Immobilization of antimony in soil and groundwater using ferro-magnesium bimetallic organic frameworks.

Sb(III) is often detected in contaminated soil and groundwater. Hence, high-efficiency technology is needed. In this study, bimetallic organic frameworks were used for the first time to immobilize Sb(III) from contaminated soil and groundwater. The materials were synthesized by the hydrothermal method. Both ends of the prepared material were hexagonal tip rods, and the length became shorter as the ratio of Fe/Mg decreased. The bimetallic organic framework with a Fe/Mg feeding ratio of 0.5 was the optimum material for Sb(III) removal, which could effectively immobilize Sb(III). The adsorption isotherm was fitted well with the Freundlich model, and the optimal adsorption capacity can reach 106.97 mg/g. The adsorption capacity of 84% can be completed in 10 min, which conformed to the pseudo-second-order kinetics. The Fe3+ could enhance the stability of the material, and the Mg2+ was conducive to freeing up adsorption sites for binding Sb(III) and forming stable chemical adsorption. Ion exchange is the predominant mechanism to remove Sb(III). After 14 days of remediation of Sb(III) contaminated soil, the Toxicity Characteristic Leaching Procedure (TCLP)-leached concentrations of Sb(III) were reduced by 86%, 91% and 94% when the material dosages were 1%, 2% and 3%, respectively. Immobilization of Sb(III) in soil resulted in a conversion of antimony speciation from more easily bioavailable species to less bioavailable species, further contributing to reduce the environmental risk of antimony. The results indicate that ferro-magnesium bimetallic organic frameworks may serve as a kind of promising materials for the immobilization of Sb(III) in contaminated soil and groundwater.

miR-21-5p targets SKP2 to reduce osteoclastogenesis in a mouse model of osteoporosis.

Osteoporosis results from an imbalance between bone formation and bone resorption. Traditional drugs for treating osteoporosis are associated with serious side effects, and thus, new treatment methods are required. This study investigated the role of differentially expressed microRNAs during osteoclast differentiation and osteoclast activity during osteoarthritis as well as the associated underlying mechanisms. We used a microarray to screen microRNAs that decreased in the process of osteoclast differentiation and verified miR-21-5p to decrease significantly using RT-qPCR. In follow-up experiments, we found that miR-21-5p targets SKP2 to regulate osteoclast differentiation. In vivo, ovariectomized mice were used to simulate perimenopausal osteoporosis induced by estrogen deficiency, and miR-21-5p treatment inhibited bone resorption and maintained bone cortex and trabecular structure. These results suggest that miR-21-5p is a new therapeutic target for osteoporosis.

Dual-dynamic-bond cross-linked injectable hydrogel of multifunction for intervertebral disc degeneration therapy.

Developing smart hydrogels with integrated and suitable properties to treat intervertebral disc degeneration (IVDD) by minimally invasive injection is of high desire in clinical application and still an ongoing challenge. In this work, an extraordinary injectable hydrogel PBNPs@OBG (Prussian blue nanoparticles@oxidized hyaluronic acid/borax/gelatin) with promising antibacterial, antioxidation, rapid gelation, and self-healing characteristics was designed via dual-dynamic-bond cross-linking among the oxidized hyaluronic acid (OHA), borax, and gelatin. The mechanical performance of the hydrogel was studied by dynamic mechanical analysis. Meanwhile, the swelling ratio and degradation level of the hydrogel was explored. Benefiting from its remarkable mechanical properties, sufficient tissue adhesiveness, and ideal shape-adaptability, the injectable PBNPs containing hydrogel was explored for IVDD therapy. Astoundingly, the as-fabricated hydrogel was able to alleviate H2O2-induced excessive ROS against oxidative stress trauma of nucleus pulposus, which was further revealed by theoretical calculations. Rat IVDD model was next established to estimate therapeutic effect of this PBNPs@OBG hydrogel for IVDD treatment in vivo. On the whole, combination of the smart multifunctional hydrogel and nanotechnology-mediated antioxidant therapy can serve as a fire-new general type of therapeutic strategy for IVDD and other oxidative stress-related diseases.

BRD4 inhibition regulates MAPK, NF-κB signals, and autophagy to suppress MMP-13 expression in diabetic intervertebral disc degeneration.

Diabetes mellitus may lead to intervertebral disc degeneration (IVDD). Matrix metalloproteinase-13 (MMP-13) is one of the major catabolic factors in extracellular matrix (ECM) metabolism of nucleus pulposus cells (NPCs) and contributes to diabetic IVDD. Bromodomain-containing protein 4 (BRD4) is a member of the bromodomain and extraterminal protein family and is implicated in chronic inflammation. Here, we report that the expression of BRD4 and MMP-13 was elevated in diabetic nucleus pulposus tissues as well as in advanced glycation end products (AGEs)-treated NPCs; also, the regulatory effect of BRD4 on MMP-13 was studied. We found that MMP-13 was regulated by MAPK and NF-κB signaling as well as autophagy in AGEs-treated NPCs. Next, we explored the role of BRD4 in regulation of MAPK, NF-κB signaling, and autophagy. The results showed that BRD4 is the upstream regulator of all of these 3 factors, and inhibition of BRD4 may suppress MAPK and NF-κB signaling while activating autophagy in AGEs-treated NPCs. Finally, we demonstrated that BRD4 inhibition may suppress MMP-13 expression in diabetic NPCs in vitro as well as in vivo; meanwhile, it may preserve ECM in diabetic rats. Our study demonstrates that inhibition of BRD4 may suppress MAPK and NF-κB signaling and activate autophagy to suppress MMP-13 expression in diabetic IVDD, and diabetic IVDD may be compromised by BRD4 inhibitors.-Wang, J., Hu, J., Chen, X., Huang, C., Lin, J., Shao, Z., Gu, M., Wu, Y., Tian, N., Gao, W., Zhou, Y., Wang, X., Zhang, X. BRD4 inhibition regulates MAPK, NF-κB signals, and autophagy to suppress MMP-13 expression in diabetic intervertebral disc degeneration.

BRD4 inhibition attenuates inflammatory response in microglia and facilitates recovery after spinal cord injury in rats.

The pathophysiology of spinal cord injury (SCI) involves primary injury and secondary injury. For the irreversibility of primary injury, therapies of SCI mainly focus on secondary injury, whereas inflammation is considered to be a major target for secondary injury; however the regulation of inflammation in SCI is unclear and targeted therapies are still lacking. In this study, we found that the expression of BRD4 was correlated with pro-inflammatory cytokines after SCI in rats; in vitro study in microglia showed that BRD4 inhibition either by lentivirus or JQ1 may both suppress the MAPK and NF-κB signalling pathways, which are the two major signalling pathways involved in inflammatory response in microglia. BRD4 inhibition by JQ1 not only blocked microglial M1 polarization, but also repressed the level of pro-inflammatory cytokines in microglia in vitro and in vivo. Furthermore, BRD4 inhibition by JQ1 can improve functional recovery and structural disorder as well as reduce neuron loss in SCI rats. Overall, this study illustrates that microglial BRD4 level is increased after SCI and BRD4 inhibition is able to suppress M1 polarization and pro-inflammatory cytokine production in microglia which ultimately promotes functional recovery after SCI.

Melatonin ameliorates intervertebral disc degeneration via the potential mechanisms of mitophagy induction and apoptosis inhibition.

Intervertebral disc degeneration (IDD) is a complicated disease in patients. The pathogenesis of IDD encompasses cellular oxidative stress, mitochondrion dysfunction and apoptosis. Melatonin eliminates oxygen free radicals, regulates mitochondrial homoeostasis and function, stimulates mitophagy and protects against cellular apoptosis. Therefore, we hypothesize that melatonin has beneficial effect on IDD by mitophagy stimulation and inhibition of apoptosis. The effects of melatonin on IDD were investigated in vitro and in vivo. For the former, melatonin diminished cellular apoptosis caused by tert-butyl hydroperoxide in nucleus pulposus (NP) cells. Mitophagy, as well as its upstream regulator Parkin, was activated by melatonin in both a dose and time-dependent manner. Mitophagy inhibition by cyclosporine A (CsA) partially eliminated the protective effects of melatonin against NP cell apoptosis, suggesting that mitophagy is involved in the protective effect of melatonin on IDD. In addition, melatonin was demonstrated to preserve the extracellular matrix (ECM) content of Collagen II, Aggrecan and Sox-9, while inhibiting the expression of matrix degeneration enzymes, including MMP-13 and ADAMTS-5. In vivo, our results demonstrated that melatonin treatment ameliorated IDD in a puncture-induced rat model. To conclude, our results suggested that melatonin protected NP cells against apoptosis via mitophagy induction and ameliorated disc degeneration, providing the potential therapy for IDD.

Genistein protects intervertebral discs from degeneration via Nrf2-mediated antioxidant defense system: An in vitro and in vivo study.

Oxidative stress has been reported to be closely associated with the development of intervertebral disc degeneration (IDD). IDD is one of the major causes of low back pain. Genistein (GES), one of the main isoflavones of soybean, has been shown to exert multiple biological functions on different diseases. Here, we tested the therapeutic potential of GES for IDD. In vitro experiments, we confirmed GES was nontoxic to rat nucleus pulposus cells (NPCs) within the concentration of 100 µM. Furthermore, GES was able to suppress apoptosis in tert-butyl hydroperoxide (TBHP)-treated NPCs. In the aspect of extracellular matrix (ECM), GES not only reduced metalloproteinase-13 (MMP-13) and a disintegrin-like and MMP thrombospondin type 1 motif 5 expression, but also increased aggrecan and type II collagen levels. Also, we found GES might rescue TBHP-induced NPCs degeneration by enhancing Nrf2-mediated antioxidant defense system. Silencing Nrf2 partly abolished the protective effects of GES on apoptosis and ECM disruption in TBHP-treated NPCs. Correspondingly, GES ameliorated IDD in a rat model by preserving morphology of degenerative intervertebral discs and promoting Nrf2 expression. To sum up, our study suggests that GES exerts protective effects in NPCs against degeneration and reveals the underlying mechanism of GES on Nrf2 activation in NPCs.

Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X.

Females have a greater immunological advantage than men, yet they are more prone to autoimmune disorders. The basis for this sex bias lies in the X chromosome, which contains many immunity-related genes. Female mammals use X chromosome inactivation (XCI) to generate a transcriptionally silent inactive X chromosome (Xi) enriched with heterochromatic modifications and XIST/Xist RNA, which equalizes gene expression between the sexes. Here, we examine the maintenance of XCI in lymphocytes from females in mice and humans. Strikingly, we find that mature naïve T and B cells have dispersed patterns of XIST/Xist RNA, and they lack the typical heterochromatic modifications of the Xi. In vitro activation of lymphocytes triggers the return of XIST/Xist RNA transcripts and some chromatin marks (H3K27me3, ubiquitin-H2A) to the Xi. Single-cell RNA FISH analysis of female T cells revealed that the X-linked immunity genes CD40LG and CXCR3 are biallelically expressed in some cells. Using knockout and knockdown approaches, we find that Xist RNA-binding proteins, YY1 and hnRNPU, are critical for recruitment of XIST/Xist RNA back to the Xi. Furthermore, we examined B cells from patients with systemic lupus erythematosus, an autoimmune disorder with a strong female bias, and observed different XIST RNA localization patterns, evidence of biallelic expression of immunity-related genes, and increased transcription of these genes. We propose that the Xi in female lymphocytes is predisposed to become partially reactivated and to overexpress immunity-related genes, providing the first mechanistic evidence to our knowledge for the enhanced immunity of females and their increased susceptibility for autoimmunity.

Polydatin suppresses nucleus pulposus cell senescence, promotes matrix homeostasis and attenuates intervertebral disc degeneration in rats.

Intervertebral disc degeneration (IVDD) is one of the major causes of low back pain. Polydatin (PD) has been shown to exert multiple pharmacological effects on different diseases; here, we test the therapeutic potential of PD for IVDD. In in-vitro experiments, we confirmed PD is nontoxic to nucleus pulposus cells (NPCs) under the concentration of 400 µmol/L. Furthermore, PD was able to decrease the level of senescence in TNF-α-treated NPCs, as indicated by ß-gal staining as well as senescence markers p53 and p16 expression. In the aspect of extracellular matrix (ECM), PD not only reduced metalloproteinase 3 (MMP-3), metalloproteinase 13 (MMP-13) and a disintegrin-like and metalloproteinase thrombospondin type 1 motif 4 (ADAMTS-4) expression, but also increased aggrecan and collagen II levels. Mitochondrion is closely related to cellular senescence and ECM homeostasis; mechanistically, we found PD may rescue TNF-α-induced mitochondrial dysfunction, and it may also promote Nrf2 expression and activity. Silencing Nrf2 partly abolished the protective effects of PD on mitochondrial homeostasis, senescence and ECM homeostasis in TNF-α-treated NPCs. Correspondingly, PD ameliorated IVDD in rat model by promoting Nrf2 activity, preserving ECM and inhibiting senescence in nucleus pulposus cells. To sum up, our study suggests that PD exerts protective effects in NPCs against IVDD and reveals the underlying mechanism of PD on Nrf2 activation in NPCs.

Polycomb protein SCML2 associates with USP7 and counteracts histone H2A ubiquitination in the XY chromatin during male meiosis.

Polycomb group proteins mediate transcriptional silencing in diverse developmental processes. Sex chromosomes undergo chromosome-wide transcription silencing during male meiosis. Here we report that mouse SCML2 (Sex comb on midleg-like 2), an X chromosome-encoded polycomb protein, is specifically expressed in germ cells, including spermatogonia, spermatocytes, and round spermatids. SCML2 associates with phosphorylated H2AX and localizes to the XY body in spermatocytes. Loss of SCML2 in mice causes defective spermatogenesis, resulting in sharply reduced sperm production. SCML2 interacts with and recruits a deubiquitinase, USP7, to the XY body in spermatocytes. In the absence of SCML2, USP7 fails to accumulate on the XY body, whereas H2A monoubiquitination is dramatically augmented in the XY chromatin. Our results demonstrate that the SCML2/USP7 complex constitutes a novel molecular pathway in modulating the epigenetic state of sex chromosomes during male meiosis.

Hydrogen sulfide protects against endoplasmic reticulum stress and mitochondrial injury in nucleus pulposus cells and ameliorates intervertebral disc degeneration.

It has been suggested that excessive apoptosis in intervertebral disc cells induced by inflammatory cytokines, such as interleukin (IL)-1ß, is related to the process of intervertebral disc degeneration (IVDD). Hydrogen sulfide (H2S), a gaseous signaling molecule, has drawn attention for its anti-apoptosis role in various pathophysiological processes in degenerative diseases. To date, there has been no investigation of the correlation of H2S production and IVDD or of the effects of H2S on IL-1ß-induced apoptosis in nucleus pulposus (NP) cells. Here, we found that the expression levels of cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CSE), two key enzymes in the generation of H2S, were significantly decreased in human degenerate NP tissues as well as in IL-1ß-treated NP cells. NaHS (H2S donor) administration showed a protective effect by inhibiting the endoplasmic reticulum (ER) stress response and mitochondrial dysfunction induced by IL-1ß stimulation in vitro, the effect was related to activation of the PI3K/Akt and ERK1/2 signaling pathways. Suppression of these pathways by specific inhibitors, LY294002 and PD98059, partially reduced the protective effect of NaHS. Moreover, in the percutaneous needle puncture disc degeneration rat tail model, disc degeneration was partially reversed by NaHS administration. Taken together, our results suggest that H2S plays a protective role in IVDD and the underlying mechanism involves PI3K/Akt and ERK1/2 signaling pathways-mediated suppression of ER stress and mitochondrial dysfunction in IL-1ß-induced NP cells.

Epigenetic regulation of miR-302 by JMJD1C inhibits neural differentiation of human embryonic stem cells.

It has been recently reported that the regulatory circuitry formed by OCT4, miR-302, and NR2F2 controls both pluripotency and neural differentiation of human embryonic stem cells (hESCs). We show here that JMJD1C, a histone 3 lysine 9 (H3K9) demethylase expressed in hESCs, directly interacts with this circuitry. hESCs with stable knockdown of JMJD1C remain pluripotent while having reduced miR-302 expression, decreased BMP signaling, and enhanced TGFß signaling. JMJD1C binds to the miR-302 promoter and reduces H3K9 methylation. Withdrawal of basic fibroblast growth factor (bFGF) from the culture induces neural differentiation of the knockdown, but not the control, cells within 3 days, accompanied by elevated NR2F2 expression. This can be attenuated with miR-302 mimics or an H3K9 methytransferase inhibitor. Together, our findings suggest that JMJD1C represses neural differentiation of hESCs at least partially by epigenetically sustaining miR-302 expression and that JMJD1C knockdown is sufficient to trigger neural differentiation upon withdrawal of exogenous bFGF.

CircRNA circTIAM1 promotes papillary thyroid cancer progression through the miR-646/HNRNPA1 signaling pathway.

Papillary thyroid cancer (PTC) is a common endocrine tumor with a rapidly increasing incidence in recent years. Although the majority of PTCs are relatively indolent and have a good prognosis, a certain proportion is highly aggressive with lymphatic metastasis, iodine resistance, and easy recurrence. Circular RNAs (circRNAs) are a class of noncoding RNAs that are linked to a variety of tumor processes in several cancers, including PTC. In the current study, circRNA high-throughput sequencing was performed to identify alterations in circRNA expression levels in PTC tissues. circTIAM1 was then selected because of its increased expression in PTC and association with apoptosis, proliferation, and migration of PTC cells in vitro and in vivo. Mechanistically, circTIAM1 acted as a sponge of microRNA-646 and functioned in PTC by targeting miR-646 and heterogeneous ribonucleoprotein A1. Fluorescence in situ hybridization and dual-luciferase reporter assays further confirmed these connections. Overall, our results reveal an important oncogenic role of circTIAM1 in PTC and may represent a potentially therapeutic target against PTC progression.

PLK1 Mitigates Intervertebral Disc Degeneration by Delaying Senescence of Nucleus Pulposus Cells.

Intervertebral disc degeneration (IVDD) is the primary cause of low back pain; however, the molecular mechanisms involved in the pathogenesis of IVDD are not fully understood. Polo-like kinase 1 (PLK1) plays numerous roles in the cell cycle, including in cell proliferation and senescence. To investigate the involvement of PLK1 in IVDD, we used patient tissues and an animal model of IVDD. Samples were analyzed via immunoblotting, quantitative real-time polymerase chain reaction (qPCR), immunofluorescence, and immunohistochemistry. Our results demonstrated that PLK1 expression was decreased in nucleus pulposus cells (NPCs) of degenerative IVDs. The inhibition of PLK1 kinase activity in normal NPCs increased the expression of p53 protein, inhibited cell proliferation, and induced senescence. Our results suggest that PLK1 regulates the degeneration of the IVD through p53, revealing the function and mechanism of PLK1 in IVDD and providing a theoretical basis and experimental evidence for the potential treatment of low back pain.

Oxidative stress-induced circKIF18A downregulation impairs MCM7-mediated anti-senescence in intervertebral disc degeneration.

Low back pain, triggered by intervertebral disc degeneration (IVDD), is one of the most common causes of disability and financial expenditure worldwide. However, except for surgical interventions, effective medical treatment to prevent the progression of IVDD is lacking. This study aimed to investigate the effects of circKIF18A, a novel circRNA, on IVDD progression and to explore its underlying mechanism in IVDD. In this study, we found that oxidative stress was positively correlated with nucleus pulposus cell (NPC) senescence in IVDD and that circKIF18A was downregulated in IVDD and attenuated senescent phenotypes such as cell cycle arrest and extracellular matrix degradation in NPCs. Mechanistically, circKIF18A competitively suppressed ubiquitin-mediated proteasomal degradation of MCM7, and the protective effects of circKIF18A on NPCs were partially mediated by MCM7 under oxidative stress. Intradiscal injection of adenoviral circKIF18A ameliorated IVDD in a rat model. This study revealed that circKIF18A regulates NPC degeneration by stabilizing MCM7 and identified a novel signaling pathway, the circKIF18A-MCM7 axis, for anti-senescence molecular therapy in IVDD.

Generation of histocompatible androgenetic embryonic stem cells using spermatogenic cells.

Androgenetic embryonic stem (aES) cells, produced by pronuclear transplantation, offer an important autologous pluripotent stem cell source. However, the isolation of aES cells, particularly individual-specific aES cells, with the use of fertilized embryos has limited the practical applications of this technology in humans. In this study, we applied a new approach, essentially described as somatic cell nuclear transfer, and generated three aES cell line types with the use of spermatogenic cells including primary spermatocytes, round spermatids, and mature spermatozoa as donor cells, omitting the need to use fertilized embryos. Although abnormality of chimeras and absent germline competency indicated that all three types of aES cells exhibited limited pluripotency, the epigenetic status of the aES cell lines tended to resemble normal ES cells during long-term culture, and some parental-specific imprinted genes were expressed at levels comparable to those of normal ES cells. Furthermore, the histocompatibility of the aES cells was investigated by transplanting the differentiation progenies of the aES cells into major histocompatibility (MHC)-matched and -mismatched recipient mice. The results indicated that these aES cells were histocompatible with MHC-matched mice after transplantation. Our study provides evidence that MHC-competent autologous aES cells could be generated from different spermatogenic cells using nuclear transfer into oocytes, a process that could avoid the use of fertilized embryos.

Microwave-enhanced reductive immobilization of high concentrations of chromium in a field soil using iron polysulfide.

High concentrations of Cr(VI) are often detected in contaminated soil. Yet, cost-effective remediation technologies have been lacking. In this study, we prepared a type of FeSx based on commercial FeSO4.7H2O and CaSx and tested a microwave-assisted technology based on FeSx for reductive immobilization of high concentrations of Cr(VI) in a field contaminated soil. The as-prepared FeSx particles appeared as a honeycomb-like and highly porous structure. The microwave-assisted FeSx reduction process was able to rapidly reduce the TCLP-based reachability of Cr(VI) from 391.8 to 2.6 mg·L-1. The dosage of FeSx, S/Fe molar ratio, initial moisture content, microwave power, and irradiation time can all affect the treatment effectiveness. After 500 days curing under atmospheric conditions, the TCLP-leached concentration of Cr remained below the regulatory limit of 5 mg·L-1, while other treatments failed to meet the goal. Sx2- or S2- served as the primary electron donors, whereas Fe facilitated the microwave absorption and the formation of the stable final product of FeCr2O4. S and Fe are mostly precipitated in soil. The microwave-assisted FeSx reduction was shown to be an effective approach to rapidly reduce the leachability of Cr(VI) in contaminated soil, especially in heavily contaminated soil.

Inhibition of intervertebral disc disease progression via the circPKNOX1-miR-370-3p-KIAA0355 axis.

The molecular mechanism underlying the development of intervertebral disc disease (IVDD) is not completely understood. Circular RNAs (circRNAs) play a significant role in the occurrence and development of various diseases, and studies have shown that circPKNOX1 is involved in the compensatory response of extracellular matrix synthesis and secretion of the nucleus pulposus (NP) cells. However, the mechanism through which circRNAs regulate IVDD progression remains unclear; therefore, in this study, we explored the significance of circPKNOX1 in IVDD. The expression of circRNAs in NP cells of normal and degenerative patients was detected using microarray analysis, and the role of circPKNOX1 in IVDD was confirmed using RT-qPCR. The interaction networks of circRNAs, miRNAs, and miRNA target genes were detected using bioinformatics analysis, RNA fluorescence in situ hybridization, and immunofluorescence analysis. We found that the expression of circPKNOX1 decreased in IVDD cells. The expression of circPKNOX1 in NP cells, observed using RT-qPCR and western blotting, was consistent with that observed using array screening. Overexpression of circPKNOX1 increased the expression of collagen II, aggrecan, and SOX9 and decreased that of ADAMTS4, ADAMTS-5, MMP3, and MMP13. We further demonstrated that circPKNOX1 played the role of a sponge by competitively binding miR-370-3p to reverse the inhibition of KIAA0355 expression. Our findings indicated that circPKNOX1 affected the progression of IVDD by regulating the expression of KIAA0355 via miR-370-3p. Therefore, circPKNOX1-based therapy may serve as an effective IVDD treatment strategy.

circSPG21 protects against intervertebral disc disease by targeting miR-1197/ATP1B3.

The abnormal expression of circular RNAs (circRNAs) is associated with numerous human diseases. This study investigated the mechanism by which circRNA acts as competitive endogenous RNA in the regulation of degenerative intervertebral disc disease (IVDD). Decreased expression of circSPG21 was detected in degenerated nucleus pulposus cells (NPCs), the function of circSPG21 in NPCs was explored and verified, and the downstream target of circSPG21 was investigated. The interaction between circSPG21 and miR-1197 and its target gene (ATP1B3) was studied by online database prediction and molecular biological verification. Finally, the circSPG21/miR-1197/ATP1B3 axis was verified in the mouse tail-looping model. The expression of circSPG21 in the nucleus pulposus in IVDD was directly related to an imbalance of anabolic and catabolic factors, which affected cell senescence. circSPG21 was found to play a role in human NPCs by acting as a sponge of miR-1197 and thereby affecting ATP1B3. The regulation of circSPG21 provides a potentially effective therapeutic strategy for IVDD.

The histone demethylase JMJD2C is stage-specifically expressed in preimplantation mouse embryos and is required for embryonic development.

Epigenetic modifications play a pivotal role in embryonic development by dynamically regulating DNA methylation and chromatin modifications. Although recent studies have shown that core histone methylation is reversible, very few studies have investigated the functions of the newly discovered histone demethylases during embryonic development. In the present study, we investigated the expression characteristics and function of JMJD2C, a histone demethylase that belongs to the JmjC-domain-containing histone demethylases, during preimplantation embryonic development of the mouse. We found that JMJD2C is stage-specifically expressed during preimplantation development, with the highest activity being observed from the two-cell to the eight-cell stage. Depletion of JMJD2C in metaphase II oocytes followed by parthenogenetic activation causes a developmental arrest before the blastocyst stage. Moreover, consistent with a previous finding in embryonic stem (ES) cells, depletion of JMJD2C causes a significant down-regulation of the pluripotency gene Nanog in embryos. However, contrary to a previous report in ES cells, we observed that other pluripotency genes, Pou5f1 and Sox2, are also significantly down-regulated in JMJD2C-depleted embryos. Furthermore, the depletion of JMJD2C in early embryos also caused significant down-regulation of the Myc and Klf4 genes, which are associated with cell proliferation. Our data suggest that the deregulation of these critical genes synergistically causes the developmental defects observed in JMJD2C-depleted embryos.