Exclusion of HDAC1/2 complexes by oncogenic nuclear condensates.

Nuclear condensates have been shown to regulate cell fate control, but its role in oncogenic transformation remains largely unknown. Here we show acquisition of oncogenic potential by nuclear condensate remodeling. The proto-oncogene SS18 and its oncogenic fusion SS18-SSX1 can both form condensates, but with drastically different properties and impact on 3D genome architecture. The oncogenic condensates, not wild type ones, readily exclude HDAC1 and 2 complexes, thus, allowing aberrant accumulation of H3K27ac on chromatin loci, leading to oncogenic expression of key target genes. These results provide the first case for condensate remodeling as a transforming event to generate oncogene and such condensates can be targeted for therapy. One sentence summary: Expulsion of HDACs complexes leads to oncogenic transformation.

Demineralized bone matrix for repair and regeneration of maxillofacial defects: A narrative review.

OBJECTIVES: Demineralized bone matrix (DBM) is a well-established bone graft material widely accepted by dentists and the public for its favorable osteoconductivity and osteoinductive potential. This article aimed to provide a narrative review of the current therapeutic applications and limitations of DBM in maxillofacial bone defects. STUDY SELECTION, DATA, AND SOURCES: Randomized controlled trials, prospective or retrospective clinical studies, case series and reports, and systematic reviews. MEDLINE, PubMed, and Google Scholar were searched using keywords. CONCLUSIONS: Some evidence supported the therapeutic application of DBM in periodontal intrabony defects, maxillary sinus lifts, ridge preservation, ridge augmentation, alveolar cleft repair, orthognathic surgery, and other regional maxillofacial bone defects. However, the limitations of DBM should be considered when using it, including potential low immunogenicity, instability of osteoinductive potential, handling of the graft material, and patient acceptance. CLINICAL SIGNIFICANCE: With the increasing demand for the treatment of maxillofacial bone defects, DBM is likely to play a greater role as a promising bone graft material. Safe and effective combination treatment strategies and how to maintain a stable osteoinductive potential will be the future challenges of DBM research.

TERT mediates the U-shape of glucocorticoids effects in modulation of hippocampal neural stem cells and associated brain function.

BACKGROUND: Glucocorticoids (GCs) are steroidal hormones produced by the adrenal cortex. A physiological-level GCs have a crucial function in maintaining many cognitive processes, like cognition, memory, and mood, however, both insufficient and excessive GCs impair these functions. Although this phenomenon could be explained by the U-shape of GC effects, the underlying mechanisms are still not clear. Therefore, understanding the underlying mechanisms of GCs may provide insight into the treatments for cognitive and mood-related disorders. METHODS: Consecutive administration of corticosterone (CORT, 10 mg/kg, i.g.) proceeded for 28 days to mimic excessive GCs condition. Adrenalectomy (ADX) surgery was performed to ablate endogenous GCs in mice. Microinjection of 1 µL of Ad-mTERT-GFP virus into mouse hippocampus dentate gyrus (DG) and behavioral alterations in mice were observed 4 weeks later. RESULTS: Different concentrations of GCs were shown to affect the cell growth and development of neural stem cells (NSCs) in a U-shaped manner. The physiological level of GCs (0.01 µM) promoted NSC proliferation in vitro, while the stress level of GCs (10 µM) inhibited it. The glucocorticoid synthesis blocker metyrapone (100 mg/kg, i.p.) and ADX surgery both decreased the quantity and morphological development of doublecortin (DCX)-positive immature cells in the DG. The physiological level of GCs activated mineralocorticoid receptor and then promoted the production of telomerase reverse transcriptase (TERT); in contrast, the stress level of GCs activated glucocorticoid receptor and then reduced the expression of TERT. Overexpression of TERT by AD-mTERT-GFP reversed both chronic stresses- and ADX-induced deficiency of TERT and the proliferation and development of NSCs, chronic stresses-associated depressive symptoms, and ADX-associated learning and memory impairment. CONCLUSION: The bidirectional regulation of TERT by different GCs concentrations is a key mechanism mediating the U-shape of GC effects in modulation of hippocampal NSCs and associated brain function. Replenishment of TERT could be a common treatment strategy for GC dysfunction-associated diseases.

Opening KATP channels induces inflammatory tolerance and prevents chronic pain.

Current treatments for chronic pain are unsatisfactory, therefore, new therapeutics are urgently needed. Our previous study indicated that KATP channel openers have analgesic effects, but the underlying mechanism has not been elucidated. We speculated that KATP channel openers might increase suppressor of cytokine signaling (SOCS)-3 expression to induce inflammatory tolerance and attenuate chronic pain. Postoperative pain was induced by plantar incision to establish a chronic pain model. Growth arrest-specific 6 (Gas6)-/- and Axl-/- mice were used for signaling studies. The microglia cell line BV-2 was cultured for the in vitro experiments. The KATP channel opener significantly attenuated incision-induced mechanical allodynia in mice associated with the upregulated expression of SOCS3. Opening KATP channels induced the expression of SOCS3 in the Gas6/Axl signaling pathway in microglia, inhibited incision-induced mechanical allodynia by activating the Gas6/Axl-SOCS3 signaling pathway, and induced inflammatory tolerance to relieve neuroinflammation and postoperative pain. We demonstrated that opening of the KATP channel opening activated Gas6/Axl/SOCS3 signaling to induce inflammatory tolerance and relieve chronic pain. We explored a new target for anti-inflammatory and analgesic effects by regulating the innate immune system and provided a theoretical basis for clinical preemptive analgesia.

Bilirubin Improves Gap Junction to Alleviate Doxorubicin-Induced Cardiotoxicity by Regulating AMPK-Axl-SOCS3-Cx43 Axis.

Doxorubicin induces severe cardiotoxicity, accompanied by the high level of bilirubin in the blood. The conventional wisdom is that bilirubin is considered as a marker of liver damage. By contrast, here we aim to explore the potential protective effect of bilirubin on doxorubicin-induced cardiotoxicity, and investigate the mechanism for drug development. Doxorubicin was used to establish cardiotoxicity model in vitro and in vivo. The electrocardiogram (ECG), echocardiography and molecular biological methods were used to detect the effects of bilirubin on doxorubicin-induced cardiotoxicity. Consecutive intraperitoneal injection of bilirubin for 7 days significantly attenuated doxorubicin-induced arrhythmia, prolonged survival time and reduced the levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB) and α-hydroxybutyrate dehydrogenase (α-HBDH) in mice. Bilirubin also markedly inhibited doxorubicin-induced phosphorylation of c-Jun N-terminal kinase (JNK) and connexin 43 (Cx43), and improved gap junction function in vitro and in vivo. In addition, bilirubin activated adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and induced suppressor of cytokine signaling 3 (SOCS3) expression, which was abolished by Axl inhibition. Moreover, pretreatment with AMPK agonist or AMPK inhibitor could mimic or abolish the cardioprotective effect of bilirubin on H9C2 cells in vitro, respectively. Altogether, bilirubin upregulates gap junctions' function to protect against doxorubicin-induced cardiotoxicity by activating AMPK-Axl-SOCS3 signaling axis. We enrich the physiological function of bilirubin, and provide theoretical support for drug development.

Predictive Value of a Combined Model Based on Pre-Treatment and Mid-Treatment MRI-Radiomics for Disease Progression or Death in Locally Advanced Nasopharyngeal Carcinoma.

PURPOSE: A combined model was established based on the MRI-radiomics of pre- and mid-treatment to assess the risk of disease progression or death in locally advanced nasopharyngeal carcinoma. MATERIALS AND METHODS: A total of 243 patients were analyzed. We extracted 10,400 radiomics features from the primary nasopharyngeal tumors and largest metastatic lymph nodes on the axial contrast-enhanced T1 weighted and T2 weighted in pre- and mid-treatment MRI, respectively. We used the SMOTE algorithm, center and scale and box-cox, Pearson correlation coefficient, and LASSO regression to construct the pre- and mid-treatment MRI-radiomics prediction model, respectively, and the risk scores named P score and M score were calculated. Finally, univariate and multivariate analyses were used for P score, M score, and clinical data to build the combined model and grouped the patients into two risk levels, namely, high and low. RESULT: A combined model of pre- and mid-treatment MRI-radiomics successfully categorized patients into high- and low-risk groups. The log-rank test showed that the high- and low-risk groups had good prognostic performance in PFS (P<0.0001, HR: 19.71, 95% CI: 12.77-30.41), which was better than TNM stage (P=0.004, HR:1.913, 95% CI:1.250-2.926), and also had an excellent predictive effect in LRFS, DMFS, and OS. CONCLUSION: Risk grouping of LA-NPC using a combined model of pre- and mid-treatment MRI-radiomics can better predict disease progression or death.

Development and Validation of a Nomogram for Predicting Radiation-Induced Temporal Lobe Injury in Nasopharyngeal Carcinoma.

BACKGROUND: The purpose was to develop and validate a nomogram for prediction on radiation-induced temporal lobe injury (TLI) in patients with nasopharyngeal carcinoma (NPC). METHODS: The prediction model was developed based on a primary cohort that consisted of 194 patients. The data was gathered from January 2008 to December 2010. Clinical factors associated with TLI and dose-volume histograms for 388 evaluable temporal lobes were analyzed. Multivariable logistic regression analysis was used to develop the predicting model, which was conducted by R software. The performance of the nomogram was assessed with calibration and discrimination. An external validation cohort contained 197 patients from January 2011 to December 2013. RESULTS: Among the 391 patients, 77 patients had TLI. Prognostic factors contained in the nomogram were Dmax (the maximum point dose) of temporal lobe, D1cc (the maximum dose delivered to a volume of 1 ml), T stage, and neutrophil-to-lymphocyte ratios (NLRs). The Internal validation showed good discrimination, with a C-index of 0.847 [95%CI 0.800 to 0.893], and good calibration. Application of the nomogram in the external validation cohort still obtained good discrimination (C-index, 0.811 [95% CI, 0.751 to 0.870]) and acceptable calibration. CONCLUSIONS: This study developed and validated a nomogram, which may be conveniently applied for the individualized prediction of TLI.

Clinical characteristics and survival outcomes of ascending, descending and mixed types of nasopharyngeal carcinoma in the non-endemic areas of china: A propensity score matching analysis.

PURPOSE: To compare the clinical characteristics and survival outcomes of patients with ascending type (type A), descending type (type D), and mixed type (type AD) of nasopharyngeal carcinoma (NPC) in non-endemic areas. MATERIALS AND METHODS: The cohort included 628 patients diagnosed with type A, type D, and type AD of NPC between January 2009 and December 2014. Type A was defined as T3-4  N0-1 , type D as T0-1  N2-3 , and type AD as T3-4  N2-3 . Propensity score matching (PSM) was performed to balance clinical factors and match patients. Kaplan-Meier methods and Cox proportional hazards models were used to evaluate the impact of different NPC types on survival outcomes. RESULTS: There were 145 patients with type A, 194 with type D, and 289 with type AD. However, after PSM, there were only 130 patients with each type. Compared with patients with type A, those with type D had lower 5-year disease-specific survival (96.9% vs 91.5%) and distant metastasis-free survival (92.3% vs 77.7%) and higher local relapse-free survival (88.5% vs 96.9%) (p < 0.05 for all). Patients with type AD may have an increased risk of disease progression (progression-free survival, 56.9% vs 74.6% and 66.2%) and death (overall survival [OS], 76.9% vs 85.4% and 85.4%) (p < 0.05 for all) compared to patients with the other two types of tumors. We further analyzed the metastasis trend. Similar metastasis patterns were observed in types AD and D, and types AD and A had similar recurrence trends. The mortality rate of patients with types AD and D in the first 3 years after metastasis was remarkably higher than that of patients with type A. CONCLUSIONS: In non-endemic areas of China, metastases and recurrence patterns differed across tumor types. Type AD has the worst OS, and the clinical process is more radical. Type D has a lower recurrence rate, higher metastasis, and disease-related mortality rates, and poorer prognosis after metastasis than type A.

Uric acid preconditioning alleviated doxorubicin induced JNK activation and Cx43 phosphorylation associated cardiotoxicity via activation of AMPK-SHP2 signaling pathway.

BACKGROUND: Doxorubicin is an anthracycline antibiotic, which is effective for treating various malignancies such as leukemias and lymphomas. However, its serious cumulative dose-dependent cardiotoxicity limits its clinical application. Previous studies have shown that doxorubicin-associated cardiotoxicity is closely related to adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Uric acid is known to exert a strong antioxidant function and moderate protection on the nerves. However, its cardioprotective properties have not been established. This study aimed to investigate the potential effect of uric acid preconditioning on doxorubicin-induced cardiotoxicity and the involvement of AMPK signaling in this process. METHODS: An acute cardiotoxicity model of doxorubicin was established by intraperitoneal injection of a single dose of doxorubicin (20 mg/kg) in mice. Uric acid (62.5, 125, and 250 mg/kg) was intragastrically administered to mice one day before doxorubicin treatment and then continuously administered every 24 h for 8 consecutive days. The mortality rate and weight of the mice were recorded every day. Electrocardiograms (ECG) and serum biochemicals were detected with an ECG instrument and enzyme-linked immunosorbent assay kit (Elisa) respectively. A real-time cell analyzer (RTCA) was used to investigate the cytotoxicity of doxorubicin in vitro. Cell signaling was assayed by western blotting. RESULTS: Uric acid (125 mg/kg) preconditioning increased the survival rate and body weight of doxorubicin-treated mice. Uric acid also effectively alleviated prolongation of the doxorubicin-induced QT interval, slowed heart rate, and reduced the plasma levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and creatine kinase (CK) in plasma in mice. Moreover, uric acid strongly activated AMPK and Src homology 2 domain-containing protein tyrosine phosphatase (SHP2), inhibiting doxorubicin-induced expression phosphorylated-c-Jun N-terminal kinases (JNK) and phosphorylated-connexin 43 (Cx43) in vitro and in vivo and effectively reversing the doxorubicin-induced decreased viability of H9C2 myocardial cells in vitro. CONCLUSIONS: We demonstrated that uric acid preconditioning alleviated doxorubicin-induced cardiotoxicity through the AMPK-SHP2-JNK-Cx43 signaling pathway.

Induction of suppressor of cytokine signaling 3 via HSF-1-HSP70-TLR4 axis attenuates neuroinflammation and ameliorates postoperative pain.

Postoperative pain is a common form of acute pain that, if not managed effectively, can become chronic pain. Evidence has shown that glia, especially microglia, mediate neuroinflammation, which plays a vital role in pain sensitization. Moreover, toll-like receptor 4 (TLR4), the tumor necrosis factor receptor (TNF-R), the interleukin-1 receptor (IL-1R), and the interleukin-6 receptor (IL-6R) have been considered key components in central pain sensitization and neuroinflammation. Therefore, we hypothesized that activation of the body's endogenous "immune brakes" will inhibit these receptors and achieve inflammation tolerance as well as relieve postoperative pain. After searching for potential candidates to serve as this immune brake, we identified and focused on the suppressor of cytokine signaling 3 (SOCS3) gene. To regulate SOCS3 expression, we used paeoniflorin to induce heat shock protein 70 (HSP70)/TLR4 signaling. We found that paeoniflorin significantly induced SOCS3 expression both in vitro and in vivo and promoted the efflux of HSP70 from the cytoplasm to the extracellular environment. Furthermore, paeoniflorin markedly attenuated incision-induced mechanical allodynia, and this effect was abolished by small interfering RNAs targeting SOCS3. These findings demonstrated an effective and safe strategy to alleviate postoperative pain.

Protective effects of asiatic acid in a spontaneous type 2 diabetic mouse model.

Asiatic acid (AA) has been demonstrated to exhibit anti-diabetic activity. However, the mechanisms and underlying signaling pathways remain to be elucidated. The present study was performed to confirm the protective effect of AA and demonstrate its ability to regulate the phosphatidylinositol 3­kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase­3ß (GSK­3ß) signaling pathway in db/db mice. Db/db mice fed on a high­fat diet were used to model diabetes mellitus. Modeled mice were divided randomly into the model control, pioglitazone hydrochloride tablet (PH) and AA groups. Age­matched C57 BL/6J mice served as normal controls. Lipid and glucose levels, and glycogen synthesis rates were assessed following treatment. Pathological changes were detected using hematoxylin and eosin staining. Expression of the PI3K/AKT/GSK­3ß signaling pathway at the mRNA level was measured using quantitative polymerase chain reaction analysis. The model control group revealed typical characteristics of obesity and diabetes, including high glucose and lipid levels, and decreased glycogen synthesis. Four weeks of treatment with AA or PH ameliorated these abnormalities. AA and PH treatments mitigated the upregulation of PI3K, AKT, insulin receptor, and insulin receptor substrate­1 mRNA expression in modeled mice. Furthermore, AA and PH treatments decreased GSK­3ß and glucose­6­phosphatase mRNA expression compared with the normal control group. The results of the present study confirmed that AA possesses anti­diabetic activity in db/db mice. The PI3K/AKT/GSK­3ß signaling pathway may mediate this protective effect.

Effect of mulberry leaf (Folium Mori) on insulin resistance via IRS-1/PI3K/Glut-4 signalling pathway in type 2 diabetes mellitus rats.

CONTEXT: Folium Mori, the leaf of Morus alba L. (Moraceae), has been used in traditional Chinese medicine (TCM) for treating diabetes. However, it is unclear which components in the mulberry leaf are effective for the treatment of type 2 diabetes mellitus (T2DM). OBJECTIVE: To investigate the flavonoids and polyphenols in mulberry leaves and their antihyperglycemic and antihyperlipidemic effects in T2DM rats. MATERIALS AND METHODS: Male Sprague-Dawley rats were divided into five groups: normal control (NC), diabetic control (DBC), diabetic group with 0.3 mg/kg b.w./day rosiglitazone (RSG), diabetic group with 7 g/kg b.w./day TCM formula and diabetic group with 2 g/kg b.w./day Folium Mori extract (FME). After 4 weeks, the rats were sacrificed; biochemical parameters, gene and protein expression were measured. RESULTS: The FBG level was significantly lower in the FME group than in the DBC group (p < 0.05). In oral glucose tolerance test, the AUC was significantly lower in the FME group (p < 0.05). The HOMA-IR level was significantly decreased in the FME group (p < 0.05). FME decreased the total cholesterol (TC), triglyceride (TG) and low density lipoprotein (LDL) levels (p < 0.05). FME increased the mRNA and protein expression of IRS-1, PI3K p85α and Glut-4 increased significantly (p < 0.05). Histological analysis revealed amelioration of lipid accumulation following FME treatment. Additionally, immunohistochemical analysis displayed stronger staining of Glut-4 in the FME group compared to the DBC group. DISCUSSION AND CONCLUSION: FME could decrease the body weight, blood glucose, TG, TC and LDL levels, and improve insulin resistance. FME possessed significant antihyperglycemic and antihyperlipidemic activities via the IRS-1/PI3K/Glut-4 signalling pathway.