Safety of tranexamic acid in surgically treated isolated spine trauma

BACKGROUND Tranexamic acid(TXA),a synthetic antifibrinolytic drug,effectively reduces blood loss by inhibiting plasmin-induced fibrin breakdown.This is the first study in the United Kingdom to investigate the effectiveness of TXA in the surgical management of isolated spine trauma.AIM To assess the safety of TXA in isolated spine trauma.The primary and secondary outcomes are to assess the rate of thromboembolic events and to evaluate blood loss and the incidence of blood transfusion,respectively.METHODS This prospective observational study included patients aged≥17 years with isolated spine trauma requiring surgical intervention over a 6-month period at two major trauma centers in the United Kingdom.RESULTS We identified 67 patients:26(39%)and 41(61%)received and did not receive TXA,respectively.Both groups were matched in terms of age,gender,American Society of Anesthesiologists grade,and mechanism of injury.A higher proportion of patients who received TXA had a subaxial cervical spine injury classification or thoracolumbar injury classification score>4(74%vs 56%).All patients in the TXA group underwent an open approach with a mean of 5 spinal levels involved and an average operative time of 203 min,compared with 24 patients(58%)in the non TXA group who underwent an open approach with an average of 3 spinal levels involved and a mean operative time of 159 min.Among patients who received TXA,blood loss was<150 and 150–300 mL in 8(31%)and 15(58%)patients,respectively.There were no cases of thromboembolic events in any patient who received TXA.CONCLUSION Our study demonstrated that TXA is safe for isolated spine trauma.It is challenging to determine whether TXA effectively reduces blood loss because most surgeons prefer TXA for open or multilevel cases.Further,larger studies are necessary to explore the rate,dosage,and mode of administration of TXA.

Transforaminal Percutaneous Endoscopic Discectomy using Transforaminal Endoscopic Spine System technique: Pitfalls that a beginner should avoid

Transforaminal Percutaneous Endoscopic Discectomy(TPED) is a minimally invasive technique mainly used for the treatment of lumbar disc herniation from a lateral approach. Performed under local anesthesia, TPED has been proven to be a safe and effective technique which has been also associated with shorter rehabilitation period, reduced blood loss, trauma, and scar tissue compared to conventional procedures. However, the procedure should be performed by a spine surgeon experienced in the specific technique and capable of recognizing or avoiding various challenging conditions. In this review, pitfalls that a novice surgeon has to be mindful of, are reported and analyzed.

Cascaded quasi-zero stiffness nonlinear low-frequency vibration isolator inspired by human spine

Human motion induced vibration has very low frequency,ranging from 2 Hz to 5 Hz.Traditional vibration isolators are not effective in low-frequency regions due to the trade-off between the low natural frequency and the high load capacity.In this paper,inspired by the human spine,we propose a novel bionic human spine inspired quasi-zero stiffness(QZS)vibration isolator which consists of a cascaded multi-stage negative stiffness structure.The force and stiffness characteristics are investigated first,the dynamic model is established by Newton’s second law,and the isolation performance is analyzed by the harmonic balance method(HBM).Numerical results show that the bionic isolator can obtain better low-frequency isolation performance by increasing the number of negative structure stages,and reducing the damping values and external force values can obtain better low-frequency isolation performance.In comparison with the linear structure and existing traditional QZS isolator,the bionic spine isolator has better vibration isolation performance in low-frequency regions.It paves the way for the design of bionic ultra-low-frequency isolators and shows potential in many engineering applications.

Microglial depletion impairs glial scar formation and aggravates inflammation partly by inhibiting STAT3 phosphorylation in astrocytes after spinal cord injury

Astrocytes and microglia play an orchestrated role following spinal cord injury;however,the molecular mechanisms through which microglia regulate astrocytes after spinal cord injury are not yet fully understood.Herein,microglia were pharmacologically depleted and the effects on the astrocytic response were examined.We further explored the potential mechanisms involving the signal transducers and activators of transcription 3(STAT3)pathway.For in vivo experiments,we constructed a contusion spinal cord injury model in C57BL/6 mice.To deplete microglia,all mice were treated with colony-stimulating factor 1 receptor inhibitor PLX3397,starting 2 weeks prior to surgery until they were sacrificed.Cell proliferation was examined by 5-ethynyl-2-deoxyuridine(EdU)and three pivotal inflammatory cytokines were detected by a specific Bio-Plex Pro^(TM) Reagent Kit.Locomotor function,neuroinflammation,astrocyte activation and phosphorylated STAT3(pSTAT3,a maker of activation of STAT3 signaling)levels were determined.For in vitro experiments,a microglia and astrocyte coculture system was established,and the small molecule STA21,which blocks STAT3 activation,was applied to investigate whether STAT3 signaling is involved in mediating astrocyte proliferation induced by microglia.PLX3397 administration disrupted glial scar formation,increased inflammatory spillover,induced diffuse tissue damage and impaired functional recovery after spinal cord injury.Microglial depletion markedly reduced EdU+proliferating cells,especially proliferating astrocytes at 7 days after spinal cord injury.RNA sequencing analysis showed that the JAK/STAT3 pathway was downregulated in mice treated with PLX3397.Double immunofluorescence staining confirmed that PLX3397 significantly decreased STAT3 expression in astrocytes.Importantly,in vitro coculture of astrocytes and microglia showed that microglia-induced astrocyte proliferation was abolished by STA21 administration.These findings suggest that microglial depletion impaired astrocyte proliferation and astrocytic scar formation,and induced inflammatory diffusion partly by inhibiting STAT3 phosphorylation in astrocytes following spinal cord injury.

A novel molecular classification method for osteosarcoma based on tumor cell differentiation trajectories

Subclassification of tumors based on molecular features may facilitate therapeutic choice and increase the response rate of cancer patients.However,the highly complex cell origin involved in osteosarcoma(OS)limits the utility of traditional bulk RNA sequencing for OS subclassification.Single-cell RNA sequencing(sc RNA-seq)holds great promise for identifying cell heterogeneity.However,this technique has rarely been used in the study of tumor subclassification.By analyzing sc RNA-seq data for six conventional OS and nine cancellous bone(CB)samples,we identified 29 clusters in OS and CB samples and discovered three differentiation trajectories from the cancer stem cell(CSC)-like subset,which allowed us to classify OS samples into three groups.The classification model was further examined using the TARGET dataset.Each subgroup of OS had different prognoses and possible drug sensitivities,and OS cells in the three differentiation branches showed distinct interactions with other clusters in the OS microenvironment.In addition,we verified the classification model through IHC staining in 138 OS samples,revealing a worse prognosis for Group B patients.Furthermore,we describe the novel transcriptional program of CSCs and highlight the activation of EZH2 in CSCs of OS.These findings provide a novel subclassification method based on sc RNA-seq and shed new light on the molecular features of CSCs in OS and may serve as valuable references for precision treatment for and therapeutic development in OS.

Reduced non-CpG methylation is a potential epigenetic target after spinal cord injury

DNA methylation is a critical epigenetic regulator in the occurrence and development of diseases and is closely related to various functional responses in relation to spinal cord injury.To investigate the role of DNA methylation in spinal cord injury,we constructed a library with reduced-representation bisulfite sequencing data obtained at various time points(day 0-42)after spinal cord injury in mice.Global DNA methylation levels,specifically non-CpG(CHG and CHH)methylation levels,decreased modestly following spinal cord injury.Stages post-spinal cord injury were classified as early(day 0-3),intermediate(day7-14),and late(day 28-42)based on similarity and hie rarchical cluste ring of global DNA methylation patterns.The non-CpG methylation level,which included CHG and CHH methylation levels,was markedly reduced despite accounting for a minor proportion of total methylation abundance.At multiple genomic sites,including the 5’untranslated regions,promoter,exon,intron,and 3’untranslated regions,the non-CpG methylation level was markedly decreased following spinal cord injury,whereas the CpG methylation level remained unchanged at these locations.Approximately one-half of the differentially methylated regions were located in intergenic areas;the other differentially methylated regions in both CpG and non-CpG regions were cluste red in intron regions,where the DNA methylation level was highest.The function of genes associated with differentially methylated regions in promoter regions was also investigated.From Gene Ontology analysis results,DNA methylation was implicated in a number of essential functional responses to spinal cord injury,including neuronal synaptic connection creation and axon regeneration.Notably,neither CpG methylation nor non-CpG methylation was implicated in the functional response of glial or inflammatory cells.In summary,our work elucidated the dynamic pattern of DNA methylation in the spinal co rd following injury and identified reduced nonCpG methylation as an epigenetic target after spinal cord injury in mice.

2007年美国骨科医师年会脊柱分会场纪要

2007年2月14-18日，美国骨科医师年会（AAOS）在加利福尼亚州圣地亚哥的国际会议中心召开。参加本次会议代表来自北美洲、欧洲、亚洲、澳洲、中南美洲等共约4万余人。现将脊柱外科分会场主题作一简要总结汇报，与同道分享。

Neuroprotection and its molecular mechanism following spinal cord injury

Acute spinal cord injury initiates a complex cascade of molecular events termed ＇secondary injury＇, which leads to progressive degeneration ranging from early neuronal apoptosis at the lesion site to delayed degeneration of intact white matter tracts, and, ultimately, expansion of the initial injury. These secondary injury processes include, but are not limited to, inflammation, free radical-induced cell death glutamate excitotoxicity, phospholipase A2 activation, and induction of extrinsic and intrinsic apoptotic pathways, which are important targets in developing neuroprotective strategies for treatment of spinal cord injury. Recently, a number of studies have shown promising results on neuroprotection and recovery of function in rodent models of spinal cord injury using treatments that target secondary injury processes including inflammation, phospholipase A2 activation, and manipulation of the PTEN-AktJmTOR signaling pathway. The present review outlines our ongoing research on the molecular mechanisms of neuroprotection in experimental spinal cord injury and briefly summarizes our earlier findings on the therapeutic potential of pharmacological treatments in spinal cord injury.

Update on diagnosis and management of cuboid fractures

Cuboid fractures due to the particular bone anatomy and its protected location in the midfoot are rare, and they are usually associated with complex injuries of the foot. Clinical examination to diagnose these fractures should be detailed and the differential diagnosis, especially in the case of vague symptoms, should include the exclusion of all lateral foot pain causes. Conventional radiographs do not always reveal occult fractures, which can be under diagnosed especially in children. In this case, further investigation including magnetic resonance imaging or scintigraphy may be required. The treatment of these injuries depends on the particular fracture characteristics. Non-displaced isolated fractures of the cuboid bone can be effectively treated conservatively by immobilization and by avoiding weight bearing on the injured leg. In the case of shortening of the lateral column> 3 mm or articular displacement > 1 mm, surgical management of the fracture is mandatory in order to avoid negative biomechanical and functional consequences for the foot and adverse effects such as arthritis and stiffness as well as painful gait. In this review, an update on diagnosis and management of cuboid fractures is presented.

Is Premenstrual Syndrome a Uterine Inflammatory Disease? Retrospective Evaluation of an Etiologic Approach

Objective: To retrospectively evaluate the efficacy of local uterine antibiotic and anti-inflammatory injections combined with cryotherapy for the treatment of severe Premenstrual Syndrome (PMS) and Premenstrual Dysphoric Disorder (PMDD). To validate the hypothesis of a uterine infectious/inflammatory etiology of PMS/PMDD. Methods: Clinical files of 161 women sequentially treated from September 1995 to April 2005, were collected for study. A subset of 148 patients (mean: 36.7 ± 7.8 years, range: 20.1 - 53.8 years) were eligible for statistical analysis. The ten most relevant PMS symptoms, namely depression, irritability, anxiety, fatigue, headache, edema, breast tenderness, abdominal bloating, pelvic pain and dysmenorrhea, were self-rated before and three menstrual cycles after treatment, using a 0 to 5 scale. The treatment consisted of cervical stromal antibiotic/anti-inflammatory injections combined with intracervical cryotherapy. Scores were compared using non-parametric tests for matched samples. Results: Before treatment, mean severity scores for the 10 symptoms were 3.97 ± 1.17, 4.26 ± 0.88, 3.41 ± 1.23, 3.91 ± 0.94, 3.35 ± 1.71, 2.28 ± 1.69, 2.13 ± 1.63, 4.51 ± 0.63, 2.28 ± 1.30, and 2.28 ± 1.88, respectively. Mean values after treatment were 0.54 ± 0.91, 0.51 ± 0.91, 0.32 ± 0.70, 0.42 ± 0.74, 0.43 ± 0.96, 0.22 ± 0.53, 0.39 ± 0.73, 1.01 ± 0.94, 0.28 ± 0.69, and 0.44 ± 0.92. All tests were statistically significant (p < 0.01). Conclusion: Both PMS physical and psycho-affective symptoms respond to local anti-inflammatory and antibiotic treatment of the uterus, showing a stable improvement after the treatment has ended. The results of this study suggest that the clinical pattern of PMS can be explained as an inflammatory mediated response to uterine infectious or traumatic insults. Further evidence is urgently needed in order to validate this innovative approach for widespread use in severe PMS/ PMDD cases.

Inhibition of Cell Growth and Telomerase Activity in Osteosarcoma Cells by DN-hTERT

In order to study the effects of dominant negative human telomerase reverse transcriptase （DN-hTERT） on cell growth and telomerase activity in osteosarcoma cell line MG63, MG63 cells were transfected with DN-hTERT-IRES2-EGFP9 （DN） or IRES2-EGF （I, blank vector） with lipofectamine 2000. The stably transfected cells were selected with G-418. Cell growth properties were examined under a fluorescence microscope. The hTERT mRNA expression was detected by reverse transcription-polymerase chain reaction （RT-PCR）. Telomerase activities were measured by TRAP-ELISE. The tumorigenicity was studied with tumor xenografts by subcutaneous injection of cancer cells into nude mice. The results showed that cell growth was suppressed in MG63 cells transfected with DN-hTERT. The hTERT mRNA was increased in N-hTERT transfected-MG63 cells （MG63/DN）. The telomerase activity was 2.45±0.11 in MG63/DN cells, while 3.40±0.12 in the cells transfected with blank vector （MG63/I）, （P〈0.05）; DN-hTERT-expressing clones did not form tumors in 2 weeks, but the ratio of tumorigenesis was 30 % in nude mice bearing MG63/I （P〈0.01）. It was concluded that DN-hTERT could specifically inhibit the cell growth and telomerase activity in MG63 cells.

GH treatment, BMI and different genotypes in patients with Prader-Willi syndrome and scoliosis: Is there any relationship?

The purpose of this study is to try to find a protocol defining a clinical diagnostic procedure for the patients to be admitted to the authors’ Institute to receive treatment for either suspected or confirmed diagnosis of spine deformity in Prader-Willi syndrome (PWS). The aim is to evaluate every subject from the diagnostic point of view, assessing variability of clinical expression and evolution of spinal deformity in the light of the related genetic aspects, thus providing a univocal protocol. The present series only includes patients (18 cases) with PWS, 7 hospitalized for surgical treatment of scoliosis, 11 followed-up at the authors’ institute only for conservative treatment of scoliosis. Both BMI tracks (weight/height2) and BMI Z-score (only for children older than 2 years) were assessed. Moreover, the GH treatment was evaluated for each group of patients as follows: being administered, suspended or no treatment. Finally, the gene was compared with BMI. No relationship was observed either between GH treatment and mean BMI or between genetics and mean BMI. More patients should be seen by the authors to confirm or refute the current findings.

Calcaneal quantitative ultrasound-bone mineral density value for evaluating bone metabolism and bone turnover in patients with osteoporotic fracture

Objective:To study the calcaneal quantitative ultrasound-bone mineral density (QUS-BMD) value for evaluating bone metabolism and bone turnover in patients with osteoporotic fracture. Methods: A total of 150 patients who were diagnosed with osteoporotic fracture in Nuclear Industry 417 Hospital between January 2010 and March 2017 were selected as the fracture group of the research, and 70 subjects with normal bone mineral density confirmed by physical examination during the same period were selected as the control group of the research. QUS-BMD apparatus was used to measure bone mineral density of calcaneus, and the serum was collected to determine the biochemical indexes of bone metabolism and bone turnover. Results:QUS-BMD value as well as serum BALP, OC, OPG levels of fracture group was significantly lower than those of control group while serum TRACP5b, RANKL, PINP, PICP, CTX and NTX levels were significantly higher than those of control group;serum BALP, OC, OPG levels of patients with osteoporosis and osteopenia were significantly lower than those of subjects with normal bone mass while TRACP5b, RANKL, PINP, PICP, CTX and NTX levels were significantly higher than those of subjects with normal bone mass;serum BALP, OC, OPG levels of patients with osteoporosis was significantly lower than those of patients with osteoporosis while TRACP5b, RANKL, PINP, PICP, CTX and NTX levels were significantly higher than those of patients with osteoporosis.Conclusion:Calcaneal QUS-BMD is valuable for evaluating the bone metabolism activity and bone turnover process in patients with osteoporotic fracture.

Spinal cord injury:molecular mechanisms and therapeutic interventions

Spinal cord injury(SCI)remains a severe condition with an extremely high disability rate.The challenges of SCI repair include its complex pathological mechanisms and the difficulties of neural regeneration in the central nervous system.In the past few decades,researchers have attempted to completely elucidate the pathological mechanism of SCI and identify effective strategies to promote axon regeneration and neural circuit remodeling.

Pericytes may facilitate SARS-CoV-2 entry into the nervous system

Objective:Although the neurological and olfactory symptoms of coronavirus disease 2019 have been identified,the neurotropic properties of the causative virus,severe acute respiratory syndrome-associated coronavirus 2(SARS-CoV-2),remain unknown.We sought to identify the susceptible cell types and potential routes of SARS-CoV-2 entry into the central nervous system,olfactory system,and respiratory system.Methods:We collected single-cell RNA data from normal brain and nasal epithelium specimens,along with bronchial,tracheal,and lung specimens in public datasets.The susceptible cell types that express SARS-CoV-2 entry genes were identified using single-cell RNA sequencing and the expression of the key genes at protein levels was verified by immunohistochemistry.We compared the coexpression patterns of the entry receptor angiotensin-converting enzyme 2(ACE2)and the spike protein priming enzyme transmembrane serine protease(TMPRSS)/cathepsin L among the specimens.Results:The SARS-CoV-2 entry receptor ACE2 and the spike protein priming enzyme TMPRSS/cathepsin L were coexpressed by pericytes in brain tissue;this coexpression was confirmed by immunohistochemistry.In the nasal epithelium,ciliated cells and sustentacular cells exhibited strong coexpression of ACE2 and TMPRSS.Neurons and glia in the brain and nasal epithelium did not exhibit coexpression of ACE2 and TMPRSS.However,coexpression was present in ciliated cells,vascular smooth muscle cells,and fibroblasts in tracheal tissue;ciliated cells and goblet cells in bronchial tissue;and alveolar epithelium type 1 cells,AT2 cells,and ciliated cells in lung tissue.Conclusion:Neurological symptoms in patients with coronavirus disease 2019 could be associated with SARS-CoV-2 invasion across the blood-brain barrier via pericytes.Additionally,SARS-CoV-2-induced olfactory disorders could be the result of localized cell damage in the nasal epithelium.

Effect of spinal manipulation on degenerative scoliosis

OBJECTIVE:To investigate the effect of spinal manipulation(SM)on degenerative scoliosis by evaluating patients’visual analog scale(VAS)scores,Cobb angles,sagittal vertical axis(SVA),and apical vertebral rotation(AVR)and to explore factors that influence treatment effect.METHODS:A total of 55 patients with degenerative scoliosis received 4 weeks of SM.After treatment,patients were divided into two groups:the remission group(VAS score<40 mm)and the non-remission group(VAS score≥40 mm).Pre-versus post-treatment VAS scores,Cobb angles,SVA,and AVR were compared in each group and in the total population.Baseline data(sex,age,symptom characteristics,duration of symptoms,VAS score,Cobb angle,SVA,and AVR)were compared between groups.Factors influencing the post-treatment VAS score were explored with multiple linear regression analysis.RESULTS:No changes were found in the Cobb angle(P=0.722)or AVR(P=0.424)after intervention in the overall population.However,the SVA(P<0.001)and VAS score(P=0.000)changed significantly after treatment.Similar changes were observed in the remission group(n=29).Multiple linear regression revealed that the only factors influencing treatment effect were symptom characteristics,SVA,and VAS score.CONCLUSION:SM relieved pain and improved sagittal imbalance in patients with degenerative scoliosis.It did not lessen the severity of coronal curvature or vertebral rotation.Factors influencing the effect of SM included symptom characteristics,VAS score,and SVA.A larger randomized trial is needed to further confirm our results.

Effect of Static Load on the Nucleus Pulposus of Rabbit Intervertebral Disc Motion Segment in Ex vivo Organ Culture

Background：The development of mechanically active culture systems helps increase the understanding of the role of mechanical stress in intervertebral disc （IVD） degeneration.Motion segment cultures allow for preservation of the native IVD structure,and adjacent vertebral bodies facilitate the application and control of mechanical loads.The purpose of this study was to establish loading and organ culture methods for rabbit IVD motion segments to study the effect of static load on the whole disc organ.Methods：IVD motion segments were harvested from rabbit lumbar spines and cultured in no-loading 6-well plates （control conditions） or custom-made apparatuses under a constant,compressive load （3 kg,0.5 MPa） for up to 14 days.Tissue integrity,matrix synthesis,and the matrix gene expression profile were assessed after 3,7,and 14 days of culturing and compared with those of fresh tissues.Results：The results showed that ex vivo culturing of motion segments preserved tissue integrity under no-loading conditions for 14 days whereas the static load gradually destroyed the morphology after 3 days.Proteoglycan contents were decreased under both conditions,with a more obvious decrease under static load,and proteoglycan gene expression was also downregulated.However,under static load,immunohistochemical staining intensity and collagen Type Ⅱ alpha 1 （COL2A 1） gene expression were significantly enhanced （61.54 ± 5.91,P =0.035） and upregulated （1.195 ± 0.040,P =0.000）,respectively,compared with those in the controls （P 〈 0.05）.In contrast,under constant compression,these trends were reversed.Our initial results indicated that short-term static load stimulated the synthesis of collagen Type Ⅱ alpha l;however,sustained constant compression led to progressive degeneration and specifically to a decreased proteoglycan content.Conclusions：A loading and organ culture system for ex vivo rabbit IVD motion segments was developed.Using this system,we were able to study the effects of mechanical stimulation on the biology of IVDs,as well as the pathomechanics of IVD degeneration.

In vitro osteoclast-suppressing effect of sodium ibandronate

Background Bisphosphonates （BPs） have been reported to reduce local recurrence in giant cell tumor （GCT） of bone because of their osteoclast-suppressing effect; however, the optimal mode of delivery and the dose and duration of treatment of BPs remain to be established. To address these issues, it is first necessary to clarify the manner of action of BPs on osteoclasts. We herein evaluated the osteoclast-suppressing effect of sodium ibandronate in vitro. Methods Mouse osteoclasts （OCLs） were generated in vitro using mouse bone marrow mononuclear cells. First, various concentrations of sodium ibandronate and equal amounts of phosphate-buffered saline were added to cell culture media. The number of multinucleated cells （over three nuclei） was recorded in each group, OCL formation was compared and the most effective concentration of sodium ibandronate was determined. Then, high concentrations of sodium ibandronate were added to the experimental cell culture media; no ibandronate was given in the control group. Comparisons were made between the two groups in terms of OCL adhesion, migration, and bone resorption. Results OCL formation was suppressed by sodium ibandronate in vitro; the most pronounced effect was observed at the concentration of 10-5 mol/L. OCL migration and bone resorption were significantly suppressed at this concentration, though there was no effect on OCL adhesion. Conclusions Sodium ibandronate was effective in suppressing OCLs and decreasing resorption in GCT. The strong anti-OCL effectiveness at a high concentration in vitro indicates a topical mode of application.

The role of ubiquitination in tumorigenesis and targeted drug discovery

Ubiquitination,an important type of protein posttranslational modification(PTM),plays a crucial role in controlling substrate degradation and subsequently mediates the“quantity”and“quality”of various proteins,serving to ensure cell homeostasis and guarantee life activities.The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels(phosphorylation,acetylation,methylation,etc.)but also at the protein level(activators or repressors).When regulatory mechanisms are aberrant,the altered biological processes may subsequently induce serious human diseases,especially various types of cancer.In tumorigenesis,the altered biological processes involve tumor metabolism,the immunological tumor microenvironment(TME),cancer stem cell(CSC)stemness and so on.With regard to tumor metabolism,the ubiquitination of some key proteins such as RagA,mTOR,PTEN,AKT,c-Myc and P53 significantly regulates the activity of the mTORC1,AMPK and PTEN-AKT signaling pathways.In addition,ubiquitination in the TLR,RLR and STING-dependent signaling pathways also modulates the TME.Moreover,the ubiquitination of core stem cell regulator triplets(Nanog,Oct4 and Sox2)and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness.Based on the altered components,including the proteasome,E3 ligases,E1,E2 and deubiquitinases(DUBs),many molecular targeted drugs have been developed to combat cancer.Among them,small molecule inhibitors targeting the proteasome,such as bortezomib,carfilzomib,oprozomib and ixazomib,have achieved tangible success.In addition,MLN7243 and MLN4924(targeting the E1 enzyme),Leucettamol A and CC0651(targeting the E2 enzyme),nutlin and MI‐219(targeting the E3 enzyme),and compounds G5 and F6(targeting DUB activity)have also shown potential in preclinical cancer treatment.In this review,we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation,TME modulation and CSC stemness maintenance.Moreover,potential therapeutic targets for cancer are reviewed,as are the therapeutic effects of targeted drugs.

Houttuynia cordata polysaccharides alleviate ulcerative colitis by restoring intestinal homeostasis

Houttuynia cordata is traditionally used as phytoantibiotics for treating lung disease in China.Houttuynia cordata polysaccharides(HCPs)have been reported to alleviate influenza virus-induced intestinal and lung immune injury by regulating the gutlung axis.The present study aims to investigate the effects and mechanisms of HCPs on ulcerative colitis(UC).Male C57BL/6 mice were induced by dextran sodium sulfate(DSS)to establish the UC animal model.Our results showed that HCPs significantly reduced the weight loss and the shortening of colon length in colitis mice,and relieved the pathological damage of colon mucosa and inhibited the expression of pro-inflammatory cytokines such as TNF-α,IL-1β,IL-6,etc.It was suggested that HCPs could significantly improve DSS-induced colitis in mice.HCPs directly protected intestinal epithelial cells,ameliorated epithelial barrier dysfunction and cell apoptosis,which was also proved in H2O2 stimulated cell apoptosis model.HCPs inhibited inflammation in the colon,which was related to suppressing the infiltration of macrophages,inhibiting the expression of pro-inflammatory cytokines and proteins(TLR4,NF-κB),and restoring the dysfunction of Th17 and Treg cells.HCPs also restored the alteration of intestinal flora induced by DSS,increased the abundance of Firmicutes and Bacteroides,and reduced the abundance of Proteobacteria.This study confirmed the protective effect of Houttuynia cordata polysaccharide extracted from traditional Chinese medicine on ulcerative colitis,of which the mechanism was closely related to the maintenance of intestinal homeostasis(intestinal barrier,immune cells,and intestinal bacteria).