Osteoporosis is a frequent complication of chronic inflammatory diseases and increases in the pro-inflammatory cytokines make an important contribution to bone loss by promoting bone resorption and impairing bone form...Osteoporosis is a frequent complication of chronic inflammatory diseases and increases in the pro-inflammatory cytokines make an important contribution to bone loss by promoting bone resorption and impairing bone formation. Omentin-1 is a newly identified adipocytokine that has anti-inflammatory effects, but little is known about the role of omentin-1 in inflammatory osteoporosis. Here we generated global omentin-1 knockout（omentin-1^-/-） mice and demonstrated that depletion of omentin-1 induces inflammatory bone loss-like phenotypes in mice, as defined by abnormally elevated pro-inflammatory cytokines, increased osteoclast formation and bone tissue destruction, as well as impaired osteogenic activities. Using an inflammatory cell model induced by tumor necrosis factor-α（TNF-α）, we determined that recombinant omentin-1 reduces the production of proinflammatory factors in the TNF-α-activated macrophages, and suppresses their anti-osteoblastic and pro-osteoclastic abilities. In the magnesium silicate-induced inflammatory osteoporosis mouse model, the systemic administration of adenoviral-delivered omentin-1 significantly protects from osteoporotic bone loss and inflammation. Our study suggests that omentin-1 can be used as a promising therapeutic agent for the prevention or treatment of inflammatory bone diseases by downregulating the proinflammatory cytokines.展开更多
Immune evasion behavior and immunosuppressive characteristics of tumor extensively impedethe immune initiation effect of therapy triggered immunogeniccell death (ICD). In this work, a carrier-adjuvantedimmunostimulato...Immune evasion behavior and immunosuppressive characteristics of tumor extensively impedethe immune initiation effect of therapy triggered immunogeniccell death (ICD). In this work, a carrier-adjuvantedimmunostimulator (designated as CoCeC) is developed toboost photodynamic immunotherapy by downregulatingprogrammed death ligand 1 (PD-L1) and impairing adenosinetriphosphate (ATP) hydrolysis. Among these, the crosslinkedchitosan oligosaccharide is applied as the drug carrier fordelivery of Ce6 and Ceritinib, which also serves as an immuneadjuvant to downregulate PD-L1. Meanwhile, the robustphotodynamic therapy (PDT) of CoCeC exhibits lethal toxicityagainst tumor cells to induce ICD and release damage-associated molecular patterns (DAMPs), which can also impairATP hydrolysis by blocking CD39. In vitro and in vivo resultsdemonstrate the robust therapeutic efficacy of CoCeC tosuppress primary tumor growth and activate a superior immune elimination against lung metastasis by amplifying theimmune initiation of ICD with the assistance of immune adjuvants.This work provides a self-adjuvanted strategy to enhance the immune response of therapy induced ICD, which ispromising to activate systemic antitumor immunity in consideration of the complicated immunosuppressive factors.展开更多
In this review,the databases searched were PubMed and Web of Science.It is believed that the main causes of acute lung injury(ALI)and acute respiratory distress syndrome(ARDS)are inflammatory response disorders,excess...In this review,the databases searched were PubMed and Web of Science.It is believed that the main causes of acute lung injury(ALI)and acute respiratory distress syndrome(ARDS)are inflammatory response disorders,excessive oxidative stress,cell death,endoplasmic reticulum stress,coagulation dysfunction,and weakened aquaporin function.展开更多
BACKGROUND The expression pattern of gamma aminobutyric acid(GABA)receptor subunits are commonly altered in patients with schizophrenia,which may lead to nerve excitation/inhibition problems,affecting cognition,emotio...BACKGROUND The expression pattern of gamma aminobutyric acid(GABA)receptor subunits are commonly altered in patients with schizophrenia,which may lead to nerve excitation/inhibition problems,affecting cognition,emotion,and behavior.AIM To explore GABA receptor expression and its relationship with schizophrenia and to provide insights into more effective treatments.METHODS This case-control study enrolled 126 patients with schizophrenia treated at our hospital and 126 healthy volunteers who underwent physical examinations at our hospital during the same period.The expression levels of the GABA receptor subunits were detected using 1H-magnetic resonance spectroscopy.The recognized cognitive battery tool,the MATRICS Consensus Cognitive Battery,was used to evaluate the scores for various dimensions of cognitive function.The correlation between GABA receptor subunit downregulation and schizophrenia was also analyzed.RESULTS Significant differences in GABA receptor subunit levels were found between the case and control groups(P<0.05).A significant difference was also found between the case and control groups in terms of cognitive function measures,including attention/alertness and learning ability(P<0.05).Specifically,as the expression levels of GABRA1(α1 subunit gene),GABRB2(β2 subunit gene),GABRD(δsubunit),and GABRE(εsubunit)decreased,the severity of the patients’condition increased gradually,indicating a positive correlation between the downregulation of these 4 receptor subunits and schizophrenia(P<0.05).However,the expression levels of GABRA5(α5 subunit gene)and GABRA6(α6 subunit gene)showed no significant correlation with schizophrenia(P>0.05).CONCLUSION Downregulation of the GABA receptor subunits is positively correlated with schizophrenia.In other words,when GABA receptor subunits are downregulated in patients,cognitive impairment becomes more severe.展开更多
BACKGROUND Liver cancer has a high mortality and morbidity rate throughout the world.In clinical practice,the prognosis of liver cancer patients is poor,and the complex reasons contribute to treatment failures,includi...BACKGROUND Liver cancer has a high mortality and morbidity rate throughout the world.In clinical practice,the prognosis of liver cancer patients is poor,and the complex reasons contribute to treatment failures,including fibrosis,hepatitis viral infection,drug resistance and metastasis.Thus,screening novel prognostic biomarkers is of great importance for guiding liver cancer therapy.Orosomucoid genes(ORMs)encode acute phase plasma proteins,including orosomucoid 1(ORM1)and ORM2.Previous studies showed their upregulation upon inflammation,but the specific function of ORMs has not yet been determined,especially in the development of liver cancer.AIM To determine the expression of ORMs and their potential function in liver cancer.METHODS Analysis of the expression of ORMs in different human tissues was performed on data from the HPA RNA-seq normal tissues project.The expression ratio of ORMs was determined using the HCCDB database,including the ratio between liver cancer and other cancers,normal liver and other normal tissues,liver cancer and adjacent normal liver tissues.Analysis of ORM expression in different cancer types was performed using The Cancer Genome Atlas and TIMER database.The expression of ORMs in liver tumor tissues and adjacent normal tissues were further confirmed using Gene Expression Omnibus data,including GSE36376 and GSE14520.The 10-year overall survival(OS),progression-free survival(PFS)and relapse-free survival(RFS)rates between high and low ORM expression groups in liver cancer patients were determined using the Kaplan-Meier plotter tool.Gene Set Enrichment Analysis(GSEA)was employed to explore the ORM2-associated signaling network.Correlations between ORM2 expression and tumor purity or the infiltration level of macrophages in liver tumor tissues were determined using the TIMER database.The correlation between ORM2 gene levels,tumor-associated macrophage(TAM)markers(including CD68 and TGFβ1)and T cell immunosuppression(including CTLA4 and PD-1)in liver tumor tissues and liver GTEx was determined using the GEPIA database.RESULTS ORM1 and ORM2 were highly expressed in normal liver and liver tumor tissues.ORM1 and ORM2 expression was significantly decreased in liver tumor tissues compared with adjacent normal tissues,and similar results were also noted in cholangiocarcinoma,esophageal carcinoma,and lung squamous cell carcinoma.Further analysis of the Gene Expression Omnibus Database also confirmed the downregulation of ORM1 and ORM2 in liver tumors.Survival analysis showed that the high ORM2 group had better survival rates in OS,PFS and RFS.ORM1 only represented better performance in PFS,but not in OS or RFS.GSEA analysis of ORM2 from The Cancer Genome Atlas liver cancer data identified that ORM2 positively associated with the G2/M checkpoint,E2F target signaling,as well as Wnt/β-catenin and Hedgehog signaling.Moreover,apoptosis,IFN-αresponses,IFN-γresponses and humoral immune responses were upregulated in the ORM2 high group.ORM2 expression was negatively correlated with the macrophage infiltration level,CD68,TGFβ1,CTLA4 and PD-1 levels.CONCLUSION The results showed that ORM1 and ORM2 were highly expressed specifically in liver tissues,whereas ORM1 and ORM2 were downregulated in liver tumor tissues.ORM2 is a better prognostic factor for liver cancer.Furthermore,ORM2 is closely associated with cancer-promoting pathways.展开更多
Objective:Esophageal squamous cell carcinoma(ESCC)has high morbidity and mortality rates worldwide.Cancer stem cells(CSCs)may cause tumor initiation,metastasis,and recurrence and are also responsible for chemotherapy ...Objective:Esophageal squamous cell carcinoma(ESCC)has high morbidity and mortality rates worldwide.Cancer stem cells(CSCs)may cause tumor initiation,metastasis,and recurrence and are also responsible for chemotherapy and radiotherapy failures.Myeloid-derived suppressor cells(MDSCs),in contrast,are known to be involved in mediating immunosuppression.Here,we aimed to investigate the mechanisms of interaction of CSCs and MDSCs in the tumor microenvironment.Methods:ESCC tissues and cell lines were evaluated.Neural precursor cell expressed,developmentally downregulated 9(NEDD9)was knocked down and overexpressed by lentiviral transfection.Quantitative PCR,Western blot,immunohistochemistry,cell invasion,flow cytometry,cell sorting,multiplex chemokine profiling,and tumor growth analyses were performed.Results:Microarray analysis revealed 10 upregulated genes in esophageal CSCs.Only NEDD9 was upregulated in CSCs using the sphere-forming method.NEDD9 expression was correlated with tumor invasion(P=0.0218),differentiation(P=0.0153),and poor prognosis(P=0.0373).Additionally,NEDD9 was required to maintain the stem-like phenotype.Screening of chemokine expression in ESCC cells with NEDD9 overexpression and knockdown showed that NEDD9 regulated C-X-C motif chemokine ligand 8(CXCL8)expression via the ERK pathway.CXCL8 mediated the recruitment of MDSCs induced by NEDD9 in vitro and in vivo.MDSCs promoted the stemness of ESCC cells through NEDD9 via the Notch pathway.Conclusions:As a marker of ESCC,NEDD9 maintained the stemness of ESCC cells and regulated CXCL8 through the ERK pathway to recruit MDSCs into the tumor,suggesting NEDD9 as a therapeutic target and novel prognostic marker for ESCC.展开更多
AIM:To discuss the expression of human leukocyte antigen (HLA) class Ⅰ antigens in gastric cancer and correlate these with pathologic type and TNM stage. METHODS: The expression of HLA class Ⅰ antigen was detected b...AIM:To discuss the expression of human leukocyte antigen (HLA) class Ⅰ antigens in gastric cancer and correlate these with pathologic type and TNM stage. METHODS: The expression of HLA class Ⅰ antigen was detected by immunohistochemistry in 185 specimens of gastric cancer, 20 gastric cancer specimens with lymphatic metastasis and 22 controls of normal gastric mucosa using four monoclonal antibodies. RESULTS: The expression of HLA class Ⅰ antigen (B/C locus) was significantly downregulated in gastric cancer and in lymphatic metastasis than that in normal gastric mucosa (x2=7.712, P<0.05). The expression of other HLA class Ⅰ antigens was also downregulated, but the change was slight. There was no relationship between the downregulation of HLA class Ⅰ antigen and that of β2m and LMP2. The expression of HLA class Ⅰ (B/C locus) was statistically correlated with pathologic stage in gastric adenocarcinoma (x2=4.164,P<0.05). CONCLUSION: The expression of HLA class Ⅰ antigen (B/C locus) was obviously downregulated in gastric cancer and in lymphatic metastasis. This abnormal expression would provide the tumor cells with a way to avoid immunological recognition.展开更多
Vitamin D co-regulates cell proliferation, differentiation and apoptosis in numerous tissues, including cancers. The known anti-proliferative and pro-apoptotic actions of the active metabolite of vitamin D, 1,25-dihyd...Vitamin D co-regulates cell proliferation, differentiation and apoptosis in numerous tissues, including cancers. The known anti-proliferative and pro-apoptotic actions of the active metabolite of vitamin D, 1,25-dihydroxy-vitamin D [1,25（OH）2D] are mediated through binding to the vitamin D receptor （VDR）. Here, we report on the unexpected finding that stable knockdown of VDR expression in the human breast and prostate cancer cell lines, MDA-MB-231 and PC3, strongly induces cell apoptosis and inhibits cell proliferation in vitro. Implantation of these VDR knockdown cells into the mammary fat pad （MDA-MB-231）, subcutaneously （PC3） or intra-tibially （both cell lines） in immune-incompetent nude mice resulted in reduced tumor growth associated with increased apoptosis and reduced cell proliferation compared with controls. These growth-retarding effects of VDR knockdown occur in the presence and absence of vitamin D and are independent of whether cells were grown in bone or soft tissues. Transcriptome analysis of VDR knockdown and non-target control cell lines demonstrated that loss of the VDR was associated with significant attenuation in the Wnt/0-catenin signaling pathway. In particular, cytoplasmic and nuclear β-catenin protein levels were reduced with a corresponding downregulation of downstream genes such as Axin2, Cyclin D1, interleukin-6 （IL-6）, and IL-8. Stabilization of 0-catenin using the GSK-3β inhibitor BIO partly reversed the growth-retarding effects of VDR knockdown. Our results indicate that the unliganded VDR possesses hitherto unknown functions to promote breast and prostate cancer growth, which appear to be operational not only within but also outside the bone environment. These novel functions contrast with the known anti-proliferative nuclear actions of the liganded VDR and may represent targets for new diagnostic and therapeutic approaches in breast and prostate cancer.展开更多
Bone formation is important for the reconstruction of bone-related structures in areas that have been damaged by inflammation.Inflammatory conditions such as those that occur in patients with rheumatoid arthritis, cys...Bone formation is important for the reconstruction of bone-related structures in areas that have been damaged by inflammation.Inflammatory conditions such as those that occur in patients with rheumatoid arthritis, cystic fibrosis, and periodontitis have been shown to inhibit osteoblastic differentiation. This study focussed on dental follicle stem cells(DFSCs), which are found in developing tooth germ and participate in the reconstruction of alveolar bone and periodontal tissue in periodontal disease. After bacterial infection of inflamed dental tissue, the destruction of bone was observed. Currently, little is known about the relationship between the inflammatory environment and bone formation. Osteogenic differentiation of inflamed DFSCs resulted in decreased alkaline phosphatase(ALP) activity and alizarin red S staining compared to normal DFSCs. Additionally, in vivo transplantation of inflamed and normal DFSCs demonstrated severe impairment of osteogenesis by inflamed DFSCs. Protein profile analysis via liquid chromatography coupled with tandem mass spectrometry was performed to analyse the differences in protein expression in inflamed and normal tissue. Comparison of inflamed and normal DFSCs showed significant changes in the level of expression of transforming growth factor(TGF)-β2. Porphyromonas gingivalis(P.g.)-derived lipopolysaccharide(LPS) was used to create in vitro inflammatory conditions similar to periodontitis. The osteogenic differentiation of LPS-treated DFSCs was suppressed, and the cells displayed low levels of TGF-β1 and high levels of TGF-β2. DFSCs treated with TGF-β2 inhibitors showed significant increases in alizarin red S staining and ALP activity. TGF-β1 expression was also increased after inhibition of TGF-β2. By examining inflamed DFSCs and LPS-triggered DFSCs, these studies showed both clinically and experimentally that the increase in TGF-β2 levels that occurs under inflammatory conditions inhibits bone formation.展开更多
Natural killer T （NKT） cells are a unique T cell population that have important immunoregulatory functions and have been shown to be involved in host immunity against a range of microorganisms. It also emerges that ...Natural killer T （NKT） cells are a unique T cell population that have important immunoregulatory functions and have been shown to be involved in host immunity against a range of microorganisms. It also emerges that they might play a role in HIV-1 infection, and therefore be selectively depleted during the early stages of infection. Recent studies are reviewed regarding the dynamics of NKT depletion during HIV-1 infection and their recovery under highly active antiretroviral treatment （HAART）. Possible mechanisms for these changes are proposed based on the recent developments in HIV pathogenesis. Further discussions are focused on HIV＇s disruption of NKT activation by downregulating CDld expression on antigen presentation cells （APC）. HIV-1 protein Nefis found to play the major role by interrupting the intracellular trafficking of nascent and recycling CDld molecules.展开更多
Taking advantage of the fast-growing knowledge of RNA-binding proteins(RBPs)we review the signature of downregulated genes for RBPs in the transcriptome of induced pluripotent stem cell neurons(iNeurons)modelling the ...Taking advantage of the fast-growing knowledge of RNA-binding proteins(RBPs)we review the signature of downregulated genes for RBPs in the transcriptome of induced pluripotent stem cell neurons(iNeurons)modelling the neurodevelopmental Rubinstein Taybi Syndrome(RSTS)caused by mutations in the genes encoding CBP/p300 acetyltransferases.We discuss top and functionally connected downregulated genes sorted to“RNA processing”and“Ribonucleoprotein complex biogenesis”Gene Ontology clusters.The first set of downregulated RBPs includes members of hnRNHP(A1,A2B1,D,G,H2-H1,MAGOHB,PAPBC),core subunits of U small nuclear ribonucleoproteins and Serine-Arginine splicing regulators families,acting in precursor messenger RNA alternative splicing and processing.Consistent with literature findings on reduced transcript levels of serine/arginine repetitive matrix 4(SRRM4)protein,the main regulator of the neural-specific microexons splicing program upon depletion of Ep300 and Crebbp in mouse neurons,RSTS iNeurons show downregulated genes for proteins impacting this network.We link downregulated genes to neurological disorders including the new HNRNPH1-related intellectual disability syndrome with clinical overlap to RSTS.The set of downregulated genes for Ribosome biogenesis includes several components of ribosomal subunits and nucleolar proteins,such NOP58 and fibrillarin that form complexes with snoRNAs with a central role in guiding post-transcriptional modifications needed for rRNA maturation.These nucleolar proteins are“dual”players as fibrillarin is also required for epigenetic regulation of ribosomal genes and conversely NOP58-associated snoRNA levels are under the control of NOP58 interactor BMAL1,a transcriptional regulator of the circadian rhythm.Additional downregulated genes for“dual specificity”RBPs such as RUVBL1 and METTL1 highlight the links between chromatin and the RBP-ome and the contribution of perturbations in their cross-talk to RSTS.We underline the hub position of CBP/p300 in chromatin regulation,the impact of its defect on neurons’post-transcriptional regulation of gene expression and the potential use of epidrugs in therapeutics of RBP-caused neurodevelopmental disorders.展开更多
Osteoarthritis(OA)is a prevalent joint disease with no effective treatment strategies.Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis.Although multiple studies have detected ...Osteoarthritis(OA)is a prevalent joint disease with no effective treatment strategies.Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis.Although multiple studies have detected potential regulatory mechanisms underlying OA and have concentrated on developing novel treatment strategies,the epigenetic control of OA remains unclear.Histone demethylase JMJD3 has been reported to mediate multiple physiological and pathological processes,including cell differentiation,proliferation,autophagy,and apoptosis.However,the regulation of JMJD3 in aberrant force-related OA and its mediatory effect on disease progression are still unknown.In this work,we confirmed the upregulation of JMJD3 in aberrant forceinduced cartilage injury in vitro and in vivo.Functionally,inhibition of JMJD3 by its inhibitor,GSK-J4,or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 could alleviate the aberrant force-induced chondrocyte injury.Mechanistic investigation illustrated that aberrant force induces JMJD3 expression and then demethylates H3K27me3 at the NR4A1 promoter to promote its expression.Further experiments indicated that NR4A1 can regulate chondrocyte apoptosis,cartilage degeneration,extracellular matrix degradation,and inflammatory responses.In vivo,anterior cruciate ligament transection(ACLT)was performed to construct an OA model,and the therapeutic effect of GSK-J4 was validated.More importantly,we adopted a peptide-si RNA nanoplatform to deliver si-JMJD3 into articular cartilage,and the severity of joint degeneration was remarkably mitigated.Taken together,our findings demonstrated that JMJD3 is flow-responsive and epigenetically regulates OA progression.Our work provides evidences for JMJD3 inhibition as an innovative epigenetic therapy approach for joint diseases by utilizing p5RHH-si RNA nanocomplexes.展开更多
BACKGROUND： Immediate early gene （lEG） c-jun is a sensitive marker for functional status of nerve cells. Caspase-3 is a cysteine protease, which is a critical regulator of apoptosis. The effect of exogenous nerve g...BACKGROUND： Immediate early gene （lEG） c-jun is a sensitive marker for functional status of nerve cells. Caspase-3 is a cysteine protease, which is a critical regulator of apoptosis. The effect of exogenous nerve growth factor （NGF） on the expression of c-jun mRNA and Caspase-3 protein in striate cortex of rats with transient global cerebral ischemia/reperfusion （IR） is unclear. OBJECTIVE： To study the protective effect of exogenous NGF on the brain of rats with transient globa cerebral IR and its effecting pathway by observing the expression of c-jun mRNA and Caspase-3 protein. DESIGN： Randomized controlled animal trial SETTING： Department of Neural Anatomy, Institute of Brain, China Medical University MATERIALS：Eighteen healthy male SD rats of clean grade, aged 1 to 3 months, with body mass of 250 to 300 g, were involved in this study. NGF was provided by Dalian Svate Pharmaceutical Co.,Ltd. c-jun in situ hybridization detection kit, Caspase-3 antibody and SABC kit were purchased from Boster Biotechnology Co.. Ltd. METHODS： This trial was carried out in the Department of Neural Anatomy, Institute of Brain, China Medical University during September 2003 to April 2005. （1） Experimental animals were randomized into three groups with 6 in each： sham-operation group, IR group and NGF group.（2）After the rats were anesthetized, the bilateral common carotid arteries and right external carotid arteries of rats were bluntly dissected and bilateral common carotid arteries were clamped for 30 minutes with bulldog clamps. Reperfusion began after buldog clamps were removed. Normal saline of lmL and NGF （1×10^6 U/L） of 1 mL was injected into the common carotid artery of rats via right external carotid arteries in the IR group and NGF group respectively. The injection was conducted within 30 minutes, and then the right external carotid arteries were ligated. In the sham-operation group, occlusion of bilateral common carotid arteries and administration of drugs were omitted.GAll the rats were executed by decollation at 3 hours after modeling. The animals were fixed with phosphate buffer solution （PBS, 0.1 mol/L） containing 40 g/L polyformaldehyde, their brains were quickly removed. The coronal section tissue mass containing striate cortex about 3 mm before line between two ears was taken and made into successive frozen sections.（4）The expression of c-jun mRNA and Caspase-3 protein in striate cortex of global cerebral ischemia rats were detected with in situ hybridization, immunohistochemistry and microscope image analysis. （5）t test was used for comparing the difference of the measurement data. MAIN OUTCOME MEASURES：Comparison of the expression of lEG c-jun mRNA and Caspase-3 protein in striate cortex of brain of rats in each group. RESULTS：All the 18 SD rats were involved in the analysis of results. The c-jun mRNA and Caspase-3 protein positive reaction cells were found brown yellow in the striate cortex of rats, and most of them were in lamellas Ⅱ and Ⅲ, mainly presenting round or oval. The expression of c-jun mRNA and Caspase-3 protein in sham-operation group was weak or negative. The average gray value of c-jun mRNA and Caspase-3 protein in the IR group was significantly lower than that in the sham-operation group （49.52±4.13 vs. 95.48± 5.28; 74.73±4.29 vs. 162.38±9.16,P 〈 0.01）. The average gray value of c-jun mRNA and Caspase-3 protein in the NGF group was significantly higher than that in the IR group （63.96±4.25 vs.49.52±4.13; 83.98± 4.13 vs. 74.73±4.29, P〈 0.05）. CONCLUSION： NGF can protect ischemic neurons by down-regulating the expression of c-jun mRNA and Caspase-3 protein in striate cortex of global cerebral ischemia rats.展开更多
Recent studies have suggested an involvement of processing pathways for the initiation of cellular responses induced by topoisomerase-targeting drugs. Here, we showed that cellular exposure to camptothecin （CPT） ind...Recent studies have suggested an involvement of processing pathways for the initiation of cellular responses induced by topoisomerase-targeting drugs. Here, we showed that cellular exposure to camptothecin （CPT） induced formation of topoisomerase I cleavable complex （TOPlcc）, degradation of TOP1 and activation of DNA damage responses （DDR）. Transcription and proteasome-dependent proteolysis, but not replication, were involved in CPTo indneed TOPl degradation, while none of above three processing activities affected TOPlcc formation. Replication- and transcription-initiated proeessing （RIP and TIP） of TOPlee were identified as two independent pathways, which contribute distinctly to various CPT-activated DDR. Specifically, in cycling cells, RIP-processed TOPlec triggered the CPT-induced RPA pbosphorylation. At higher CPT dosages, the TIP pathway is required for other DDR activation, including ATM, p53 and Chkl/2 phosphorylation. The TIP pathway was further demonstrated to be S-phase independent by using three nonreplicating cell models. Furthermore, the effect of proteasome inhibitors mimicked that of transcription inhibition on the CPT-induced activation of DDR, suggesting the involvement of proteasome in the TIP pathway. Interestingly, the TIP pathway was important for TOPlcc-activated, but not ionization radiationactivated ATM, p53 and Chk2 phosphorylation. We have also found that pharmacological interferences of TIP and RIP pathways distinctively modulated the CPT-induced cell killing with treatments at low and high dosages, respec- tively. Together, our results support that both RIP and TIP pathways of TOPlcc are required for the activation of CPT-induced DDR and cytotoxicity.展开更多
In this editorial,the roles of orosomucoid(ORM)in the diagnoses and follow-up assessments of both nonneoplastic diseases and liver tumors are discussed with respect to the publication by Zhu et al presented in the pre...In this editorial,the roles of orosomucoid(ORM)in the diagnoses and follow-up assessments of both nonneoplastic diseases and liver tumors are discussed with respect to the publication by Zhu et al presented in the previous issue of World Journal of Gastroenterology(2020;26(8):840-817).ORM,or alpha-1 acid glycoprotein(AGP),is an acute-phase protein that constitutes 1%to 3%of plasma proteins in humans and is mainly synthesized in the liver.ORM exists in serum as two variants:ORM1 and ORM2.Although the variants share 89.6%sequence identity and have similar biological properties,ORM1 constitutes the main component of serum ORM.An interesting feature of ORM is that its biological effects differ according to variations in glycosylation patterns.This variable feature makes ORM an attractive target for diagnosing and monitoring many diseases,including those of the liver.Recent findings suggest that a sharp decrease in ORM level is an important marker for HBV-associated acute liver failure(ALF),and ORM1 plays an important role in liver regeneration.In viral hepatitis,increases in both ORM and its fucosylated forms and the correlation of these increases with fibrosis progression suggest that this glycoprotein can be used with other markers as a noninvasive method in the follow-up assessment of diseases.In addition,similar findings regarding the level of the asialylated form of ORM,called asialo-AGP(AsAGP),have been reported in a follow-up assessment of fibrosis in chronic liver disease.An increase in ORM in serum has also been shown to improve hepatocellular carcinoma(HCC)diagnosis performance when combined with other markers.In addition,determination of the ORM level has been useful in the diagnosis of HCC with AFP concentrations less than 500 ng/mL.For monitoring patients with AFP-negative HCC,a unique trifucosylated tetra-antennary glycan of ORM may also be used as a new potential marker.The fact that there are very few studies investigating the expression of this glycoprotein and its variants in liver tissues constitutes a potential limitation,especially in terms of revealing all the effects of ORM on carcinogenesis and tumor behavior.Current findings indicate that ORM2 expression is decreased in tumors,and this is related to the aggressive course of the disease.Parallel to this finding,in HCC cell lines,ORM2 decreases HCC cell migration and invasion,supporting reports of its tumor suppressor role.In conclusion,the levels of ORM and its different glycosylated variants are promising additional biomarkers for identifying ALF,for monitoring fibrosis in viral hepatitis,and for diagnosing early HCC.Although there is evidence that the loss of ORM2 expression in HCC is associated with poor prognosis,further studies are needed to support these findings.Additionally,investigations of ORM expression in borderline dysplastic nodules and hepatocellular adenomas,which pose diagnostic problems in the differential diagnosis of HCC,especially in biopsy samples,may shed light on whether ORM can be used in histopathological differential diagnosis.展开更多
The microRNA-21 （miR-21） is known to play a major role in cancer progression; however, its function in the cardiovascular system appears to be even more complex and conflicting. To characterize miR-21 expression in ...The microRNA-21 （miR-21） is known to play a major role in cancer progression; however, its function in the cardiovascular system appears to be even more complex and conflicting. To characterize miR-21 expression in the plasma of individuals with or without metabolic syndrome （MetS）, 58 MetS cases and 96 non-MetS controls were investigated.展开更多
STAT3 plays a particularly important role in several cancer-related signal transduction pathways.Silencing STAT3 via RNA interference or small molecule inhibitors induces the apoptosis of tumor cells,thereby inhibitin...STAT3 plays a particularly important role in several cancer-related signal transduction pathways.Silencing STAT3 via RNA interference or small molecule inhibitors induces the apoptosis of tumor cells,thereby inhibiting the growth of the tumors.In this study,short-hairpin RNA sequences targeting the STAT3 genes were designed,synthesized,and then connected to pGPU6/GFP/Neo plasmids as the shRNA-expression vectors.The expression of STAT3-shRNA was analyzed by real-time PCR,western blotting,and cell apoptosis assay to study the growth and apoptosis of the cells.Then,the effect of STAT3 knockdown on the NCI-H1650 cells was studied in a tumor mouse model.The results revealed that,after an in vitro transfection,the proliferation of NCI-H1650 cells was inhibited,and the cells were induced to apoptosis.The mRNA and protein expression levels of STAT3 were downregulated in the STAT3-shRNA group.In vivo,the tumor mass and volume in the STAT3-shRNA group were significantly lower than in the other two groups.Both the in vivo and in vitro results demonstrated a long-period inhibiting effect on NSCLC,especially in vivo,when the tumor inhibition rate could reach 50%in the STAT3-shRNA group,which is an exciting outcome.Moreover,the study of the conjugation of STAT3-shRNA and chitosan-based vectors revealed that they could be combined steadily with good cytocompati-bility and transfection efficiency.These results together provide convincing evidence for the application of STAT3-shRNA used in the treatment of non-small lung cancer,which could be a promoting prospect for the development of gene therapy.展开更多
Although there are no effective therapies to block or reverse Alzheimer’s disease(AD)progression at present,a promising therapeutic strategy is to reduce levels of amyloid𝛽(Aβ)proteins,which drive the format...Although there are no effective therapies to block or reverse Alzheimer’s disease(AD)progression at present,a promising therapeutic strategy is to reduce levels of amyloid𝛽(Aβ)proteins,which drive the formation of amyloid plaque,a primary hallmark in AD brains.Herein,we report that amphiphilic lipid-DNA molecules(LD)were designed by incorporating a long alkyl chain into the nucleotide base.It significantly down-regulated Alzheimer’s Aβ levels in vivo and in vitro.In contrast to small-molecule chemical drugs and antibody therapies,the assembled DNA nanoparticles allowed them to effectively cross the blood-brain barrier(BBB)and accumulate in the brain,increasing the therapeutic effects.Notably,lipid-DNA downregulated the levels of Aβ peptides significantly in vitro.AD mice model experiments demonstrated that the LD-treated groups exhibited a rapid cognition behavioral improvement,which was associated with brain engagement of LD and reduced Aβ levels.Thus,the molecularly engineered DNA nanomaterials effectively regulated Aβ peptides.This work might provide a promising DNA engineering strategy for AD treatment.展开更多
Brassinosteroids are known regulators of meristem activity in Arabidopsis,with low levels being sufficient for normal growth within the proliferating cells of the meristem.Brassinosteroid biosynthesis enzymes are tran...Brassinosteroids are known regulators of meristem activity in Arabidopsis,with low levels being sufficient for normal growth within the proliferating cells of the meristem.Brassinosteroid biosynthesis enzymes are transcriptionally downregulated in response to increased brassinosteroid signaling activity,forming a negative feedback loop to modulate their own expression(Ackerman-Lavert et al.,2021;Vukašinovićet al.,2021).展开更多
Elevated CO2 leads to a decrease in potential net photosynthesis in long-term experiments and thus to a reduction in potential growth. This process is known as photosynthetic downregulation. There is no agreement on t...Elevated CO2 leads to a decrease in potential net photosynthesis in long-term experiments and thus to a reduction in potential growth. This process is known as photosynthetic downregulation. There is no agreement on the definition of which parameters are the most sensitive for detecting CO2 acclimation. In order to investigate the most sensitive photosynthetic and molecular markers of CO2 acclimation, the effects of elevated CO2, and associated elevated temperature were analyzed in alfalfa plants inoculated with different Sinorhizobium meliloti strains. Plants （Medicago sativa L. cv. Aragon） were grown in summer or autumn in temperature gradient greenhouses （TGG）. At the end of the experiment, all plants showed acclimation in both seasons, especially under elevated summer temperatures. This was probably due to the lower nitrogen （N） availability caused by decreased N2-fixation under higher temperatures. Photosynthesis measured at growth CO2 concentration, rubisco in vitro activity and maximum rate of carboxylation were the most sensitive parameters for detecting downregulation. Severe acclimation was also related with decreases in leaf nitrogen content associated with declines in rubisco content （large and small subunits） and activity that resulted in a drop in photosynthesis. Despite the sensitivity of rubisco content as a marker of acclimation, it was not coordinated with gene expression, possibly due to a lag between gene transcription and protein translation.展开更多
基金supported by the Excellent Young Scientist Foundation of the National Natural Science Foundation of China(Grant No.81522012)the National Natural Science Foundation of China(Grant No.81670807,81600699,81702237,81701383,81400858)+8 种基金the Thousand Youth Talents Plan of China(Grant No.D1119003)the Hunan Youth Talent Project(Grant No.2016RS3021)the Innovation Driven Project of Central South University(2016CX028)the Youth Foundation of Xiangya Hospital in Central South University(Grant No.2016Q10)the Fundamental Research Funds for the Central Universities of Central South University(Grant No.2017zzts032,2017zzts014)the Hunan Province Natural Science Foundation of China(Grant No.2017JJ3501)the China Postdoctoral Science Foundation(Grant No.2017M612596)the Natural Science Foundation for Distinguished Yong Scholars of Guangdong Province(2016A030306051)the National Basic Research Program of China(973 Program,Grant no.2014CB942903)
文摘Osteoporosis is a frequent complication of chronic inflammatory diseases and increases in the pro-inflammatory cytokines make an important contribution to bone loss by promoting bone resorption and impairing bone formation. Omentin-1 is a newly identified adipocytokine that has anti-inflammatory effects, but little is known about the role of omentin-1 in inflammatory osteoporosis. Here we generated global omentin-1 knockout（omentin-1^-/-） mice and demonstrated that depletion of omentin-1 induces inflammatory bone loss-like phenotypes in mice, as defined by abnormally elevated pro-inflammatory cytokines, increased osteoclast formation and bone tissue destruction, as well as impaired osteogenic activities. Using an inflammatory cell model induced by tumor necrosis factor-α（TNF-α）, we determined that recombinant omentin-1 reduces the production of proinflammatory factors in the TNF-α-activated macrophages, and suppresses their anti-osteoblastic and pro-osteoclastic abilities. In the magnesium silicate-induced inflammatory osteoporosis mouse model, the systemic administration of adenoviral-delivered omentin-1 significantly protects from osteoporotic bone loss and inflammation. Our study suggests that omentin-1 can be used as a promising therapeutic agent for the prevention or treatment of inflammatory bone diseases by downregulating the proinflammatory cytokines.
基金financially supported by the National Key R&D Program of China (2021YFD1800600)the National Natural Science Foundation of China (32371394)the Open Research Foundation of State Key Laboratory of Respiratory Diseases (SKLRD-OP-202204)。
文摘Immune evasion behavior and immunosuppressive characteristics of tumor extensively impedethe immune initiation effect of therapy triggered immunogeniccell death (ICD). In this work, a carrier-adjuvantedimmunostimulator (designated as CoCeC) is developed toboost photodynamic immunotherapy by downregulatingprogrammed death ligand 1 (PD-L1) and impairing adenosinetriphosphate (ATP) hydrolysis. Among these, the crosslinkedchitosan oligosaccharide is applied as the drug carrier fordelivery of Ce6 and Ceritinib, which also serves as an immuneadjuvant to downregulate PD-L1. Meanwhile, the robustphotodynamic therapy (PDT) of CoCeC exhibits lethal toxicityagainst tumor cells to induce ICD and release damage-associated molecular patterns (DAMPs), which can also impairATP hydrolysis by blocking CD39. In vitro and in vivo resultsdemonstrate the robust therapeutic efficacy of CoCeC tosuppress primary tumor growth and activate a superior immune elimination against lung metastasis by amplifying theimmune initiation of ICD with the assistance of immune adjuvants.This work provides a self-adjuvanted strategy to enhance the immune response of therapy induced ICD, which ispromising to activate systemic antitumor immunity in consideration of the complicated immunosuppressive factors.
基金Yunnan Fundamental Research Projects(202201AU070167,202301AT070258)Yunnan Key Laboratory of Formulated Granules(202105AG070014).
文摘In this review,the databases searched were PubMed and Web of Science.It is believed that the main causes of acute lung injury(ALI)and acute respiratory distress syndrome(ARDS)are inflammatory response disorders,excessive oxidative stress,cell death,endoplasmic reticulum stress,coagulation dysfunction,and weakened aquaporin function.
文摘BACKGROUND The expression pattern of gamma aminobutyric acid(GABA)receptor subunits are commonly altered in patients with schizophrenia,which may lead to nerve excitation/inhibition problems,affecting cognition,emotion,and behavior.AIM To explore GABA receptor expression and its relationship with schizophrenia and to provide insights into more effective treatments.METHODS This case-control study enrolled 126 patients with schizophrenia treated at our hospital and 126 healthy volunteers who underwent physical examinations at our hospital during the same period.The expression levels of the GABA receptor subunits were detected using 1H-magnetic resonance spectroscopy.The recognized cognitive battery tool,the MATRICS Consensus Cognitive Battery,was used to evaluate the scores for various dimensions of cognitive function.The correlation between GABA receptor subunit downregulation and schizophrenia was also analyzed.RESULTS Significant differences in GABA receptor subunit levels were found between the case and control groups(P<0.05).A significant difference was also found between the case and control groups in terms of cognitive function measures,including attention/alertness and learning ability(P<0.05).Specifically,as the expression levels of GABRA1(α1 subunit gene),GABRB2(β2 subunit gene),GABRD(δsubunit),and GABRE(εsubunit)decreased,the severity of the patients’condition increased gradually,indicating a positive correlation between the downregulation of these 4 receptor subunits and schizophrenia(P<0.05).However,the expression levels of GABRA5(α5 subunit gene)and GABRA6(α6 subunit gene)showed no significant correlation with schizophrenia(P>0.05).CONCLUSION Downregulation of the GABA receptor subunits is positively correlated with schizophrenia.In other words,when GABA receptor subunits are downregulated in patients,cognitive impairment becomes more severe.
基金Supported by Medicine and Health Science and Technology Plan Projects of Zhejiang Province,No.2018KY569Zhejiang Provincial Natural Science Foundation of China,No.LY17H030002
文摘BACKGROUND Liver cancer has a high mortality and morbidity rate throughout the world.In clinical practice,the prognosis of liver cancer patients is poor,and the complex reasons contribute to treatment failures,including fibrosis,hepatitis viral infection,drug resistance and metastasis.Thus,screening novel prognostic biomarkers is of great importance for guiding liver cancer therapy.Orosomucoid genes(ORMs)encode acute phase plasma proteins,including orosomucoid 1(ORM1)and ORM2.Previous studies showed their upregulation upon inflammation,but the specific function of ORMs has not yet been determined,especially in the development of liver cancer.AIM To determine the expression of ORMs and their potential function in liver cancer.METHODS Analysis of the expression of ORMs in different human tissues was performed on data from the HPA RNA-seq normal tissues project.The expression ratio of ORMs was determined using the HCCDB database,including the ratio between liver cancer and other cancers,normal liver and other normal tissues,liver cancer and adjacent normal liver tissues.Analysis of ORM expression in different cancer types was performed using The Cancer Genome Atlas and TIMER database.The expression of ORMs in liver tumor tissues and adjacent normal tissues were further confirmed using Gene Expression Omnibus data,including GSE36376 and GSE14520.The 10-year overall survival(OS),progression-free survival(PFS)and relapse-free survival(RFS)rates between high and low ORM expression groups in liver cancer patients were determined using the Kaplan-Meier plotter tool.Gene Set Enrichment Analysis(GSEA)was employed to explore the ORM2-associated signaling network.Correlations between ORM2 expression and tumor purity or the infiltration level of macrophages in liver tumor tissues were determined using the TIMER database.The correlation between ORM2 gene levels,tumor-associated macrophage(TAM)markers(including CD68 and TGFβ1)and T cell immunosuppression(including CTLA4 and PD-1)in liver tumor tissues and liver GTEx was determined using the GEPIA database.RESULTS ORM1 and ORM2 were highly expressed in normal liver and liver tumor tissues.ORM1 and ORM2 expression was significantly decreased in liver tumor tissues compared with adjacent normal tissues,and similar results were also noted in cholangiocarcinoma,esophageal carcinoma,and lung squamous cell carcinoma.Further analysis of the Gene Expression Omnibus Database also confirmed the downregulation of ORM1 and ORM2 in liver tumors.Survival analysis showed that the high ORM2 group had better survival rates in OS,PFS and RFS.ORM1 only represented better performance in PFS,but not in OS or RFS.GSEA analysis of ORM2 from The Cancer Genome Atlas liver cancer data identified that ORM2 positively associated with the G2/M checkpoint,E2F target signaling,as well as Wnt/β-catenin and Hedgehog signaling.Moreover,apoptosis,IFN-αresponses,IFN-γresponses and humoral immune responses were upregulated in the ORM2 high group.ORM2 expression was negatively correlated with the macrophage infiltration level,CD68,TGFβ1,CTLA4 and PD-1 levels.CONCLUSION The results showed that ORM1 and ORM2 were highly expressed specifically in liver tissues,whereas ORM1 and ORM2 were downregulated in liver tumor tissues.ORM2 is a better prognostic factor for liver cancer.Furthermore,ORM2 is closely associated with cancer-promoting pathways.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.81602599,31400752,81771781,and U1804281)the National Key Research and Development Program of China(Grant No.2016YFC1303501)。
文摘Objective:Esophageal squamous cell carcinoma(ESCC)has high morbidity and mortality rates worldwide.Cancer stem cells(CSCs)may cause tumor initiation,metastasis,and recurrence and are also responsible for chemotherapy and radiotherapy failures.Myeloid-derived suppressor cells(MDSCs),in contrast,are known to be involved in mediating immunosuppression.Here,we aimed to investigate the mechanisms of interaction of CSCs and MDSCs in the tumor microenvironment.Methods:ESCC tissues and cell lines were evaluated.Neural precursor cell expressed,developmentally downregulated 9(NEDD9)was knocked down and overexpressed by lentiviral transfection.Quantitative PCR,Western blot,immunohistochemistry,cell invasion,flow cytometry,cell sorting,multiplex chemokine profiling,and tumor growth analyses were performed.Results:Microarray analysis revealed 10 upregulated genes in esophageal CSCs.Only NEDD9 was upregulated in CSCs using the sphere-forming method.NEDD9 expression was correlated with tumor invasion(P=0.0218),differentiation(P=0.0153),and poor prognosis(P=0.0373).Additionally,NEDD9 was required to maintain the stem-like phenotype.Screening of chemokine expression in ESCC cells with NEDD9 overexpression and knockdown showed that NEDD9 regulated C-X-C motif chemokine ligand 8(CXCL8)expression via the ERK pathway.CXCL8 mediated the recruitment of MDSCs induced by NEDD9 in vitro and in vivo.MDSCs promoted the stemness of ESCC cells through NEDD9 via the Notch pathway.Conclusions:As a marker of ESCC,NEDD9 maintained the stemness of ESCC cells and regulated CXCL8 through the ERK pathway to recruit MDSCs into the tumor,suggesting NEDD9 as a therapeutic target and novel prognostic marker for ESCC.
基金Supported by the Provincial Natural Science Fund of Jiangsu,No.BK2002055National Science Fund for Distinguished Young Scholars,No.30325017
文摘AIM:To discuss the expression of human leukocyte antigen (HLA) class Ⅰ antigens in gastric cancer and correlate these with pathologic type and TNM stage. METHODS: The expression of HLA class Ⅰ antigen was detected by immunohistochemistry in 185 specimens of gastric cancer, 20 gastric cancer specimens with lymphatic metastasis and 22 controls of normal gastric mucosa using four monoclonal antibodies. RESULTS: The expression of HLA class Ⅰ antigen (B/C locus) was significantly downregulated in gastric cancer and in lymphatic metastasis than that in normal gastric mucosa (x2=7.712, P<0.05). The expression of other HLA class Ⅰ antigens was also downregulated, but the change was slight. There was no relationship between the downregulation of HLA class Ⅰ antigen and that of β2m and LMP2. The expression of HLA class Ⅰ (B/C locus) was statistically correlated with pathologic stage in gastric adenocarcinoma (x2=4.164,P<0.05). CONCLUSION: The expression of HLA class Ⅰ antigen (B/C locus) was obviously downregulated in gastric cancer and in lymphatic metastasis. This abnormal expression would provide the tumor cells with a way to avoid immunological recognition.
基金supported by Cancer Institute NSW CDF fellowship (YZ)Cure Cancer Foundation of Australia (YZ)+3 种基金Cancer Council New South Wales (MJS, YZ, HZ, and CRD)Prostate Cancer Foundation of Australia (MJS, YZ, HZ, and CRD)NH and MRC Early Career Fellowship 596870 (YZ)German Research Foundation HO 5109/2-1 and HO 5109/2-2 (KH)
文摘Vitamin D co-regulates cell proliferation, differentiation and apoptosis in numerous tissues, including cancers. The known anti-proliferative and pro-apoptotic actions of the active metabolite of vitamin D, 1,25-dihydroxy-vitamin D [1,25（OH）2D] are mediated through binding to the vitamin D receptor （VDR）. Here, we report on the unexpected finding that stable knockdown of VDR expression in the human breast and prostate cancer cell lines, MDA-MB-231 and PC3, strongly induces cell apoptosis and inhibits cell proliferation in vitro. Implantation of these VDR knockdown cells into the mammary fat pad （MDA-MB-231）, subcutaneously （PC3） or intra-tibially （both cell lines） in immune-incompetent nude mice resulted in reduced tumor growth associated with increased apoptosis and reduced cell proliferation compared with controls. These growth-retarding effects of VDR knockdown occur in the presence and absence of vitamin D and are independent of whether cells were grown in bone or soft tissues. Transcriptome analysis of VDR knockdown and non-target control cell lines demonstrated that loss of the VDR was associated with significant attenuation in the Wnt/0-catenin signaling pathway. In particular, cytoplasmic and nuclear β-catenin protein levels were reduced with a corresponding downregulation of downstream genes such as Axin2, Cyclin D1, interleukin-6 （IL-6）, and IL-8. Stabilization of 0-catenin using the GSK-3β inhibitor BIO partly reversed the growth-retarding effects of VDR knockdown. Our results indicate that the unliganded VDR possesses hitherto unknown functions to promote breast and prostate cancer growth, which appear to be operational not only within but also outside the bone environment. These novel functions contrast with the known anti-proliferative nuclear actions of the liganded VDR and may represent targets for new diagnostic and therapeutic approaches in breast and prostate cancer.
基金supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI)funded by the Ministry of Health & Welfare, Republic of Korea [grant number HI12C0763]
文摘Bone formation is important for the reconstruction of bone-related structures in areas that have been damaged by inflammation.Inflammatory conditions such as those that occur in patients with rheumatoid arthritis, cystic fibrosis, and periodontitis have been shown to inhibit osteoblastic differentiation. This study focussed on dental follicle stem cells(DFSCs), which are found in developing tooth germ and participate in the reconstruction of alveolar bone and periodontal tissue in periodontal disease. After bacterial infection of inflamed dental tissue, the destruction of bone was observed. Currently, little is known about the relationship between the inflammatory environment and bone formation. Osteogenic differentiation of inflamed DFSCs resulted in decreased alkaline phosphatase(ALP) activity and alizarin red S staining compared to normal DFSCs. Additionally, in vivo transplantation of inflamed and normal DFSCs demonstrated severe impairment of osteogenesis by inflamed DFSCs. Protein profile analysis via liquid chromatography coupled with tandem mass spectrometry was performed to analyse the differences in protein expression in inflamed and normal tissue. Comparison of inflamed and normal DFSCs showed significant changes in the level of expression of transforming growth factor(TGF)-β2. Porphyromonas gingivalis(P.g.)-derived lipopolysaccharide(LPS) was used to create in vitro inflammatory conditions similar to periodontitis. The osteogenic differentiation of LPS-treated DFSCs was suppressed, and the cells displayed low levels of TGF-β1 and high levels of TGF-β2. DFSCs treated with TGF-β2 inhibitors showed significant increases in alizarin red S staining and ALP activity. TGF-β1 expression was also increased after inhibition of TGF-β2. By examining inflamed DFSCs and LPS-triggered DFSCs, these studies showed both clinically and experimentally that the increase in TGF-β2 levels that occurs under inflammatory conditions inhibits bone formation.
文摘Natural killer T （NKT） cells are a unique T cell population that have important immunoregulatory functions and have been shown to be involved in host immunity against a range of microorganisms. It also emerges that they might play a role in HIV-1 infection, and therefore be selectively depleted during the early stages of infection. Recent studies are reviewed regarding the dynamics of NKT depletion during HIV-1 infection and their recovery under highly active antiretroviral treatment （HAART）. Possible mechanisms for these changes are proposed based on the recent developments in HIV pathogenesis. Further discussions are focused on HIV＇s disruption of NKT activation by downregulating CDld expression on antigen presentation cells （APC）. HIV-1 protein Nefis found to play the major role by interrupting the intracellular trafficking of nascent and recycling CDld molecules.
基金This work was supported by Italian Ministery of Health RC 08C921 to LL,Istituto Auxologico Italiano,IRCCs.
文摘Taking advantage of the fast-growing knowledge of RNA-binding proteins(RBPs)we review the signature of downregulated genes for RBPs in the transcriptome of induced pluripotent stem cell neurons(iNeurons)modelling the neurodevelopmental Rubinstein Taybi Syndrome(RSTS)caused by mutations in the genes encoding CBP/p300 acetyltransferases.We discuss top and functionally connected downregulated genes sorted to“RNA processing”and“Ribonucleoprotein complex biogenesis”Gene Ontology clusters.The first set of downregulated RBPs includes members of hnRNHP(A1,A2B1,D,G,H2-H1,MAGOHB,PAPBC),core subunits of U small nuclear ribonucleoproteins and Serine-Arginine splicing regulators families,acting in precursor messenger RNA alternative splicing and processing.Consistent with literature findings on reduced transcript levels of serine/arginine repetitive matrix 4(SRRM4)protein,the main regulator of the neural-specific microexons splicing program upon depletion of Ep300 and Crebbp in mouse neurons,RSTS iNeurons show downregulated genes for proteins impacting this network.We link downregulated genes to neurological disorders including the new HNRNPH1-related intellectual disability syndrome with clinical overlap to RSTS.The set of downregulated genes for Ribosome biogenesis includes several components of ribosomal subunits and nucleolar proteins,such NOP58 and fibrillarin that form complexes with snoRNAs with a central role in guiding post-transcriptional modifications needed for rRNA maturation.These nucleolar proteins are“dual”players as fibrillarin is also required for epigenetic regulation of ribosomal genes and conversely NOP58-associated snoRNA levels are under the control of NOP58 interactor BMAL1,a transcriptional regulator of the circadian rhythm.Additional downregulated genes for“dual specificity”RBPs such as RUVBL1 and METTL1 highlight the links between chromatin and the RBP-ome and the contribution of perturbations in their cross-talk to RSTS.We underline the hub position of CBP/p300 in chromatin regulation,the impact of its defect on neurons’post-transcriptional regulation of gene expression and the potential use of epidrugs in therapeutics of RBP-caused neurodevelopmental disorders.
基金supported by National Natural Science Foundation of China(11932012,81870790 and 31801233)Science and Technology Commission of Shanghai Municipality(18441903600)+1 种基金Clinical Research Plan of SHDC(No.SHDC2020CR3009A)Innovative Research Team of High-level Local Universities in Shanghai(SSMU-ZDCX20180902)。
文摘Osteoarthritis(OA)is a prevalent joint disease with no effective treatment strategies.Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis.Although multiple studies have detected potential regulatory mechanisms underlying OA and have concentrated on developing novel treatment strategies,the epigenetic control of OA remains unclear.Histone demethylase JMJD3 has been reported to mediate multiple physiological and pathological processes,including cell differentiation,proliferation,autophagy,and apoptosis.However,the regulation of JMJD3 in aberrant force-related OA and its mediatory effect on disease progression are still unknown.In this work,we confirmed the upregulation of JMJD3 in aberrant forceinduced cartilage injury in vitro and in vivo.Functionally,inhibition of JMJD3 by its inhibitor,GSK-J4,or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 could alleviate the aberrant force-induced chondrocyte injury.Mechanistic investigation illustrated that aberrant force induces JMJD3 expression and then demethylates H3K27me3 at the NR4A1 promoter to promote its expression.Further experiments indicated that NR4A1 can regulate chondrocyte apoptosis,cartilage degeneration,extracellular matrix degradation,and inflammatory responses.In vivo,anterior cruciate ligament transection(ACLT)was performed to construct an OA model,and the therapeutic effect of GSK-J4 was validated.More importantly,we adopted a peptide-si RNA nanoplatform to deliver si-JMJD3 into articular cartilage,and the severity of joint degeneration was remarkably mitigated.Taken together,our findings demonstrated that JMJD3 is flow-responsive and epigenetically regulates OA progression.Our work provides evidences for JMJD3 inhibition as an innovative epigenetic therapy approach for joint diseases by utilizing p5RHH-si RNA nanocomplexes.
基金the Natural Science Foundation of LiaoningProvince, No. 619019
文摘BACKGROUND： Immediate early gene （lEG） c-jun is a sensitive marker for functional status of nerve cells. Caspase-3 is a cysteine protease, which is a critical regulator of apoptosis. The effect of exogenous nerve growth factor （NGF） on the expression of c-jun mRNA and Caspase-3 protein in striate cortex of rats with transient global cerebral ischemia/reperfusion （IR） is unclear. OBJECTIVE： To study the protective effect of exogenous NGF on the brain of rats with transient globa cerebral IR and its effecting pathway by observing the expression of c-jun mRNA and Caspase-3 protein. DESIGN： Randomized controlled animal trial SETTING： Department of Neural Anatomy, Institute of Brain, China Medical University MATERIALS：Eighteen healthy male SD rats of clean grade, aged 1 to 3 months, with body mass of 250 to 300 g, were involved in this study. NGF was provided by Dalian Svate Pharmaceutical Co.,Ltd. c-jun in situ hybridization detection kit, Caspase-3 antibody and SABC kit were purchased from Boster Biotechnology Co.. Ltd. METHODS： This trial was carried out in the Department of Neural Anatomy, Institute of Brain, China Medical University during September 2003 to April 2005. （1） Experimental animals were randomized into three groups with 6 in each： sham-operation group, IR group and NGF group.（2）After the rats were anesthetized, the bilateral common carotid arteries and right external carotid arteries of rats were bluntly dissected and bilateral common carotid arteries were clamped for 30 minutes with bulldog clamps. Reperfusion began after buldog clamps were removed. Normal saline of lmL and NGF （1×10^6 U/L） of 1 mL was injected into the common carotid artery of rats via right external carotid arteries in the IR group and NGF group respectively. The injection was conducted within 30 minutes, and then the right external carotid arteries were ligated. In the sham-operation group, occlusion of bilateral common carotid arteries and administration of drugs were omitted.GAll the rats were executed by decollation at 3 hours after modeling. The animals were fixed with phosphate buffer solution （PBS, 0.1 mol/L） containing 40 g/L polyformaldehyde, their brains were quickly removed. The coronal section tissue mass containing striate cortex about 3 mm before line between two ears was taken and made into successive frozen sections.（4）The expression of c-jun mRNA and Caspase-3 protein in striate cortex of global cerebral ischemia rats were detected with in situ hybridization, immunohistochemistry and microscope image analysis. （5）t test was used for comparing the difference of the measurement data. MAIN OUTCOME MEASURES：Comparison of the expression of lEG c-jun mRNA and Caspase-3 protein in striate cortex of brain of rats in each group. RESULTS：All the 18 SD rats were involved in the analysis of results. The c-jun mRNA and Caspase-3 protein positive reaction cells were found brown yellow in the striate cortex of rats, and most of them were in lamellas Ⅱ and Ⅲ, mainly presenting round or oval. The expression of c-jun mRNA and Caspase-3 protein in sham-operation group was weak or negative. The average gray value of c-jun mRNA and Caspase-3 protein in the IR group was significantly lower than that in the sham-operation group （49.52±4.13 vs. 95.48± 5.28; 74.73±4.29 vs. 162.38±9.16,P 〈 0.01）. The average gray value of c-jun mRNA and Caspase-3 protein in the NGF group was significantly higher than that in the IR group （63.96±4.25 vs.49.52±4.13; 83.98± 4.13 vs. 74.73±4.29, P〈 0.05）. CONCLUSION： NGF can protect ischemic neurons by down-regulating the expression of c-jun mRNA and Caspase-3 protein in striate cortex of global cerebral ischemia rats.
文摘Recent studies have suggested an involvement of processing pathways for the initiation of cellular responses induced by topoisomerase-targeting drugs. Here, we showed that cellular exposure to camptothecin （CPT） induced formation of topoisomerase I cleavable complex （TOPlcc）, degradation of TOP1 and activation of DNA damage responses （DDR）. Transcription and proteasome-dependent proteolysis, but not replication, were involved in CPTo indneed TOPl degradation, while none of above three processing activities affected TOPlcc formation. Replication- and transcription-initiated proeessing （RIP and TIP） of TOPlee were identified as two independent pathways, which contribute distinctly to various CPT-activated DDR. Specifically, in cycling cells, RIP-processed TOPlec triggered the CPT-induced RPA pbosphorylation. At higher CPT dosages, the TIP pathway is required for other DDR activation, including ATM, p53 and Chkl/2 phosphorylation. The TIP pathway was further demonstrated to be S-phase independent by using three nonreplicating cell models. Furthermore, the effect of proteasome inhibitors mimicked that of transcription inhibition on the CPT-induced activation of DDR, suggesting the involvement of proteasome in the TIP pathway. Interestingly, the TIP pathway was important for TOPlcc-activated, but not ionization radiationactivated ATM, p53 and Chk2 phosphorylation. We have also found that pharmacological interferences of TIP and RIP pathways distinctively modulated the CPT-induced cell killing with treatments at low and high dosages, respec- tively. Together, our results support that both RIP and TIP pathways of TOPlcc are required for the activation of CPT-induced DDR and cytotoxicity.
文摘In this editorial,the roles of orosomucoid(ORM)in the diagnoses and follow-up assessments of both nonneoplastic diseases and liver tumors are discussed with respect to the publication by Zhu et al presented in the previous issue of World Journal of Gastroenterology(2020;26(8):840-817).ORM,or alpha-1 acid glycoprotein(AGP),is an acute-phase protein that constitutes 1%to 3%of plasma proteins in humans and is mainly synthesized in the liver.ORM exists in serum as two variants:ORM1 and ORM2.Although the variants share 89.6%sequence identity and have similar biological properties,ORM1 constitutes the main component of serum ORM.An interesting feature of ORM is that its biological effects differ according to variations in glycosylation patterns.This variable feature makes ORM an attractive target for diagnosing and monitoring many diseases,including those of the liver.Recent findings suggest that a sharp decrease in ORM level is an important marker for HBV-associated acute liver failure(ALF),and ORM1 plays an important role in liver regeneration.In viral hepatitis,increases in both ORM and its fucosylated forms and the correlation of these increases with fibrosis progression suggest that this glycoprotein can be used with other markers as a noninvasive method in the follow-up assessment of diseases.In addition,similar findings regarding the level of the asialylated form of ORM,called asialo-AGP(AsAGP),have been reported in a follow-up assessment of fibrosis in chronic liver disease.An increase in ORM in serum has also been shown to improve hepatocellular carcinoma(HCC)diagnosis performance when combined with other markers.In addition,determination of the ORM level has been useful in the diagnosis of HCC with AFP concentrations less than 500 ng/mL.For monitoring patients with AFP-negative HCC,a unique trifucosylated tetra-antennary glycan of ORM may also be used as a new potential marker.The fact that there are very few studies investigating the expression of this glycoprotein and its variants in liver tissues constitutes a potential limitation,especially in terms of revealing all the effects of ORM on carcinogenesis and tumor behavior.Current findings indicate that ORM2 expression is decreased in tumors,and this is related to the aggressive course of the disease.Parallel to this finding,in HCC cell lines,ORM2 decreases HCC cell migration and invasion,supporting reports of its tumor suppressor role.In conclusion,the levels of ORM and its different glycosylated variants are promising additional biomarkers for identifying ALF,for monitoring fibrosis in viral hepatitis,and for diagnosing early HCC.Although there is evidence that the loss of ORM2 expression in HCC is associated with poor prognosis,further studies are needed to support these findings.Additionally,investigations of ORM expression in borderline dysplastic nodules and hepatocellular adenomas,which pose diagnostic problems in the differential diagnosis of HCC,especially in biopsy samples,may shed light on whether ORM can be used in histopathological differential diagnosis.
基金supported by Qianjiang Talents Project of Science Technology Department of Zhejiang Province(project number 2013R10078)(http://www.zjkjt.gov.cn/)Medical and Health Science Research Fund of Zhejiang Province(project number 2013KYB053,2008A034,2007A035,2006A019)(http://www.zjwst.gov.cn)
文摘The microRNA-21 （miR-21） is known to play a major role in cancer progression; however, its function in the cardiovascular system appears to be even more complex and conflicting. To characterize miR-21 expression in the plasma of individuals with or without metabolic syndrome （MetS）, 58 MetS cases and 96 non-MetS controls were investigated.
基金The authors wish to thank the National Natural Science Foundation of China(No.51773188)the Natural Science Foundation of Shandong Province(No.ZR2017MC072)+3 种基金the National Key Research and Development Program(No.2018YFC1105602)the Key Research and Development Program of Shandong Province(No.2016YYSP018)the Second Maker Program of Marine Biomedical Research Institute of Qingdao(No.MGTD20170002M)the Scientific and Technological Innovation Project Financially Supported by Qingdao National Laboratory for Marine Science and Technology(No.2015ASKJ02).
文摘STAT3 plays a particularly important role in several cancer-related signal transduction pathways.Silencing STAT3 via RNA interference or small molecule inhibitors induces the apoptosis of tumor cells,thereby inhibiting the growth of the tumors.In this study,short-hairpin RNA sequences targeting the STAT3 genes were designed,synthesized,and then connected to pGPU6/GFP/Neo plasmids as the shRNA-expression vectors.The expression of STAT3-shRNA was analyzed by real-time PCR,western blotting,and cell apoptosis assay to study the growth and apoptosis of the cells.Then,the effect of STAT3 knockdown on the NCI-H1650 cells was studied in a tumor mouse model.The results revealed that,after an in vitro transfection,the proliferation of NCI-H1650 cells was inhibited,and the cells were induced to apoptosis.The mRNA and protein expression levels of STAT3 were downregulated in the STAT3-shRNA group.In vivo,the tumor mass and volume in the STAT3-shRNA group were significantly lower than in the other two groups.Both the in vivo and in vitro results demonstrated a long-period inhibiting effect on NSCLC,especially in vivo,when the tumor inhibition rate could reach 50%in the STAT3-shRNA group,which is an exciting outcome.Moreover,the study of the conjugation of STAT3-shRNA and chitosan-based vectors revealed that they could be combined steadily with good cytocompati-bility and transfection efficiency.These results together provide convincing evidence for the application of STAT3-shRNA used in the treatment of non-small lung cancer,which could be a promoting prospect for the development of gene therapy.
基金supported by the National Natural Science Foundation of China(22020102003,22388101,22125701,22277064)National Key R&D Program of China(2021YFF1200300,2021YFF0701800,and 2022YFF0710000)China Postdoctoral Science Foundation(2022M711785)。
文摘Although there are no effective therapies to block or reverse Alzheimer’s disease(AD)progression at present,a promising therapeutic strategy is to reduce levels of amyloid𝛽(Aβ)proteins,which drive the formation of amyloid plaque,a primary hallmark in AD brains.Herein,we report that amphiphilic lipid-DNA molecules(LD)were designed by incorporating a long alkyl chain into the nucleotide base.It significantly down-regulated Alzheimer’s Aβ levels in vivo and in vitro.In contrast to small-molecule chemical drugs and antibody therapies,the assembled DNA nanoparticles allowed them to effectively cross the blood-brain barrier(BBB)and accumulate in the brain,increasing the therapeutic effects.Notably,lipid-DNA downregulated the levels of Aβ peptides significantly in vitro.AD mice model experiments demonstrated that the LD-treated groups exhibited a rapid cognition behavioral improvement,which was associated with brain engagement of LD and reduced Aβ levels.Thus,the molecularly engineered DNA nanomaterials effectively regulated Aβ peptides.This work might provide a promising DNA engineering strategy for AD treatment.
文摘Brassinosteroids are known regulators of meristem activity in Arabidopsis,with low levels being sufficient for normal growth within the proliferating cells of the meristem.Brassinosteroid biosynthesis enzymes are transcriptionally downregulated in response to increased brassinosteroid signaling activity,forming a negative feedback loop to modulate their own expression(Ackerman-Lavert et al.,2021;Vukašinovićet al.,2021).
基金supported by Ministerio de Ciencia e Innovación (MICINN BFU2008-01405)Ministerio de Economia y Competitividad (BFU2011-26989)+1 种基金Fundación Universitaria de Navarra (PIUNA-2008)Fundación Caja Navarra
文摘Elevated CO2 leads to a decrease in potential net photosynthesis in long-term experiments and thus to a reduction in potential growth. This process is known as photosynthetic downregulation. There is no agreement on the definition of which parameters are the most sensitive for detecting CO2 acclimation. In order to investigate the most sensitive photosynthetic and molecular markers of CO2 acclimation, the effects of elevated CO2, and associated elevated temperature were analyzed in alfalfa plants inoculated with different Sinorhizobium meliloti strains. Plants （Medicago sativa L. cv. Aragon） were grown in summer or autumn in temperature gradient greenhouses （TGG）. At the end of the experiment, all plants showed acclimation in both seasons, especially under elevated summer temperatures. This was probably due to the lower nitrogen （N） availability caused by decreased N2-fixation under higher temperatures. Photosynthesis measured at growth CO2 concentration, rubisco in vitro activity and maximum rate of carboxylation were the most sensitive parameters for detecting downregulation. Severe acclimation was also related with decreases in leaf nitrogen content associated with declines in rubisco content （large and small subunits） and activity that resulted in a drop in photosynthesis. Despite the sensitivity of rubisco content as a marker of acclimation, it was not coordinated with gene expression, possibly due to a lag between gene transcription and protein translation.
