HDA6 modulates Arabidopsis pavement cell morphogenesis through epigenetic suppression of ROP6 GTPase expression and signaling.

The transcriptional regulation of Rho-related GTPase from plants (ROPs), which determine cell polarity formation and maintenance during plant development, still remains enigmatic. In this study, we elucidated the epigenetic mechanism of histone deacetylase HDA6 in transcriptional repression of ROP6 and its impact on cell polarity and morphogenesis in Arabidopsis leaf epidermal pavement cells (PCs). We found that the hda6 mutant axe1-4 exhibited impaired jigsaw-shaped PCs and convoluted leaves. This correlated with disruptions in the spatial organizations of cortical microtubules and filamentous actin, which is integral to PC indentation and lobe formation. Further transcriptional analyses and chromatin immunoprecipitation assay revealed that HDA6 specifically represses ROP6 expression through histone H3K9K14 deacetylation. Importantly, overexpression of dominant negative-rop6 in axe1-4 restored interdigitated cell morphology. Our study unveils HDA6 as a key regulator in Arabidopsis PC morphogenesis through epigenetic suppression of ROP6. It reveals the pivotal role of HDA6 in the transcriptional regulation of ROP6 and provides compelling evidence for the functional interplay between histone deacetylation and ROP6-mediated cytoskeletal arrangement in the development of interdigitated PCs.

Serum uric acid predicts therapeutic response to midodrine hydrochloride in children with vasovagal syncope: a pilot study.

Serum uric acid (UA) level has been proven to be related to several cardiovascular and metabolic diseases. In the present study, we examined if baseline serum UA level could predict the therapeutic efficacy of midodrine hydrochloride on vasovagal syncope (VVS) in children. The pediatric VVS patients who received midodrine hydrochloride from November 2008 to October 2022 were enrolled. After a median treatment duration of 3 months, the therapeutic effect was evaluated. According to the patients' responses to midodrine hydrochloride, which was determined by the recurrence of syncope, they were divided into effective and ineffective groups. The baseline variables were explored using univariable and multivariate logistic analysis. The predictive efficacy was assessed by receiver operating characteristic curve (ROC), precision-recall curve (PR), Hosmer-Lemeshow test, calibration curve, and decision curve analysis (DCA). Totally, 53 participants were included in the study. Among the 51 patients who were successfully followed up, 29 (56.9%) responded to midodrine hydrochloride (effective group), and the other 22 (43.1%) failed to respond to midodrine hydrochloride (ineffective group). The participants in effective group had lower baseline serum UA level than those in ineffective group (276.5 ± 73 µmol/L vs. 332.7 ± 56 µmol/L, p = 0.004). Multivariable logistic analysis showed that serum UA was associated with the therapeutic response (odds ratio (OR): 0.985, 95% confidence interval (CI): 0.974-0.997, p = 0.01). ROC analysis indicated that using baseline serum UA < 299 µmol/L as a threshold value yielded a sensitivity of 77.3% and a specificity of 79.3% in predicting the treatment response to midodrine hydrochloride. The area under the PR curve was 0.833. Hosmer-Lemeshow test yielded a p value of 0.58, and calibration plot indicated that the model was well-fitted. DCA demonstrated that treatment decision depending on the baseline serum UA level resulted in a favorable net benefit.   Conclusion: This pilot study suggested that the baseline serum UA level could be taken as a predictor of therapeutic effect of midodrine hydrochloride on VVS in children. What is Known: • Empirical and unselected use of midodrine hydrochloride has an unfavorable therapeutic effect on VVS in children. Serum uric acid (UA) is closely linked to cardiovascular events. What is New: • A low baseline serum UA level successfully predicts the therapeutic effectiveness of midodrine hydrochloride on VVS in children.

Nonlinear relationship between oxidative balance score and hyperuricemia: analyses of NHANES 2007-2018.

BACKGROUND: Limited data regarding the correlation between oxidative balance score (OBS) and hyperuricemia highlights the necessity for thorough investigations. This study aims to examine the link between OBS, which incorporates dietary and lifestyle factors, and the occurrence of hyperuricemia. METHODS: We conducted a cross-sectional study involving 13,636 participants from the 2007-2018 National Health and Nutrition Examination Survey (NHANES). The oxidative balance score (OBS) was determined based on four lifestyle factors and sixteen dietary nutrients. We assessed the levels of serum uric acid (SUA) and the occurrence of hyperuricemia as outcomes. Weighted logistic regression and linear models were used for statistical analysis, using Restricted Cubic Splines (RCS) to examine potential nonlinear associations. Subgroup analysis and sensitivity assessments were performed to identify any variations and ensure the robustness of the findings. RESULTS: Higher OBS was consistently correlated with decreased SUA levels and a reduced prevalence of hyperuricemia. RCS highlighted a significant negative nonlinear association, particularly in females. Subgroup analysis revealed gender-based differences and interactive correlation, providing additional insights regarding OBS and hyperuricemia relationship. CONCLUSION: This study underscores a robust negative correlation between OBS and SUA levels as well as the incidence of hyperuricemia, emphasizing the importance of dietary and lifestyle factors. Incorporating RCS, subgroup analysis, and sensitivity assessments enhances the depth of our findings, providing valuable insights for further research.

Localized calcium transients in phragmoplast regulate cytokinesis of tobacco BY-2 cells.

KEY MESSAGE: Plants exhibit a unique pattern of cytosolic Ca2+ dynamics to correlate with microtubules to regulate cytokinesis, which significantly differs from those observed in animal and yeast cells. Calcium (Ca2+) transients mediated signaling is known to be essential in cytokinesis across eukaryotic cells. However, the detailed spatiotemporal dynamics of Ca2+ during plant cytokinesis remain largely unexplored. In this study, we employed GCaMP5, a genetically encoded Ca2+ sensor, to investigate cytokinetic Ca2+ transients during cytokinesis in Nicotiana tabacum Bright Yellow-2 (BY-2) cells. We validated the effectiveness of GCaMP5 to capture fluctuations in intracellular free Ca2+ in transgenic BY-2 cells. Our results reveal that Ca2+ dynamics during BY-2 cell cytokinesis are distinctly different from those observed in embryonic and yeast cells. It is characterized by an initial significant Ca2+ spike within the phragmoplast region. This spike is followed by a decrease in Ca2+ concentration at the onset of cytokinesis in phragmoplast, which then remains elevated in comparison to the cytosolic Ca2+ until the completion of cell plate formation. At the end of cytokinesis, Ca2+ becomes uniformly distributed in the cytosol. This pattern contrasts with the typical dual waves of Ca2+ spikes observed during cytokinesis in animal embryonic cells and fission yeasts. Furthermore, applications of pharmaceutical inhibitors for either Ca2+ or microtubules revealed a close correlation between Ca2+ transients and microtubule organization in the regulation of cytokinesis. Collectively, our findings highlight the unique dynamics and crucial role of Ca2+ transients during plant cell cytokinesis, and provides new insights into plant cell division mechanisms.

[Research progress on induced hepatic stellate cell ferroptosis in prevention and treatment of liver fibrosis].

Liver fibrosis is a key pathological stage in the progression of chronic liver disease. If the disease is mistreated, it can further deteriorate into liver failure, which seriously affects the quality of life of patients and brings heavy medical costs. Hepatic stellate cell(HSC) activation triggers extracellular matrix(ECM) deposition, which plays an important driving role in liver fibrosis, and ferroptosis is an effective strategy to clear or reverse the activation of HSCs into a deactivated phenotype. Therefore, inhibiting the activation and proliferation of HSCs by regulating ferroptosis is the key to the treatment of this disease, so as to derive the prospect of inducing ferroptosis of HSCs(including RNA-binding proteins, non-coding RNA, chemicals, and active components of traditional Chinese medicine) to intervene in liver fibrosis. On this basis, this paper started from the activation of HSCs to induce ECM deposition and focused on summarizing the mechanism of inducing HSC ferroptosis in delaying the progression of liver fibrosis, so as to continuously enrich the clinical practice of liver fibrosis and provide a reference for subsequent basic research.

Long noncoding RNA LINC01234 promotes hepatocellular carcinoma progression through orchestrating aspartate metabolic reprogramming.

Amino acids metabolism, especially aspartate metabolism, is often altered in human cancers including hepatocellular carcinoma (HCC) and this metabolic remodeling is required for supporting cancer cell malignant activities. Argininosuccinate synthase 1 (ASS1), as a crucial rate-limiting enzyme in aspartate metabolism, participates in repressing tumor progression. However, the roles of long noncoding RNAs (lncRNAs) in aspartate metabolism remodeling and the underlying mechanisms remain unclear. Here, we screen LINC01234 as an aspartate metabolism-related lncRNA in HCC. Clinically, LINC01234 was highly expressed in HCC, and a high LINC01234 expression level was correlated with a poor prognosis of patients with HCC. LINC01234 promoted cell proliferation, migration, and drug resistance by orchestrating aspartate metabolic reprogramming in HCC cells. Mechanistically, LINC01234 downregulated the expression of ASS1, leading to am increased aspartate level and activation of the mammalian target of rapamycin pathway. LINC01234 bound to the promoter of ASS1 and inhibited transcriptional activation of ASS1 by transcriptional factors, including p53. Finally, inhibiting LINC01234 dramatically impaired tumor growth in nude mice and sensitized HCC cells to sorafenib. These findings demonstrate that LINC01234 promotes HCC progression by modulating aspartate metabolic reprogramming and might be a prognostic or therapeutic target for HCC.

Inhibition of miR-188-5p alleviates hepatic fibrosis by significantly reducing the activation and proliferation of HSCs through PTEN/PI3K/AKT pathway.

Persistent hepatic damage and chronic inflammation in liver activate the quiescent hepatic stellate cells (HSCs) and cause hepatic fibrosis (HF). Several microRNAs regulate the activation and proliferation of HSCs, thereby playing a critical role in HF progression. Previous studies have reported that miR-188-5p is dysregulated during the process of HF. However, the role of miR-188-5p in HF remains unclear. This study investigated the potential role of miR-188-5p in HSCs and HF. Firstly, we validated the miR-188-5p expression in primary cells isolated from liver of carbon tetrachloride (CCl4 )-induced mice, TGF-ß1-induced LX-2 cells, livers from 6-month high-fat diet (HFD)-induced rat and 4-month HFD-induced mice NASH models, and human non-alcoholic fatty liver disease (NAFLD) patients. Furthermore, we used miR-188-5p inhibitors to investigate the therapeutic effects of miR-188-5p inhibition in the HFD + CCl4 induced in vivo model and the potential role of miR-188-5p in the activation and proliferation of HSCs. This present study reported that miR-188-5p expression is significantly increased in the human NAFLD, HSCs isolated from liver of CCl4 induced mice, and in vitro and in vivo models of HF. Mimicking the miR-188-5p resulted in the up-regulation of HSC activation and proliferation by directly targeting the phosphatase and tensin homolog (PTEN). Moreover, inhibition of miR-188-5p reduced the activation and proliferation markers of HSCs through PTEN/AKT pathway. Additionally, in vivo inhibition of miR-188-5p suppressed the HF parameters, pro-fibrotic and pro-inflammatory genes, and fibrosis. Collectively, our results uncover the pro-fibrotic role of miR-188-5p. Furthermore, we demonstrated that miR-188-5p inhibition decreases the severity of HF by reducing the activation and proliferation of HSCs through PTEN/AKT pathway.

Induction of PDCD4 by albumin in proximal tubule epithelial cells potentiates proteinuria-induced dysfunctional autophagy by negatively targeting Atg5.

Autophagy dysfunction is a hallmark of type 1 diabetes. However, the precise molecular mechanism of proteinuria-induced dysfunctional autophagy remains unclear. Herein, we investigated the role of programmed cell death 4 (PDCD4) in the regulation of autophagy in the pathogenesis of diabetic kidney disease (DKD) in vivo and in vitro. RT-qPCR, immunohistochemistry (IHC), and western blotting demonstrated an upregulation of Pdcd4 mRNA and protein in streptozotocin (STZ)-induced DKD rats, as compared to the control. In addition, IHC and western blotting of a unilateral ureteral obstruction mouse model showed an upregulation of PDCD4 in the disease group, as compared to their respective controls. IHC analysis of kidney biopsy samples of human DKD patients showed an upregulation of PDCD4 compared to the control. Western blotting of the STZ-induced DKD rat tissues displayed a low microtubule-associated protein 1A/1B-light chain 3 (LC3)-II, as compared to the control. It was found that albumin overload in cultured PTECs upregulated the expression of PDCD4 and p62 and decreased the expression of LC3-II and autophagy-related 5 (Atg5) proteins. The knockout of Pdcd4 in cultured PTECs could reduce albumin-induced dysfunctional autophagy, as evidenced by the recovery of Atg5 and LC3-II protein. The forced expression of PDCD4 could further suppress the expression of the crucial autophagy-related gene Atg5. Evidence suggests that endogenous PDCD4 promotes proteinuria-induced dysfunctional autophagy by negatively regulating Atg5. Therefore, PDCD4 may be a potential therapeutic target in DKD.

Deacetylation of NAT10 by Sirt1 promotes the transition from rRNA biogenesis to autophagy upon energy stress.

Anabolism and catabolism are tightly regulated according to the cellular energy supply. Upon energy stress, ribosomal RNA (rRNA) biogenesis is inhibited, and autophagy is induced. However, the mechanism linking rRNA biogenesis and autophagy is unclear. Here, we demonstrate that the nucleolar protein NAT10 plays a role in the transition between rRNA biogenesis and autophagy. Under normal conditions, NAT10 is acetylated to activate rRNA biogenesis and inhibit autophagy induction. Mechanistic studies demonstrate that NAT10 binds to and acetylates the autophagy regulator Che-1 at K228 to suppress the Che-1-mediated transcriptional activation of downstream genes Redd1 and Deptor under adequate energy supply conditions. Upon energy stress, NAT10 is deacetylated by Sirt1, leading to suppression of NAT10-activated rRNA biogenesis. In addition, deacetylation of NAT10 abolishes the NAT10-mediated transcriptional repression of Che-1, leading to the release of autophagy inhibition. Collectively, we demonstrate that the acetylation status of NAT10 is important for the anabolism-catabolism transition in response to energy stress, providing a novel mechanism by which nucleolar proteins control rRNA synthesis and autophagy in response to the cellular energy supply.

Human UTP14a promotes angiogenesis through upregulating PDGFA expression in colorectal cancer.

The human UTP14a (hUTP14a) promotes degradation of p53 and RB. Moreover, hUTP14a stabilizes c-Myc and is associated with the metastasis of human colorectal cancer (CRC). Angiogenesis plays a key role in tumor growth and metastasis. However, how hUTP14a regulates angiogenesis is unknown. Here, we show that nucleolar expression of hUTP14a is positively associated with higher microvascular density (MVD) in the CRC tumor tissues. The conditioned medium (CM) from CRC cells HCT116 and LoVo with hUTP14a knockdown impairs tube formation and migration of human umbilical vein endothelial cells (HUVECs). RNA-seq analysis indicates that hUTP14a might regulate expression of angiogenic factors in tumor cells. We further demonstrate that hUTP14a upregulates transcription and secretion of platelet-derived growth factor subunit A (PDGFA) in CRC cells. The CRC-CM derived from hUTP14a-depleted cells inhibits the PDGFA-mediated signaling pathway and induces apoptosis in HUVECs. In contrast, the CRC-CM derived from cells expressing Flag-hUTP14a activates the PDGFA-mediated signaling pathway in HUVECs. Importantly, the CRC-CM derived from Flag-hUTP14a-expressing cells promotes angiogenesis in HUVECs, which is counteracted by PDGFR inhibitor imatinib. We thus demonstrate that hUTP14a promotes angiogenesis by upregulating expression and secretion of PDGFA. The in vivo Matrigel plug assay shows that depletion of hUTP14a dramatically decreased MVD in mice xenografts. Collectively, we demonstrate that hUTP14a promotes angiogenesis in CRC and indicate that targeting hUTP14a might improve the prognosis of the hUTP14a-expressing CRC patients.

Anti-Toll-like receptor 2 antibody inhibits nuclear factor kappa B activation and attenuates cardiac damage in high-fat-feeding rats.

Long-time consumption of high-fat food is a direct cause of cardiovascular diseases, and high-fat-related inflammation plays an important role in it. Toll-like receptors (TLRs), especially TLR2 and TLR4, play important roles in high-fat-related inflammation. However, the impact of TLR2 on high-fat-associated cardiovascular complications is still unknown. In this study, we try to investigate the relationship between TLR2 and high-fat-related cardiac injury. SD rats were allocated to either a control group which were fed with normal diet or a high-fat group which were fed with high-fat diet for 5 months. At the last month, rats fed with high-fat diet were intraperitoneally injected with control normal mouse IgG or anti-TLR2 antibody. Heart tissues were collected for further analysis. RT-qPCR and western blot analysis results revealed that TLR2 expression was increased in the heart tissues from rats fed with high-fat diet and anti-TLR2 antibody had no effect on TLR2 expression. However, anti-TLR2 antibody alleviated masson staining area, levels of TGF-ß1 and Collagen I mRNA, and decreased TUNEL-positive myocardial cells and caspase-3 activity, suggesting that anti-TLR2 antibody protected cardiac cells against high-fat-induced cardiac fibrosis and cell apoptosis. By using immunohistochemistry, RT-qPCR and ELISA, we found that anti-TLR2 antibody blocked NF-κB activation, inhibited the expression of inflammatory factors such as TNF-α, IL-1ß, IL-6 and IL-18 in the heart tissues from rats fed with high-fat diet. These results hinted that anti-TLR2 antibody might exert its protective effect via inhibition of the TLR2/NF-κB/inflammation pathway. Our findings suggest that anti-TLR2 antibody has a preventive function against high-fat-induced deleterious effects in the heart, and anti-TLR2 antibody may be used as an attractive therapeutic option for high-fat-induced cardiac injury.

Seeing the Unseen of the Combination of Two Natural Resins, Frankincense and Myrrh: Changes in Chemical Constituents and Pharmacological Activities.

For the treatment of diseases, especially chronic diseases, traditional natural drugs have more effective therapeutic advantages because of their multi-target and multi-channel characteristics. Among many traditional natural medicines, resins frankincense and myrrh have been proven to be effective in the treatment of inflammation and cancer. In the West, frankincense and myrrh have been used as incense in religious and cultural ceremonies since ancient times; in traditional Chinese and Ayurvedic medicine, they are used mainly for the treatment of chronic diseases. The main chemical constituents of frankincense and myrrh are terpenoids and essential oils. Their common pharmacological effects are anti-inflammatory and anticancer. More interestingly, in traditional Chinese medicine, frankincense and myrrh have been combined as drug pairs in the same prescription for thousands of years, and their combination has a better therapeutic effect on diseases than a single drug. After the combination of frankincense and myrrh forms a blend, a series of changes take place in their chemical composition, such as the increase or decrease of the main active ingredients, the disappearance of native chemical components, and the emergence of new chemical components. At the same time, the pharmacological effects of the combination seem magically powerful, such as synergistic anti-inflammation, synergistic anticancer, synergistic analgesic, synergistic antibacterial, synergistic blood-activation, and so on. In this review, we summarize the latest research on the main chemical constituents and pharmacological activities of these two natural resins, along with chemical and pharmacological studies on the combination of the two.

Loss of nucleolar localization of NAT10 promotes cell migration and invasion in hepatocellular carcinoma.

NAT10, a nucleolar acetyltransferase, participates in a variety of cellular processes including ribosome biogenesis and DNA damage response. Immunohistochemistry staining showed that cytoplasmic and membranous NAT10 is related to the clinical pathologic characteristics in human cancer tissues. However, the mechanism about how NAT10 translocates from the nucleolus to cytoplasm and membrane is unclear. Here, we obtain a NAT10 deletion mutant localizing in cytoplasm and membrane. Bioinformatics analysis showed that residues 68-75 and 989-1018 are two potential nuclear localization signals (NLS) of NAT10. GFP-NAT10 deletion mutant (Δ989-1018) predominantly translocates into cytoplasm with faint signal retained in the nucleolus, while GFP-NAT10(Δ68-75) still remains in the nucleolus and nucleoplasm, indicating residues 989-1018 is the main nucleolar localization signal (NuLS). GFP-NAT10-D3, with both fragments (residues 68-75 and 989-1018) deleted, completely excludes from the nucleolus and translocates to cytoplasm and membrane. Therefore, complete NuLSs of NAT10 should include residues 68-75 and 989-1018. The cytoplasmic and membranous NAT10 mutant (Flag-NAT10-D3) colocalizes with α-tubulin in cytoplasm and with integrin on cell membrane. Importantly, Flag-NAT10-D3 promotes α-tubulin acetylation and stabilizes microtubules. Consequently, Flag-NAT10-D3 promotes migration and invasion in hepatocellular carcinoma (HCC) cells. Statistical analysis of immunohistochemistry staining of NAT10 in HCC tissues demonstrates that the cytoplasmic NAT10 is correlated with poorer prognosis compared with nuclear NAT10, while the membranous NAT10 predicts the poorest clinical outcome of the patients. We thus provide the evidence for the function of cytoplasmic and membranous NAT10 in the metastasis and prognosis of HCC patients.

DRm217 attenuates myocardial ischemia-reperfusion injury via stabilizing plasma membrane Na+-K+-ATPase, inhibiting Na+-K+-ATPase/ROS pathway and activating PI3K/Akt and ERK1/2.

Na+-K+-ATPase has close relationship with myocardial ischemia/reperfusion (IR) injury. Activation of Na+-K+-ATPase with its DR region specific antibody produces cardioprotective effect. In this study, we aimed to explore whether DRm217, a proved DR region specific antibody, could protect myocardial cells against IR injury and uncover the mechanisms under it. By employing H9c2 myocardial cell and SD rat, we found that DRm217 protected cardiac cells against IR-induced cell injury and apoptosis. DRm217 produced protective effect via stabilizing Na+-K+-ATPase membrane expression and inhibiting Na+-K+-ATPase/Src/NADPH oxidase dependent ROS accumulation. PI3K/Akt and ERK1/2 participated in DRm217-induced cardiomyocyte survival, but not in DRm217-related ROS reduction. Therefore, DRm217 can be used as a potential cardioprotective adjuvant in myocardial IR therapy and interference of Na+-K+-ATPase/ROS pathway will be a promising modality for clinical myocardial IR therapy.

NAT10 regulates p53 activation through acetylating p53 at K120 and ubiquitinating Mdm2.

As a genome guardian, p53 maintains genome stability by arresting cells for damage repair or inducing cell apoptosis to eliminate the damaged cells in stress response. Several nucleolar proteins stabilize p53 by interfering Mdm2-p53 interaction upon cellular stress, while other mechanisms by which nucleolar proteins activate p53 remain to be determined. Here, we identify NAT10 as a novel regulator for p53 activation. NAT10 acetylates p53 at K120 and stabilizes p53 by counteracting Mdm2 action. In addition, NAT10 promotes Mdm2 degradation with its intrinsic E3 ligase activity. After DNA damage, NAT10 translocates to nucleoplasm and activates p53-mediated cell cycle control and apoptosis. Finally, NAT10 inhibits cell proliferation and expression of NAT10 decreases in human colorectal carcinomas. Thus, our data demonstrate that NAT10 plays a critical role in p53 activation via acetylating p53 and counteracting Mdm2 action, providing a novel pathway by which nucleolar protein activates p53 as a cellular stress sensor.

Autoacetylation of NAT10 is critical for its function in rRNA transcription activation.

NAT10, an important member of GNAT family, harbors histone acetyltransferase and participates in many cellular processes such as ribosome production and cell cycle. Here, we report that NAT10 is acetylated in vivo and autoacetylated in vitro. The lysine residue at 426 (K426) is the acetylation site of NAT10. K426R mutant of NAT10 fails to activate rRNA transcription. NAT10 K426R loses its capability of acetylating UBF though it still binds UBF, which fails to recruit PAF53 and RNA polymerase I to rDNA, eventually resulting in inhibition of pre-rRNA transcription. Therefore, acetylation of K426 in NAT10 is required for its function in activating rRNA transcription. These findings identify a new post-translational modification on NAT10 which regulates its function.

Human U3 protein 14a plays an anti-apoptotic role in cancer cells.

Human U three protein 14a (hUTP14a) binds p53 and promotes p53 degradation. Here, we report that hUTP14a plays an anti-apoptotic role in tumor cells through a p53-independent pathway. Knockdown of hUTP14a activated the intrinsic pathway of apoptosis and sensitized tumor cells to chemotherapeutic drug-induced apoptosis. In addition, the protein level of hUTP14a decreased upon chemotherapeutic drug- or irradiation-induced apoptosis. Importantly, the decrease of hUTP14a during induced apoptosis was not blocked by pan-caspase inhibitor z-VAD-FMK, indicating that the down-regulation of hUTP14a is an upstream event in apoptosis. Furthermore, ectopically expressed hUTP14a protected tumor cells from chemotherapeutic drug-induced apoptosis. In summary, our data showed that hUTP14a protected tumor cells from chemotherapeutic drug-induced apoptosis and thus might possess a potential as a target for anti-tumor therapy.

NAT10 is upregulated in hepatocellular carcinoma and enhances mutant p53 activity.

BACKGROUND: N-acetyltransferase 10 (NAT10) is a histone acetyltransferase which is involved in a wide range of cellular processes. Recent evidences indicate that NAT10 is involved in the development of human cancers. Previous study showed that NAT10 acetylates the tumor suppressor p53 and regulates p53 activation. As Tp53 gene is frequently mutated in hepatocellular carcinoma (HCC) and associates with the occurrence and development of HCC, the relationship between NAT10 and HCC was investigated in this study. METHODS: Immunohistochemistry (IHC) and western blot analysis were performed to evaluate the NAT10 expression in HCC. Immunoprecipitation experiments were performed to verify the interaction of NAT10 with mutant p53 and Mdm2. RNA interference and Western blot were applied to determine the effect of NAT10 on mutant p53. Cell growth curve was used to examine the effect of NAT10 on HCC cell proliferation. RESULTS: NAT10 was upregulated in HCC and increased NAT10 expression was correlated with poor overall survival of the patients. NAT10 protein levels were significantly correlated with p53 levels in human HCC tissues. Furthermore, NAT10 increased mutant p53 levels by counteracting Mdm2 action in HCC cells and promoted proliferation in cells carrying p53 mutation. CONCLUSION: Increased NAT10 expression levels are associated with shortened patient survival and correlated with mutant p53 levels. NAT10 upregulates mutant p53 level and might enhance its tumorigenic activity. Hence, we propose that NAT10 is a potential prognostic and therapeutic candidate for p53-mutated HCC.

[Current situation of neglect and its influencing factors for rural children aged 12 to 17 years old of Tujia and Miao minorities in Wuling mountainous area in 2014].

OBJECTIVE: In order to have a basic understanding of the neglect condition of rural children aged 12 to 17 years old of Tujia and Miao minorities in Wuling mountainous area as well as its causes. METHODS: According to the principle of multistage stratified cluster samplingmethod, a total of 1974 students of eight middle schoolsfrom rural areas in four counties of Tujia-Miao Autonomous Prefecture of Xiangxi had been selected from November to December in 2014( 1020 students from Tujia minority and 954 students from Miao minority). In addition, by adopting themethod of "The Normal Value of Evaluation on the Neglect of Middle School Students from 12 to 17 Years Old in Rural China", the neglect rate and degree can reflect how often and how strong children in rural areas have been neglected. Also, relative factors of the neglect was analyzed by logistic multi-factor regression analysismethod. RESULTS: The total neglect rate of children in rural areas from 12 to 17 years old of Tujia and Miao minorities was 67. 83 %( 1339/1974). The proportion of male students which was 70. 42%( 631/896) was higher than the female students counterpart, which was 65. 68%( 708/1078)( χ~2= 5. 053, P <0. 05). The total neglect degree was( 54. 96 ± 10. 31), and the degree of children between 12 and 14 years old( 55. 45 ± 9. 51) was higher than that of children between 15 and 17 years old( 54. 54 ± 10. 95)( t = 1. 980, P < 0. 05). The neglect rate and degree in medication for female students were higher than male students( χ~2= 10. 233, P < 0. 01, t =2. 139, P < 0. 05), while the neglect rate and degree in education and the neglect degree in security male students had a higher rate and a more severe degree than female students( χ~2= 3. 969, t = 1. 989, t = 2. 014, P < 0. 05). In addition to the neglect of education, the neglect rate and degree of other aspects for children of Tujia and Miao minorities in rural areas had statistical significance( P < 0. 05). The neglect rate of left-behind children was higher than that of un-left-behind children in physical and medical aspects( χ~2= 6. 267, χ~2= 4. 040, P < 0. 05). As theresult of logistic multi-factor regression analysis showed, male students( OR = 1. 292, 95% CI 1. 062-1. 573), children who have less intimate relationship with parents( OR = 1. 344, 95% CI 1. 009-1. 791, OR = 1. 475, 95% CI 1. 063-2. 046), whose parents do not share a close relationship( OR = 1. 396, 95% CI 1. 042-1. 870), those without a single room( OR = 0. 577, 95% CI 0. 464-0. 719) were more likely to be neglected. CONCLUSION: Children of Tujia and Miao minorities in Wuling mountainous area are under a serious neglecting state, and the main influencing factors are whether children have single rooms, the relationship between children and parents and the relationship between parents.

A Novel Retinoblastoma Protein (RB) E3 Ubiquitin Ligase (NRBE3) Promotes RB Degradation and Is Transcriptionally Regulated by E2F1 Transcription Factor.

Retinoblastoma protein (RB) plays critical roles in tumor suppression and is degraded through the proteasomal pathway. However, E3 ubiquitin ligases responsible for proteasome-mediated degradation of RB are largely unknown. Here we characterize a novel RB E3 ubiquitin ligase (NRBE3) that binds RB and promotes RB degradation. NRBE3 contains an LXCXE motif and bound RB in vitro. NRBE3 interacted with RB in cells when proteasome activity was inhibited. NRBE3 promoted RB ubiquitination and degradation via the ubiquitin-proteasome pathway. Importantly, purified NRBE3 ubiquitinated recombinant RB in vitro, and a U-box was identified as essential for its E3 activity. Surprisingly, NRBE3 was transcriptionally activated by E2F1/DP1. Consequently, NRBE3 affected the cell cycle by promoting G1/S transition. Moreover, NRBE3 was up-regulated in breast cancer tissues. Taken together, we identified NRBE3 as a novel ubiquitin E3 ligase for RB that might play a role as a potential oncoprotein in human cancers.