MicroRNA-584-5p/RUNX family transcription factor 2 axis mediates hypoxia-induced osteogenic differentiation of periosteal stem cells

BACKGROUND The hypoxic environment during bone healing is important in regulating the differentiation of periosteal stem cells(PSCs)into osteoblasts or chondrocytes;however,the underlying mechanisms remain unclear.AIM To determine the effect of hypoxia on PSCs,and the expression of microRNA-584-5p(miR-584-5p)and RUNX family transcription factor 2(RUNX2)in PSCs was modulated to explore the impact of the miR-584-5p/RUNX2 axis on hypoxiainduced osteogenic differentiation of PSCs.METHODS In this study,we isolated primary mouse PSCs and stimulated them with hypoxia,and the characteristics and functional genes related to PSC osteogenic differentiation were assessed.Constructs expressing miR-584-5p and RUNX2 were established to determine PSC osteogenic differentiation.RESULTS Hypoxic stimulation induced PSC osteogenic differentiation and significantly increased calcified nodules,intracellular calcium ion levels,and alkaline phosphatase(ALP)activity in PSCs.Osteogenic differentiation-related factors such as RUNX2,bone morphogenetic protein 2,hypoxia-inducible factor 1-alpha,and ALP were upregulated;in contrast,miR-584-5p was downregulated in these cells.Furthermore,upregulation of miR-584-5p significantly inhibited RUNX2 expression and hypoxia-induced PSC osteogenic differentiation.RUNX2 was the target gene of miR-584-5p,antagonizing miR-584-5p inhibition in hypoxia-induced PSC osteogenic differentiation.CONCLUSION Our study showed that the interaction of miR-584-5p and RUNX2 could mediate PSC osteogenic differentiation induced by hypoxia.

Oligodendrocyte transcription factor 1 overexpression promotes oligodendrocyte transcription factor 2 expression in the brains of neonatal rats exposed to hypoxia

To examine the expression profiles of oligodendrocyte transcription factors 1 and 2 （Oligl and Olig2） and the interaction between these two proteins, Oligl was transfected into the lateral ventricles of neonatal rats subjected to hypoxia. Immunohistochemistry demonstrated that Olig2 was expressed throughout the nuclei in the brain, and expression increased at 3 days following hypoxia and was higher than levels at 7 days following Ad5-Oligl transfection. Western blot revealed that Oligl and Olig2 expression increased in Oligl-transfected brain cells 3 days after hypoxia, but Oligl and Olig2 expression decreased at 7 days. These results indicate that Oligl overexpression enhances Olig2 expression in brain tissues of hypoxia rats.

Prognostic significance of oligodendrocyte transcription factor 2 expression in glioma patients:A systematic review and metaanalys

BACKGROUND Gliomas are the most common primary central nervous system neoplasm.Despite recent advances in the diagnosis and treatment of gliomas,patient prognosis remains dismal.Therefore,it is imperative to identify novel diagnostic biomarkers and therapeutic targets of glioma to effectively improve treatment outcomes.AIM To investigate the association between oligodendrocyte transcription factor 2(Olig2)expression and the outcomes of glioma patients.METHODS The PubMed,Embase,Cochrane Library,and China National Knowledge Infrastructure databases were searched for studies(published up to October 2023)that investigated the relationship between Olig2 expression and prognosis of glioma patients.The quality of the studies was assessed using the Newcastle Ottawa Scale.Data analyses were performed using Stata Version 12.0 software.RESULTS A total of 1205 glioma patients from six studies were included in the metaanalysis.High Olig2 expression was associated with better outcomes in glioma patients[hazard ratio(HR):0.81;95%(confidence interval)CI:0.51-1.27;P=0.000].Furthermore,the results of subgroup meta-analysis showed that high expression of Olig2 was associated with poor overall survival in European patients(HR:1.34;95%CI:0.79-2.27)and better prognosis in Asian patients(HR:0.43;95%CI:0.22-0.84).The sensitivity analysis showed that no single study had a significant effect on pooled HR,and there was also no indication of publication bias according to the Egger’s and Begger’s P value test or funnel plot test.CONCLUSION High Olig2 expression may have a positive impact on the prognosis of glioma patients,and should be investigated further as a prognostic biomarker and therapeutic target for glioma.

Long non-coding RNA CDKN2B-AS1 promotes hepatocellular carcinoma progression via E2F transcription factor 1/G protein subunit alpha Z axis

BACKGROUND A series of long non-coding RNAs(lncRNAs)have been reported to play a crucial role in cancer biology.Some previous studies report that lncRNA CDKN2B-AS1 is involved in some human malignancies.However,its role in hepatocellular carcinoma(HCC)has not been fully deciphered.AIM To decipher the role of CDKN2B-AS1 in the progression of HCC.METHODS CDKN2B-AS1 expression in HCC was detected by quantitative real-time polymerase chain reaction.The malignant phenotypes of Li-7 and SNU-182 cells were detected by the CCK-8 method,EdU method,and flow cytometry,respectively.RNA immunoprecipitation was executed to confirm the interaction between CDKN2B-AS1 and E2F transcription factor 1(E2F1).Luciferase reporter assay and chromatin immunoprecipitation were performed to verify the binding of E2F1 to the promoter of G protein subunit alpha Z(GNAZ).E2F1 and GNAZ were detected by western blot in HCC cells.RESULTS In HCC tissues,CDKN2B-AS1 was upregulated.Depletion of CDKN2B-AS1 inhibited the proliferation of HCC cells,and the depletion of CDKN2B-AS1 also induced cell cycle arrest and apoptosis.CDKN2B-AS1 could interact with E2F1.Depletion of CDKN2B-AS1 inhibited the binding of E2F1 to the GNAZ promoter region.Overexpression of E2F1 reversed the biological effects of depletion of CDKN2B-AS1 on the malignant behaviors of HCC cells.CONCLUSION CDKN2B-AS1 recruits E2F1 to facilitate GNAZ transcription to promote HCC progression.

The R2R3-MYB transcription factor GaPC controls petal coloration in cotton

Although a few cases of genetic epistasis in plants have been reported, the combined analysis of genetically phenotypic segregation and the related molecular mechanism remains rarely studied. Here, we have identified a gene(named GaPC) controlling petal coloration in Gossypium arboreum and following a heritable recessive epistatic genetic model. Petal coloration is controlled by a single dominant gene,GaPC. A loss-of-function mutation of GaPC leads to a recessive gene Gapc that masks the phenotype of other color genes and shows recessive epistatic interactions. Map-based cloning showed that GaPC encodes an R2R3-MYB transcription factor. A 4814-bp long terminal repeat retrotransposon insertion at the second exon led to GaPC loss of function and disabled petal coloration. GaPC controlled petal coloration by regulating the anthocyanin and flavone biosynthesis pathways. Expression of core genes in the phenylpropanoid and anthocyanin pathways was higher in colored than in white petals. Petal color was conferred by flavonoids and anthocyanins, with red and yellow petals rich in anthocyanin and flavonol glycosides, respectively. This study provides new insight on molecular mechanism of recessive epistasis,also has potential breeding value by engineering GaPC to develop colored petals or fibers for multifunctional utilization of cotton.

Novel Mutation of Cleidocranial Dysplasia-related Frameshift Runt-related Transcription Factor 2 in a Sporadic Chinese Case

Background： Cleidocranial dysplasia （CCD） is an autosomal dominant disease that affects the skeletal system. Common symptoms of CCD include hypoplasia or aplasia of the clavicles, delayed or even absent closure of the fontanels, midface hypoplasia, short stature, and delayed eruption of permanent and supernumerary teeth. Previous studies reported a connection between CCD and the haploinsufficiency of runt-related transcription factor 2 （RUNX2）. Here, we report a sporadic Chinese case presenting typical symptoms of CCD. Methods： We made genetic testing on this sporadic Chinese case and identified a novel RUNX2 ffameshift mutation： c.1111 dupT. In situ immunofluorescence microscopy and osteocalcin promoter luciferase assay were performed to compare the functions of the RUNX2 mutation with those of wild-type RUNX2. Results： RUNX2 mutation was observed in the perinuclear region, cytoplasm, and nuclei. In contrast, wild-type RUNX2 was confined in the nuclei, which indicated that the subcellular compartmentalization of RUNX2 mutation was partially perturbed. The transactivation function on osteocalcin promoter of the RUNX2 mutation was obviously abrogated. Conclusions： We identified a sporadic CCD patient carrying a novel insertion/frameshift mutation of RUNX2. This finding expanded our understanding of CCD-related phenotypes.

Upregulation of miR-34c after silencing E2F transcription factor 1 inhibits paclitaxel combined with cisplatin resistance in gastric cancer cells

BACKGROUND MicroRNA 34c(miR-34c)has been reported to be associated with malignant types of cancer,however,it remains unknown whether miR-34c is involved in chemoresistance in gastric cancer(GC).AIM To investigate the effect of miR-34c and its upstream transcription factor E2F1 on paclitaxel combined with cisplatin resistance in GC cells.METHODS Paired GC tissues and adjacent normal tissues were randomly sampled from 74 GC patients.miR-34c and E2F1 were detected by real-time quantitative PCR(qPCR)and Western blot.In addition,the drug resistance of GC cells to paclitaxel and cisplatin was induced by concentration gradient increasing methods,and changes in miR-34c and E2F1 during this process were measured.Furthermore,E2F1 and miR-34c overexpression or underexpression vectors were constructed and transfected into drug-resistant GC cells.MTT was employed to test the sensitivity of cells to paclitaxel combined with cisplatin,qPCR was adopted to detect the expression of miR-34c,Western blot was applied to detect the expression levels of E2F1,drug resistance-related proteins and apoptosis-related proteins,and flow cytometry was used for the determination of cell apoptosis and cell cycle status.RESULTS E2F1 was overexpressed while miR-34c was underexpressed in GC.After inducing GC cells to be resistant to paclitaxel and cisplatin,E2F1 expression increased while miR-34c expression decreased.Both silencing E2F1 and overexpressing miR-34c could increase the sensitivity of drug-resistant GC cells to paclitaxel combined with cisplatin,promote cell apoptosis and inhibit cell proliferation.Among which,silencing E2F1 could reduce the expression of drug resistance-related proteins and apoptosis-related proteins,while over-expression of miR-34c could upregulate the expression of apoptosis-related proteins without affecting the expression of MDR-1,MRP and other drug resistance-related proteins.Rescue experiments demonstrated that inhibiting miR-34c could significantly weaken the sensitization of drug resistant cells,and Si E2F1 to paclitaxel combined with cisplatin.CONCLUSION E2F1 inhibits miR-34c to promote the proliferation of GC cells and enhance the resistance to paclitaxel combined with cisplatin,and silencing E2F1 is conducive to improving the efficacy of paclitaxel combined with cisplatin in GC cells.

Genome-Wide Identification of Zn_(2)Cys_(6 ) Class Fungal-Specific Transcription Factors(ZnFTFs)and Functional Analysis of UvZnFTFI in Ustilaginoidea virens

Transcription factors(TFs)orchestrate the regulation of cellular gene expression and thereby determine cell functionality.In this study,we analyzed the distribution of TFs containing domains,which named as ZnFTFs,both in ascomycete and basidiomycete fungi.We found that ZnFTFs were widely distributed in these fungal species,but there was more expansion of the ZnFTF class in Ascomycota than Basidiomycota.We identified 40 ZnFTFs in Ustilaginoidea virens,and demonstrated the involvement of UvZnFTF1 in vegetative growth,conidiation,pigment biosynthesis and pathogenicity.RNA-Seq analysis suggested that UvZnFTF1 may regulate different nutrient metabolism pathways,the production of secondary metabolites,and the expression of pathogen-host interaction genes and secreted protein-encodi ng genes.Analysis of the distributi on of differe nt fungal TFs in U.virens further dem on strated that UvZnFTFs make up a large TF family and may play essential biological roles in U.virens.

JA-mediated MYC2/LOX/AOS feedback loop regulates osmotic stress response in tea plant

Osmotic stress caused by low-temperature,drought and salinity was a prevalent abiotic stress in plant that severely inhibited plant development and agricultural yield,particularly in tea plant.Jasmonic acid(JA)is an important phytohormone involving in plant stress.However,underlying molecular mechanisms of JA modulated osmotic stress response remains unclear.In this study,high concentration of mannitol induced JA accumulation and increase of peroxidase activity in tea plant.Integrated transcriptome mined a JA signaling master,MYC2 transcription factor is shown as a hub regulator that induced by mannitol,expression of which positively correlated with JA biosynthetic genes(LOX and AOS)and peroxidase genes(PER).CsMYC2 was determined as a nuclei-localized transcription activator,furthermore,ProteinDNA interaction analysis indicated that CsMYC2 was positive regulator that activated the transcription of CsLOX7,CsAOS2,CsPER1 and CsPER3via bound with their promoters,respectively.Suppression of CsMYC2 expression resulted in a reduced JA content and peroxidase activity and osmotic stress tolerance of tea plant.Overexpression of CsMYC2 in Arabidopsis improved JA content,peroxidase activity and plants tolerance against mannitol stress.Together,we proposed a positive feedback loop mediated by CsMYC2,CsLOX7 and CsAOS2 which constituted to increase the tolerance of osmotic stress through fine-tuning the accumulation of JA levels and increase of POD activity in tea plant.

MND1通过与KLF6结合形成MND1-KLF6-E2F1正反馈环加速细胞周期进程促进肺腺癌进展

背景与目的在全球范围内,肺腺癌(lung adenocarcinoma,LUAD)在肺癌患者中所占比例不断升高,肺腺癌在癌症相关死亡中所占比例很高。本研究旨在筛选出新的癌基因,为肺腺癌治疗提供潜在靶点,探究肺腺癌发生发展的机制。方法我们通过分析基因表达综合数据库(Gene Expression Omnibus,GEO)和癌症基因组图谱(The Cancer Genome Atlas,TCGA)的数据,并进行转录组筛选和生存分析,获得了一个潜在的肺腺癌风险生物标志物——减数分裂核分裂1(meiotic nuclear divisions 1,MND1)。我们通过细胞活力检测和皮下异种移植瘤模型验证MND1在肺腺癌细胞增殖和肿瘤生长中的致癌作用。通过质谱、免疫共沉淀(co-immunoprecipitation,Co-IP)和染色质免疫共沉淀(chromatin immunoprecipitation,ChIP)等实验探讨其潜在分子机制。结果通过组织芯片染色和第三方数据分析评估,MND1高表达是肺腺癌患者总生存期的独立风险因素。体内和体外试验结果表明,MND1通过加速细胞周期进程促进肺腺癌细胞增殖。Co-IP、ChIP和双荧光素酶报告基因实验结果显示,MND1竞争性地与肿瘤抑制基因KLF6(kruppel-like factor 6,KLF6)结合,从而保护E2F转录因子1(E2F transcription factor 1,E2F1)免受KLF6诱导的转录抑制。荧光素酶报告基因和ChIP分析发现,E2F1通过反馈方式与MND1启动子结合,进而激活MND1转录。结论在肺腺癌中,MND1、KLF6和E2F1形成正反馈环调控细胞周期,导致肺腺癌顺铂耐药。MND1对肿瘤恶性进展至关重要,可能是肺腺癌潜在的治疗靶点。

The bHLH Transcription Factors MYC2, MYC3, and MYC4 Are Required for Jasmonate-Mediated Inhibition of Flowering in Arabidopsis

Dear Editor,In plants, the floral transition is flexibly controlled by various environmental conditions and endogenous developmental cues. In Arabidopsis, six major flowering pathways respond to changes in these factors （Fornara et al., 2010）. The photoperiod, vernalization, and ambient pathways monitor exogenous signals from the environment such as day length, minimum winter temperature, and ambient temperature （Fornara et al., 2010）. By contrast, the autonomous, gibberellin, and age pathways respond to endogenous cues linked to developmental status （Fornara et al., 2010）. Accumulating evidence indicates that the six flowering pathways converge in a network to regulate floral integrator genes FLOWERING LOCUS T （FT）, TWIN SISTER OF FT （TSF）, and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 （Fornara et al., 2010）.

The Jasmonate-Responsive AP2/ERF Transcription Factors AaERF1 and AaERF2 Positively Regulate Artemisinin Biosynthesis in Artemisia annua L.

Plants of Artemisia annua produce artemisinin, a sesquiterpene lactone widely used in malaria treatment. Amorpha-4,11-diene synthase （ADS）, a sesquiterpene synthase, and CYP71AV1, a P450 monooxygenase, are two key enzymes of the artemisinin biosynthesis pathway. Accumulation of artemisinin can be induced by the phytohormone jasmonate （JA）. Here, we report the characterization of two JA-responsive AP2 family transcription factors-AaERF1 and AaERF2-from A. annua L. Both genes were highly expressed in inflorescences and strongly induced by JA. Yeast one- hybrid and electrophoretic mobility shift assay （EMSA） showed that they were able to bind to the CRTDREHVCBF2 （CBF2） and RAVlAAT （RAA） motifs present in both ADS and CYP71AV1 promoters. Transient expression of either AaERF1 or AaERF2 in tobacco induced the promoter activities of ADS or CYP71AV1, and the transgenic A. annua plants overexpressing either transcription factor showed elevated transcript levels of both ADS and CYP71AV1, resulting in increased accumulation of artemisinin and artemisinic acid. By contrast, the contents of these two metabolites were reduced in the RNAi transgenic lines in which expression of AaERF1 or AaERF2 was suppressed. These results demonstrate that AaERF1 and AaERF2 are two positive regulators of artemisinin biosynthesis and are of great value in genetic engineering of arte- misinin production.

Hairy Leaf 6, an AP2/ERF Transcription Factor, Interacts with OsWOX3B and Regulates Trichome Formation in Rice

Trichome formation has been extensively studied as a mechanistic model for epidermal cell differentiation and cell morphogenesis in plants. However, the genetic and molecular mechanisms underlying trichome formation （i.e., initiation and elongation） in rice remain largely unclear. Here, we report an AP2/ERF transcription factor, Hairy Leaf 6 （HL6）, which controls trichome formation in rice. Functional analyses revealed that HL6 transcriptionally regulates trichome elongation in rice, which is dependent on functional OsWOX3B, a homeodomain-containing protein that acts as a key regulator in trichome initiation. Biochemical and molecular genetic analyses demonstrated that HL6 physically interacts with OsWOX3B, and both of them regulate the expression of some auxin-related genes during trichome formation, in which OsWOX3B likely enhances the binding ability of HL6 with one of its direct target gene, OsYUCCA5. Popu- lation genetic analysis indicated that HL6 was under negative selection during rice domestication. Taken together, our findings provide new insights into the molecular regulatory network of trichome formation in rice.

Genome-wide identification and analysis of AP2/ERF transcription factors related to camptothecin biosynthesis in Camptotheca acuminata

Camptotheca acuminata produces camptothecin(CPT),a monoterpene indole alkaloid(MIA)that is widely used in the treatment of lung,colorectal,cervical,and ovarian cancers.Its biosynthesis pathway has attracted significant attention,but the regulation of CPT biosynthesis by the APETALA2/ethylene-responsive factor(AP2/ERF)transcription factors(TFs)remains unclear.In this study,a systematic analysis of the AP2/ERF TFs family in C.acuminata was performed,including phylogeny,gene structure,conserved motifs,and gene expression profiles in different tissues and organs(immature bark,cotyledons,young flower,immature fruit,mature fruit,mature leaf,roots,upper stem,and lower stem)of C.acuminata.A total of 198 AP2/ERF genes were identified and divided into five relatively conserved subfamilies,including AP2(26 genes),DREB(61 genes),ERF(92 genes),RAV(18 genes),and Soloist(one gene).The combination of gene expression patterns in different C.acuminata tissues and organs,the phylogenetic tree,the co-expression analysis with biosynthetic genes,and the analysis of promoter sequences of key enzymes genes involved in CPT biosynthesis pathways revealed that eight AP2/ERF TFs in C.acuminata might be involved in CPT synthesis regulation,which exhibit relatively high expression levels in the upper stem or immature bark.Among these,four genes(Cac AP2/ERF123,Cac AP2/ERF125,Cac AP2/ERF126,and Cac AP2/ERF127)belong to the ERF–B2 subgroup;two genes(Cac AP2/ERF149 and Cac AP2/ERF152)belong to the ERF–B3 subgroup;and two more genes(Cac AP2/ERF095 and Cac AP2/ERF096)belong to the DREB–A6 subgroup.These results provide a foundation for future functional characterization of the AP2/ERF genes to enhance the biosynthesis of CPT compounds of C.acuminata.

Alternative Splicing in the Anthocyanin Fruit Gene Encoding an R2R3 MYB Transcription Factor Affects Anthocyanin Biosynthesis in Tomato Fruits

Tomato(Solanum lycopersicum)fruits are typically red at ripening,with high levels of carotenoids and a low content in flavonoids.Considerable work has been done to enrich the spectrum of their healthbeneficial phytochemicals,and interspecific crosses with wild species have successfully led to purple anthocyanin-colored fruits.The Aft(Anthocyanin fruit)tomato accession inherited from Solanum chilense the ability to accumulate anthocyanins in fruit peel through the introgression of loci controlling anthocyanin pigmentation,including four R2R3 MYB transcription factor-encoding genes.Here,we carried out a comparative functional analysis of these transcription factors in wild-type and Aft plants,and tested their ability to take part in the transcriptional complexes that regulate the biosynthetic pathway and their effi-ciency in inducing anthocyanin pigmentation.Significant differences emerged for SlAN2like,both in the expression level and protein functionality,with splicing mutations determining a complete loss of function of the wild-type protein.This transcription factor thus appears to play a key role in the anthocyanin fruit pigmentation.Our data provide new clues to the long-awaited genetic basis of the Aft phenotype and contribute to understand why domesticated tomato fruits display a homogeneous red coloration without the typical purple streaks observed in wild tomato species.

The contribution of oligodendrocytes and oligodendrocyte progenitor cells to central nervous system repair in multiple sclerosis： perspectives for remyelination therapeutic strategies

Oligodencrocytes（OLs） are the main glial cells of the central nervous system involved in myelination of axons. In multiple sclerosis（MS）, there is an imbalance between demyelination and remyelination processes, the last one performed by oligodendrocyte progenitor cells（OPCs） and OLs, resulting into a permanent demyelination, axonal damage and neuronal loss. In MS lesions, astrocytes and microglias play an important part in permeabilization of blood-brain barrier and initiation of OPCs proliferation. Migration and differentiation of OPCs are influenced by various factors and the process is finalized by insufficient acummulation of OLs into the MS lesion. In relation to all these processes, the author will discuss the potential targets for remyelination strategies.

Identification of a novel pathway involving a GATA transcription factor in yeast and possibly in plant Zn uptake and homeostasis

To gain a better understanding of the regulation of Zn homeostasis in plants and the degree of conservation of Zn homeostasis between plants and yeast, a cDNA library from the Zn/Cd hyperaccumulating plant species, Noccaea caerulescens, was screened for its ability to restore growth under Zn limiting conditions in the yeast mutant zaplA. ZAP1 is a transcription factor that activates the Zn dependent transcription of yeast genes involved in Zn uptake, including ZRT1, the yeast high affinity Zn transporter. From this screen two members of the E2F family of transcription factors were found to activate ZRT1 expression in a Zn independent manner. The activation of ZRTI by the plant E2F proteins involves E2F- mediated activation of a yeast GATA transcription factor which in turn activates ZRT1 expression. A ZRT1 promoter region necessary for activation by E2F and GATA proteins is upstream of two zinc responsive elements previously shown to bind ZAP1 in ZRT1. This activation may not involve direct binding of E2F to the ZRT1 promoter. The expression of E2F genes in yeast does not replace function of ZAP1; instead it appears to activate a novel GATA regulatory pathway involved in Zn uptake and homeostasis that is not Zn responsive.

Edaravone protects against oxygen-glucose-serum deprivation/restoration-induced apoptosis in spinal cord astrocytes by inhibiting integrated stress response

We previously found that oxygen-glucose-serum deprivation/restoration（OGSD/R） induces apoptosis of spinal cord astrocytes, possibly via caspase-12 and the integrated stress response, which involves protein kinase R-like endoplasmic reticulum kinase（PERK）, eukaryotic initiation factor 2-alpha（eIF2α） and activating transcription factor 4（ATF4）. We hypothesized that edaravone, a low molecular weight, lipophilic free radical scavenger, would reduce OGSD/R-induced apoptosis of spinal cord astrocytes. To test this, we established primary cultures of rat astrocytes, and exposed them to 8 hours/6 hours of OGSD/R with or without edaravone（0.1, 1, 10, 100 μM） treatment. We found that 100 μM of edaravone significantly suppressed astrocyte apoptosis and inhibited the release of reactive oxygen species. It also inhibited the activation of caspase-12 and caspase-3, and reduced the expression of homologous CCAAT/enhancer binding protein, phosphorylated（p）-PERK, p-eIF2α, and ATF4. These results point to a new use of an established drug in the prevention of OGSD/R-mediated spinal cord astrocyte apoptosis via the integrated stress response.

MoLrp1-mediated signaling induces nuclear accumulation of MoMsn2 to facilitate fatty acid oxidation for infectious growth of the rice blast fungus

Fatty acid b-oxidation is critical for fatty acid degradation and cellular development.In the rice blast fungus Magnaporthe oryzae,fatty acid b-oxidation is reported to be important mainly for turgor generation in the appressorium.However,the role of fatty acid b-oxidation during invasive hyphal growth is rarely documented.We demonstrated that blocking peroxisomal fatty acid b-oxidation impaired lipid droplet(LD)degradation and infectious growth of M.oryzae.We found that the key regulator of pathogenesis,MoMsn2,which we identified previously,is involved in fatty acid b-oxidation by targeting MoDCI1(encoding dienoyl-coenzyme A[CoA]isomerase),which is also important for LD degradation and infectious growth.Cytological observations revealed that MoMsn2 accumulated from the cytosol to the nucleus during early infection or upon treatment with oleate.We determined that the low-density lipoprotein receptor-related protein MoLrp1,which is also involved in fatty acid b-oxidation and infectious growth,plays a critical role in the accumulation of MoMsn2 from the cytosol to the nucleus by activating the cyclic AMP signaling pathway.Our results provide new insights into the importance of fatty acid oxidation during invasive hyphal growth,which is modulated by MoMsn2 and its related signaling pathways in M.oryzae.

Rhizoma Drynariae-derived nanovesicles reverse osteoporosis by potentiating osteogenic differentiation of human bone marrow mesenchymal stem cells via targeting ERα signaling

Although various anti-osteoporosis drugs are available,the limitations of these therapies,including drug resistance and collateral responses,require the development of novel anti-osteoporosis agents.Rhizoma Drynariae displays a promising anti-osteoporosis effect,while the effective component and mechanism remain unclear.Here,we revealed the therapeutic potential of Rhizoma Drynariae-derived nanovesicles(RDNVs)for postmenopausal osteoporosis and demonstrated that RDNVs potentiated osteogenic differentiation of human bone marrow mesenchymal stem cells(hBMSCs)by targeting estrogen receptor-alpha(ERα).RDNVs,a natural product isolated from fresh Rhizoma Drynariae root juice by differential ultracentrifugation,exhibited potent bone tissue-targeting activity and anti-osteoporosis efficacy in an ovariectomized mouse model.RDNVs,effectively internalized by hBMSCs,enhanced proliferation and ERαexpression levels of hBMSC,and promoted osteogenic differentiation and bone formation.Mechanistically,via the ERαsignaling pathway,RDNVs facilitated mRNA and protein expression of bone morphogenetic protein 2 and runt-related transcription factor 2 in hBMSCs,which are involved in regulating osteogenic differentiation.Further analysis revealed that naringin,existing in RDNVs,was the active component targeting ERαin the osteogenic effect.Taken together,our study identified that naringin in RDNVs displays exciting bone tissue-targeting activity to reverse osteoporosis by promoting hBMSCs proliferation and osteogenic differentiation through estrogen-like effects.