Comprehensive regulation of traditional Chinese medicine on proliferation and differentiation of neural stem cells

Since the diccovery of neural stem cells(NSCs)in the embryonic and adult mammalian central nerous system,it provided novel ideas forneurogenesis as the potential of proliferation and differentiation of NSCs.One of the ways to promote the clinical application of neural stem cells(NSCs)is searching effective methods which regulate the proliferation and differentiation.This is also a problem urgently to be solved in medical field.Plenty of earlier studies have shown that traditional chinese medicine can promote the proliferation and differentiation of NSCs by regulating the related signaling pathway in vivo and in vitro.The reports of Chinese and foreign literatures on regulating the proliferation and differentiation of neural stem cells in recent ten years and their target and signaling pathways is analyzed in this review.The traditional chinese medicine regulate proliferation and differentiation of NSCs by the signaling pathways of Notch,PI3K/Akt,Wnt/β-catenin,and GFs.And,those signaling pathways have cross-talk in the regulation progress.Moreover,some traditional Chinese medicine,such as astragalus,has a variety of active ingredients to regulate proliferation and differentiation of NSCs through different signaling pathways.However,to accelerate the clinical application of neural stem cells,the studies aboutthe proliferation and differentiation of NSCs and Chinese medicine should be further deepened,the mechanism of multiple targets and the comprehensive regulation function of traditional Chinese medicine should be clarified.

Fetal bovine serum versus Chinese herbal formula Naoluoxintong serum supplementation for proliferation and differentiation of rat embryonic neural stem cells

BACKGROUND： How to induce endogenous neural stem cells （NSCs） to differentiate into needed neural cell types is a hot spot of current researches. OBJECTIVE： To compare differences between fetal bovine serum and Chinese herbal formula Naoluoxintong serum supplementation for inducing proliferation and differentiation in rat embryonic NSCs. DESIGN, TIME AND SETTING： An in vitro, serum pharmacology, comparative, observation study was performed from March to September in 2008 at the Laboratory of Neurodegenerative Diseases, College of Life Science in University of Science and Technology of China, the Key Laboratory Breeding Base of Acupuncture Foundation and Technology in Anhui University of Traditional Chinese Medicine, the Anhui Province Key Laboratory of R ＆ D of Chinese Medicine, and at the Level 3 Laboratory of Molecular Biology of the State Administration of Traditional Chinese Medicine. MATERIALS： The Chinese herbal formula Naoluoxintong was produced by Radix Astragali, Radix Notoginseng, Rhizoma Chuanxiong, Scolopendra at Anhui University of Traditional Chinese Medicine. Mouse anti-rat nestin, gliat fibrillary acidic protein, and galactocerebroside monoclonal antibodies, as well as rabbit anti-neuron-specific enolase polyclonal antibody were produced by Chemicon, Billerica, MA, USA. METHODS： Wistar rats aged 3 months were intragastrically infused with Naoluoxintong. Wistar rat embryonic NSCs （passage 8） were induced to proliferate and differentiate using 10% fetal bovine serum, 10% Naoluoxintong serum, and 10% rat serum. MAIN OUTCOME MEASURES： Phenotypic changes in cultured cells were detected using phase contrast microscopy, and cell proliferation and differentiation were observed using immunofluorescence staining. RESULTS： Proliferation and differentiation of embryonic NSCs was induced by three different types of blood serum. Although the differentiation time course with Nao/uoxintongserum was later than with the other two methods, the differentiated cells were morphologically similar to mature neurons to a greater extent. CONCLUSION： Nao/uoxintong serum supplementation induced differentiation of NSCs into neuronal-like cells and stimulated neuronal maturation.

Effects of Ginkgo biloba extract EGb761 on neural differentiation of stem cells offer new hope for neurological disease treatment

Stem cell transplantation has brought new hope for the treatment of neurological diseases.The key to stem cell therapy lies in inducing the specific differentiation of stem cells into nerve cells.Because the differentiation of stem cells in vitro and in vivo is affected by multiple factors,the final differentiation outcome is strongly associated with the microenvironment in which the stem cells are located.Accordingly,the optimal microenvironment for inducing stem cell differentiation is a hot topic.EGb761 is extracted from the leaves of the Ginkgo biloba tree.It is used worldwide and is becoming one of the focuses of stem cell research.Studies have shown that EGb761 can antagonize oxygen free radicals,stabilize cell membranes,promote neurogenesis and synaptogenesis,increase the level of brain-derived neurotrophic factors,and replicate the environment required during the differentiation of stem cells into nerve cells.This offers the possibility of using EGb761 to induce the differentiation of stem cells,facilitating stem cell transplantation.To provide a comprehensive reference for the future application of EGb761 in stem cell therapy,we reviewed studies investigating the influence of EGb761 on stem cells.These started with the composition and neuropharmacology of EGb761,and eventually led to the finding that EGb761 and some of its important components play important roles in the differentiation of stem cells and the protection of a beneficial microenvironment for stem cell transplantation.

A ginkgo biloba extract promotes proliferation of endogenous neural stem cells in vascular dementia rats

The ginkgo biloba extract EGb761 improves memory loss and cognitive impairments in patients with senile dementia. It also promotes proliferation of neural stem cells in the subventricular zone in Parkinson＇s disease model mice and in the hippocampal zone of young epileptic rats. However, it remains unclear whether EGb761 enhances proliferation of endogenous neural stem cells in the brain of rats with vascular dementia. In this study, a vascular dementia model was established by repeatedly clipping and reperfusing the bilateral common carotid arteries of rats in combination with an intraperitoneal injection of a sodium nitroprusside solution. Seven days after establishing the model, rats were intragastrically given EGb761 at 50 mg/kg per day. Learning and memory abilities were assessed using the Morris water maze and proliferation of endogenous neural stem cells in the subventricular zone and dentate gyrus were labeled by 5-bromo-2-deoxyuridine immunofluorescence in all rats at 15 days, and 1, 2, and 4 months after model establishment. The escape latencies in Morris water maze tests of rats with vascular dementia after EGb761 treatment were significantly shorter than the model group. Immunofluorescence staining showed that the number and proliferation of 5-bromo-2-deoxyuridine-positive cells in the subventricular zone and dentate gyrus of the EGb761-treated group were significantly higher than in the model group. These experimental findings suggest that EGb761 enhances proliferation of neural stem cells in the subventricular zone and dentate gyrus, and significantly improves learning and memory in rats with vascular dementia.

Effects of resveratrol on hydrogen peroxide-induced oxidative stress in embryonic neural stem cells

Resveratrol, a natural phenolic compound, has been shown to prevent cardiovascular diseases and cancer and exhibit neuroprotective effects. In this study, we examined the neuroprotective and antJoxJdant effects of resveratrol against hydrogen peroxide in embryonic neural stem cells. Hydrogen peroxide treatment alone increased catalase and glutathione peroxidase activities but did not change superoxide dismutase levels compared with hydrogen peroxide ＋ resveratrol treatment. Nitric oxide synthase activity and concomitant nitric oxide levels increased in response to hydrogen peroxide treatment. Conversely, resveratrol treatment decreased nitric oxide synthase activity and nitric oxide levels. Resveratrol also attenuated hydrogen peroxide-induced nuclear or mitochondrial DNA damage. We propose that resveratrol may be a promising agent for protecting embryonic neural stem cells because of its potential to decrease oxidative stress by inducing higher activity of antioxidant enzymes, decreasing nitric oxide production and nitric oxide synthase activity, and alleviating both nuclear and mitochondrial DNA damage.

Ocular manifestations and quality of life in patients after hematopoietic stem cell transplantation

AIM:To explore the relationship between ocular and systemic conditions and the impact of ocular complications on the quality of life(QOL)in patients after allogeneic hematopoietic stem cell transplantation(ALLO-HSCT).METHODS:Forty-four patients with severe hematopoietic disease were enrolled after ALLO-HSCT at our center from July 2018 to October 2020.They completed two questionnaires:the Ocular Surface Disease Index(OSDI)and the quality-of-life scale for Chinese patients with visual impairment(SQOL-DV1).Ocular conditions and systemic conditions were also assessed.RESULTS:Eye damage was correlated with total bilirubin(P=0.005),and gamma-glutamyl transferase(GGT)(P=0.021).There was no significant correlation between the overall QOL score and OSDI(P=0.8226)or SQOLDV1(P=0.9526)scores.The OSDI and the overall QOL score were not correlated with ocular conditions,including best-corrected visual acuity(BCVA),intraocular pressure,Schirmer tear test II,sodium fluorescein staining,tear film breakup time,and tear meniscus height.SQOLDV1 was correlated with BCVA(P=0.0007),sodium fluorescein staining(P=0.007),and tear film breakup time(P=0.0146).CONCLUSION:In some patients,early ocular symptoms are not evident after ALLO-HSCT,while ocular surface complications can be observed after a comprehensive ophthalmological examination.Especially for those with elevated total bilirubin or GGT,regular ophthalmic follow-up visits are essential to diagnose and treat ocular graft versus host disease(o GVHD),especially for patients with elevated total bilirubin or GGT.

Fu-Zheng-Yi-Liu Formula inhibits the stem cells and metastasis of prostate cancer via tumor-associated macrophages/C-C motif chemokine ligand 5 pathway in tumor microenvironment

Prostate cancer(PCa)is the second most common malignancy among men globally.The Fu-Zheng-Yi-Liu(FZYL)Formula has been widely utilized in the treatment of PCa.This study investigates whether the FZYL Formula can inhibit PCa by tar-geting the TAMs/CCL5 pathway.We conducted in vitro co-cultures and in vivo co-injections of PCa cells and TAMs to mimic their in-teraction.Results showed that the FZYL Formula significantly reduced the proliferation,colony formation,subpopulations of PCSCs,and sphere-formation efficacy of PCa cells,even in the presence of TAM co-culture.Additionally,the Formula markedly decreased the migration,invasion,and epithelial-mesenchymal transition(EMT)of PCa cells induced by TAMs.The FZYL Formula also reversed M2 phenotype polarization in TAMs and dose-dependently reduced their CCL5 expression and secretion,with minimal cytotoxicity observed.Mechanistic studies confirmed that the TAMs/CCL5 axis is a critical target of the FZYL Formula,as the addition of exogen-ous CCL5 partially reversed the formula’s inhibitory effects on PCSCs self-renewal in the co-culture system.Importantly,the Formula also significantly inhibited the growth of PCa xenografts,bone metastasis,and PCSCs activity in vivo by targeting the TAMs/CCL5 pathway.Overall,this study not only elucidates the immunomodulatory mechanism of the FZYL Formula in PCa therapy but also highlights the TAMs/CCL5 axis as a promising therapeutic target.

Buyang Huanwu Decoction regulates neural stem cell behavior in ischemic brain

The traditional Chinese medicine Buyang Huanwu Decoction has been shown to improve the neu- rological function of patients with stroke. However, the precise mechanisms underlying its effect remain poorly understood. In this study, we established a rat model of cerebral ischemia by middle cerebral artery occlusion and intragastrically administered 5 g/kg Buyang Huanwu Decoction, once per day, for 1, 7, 14 and 28 days after cerebral ischemia. Immunohistochemical staining revealed a number of cells positive for the neural stem cell marker nestin in the cerebral cortex, the subven- tricular zone and the ipsilateral hippocampal dentate gyrus in rat models of cerebral ischemia. Buyang Huanwu Decoction significantly increased the number of cells positive for 5-bromodeoxyuridine （BrdU）, a cell proliferation-related marker, microtubule-associated protein-2, a marker of neuronal differentiation, and growth-associated protein 43, a marker of synaptic plasticity in the ischemic rat cerebral regions. The number of positive cells peaked at 14 and 28 days after intragastric administration of Buyang Huanwu Decoction. These findings suggest that Buyang Huanwu Decoction can promote the proliferation and differentiation of neural stem cells and en- hance synaptic plasticity in ischemic rat brain tissue.

Combined acupuncture and HuangDiSan treatment affects behavior and synaptophysin levels in the hippocampus of senescence-accelerated mouse prone 8 after neural stem cell transplantation

Sanjiao acupuncture and HuangDiSan can promote the proliferation, migration and differentiation of exogenous neural stem cells in senescence-accelerated mouse prone 8 （SAMP8） mice and can improve learning and memory impairment and behavioral function in dementia-model mice. Thus, we sought to determine whether Sanjiao acupuncture and HuangDiSan can elevate the effect of neural stem cell transplantation in Alzheimer’s disease model mice. Sanjiao acupuncture was used to stimulate Danzhong （CV17）, Zhongwan （CV12）,Qihai （CV6）, bilateral Xuehai （SP10） and bilateral Zusanli （ST36） 15 days before and after implantation of neural stem cells （5 × 10^5） into the hippocampal dentate gyrus of SAMP8 mice. Simultaneously, 0.2 mL HuangDiSan, containing Rehmannia Root and Chinese Angelica,was intragastrically administered. Our results demonstrated that compared with mice undergoing neural stem cell transplantation alone,learning ability was significantly improved and synaptophysin mRNA and protein levels were greatly increased in the hippocampus of mice undergoing both Sanjiao acupuncture and intragastric administration of HuangDiSan. We conclude that the combination of Sanjiao acupuncture and HuangDiSan can effectively improve dementia symptoms in mice, and the mechanism of this action might be related to the regulation of synaptophysin expression.

Zhichan decoction induces differentiation of dopaminergic neurons in Parkinson's disease rats after neural stem cell transplantation

The goal of this study was to increase the dopamine content and reduce dopaminergic metabolites in the brain of Parkinson’s disease rats. Using high-performance liquid chromatography, we found that dopamine and dopaminergic metabolite（dihydroxyphenylacetic acid and homovanillic acid） content in the midbrain of Parkinson’s disease rats was increased after neural stem cell transplantation ＋ Zhichan decoction, compared with neural stem cell transplantation alone. Our genetic algorithm results show that dihydroxyphenylacetic acid and homovanillic acid levels achieve global optimization. Neural stem cell transplantation ＋ Zhichan decoction increased dihydroxyphenylacetic acid levels up to 10-fold, while transplantation alone resulted in a 3-fold increment. Homovanillic acid levels showed no apparent change. Our experimental findings show that after neural stem cell transplantation in Parkinson’s disease rats, Zhichan decoction can promote differentiation of neural stem cells into dopaminergic neurons.

Neural stem cell proliferation and differentiation in a neonatal rat model of hypoxia/ischemia injury Acupuncture at Ren,Du,and urinary bladder meridians

BACKGROUND： Acupuncture improves the prognosis of neonatal hypoxic-ischemic encephalopathy （HIE）. However, the cytological mechanism of acupuncture therapy remains poorly understood. In situ neural stem cell （NSC） proliferation theory proposes that the proliferation and differentiation of NSCs plays an important role in HIE treatment with acupuncture. OBJECTIVE： To investigate NSC proliferation and differentiation in the brain of a rat model of HIE during acupuncture at Ren, Du, and urinary bladder meridians. DESIGN, TIME AND SEB＇ING： A randomized, controlled animal experiment was performed at the Central Laboratory of Shantou University Medical College from July 2005 to June 2009. MATERIALS： A 32# 1-cun stainless steel acupuncture needle was purchased from Suzhou Acupuncture Supplies Co. Ltd., China.METHODS： A total of 90 Sprague-Dawley rats, aged 7 days, were randomly assigned to acupuncture, model and normal groups, with 30 animals in each group. Animals in acupuncture and model groups were subjected to left common carotid artery ligation followed by hypoxia for 2 hours to establish neonatal HIE models. Acupuncture group rats underwent acupuncture at Ren, Du, and urinary bladder meridians, once a day. MAIN OUTCOME MEASURES： The number, appearance, and distribution of bromodeoxyuridine （BrdU）-positive cells in the cerebral cortex and hippocampus of each group were compared. In addition, NSC differentiation in the occipital cortex and hippocampal dentate gyrus 40 days following model establishment was detected.RESULTS： BrdU-positive cells were dispersed in the cerebral cortex and hippocampus. The number of BrdU-positive cells in occipital cortex and hippocampal dentate gyrus of HIE rats remained unchanged following 3 and 7 days of acupuncture, but a significant increase was detected on days 14 and 28 （P 〈 0.01 or P 〈 0.05）. At 40 days, immunofluorescence showed that a majority of BrdU-positive cells were co-lableled with the neuron marker, and neuron specific enolase, and a few were co-labeled with the astrocyte marker, and glial fibrillary acidic protein. CONCLUSION： Acupuncture at Ren, Du, and urinary bladder meridians promoted NSC proliferation in the occipital cortex and hippocampal dentate gyrus of HIE rats. Moreover, acupuncture-induced neoformative NSCs mostly differentiated into neurons.

中医药调控胃干细胞对胃癌前疾病作用的研究进展

胃干细胞是存在于胃组织中的成体干细胞,具有自我更新和定向分化潜能。最新研究表明,胃干细胞的增殖和分化影响胃癌前疾病的发病、病理改变及预后。近年来,中医药对胃干细胞调控作用的研究取得了进展,文献报道显示,胃干细胞功能特征与中医理论存在一定的相关性,中医药能通过影响胃干细胞标志物表达、调控胃干细胞相关信号通路的异常以及对癌变胃干细胞增殖的影响而发挥对胃溃疡、慢性萎缩性胃炎(Chronic Atrophic Gastritis,CAG)等胃癌前疾病的生物学作用。就近10年上述内容的相关研究进展进行综述。

Advances in mesenchymal stem cells combined with traditional Chinese medicine therapy for liver fibrosis

Liver fibrosis is a primary cause of liver cirrhosis, and even hepatocarcinoma. Recently, the usage of mesenchyrnal stem cells （MSCs） has been investigated to improve liver fibrosis. It has been reported that the differentiation, proliferation and migration of MSCs can be regulated by traditional Chinese medicine treatment; however, the mechanisms are still unclear. In this article, the authors review the characteristics of MSCs such as multidirectional differentiation and homing, and its application in animal experiments and clinical trials. The authors also list areas that need further investigation, and look at the future prospects of clinical application of MSCs.

Traditional Chinese medicine targeting cancer stem cells as an alternative treatment for hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is a prevalent and highly malignant cancer throughout the world.Effective treatment of this disease is impeded by the high rate of metastasis, recurrence, and chemoresistance. Recent studies have revealed the close relationship between the malignant phenotype of HCC and cancer stem cells(CSCs). Therefore, CSC-targeted therapy is considered a promising strategy to eradicate HCC. Traditional Chinese medicine(TCM) can be effective in preventing recurrence and metastasis of some advanced HCC. A growing amount of literature has discovered that extracts or compounds derived from TCM exert an anti-CSC effect. This review introduces some formulas and chemical compounds derived from TCMs that have been reported to inhibit CSCs of HCC;these TCM-related drugs may help to provide an alternative approach to help manage cancers, especially for HCC which has a great potential of metastasis, recurrence, and chemoresistance.

造血干细胞移植患者中医序贯式运动方案的构建及应用

目的探讨中医序贯式运动方案对造血干细胞移植患者的康复效果。方法干预小组基于循证方法学,构建造血干细胞移植患者序贯式中医运动方案。选取44例患者作为研究对象,将患者随机分为干预组和对照组各22例。对照组实施常规造血干细胞移植运动康复方案,干预组在此基础上实施序贯式中医运动康复方案。比较两组不同时间简易体能状况、疲劳严重程度、身体质量指数、改良Barthel指数和运动康复过程中不良事件发生率、运动康复依从性。结果移植后14 d、28 d,干预组体能状况、疲劳严重程度、改良Barthel指数和运动康复依从性评分显著优于对照组(均P<0.05),均未发生运动相关不良事件。结论对造血干细胞移植患者实施中医序惯运动方案可行和安全,可提高造血干细胞移植患者运动能力,促进康复。

Essential Role of Chinese Medicines in Mesenchymal Stem Cells Transplantation for Treatment of Ischemic Stroke

Ischemic stroke accounts for the majority of all strokes and has been primary causes of long-term disability and mortality in worldwide. Mesenchymal stem cell(MSC) therapy suggests significantly improved effects on neurological functional outcome, neurogenesis, angiogenesis, blood-brain barrier permeability, inflammatory injury, neuroprotection and so on, following stroke. However, the occurrence of adverse effects results in restriction of the therapy. Chinese medicine accumulates abundant clinical experiences on stroke for over two thousand years, and some formulae and active ingredients of Chinese medicines have presented obvious efficacies in clinical treatment. Therefore, based on Chinese medicine theory, we provide some ideas of screening agents for combination treatment of Chinese medicines and MSC for ischemic stroke, and summarize the potentials of Chinese medicines in MSC treatment and analyze the feasibilities of Chinese medicines against side effects of MSC therapy. Consequently, we propose Chinese medicines combing with MSC should be a promising approach to clinical stroke treatment in future.

Treatment of Cerebral Ischemia with Combination of Bone Marrow-Derived Mesenchymal Stem Cells and Chinese Medicine

Many laboratories have been attempting to integrate Chinese medicine（CM） with the research of stem cells in order to explore this promising frontier.Studies on the combination of CM and bone marrow-derived mesenchymal stem cells（BMSCs） have found that some effective components from CM could activate endogenous stem cells and induce stem cells to differentiate into neural-like cells in vitro and promote angiogenesis.This review summarized the latest research findings of BMSCs and their application combined with CM in the treatment of cerebral ischemia.

Application of Chinese Herbal Medicines to Revitalize Adult Stem Cells for Tissue Regeneration

It has been established in the recent several decades that adult stem cells play a crucial role in tissue renewal and regeneration. Adult stem cells locate in certain organs can differentiate into functional entities such as macrophages and bone cells. Hematopoietic stem cells （HSCs） and mesenchymal stem cells （MSCs） are two of the most important populations of adult stem cells. The application of these stem cells offers a new insight in treating various pathological conditions, through replenishing cells of specific functions by turning on or off the differentiating program within quiescent stem cell niches. Apart from that, they are also capable to travel through the circulation, migrate to injury sites and differentiate to enhance regeneration process. Recently, Chinese medicine （CM） has shown to be potential candidates to activate adult stem cells for tissue regeneration. This review summarizes our own, as well as others＇ findings concerning the use of Chineseherbal medicine in the regulation processes of adult stem cells differentiation and their movement in tissue repair and rejuvenation. A number of Chinese herbs are used as therapeutic agents and presumably preventive agents on metabolic disorders. In our opinion, the activation of adult stem cells self-regeneration not only provides a novel way to repair tissue damage, but also reduces the use of targeted drug that adversely altering the normal metabolism of human subjects.

中药诱导干细胞在骨组织工程学中应用的研究概况

随着组织工程学的飞速发展以及科研人员的不断深入研究发现,用中药诱导干细胞在组织工程学中修复骨缺损具有一定的优势。骨组织工程学因具有良好的组织相容性、生物降解材料降解性而成为了研究的热点。近年来,骨组织工程技术的不断发展为修复骨缺损带来了希望,而干细胞移植是组织工程学中非常重要的环节之一,因其具有能够在特定条件下分化为不同类型细胞的能力,所以对于组织器官的损伤修复具有重要意义。而单纯利用干细胞治疗骨缺损疾病则存在治疗周期延长、靶向性不高等缺陷。中药参与治疗可促进干细胞增殖、诱导干细胞定向分化、促进移植后的干细胞定向迁移,从而缩短治疗周期并增强靶向性,可大大提高临床治疗效果。基于此,文章以中药诱导干细胞在骨组织工程学中应用的最新研究进展为契入点进行综述,探讨中药诱导干细胞在骨组织工程学中发挥的重要作用。

The Mobilization of Autologous Bone Marrow Stem Cells in the Treatment of Heart Failure with Chinese Medicine

Heart failure （HF） is a severe heart disease. The use of autologous bone marrow stem cells （BMCs） mobilization in the treatment of HF has been a hot topic to research both in Western medicine and Chinese medicine （CM）. There are many clinical trials and experiments on study of BMCs mobilization for HF therapy, including integrative medicine. The effect of BMCs mobilization is favorable for cardiac repair, while some advantages of CM support the advanced study of its application in BMCs mobilization to treat HF. In addition, with mechanisms of autologous BMCs mobilization for the treatment of HF that will be revealed in the future, especially stem cells niches, integrative medicine would play an important role in this clinical thought of therapy model gradually. Simultaneously, CM should adapt the new approaches of stem cells progresses on HF treatment as holding characteristics of itself.