Effect of anti-skin disorders of ginsenosides- A Systematic Review.

Ginsenosides are bioactive components of Panax ginseng with many functions such as anti-aging, anti-oxidation, anti-inflammatory, anti-fatigue, and anti-tumor. Ginsenosides are categorized into dammarane, oleanene, and ocotillol type tricyclic triterpenoids based on the aglycon structure. Based on the sugar moiety linked to C-3, C-20, and C-6, C-20, dammarane type was divided into protopanaxadiol (PPD) and protopanaxatriol (PPT). The effects of ginsenosides on skin disorders are noteworthy. They play anti-aging roles by enhancing immune function, resisting melanin formation, inhibiting oxidation, and elevating the concentration of collagen and hyaluronic acid. Thus, ginsenosides have previously been widely used to resist skin diseases and aging. This review details the role of ginsenosides in the anti-skin aging process from mechanisms and experimental research.

Albumin-based nanoparticle for dual-modality imaging of the lymphatic system.

The lymphatic system is a complex network of lymphatic vessels, lymph nodes, and lymphoid organs. The current understanding of the basic mechanism and framework of the lymphatic system is relatively limited and not ideal for exploring the function of the lymphatic system, diagnosing lymphatic system diseases, and controlling tumor metastasis. Imaging modalities for evaluating lymphatic system diseases mainly include lymphatic angiography, reactive dye lymphatic angiography, radionuclide lymphatic angiography, computed tomography, and ultrasonography. However, these are insufficient for clinical diagnosis. Some novel imaging methods, such as magnetic resonance imaging, positron emission computed tomography, single-photon emission computed tomography, contrast-enhanced ultrasonography, and near-infrared imaging with agents such as cyanine dyes, can reveal lymphatic system information more accurately and in detail. We fabricated an albumin-based fluorescent probe for dual-modality imaging of the lymphatic system. A near-infrared cyanine dye, IR-780, was absorbed into bovine serum albumin (BSA), which was covalently linked to a molecule of diethylenetriaminepentaacetic acid to chelate gadolinium Gd3+. The fabricated IR-780@BSA@Gd3+ nanocomposite demonstrates strong fluorescence and high near-infrared absorption and can be used as a T1 contrast agent for magnetic resonance imaging. In vivo dual-modality fluorescence and magnetic resonance imaging showed that IR-780@BSA@Gd3+ rapidly returned to the heart through the lymphatic circulation after it was injected into the toe webs of mice, facilitating good lymphatic imaging. The successful fabrication of the new IR-780@BSA@Gd3+ nanocomposite will facilitate the study of the mechanism and morphological structure of the lymphatic system.

Visual analysis of global research output of lymphedema based on bibliometrics.

Background: Globally, several generations of doctors in the field of lymphedema have created numerous publications. To date, no bibliometric analysis has been performed specifically on these publications. For the further promotion of research on lymphedema and to align with the international research frontiers, it is essential to understand the current state of Lymphedema research output. Objective: This study aims to statistically and visually analyze the characteristics of publications output, distribution of contributions and development process of lymphedema, enriching the knowledge base of Lymphedema, and then seek potential research topics and collaborators. Methods: Based on the Web of Science core collection database, we firstly analyzed the quantity and quality of publications in the field of lymphedema, secondly profiled the publishing groups in terms of country, institution, author's publication and cooperation network, and finally sorted out and summarized the hot topics of research. Results: A total of 8569 papers were retrieved from 1900-2021. The top4 journals with the most publications were LYMPHOLOGY, LYMPHATIC RESEARCH AND BIOLOGY, PLASTIC AND RECONSTRUCTIVE SURGERY and ANNALS OF SURGICAL ONCOLOGY. The top 4 countries with the most publications were USA, Japan, UK, and China. The United States dominates the total number of publications and the international cooperation network. The most productive research institution is Harvard University, and the research institution with the most collaborating institutions is Memorial Sloan Kettering Cancer Center. Mortimer, Peter S contributes the most research in this field. The research achievements of Japanese scholars in this field are of great significance. The top 5 ranked keywords are "Breast Cancer", "Health-Related Quality Of Life", "Lymphscintigraphy", "Lymphovenous Anastomosis", and "Lymphangiogenesis". Conclusion: More and more scholars are devoted to the research of cancer-related Lymphedema. It is foreseeable that breast cancer-related lymphedema and lymphangiogenesis will remain a focus of future research. Advances in Lymphatic vessel imaging and the development of lymphatic microsurgery will further play a role in the clinical workup of lymphedema. Meanwhile, This study can help researchers identify potential collaborators and partner institutions and contribute to further research.

IL6 Induces mtDNA Leakage to Affect the Immune Escape of Endometrial Carcinoma via cGAS-STING.

Endometrial carcinoma (EC) is a commonly diagnosed gynecological malignancy. Interleukin-6 (IL6) plays a critical role in modulating the progression of several types of tumors, including EC. However, the specific mechanism of IL6 in regulating EC progression has not been clearly elucidated. In this study, we performed a series of functional experiments to explore the potential mechanisms involved in IL6 function in the progression of EC. Here, we found that IL6 increased reactive oxygen species (ROS) generation by enhancing the NADPH oxidase (NOX) level and induced mtDNA leakage in EC cells, which further caused the activation of the downstream cGAS-STING signaling and increased production of extracellular vesicle (EV) production from EC cells. Besides, the activation of cGAS-STING signaling enhanced the expression of type I IFN and its downstream molecule PD-L1 through the TBK1-IRF3 pathway. Importantly, a high level mtDNA and PD-L1 were present in EVs derived from IL6-induced EC cells; these vesicles were shown to be able to induce T cell apoptosis. Finally, anti-PD-L1 treatment in mice showed that blockade of PD-L1 significantly reversed tumor immune escape mediated by IL6-induced EVs. Together, we provide evidence that IL6 induced mtDNA leakage to regulate the immune escape of EC cells. Our findings may provide a novel clue for the development of therapeutic targets for EC.

Activated Drp1 regulates p62-mediated autophagic flux and aggravates inflammation in cerebral ischemia-reperfusion via the ROS-RIP1/RIP3-exosome axis.

BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) refers to a secondary brain injury that can occur when the blood supply to the ischemic brain tissue is restored. However, the mechanism underlying such injury remains elusive. METHODS: The 150 male C57 mice underwent middle cerebral artery occlusion (MCAO) for 1 h and reperfusion for 24 h, Among them, 50 MCAO mice were further treated with Mitochondrial division inhibitor 1 (Mdivi-1) and 50 MCAO mice were further treated with N-acetylcysteine (NAC). SH-SY5Y cells were cultured in a low-glucose culture medium for 4 h under hypoxic conditions and then transferred to normal conditions for 12 h. Then, cerebral blood flow, mitochondrial structure, mitochondrial DNA (mtDNA) copy number, intracellular and mitochondrial reactive oxygen species (ROS), autophagic flux, aggresome and exosome expression profiles, cardiac tissue structure, mitochondrial length and cristae density, mtDNA and ROS content, as well as the expression of Drp1-Ser616/Drp1, RIP1/RIP3, LC3 II/LC3 I, TNF-α, IL-1ß, etc., were detected under normal or Drp1 interference conditions. RESULTS: The mtDNA content, ROS levels, and Drp1-Ser616/Drp1 were elevated by 2.2, 1.7 and 2.7 times after CIRI (P < 0.05). However, the high cytoplasmic LC3 II/I ratio and increased aggregation of p62 could be reversed by 44% and 88% by Drp1 short hairpin RNA (shRNA) (P < 0.05). The low fluorescence intensity of autophagic flux and the increased phosphorylation of RIP3 induced by CIRI could be attenuated by ROS scavenger, NAC (P < 0.05). RIP1/RIP3 inhibitor Necrostatin-1 (Nec-1) restored 75% to a low LC3 II/LC3 I ratio and enhanced 2 times to a high RFP-LC3 after Drp1 activation (P < 0.05). In addition, although CIRI-induced ROS production caused no considerable accumulation of autophagosomes (P > 0.05), it increased the packaging and extracellular secretion of exosomes containing p62 by 4 - 5 times, which could be decreased by Mdivi-1, Drp1 shRNA, and Nec-1 (P < 0.05). Furthermore, TNF-α and IL-1ß increased in CIRI-derived exosomes could increase RIP3 phosphorylation in normal or oxygen-glucose deprivation/reoxygenation (OGD/R) conditions (P < 0.05). CONCLUSIONS: CIRI activated Drp1 and accelerated the p62-mediated formation of autophagosomes while inhibiting the transition of autophagosomes to autolysosomes via the RIP1/RIP3 pathway activation. Undegraded autophagosomes were secreted extracellularly in the form of exosomes, leading to inflammatory cascades that further damaged mitochondria, resulting in excessive ROS generation and the blockage of autophagosome degradation, triggering a vicious cycle.

Downregulation of TET1 Promotes Glioma Cell Proliferation and Invasion by Targeting Wnt/ß-Catenin Pathway.

Glioma is the most common malignant tumor in adult brain characteristic with poor prognosis and low survival rate. Despite the application of advanced surgery, chemotherapy, and radiotherapy, the patients with glioma suffer poor treatment effects due to the complex molecular mechanisms of pathological process. In this paper, we conducted the experiments to prove the critical roles TET1 played in glioma and explored the downstream targets of TET1 in order to provide a novel theoretical basis for clinical glioma therapy. RT-qPCR was adopted to detect the RNA level of TET1 and ß-catenin; Western blot was taken to determine the expression of proteins. CCK8 assay was used to detect the proliferation of glioma cells. Flow cytometry was used to test cell apoptosis and distribution of cell cycle. To detect the migration and invasion of glioma cells, wound healing assay and Transwell were performed. It was found that downregulation of TET1 could promote the proliferation migration and invasion of glioma cells and the concomitant upregulation of ß-catenin, and its downstream targets like cyclinD1 and c-myc were observed. The further rescue experiments were performed, wherein downregulation of ß-catenin markedly decreases glioma cell proliferation in vitro and in vivo. This study confirmed the tumor suppressive function of TET1 and illustrated the underlying molecular mechanisms regulated by TET1 in glioma.

RANBP10 promotes glioblastoma progression by regulating the FBXW7/c-Myc pathway.

RAN binding protein 10 (RANBP10), a ubiquitously expressed and evolutionarily conserved protein, as a RAN-GTP exchange factor (GEF) to regulate several factors involved in cellular progression. Previous studies showed that RANBP10 was overexpressed in prostate cancer cells and was responsible for androgen receptor (AR) activation. However, the biological function of RANBP10 in glioblastoma (GBM) has not been studied. Here, we found that RANBP10 was overexpressed in GBM, and high RANBP10 expression was closely linked to poor survival of patients with GBM. Downregulation of RANBP10 significantly inhibited cell proliferation, migration, invasion, and tumor growth of GBM cells. In addition, we revealed that RANBP10 could suppress the promoter activity of FBXW7, and thereby increase the protein stability of c-Myc in GBM cells. Silencing of FBXW7 in RANBP10-knockdown GBM cells could partly negate the effects induced by RANBP10 downregulation. Taken together, our findings established that RANBP10 significantly promoted GBM progression by control of the FBXW7-c-Myc axis, and suggest that RANBP10 may be a potential target in GBM.

Germacranolide sesquiterpenes from Carpesium cernuum and their anti-leukemia activity.

In this study, three new germacranolide sesquiterpenes (1-3), together with six related known analogues (4-9) were isolated from the whole plant of Carpesium cernuum. Their structures were established by a combination of extensive NMR spectroscopic analysis, HR-ESIMS data, and ECD calculations. The anti-leukemia activities of all compounds towards three cell lines (HEL, KG-1a, and K562) were evaluated in vitro. Compounds 1-3 exhibited moderate cytotoxicity with IC50 values ranging from 1.59 to 5.47 µmol·L-1. Mechanistic studies indicated that 2 induced apoptosis by decreasing anti-apoptotic protein Bcl-2 and activating the caspase family in K562 cells. These results suggest that compound 2 is a potential anti-leukemia agent.

Bloom helicase explicitly unwinds 3'-tailed G4DNA structure in prostate cancer cells.

G-quadruplex DNA (G4DNA) structure, which widely exists in the chromosomal telomeric regions and oncogenic promoter regions, plays a pivotal role in extending telomeric DNA with the help of telomerase in human cells. Bloom (BLM) helicase, a crucial member of the family of genome surveillance proteins, plays an essential role in DNA metabolic and repair pathways, including DNA replication, repair, transcription, recombination during chromosome segregation, and assuring telomere stability. The unwinding of G4DNA requires the participation of DNA helicase, which is crucial for maintaining chromosomal stability in cancer cells. Using fluorescence polarization and the electrophoretic mobility shift assay (EMSA), this study aimed to investigate the DNA-binding and unwinding properties of BLM helicase, cloned and purified from prostate cancer cells, toward G4DNA. The results revealed that BLM helicase derived from prostate cancer cells could bind and unwind G4DNA. The molecular affinity of bond between G4DNA and the helicase was dependent on the single-stranded DNA (ssDNA) terminals in G4DNA; the helicase was effectively bound to the G4DNA when the helicase monomer sufficiently covered approximately 10 nucleotides at the 3' or 5' ssDNA tail of G4DNA. For the unwinding of G4DNA, there was an apparent requirement of a 3' ssDNA tail and ATP; a G4DNA with only a 3' ssDNA tail was identified to be the most suitable substrate to be unwound by BLM helicase and required 3' ssDNA tails of at least 10 nt in length for efficient unwinding. Besides, BLM helicase was loosely bound and partly unwound the blunt-ended G4DNA. Although further mechanistic studies are warranted, the experimental results presented in this study are beneficial to further our understanding of the functional implication of BLM helicase in prostate cancer cells.

Long Non-Coding RNA UBA6-AS1 Promotes the Malignant Properties of Glioblastoma by Competitively Binding to microRNA-760 and Enhancing Homeobox A2 Expression.

BACKGROUND: The dysregulation of long non-coding RNAs is a frequent finding in glioblastoma (GBM) and is considered as a crucial mechanism contributing to GBM oncogenesis and progression. The biological roles and underlying mechanisms of action of UBA6 antisense RNA 1 (UBA6-AS1) in GBM have been rarely investigated. Therefore, the aim of the present study was to investigate in detail the role of UBA6-AS1 in the modulation of the malignant properties of GBM and explore the possible underlying mechanism(s). METHODS: The expression of UBA6-AS1 in GBM was determined via reverse transcription-quantitative PCR. Cell Counting Kit-8 assay, flow cytometric analysis, Transwell migration and invasion assays, and in vivo tumorigenicity assay were applied to elucidate the biological effects of UBA6-AS1 on GBM cells. The possible biological events associated with UBA6-AS1 were investigated by luciferase reporter, RNA immunoprecipitation (RIP) and rescue assays. RESULTS: UBA6-AS1 was overexpressed in GBM, which was consistent with the data from The Cancer Genome Atlas database. In the case of UBA6-AS1 depletion, GBM cell proliferation, migration and invasion were notably decreased and cell apoptosis was enhanced in vitro. Additionally, knockdown of UBA6-AS1 suppressed the proliferation of GBM cells in vivo. Mechanistically, UBA6-AS1 functioned as a competing endogenous RNA by adsorbing miR-760 and, consequently, upregulating homeobox A2 (HOXA2) expression. Rescue experiments demonstrated that the UBA6-AS1 silencing-mediated regulatory effects on GBM cells were reversed by the decrease of miR-760 or restoration of HOXA2 expression. CONCLUSION: Therefore, the results of the present study revealed that UBA6-AS1 promoted the malignant progression of GBM via targeting the miR-760/HOXA2 axis, thereby representing a promising effective target for the treatment of GBM.

Novel 3,4-dihydroquinolin-2(1H)-one derivatives as dual inhibitor targeting AKR1B1/ROS for treatment of diabetic complications: Design, synthesis and biological evaluation.

AKR1B1 (Aldose reductase) has been used as therapeutic intervention target for treatment of diabetic complications over 50 years, and more recently for inflammation and cancer. However, most developed small molecule inhibitors have the defect of low bioactivity. To address this limitation, novel series of 3,4-dihydroquinolin-2(1H)-one derivatives as dual inhibitor targeting AKR1B1/ROS (Reactive Oxygen Species) were designed and synthesized. Most of these derivatives were found to be potent and selective against AKR1B1, and compound 8a was the most active with an IC50 value of 0.035 µM. Moreover, some prepared derivatives showed strong anti-ROS activity, and among them the phenolic 3,5-dihydroxyl compound 8b was proved to be the most potent, even comparable to that of the well-known antioxidant Trolox at a concentration of 100 µM. Thus the results suggested a success in the construction of potent dual inhibitor for the therapeutic intervention target of AKR1B1/ROS.

Circ_101064 regulates the proliferation, invasion and migration of glioma cells through miR-154-5p/ PIWIL1 axis.

This study aimed to investigate the effects of Circ_101064 on glioma cell proliferation, invasion, migration and explore the underlying mechanisms. The expression levels of Circ_101064 in glioma/para-carcinoma tissues and glioma cells were analyzed using RT-qPCR. Moreover, U251 and U87 cells were transfected with si-Circ_101064 or miR-154-5p mimics. Cell proliferation rate was determined by CCK-8 assay; the invasion and migration activities were examined using Transwell assay; the expression levels of PIWIL1 were evaluated by RT-qPCR and western blotting. The expression level of Circ_101064 was significantly upregulated in glioma tissues compared with control, and was closely associated with tumor grading and diameter. Furthermore, increased Circ_101064 expression was detected in human glioma cell lines. In addition, knockdown of Circ_101064 remarkably suppressed cell proliferation, invasion and migration in glioma cells in vitro. Moreover, microRNA-154-5p (miR-154-5p) could be a target of Circ_101064. Additionally, PIWIL1 is a putative downstream molecule of miR-154-5p, and its expression was downregulated by knockdown of Circ_101064. The effects on cell growth and metastasis caused by si-Circ_101064 were notably enhanced by miR-154-5p mimics. However, the influences of miR-154-5p-suppressed proliferation, migration and invasion of glioma cells could be abolished by overexpressed PIWIL1. In summary, our findings provided novel insight into the regulatory functions of Circ_101064 during tumor development in glioma. More importantly, Circ_101064/miR-154-5p/PIWIL1 axis could be a promising therapeutic target for the treatment of this disease.

Overexpression of TRIM26 suppresses the proliferation, metastasis, and glycolysis in papillary thyroid carcinoma cells.

Papillary thyroid carcinoma (PTC) is the common subtype of thyroid cancer, which is a common endocrine malignancy. Tripartite motif 26 (TRIM26) has been found to act as a tumor suppressor in several cancers. However, the functional roles of TRIM26 in PTC remain unknown. In this study, we examined the TRIM26 expression in PTC and evaluated the effects of TRIM26 on proliferation, metastasis, and glycolysis in PTC cells. The results proved that TRIM26 was significantly downregulated in PTC tissues and cell lines. TRIM26 overexpression inhibited cell proliferation, migration, and invasion in PTC cells. TRIM26 overexpression also suppressed the epithelial-to-mesenchymal transition process. Besides, overexpression of TRIM26 caused significant decrease in glucose uptake and lactate production in PTC cells. Further investigations revealed that TRIM26 overexpression inhibited the activation of PI3K/Akt pathway. Treatment with an activator (740Y-P) of the PI3K/AKT pathway reversed the antitumor effects of TRIM26 on PTC cells. These findings provided evidence that TRIM26 acted as a tumor suppressor in PTC.

Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study.

The lung cancer incidence in the Xuanwei and neighboring region, Yunnan, China, is among the highest in China and is attributed to severe air pollution with high benzo(a)pyrene levels. We systematically and comparatively analyzed DNA methylation alterations at genome and gene levels in Xuanwei lung cancer tissues and cell lines, as well as benzo(a)pyrene-treated cells and mouse samples. We obtained a comprehensive dataset of genome-wide cytosine-phosphate-guanine island methylation in air pollution-related lung cancer samples. Benzo(a)pyrene exposure induced multiple alterations in DNA methylation and in mRNA expressions of DNA methyltransferases and ten-11 translocation proteins; these alterations partially occurred in Xuanwei lung cancer. Furthermore, benzo(a)pyrene-induced DKK2 and EN1 promoter hypermethylation and LPAR2 promoter hypomethylation led to down-regulation and up-regulation of the genes, respectively; the down-regulation of DKK2 and EN1 promoted the cellular proliferation. Thus, DNA methylation alterations induced by benzo(a)pyrene contribute partially to abnormal DNA methylation in air pollution-related lung cancer, and these DNA methylation alterations may affect the development and progression of lung cancer. Additionally, vitamin C and B6 can reduce benzo(a)pyrene-induced DNA methylation alterations and may be used as chemopreventive agents for air pollution-related lung cancer.

Tirucallane-type triterpenoids from the fruits of Phellodendron chinense Schneid and their cytotoxic activities.

Eleven triterpenoids were isolated from the fruits of Phellodendron chinense Schneid, and their structures were determined by spectroscopic analysis. The results show that four new tirucallane-type triterpenoids 1, 2, 5, and 6 and seven known compounds 3, 4, 7, 8, 9, 10, and 11 were isolated. Structurally, compound 6 was uncommon; it has a chlorine atom instead of a methyl group at the C-20 position. The cytotoxicities of the compounds was evaluated against the in vitro proliferation of four human tumor cell lines HEL, K562, MDA, and PC3 using adriamycin as the positive control. Compound 1 showed a similar cytotoxicity as the positive control; compounds 3 and 10 showed moderate cytotoxicities compared to the control (P<0.05). This indicates that these compounds have great potential for the development of new antitumor drugs.

High expression of BAG3 predicts a poor prognosis in human medulloblastoma.

Bcl2-associated athanogene 3 (BAG3), a co-chaperone of the heat shock protein (Hsp) 70, regulates various physiological and pathological processes. However, its role in human medulloblastoma has not been clarified. First of all, the expression of BAG3 was examined in formalin-fixed, paraffin-embedded specimens by immunohistochemical staining. And then, the prognostic role of BAG3 was analyzed in 51 medulloblastoma samples. Finally, the roles of BAG3 in the proliferation, migration, and invasion of Daoy medulloblastoma cell were investigated using a specific short hairpin RNA (shRNA). The expression of BAG3 in medulloblastoma tissues was higher than nontumorous samples. Furthermore, BAG3 overexpression significantly correlated with poor prognosis of patients with medulloblastoma. The overall survival and tumor-free survival in patients with BAG3 low expression were higher than high expression. Univariate and multivariate analysis showed that BAG3 overexpression was an independent prognostic marker for medulloblastoma. After the BAG3 knockdown, the Daoy cells exhibited decreased the ability to proliferate and form neurosphere. The preliminary mechanism study showed that overexpression of BAG3 might facilitate the cell cycle transition from G1 to S phase by modulating the cyclin-dependent kinase 2 (CDK2) and cyclin E expression. Additionally, we found that BAG3 might enhance the medulloblastoma cell migratory and invasive ability. In summary, BAG3 overexpression may regulate the survival and invasive properties of medulloblastoma and may serve as a potential therapy target for medulloblastoma.

Effects of icotinib on early-stage non-small-cell lung cancer as neoadjuvant treatment with different epidermal growth factor receptor phenotypes.

PURPOSE: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated efficacy in treating advanced non-small-cell lung cancer (NSCLC). Preliminary findings suggested that EGFR-TKIs might also be beneficial in neoadjuvant therapy in treating NSCLC. Therefore, this study aimed to evaluate the efficacy and safety of neoadjuvant therapy with icotinib in patients with early-stage NSCLC. PATIENTS AND METHODS: We retrospectively reviewed the medical history of patients who were initially diagnosed with stage IA-IIIA NSCLC and were under icotinib administration before surgery between December 2011 and December 2014. Tumor assessment was conducted between the second and fourth week from initial icotinib treatment. The association between personal characteristics, smoking status, disease stage, EGFR mutation status, and clinical outcomes were investigated using multivariate logistic regression analysis. RESULTS: A total of 67 patients with NSCLC were reviewed, and approximately half (38/67) of them were identified as having EGFR-mutant tumors. The overall response rate of all patients was 26.7% at 2-4 weeks' assessment. Multivariate analysis showed that female sex (38.5% versus 10.7% in males, P=0.028) and EGFR mutation status (42.1% versus 6.9% in EGFR wild type, P=0.011) were independent predictive factors. The analysis also showed that the most common adverse effects were rash (43.3%) and dry skin (34.4%), which were tolerable. CONCLUSION: Icotinib induced clinical response with minimal toxicity as neoadjuvant treatment in early NSCLC, especially in patients with common EGFR mutations. Further studies are warranted to confirm our findings.

PHOX2B Is Associated with Neuroblastoma Cell Differentiation.

Neuroblastoma is a common pediatric malignancy that accounts for ∼15% of tumor-related deaths in children. The tumor is generally believed to originate from neural crest cells during early sympathetic neurogenesis. As the degree of neuroblastoma differentiation has been correlated with clinical outcome, clarifying the molecular mechanisms that drive neuroblastoma progression and differentiation is important for increasing the survival of these patients. In a previous study, the authors identified paired-like homeobox 2b (PHOX2B) as a key mediator of neuroblastoma pathogenesis in a TH-MYCN mouse model. In the present study, they aimed to define whether PHOX2B is also associated with proliferation and differentiation of human neuroblastoma cells. PHOX2B expression in neuroblastoma cells was evaluated by immunoblot analyses, and the effects of PHOX2B on the proliferation of neuroblastoma cells in vitro were determined using clonogenic and sphere formation assays. Xenograft experiments in NOD/SCID mice were used to examine the in vivo response to PHOX2B knockdown. Their data demonstrated that PHOX2B acts as a prognostic marker in neuroblastoma and that retinoic acid-induced neuronal differentiation downregulates PHOX2B expression, thereby suppressing the self-renewal capacity of neuroblastoma cells and inhibiting tumorigenicity. These findings confirmed that PHOX2B is a key regulator of neuroblastoma differentiation and stemness maintenance and indicated that PHOX2B might serve as a potential therapeutic target in neuroblastoma patients.

Characterization of Somatic Mutations in Air Pollution-Related Lung Cancer.

Air pollution has been classified as Group 1 carcinogenic to humans, but the underlying tumorigenesis remains unclear. In Xuanwei City of Yunnan Province, the lung cancer incidence is among the highest in China attributed to severe air pollution generated by combustion of smoky coal, providing a unique opportunity to dissect lung carcinogenesis of air pollution. Here we analyzed the somatic mutations of 164 non-small cell lung cancers (NSCLCs) from Xuanwei and control regions (CR) where smoky coal was not used. Whole genome sequencing revealed a mean of 289 somatic exonic mutations per tumor and the frequent C:G â†’ A:T nucleotide substitutions in Xuanwei NSCLCs. Exome sequencing of 2010 genes showed that Xuanwei and CR NSCLCs had a mean of 68 and 22 mutated genes per tumor, respectively (p < 0.0001). We found 167 genes (including TP53, RYR2, KRAS, CACNA1E) which had significantly higher mutation frequencies in Xuanwei than CR patients, and mutations in most genes in Xuanwei NSCLCs differed from those in CR cases. The mutation rates of 70 genes (e.g., RYR2, MYH3, GPR144, CACNA1E) were associated with patients' lifetime benzo(a)pyrene exposure. This study uncovers the mutation spectrum of air pollution-related lung cancers, and provides evidence for pollution exposure-genomic mutation relationship at a large scale.

CRH knockout inhibits the murine innate immune responses in association with endoplasmic reticulum stress after thermal injury.

BACKGROUND: Previous studies in our laboratory have demonstrated the hypothalamus destruction and adrenalectomy could blunt the innate immunity while boosting the excessive inflammation after injury. We aimed to investigate the effects of corticotrophin-releasing hormone knockout (CRH KO) on the innate immune responses in macrophages as well as to elucidate the underlying mechanism. METHODS: The chemotaxis and phagocytosis activities of macrophages, bacteria translocation, plasma tumor necrosis factor (TNF)-α secretion, and intestinal injury were observed in the presence of the endoplasmic reticulum stress after thermal injury in CRH KO mice. Meanwhile, the messenger RNA (mRNA) and protein expression of glucose response protein 78 (GRP78), X-box binding protein 1 (XBP1), and activating transcription factor 6 (ATF6) in macrophages was also determined. RESULTS: After thermal injury, the chemotaxis and phagocytosis of peritoneal macrophages were increased, which were both reversed by CRH gene deficiency. The gut-derived bacteria translocation to liver tissues, lung tissues and mesenteric lymph nodes was significantly strengthened in CRH KO mice compared with CRH wild-type littermates. Circulating TNF-α level was increased markedly in response to thermal injury and CRH KO further increased its secretion. Furthermore, the mRNA and protein levels of GRP78, XBP1, and ATF6 in peritoneal macrophages increased, while their expressions in CRH KO mice all decreased significantly. CRH KO mice showed enhancement of inflammatory responses and severe tissue injuries after thermal injury. CONCLUSION: CRH exerted immune defensive actions on immune cells and organs in the early phase of injury, suggesting that the underlying mechanisms are related to endoplasmic reticulum stress.