated with PTB in T2DM patients;married,history of hypertension,treatment of oral hypoglycemic drugs plus insulin,overweight,obesity and regular exercise were negatively associated with PTB in T2DM patients.Results of multivariate stepwise regression analysis found lymphopenia(OR=17.75,95%CI:3.40-92.74),smoking(OR=12.25,95%CI:2.53-59.37),history of TB contact(OR=6.56,95%CI:1.23-35.03)and poor glycemic control(OR=3.37,95%CI:1.11-10.25)was associated with an increased risk of developing PTB in patients with T2DM,While being overweight(OR=0.23,95%CI:0.08-0.72)and obesity(OR=0.11,95%CI:0.02-0.72)was associated with a reduced risk of developing PTB in patients with T2DM.CONCLUSION T2DM-PTB patients are prone to worse glycemic control,higher infection frequency,and a higher proportion of people smoking,drinking alcohol,and lack of exercise.Lymphopenia,smoking,history of TB exposure,poor glycemic control were independent risk factors for T2DM-PTB,and overweight and obesity were associated with reduced risk of concurrent PTB in patients with T2DM.
文摘In Africa, the prevalence of diabetes is escalating and remains a concern due to the numerous complications it causes. Vascular damage associated with diabetes leads to a prothrombotic state observed in diabetic individuals. Diabetes is a complex and multifactorial disease involving genetic components. With the aim of preventing complications and contributing to an efficient management of diabetes, we investigated genes likely to lead to a risk of thrombosis, in particular the C677T of MTHFR, G20210A of prothrombin, and R506Q of factor V Leiden in type 2 diabetics in Abidjan receiving ambulatory care. A descriptive cross-sectional study was carried out on consenting type 2 diabetic patients. Mutation detection was carried out using the PCR-RFLP method employing restriction enzymes. Hemostasis tests (fibrinogen, D-dimers, fibrin monomers, and von Willebrand factor) were performed using citrate tubes on the Stage? Star Max automated system. Plasminogen activator inhibitor was assayed by ELISA method, and biochemical parameters were determined using the COBAS C311. The study population consisted of 45 diabetic patients, 51.1% of whom presented vascular complications, mainly neuropathy. Disturbances in hemostasis parameters were observed, with 15.5% of patients showing an increase in fibrin monomers. Mutation analysis revealed an absence of factor V mutation (factor V Leiden) and of G20210A mutation of the prothrombin gene. However, 15.6% of subjects had a heterozygous C677T mutation of MTHFR, with 57% of them being anemic. The exploration of biological and genetic factors associated with thrombotic risk is of significant interest in the optimal management of African type 2 diabetics.
文摘Self-efficacy plays an important role in the management of type 2 diabetes mellitus (T2DM) patients, and it runs through the whole process of diabetes treatment, which is conducive to controlling and delaying the occurrence and development of complications, as well as improving the quality of life of patients. This paper mainly describes the concept of self-efficacy, the current situation of self-efficacy of diabetic patients at home and abroad, the functional aspects and their influencing factors, so as to take relevant measures on how to improve self-efficacy. It aims to provide a theoretical basis for the development of self-efficacy interventions for patients with type 2 diabetes mellitus.
文摘Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance.Human epidermal growth factor receptor 2(HER2)is one of the most important targets in targeted therapy for gastric cancer.Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer.The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified.However,monoclonal antibodies,due to their large molecular weight,inability to penetrate the blood-brain barrier,and drug resistance,lead to decreased therapeutic efficacy,so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer.Small-molecule tyrosine kinase inhibitors,such as lapatinib and pyrrotinib,have the advantages of small molecular weight,penetrating the blood-brain barrier and high oral bioavailability,and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future.Antibo-drug conjugate,such as T-DM1 and T-DXd,can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing,and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab.Therefore,after more detailed stratification of gastric cancer patients,various gastric cancer drugs targeting HER2 are expected to play a more significant role.
基金Supported by the Science and Technology Innovation Development Project of Tai’an,No.2021NS160the Medical and Health Science and Technology Development Plan of Shandong Province,No.202102010647。
文摘BACKGROUND Human epidermal growth factor receptor-2(HER-2)plays a vital role in tumor cell proliferation and metastasis.However,the prognosis of HER2-positive gastric cancer is poor.Inetetamab,a novel anti-HER2 targeting drug independently developed in China,exhibits more potent antibody-dependent cell-mediated cytotoxicity than trastuzumab,which is administered as the first-line treatment for HER2-positive gastric cancer in combination with chemotherapy.In this case,the efficacy and safety of inetetamab combined with tegafur was investigated as a second-line treatment for HER2-positive gastric cancer.CASE SUMMARY A 52-year-old male patient with HER2-positive gastric cancer presented with abdominal distension,poor appetite,and fatigue two years after receiving six cycles of oxaliplatin combined with tegafur as first-line treatment after surgery,followed by tegafur monotherapy for six months.The patient was diagnosed with postoperative recurrence of gastric adenocarcinoma.He received 17 cycles of a combination of inetetamab,an innovative domestically developed anti-HER2 monoclonal antibody,and tegafur chemotherapy as the second-line treatment(inetetamab 200 mg on day 1,every 3 wk combined with tegafur twice daily on days 1–14,every 3 wk).Evaluation of the efficacy of the second-line treatment revealed that the patient achieved a stable condition and progression-free survival of 17 months.He tolerated the treatment well without exhibiting any grade 3-4 adverse events.CONCLUSION Inetetamab combined with chemotherapy for the treatment of metastatic HER2-positive gastric cancer demonstrates significant survival benefits and acceptable safety.
基金the Suzhou Medical Center,No.Szlcyxzx202103the National Natural Science Foundation of China,No.82171828+9 种基金the Key R&D Plan of Jiangsu Province(Social Development),No.BE2021652the Subject Construction Support Project of The Second Affiliated Hospital of Soochow University,No.XKTJHRC20210011Wu Jieping Medical Foundation,No.320.6750.2021-01-12the Special Project of“Technological Innovation”Project of CNNC Medical Industry Co.Ltd,No.ZHYLTD2021001Suzhou Science and Education Health Project,No.KJXW2021018Foundation of Chinese Society of Clinical Oncology,No.Y-pierrefabre202102-0113Beijing Bethune Charitable Foundation,No.STLKY0016Research Projects of China Baoyuan Investment Co.,No.270004Suzhou Gusu Health Talent Program,No.GSWS2022028Open Project of State Key Laboratory of Radiation Medicine and Protection of Soochow University,No.GZN1202302.
文摘BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly fatal disease with limited effective treatment especially after first-line chemotherapy.The human epidermal growth factor receptor 2(HER-2)immunohistochemistry(IHC)positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC.CASE SUMMARY We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn’t have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment.A novel combination therapy PRaG 3.0 of RC48(HER2-antibody-drug conjugate),radio-therapy,PD-1 inhibitor,granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month.She had not developed any grade 2 or above treatment-related adverse events at any point.Percentage of peripheral CD8^(+) Temra and CD4^(+) Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy.CONCLUSION PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.
基金funded by the Social Sciences Annual Research Project of Shanghai“A Study on the Interactive Processing Mechanism of English L2 Text Reading”(Grant No.2021BYY008).
文摘This paper takes college students as research subjects to investigate the factors affecting L2 Reading ability and their regulation strategies through scale surveys.The findings are as follows:(1)Linguistic factors have significant impacts on L2 Reading ability,and the influence of non-linguistic factors,such as non-intellectual factors and cultural background knowledge,is also important;and(2)flexible use of reading regulation strategies according to the learning conditions(such as the information extraction strategy,the metacognitive reading regulation strategy,and the interactive reading strategy)can effectively improve learners’L2 Reading ability.The findings of this study have important theoretical and practical value for improving L2 learners’Reading ability.
基金Supported by Beijing CSCO Clinical Oncology Research Foundation,No.Y-HH202102-0314。
文摘BACKGROUND Although treatment options for gastric cancer(GC)continue to advance,the overall prognosis for patients with GC remains poor.At present,the predictors of treatment efficacy remain controversial except for high microsatellite instability.AIM To develop methods to identify groups of patients with GC who would benefit the most from receiving the combination of a programmed cell death protein 1(PD-1)inhibitor and chemotherapy.METHODS We acquired data from 63 patients with human epidermal growth factor receptor 2(HER2)-negative GC with a histological diagnosis of GC at the Cancer Hospital,Chinese Academy of Medical Sciences between November 2020 and October 2022.All of the patients screened received a PD-1 inhibitor combined with chemotherapy as the first-line treatment.RESULTS As of July 1,2023,the objective response rate was 61.9%,and the disease control rate was 96.8%.The median progression-free survival(mPFS)for all patients was 6.3 months.The median overall survival was not achieved.Survival analysis showed that patients with a combined positive score(CPS)≥1 exhibited an extended trend in progression-free survival(PFS)when compared to patients with a CPS of 0 after receiving a PD-1 inhibitor combined with oxaliplatin and tegafur as the first-line treatment.PFS exhibited a trend for prolongation as the expression level of HER2 increased.Based on PFS,we divided patients into two groups:A treatment group with excellent efficacy and a treatment group with poor efficacy.The mPFS of the excellent efficacy group was 8 months,with a mPFS of 9.1 months after excluding a cohort of patients who received interrupted therapy due to surgery.The mPFS was 4.5 months in patients in the group with poor efficacy who did not receive surgery.Using good/poor efficacy as the endpoint of our study,univariate analysis revealed that both CPS score(P=0.004)and HER2 expression level(P=0.015)were both factors that exerted significant influence on the efficacy of treatment the combination of a PD-1 inhibitor and chemotherapy in patients with advanced GC(AGC).Finally,multivariate analysis confirmed that CPS score was a significant influencing factor.CONCLUSION CPS score and HER2 expression both impacted the efficacy of immunotherapy combined with chemotherapy in AGC patients who were non-positive for HER2.
基金Supported by Sailing Program of Naval Medical University,Program of Shanghai Hongkou District Health Commission,No.2202-27Special Funds for Activating Scientific Research of Shanghai Fourth People’s Hospital,No.sykyqd05801.
文摘BACKGROUND The hypoxic environment during bone healing is important in regulating the differentiation of periosteal stem cells(PSCs)into osteoblasts or chondrocytes;however,the underlying mechanisms remain unclear.AIM To determine the effect of hypoxia on PSCs,and the expression of microRNA-584-5p(miR-584-5p)and RUNX family transcription factor 2(RUNX2)in PSCs was modulated to explore the impact of the miR-584-5p/RUNX2 axis on hypoxiainduced osteogenic differentiation of PSCs.METHODS In this study,we isolated primary mouse PSCs and stimulated them with hypoxia,and the characteristics and functional genes related to PSC osteogenic differentiation were assessed.Constructs expressing miR-584-5p and RUNX2 were established to determine PSC osteogenic differentiation.RESULTS Hypoxic stimulation induced PSC osteogenic differentiation and significantly increased calcified nodules,intracellular calcium ion levels,and alkaline phosphatase(ALP)activity in PSCs.Osteogenic differentiation-related factors such as RUNX2,bone morphogenetic protein 2,hypoxia-inducible factor 1-alpha,and ALP were upregulated;in contrast,miR-584-5p was downregulated in these cells.Furthermore,upregulation of miR-584-5p significantly inhibited RUNX2 expression and hypoxia-induced PSC osteogenic differentiation.RUNX2 was the target gene of miR-584-5p,antagonizing miR-584-5p inhibition in hypoxia-induced PSC osteogenic differentiation.CONCLUSION Our study showed that the interaction of miR-584-5p and RUNX2 could mediate PSC osteogenic differentiation induced by hypoxia.
基金supported by NIH grants AR049510 (TLC) and AR045955 (LDQ)
文摘Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 (FGF23) by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la (HIF-la) in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.
基金financially supported by the National Natural Science Foundation of China,No.81371366(to HFW)the Natural Science Foundation of Guangdong Province of China,No.2015A030313515(to HFW)+1 种基金the Dongguan International Science and Technology Cooperation Project,No.2013508152010(to HFW)the Key Project of Social Development of Dongguan of China,No.20185071521640(to HFW)
文摘Brachial plexus avulsion often results in massive motor neuron death and severe functional deficits of target muscles. However, no satisfactory treatment is currently available. Hypoxia-inducible factor 1α is a critical molecule targeting several genes associated with ischemia-hypoxia damage and angiogenesis. In this study, a rat model of brachial plexus avulsion-reimplantation was established, in which C5–7 ventral nerve roots were avulsed and only the C6 root reimplanted. Different implants were immediately injected using a microsyringe into the avulsion-reimplantation site of the C6 root post-brachial plexus avulsion. Rats were randomly divided into five groups: phosphate-buffered saline, negative control of lentivirus, hypoxia-inducible factor 1α(hypoxia-inducible factor 1α overexpression lentivirus), gel(pluronic F-127 hydrogel), and gel + hypoxia-inducible factor 1α(pluronic F-127 hydrogel + hypoxia-inducible factor 1α overexpression lentivirus). The Terzis grooming test was performed to assess recovery of motor function. Scores were higher in the hypoxia-inducible factor 1α and gel +hypoxia-inducible factor 1α groups(in particular the gel + hypoxia-inducible factor 1α group) compared with the phosphate-buffered saline group. Electrophysiology, fluorogold retrograde tracing, and immunofluorescent staining were further performed to investigate neural pathway reconstruction and changes of neurons, motor endplates, and angiogenesis. Compared with the phosphate-buffered saline group, action potential latency of musculocutaneous nerves was markedly shortened in the hypoxia-inducible factor 1α and gel + hypoxia-inducible factor1α groups. Meanwhile, the number of fluorogold-positive cells and ChAT-positive neurons, neovascular area(labeled by CD31 around av ulsed sites in ipsilateral spinal cord segments), and the number of motor endplates in biceps brachii(identified by α-bungarotoxin) were all visibly increased, as well as the morphology of motor endplate in biceps brachil was clear in the hypoxia-inducible factor 1α and gel + hypoxia-inducible factor 1α groups. Taken together, delivery of hypoxia-inducible factor 1α overexpression lentiviral vectors mediated by pluronic F-127 effectively promotes spinal root regeneration and functional recovery post-brachial plexus avulsion. All animal procedures were approved by the Institutional Animal Care and Use Committee of Guangdong Medical University, China.
基金Stem Cell and Translational Research from the National Key Research and Development Program of China,No.2020YFA0113003National Natural Science Foundation of China, No. 81971756.
文摘BACKGROUND As human placenta-derived mesenchymal stem cells(hP-MSCs)exist in a physiologically hypoxic microenvironment,various studies have focused on the influence of hypoxia.However,the underlying mechanisms remain to be further explored.AIM The aim was to reveal the possible mechanisms by which hypoxia enhances the proliferation of hP-MSCs.METHODS A hypoxic cell incubator(2.5%O2)was used to mimic a hypoxic microenvironment.Cell counting kit-8 and 5-ethynyl-20-deoxyuridine incorporation assays were used to assay the proliferation of hP-MSCs.The cell cycle was profiled by flow cytometry.Transcriptome profiling of hP-MSCs under hypoxia was performed by RNA sequencing.CD99 mRNA expression was assayed by reverse transcription-polymerase chain reaction.Small interfering RNA-mediated hypoxia-inducible factor 1α(HIF-1α)or CD99 knockdown of hP-MSCs,luciferase reporter assays,and the ERK1/2 signaling inhibitor PD98059 were used in the mechanistic analysis.Protein expression was assayed by western blotting;immunofluorescence assays were conducted to evaluate changes in expression levels.RESULTS Hypoxia enhanced hP-MSC proliferation,increased the expression of cyclin E1,cyclin-dependent kinase 2,and cyclin A2,and decreased the expression of p21.Under hypoxia,CD99 expression was increased by HIF-1α.CD99-specific small interfering RNA or the ERK1/2 signaling inhibitor PD98059 abrogated the hypoxia-induced increase in cell proliferation.CONCLUSION Hypoxia promoted hP-MSCs proliferation in a manner dependent on CD99 regulation of the MAPK/ERK signaling pathway in vitro.