Cancer-specific epigenome identifies oncogenic hijacking by nuclear factor I family proteins for medulloblastoma progression.

Normal cells coordinate proliferation and differentiation by precise tuning of gene expression based on the dynamic shifts of the epigenome throughout the developmental timeline. Although non-mutational epigenetic reprogramming is an emerging hallmark of cancer, the epigenomic shifts that occur during the transition from normal to malignant cells remain elusive. Here, we capture the epigenomic changes that occur during tumorigenesis in a prototypic embryonal brain tumor, medulloblastoma. By comparing the epigenomes of the different stages of transforming cells in mice, we identify nuclear factor I family of transcription factors, known to be cell fate determinants in development, as oncogenic regulators in the epigenomes of precancerous and cancerous cells. Furthermore, genetic and pharmacological inhibition of NFIB validated a crucial role of this transcription factor by disrupting the cancer epigenome in medulloblastoma. Thus, this study exemplifies how epigenomic changes contribute to tumorigenesis via non-mutational mechanisms involving developmental transcription factors.

Cross-sectional study of factors affecting the receipt of mental health education in older migrants in China.

BACKGROUND: Population migration in China has increasingly included middle-aged and older populations. Relatedly, the lack of mental health education among China's older migrants is still an important but neglected problem. This study aimed to understand the current situation of mental health education received by the older migrant population in China and to explore related influencing factors. METHODS: This cross-sectional study included 5729 older migrants who participated in the 2017 China Migrants Dynamic Survey. The independent variables included four components: demographic and socioeconomic characteristics, migration factors, public health service utilization, and social integration factors. Data were analyzed using the chi-square test for single factors and a binary logistic regression model for multiple factors. RESULTS: A total of 1749 older migrants received mental health education, for a receipt rate of 30.53%. Regression analysis showed that older migrant individuals who had an average monthly household income > 3000 CNY, self-rated their health as healthy, had chronic diseases, had heard of National Basic Public Health Services, had established health records, received ≥2 types of health education were willing to integrate into the local population, and were highly involved in the community were more likely to receive mental health education. Older migrants who were ≥ 70 years old, had an elementary school education or below, had difficulties in the local community, had migrated ≥11 years prior, moved for their offspring, and moved across provinces were less likely to receive mental health education. CONCLUSIONS: The older migrant population does not receive sufficient mental health education. Mental health interventions should be tailored to the characteristics of older migrants to increase their mental health literacy and meet their psychological needs.

The status of emotional labour and its influence on job burnout among village doctors during the COVID-19 pandemic in China: a cross-sectional study.

BACKGROUND: Village doctors in China are not only the gatekeepers of rural residents' health but also the net bottom of the medical security system. However, emotional labour is increasingly threatening the stability of the rural primary medical system. In addition, the ongoing coronavirus disease 2019 (COVID-19) pandemic has further exposed the vulnerability of human resources in China's rural health system. This study aims to evaluate the current situation of emotional labour among village doctors and explore the impact of emotional labour on job burnout during the COVID-19 pandemic in China. METHODS: A cross-sectional survey was conducted in December 2021 in Shandong Province. We used structured questionnaires to collect data, including sociodemographic characteristics, emotional labour, and job burnout. Data were analysed by t test, analysis of variance (ANOVA), Pearson correlation analysis, and hierarchical multiple linear regression. RESULTS: A total of 1,093 village doctors from Shandong Province participated in the study. More than half of the participants were male (62.40%) and were between 41 and 50 years old (53.43%). The total mean score of emotional labour was 3.17 ± 0.67, of which the surface acting (SA) score was 2.28 ± 0.90, and the deep acting (DA) score was 3.91 ± 0.93. There were significant differences in SA according to gender and work content (P < 0.05) and in DA according to gender, age, education level, and work content (P < 0.05). Pearson correlation analysis showed that SA was positively correlated with job burnout (P < 0.001), and DA was negatively correlated with job burnout (P < 0.001). Hierarchical multiple linear regression analysis revealed that 29% of the variance in job burnout is attributable to SA (ß = 0.530, P < 0.001) and DA (ß = -0.154, P < 0.001). CONCLUSION: Village doctors in Shandong Province performed moderate levels of emotional labour during the COVID-19 pandemic. SA had a significant positive effect on job burnout, while DA had a significant negative effect on job burnout among village doctors. Administrators should enhance training on emotional labour for village doctors to play a positive role in alleviating their job burnout.

Association of individual resilience with organizational resilience, perceived social support, and job performance among healthcare professionals in township health centers of China during the COVID-19 pandemic.

Background: Primary healthcare professionals were overworked and psychologically overwhelmed during the COVID-19 pandemic. Resilience is an important shield for individuals to cope with psychological stress and improve performance in crises. This study aims to explore the association of individual resilience with organizational resilience, perceived social support and job performance among healthcare professionals in township health centers of China during the COVID-19 pandemic. Methods: Data from 1,266 questionnaires were collected through a cross-sectional survey conducted in December 2021 in Shandong Province, China. Descriptive analysis of individual resilience, organizational resilience, perceived social support, and job performance was conducted. Pearson correlation analysis was used to examine the correlations among these variables, and structural equation modeling was performed to verify the relationships between these variables. Results: The score of individual resilience was 101.67 ± 14.29, ranging from 24 to 120. Organizational resilience (ß = 0.409, p < 0.01) and perceived social support (ß = 0.410, p < 0.01) had significant direct effects on individual resilience. Individual resilience (ß = 0.709, p < 0.01) had a significant direct effect on job performance. Organizational resilience (ß = 0.290, p < 0.01) and perceived social support (ß = 0.291, p < 0.01) had significant indirect effects on job performance. Conclusion: During the COVID-19 pandemic, the individual resilience of healthcare professionals in township health centers was at a moderate level. Organizational resilience and perceived social support positively affected individual resilience, and individual resilience positively affected job performance. Furthermore, individual resilience mediated the effect of organizational resilience and perceived social support on job performance. It is recommended that multiple stakeholders work together to improve the individual resilience of primary healthcare professionals.

Sonic Hedgehog Signaling in Cerebellar Development and Cancer.

The sonic hedgehog (SHH) pathway regulates the development of the central nervous system in vertebrates. Aberrant regulation of SHH signaling pathways often causes neurodevelopmental diseases and brain tumors. In the cerebellum, SHH secreted by Purkinje cells is a potent mitogen for granule cell progenitors, which are the most abundant cell type in the mature brain. While a reduction in SHH signaling induces cerebellar structural abnormalities, such as hypoplasia in various genetic disorders, the constitutive activation of SHH signaling often induces medulloblastoma (MB), one of the most common pediatric malignant brain tumors. Based on the existing literature on canonical and non-canonical SHH signaling pathways, emerging basic and clinical studies are exploring novel therapeutic approaches for MB by targeting SHH signaling at distinct molecular levels. In this review, we discuss the present consensus on SHH signaling mechanisms, their roles in cerebellar development and tumorigenesis, and the recent advances in clinical trials for MB.

Emodin Suppresses the Migration and Invasion of Melanoma Cells.

Emodin (1,3,8-trihydroxy-6-methylanthraquinone), as an active ingredient in rhubarb roots and rhizomes, has been reported to possess various pharmacological properties including anti-tumor effects. Recent studies have confirmed that emodin inhibited cell proliferation and induced apoptosis of cancer cells. However, the inhibitory effect of emodin on the migration and invasion of melanoma cells and its underlying mechanism are still unclear. In the study, we observed the impercipient effects of emodin in B16F10 and A375 melanoma cells with strong metastatic abilities, focusing on the functions and mechanisms of migration and invasion of B16F10 and A375 melanoma cells. Cell counting kit-8 (CCK-8), colony formation test and Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining tests confirmed that emodin possessed anti-proliferative and pro-apoptotic activities in B16F10 and A375 cells. The inhibitory effects on the migration and invasion of B16F10 and A375 cells were proved by wound healing assay and Transwell methods. Moreover, immunofluorescence assay approved the decrease in protein expression of matrix metalloproteinas (MMP)-2/-9 by emodin, and Western blot analyses revealed that emodin could increase the Bax/Bcl-2 ratio and inhibit the MMP-2/-9 protein expression and Wnt/ß-catenin pathway in a dose-depended manner. BML-284, as an agonist of Wnt/ß-catenin signaling pathway, reversed the effects of emodin on cell growth, migration and invasion in B16F10 cells. These findings may suggest that emodin treatment can be a promising therapeutic strategy for melanoma with highly metastatic abilities.

Emodin inhibits the proliferation and migration of B16F10 cells and induces their apoptosis.

BACKGROUND: Emodin, extracted from the rhizomes of various Chinese herbs, is a natural anthraquinone derivative with the formula C15H10O5. Many recent studies have shown that emodin has an antitumour effect. In this study, emodin was investigated in vitro to observe its effect on the proliferation, migration, and apoptosis of the B16F10 melanoma cell line. METHODS: B16F10 cells were treated with 20, 40, 60, or 80 µM emodin for 24 h. A Cell Counting Kit-8 (CCK-8) was used to measure the effect of emodin on cell proliferation. After 24 h of emodin treatment, a scratch test was used to detect the wound healing rate of each group. A Transwell test was used to measure the effect of emodin on cell migration ability. The apoptosis rate of the B16F10 cells was determined by a TUNEL assay. The expression of caspase-3 was measured by western blot analysis. RESULTS: Compared with the control group, emodin significantly inhibited the proliferation and migration of the B16F10 cells in a concentration-dependent manner. Emodin also inhibited the migration of the B16F10 cells and induced their apoptosis. CONCLUSIONS: Emodin can effectively suppress the viability and migration of B16F10 cells and may induce apoptosis through the mitochondrial pathway or death receptor-mediated pathway.

IL-33/ST2 axis mediates hyperplasia of intrarenal urothelium in obstructive renal injury.

The monolayered intrarenal urothelium covers the renal papilla and ureteropelvic junction (UPJ). In response to increased renal pressure during obstruction or ischemic injuries, intrarenal urothelial cells begin to proliferate and form a multilayered urothelium. Little is known regarding the mechanism and pathophysiological role of urothelium hyperplasia during renal obstruction. In this study, we investigated the expression of interleukin (IL)-33, an IL-1 family cytokine, in kidneys with unilateral ureteral obstruction (UUO)-induced obstructive injury. IL-33 levels in hydronephrotic urine and serum were upregulated 2 days after UUO. The number of ST2-expressing immune cells was increased in the UUO kidney. We found that IL-33 was upregulated in vimentin-positive cells in the cortical and medullar layers and the UPJ stroma. Moreover, IL-33 expression was predominantly induced in multilayered keratin 5-positive urothelial cells in the UPJ. IL-33 was not detected in terminally differentiated superficial umbrella cells expressing uroplakin 3a. In vivo, we confirmed that deficiency of IL33 or its receptor ST2 attenuated UUO-induced hyperplasia of the UPJ urothelium. Deficiency of IL33 attenuated the expression of UUO-induced type 2 inflammatory cytokines and upregulated uroplakins and urothelial differentiation signaling in UPJ tissues. Our results collectively suggest that the IL-33/ST2 axis mediates the activation of innate immune responses and contributes to urothelial hyperplasia by regulating urothelial differentiation in obstructive kidney injury.

Dietary miR-451 protects erythroid cells from oxidative stress via increasing the activity of Foxo3 pathway.

One fundamental issue in public health is the safety of food products derived from plants and animals. A recent study raised a concern that microRNAs, which widely exist in everyday foods, may alter consumers' functions. However, some studies have strongly questioned the likelihood of dietary uptake of functional microRNAs in mammals. Here we use a microRNA gene knockout animal model to show that miR-144/451 null mice can orally uptake miR-451 from a daily chow diet, and ingestion of wild type blood, that contains abundant miR-451, also enhances the level of miR-451 in the circulating blood of knockout mice. Moreover, reducing miR-451 level in miR-144/451 knockout blood by consuming food lacking miR-451 reduces the anti-oxidant capacity of miR-144/451 null red blood cells by targeting the 14-3-3ζ/Foxo3 pathway, while increasing miR-451 level via gavage-feeding of wild type blood increases the anti-oxidant capacity of miR-144/451 null red blood cells. We conclude that 1) some miRNAs in food can pass through the gastrointestinal tract into the blood to affect consumers' function and 2) microRNA knockout animals such as miR-144/451 null mice can acquire the deleted genetic information from daily foods, which might alter the results and conclusions from the studies using such animals.

Coexpression of auxiliary subunits KChIP and DPPL in potassium channel Kv4-positive nociceptors and pain-modulating spinal interneurons.

Subthreshold A-type K(+) currents (ISA s) have been recorded from the somata of nociceptors and spinal lamina II excitatory interneurons, which sense and modulate pain, respectively. Kv4 channels are responsible for the somatodendritic ISA s. Accumulative evidence suggests that neuronal Kv4 channels are ternary complexes including pore-forming Kv4 subunits and two types of auxiliary subunits: K(+) channel-interacting proteins (KChIPs) and dipeptidyl peptidase-like proteins (DPPLs). Previous reports have shown Kv4.3 in a subset of nonpeptidergic nociceptors and Kv4.2/Kv4.3 in certain spinal lamina II excitatory interneurons. However, whether and which KChIP and DPPL are coexpressed with Kv4 in these ISA -expressing pain-related neurons is unknown. In this study we mapped the protein distribution of KChIP1, KChIP2, KChIP3, DPP6, and DPP10 in adult rat dorsal root ganglion (DRG) and spinal cord by immunohistochemistry. In the DRG, we found colocalization of KChIP1, KChIP2, and DPP10 in the somatic surface and cytoplasm of Kv4.3(+) nociceptors. KChIP3 appears in most Aß and Aδ sensory neurons as well as a small population of peptidergic nociceptors, whereas DPP6 is absent in sensory neurons. In the spinal cord, KChIP1 is coexpressed with Kv4.3 in the cell bodies of a subset of lamina II excitatory interneurons, while KChIP1, KChIP2, and DPP6 are colocalized with Kv4.2 and Kv4.3 in their dendrites. Within the dorsal horn, besides KChIP3 in the inner lamina II and lamina III, we detected DPP10 in most projection neurons, which transmit pain signal to brain. The results suggest the existence of Kv4/KChIP/DPPL ternary complexes in ISA -expressing nociceptors and pain-modulating spinal interneurons.

Cell Signaling and Differential Protein Expression in Neuronal Differentiation of Bone Marrow Mesenchymal Stem Cells with Hypermethylated Salvador/Warts/Hippo (SWH) Pathway Genes.

Human mesenchymal stem cells (MSCs) modified by targeting DNA hypermethylation of genes in the Salvador/Warts/Hippo pathway were induced to differentiate into neuronal cells in vitro. The differentiated cells secreted a significant level of brain-derived neurotrophy factor (BDNF) and the expression of BDNF receptor tyrosine receptor kinase B (TrkB) correlated well with the secretion of BDNF. In the differentiating cells, CREB was active after the binding of growth factors to induce phosphorylation of ERK in the MAPK/ERK pathway. Downstream of phosphorylated CREB led to the functional maturation of differentiated cells and secretion of BDNF, which contributed to the sustained expression of pERK and pCREB. In summary, both PI3K/Akt and MAPK/ERK signaling pathways play important roles in the neuronal differentiation of MSCs. The main function of the PI3K/Akt pathway is to maintain cell survival during neural differentiation; whereas the role of the MAPK/ERK pathway is probably to promote the maturation of differentiated MSCs. Further, cellular levels of protein kinase C epsilon type (PKC-ε) and kinesin heavy chain (KIF5B) increased with time of induction, whereas the level of NME/NM23 nucleoside diphosphate kinase 1 (Nm23-H1) decreased during the time course of differentiation. The correlation between PKC-ε and TrkB suggested that there is cross-talk between PKC-ε and the PI3K/Akt signaling pathway.

Ponicidin suppresses HT29 cell growth via the induction of G1 cell cycle arrest and apoptosis.

Ponicidin is a diterpenoid extracted from the Chinese herb Isodon adenolomus, which has been reported as a therapeutic cytotoxic drug that may be used to treat various types of human cancer. The present study aimed to determine the antitumor effects of ponicidin, and to investigate its underlying mechanisms in colorectal cancer. The HT29 colorectal cancer cell line was used to detect the cytotoxicity of various doses of ponicidin. Cell proliferation was measured using a Cell Counting kit­8 assay. Cell cycle and apoptosis analyses were performed using flow cytometry and fluorescent microscopy. Western blot analysis was used to measure the expression levels of apoptosis­associated proteins following treatment with ponicidin. Treatment with ponicidin significantly suppressed HT29 cell growth by inducing G1 cell cycle arrest and apoptosis. The AKT and MEK signaling pathways were also suppressed by ponicidin; however, the p38 signaling pathway was significantly activated. The expression levels of caspase 3 and Bax protein were markedly upregulated following treatment with ponicidin. These results suggest that ponicidin exerts significant antitumor effects via the induction of cell cycle arrest and apoptosis in colorectal cells. In conclusion, ponicidin acted as an inducer of apoptosis, and may be used as a therapeutic cytotoxic drug to treat human cancer, including colorectal cancer.

Immunohistochemical localization of DPP10 in rat brain supports the existence of a Kv4/KChIP/DPPL ternary complex in neurons.

Subthreshold A-type K(+) currents (ISA s) have been recorded from the cell bodies of hippocampal and neocortical interneurons as well as neocortical pyramidal neurons. Kv4 channels are responsible for the somatodendritic ISA s. It has been proposed that neuronal Kv4 channels are ternary complexes including pore-forming Kv4 subunits, K(+) channel-interacting proteins (KChIPs), and dipeptidyl peptidase-like proteins (DPPLs). However, colocalization evidence was still lacking. The distribution of DPP10 mRNA in rodent brain has been reported but its protein localization remains unknown. In this study, we generated a DPP10 antibody to label DPP10 protein in adult rat brain by immunohistochemistry. Absent from glia, DPP10 proteins appear mainly in the cell bodies of DPP10(+) neurons, not only at the plasma membrane but also in the cytoplasm. At least 6.4% of inhibitory interneurons in the hippocampus coexpressed Kv4.3, KChIP1, and DPP10, with the highest density in the CA1 strata alveus/oriens/pyramidale and the dentate hilus. Colocalization of Kv4.3/KChIP1/DPP10 was also detected in at least 6.9% of inhibitory interneurons scattered throughout the neocortex. Both hippocampal and neocortical Kv4.3/KChIP1/DPP10(+) inhibitory interneurons expressed parvalbumin or somatostatin, but not calbindin or calretinin. Furthermore, we found colocalization of Kv4.2/Kv4.3/KChIP3/DPP10 in neocortical layer 5 pyramidal neurons and olfactory bulb mitral cells. Together, although DPP10 is also expressed in some brain neurons lacking Kv4 (such as parvalbumin- and somatostatin-positive Golgi cells in the cerebellum), colocalization of DPP10 with Kv4 and KChIP at the plasma membrane of ISA -expressing neuron somata supports the existence of Kv4/KChIP/DPPL ternary complex in vivo.