Glioblastoma is refractory to conventional therapies. The bromodomain and extraterminal domain (BET) proteins are epigenetic readers that selectively bind to acetylated lysine residues on histone ...tails. These proteins recently emerged as important therapeutic targets in NUT midline carcinoma and several types of hematopoietic cancers. In this study, the therapeutic potential of a novel BET bromodomain inhibitor, JQ1, was assessed in a panel of genetically heterogeneous glioblastoma samples.
The antineoplastic effects of JQ1 were shown using ex vivo cultures derived from primary glioblastoma xenograft lines and surgical specimens of different genetic background. The in vivo efficacy was assessed in orthotopic glioblastoma tumors.
We showed that JQ1 induced marked G1 cell-cycle arrest and apoptosis, which was phenocopied by knockdown of individual BET family members. JQ1 treatment resulted in significant changes in expression of genes that play important roles in glioblastoma such as c-Myc, p21(CIP1/WAF1), hTERT, Bcl-2, and Bcl-xL. Unlike the observations in some hematopoietic cancer cell lines, exogenous c-Myc did not significantly protect glioblastoma cells against JQ1. In contrast, ectopically expressed Bcl-xL partially rescued cells from JQ1-induced apoptosis, and knockdown of p21(CIP1/WAF1) attenuated JQ1-induced cell-cycle arrest. Cells genetically engineered for Akt hyperactivation or p53/Rb inactivation did not compromise JQ1 efficacy, suggesting that these frequently mutated signaling pathways may not confer resistance to JQ1. Furthermore, JQ1 significantly repressed growth of orthotopic glioblastoma tumors.
Our results suggest potentially broad therapeutic use of BET bromodomain inhibitors for treating genetically diverse glioblastoma tumors.
The risk of cardiovascular disease (CVD) is a serious health threat to human society worldwide. The use of machine learning methods to predict the risk of CVD is of great relevance to identify ...high-risk patients and take timely interventions. In this study, we propose the XGBH machine learning model, which is a CVD risk prediction model based on key contributing features. In this paper, the generalisation of the model was enhanced by adding retrospective data of 14,832 Chinese Shanxi CVD patients to the kaggle dataset. The XGBH risk prediction model proposed in this paper was validated to be highly accurate (AUC = 0.81) compared to the baseline risk score (AUC = 0.65), and the accuracy of the model for CVD risk prediction was improved with the inclusion of the conventional biometric BMI variable. To increase the clinical application of the model, a simpler diagnostic model was designed in this paper, which requires only three characteristics from the patient (age, value of systolic blood pressure and whether cholesterol is normal or not) to enable early intervention in the treatment of high-risk patients with a slight reduction in accuracy (AUC = 0.79). Ultimately, a CVD risk score model with few features and high accuracy will be established based on the main contributing features. Of course, further prospective studies, as well as studies with other populations, are needed to assess the actual clinical effectiveness of the XGBH risk prediction model.
Acute kidney injury (AKI) leads to a worse prognosis in diabetic patients compared with prognoses in non-diabetic patients, but whether and how diabetes affects kidney repair after AKI remains ...unknown. Here, we used scratch-wound healing and transwell migration models to examine whether and how wound healing is affected by high glucose levels in cultured kidney proximal tubular cells (RPTC). The results show that scratch-wound healing and transwell migration were significantly slower in high-glucose-treated kidney tubular cells (30 mM glucose) than in low-glucose-treated cells (5.5 mM). Toll-like receptor 4 (TLR4), MyD88, phospho-protein kinase C (PKC), phospho-p38 MAPK and monocyte chemoattractant protein-1 (MCP-1) mRNA levels were upregulated after high glucose treatments. Staurosporine, a selective PKC inhibitor, inhibited TLR4, MyD88 and p-p38 upregulation in the high-glucose-treated cells, indicating the involvement of PKC in high-glucose-induced TLR4 upregulation. The pharmacological inhibition of TLR4 or shRNA-mediated TLR4 knockdown improved wound healing and transwell migration in high-glucose-treated RPTC. In contrast, the overexpression of TLR4 in low-glucose-treated RPTC suppressed wound healing, mimicking the effects of high glucose levels. These results suggest that the upregulation of TLR4 expression via PKC activation contributes to defective wound healing in high-glucose-treated kidney tubular cells.
Chemotherapy‐induced peripheral neuropathy (CIPN) is a significant side effect of chemotherapeutics. The mechanisms of CIPN remain substantially unidentified, although inflammation‐induced peripheral ...sensitization has been indicated as an important factor. Here, we aimed to illustrate the role of the matrix metalloproteinase (MMP)‐9‐related signaling pathway in the process of CIPN. Oxaliplatin (L‐OHP) was administered to mice to establish the CIPN model. Gelatin zymography was used to measure MMP‐9/2 activities. Western blotting and immunohistochemistry were used to measure the expression of high‐mobility group box‐1 (HMGB‐1), calcitonin gene‐related peptide and ionized calcium‐binding adapter molecule 1. Mechanical withdrawal was measured by von Frey hairs testing. Raw 264.7 cells and SH‐SY5Y cells were cultured to investigate cell signaling in vitro. Here, we report that L‐OHP‐induced mechanical pain in mice with significant MMP‐9/2 activation in dorsal root ganglion (DRG) neurons. MMP‐9 inhibition or knockout alleviated the occurrence of CIPN directly. MMP‐9/2 were released from macrophages and neurons in the DRG via the HMGB‐1‐toll‐like receptor 4 (TLR4)‐phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (Akt) axis, because MMP‐9/2 activities could be reduced by macrophage scavengers or PI3Kγ knockout in CIPN mice. The in vitro data revealed that induced MMP‐9 activity by recombinant HMGB‐1 could be abolished by TLR4, PI3K or Akt inhibitors. Finally, it was shown that N‐acetyl‐cysteine (NAC) could reduce MMP‐9/2 activities and attenuate CIPN effectively and safely. The HMGB‐1‐TLR4‐PI3K/Akt‐MMP‐9 axis is involved in the crosstalk between macrophages and neurons in the pathological process of CIPN in mice. Direct inhibition of MMP‐9 by NAC may be a potential therapeutic regimen for CIPN treatment.
What's new?
Chemotherapy‐induced peripheral neuropathy (CIPN) is a common complication of cancer chemotherapy associated with cold and mechanical hypersensitivity. The mechanisms of CIPN remain unclear, although inflammation‐induced peripheral sensitization is an important factor. This study reveal that matrix metalloproteinases (MMP)‐9/2, especially MMP‐9, play important roles in the induction of CIPN. The data demonstrate the role of the HMGB‐1‐TLR4‐PI3K/Akt‐MMP‐9 axis in the crosstalk between macrophages and neurons in CIPN mice and highlight MMP‐9 as a promising target for the development of CIPN therapeutic drugs. The study also provides first evidence that N‐acetylcysteine, a well‐known expectorant, attenuates CIPN via potent inhibition of MMP‐9 activity.
Modification of eukaryotic RNA by methylation of adenosine residues to generate N6-methyladenosine (m6A) is a highly prevalent process. m6A is dynamically regulated during cell metabolism and embryo ...development, and it is mainly involved in various aspects of RNA metabolism, including RNA splicing, processing, transport from the nucleus, translation, and degradation. Accumulating evidence shows that dynamic changes to m6A are closely related to the occurrence and development of cancer and that methyltransferases, as key elements in the dynamic regulation of m6A, play a crucial role in these processes. Therefore, in this review, we describe the role of methyltransferases as m6A writers in cancer and summarize their potential molecular mechanisms of action.
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Wang and colleagues demonstrated that m6A is an important gene regulation mode involved in cancer progression. This review focuses on the key roles of methyltransferases, m6A “writers,” in cancer and future medical treatment.
Non-small cell lung cancer (NSCLC) ranks the first in incidence and mortality among malignant tumors in China. Molecular targeted therapies such as gefitinib, an oral inhibitor of the epidermal ...growth factor receptor tyrosine kinase, have shown significant benefits in patients with advanced NSCLC. However, most patients have unsatisfactory outcomes due to the development of drug resistance, and there is an urgent need to better understand the pathways involved in the resistance mechanisms. In this study, we found that HMGB1 is highly expressed in drug-resistant cells and confers to gefitinib resistance in NSCLC cells via activating autophagy process. Gefitinib upregulates HMGB1 expression in time-dependent and dose-dependent manners in human NSCLC cells. RNA interference-mediated knockdown of HMGB1 reduces PC9GR cell viability, induces apoptosis, and partially restores gefitinib sensitivity. Mechanistic analyses indicate that elevated HMGB1 expression contributes to gefitinib resistance by inducing autophagy. Thus, our results suggest that HMGB1 is an autophagy regulator and plays a key role in gefitinib resistance of NSCLC.
This paper aims to propose a multicriteria decision analysis (MCDA) method to evaluate and select solvent in a dispersive liquid-liquid microextraction (DLLME) approach. The DLLME is applied to the ...determination of itraconazole and hydroxy itraconazole in plasma by high performance liquid chromatography with fluorescence detection (HPLC-FLD). To achieve this goal, extraction efficiency, chromatographic resolution, and greenness of solvent were identified as the three indicators in MCDA. Then, Technique for Order of Preference by Similarity to Ideal Solution (TOPSIS) was employed to evaluate and select the solvent. Weight assignment was set up by integrating the subjective scoring from experienced analysts and the objective approach using Shannon’s entropy weight method. Under chosen parameters (extraction solvent: 1-decanol 40 μL, dispersing solvent: methanol 400 μL), the method was validated satisfactorily and applied successfully to the analysis of itraconazole and hydroxy itraconazole in real human plasma samples. The results show that the comprehensive weighted TOPSIS analysis is a promising tool to choose experimental conditions toward an integrative goal. It can provide analysts with a decision making reference to maintain a balance between the analytical performance and eco-friendliness.
Abstract
Background
Activation of adenosine monophosphate–activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception and the attenuation of morphine antinociceptive ...tolerance. In this study, the authors investigated the impact of AMPK activation through resveratrol treatment on bone cancer pain.
Methods
The nociception was assessed by measuring the incidence of foot withdrawal in response to mechanical indentation in rats (n = 8). Cytokine expression was measured using quantitative polymerase chain reaction (n = 8). Cell signalings were assayed by western blot (n = 4) and immunohistochemistry (n = 5). The microglial cell line BV-2, primary astrocytes, and neuron-like SH-SY5Y cells were cultured to investigate the in vitro effects.
Results
Resveratrol and 5-amino-1-β-d-ribofuranosyl-imidazole-4-carboxamide, the AMPK activators, significantly attenuated bone cancer pain in rats with tumor cell implantation (TCI; threshold of mechanical withdrawal, resveratrol vs. vehicle: 10.1 ± 0.56 vs. 4.1 ± 0.37; 5-amino-1-β-d-ribofuranosyl-imidazole-4-carboxamide vs. vehicle: 8.2 ± 0.17 vs. 4.1 ± 0.37, mean ± SEM); these effects were reversed by the AMPK inhibitor compound C (compound C vs. resveratrol: 6.2 ± 1.35 vs. 10.1 ± 0.56, mean ± SEM). Resveratrol has an AMPK-dependent inhibitory effect on TCI-evoked astrocyte and microglial activation. The antinociceptive effects of resveratrol were partially mediated by the reduced phosphorylation of mitogen-activated protein kinases and decreased production of proinflammatory cytokines in an AMPK-dependent manner. Furthermore, resveratrol potently inhibited inflammatory factors–mediated protein kinase B/mammalian target of rapamycin signaling in neurons. Acute pain evoked by proinflammatory cytokines in the spinal cord was significantly attenuated by resveratrol.
Conclusions
AMPK activation in the spinal glia by resveratrol may have utility in the treatment of TCI-induced neuroinflammation, and our results further implicate AMPK as a novel target for the attenuation of bone cancer pain.
Glioblastoma multiforme (GBM) is a highly heterogeneous disease, which is initiated and sustained by various molecular alterations in an array of signal transduction pathways. Heat-shock protein 90 ...(Hsp90) is a molecular chaperone and is critically implicated in folding and activation of a diverse group of client proteins, many of which are key regulators for glioblastoma biology. We here assessed the anti-neoplastic efficacy of a novel brain-penetrating Hsp90 inhibitor NXD30001 as a monotherapy and combined with radiation
and
. Our results demonstrated that NXD30001 potently inhibited neurosphere formation, growth, and survival of CD133+ GBM cells with the half maximal inhibitory concentration at low nanomolar range, but CD133- GBM cells were less sensitive to NXD30001. NXD30001 also increased radio-sensitivity in glioblastoma stem cells (GSCs) at suboptimal concentrations. Moreover, NXD30001 dose-dependently decreased phosphorylation levels of multiple Hsp90 client proteins which play key roles in GBM, such as EGFR, Akt, c-Myc, and Notch1. In addition, NXD30001 could impair DNA damage response and endoplasmic reticulum stress response after radiotherapy by alteration of the related proteins expression. In a murine orthotopic model of human glioblastoma, NXD30001 marvelously induced tumor regression and extended median survival of tumor-bearing mice by approximately 20% when compared with the vehicle group (37 d vs 31 d,
<0.05). Radiotherapy solely increased median survival of tumor-bearing mice from 31 d to 38 d (
<0.05), while NXD30001 combined with radiation further extended survival to 43 d (
<0.05). We concluded that GSCs are more sensitive to NXD30001 than non-stem GBM cells, and NXD30001 in combination with radiation exerts better inhibitive effect in GBM progression than monotherapy.
Cardiovascular disease (CVD) risk prediction shows great significance for disease diagnosis and treatment, especially early intervention for CVD, which has a direct impact on preventing and reducing ...adverse outcomes. In this paper, we collected clinical indicators and outcomes of 14,832 patients with cardiovascular disease in Shanxi, China, and proposed a cardiovascular disease risk prediction model, XGBH, based on key contributing characteristics to perform risk scoring of patients’ clinical outcomes. The XGBH risk prediction model had high accuracy, with a significant improvement compared to the baseline risk score (AUC = 0.80 vs. AUC = 0.65). At the same time, we found that with the addition of conventional biometric variables, the accuracy of the model’s CVD risk prediction would also be improved. Finally, we designed a simpler model to quantify disease risk based on only three questions answered by the patient, with only a modest reduction in accuracy (AUC = 0.79), and providing a valid risk assessment for CVD. Overall, our models may allow early-stage intervention in high-risk patients, as well as a cost-effective screening approach. Further prospective studies and studies in other populations are needed to assess the actual clinical effect of XGBH risk prediction models.
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