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Background and Objective: Terminalia chebula is a classical medicine for the treatment of lingering dysentery, and both raw and processed T. chebula can alleviate ulcerative colitis (UC). The therapeutic efficacy of T. chebula is enhanced after processing, but the mechanism that processing improves this efficacy is still unknown. We investigated the medicinal effects of raw and processed T. chebula on dextran sulfate sodium (DSS)-induced UC model rats using intestinal flora and metabolomics analyses, in order to elucidate the mechanism by which processing enhances the therapeutic effect., Methods: The major constituents of raw and processed T. chebula were detected by high-performance liquid chromatography (HPLC). UC model was replicated using the DSS method, and then UC rats were administered raw and processed T. chebula. The general physical signs, disease activity index (DAI) scores, colon histopathological morphology, and the expressions of inflammatory cytokines were used to evaluate the therapeutic effect of T. chebula. In addition, 16 s rRNA sequencing and gas chromatography-mass spectrometry (GC-MS) were used to characterize the intestinal flora and contents of short-chain fatty acids (SCFAs). Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was utilized to identify the nontargeted fecal metabolites., Results: Raw and processed T. chebula significantly improved the general physical signs and colon inflammatory symptoms and decreased DAI scores of UC rats. Both raw and processed T. chebula mitigated intestinal flora disorders in UC rats, increasing probiotic bacteria, including Lactobacillus and Romboutsia. However, the effect of processed T. chebula was more pronounced. Moreover, the levels of SCFAs of DSS-induced UC rats were restored after drug administration, and the processed T. chebula had a better regulatory effect than raw T. chebula. In the fecal nontargeted metabolomics analysis, differential metabolites such as lipids and amino acids were identified. The processed T. chebula can regulate purine metabolism and other pathways to improve UC, and the levels of the disordered metabolites gradually approached those of the control group., Conclusion: Raw and processed T. chebula had the capacity to mitigate DSS-induced UC by rebalancing the intestinal flora, restoring the contents of SCFAs, and regulating fecal metabolites, while processed T. chebula showed preferable effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The association between mitochondrial dysfunction and multiple metabolic adaptations is increasingly being proven. We previously elucidated that mitochondrial complex I deficiency can promote glycolysis in mut-p53 SW480 cells. However, studies have revealed a phenotype with attenuated glycolysis but enhanced fatty acid oxidation (FAO) in invasive tumors. The interplay between complex I and FAO in carcinogenesis remains obscure., Methods: The p53 wild-type RKO cells were exposed to rotenone over at least 2 months to acquire rotenone adaptation cells. Then the transwell invasion assays and expression of metabolic enzymes were first detected in rotenone adaptation cells to illustrate whether rotenone adaptation is correlated with the invasion and FAO. The levels of epithelial-to-mesenchymal transition (EMT)-related proteins and acetyl-CoA in rotenone adaptation cells treated with etomoxir (ETO) and acetate were evaluated to verify the role of CPT1A in regulating invasion. Finally, the levels of reactive oxygen species (ROS) were detected. Meanwhile, the invasiveness and histone acetylation levels of rotenone adaptation cells were observed after adding an ROS inhibitor (N-acetyl-L-cysteine NAC) to demonstrate the molecular connection between FAO and invasion during rotenone adaptation., Results: We found long-term exposure to rotenone (a mitochondrial complex I inhibitor) led to EMT and high CPT1A expression in wt-p53 colon cancer. The inhibition of CPT1A suppressed the invasion and reduced histone acetylation, which was rescued by supplementing with acetate. Mechanistically, ROS is crucial for lipid metabolism remodeling., Conclusion: Our study provides a novel understanding of the role of complex I in lipid reprogramming facilitating colon cancer invasion and metastasis., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: The Medical Ethics Committee Zhongnan Hospital of Wuhan University approved all study procedures., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Introduction: Resistance of intracellular pathogens is a challenge in microbial therapy. Methicillin-resistant Staphylococcus aureus (MRSA), which is able to persist inside the cells of infected tissues, is protected from attack by the immune system and many antimicrobial agents. To overcome these limitations, nano-delivery systems can be used for targeted therapy of intracellular MRSA., Methods: Hyaluronic acid-modified azithromycin/quercetin micelles (HA-AZI/Qe-M) were synthesized by thin film hydration. The micelles were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) and Fourier transform infrared spectroscopy (FTIR), and the drug loading (DL) and encapsulation efficiency (EE) were detected by high performance liquid chromatography (HPLC). The uptake ability of RAW264.7 cells was investigated, and its distribution in mice was evaluated by in vivo imaging. The inhibitory effect of the micelles against MRSA in vitro and its ability to eliminate intracellular bacteria were evaluated. Bacterial muscle-infected mice were constructed to evaluate the therapeutic effect of the micelles on bacterial infections in vivo and the biocompatibility of the micelles was investigated., Results: HA-AZI/Qe-M had suitable physical and chemical properties and characterization. In vitro a ntibacterial experiments showed that HA-AZI/Qe-M could effectively inhibit the growth of MRSA, inhibit and eliminate the biofilm formed by MRSA, and have an excellent therapeutic effect on intracellular bacterial infection. The results of RAW264.7 cells uptake and in vivo imaging showed that HA-AZI/Qe-M could increase the cellular uptake, target the infection site, and prolong the treatment time. The results of in vivo antibacterial infection experiments showed that HA-AZI/Qe-M was able to ameliorate the extent of thigh muscle infections in mice and reduce the expression of inflammatory factors., Conclusion: HA-AZI/Qe-M is a novel and effective nano-drug delivery system that can target intracellular bacterial infection, and it is expected to be safely used for the treatment of MRSA infection., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Zhang et al.)

Targeting delivery to the infection site and good affinity of vehicle to the bacterial are two main concerns in therapy of bacterial infection, and on-demand release of drug is another important issue. In this work, a liposome drug delivery system (HA/P/BAI-lip) incorporated with baicalein and modified by PHMG and HA was prepared. Several characterizations were conducted to examine the physical properties of liposome. Then it was applied to treatments of MRSA induced dorsal subcutaneous abscess model and the thigh muscle infected model. The presence of guanidine group in HA/P/BAI-lip rendered the liposome satisfactory bacterial target ability and good pH sensitive properties. The lipase secreted by bacterial could promote the hydrolysis of soybean phosphatidylcholine (SPC) in liposome. The modification of HA in HA/P/BAI-lip could lead the drug system to the exact infected site where CD44 was abundant because of inflammation. The low pH microenvironment characteristic of bacterial infection could induce the swelling of liposome following by degradation. Taken together, baicalein could be released selectively at the infected site to exert antibacterial capacity. HA/P/BAI-lip showed impressive antibacterial ability and dramatically decrease the bacterial burden of infection site and alleviate the infiltration of inflammatory cells, facilitating the recovery of infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

As the aging population continues to increase, aging-related inflammation, oxidative stress, and neurodegenerative diseases have become serious global health threats. Resveratrol, a star molecule in natural polyphenols, has been widely reported to have physiological activities such as anti-aging, anti-inflammatory, antioxidant, and neuroprotection. However, its poor water solubility, rapid metabolism, low bioavailability and poor targeting ability, which limits its application. Accordingly, a brain-targeted resveratrol liposome (ANG-RES-LIP) was developed to solve these issues. Experimental results showed that ANG-RES-LIP has a uniform size distribution, good biocompatibility, and a drug encapsulation rate of over 90%. Furthermore, in vitro cell experiments showed that the modification of the targeting ligand ANG significantly increased the capability of RES to cross the BBB and neuronal uptake. Compared with free RES, ANG-RES-LIP demonstrated stronger antioxidant activity and the ability to rescue oxidatively damaged cells from apoptosis. Additionally, ANG-RES-LIP showed the ability to repair damaged neuronal mitochondrial membrane potential. In vivo experiments further demonstrated that ANG-RES-LIP improved cognitive function by reducing oxidative stress and inflammation levels in the brains of aging model mice, repairing damaged neurons and glial cells, and increasing brain-derived neurotrophic factor. In summary, this study not only provides a new method for further development and application of resveratrol but also a promising strategy for preventing and treating age-related neurodegenerative diseases.

Background: The preservation of the Lingguizhugan (LGZG) decoction and patient compliance issue often limit the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Hence, herein, an LGZG oral solution was developed for alleviating MASLD. Additionally, the potential mechanisms underlying LGZG-mediated MASLD mitigation were explored., Methods: A MASLD mouse model was constructed using oleic and palmitic acid-induced LO2 cells and a high-fat diet. The apoptosis, lipid deposition, and mouse liver function were analyzed to assess the therapeutic effects of the LGZG oral solution on MASLD. Serum untargeted metabolomics, gut microbiota, bile acid (BA) metabolism, immunohistochemistry, and Western blotting analyses were performed to investigate the potential mechanism of action of LGZG oral solution on MASLD., Results: The LGZG oral solution ameliorated lipid deposition, oxidative stress, inflammation, and pathological damage. Serum untargeted metabolomics results revealed the LGZG-mediated regulation of the primary BA biosynthetic pathway. The 16S ribosomal RNA sequencing of the fecal microbiota showed that LGZG oral solution increased the relative abundance of the BA metabolism-associated Bacteroides , Akkermansia , and decreased that of Lactobacillus . Additionally, the BA metabolism analysis results revealed a decrease in the total taurine-α/β-muricholic acid levels, whereas those of deoxycholic acid were increased, which activated specific receptors in the liver and ileum, including farnesoid X receptor (FXR) and takeda G protein-coupled receptor 5 (TGR5). Activation of FXR resulted in an increase in short heterodimer partner and subsequent inhibition of cholesterol 7α-hydroxylase and sterol regulatory element-binding protein-1c expression, and activation of FXR also results in the upregulation of fibroblast growth factor 15/19 expression, and consequently inhibition of cholesterol 7α-hydroxylase, which correlated with hepatic BA synthesis and lipogenesis, ultimately attenuating lipid deposition and bile acid stasis, thereby improving MASLD., Conclusion: Altogether, the findings of this study suggest that modulating microbiota-BA-FXR/TGR5 signaling pathway may be a potential mechanism of action of LGZG oral solution for the treatment of MASLD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Zang, Yu, Liu, Cao, Guo, Zhang, Liu, Zhang, Li and Kong.)

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, leading to severe inflammatory infiltration and joint damage, accompanied by a decrease in pH of joint microenvironment. Macrophages play an important role in the pathogenesis of RA, with high expression of bovine serum albumin (BSA) receptors on the surface of macrophages. Resveratrol (Res) has strong anti-inflammatory effects, but its application is limited due to its poor water solubility and low bioavailability. Therefore, we constructed pH-sensitive micelles by encapsulating Res and modifying BSA on the surface of the micelles (BSA-Res@Ms), thereby greatly improving the therapeutic effect of RA. Our research results indicated that BSA-Res@Ms had a smooth and uniform appearance, small particle size, high drug encapsulation efficiency, good stability, and pH-sensitive properties. In vitro, BSA-Res@Ms increased the uptake of Res by RAW264.7 cells, reduced the levels of pro-inflammatory cytokines and cleared excess ROS produced by activated RAW264.7 cells, and inhibited the generation of osteoclasts. In vivo, BSA-Res@Ms could target inflamed joint sites, significantly alleviate joint inflammation symptoms, inhibit activated macrophages, improve synovial hyperplasia and inflammatory cell infiltration, and protect cartilage. BSA-Res@Ms provide a very promising method for the treatment of RA, which can effectively improve the inflammatory manifestations of RA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: MicroRNAs (miRNAs) have pivotal roles in gene regulation. Circulating miRNAs have been developed as novel candidate non-invasive biomarkers for diagnosis, prognosis, and treatment response for diseases. However, miRNAs that have causal effects on Parkinson's Disease (PD) remain largely unknown. To investigate the causal relationships between miRNAs and PD, here we conduct a Mendelian randomization (MR) study., Methods: This study utilized the summary-level data of respective genome-wide association studies (GWAS) for 2083 miRNAs and seven PD-related outcomes to comprehensively reveal the causal associations between the circulating miRNAs and PD. Two-sample MR design was deployed and the causal effects were estimated with inverse variance weighted, MR-Egger, and weighted median. Comprehensively sensitive analyses were followed, including Cochran's Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis, to validate the robustness of our results. Finally, we investigated the potential role of the MR significant miRNAs by predicting their target genes and functional enrichment analysis., Results: Inverse variance weighted estimates suggested that two miRNAs, miR-205-5p (β = -0.46, 95%CI: -0.690 to -0.229, p  = 9.3 × 10 -5 ) and miR-6800-5p (β = -0.389, 95%CI: -0.575 to -0.202, p  = 4.32 × 10 -5 ), significantly decreased the rate of cognitive decline among PD patients. In addition, eight miRNAs were nominally associated with more than three PD-related outcomes each. No significant heterogeneity of instrumental variables or horizontal pleiotropy was found. Gene Ontology (GO) analysis showed that the targets of these causal miRNAs were significantly enriched in cell cycle, apoptotic, and aging pathways., Conclusion: This MR study identified two miRNAs whose genetically regulated expression might have a causal role in the development of PD dementia. Our findings provided potential miRNA biomarkers to make better and early diagnoses and risk assessments of PD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shi, Wu, Li, Zhao, Yin and Zhu.)

Background: The intra- and inter-tumoral heterogeneity of gliomas and the complex tumor microenvironment make accurate treatment of gliomas challenging. At present, research on gliomas mainly relies on cell lines, stem cell tumor spheres, and xenotransplantation models. The similarity between traditional tumor models and patients with glioma is very low., Aims: In this study, we aimed to address the limitations of traditional tumor models by generating patient-derived glioma organoids using two methods that summarized the cell diversity, histological features, gene expression, and mutant profiles of their respective parent tumors and assess the feasibility of organoids for personalized treatment., Materials and Methods: We compared the organoids generated using two methods through growth analysis, immunohistological analysis, genetic testing, and the establishment of xenograft models., Results: Both types of organoids exhibited rapid infiltration when transplanted into the brains of adult immunodeficient mice. However, organoids formed using the microtumor method demonstrated more similar cellular characteristics and tissue structures to the parent tumors. Furthermore, the microtumor method allowed for faster culture times and more convenient operational procedures compared to the Matrigel method., Discussion: Patient-derived glioma organoids, especially those generated through the microtumor method, present a promising avenue for personalized treatment strategies. Their capacity to faithfully mimic the cellular and molecular characteristics of gliomas provides a valuable platform for elucidating tumor biology and evaluating therapeutic modalities., Conclusion: The success rates of the Matrigel and microtumor methods were 45.5% and 60.5%, respectively. The microtumor method had a higher success rate, shorter establishment time, more convenient passage and cryopreservation methods, better simulation of the cellular and histological characteristics of the parent tumor, and a high genetic guarantee., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: The high invasiveness and infiltrative nature of Glioblastoma (GBM) pose significant challenges for surgical removal. This study aimed to investigate the role of KCNA1 in GBM progression., Methods: CCK8, colony formation assay, scratch assay, transwell assay, and 3D tumor spheroid invasion assays were to determine how KCNA1 affects the growth and invasion of GBM cells. Subsequently, to confirm the impact of KCNA1 in ferroptosis, western blot, transmission electron microscopy and flow cytometry were conducted. To ascertain the impact of KCNA1 in vivo, patient-derived orthotopic xenograft models were established., Results: In functional assays, KCNA1 promotes the growth and invasion of GBM cells. Besides, KCNA1 can increase the expression of SLC7A11 and protect cells from ferroptosis. The vivo experiments demonstrated that knocking down KCNA1 inhibited the growth and infiltration of primary tumors in mice and extended survival time., Conclusion: Therefore, our research suggests that KCNA1 may promote tumor growth and invasion by upregulating the expression of SLC7A11 and inhibiting ferroptosis, making it a promising therapeutic target for GBM., (© 2024. The Author(s).)

DMC-HA, a novel HDAC inhibitor, has previously demonstrated antiproliferative activity against various cancers, including gliomas. However, the role of DMC-HA in the regulation of EMT and its underlying mechanisms remain unknown. This study aimed to explore the effects of DMC-HA on TGF-β1-induced EMT in human gliomas and the underlying mechanisms involved. Our results showed that TGF-β1 induced EMT of U87 and U251 cells, leading to a decrease in epithelial marker ZO-1 and an increase in mesenchymal markers N-cadherin and Vimentin. Moreover, TGF-β1 treatment resulted in a significant increase in the migratory and invasive abilities of the cells. However, treatment with DMC-HA effectively inhibited the augmented migration and invasion of glioma cells induced by TGF-β1. Additionally, DMC-HA inhibits TGF-β1-induced EMT by suppressing canonical Smad pathway and non-canonical TGF-β/Akt and Erk signalling pathways. These findings suggest that DMC-HA has potential therapeutic implications for gliomas by inhibiting EMT progression.

Background: Glioblastoma multiforme (GBM), the most malignant tumor of the central nervous system, is characterized by poor survival and high recurrence. Glioma stem cells (GSCs) are key to treating GBM and are regulated by various signaling pathways. Ubiquitination, a post-translational modification, plays an important regulatory role in many biological processes. Ring finger protein 138 (RNF138) is an E3 ubiquitin-protein ligase that is highly expressed in several tumors; however, its role in GBM is unclear. This study investigated whether RNF138 regulates the self-renewal ability of glioma stem GSCs to treat GBM., Materials and Methods: The expression of RNF138 in glioma tissues and its correlation with GSCs were analyzed using bioinformatics. Short hairpin ribonucleic acid (RNA) was designed to downregulate the expression of RNF138 in GSCs, and immunofluorescence, secondary pellet formation, and western blotting were used to detect changes in GSC markers and self-renewal ability. The effects of RNF138 on p53 protein expression were determined by immunofluorescence and western blotting. The effects of RNF138 on the self-renewal and tumorigenic abilities of GSCs were evaluated in vivo., Results: RNF138 expression was higher in glioma tissues than in normal brain tissues, and was highly expressed in GSCs. RNF138 downregulation significantly decreased the expression of the GSC markers cluster of differentiation 133 (CD133) and nestin. Mechanistically, RNF138 may interfere with the self-renewal ability of GSCs by regulating the expression of p53. RNF138 downregulation in vivo prolonged survival time and regulated the expression of p53 protein in tumor-bearing mice., Conclusion: RNF138 may regulate the expression of p53 protein through ubiquitination, thereby affecting the self-renewal and tumorigenic ability of GSCs. This study provides a scientific basis for the treatment of glioblastoma by targeting RNF138 to inhibit GSCs., (Copyright © 2023 Copyright: © 2023 Journal of Cancer Research and Therapeutics.)

Glioma is the most common malignant brain tumor, and its behavior is closely related to the presence of glioma stem cells (GSCs). We found that the enhancer of zeste homolog 2 (EZH2) is highly expressed in glioma and that its expression is correlated with the prognosis of glioblastoma multiforme (GBM) in two databases: The Cancer Genome Atlas and the Chinese Glioma Genome Atlas. Additionally, EZH2 is known to regulate the stemness-associated gene expression, proliferation, and invasion ability of GSCs, which may be achieved through the activation of the STAT3 and Notch1 pathways. Furthermore, we demonstrated the effect of the EZH2-specific inhibitor GSK126 on GSCs; these results not only corroborate our hypothesis, but also provide a potential novel treatment approach for glioma., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The blood-brain barrier (BBB) is a barrier that maintains brain homeostasis, but it is also one of the major problems that must be overcome in the development of Alzheimer's disease (AD) drugs. To solve this problem, Salidroside (Sal) and Icariin (Ica), drugs with neuroprotective effects were loaded into liposomes, and the targeting molecule Angiopep-2 was modified on the surface of liposomes (Ang-Sal/Ica-Lip), so that the constructed nano-drug delivery system could effectively cross the BBB and exert anti-AD effects. The prepared liposomes exhibited ideal physicochemical properties. In vitro and in vivo targeting studies showed that Ang-Sal/Ica liposome could cross the BBB to increase drug accumulation in the brain, and increase the uptake of N2a cells and bEnd.3 cells. The pharmacodynamic analysis in vivo showed that Ang-Sal/Ica liposome could reverse neuronal and synaptic damage, inhibit neuroinflammation and oxidative stress and improve learning and cognitive function. Therefore, Ang-Sal/Ica liposome may be a promising therapeutic strategy for mitigating AD-related symptoms.

Introduction: Transcatheter aortic valve replacement (TAVR) is the first-line treatment for patients with moderate-to-high surgical risk of severe aortic stenosis. Paravalvular leakage (PVL) is a serious complication of TAVR, and aortic valve calcification contributes to the occurrence of PVL. This study aimed to investigate the effect of location and quantity of calcification in the aortic valve complex (AVC) and left ventricular outflow tract (LVOT) on PVL after TAVR., Method: We performed a systematic review and meta-analysis to evaluate the effect of quantity and location of aortic valve calcification on PVL after TAVR using observational studies from PubMed and EMBASE databases from inception to February 16, 2022., Results: Twenty-four observational studies with 6,846 patients were included in the analysis. A high quantity of calcium was observed in 29.6% of the patients; they showed a higher risk of significant PVL. There was heterogeneity between studies (I2 = 15%). In the subgroup analysis, PVL after TAVR was associated with the quantity of aortic valve calcification, especially those located in the LVOT, valve leaflets, and the device landing zone. A high quantity of calcium was associated with PVL, regardless of expandable types or MDCT thresholds used. However, for valves with sealing skirt, the amount of calcium has no significant effect on the incidence of PVL., Conclusion: Our study elucidated the effect of aortic valve calcification on PVL and showed that the quantity and location of aortic valve calcification can help predict PVL. Furthermore, our results provide a reference for the selection of MDCT thresholds before TAVR. We also showed that balloon-expandable valves may not be effective in patients with high calcification, and valves with sealing skirts instead of those without sealing skirts should be applied more to prevent PVL from happening., Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=354630, identifier: CRD42022354630., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Shi, Li, Zhang, Han, Wang, Pei, Li, Zhao, Wang, Han and Chen.)

Background: Sex-related differences in cancer epidemiology, tumor biology, immune system activity, and pharmacogenomics have been suggested to be important considerations for precision cancer control. Here we elucidated systematically sex biases in genetic variants, gene expression profiles, and immunological landscapes of lung adenocarcinoma patients (LUADs) with different ancestry and smoking status., Methods: Somatic mutation and mRNA expression data of Asian and Non-Asian LUADs were obtained from public databases. Sex-biased genetic mutations, gene expression, biological pathways, and immune infiltration were identified in the context of smoking status and race., Results: Among nonsmokers, male-biased mutations were prevalent in Asian LUADs, while few sex-biased mutations were detected in Non-Asian LUADs. EGFR was the only mutation whose frequency was significantly higher in females than males in both Asian and Non-Asian nonsmokers. More genes exhibited sex-biased expression in Non-Asian LUADs compared to Asian LUADs. Moreover, genes distinctly expressed in females were mainly related to immune-related pathways, whereas those in males were more involved in activation of DNA repair, E2F_targets, and MYC_targets pathways. We also detected sex-specific immune infiltration in the context of genetic variation. In EGFR-mutant LUADs, males had a significantly increased infiltration of CD8 + T cells, whereas resting CD4 + memory T cells were more abundant in females. Additionally, in KRAS-mutant LUADs, CD8 + and CD4 + T cells were more abundant in females than males. In addition, we detected all female patients with high SCGB3A2 expression were exclusively sensitive to immunotherapy, while this phenomenon was not observed in male patients., Conclusions: Our findings provided evidence that sex-related molecular and cellular components are involved in shaping tumor distinct genetic and immune features, which might have important impact on personalized targeted and immune therapy., (© 2023. The Author(s).)

Glioma stem cells (GSCs) are the important cause of tumorigenesis, recurrence, and chemo(radio)resistance in glioma. Targeting GSCs helps improve the outcomes of glioma treatment. Polo-like kinase 1 (PLK1) is a member of the serine/threonine protein kinase family, which is highly conserved. In recent years, it has been suggested that increased levels of PLK1 and its activity are associated with tumor progression and poor prognosis. We aimed to identify whether PLK1 plays a critical role in stemness maintenance and apoptosis regulation in GSCs. Here we identify that PLK1 inhibition can induce apoptosis and DNA damage of GSCs, we have also delineat the possible underlying molecular mechanisms: PLK1 interacts with YBX1 and directly phosphorylates serine 174 and serine 176 of YBX1. Inhibition of PLK1 reduces the phosphorylation level of YBX1, and decreased phosphorylation of YBX1 prevents its nuclear translocation, thereby inducing apoptosis and DNA damage of GSCs. We confirmed that YBX1 knockdown resulted in the apoptosis and DNA damage of GSCs. These findings uncover that PLK1 inhibition induces cell apoptosis and DNA damage in GSCs through YBX1 phosphorylation, providing new insights into the mechanism by which PLK1 inhibition contributes to the apoptosis of and DNA damage in gliomas., (© 2023. The Author(s).)

Introduction: The activation of STING (stimulator of interferon genes) pathway enhances antitumor immunity in small-cell lung cancer (SCLC), while the DNA damage induced by non-cGAMP-based agonists is a potent inducer of STING activity. Here, we investigate the intrinsic expression of STING in cancer cells and evaluate the value of the combination of ATR and TOP1 inhibitors in enhancing antitumor immunity., Methods: STING expression was assessed at mRNA and protein levels in SCLC and normal lung tissues. Transcriptomic subsets of SCLC were identified based on STING-related genes. Distinct mutation and immunogenomic profiles of these subsets were determined. The direct antitumor efficacy and the potential of enhancing antitumor immunity of the strategy using the ATR-TOP1-inhibitor combination were tested in SCLC cell lines., Results: The intrinsic expression of STING was significantly reduced in SCLC compared to normal lung tissues (p < 0.0001). Three STING-related SCLC subtypes were identified in which the STING-high subtype was associated with (1) high immune infiltration, (2) high expression of genes related to MHC and immune checkpoints, and (3) high EMT and ferroptosis score. On the contrary, the STING-low subtype was enriched with pathways related to DNA damage response (DDR) and cell cycle progression. The association between the DDR pathway activity and the STING-IFN innate immune response was verified by in vitro experiments in which the inhibition of ATR and TOP1 triggered the expression of genes encoding type I IFN signaling and pro-inflammatory cytokines/chemokines in a STING-low SCLC cell line., Conclusion: Our study verifies that activation of the STING-IFN response by ATR and TOP1 inhibitors might be a therapeutic strategy to improve the response to immune checkpoint therapy in STING-low SCLC. Furthermore, the combinations of ATR and TOP1 inhibitors can augment tumor inflammation in STING-low SCLC., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Returning manure to the land is a critical link in the internal cycle of agricultural systems, but excess manure leads to water eutrophication. The traditional manure re-use method brings pathogenic microorganisms, heavy metals, antibiotic resistance genes (ARGs), insect eggs, and other contaminants into the soil, posing a great threat to the ecological environment and human health. Clarifying the spatial distribution patterns of manure nutrient supply and farmland nutrient demand can help guide a more efficient and harmless way to return manure to farmland. This work counted data on cultivation and breeding in 356 cities on the Chinese mainland from 2015 to 2019 and calculated the livestock breeding volume (LB), total environmental capacity (C), and remaining environmental capacity (RC) accordingly. The Spatial Autocorrelation Model (SAC) was used to analyze the distribution patterns of the three. Data results show that China currently has the potential to double LB, but most cities in the west have excess manure due to the mismatched distribution of LB and C. The hot spot analysis results demonstrate the priority/general areas of manure management and the export/import areas of manure resources. The results of the outlier analysis show that some cities located at the boundary of RC Cold/Hot spot areas (e.g., Chengdu City) can perform resource replacement nearby to relieve local environmental pressure. This study analyzes the potential and realistic resistance to utilizing manure as an organic nutrient resource and provides a reference for developing manure management links., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Angiogenesis is a key physiological process that plays a key role in glioblastoma (GBM) progression and displays therapeutic resistance to antiangiogenic therapies. In this study, we aimed to identify whether vascular endothelial growth factor receptor 2(VEGFR2)monoclonal antibodies(mab)could inhibit tumorigenicity and the formation of vascular mimicry (VM) in GBM. The bioinformatic analysis from TCGA, CGGA, and TCPA databases and Immunohistochemistry (IHC) revealed that VEGFR2 is highly expressed in glioma tissues and results in a poor prognosis and is positively associated with VM markers (CD34 and PAS). The anti-VEGFR2 monoclonal antibodies(MSB0254)could inhibit the invasion, migration, and VM formation of U251 and primary glioma cells in vitro. In vivo, MSB0254 (m) could not only inhibit the growth of transplanted tumors of U251 and GL261 cells, but also significantly inhibit the expression of CD34, VEGFR2, Ki67, MMP2, MMP9 and reduce the expression of CD34/PAS and inhibit VM formation. The VEGFR2 monoclonal antibody could inhibit the angiogenesis and tumor growth of GBM by blocking the signaling pathway mediated by VEGFR2. It may become a new supplementary treatment for GBM., Competing Interests: Declaration of competing interest The authors declare there is no conflicts of interest regarding the publication of this manuscript., (Copyright © 2022. Published by Elsevier Inc.)

Background: Beckwith-Wiedemann syndrome (BWS) is an inherited disorder affecting 1 in 10,500 to 13,700 newborns worldwide. The disease is caused in a vast majority of patients by a molecular defect in the imprinted chromosome 11p15.5. Hereditary spherocytosis (HS) is a form of hemolytic anemia associated with a variety of mutations leading to congenital red blood cell (RBC) membrane defects. The prevalence of HS varies by geographic regions around the world, ranging from 1.2 in 100,000 in Asia to 1 in 2000 in Northern Europe., Methods and Results: Herein, we report for the first time a rare case diagnosed with co-existing BWS and HS. Based on the classical presentations, including macroglossia, hepatosplenomegaly, and macrosomia, the patient was first suspected with BWS. MS-MLPA confirmed the BWS diagnosis based on hypomethylation of maternal 11p15.5 (KCNQ1OT1), but no copy number variations in chromosome 11 was detected by CNV-seq. Nevertheless, to scrutinize molecular causes of other symptoms of the patient, including anemia, hyperbilirubinemia, and jaundice, a whole exome sequencing (WES) was performed. We identified a novel and de novo mutation in ANK1 gene (c.520delC). This frameshift mutation of ANK1 gene results in a truncated protein without important functional domains and impaired membrane stability and structure of the resultant red blood cells (RBCs), leading to a definitive diagnosis of HS., Conclusion: The present case demonstrated that multiple genetic and epigenetic aberrations might co-exist in the complex genetic diseases. For such kind of complicated cases, the different types of molecular tests, such as WES and MS-MLPA, should be utilized in combination to reveal independent causal molecular events. The identifications from this study added new insights into the understanding of molecular mechanisms underlying the co-existing HS and BWS., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

We determined the antitumor mechanism of apatinib in glioma using a patient-derived orthotopic xenograft (PDOX) glioma mouse model and glioblastoma (GBM) cell lines. The PDOX mouse model was established using tumor tissues from two glioma patients via single-cell injections. Sixteen mice were successfully modeled and randomly divided into two equal groups (n = 8/group): apatinib and normal control. Survival analysis and in vivo imaging was performed to determine the effect of apatinib on glioma proliferation in vivo. Candidate genes in GBM cells that may be affected by apatinib treatment were screened using RNA-sequencing coupled with quantitative mass spectrometry, data mining of The Cancer Genome Atlas, and Chinese Glioma Genome Atlas databases, and immunohistochemistry analysis of clinical high-grade glioma pathology samples. Quantitative reverse transcription-polymerase chain reaction (qPCR), western blotting, and co-immunoprecipitation (co-IP) were performed to assess gene expression and the apatinib-mediated effect on glioma cell malignancy. Apatinib inhibited the proliferation and malignancy of glioma cells in vivo and in vitro. Thrombospondin 1 (THBS1) was identified as a potential target of apatinib that lead to inhibited glioma cell proliferation. Apatinib-mediated THBS1 downregulation in glioma cells was confirmed by qPCR and western blotting. Co-IP and mass spectrometry analysis revealed that THBS1 could interact with myosin heavy chain 9 (MYH9) in glioma cells. Simultaneous THBS1 overexpression and MYH9 knockdown suppressed glioma cell invasion and migration. These data suggest that apatinib targets THBS1 in glioma cells, potentially via MYH9, to inhibit glioma cell malignancy and may provide novel targets for glioma therapy., (© 2021. The Author(s).)

Background: Glioblastomas (GBMs) are grade IV central nervous system tumors characterized by a poor prognosis and a short median overall survival. Effective induction of GBM cell death is difficult because the GBM cell population is genetically unstable, resistant to chemotherapy and highly angiogenic. In recent studies, ubiquitin-specific protease 7 (USP7) is shown to scavenge ubiquitin from oncogenic protein substrates, so effective inhibition of USP7 may be a potential key treatment for GBM., Methods: Immunohistochemistry and western blotting were used to detect the expression of USP7 in GBM tissues. In vitro apoptosis assay of USP7 inhibition was performed by western blotting, immunofluorescence, and flow cytometry. Anti-apoptotic substrates of USP7 were defined by Co-IP and TMT proteomics. Western blotting and IP were used to verify the relationship between USP7 and its substrate. In an in vivo experiment using an intracranial xenograft model in nude mice was constructed to assess the therapeutic effect of target USP7., Results: Immunohistochemistry and western blotting confirmed that USP7 was significantly upregulated in glioblastoma samples. In in vitro experiments, inhibition of USP7 in GBM induced significant apoptosis. Co-IP and TMT proteomics identified a key anti-apoptotic substrate of USP7, ADP-ribosylation factor 4 (ARF4). Western blotting and IP confirmed that USP7 interacted directly with ARF4 and catalyzed the removal of the K48-linked polyubiquitinated chain that binded to ARF4. In addition, in vivo experiments revealed that USP7 inhibition significantly suppressed tumor growth and promoted the expression of apoptotic genes., Conclusions: Targeted inhibition of USP7 enhances the ubiquitination of ARF4 and ultimately mediates the apoptosis of GBM cells. In a clinical sense, P5091 as a novel specific inhibitor of USP7 may be an effective approach for the treatment of GBM., (© 2021. The Author(s).)

Objectives: Recurrent high-grade glioma, a malignant tumor of the brain or spinal cord associated with poor prognosis with a median survival of <6 months. Recurrent high-grade glioma does not have standard treatment even if some strategies have some effect in recurrent gliomas. Apatinib, as a tyrosine kinase inhibitor shown to be effective in treating the lung and gastric cancer. The present study investigated the efficacy and safety of apatinib in combination with dose-dense regimens of temozolomide for treating recurrent glioma., Patients and Methods: Eighteen patients with recurrent high-grade glioma were enrolled and treated with apatinib (500 mg/day) and TMZ (50 mg/m 2 /day). Patients who achieved partial response or stable disease continued treatment. Administration of drug was terminated for patients with progressive disease, who could not tolerate toxicity, and who required discontinuation due to other medical conditions., Results: From the 18 cases, only 17 were included in the evaluation of the curative effect of the drug and in that four showed partial responses, ten had stable disease, remaining three exhibited progressive disease. The disease control rate was 82.3% (14/17). Progression-free and overall survival was found to be 4 months and 9.1 months, respectively. Three patients became transiently capable of self-care (Karnofsky performance status >70). Cognition and quality of life improved after treatment and from the safety perspective, three most common adverse reactions included epilepsy (24.1%), hypertension (20.7%), and fatigue (17.2%)., Conclusion: Apatinib and TMZ may represent an alternative treatment option for patients with recurrent high-gradeglioma, especially those with a low Karnofsky performance status. However, studies using a larger sample size are required to confirm these findings., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Early detection and diagnosis are the key to successful clinical management of pancreatic cancer and improve the patient outcome. However, due to the absence of early symptoms and the aggressiveness of pancreatic cancer, its 5-year survival rate remains below 5 %. Compared to tissue samples, liquid biopsies are of particular interest in clinical settings with respect to minimal invasiveness, repeated sampling, complete representation of the entire or multi-site tumor bulks. The potential of liquid biopsies in pancreatic cancer has been demonstrated by many studies which prove that liquid biopsies are able to detect early emergency of pancreatic cancer cells, residual disease, and recurrence. More interestingly, they show potential to delineate the heterogeneity, spatial and temporal, of pancreatic cancer. However, the performance of liquid biopsies for the diagnosis varies largely across different studies depending of the technique employed and also the type and stage of the tumor. One approach to improve the detect performance of liquid biopsies is to intensively inspect circulome and to define integrated biomarkers which simultaneously profile circulating tumor cells and DNA, extracellular vesicles, and circulating DNA, or cell free DNA and proteins. Moreover, the diagnostic validity and accuracy of liquid biopsies still need to be comprehensively demonstrated and validated.

A new trace alkaloid possessing the lignan structure, named oleraisoindole A, was obtained from the extract of the Portulaca oleracea L.. The structure of oleraisoindole A was elucidated by 1D and 2D NMR and high resolution electrospray ionization time-of-flight mass spectroscopic methods. The compound presented an anticholinesterase effect with the IC 50 value of 60.4 μM.

Glioblastoma (GBM) is the deadliest primary brain tumor that is highly resistant to current treatments. Polo-like kinase 1 (PLK1) and signal transducer and activator of transcription 3 (STAT3) are highly expressed in gliomas, especially GBM. Previous studies have shown reciprocal activation between PLK1 and STAT3 and that they regulate the same pools of MYC downstream. We have demonstrated that PLK1 and STAT3 levels are elevated in gliomas compared with those in normal brain tissues, and high expression of both PLK1 and STAT3 is associated with poor prognosis in TCGA. Moreover, there was direct or indirect reciprocal regulation between PLK1 and STAT3. Furthermore, we found that PLK1 and STAT3 can regulate the same pools of MYC downstream. Compared to monotherapy, combined treatment of glioma cells with PLK1 and STAT3 inhibitors, BI2536 and Stattic, respectively, showed lower expression of MYC, synergistic induction of cell invasion and apoptosis in vitro, and tumor inhibition in xenografts. PLK1 and STAT3 were able to directly regulate the expression of MYC and induce apoptosis of glioma cells through the regulation of MYC. These findings may help develop a therapeutic strategy for dual inhibition of PLK1 and STAT3 against the tumorigenesis of glioma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. A, The Cancer Genome Atlas (TCGA) shows PLK1 and STAT3 are elevated in glioblastoma (GBM) compared with normal brain tissues. B, Kaplan–Meier curve shows poor overall glioma cell survival with both intratumor PLK1 and STAT3, above median (n = 672; log-rank P < 0.001). C and D, U87, U251, and N13002 cells were transfected with PLK1-siRNA or STAT3-siRNA for 24 h. C, Protein expression of PLK1, STAT3, and p-STAT3. D, Quantitative reverse-transcription PCR analysis of PLK1 and STAT3. Data are mean ± SEM, n = 3, #P = no significant difference, ∗P < 0.05, ∗∗P < 0.01, Student’s t-test. E, U87, U251, and N13002 cells were treated with BI2536 and Stattic for 24, 48, and 72 h and cell viability was detected using the Cell Counting Kit-8(CCK-8) assay. F and G, U87, U251, and N13002 cells were treated with BI2536 or Stattic for 24 h; protein expression of PLK1, STAT3, and p-STAT3 was detected by Western blot. H, Cells were immunostained for PLK1 (green) and STAT3 (red) and stained with DAPI (blue). Scale bar = 100 μm. A–F, U87, U251, and N13002 cells were treated with BI2536, Stattic, or both for 24 h. A and B, The transwell system showing the invasion of glioma cells. Scale bar = 100 μm. C and D, Flow cytometry showing the apoptosis of glioma cells. E and F, Expression of PARP, cleaved PARP, Caspase-3, and cleaved Caspase-3, detected by Western blot. Data in B, D and F are shown as mean ± SD, n = 3, ∗P < 0.05, ∗∗P < 0.01, Student’s t-test. G–I, Stable clone cells were implanted subcutaneously into athymic mice (nu/nu) (n = 5 per group), and subcutaneous tumors were excised at 4.5 weeks after inoculation. Mice were treated with BI2536, Stattic, or both. G, Photographs of subcutaneous tumors. H, Graph showing mean volume ±SD. I, Quantification of tumor weight and volume. J, The overall survival of mice in the DMSO, BI2536, Stattic or BI2536 + Statti treatment groups. Data are shown as the mean ± S.D. n = 6, ∗∗P < 0.01 compared to the control, ANOVA test. K, Representative images of the HE staining in tumor sections. Scale bar = 200 μm. A and B, U87, U251, and N13002 cells were treated with BI2536, Stattic, or both for 24 h. Expression of MYC and p-MYC, detected by Western blot. Data are shown as mean ± SD, n = 3, ∗P < 0.05, ∗∗P < 0.01, Student’s t-test. C and D, Coimmunoprecipitation assay demonstrating that PLK1 can interact with MYC. E, Full sequence of the human MYC promoter (−1800 bp-+200 bp). P1 and P2 showed the regions of MYC promoter detected by the paired primers. F and G, ChIP-qRT-PCR analysis of DKC1 binding at P1 and P2. A and B, U87, U251, and N13002 cells were transfected with MYC lentivirus (LV) for 24 h. Protein expression of MYC and p-MYC was detected by Western blot. C–F, U87 LV-MYC, U251 LV-MYC, and N13002 LV-MYC were treated with BI2536, Stattic, or both for 24 h. C and D, Flow cytometry results showing apoptosis of glioma cells. E and F, Expression of cleaved PARP and cleaved Caspase-3, detected by Western blot. Data in B, D, and F are shown as mean ± SD, n = 3, ∗P < 0.05, ∗∗P < 0.01, Student’s t-test., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Glioma stem cells (GSCs) have been implicated in the promotion of malignant progression. Epidermal growth factor receptor variant (EGFRv) has been associated with glioma "stemness". However, the molecular mechanism is not clear. In this study, we were committed to investigate the role of EGFRv in GSCs and presented a new therapeutic target in EGFRvIII positive GSCs. The results showed that EGFRvIII could induce the expression of p-Src and PLK1, and both could induce the Notch1-SOX2 signaling pathway to promote self-renewal and tumor progression of GSCs. Mechanistically, both p-Src and PLK1 can induce Notch1, and the intracellular domain of Notch1 (NICD) can directly bind to SOX2, thereby promoting the maintenance of glioma stem cells. Furthermore, Saracatinib (Src inhibition) and BI2536 (PLK1 inhibition) diminished GSC self-renewal in vitro, and combining the two inhibitors increased survival of orthotopic tumor-bearing mice. Taken together, these data indicate that p-Src and PLK1 contribute to cancer stemness in EGFRvIII-positive GSCs by driving Notch1-SOX2 signaling, a finding that has important clinical implications., (Copyright © 2020. Published by Elsevier Inc.)

Bromodomain and extraterminal domain (BET) family proteins are considered to be epigenetic readers that regulate gene expression by recognizing acetyl lysine residues on histones and nonhistone chromatin factors and have been classified as curative targets for a variety of cancers. Glioma-initiating cells (GICs), which commit self-renewal, perpetual proliferation, multidirectional differentiation, and vigorous tumorigenicity, sustain the peculiar genetic and epigenetic diversification in the GBM patients, thus, GICs result in tumor recurrence. Abundant evidence demonstrates that BET proteins regulate differentiation of stem cells. However, it endures ambiguous how individual BET proteins take part in GIC advancement, and how do small molecule inhibitors like I-BET151 target functional autonomous BET proteins. Here, we validated that BRD4, not BRD2 or BRD3, has value in targeted glioma therapy. We announce a signaling pathway concerning BRD4 and Notch1 that sustains the self-renewal of GICs. Moreover, in-depth mechanistic research showed that BRD4 was concentrated at the promoter region of Notch1 and may be involved in the process of tumor metabolism. Furthermore, in intracranial models, I-BET151 eliminated U87 GICs' tumorigenicity. The outcomes of this research could be conducive to design clinical trials for treatment of glioma based on BRD4., (© 2020 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Glioblastoma multiforme (GBM) is an intracranial tumor; the feature is higher malignant and poorer prognosis. The search for therapeutic targets for gliomas has always been a focus of research in the field of neurology. The unusual expression of epithelial membrane protein 1 (EMP1) has been proved in most tumors. In our study, we determined the expression level of EMP1 expression in glioma tissues. There were higher levels of EMP1 in glioma tissues-particularly GBM tissues-than those in normal brain tissues. Then we discovered that silencing EMP1 inhibited glioma cell invasion and proliferation through inhibiting the PI3K-AKT signaling pathway. Subsequently, we investigated the function of EMP1 on glioma stem cells and found that it regulates the expression of CD44 in such cells to promote stemness. Taken together, the new strategies for the treatment of glioma may be provided by these finding, thereby improving the prognosis associated with it., (© 2019 Wiley Periodicals, Inc.)

Background : Immune cells recognize tumor antigens presented on major histocompatibility complex class I (MHC-I) molecule. Increase of MHC-I molecular expression makes tumor cells more susceptible to lysis by immune cells. Methods : Tumor lysate vaccine was prepared to damage glioma cells including cell lines and primary cultured cells from surgical samples. The enhanced effect of histone deacetylase inhibitors (HDACi) to tumor lysate vaccine was observed. The expressions of MHC-I pathway molecules were detected by flow cytometry and western blot after HDACi treatment. Cell apoptosis and cell lysis were measured following blocking cytotoxic T lymphocyte (CTL) pathway. Tumor size and mice survival were analyzed in combinative treatment with HDACi and tumor lysate. Results : HDACi up-regulated the expressions of MHC-I pathway molecules, and enhanced the recognition and killing of immune cells, which was activated by tumor lysate. Activated antigen specific immune responses regulated CTL activity, and HDACi promoted immune response through cytotoxic effect of CTL. Anti-tumor effect of tumor lysate pulse immunogenicity in vivo was elevated by HDACi due to up-regulation of antigen presentation. Conclusions : Our study showed that HDACi enhanced recognition of glioma cell by immune cells and sensitivity of tumor immunotherapy, and improved the anti-tumor effect of tumor lysate vaccine through activating CTL immune response. These pharmacological molecular mechanisms of increasing immune recognition suggest that epigenetic modulation is a promising strategy for sensitizing immunotherapy for glioma treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

A new alkaloid, (10 E , 12 E )-9-ureidooctadeca-10, 12-dienoic acid, named oleraurea (1) and 10 known compounds, p -hydroxybenzaldehyde (2) , p -hydroxybenzoic acid (3) , p -hydroxyacetophenone (4) , benzamide (5) , ( E) - p -coumaramide (6) , ( E )-ferulamide (7) , soyalkaloid A (8) , β -carboline-3-carboxylic acid (9) , 2, 3, 4, 9-tetrahydro- 1H -pyrido [3, 4- b ] indole-3-carboxylic acid (10) , (1 S , 3 S )-1-methyl-1, 2, 3, 4-tetrahydro- β -carboline-3-carboxylic acid (11) were obtained from Portulaca oleracea L., in which, compounds 4 , 5 , 8-11 were isolated from the plant for the first time. The structure of the compound 1 was identified using spectroscopic methods including 1D and 2D NMR, HR-ESI-TOF-MS. The compounds 1, 5-11 presented anticholinesterase activities, but the P. oleracea extract (POE) presented very low anticholinesterase activity.

Background: In recent years, many studies have confirmed that STIP1 (phosphorylation-induced protein 1) is involved in the development and progression of various tumors. However, its potential role in glioma progression and the underlying mechanisms of glioma development remain unclear., Methods: We analyzed the expression of STIP1 in 35 human glioma tissue specimens of different grades, using 6 normal brain tissues for comparison. We transfected U87 and U251 cell lines with small interfering RNA (siRNA) to downregulate STIP1, and set up a negative control group and a blank group for comparison. The MTT assay was used to detect cell proliferation, and cell cycle progression and apoptosis were analyzed through flow cytometry. Transwell experiments were employed to detect the invasion and migration of STIP1-depleted and control U87 and U251 cells and western blotting was used to detect the expression of TRAP1/Akt pathway proteins. In addition, immunohistochemical analysis was used to reveal differences in expression and localization between transplanted tumor specimens of each group., Results: We observed a high expression of STIP1 in glioblastoma, MTT assay revealed a decreased cell proliferation rate in the STIP1-downregulated cells. Cell cycle analysis revealed an increased proportion of cells in G1 phase, as well as an increase in apoptosis, upon STIP1 downregulation. Western blotting showed that TRAP1, pAkt, and MMP2 expression was decreased upon STIP1 downregulation. In addition, TRAP1, ki-67, and MMP2 displayed a decreased expression in vivo., Conclusions: STIP1 is highly expressed in glioblastoma compared to normal brain tissues. Downregulation of STIP1 in glioma cells reduces cell proliferation rate and invasion and increases cell apoptosis., (Copyright © 2019. Published by Elsevier Inc.)

Background: Cancer-specific autoantibodies found in serum of cancer patients have been characterized as potential predictors of the high risk of recurrence and treatment response. The objective of this study is to investigate the clinical utility of serum O-6-methylguanine-DNA methyltransferase (MGMT) autoantibodies as novel biomarkers for prediction of recurrence and treatment response for glioma through MGMT peptides microarray., Methods: A total of 201 serum samples of glioma patients with various WHO grade and 311 serum samples of healthy donors were examined for the detection of MGMT autoantibodies by peptides microarray. The clinical value of MGMT autoantibodies was studied through univariable and multivariable analyses., Results: Autoantibodies to MGMT peptides were detected in sera from glioma patients and five highly responsive autoantibodies to peptides were identified in the glioma group. The positive rate of MGMT autoantibody to 20 peptides in glioma groups is compared with healthy individuals, the positive rate of MGMT-02 (45%), MGMT-04 (27%), MGMT-07 (21%), MGMT-10 (13%), and MGMT-18 (24%) were significantly elevated in patients with glioma. MGMT autoantibody and its protein expression exhibited a significant correlation. The levels of MGMT autoantibodies decreased on the 30th day after operation, reaching preoperative levels, similar to those when tumor recurrence developed. Univariable and multivariable analyses revealed that the only preoperative autoantibodies to MGMT-02 peptide were independently correlated with recurrence-free survival. Preoperative seropositive patients were more likely than seronegative patients to have shorter recurrence times and to be resistant to chemoradiotherapy or chemotherapy with temozolomide., Conclusion: Monitoring the levels of preoperative serum autoantibodies to MGMT-02 peptide was useful for predicting patients at high risk of recurrence and treatment response., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Chemotherapy for non-small-cell lung cancer (NSCLC) still leads to unsatisfactory clinical prognosis because of poor active targeting and tumor metastasis. Purpose: The objective of this study was to construct a kind of PFV peptide modified targeted daunorubicin and dioscin codelivery liposomes, which could enhance tumor targeting and inhibit tumor cell metastasis. Methods and results: Targeted daunorubicin and dioscin codelivery liposomes were prepared by film dispersion and the ammonium sulfate gradient method. With the ideal physicochemical properties, targeted daunorubicin and dioscin codelivery liposomes exhibited enhanced cellular uptake and showed strong cytotoxicity to tumor cells. The encapsulation of dioscin increased the inhibitory effects of daunorubicin on A549 cells, vasculogenic mimicry (VM) channels and tumor metastasis. The enhanced antimetastatic mechanism of the targeted liposomes was attributed to the downregulation of matrix metalloproteinase-2 (MMP-2), vascular endothelial cadherin (VE-Cad), transforming growth factor-β1 (TGF-β1) and hypoxia inducible factor-1α (HIF-1α). Meanwhile, the targeted daunorubicin and dioscin codelivery liposomes exhibited significant antitumor effects in tumor-bearing mice. H&E staining, immunohistochemistry with Ki-67 and TUNEL assay also showed the promoted antitumor activity of the targeted liposomes. Conclusion: Targeted daunorubicin and dioscin codelivery liposomes may provide an effective strategy for the treatment of NSCLC., Competing Interests: The authors report no conflicts of interest in this work.

Gliomas are the most common primary brain malignant tumors in humans. Glioblastoma multiforme(GBM) is the most malignant intracranial tumor with a relatively poor prognosis. There promote us to find effective anti-cancer therapies to reduce cancer mortality. By using bioinformatic analysis, we found SSFA2 as a gene with elevated expression in the glioma tissues. We detected the expression of SSFA2 in glioma tissues and in the glioma cell lines, as well as in normal brain tissues. SSFA2 expression was higher in glioma tissues, especially in glioblastoma multiforme than normal brain tissues. Subsequently, we found that down-regulate SSFA2 in glioma cell lines can regulate the cell cycle to reduce the proliferation ability and induce the early apoptosis rate in shSSFA2 cells relative to control cells. Moreover, we found that down-regulate SSFA2 in glioma cell line U87(shSSFA2-U87) inhibited the growth effectiveness compared to the control cell line U87. These result reveals us that SSFA2 may act as oncogene to promote the progression of glioma. For further research specific mechanisms of SSFA2 in gliomas, we used the gene chip to detect the downstream gene in U87. We found that 30 genes also may be as target gene of SSFA2, and we testify the protein expression by western-blot. The result reveal that IL1A, IL1B and CDK6 as target gene of SSFA2 to regulate the progression of glioma. These finding suggest that SSFA2 could be a new therapeutic target for gliomas., (Copyright © 2019. Published by Elsevier GmbH.)

Glioma is the most common adult malignant primary brain tumor; however, the effect of chemotherapy is often limited by drug‑resistance and poor prognosis is common. Ring finger protein 138 (RNF138) belongs to the E3 ligase family, and has significantly higher expression level in glioma tissue than in noncancerous brain tissues. Epithelial-mesenchymal-transition (EMT) has a critical role in cancer invasion and metastasis, ultimately leading to increased cell motility and resistance to genotoxic agents. Extracellular‑signal regulated kinase (Erk) pathways promote the growth of glioma cells and enhance tumor invasion, with a role in the progression of EMT. However, the association between RNF138 and human glioma progression remains poorly understood. Relatively little is known about the association between RNF138, Erk, and EMT in glioma progression. In the current study, experiments were performed to explore the potential roles and mechanisms of RNF138 in glioblastoma in vitro and in vivo. Glioma cell line proliferation, migration and invasion were inhibited by knockdown of RNF138 in vitro. By lowering the RNF138 expression, cleaved caspase3 and E‑cadherin were upregulated, while phospho‑Erk1/2, vimentin, MMP2, HIF‑1α and VEGF were downregulated in U87 and U251 cells in vitro. In vivo findings revealed that the growth of U87 cell‑transplanted tumors in nude mice was inhibited in tumors with RNF138 knockdown. These findings suggested that downregulation of RNF138 inhibited glioma cell proliferation, migration, and invasion, and reversed EMT, potentially via Erk signaling pathway. Therefore, RNF138 may be a potential therapeutic target against glioma.

Background: Recently, minimal invasive surgery (MIS) has been applied as a common therapeutic approach for treatment of hypertensive intracerebral hemorrhage (HICH). However, the efficacy and safety of MIS is still controversial compared with conservative medical treatment or conventional craniotomy. This meta-analysis aimed to systematically assess the safety and efficacy of MIS compared with conservative method and craniotomy in treating HICH patients., Methods: PubMed, Embase, Web of Science, and Cochrane Controlled Trials Register were used to identify relevant studies on MIS treatment of HICH up to November 2017. This study evaluated Glasgow Outcome Scale (GOS) score, Activities of Daily Living (ADL) score, pulmonary infection rate, mortality rate, and rebleeding rate for patients who underwent MIS, or conservative method, or craniotomy. Subgroup analyses were performed to compare randomization versus non-randomization and large hematoma versus small or mild hematoma. Begg's test and Egger's test were used to determine the potential presence of publication bias., Results: Sixteen studies consisting of 1912 patients were included in this study to compare the efficacy and safety of MIS to conservative method or craniotomy. MIS contributed to a significant improvement on the prognosis of the patients comparing with conservative group or craniotomy group. Patients undergoing MIS had a lower mortality rate when compared to those receiving conservative method. Also, MIS led to a notable reduction of rebleeding rate and an effective improvement of the patient's quality of life by contrast with craniotomy. No obvious difference was found in terms of the pulmonary infection rate among the comparisons of three treatment methods. Randomization is not the potential source of heterogeneity, but hematoma volume may be a risk factor for post-operative mortality rate. No statistical evidence of publication bias among studies was found under most of comparison models., Conclusion: This meta-analysis suggests that minimal invasive surgery is an efficient and safe method for the treatment of hypertensive intracerebral hemorrhage, which is associated with a low mortality rate and rebleeding rate, as well as a significant improvement of the prognosis and the quality life of patients when compared with conservative medical treatment or craniotomy.

The ability of non-small cell lung cancer (NSCLC) cells to invade and metastasize is associated with epithelial-to-mesenchymal transition (EMT). The process of EMT is, at least in part, regulated by microRNAs. However, it is unknown whether microRNAs regulate EMT in cancer stem-like cells (CSLCs), or which microRNAs are involved. In the present study, we compared microRNA expression in A549 cells, TGF‑β1-treated A549 cells, CSLCs characterized by the CD133+/CD326+ phenotype, and TGF‑β1-treated CSLCs. We found that miR‑181b‑5p expression was upregulated by TGF‑β1. Moreover, the overexpression of the miR‑181b‑5p in A549 cells and CD133+/CD326+ cells resulted in the downregulation of the E-cadherin and increased invasion and metastasis in vitro and in vivo. Accordingly, the knockdown of miR‑181b‑5p partially restored E-cadherin expression. These results suggest that miR‑181b‑5p regulates TGF‑β1-induced EMT by targeting E-cadherin not only in normal A549 cells but also in CD133+/CD326+ cells which have characteristics of CSLCs. Thus, miR‑181b‑5p represents a new therapeutic target in NSCLC.

Huanglian Jiedu Decoction (HJD), one of the classic recipes for relieving toxicity and fever, is a common method for treating sepsis in China. However, the effective components of HJD have not yet been identified. This experiment was carried out to elucidate the effective components of HJD against sepsis. Thus, seven fractions from HJD were tested using a biosensor to test their affinity for lipid A. The components obtained that had high lipid A-binding fractions were further separated, and their affinities to lipid A were assessed with the aid of a biosensor. The levels of LPS in the blood were measured, and pathology experiments were conducted. The LPS levels and mRNA expression analysis of TNF-α and IL-6 of the cell supernatant and animal tissue were evaluated to investigate the molecular mechanisms. Palmatine showed the highest affinity to lipid A and was evaluated by in vitro and in vivo experiments. The results of the in vitro and in vivo experiments indicated that the levels of LPS, TNF-α and IL-6 of the palmatine group were significantly lower than those of the sepsis model group (p<0.01). The group treated with palmatine showed strong neutralizing LPS activity in vivo. The palmatine group exhibited stronger protective activity on vital organs compared to the LPS-induced animal model. This verifies that HJD is a viable treatment option for sepsis given that there are multiple components in HJD that neutralize LPS, decrease the release of IL-6 and TNF-α induced by LPS, and protect vital organs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is among the most abundant and highly conserved lncRNAs, which has been detected in a wide variety of human tumors, including gastric cancer, gallbladder cancer, and so on. Previous research has showed that MALAT1 can activate LTBP3 gene in mesenchymal stem cells. However, the specific roles of MALAT1 in glioma stem cells (GSCs) remain unclear. In this study, we aimed to identify the effects of MALAT1 on proliferation and the expression of stemness markers on glioma stem cell line SHG139S. Our results showed that downregulation of MALAT1 suppressed the expression of Sox2 and Nestin which are related to stemness, while downregulation of MALAT1 promoted the proliferation in SHG139S. Further research on the underlying mechanism showed that the effects of MALAT1 downregulation on SHG139S were through regulating ERK/MAPk signaling activity. And we also found that downregulation of MALAT1 could activate ERK/MAPK signaling and promoted proliferation in SHG139 cells. These findings show that MALAT1 plays an important role in regulating the expression of stemness markers and proliferation of SHG139S, and provide a new research direction to target the progression of GSCs.

Tanshinone IIA is the active compound isolated from Salvia miltiorrhiza bunge, which is a traditional Chinese medicine known as Danshen. The aim of the present study was to assess the effect of Tanshinone IIA on the regulation of lipid metabolism in the livers of hyperlipidemic rats and the underlying molecular events. An in vivo model of hyperlipidemia was established in rats, with the animals receiving a daily dose of Tanshinone IIA. The serum lipid profiles were analyzed using an automatic biochemical analyzer, and the histopathological alterations and lipid deposition in liver tissue were assessed using hematoxylin and eosin staining, and oil red O staining, respectively. The mRNA expression levels of microRNA (miR)‑33a, ATP‑binding cassette transporter (ABC)A1, ABCG1, sterol regulatory element‑binding protein 2 (SREBP‑2), proprotein convertase subtilisin/kexin type 9 (Pcsk9) and low‑density lipoprotein receptor (LDL‑R) in liver tissues were measured using reverse transcription‑quantitative polymerase chain reaction, and the protein expression levels of ABCA1, ABCG1, SREBP‑2, Pcsk9, and LDL‑R were analyzed using western blotting. Tanshinone IIA reduced lipid deposition and improved histopathology in the rat liver tissue, however, did not alter the lipid profile in rat serum. In addition, Tanshinone IIA treatment suppressed the expression of miR‑33a, whereas the protein expression levels of ABCA1, SREBP‑2, Pcsk9 in addition to LDL‑R mRNA and protein were upregulated. In conclusion, the present study indicated that Tanshinone IIA attenuated lipid deposition in the livers of hyperlipidemic rats and modulated the expression of miR‑33a and SREBP‑2/Pcsk9 signaling pathway proteins.

Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, is a critical issue for the treatment of EGFR mutant-positive non-small cell lung cancer (NSCLC). Recent evidence supports the role of microRNA-223 (miR‑223) in modulating chemotherapeutic drug sensitivity, but its role in the resistance to EGFR-TKIs in NSCLC remains unclear. To this end, we investigated the involvement of miR‑223 in erlotinib resistance, using two pairs of TKI-sensitive or resistant cell lines, PC9 vs PC9/ER, and HCC827 vs HCC827/ER, as well as PC9/CD133+, which are lung cancer stem-like cells derived from PC9 cells. Downregulation of miR‑223 expression in PC9/ER and PC9/CD133+ cells was detected, and the reverse correlation of miR-233 and insulin-like growth factor 1 receptor (IGF1R) in these cells was also revealed. Next, levels of IGF1R mRNA and p-Akt were significantly reduced in miR‑223 stably transfected PC9/ER and PC9/CD133+ cells. However, the sensitivity of PC9/ER and PC9/CD133+ cells to erlotinib was partially restored, after overexpression of miR‑223 in those cells. Similar results were also observed in vivo. Furthermore, miR‑223-mediated inhibition of the IGF1R/PI3K/Akt signaling pathway may have been reversed by the agonist of IGF1R in miR‑223 transfected cells. Our findings indicated that downregulation of miR‑223, which can induce activation of the IGF1R/phosphatidylinositol 3-kinase (PI3K)/Akt pathway in PC9/ER and PC9/CD133+ cells, may be responsible for the resistance of PC9/ER and PC9/CD133+ cells to erlotinib, suggesting that miR‑223 is a potential therapeutic target for overcoming EGFR-TKIs resistance.

In this study a gastric-retentive delivery system was prepared by a novel method which is reported here for the first time. An innovative floating and bioadhesive drug delivery system with a hollow structure was designed and prepared. The floating and bioadhesive drug delivery system was composed of a hollow spherical shell, a waterproof layer (Stearic acid), a drug layer (Ofloxacin), a release retarding film (the novel blended coating materials) and a bioadhesive layer (Carbomer 934P) prepared by using a liquid multi-layering process. A novel blended coating material was designed and investigated to solve the problem of the initial burst release of the formulation and the release mechanism of the novel material was analyzed in this study. The optimized formulation provided the sustained release characteristic and was able to float for 24h. The SEM cross-section images showed that the particulates were hollow with a spherical shell. X-ray images and pharmacokinetic studies (Frel = 124.1 ± 28.9%) in vivo showed that the gastric-retentive delivery system can be retained in the stomach for more than 6h. The floating and bioadhesive particulate drug delivery system based on a hollow structure with a dual function presented here is a viable alternative to other for gastroretentive drug delivery system., (Copyright © 2016 Elsevier B.V. All rights reserved.)

MicroRNAs (miRs) act as oncogenes or tumor-suppressor genes, and regulate the proliferation, apoptosis, invasion, differentiation, angiogenesis and behavior of glioma stem cells, which are important in glioma development and recurrence. The present study was performed to investigate the impact of miR-218-5p on stem cell properties and invasive ability of the A2B5+CD133- human glioma stem cell subgroup. qRT-PCR was used to detect miR-218-5p expression in non-cancerous brain and human glioma tissues, human glioma cell lines and human glioma stem cell lines. Lentivirus vectors encoding miR-218-5p and anti-miR-218-5p were constructed and stably transfected into A2B5+CD133- SHG-139s cells. Neurosphere formation Cell Counting Kit-8 (CCK-8) and Transwell assays, immunofluorescence and qRT-PCR analyses were used to explore the role of miR-218-5p in SHG-139s cells. qRT-PCR analysis showed that miR-218-5p expression was lower in human glioma tissues and cells than in non-cancerous brain tissues and normal human astrocyte cells, and lower in A2B5+CD133- (SHG-139s) cells than in CD133+ (SU2 and U87s) cells. The CCK-8 assay demonstrated that the growth curve was significantly inhibited in the miR-218-5p-SHG-139s cells compared to the miR-control, blank and anti-miR‑218-5p groups. The neurosphere formation assay indicated that upregulation of miR‑218-5p expression inhibited SHG-139s neurosphere formation. Immunofluorescence staining and qRT-PCR showed that miR-218-5p reduced stem cell marker (A2B5, nestin, PLAGL2, ALDH1 and Sox2) expression compared with the controls; however, immunofluorescence staining analysis showed that upregulation of miR-218-5p expression led to no difference in CD133 expression. miR‑218-5p reduced SHG-139s cell invasiveness in the Transwell assay and reduced MMP9 expression as detected in qRT-PCR and immunofluorescence analyses. All differences were statistically significant. miR-218-5p expression was lower in human glioma tissues, cells and the A2B5+CD133- human glioma stem cell subgroup. miR-218-5p may be a tumor-suppressor gene in glioma that functions by upregulating miR-218-5p expression, which inhibits the stem cell properties and invasive properties of SHG-139s cells.

Objective: Central nervous system (CNS) injury can increased the risk of secondary mortality because of its late inflammatory complications. Alcohol intake increases the risk of damage and complications subsequent to a (CNS) injury. How about the risk of pneumonia after CNS injury under the effect of alcoholic drink? Though animal trails of material prosperity and studies for human have been investigated in recent decades, the outcome maintains poor understanding. Pneumonia is one of the serious complication at the time of hospitalization and it should be known as more as possible for steadying patient conditions in intensive care unit and shortening length of stay. Thus, we conducted a meta-analysis of published materials to assess the association between alcohol intake and pneumonia in CNS injury., Methods: Two authors searched the PUBMED, EMBASE, Cochrane Library, and web of science up to September, 2014 for published literatures without any limitations. Reference lists from identified studies were also screened carefully by us for additional data. The summary relative risks (RRs) and 95% confidence intervals (CI) were calculated by statistical analysis software (Stata 12.0) with fixed-effects models to estimate the risk., Result: The results indicated that a higher incidence of pneumonia was found in CNS injury under the influence of alcohol (RR = 1.32, 95% CI = 1.21-1.43), and the risk has no relation to blood alcohol concentration (BAC) (BAC ≥ 80 mg/dl vs < 80 mg/dl, BAC ≥ 100 mg/dl vs < 100 mg/dl)., Conclusion: Traumatic brain injury (TBI) and spinal cord injury patients who are under the influence of alcoholic drink have a higher risk of pneumonia.