Mesenchymal stem cell therapy for liver fibrosis need“partner”:Results based on a meta-analysis of preclinical studies

BACKGROUND The efficacy of mesenchymal stem cells(MSCs)in treating liver fibrosis has been demonstrated in several clinical studies.However,their low survival and liver implantation rates remain problematic.In recent years,a large number of studies in animal models of liver fibrosis have shown that MSCs combined with drugs can improve the efficacy of MSCs in the treatment of liver fibrosis alone and inhibit its progression to end-stage liver disease.This has inspired new ways of thinking about treating liver fibrosis.AIM To investigate the effectiveness and mechanisms of MSCs combined with drugs in treating liver fibrosis.METHODS Data sources included four electronic databases and were constructed until January 2024.The subjects,interventions,comparators,outcomes,and study design principle were used to screen the literature,and the quality of the literature was evaluated to assess the risk of bias.Relevant randomised controlled trials were selected,and the final 13 studies were included in the final study.RESULTS A total of 13 studies were included after screening.Pooled analysis showed that MSCs combined with drug therapy significantly improved liver function,promoted the repair of damaged liver tissues,reduced the level of liver fibrosis-related indexes,and effectively ameliorated hepatic fibrosis by modulating the hepatic inflammatory microenvironment,promoting the homing of MSCs,and regulating the relevant signaling pathways,and the treatment efficacy was superior to MSCs alone.However,the combined treatment statistics showed no amelioration in serum albumin levels(standardized mean difference=0.77,95%confidence interval:-0.13 to 1.68,P=0.09).CONCLUSION In conclusion,MSCs combined with drugs for treating liver fibrosis effectively make up for the shortcomings of MSCs in their therapeutic effects.However,due to the different drugs,the treatment mechanism and effect also differ.Therefore,more randomized controlled trials are needed to compare the therapeutic efficacy of different drugs in combination with MSCs,aiming to select the“best companion”of MSCs in treating hepatic fibrosis.

Preventive electroacupuncture reduces cognitive deficits in a rat model of D-galactose-induced aging

Acupuncture can reduce cognitive deficits in Alzheimer’s disease.However,whether electroacupuncture can prevent or alleviate the cognitive deficits in animal models of aging remains poorly understood.Studies have shown that disordered epigenetic modifications play a critical role in age-related cognitive decline.Therefore,we hypothesized that preventive electroacupuncture might improve cognitive functions during aging by regulating epigenetic modifications.A rat model of aging was produced by intraperitoneal injection of 120 mg/kg D-galactose for 8 weeks.Baihui and Shenshu acupoints were stimulated by electroacupuncture for 8 weeks from the first day of D-galactose administration.Preventive electroacupuncture alleviated memory impairment,decreased tau hyperphosphorylation,and reduced glycogen synthase kinase-3βprotein and mRNA expression levels in the brainstem dorsal raphe nucleus,where intracellular neurofibrillary tangle lesions first occur.In addition,the DNA methylation level in the promoter region of the glycogen synthase kinase-3βgene was increased.The effects of preventive electroacupuncture were stronger than those of preventive acupuncture.Intraperitoneal injection of 0.4 mg/kg 5-aza-2ʹ-deoxycytidine,an inhibitor of DNA methyltransferase that blocks epigenetic modifications,antagonized the effects of preventive electroacupuncture.Our results suggest that preventive electroacupuncture treatment alleviates cognitive impairment in aging rats probably by affecting the epigenetic modification of the glycogen synthase kinase-3βgene in the dorsal raphe nucleus.This study was approved by the Animal Ethics Committee of Hubei University of Chinese Medicine,China(approval No.HUCMS201712001)on November 28,2017.

Muse cells decrease the neuroinflammatory response by modulating the proportion of M1 and M2 microglia in vitro

Neuroinflammation hinders repair of the central nervous system(CNS).Stem cell transplantation is a very promising approach for treatment of CNS injuries.However,it is difficult to select seed cells that can both facilitate nerve regeneration and improve the microenvironment in the CNS.In this study,we isolated multilineage-differentiating stress-enduring(Muse)cells from bone marrow mesenchymal stem cells.We explored the anti-inflammatory effect and mechanism of Muse cells in vitro by coculture of Muse cells with lipopolysaccharide-stimulated microglia.Our results showed that Muse cells effectively reduced the transcription and secretion of tumor necrosis factorαand interleukin-1βand increased the expression of transforming growth factor-βand interleukin-10 in microglia.In addition,Muse cells decreased the number of M1 microglia and increased the proportion of M2 microglia in an inflammatory environment more effectively than bone marrow mesenchymal stem cells.We also show that Muse cells inhibited the protein expression of toll-like receptor 4(TLR4)and myeloid differentiation primary response protein(MyD88)and inhibited the expression of the phosphorylated forms of transcription factor p65,nuclear factor(NF)-κB inhibitor alpha,and p38 mitogen-activated protein kinase(MAPK)in microglia.Therefore,we suggest Muse cells cause antineuroinflammatory effects by inhibition of the TLR4/MyD88/NF-κB and p38 MAPK signaling pathways in microglia.Our results shed light on the function of Muse cells in relation to CNS diseases and provide insight into the selection of seed cells.

骨肉瘤的分化疗法与研究进展

骨肉瘤是一种恶性程度极高的骨肿瘤,常发于儿童和青少年。虽然传统外科手术联合新辅助化疗可提高患者5年生存率,但当骨肉瘤发生复发和转移时,患者往往会面临死亡的威胁。约10%~20%患者被确诊为骨肉瘤时已伴随肿瘤肺部转移。此外,大剂量的化疗药物存在副作用,给患者的预后生活质量造成影响,因而学者们提出一些新的治疗方法和研究方向。该文就骨肉瘤的诱导分化疗法、骨肉瘤干细胞及其成骨分化研究做一综述。

Axonotmesis-evoked plantar vasodilatation as a novel assessment of C-fiber afferent function after sciatic nerve injury in rats

Quantitative assessment of the recovery of nerve function, especially sensory and autonomic nerve function, remains a challenge in the field of nerve regeneration research. We previously found that neural control of vasomotor activity could be potentially harnessed to evaluate nerve function. In the present study, five different models of left sciatic nerve injury in rats were established: nerve crush injury, nerve transection/ suturing, nerve defect/autografting, nerve defect/conduit repair, and nerve defect/non-regeneration. Laser Doppler perfusion imaging was used to analyze blood perfusion of the hind feet. The toe pinch test and walking track analysis were used to assess sensory and motor functions of the rat hind limb, respectively. Transmission electron microscopy was used to observe the density of unmyelinated axons in the injured sciatic nerve. Our results showed that axonotmesis-evoked vasodilatation in the foot 6 months after nerve injury/repair recovered to normal levels in the nerve crush injury group and partially in the other three repair groups;whereas the nerve defect/non-regeneration group exhibited no recovery in vasodilatation. Furthermore, the recovery index of axonotmesis-evoked vasodilatation was positively correlated with toe pinch reflex scores and the density of unmyelinated nerve fibers in the regenerated nerve. As C-fiber afferents are predominantly responsible for dilatation of the superficial vasculature in the glabrous skin in rats, the present findings indicate that axonotmesis-evoked vasodilatation can be used as a novel way to assess C-afferent function recovery after peripheral nerve injury. This study was approved by the Ethics Committee for Laboratory Animals of Nantong University of China (approval No. 20130410-006) on April 10, 2013.

A method of determining nonlinear large strain consolidation parameters of dredged clays

A method of obtaining the large strain consolidation parameters of dredged clays considering the influence of the initial water content is investigated in this study. According to the test results of remolded clays with high initial water contents reported by Hong et al. （2010）, a relationship between the void ratio （e） and effective stress （a3 is established. Furthermore, based on the available permeability data from the literature, a new relationship between the permeability coefficient （k） and the ratio （e/eL） of the void ratio to the void ratio at the liquid limit （eL） is proposed. The new proposed expression considering the initial water content improves the e-k equation established by Nagaraj et al. （1994）. Finally, the influence of the initial void ratio and effective stress on the large strain consolidation coefficient g（e） defined by Gibson et al. （1981） and k/（1 ＋e） in large strain analysis is discussed. The results show that, under a constant effective stress, the value of k/（1 ＋e） increases with the initial void ratio. The large strain consolidation coefficient shows the law of segmentation change, which decreases with the increase of the effective stress when the effective stress is less than the remolded yield stress, but increases rapidly with the effective stress when the effective stress is larger than the remolded yield stress.

Electroacupuncture Alleviates Memory Deficits in APP/PS1 Mice by Targeting Serotonergic Neurons in Dorsal Raphe Nucleus

Objective Alzheimer’s disease(AD)has become a significant global concern,but effective drugs able to slow down AD progression is still lacked.Electroacupuncture(EA)has been demonstrated to ameliorate cognitive impairment in individuals with AD.However,the underlying mechanisms remains poorly understood.This study aimed at examining the neuroprotective properties of EA and its potential mechanism of action against AD.Methods APP/PS1 transgenic mice were employed to evaluate the protective effects of EA on Shenshu(BL 23)and Baihui(GV 20).Chemogenetic manipulation was used to activate or inhibit serotonergic neurons within the dorsal raphe nucleus(DRN).Learning and memory abilities were assessed by the novel object recognition and Morris water maze tests.Golgi staining,western blot,and immunostaining were utilized to determine EA-induced neuroprotection.Results EA at Shenshu(BL 23)and Baihui(GV 20)effectively ameliorated learning and memory impairments in APP/PS1 mice.EA attenuated dendritic spine loss,increased the expression levels of PSD95,synaptophysin,and brain-derived neurotrophic factor in hippocampus.Activation of serotonergic neurons within the DRN can ameliorate cognitive deficits in AD by activating glutamatergic neurons mediated by 5-HT1B.Chemogenetic inhibition of serotonergic neurons in the DRN reversed the effects of EA on synaptic plasticity and memory.Conclusion EA can alleviate cognitive dysfunction in APP/PS1 mice by activating serotonergic neurons in the DRN.Further study is necessary to better understand how the serotonergic neurons-related neural circuits involves in EA-induced memory improvement in AD.

Advances in targeted drugs for allergic diseases

To the Editor:Since the first IgE monoclonal antibody was approved by the Food and Drug Administration in the USA in 2003,at least 14 kinds of targeted drugs are in the clinical application or pre-clinical trials.The two monoclonal antibodies targeting IgE are omalizumab and ligelizumab.Four drugs targeting interleukin 4(IL-4)or IL-4R are pascolizumab,pitrakinra,altrakincept,and dupilumab.Three monoclonal antibodies targeting IL-5/IL-5R are mepolizumab,reslizumab,and benralizumab.Two monoclonal antibodies targeting IL-13 are lebrikizumab and tralokinumab.The monoclonal antibody targeting thymic stromal lymphopoietin(TSLP)is tezepelumab.Th2 cytokine inhibitor is mesylate.These targeted drugs have achieved good results,but most of them are still in the pre-clinical stage.This article reviews the history,marketing situation,indications,contraindications,efficacy,and safety of these targeted drugs.

Development and Evaluation of a PCR Kit for Authentication of Panax quinquefolius L.with PCR-Restriction Fragment Length Polymorphism

Panax quinquefolius L.(American ginseng)and Panax ginseng C.A.Meyer are famous herbal medicines.Accurate authentication of the species has grown to be a significant impact.This study aims to develop a PCR kit for the authentication of Panax quinquefolius L.and Panax ginseng based on the nuclear internal transcribed spacer 2(ITS2)gene with the improved PCR-restriction fragment length polymorphism(PCR-RFLP)method.The reagent components in the development work were prepared and determined by the kit consisting of the DNA extraction,PCR amplification,and restriction enzyme digestion systems.A total of 21 batches of Panax quinquefolius L.and Panax ginseng samples collected from different areas were validated.Their specificity,stability,and repeatability were evaluated.The purity of genomic DNA extracted was 1.73±0.13 according to the ratio of A_(260)/A_(280),and the mass concentration was 3.15±0.22μg/g(using the kit).PCR amplicons of Panax quinquefolius L.and Panax ginseng were 122 bp in length.After the PCR products were digested by restriction enzyme Hinf I,a distinct pattern exhibited in the species of Panax quinquefolius L.with two fragments of 40 bp and 80 bp respectively,whereas those from Panax ginseng in addition to adulterated samples could not.Evaluation confirmed that the DNA kit results were stable and repeatable after 10,15,and 20 freeze-thaw cycles:the evaluation was 100%specific.The DNA kit proposed in the study can be used for the identification of Panax quinquefolius L.