Short human eccDNAs are predictable from sequences.

BACKGROUND: Ubiquitous presence of short extrachromosomal circular DNAs (eccDNAs) in eukaryotic cells has perplexed generations of biologists. Their widespread origins in the genome lacking apparent specificity led some studies to conclude their formation as random or near-random. Despite this, the search for specific formation of short eccDNA continues with a recent surge of interest in biomarker development. RESULTS: To shed new light on the conflicting views on short eccDNAs' randomness, here we present DeepCircle, a bioinformatics framework incorporating convolution- and attention-based neural networks to assess their predictability. Short human eccDNAs from different datasets indeed have low similarity in genomic locations, but DeepCircle successfully learned shared DNA sequence features to make accurate cross-datasets predictions (accuracy: convolution-based models: 79.65 ± 4.7%, attention-based models: 83.31 ± 4.18%). CONCLUSIONS: The excellent performance of our models shows that the intrinsic predictability of eccDNAs is encoded in the sequences across tissue origins. Our work demonstrates how the perceived lack of specificity in genomics data can be re-assessed by deep learning models to uncover unexpected similarity.

Inhibition of tumor migration and invasion by fenofibrate via suppressing epithelial-mesenchymal transition in breast cancers.

The recurrence and metastasis in breast cancer within 3 years after the chemotherapies or surgery leads to poor prognosis with approximately 1-year overall survival. Large-scale scanning research studies have shown that taking lipid-lowering drugs may assist to reduce the risk of death from many cancers, since cholesterol in lipid rafts are essential for maintain integral membrane structure and functional signaling regulation. In this study, we examined five lipid-lowering drugs: swertiamarin, gemfibrozil, clofibrate, bezafibrate, and fenofibrate in triple-negative breast cancer, which is the most migration-prone subtype. Using human and murine triple-negative breast cancer cell lines (Hs 578 t and 4 T1), we found that fenofibrate displays the highest potential in inhibiting the colony formation, wound healing, and transwell migration. We further discovered that fenofibrate reduces the activity of pro-metastatic enzymes, matrix metalloproteinases (MMP)-9 and MMP-2. In addition, epithelial markers including E-cadherin and Zonula occludens-1 are increased, whereas mesenchymal markers including Snail, Twist and α-smooth muscle actin are attenuated. Furthermore, we found that fenofibrate downregulates ubiquitin-dependent GDF-15 degradation, which leads to enhanced GDF-15 expression that inhibits cell migration. Besides, nuclear translocation of FOXO1 is also upregulated by fenofibrate, which may responsible for GDF-15 expression. In summary, fenofibrate with anti-cancer ability hinders TNBC from migration and invasion, and may be beneficial to repurposing use of fenofibrate.

Protective effects of paeonol against cognitive impairment in lung diseases.

Pulmonary inflammation may lead to neuroinflammation resulting in neurological dysfunction, and it is associated with a variety of acute and chronic lung diseases. Paeonol is a herbal phenolic compound with anti-inflammatory and anti-oxidative properties. The aim of this study is to understand the beneficial effects of paeonol on cognitive impairment, pulmonary inflammation and its underlying mechanisms. Pulmonary inflammation-associated cognitive deficit was observed in TNFα-stimulated mice, and paeonol mitigated the cognitive impairment by reducing the expressions of interleukin (IL)-1ß, IL-6, and NOD-like receptor family pyrin domain-containing 3 (NLRP3) in hippocampus. Moreover, elevated plasma miR-34c-5p in lung-inflamed mice was also reduced by paeonol. Pulmonary inflammation induced by intratracheal instillation of TNFα in mice resulted in immune cells infiltration in bronchoalveolar lavage fluid, pulmonary edema, and acute fibrosis, and these inflammatory responses were alleviated by paeonol orally. In MH-S alveolar macrophages, tumor necrosis factor (TNF) α- and phorbol myristate acetate (PMA)-induced inflammasome activation was ameliorated by paeonol. In addition, the expressions of antioxidants were elevated by paeonol, and reactive oxygen species production was reduced. In this study, paeonol demonstrates protective effects against cognitive deficits and pulmonary inflammation by exerting anti-inflammatory and anti-oxidative properties, suggesting a powerful benefit as a potential therapeutic agent.

Eliminating mother-to-child transmission of hepatitis B virus: practice and progress in Baoan, a national pilot district of China.

BACKGROUND: While mother-to-child transmission (MTCT) of hepatitis B virus (HBV) remains a significant challenge in China, research investigating the effectiveness of the September 2017 pilot program to eliminate MTCT of HIV, syphilis, and HBV is limited. Baoan district, which has a higher-than-average rate of hepatitis B infection among pregnant women and strong support from the government, was one of six national pilot districts selected for the program. Therefore, this study aims to assess the progress and implementation of the elimination of MTCT of HBV in Baoan district over a period of 5 years. METHODS: Data was collected from the national information system for the prevention of MTCT, registration forms, and follow-up forms of pregnant women and their live births from 2018 to 2022. Joinpoint models were used to analyze changing trends over time, calculating annual percentage change (APC) and the corresponding 95% confidence interval (95%CI). Multivariate logistic regression models were used to analyze risk factors for HBV MTCT. RESULTS: From 2018 to 2022, the coverage of HBV screening during pregnancy increased from 98.29 to 99.55% (APC = 0.30, P = 0.012). The coverage of HBV early screening within 13 gestational weeks increased from 40.76 to 86.42% (APC = 18.88, P = 0.033). The prevalence of maternal HBV infection declined by an APC of - 3.50 (95% CI -6.28 ~ - 0.63). The coverage of antiviral therapy among high-risk pregnant women increased from 63.59 to 90.04% (APC = 11.90, P = 0.031). Coverage for timely administration of hepatitis B immunoglobulin, hepatitis B birth dose vaccine, and three-dose hepatitis B vaccination remained consistently above 97.50%. The coverage of post-vaccination serological testing (PVST) in high-risk infants was 56.15% (1352/2408), and the MTCT rate of HBV was 0.18%. Mothers with high-school education or below (OR = 3.76, 95% CI 1.04 ~ 13.60, P = 0.04) and hepatitis B e antigen (HBeAg) positivity (OR = 18.89, 95% CI 1.98 ~ 18.50, P = 0.01) had increased MTCT risk. CONCLUSIONS: The implementation of comprehensive prevention strategies in Baoan district, including screening, treatment, and immunoprophylaxis, has proven effective in maintaining the MTCT of HBV at an extremely low level. However, it remains crucial to raise public awareness, specifically on the importance of improving the coverage of PVST for infants exposed to HBV.

Benefit of Uracil-Tegafur Used as a Postoperative Adjuvant Chemotherapy for Stage IIA Colon Cancer.

Background and Objectives: Postoperative adjuvant therapy with uracil and tegafur (UFT) is often used for stage II colon cancer in Japan, but a limited number of studies have investigated the effects of UFT in these patients. Materials and Methods: We conducted a population-based cohort study in patients with resected stage II colon cancer comparing the outcomes after postoperative adjuvant chemotherapy with UFT with an observation-only group. The data were collected from the Taiwan National Health Insurance Research Database from 2000 to 2015. The outcomes of the study were disease-free survival (DFS) and overall survival (OS). The hazard ratios (HRs) were calculated using multivariate Cox proportional hazard regression models. Results: No differences in the DFS and OS were detected between the UFT (1137 patients) and observation (2779 patients) cohorts (DFS: adjusted HR 0.702; 95% confidence interval (CI) 0.489-1.024; p = 0.074) (OS: adjusted HR 0.894; 95% CI 0.542-1.186; p = 0.477). In the subgroup analyses of the different substages, UFT prolonged DFS in patients with stage IIA colon cancer (adjusted HR 0.652; 95% CI 0.352-0.951; p = 0.001) compared with DFS in the observation cohort, but no differences in the OS were detected (adjusted HR 0.734; 95% CI 0.475-1.093; p = 0.503). Conclusions: Our results show that DFS improved significantly in patients with stage IIA colon cancer receiving UFT as a postoperative adjuvant chemotherapy compared with DFS in the observation group.

Oral tegafur-uracil as a metronomic therapy in stage IVa and IVb cancer of the oral cavity.

PURPOSE: This study aimed to evaluate the impact of accumulated oral tegafur-uracil (UFUR) as maintenance chemotherapy on overall survival (OS) and disease-free survival (DFS) rates after definitive treatment for non-distant metastatic stage IV cancer of the oral cavity. MATERIALS AND METHODS: This retrospective, hospital center-based study analyzed data of patients diagnosed with stage IVa and IVb cancer of the oral cavity who underwent surgical resection and concurrent chemoradiotherapy (CCRT) obtained from a database between October 2008 and December 2014. RESULTS: Forty-two patients were treated with CCRT (non-UFUR group); the remaining 51 patients received the same regimen, followed by additional oral UFUR (UFUR group). For all study patients, the 3-year DFS rates were 53.05% and 35.41% in the UFUR and non-UFUR groups, respectively (p = 0.011), while the 3-year OS rates were 74.96% and 48.47%, respectively (p = 0.001). CONCLUSIONS: Adding UFUR to CCRT significantly improved the DFS and OS rates in patients with non-distant metastatic stage IV cancer of the oral cavity.

Application of Color Doppler Ultrasound to Evaluate Chemotherapeutic Effect on Primary Thyroid Lymphoma.

Primary thyroid lymphoma (PTL) is a rare disease which responds well to rituximab-based chemotherapy. Here, we describe a case who was diagnosed through core needle biopsy as having diffuse large B-cell lymphoma in the right lobe of thyroid gland. Positron emission tomography computed tomography (PET-CT) revealed no other foci of hot spots, so PTL was considered. She was treated with rituximab plus bendamustine for three cycles, and color Doppler ultrasound revealed significant reduction of blood flow signals in the tumor but no significant decrease of its size (<25% extent). Then, the chemotherapy regimen was adjusted to rituximab, cyclophosphamide, vincristine, prednisone (R-COP), and complete remission was noted on ultrasound and PET-CT after three cycles of R-COP treatment. This case is reported to tell that color Doppler ultrasound, in addition to PET-CT, is useful to evaluate chemotherapeutic effect on PTLs.

Hepatitis B Surface Antigen Positivity Is an Independent Unfavorable Prognostic Factor in Diffuse Large B-Cell Lymphoma in the Rituximab Era.

BACKGROUND: Patients with diffuse large B-cell lymphoma (DLBCL) with concurrent hepatitis B surface antigen (HBsAg)-positive hepatitis B virus (HBV) infection have distinct clinical features. Nevertheless, the prognostic value of HBsAg in DLBCL in the rituximab era remains unclear. MATERIALS AND METHODS: We conducted a retrospective cohort study to investigate the clinical relevance of HBsAg in immunocompetent patients with DLBCL treated with homogeneous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone between 2002 and 2016. RESULTS: Among 416 analyzed patients, 98 (23.6%) were HBsAg positive. HBsAg positivity was associated with a younger age and more advanced stage at diagnosis, more frequent hepatic impairment during perichemotherapy, and a trend of higher National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score at diagnosis. Compared with the HBsAg-negative patients, the HBsAg-positive patients had a lower overall response rate (76.5% vs. 85.5%, p = .043), poorer 5-year overall survival (OS) rate (57.2% vs. 73.5%, p < .001), and shorter 5-year progression-free survival (PFS) rate (47.2% vs. 60.7%, p = .013). Multivariate analyses showed that HBsAg positivity was an independent unfavorable prognostic indicator for OS and PFS. A scoring system incorporating HBsAg positivity, the NCCN-IPI score, and serum albumin levels proved to be useful for stratifying prognostically relevant subgroups of patients with DLBCL. CONCLUSION: This study demonstrated that HBV infection is uniquely relevant to DLBCL. HBsAg might serve as a novel biomarker to improve clinical risk stratification of patients with DLBCL in areas with high prevalence of HBV infection. Further research investigating the etiopathogenesis of HBV infection in DLBCL is imperative. IMPLICATIONS FOR PRACTICE: A considerable disparity exists regarding the prognostic relevance of hepatitis B surface antigen (HBsAg)-positive hepatitis B virus (HBV) infection in patients with diffuse large B-cell lymphoma (DLBCL). In this large, retrospective cohort study from an area with high prevalence of HBV infection, the authors demonstrated that HBsAg was an independent unfavorable factor significantly associated with survival, highlighting its potential as a novel prognostic indicator to improve the risk stratification of patients with DLBCL in the rituximab era.

Surface plasmons manipulated Smith-Purcell radiation on Yagi-Uda nanoantenna arrays.

An electron bunch (e-bunch) passing through an insulator-metal-insulator (IMI) substrate can excite surface plasmons (SPs) on the substrate. Recent studies demonstrate that Smith-Purcell radiation (SPR) from one-dimensional gratings on an IMI substrate can be manipulated and enhanced by e-bunch excited SPs. However, under this configuration, only the emission along the direction of electron moving can be controlled. To steer both the azimuthal and polar angles of the far-field emission pattern requires other mechanisms. In this work, the SP-manipulated SPR with a Yagi-Uda nanoantenna (YUNA) array on an IMI substrate for generation of light beams with designed far-field patterns is proposed and explored by computer simulations. Emission of SPR along and perpendicular to the direction of electron movement can be manipulated by designing grating period and YUNA structure, respectively. Dependence of the azimuthal and polar angles of emitted light beam on geometry parameters of feed and directors of YUNA are elucidated. Furthermore, emission of multiple beams containing a single wavelength and multiple wavelengths with required far-field angles can be achieved using different groups of YUNA arrays on different IMI substrates. The proposed mechanism may have applications for light sources, optical imaging, optical beam steering, holography, microdisplay and cryptography.

Pulmonary fibroblasts-secreted CXCL10 polarizes alveolar macrophages under pro-inflammatory stimuli.

BACKGROUND: During acute lung injury, lung fibroblasts produce chemokines that assist the activation and migration of resident macrophages. The interactions between pulmonary fibroblasts and alveolar macrophages demonstrate the early event in the recruitment of immune cells, and the production of chemokines appear to be central mediators of the initiation and progression of inflammatory responses. In this study, the aim was to investigate the signaling pathway leading to CXCL10 secretion and the effects of CXCL10 released by activated fibroblasts on regulating macrophage polarization in a pro-inflammatory microenvironment. METHODS: The expression of chemokines CCL2, CCL5, CXCL10, and CXCL12, and the phosphorylation of signaling molecules STAT3, FAK, GSK3αß and PKCδ were investigated by real time-PCR, ELISA, or Western blot on TNFα- or IL-1ß-activated MRC-5 pulmonary fibroblasts. By collecting conditioned medium from TNFα-activated fibroblasts, the expression of iNOS and arginase I on MH-S alveolar macrophages were examined by real-time PCR. Surface markers CD86 and CD206 expressions on alveolar macrophages were also evaluated by flow cytometry. RESULTS: We found that CXCL10 production was significantly elevated on MRC-5 fibroblasts under TNFα- or IL-1ß treatment. In addition, we revealed that TNFα and IL-1ß initiated phosphorylation of STAT3, FAK, GSK3αß and PKCδ signaling cascade, leading to the elevation of CXCL10 expression. Moreover, conditioned medium collected from TNFα-activated MRC-5 fibroblasts increased iNOS and CD86 expressions and decreased arginase I and CD206 expressions on MH-S alveolar macrophages, and neutralization of CXCL10 abolished these observed phenomena. CONCLUSION: These results suggest that CXCL10 is crucial in activated fibroblasts-promoted M1 phenotype polarization of alveolar macrophages. In this regard, targeting fibroblasts-released CXCL10 may be promising as anti-inflammatory therapy against acute lung injury.

Monospecific antibody targeting of CDH11 inhibits epithelial-to-mesenchymal transition and represses cancer stem cell-like phenotype by up-regulating miR-335 in metastatic breast cancer, in vitro and in vivo.

BACKGROUND: Metastasis is a leading cause of breast cancer mortality. The induction of epithelial-to-mesenchymal transition (EMT) and complex oncogenic signaling is a vital step in the evolution of highly metastatic and therapeutically-intractable breast cancer; necessitating novel target discovery or development of therapeutics that target metastatic breast cells (MBCs). METHODS: To achieve this, this study employs a combination of in silico bioinformatics analyses, protein and transcript analyses, drug sensitivity assays, functional assays and animal studies. RESULTS: The present study identified CDH11 as an inductor and/or facilitator of metastatic signaling, and biomarker of poor prognosis in MBCs. Furthermore, we showed that in the presence of CDH11-rich cancer-associated fibroblasts (CAFs), MCF7 and MDA-MB-231 MBC cell lines acquired enhanced metastatic phenotype with increased CDH11, ß-catenin, vimentin, and fibronectin (FN) expression. We also demonstrated, for the first time to the best of our knowledge that exposure to anti-CDH11 antibody suppresses metastasis, reduces CDH11, FN and ß-catenin expression, and abrogate the cancer stem cell (CSC)-like traits of MBC cells. Interestingly, ectopic expression of miR-335 suppressed CDH11, ß-catenin and vimentin expression, in concert with attenuated metastatic and CSC potentials of the MBC cells; conversely, inhibition of miR-335 resulted in increased metastatic potential. Finally, corroborating the in silica and in vitro findings, in vivo assays showed that the administration of anti-CDH11 antibody or miR-335 mimic suppressed tumorigenesis and inhibited cancer metastasis. CONCLUSIONS: These findings validate our hypotheses that miR-335 mediates anti-CDH11 antibody therapy response and that an enhanced miR-335/CDH11 ratio elicits marked suppression of the MBC CSC-like and metastatic phenotypes, thus revealing a therapeutically-exploitable inverse correlation between CDH11-enhanced CSC-like and metastatic phenotype and miR-335 expression in MBCs. Thus, we highlight the therapeutic promise of humanized anti-CDH11 antibodies or miR-335-mimic, making a case for their clinical application as efficacious therapeutic option in patients with MBC.

Anti-inflammatory Property of Imperatorin on Alveolar Macrophages and Inflammatory Lung Injury.

Imperatorin is one of the furanocoumarin derivatives and exists in many medicinal herbs with anticancer, antiviral, antibacterial, and antihypertensive activities. In this study, we examined the anti-inflammatory effects of imperatorin on inflammation-associated lung diseases. Imperatorin reduced iNOS and COX-2 expression and also IL-6 and TNFα production enhanced by zymosan. Imperatorin also inhibited the signaling pathways of JAK/STAT and NF-κB. Moreover, in vivo study also revealed that zymosan-induced immune cell infiltration, pulmonary fibrosis, and edema were relieved by imperatorin in mice. We found that imperatorin exerts anti-inflammatory effects that are associated with amelioration of lung inflammation, edema, and rapid fibrosis. Studies on alveolar macrophages also reveal that imperatorin reduced the production of pro-inflammatory mediators and cytokines and inhibited pro-inflammatory JAK1/STAT3 and NF-κB signaling pathways. These results indicate that imperatorin may be a potential anti-inflammatory agent for inflammatory-associated lung diseases.

Upregulated SCUBE2 expression in breast cancer stem cells enhances triple negative breast cancer aggression through modulation of notch signaling and epithelial-to-mesenchymal transition.

BACKGROUND: Metastatic and/or recurrent breast carcinomas are leading causes of cancer-related death worldwide. Breast cancer stem cells (BCSCs) have been implicated in cancer metastases and progression, thus, the need for the discovery and development of effective BCSCs-specific therapies against metastatic and triple negative breast cancer (TNBC). The expression of SCUBE2, originally identified in vascular endothelia, then in several non-endothelial cell types, is downregulated in invasive breast carcinomas. However, the role of SCUBE2 in BCSCs remains unknown. This present study investigated the probable involvements of SCUBE2 in BCSCs and TNBC metastasis. METHODS: The mRNA expression of SCUBE2, stemness and EMT markers in MDA-MB-231 and Hs578T tumorspheres or adherent cells were evaluated by qRT-PCR and microarray analyses. Using gene overexpression, in vitro migration and invasion assays, as well as in vivo bioluminescence imaging, we evaluated the role of SCUBE2 in MDA-MB-231 or Hs578T BCSCs. Western blot and cytotoxicity assays helped identify and validate SCUBE2 molecular target(s) and inhibitor(s). RESULTS: Concurrently increased SCUBE2 expression and cell motility were observed in TNBC tumorspheres compared to the parental adherent cells. SCUBE2 overexpression augmented BCSCs motility in vitro, and enhanced TNBC metastasis in vivo. While SCUBE2 overexpression activated Notch signaling its downregulation suppressed Notch signal effectors NICD, Jagged 1, HEY1, and HES1. CONCLUSIONS: We demonstrate that SCUBE2 expression is upregulated in BCSCs, promote EMT and enhance TNBC metastasis by activating Notch signaling. This reveals a potential druggable molecular target and an effective therapeutic strategy against metastatic and aggressive TNBC.

Quantification of HBV core antibodies may help predict HBV reactivation in patients with lymphoma and resolved HBV infection.

BACKGROUND & AIMS: Absence or low anti-HBV surface antibody (anti-HBs) is associated with an increased risk of HBV reactivation in patients with lymphoma and resolved HBV infection receiving rituximab-containing chemotherapy. Quantification of anti-HBV core antibody (anti-HBc) is a new marker associated with the natural history and treatment response of chronic HBV infection. This study investigated whether baseline anti-HBc and anti-HBs levels may better predict HBV reactivation. METHODS: We prospectively measured the HBV DNA levels of patients with lymphoma and resolved HBV infection receiving rituximab-cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone-based chemotherapy and started an antiviral therapy upon HBV reactivation, defined as a greater than 10-fold increase in HBV DNA compared with previous nadir levels. Anti-HBs and anti-HBc were quantified by a double-sandwich assay. Receiver-operating-characteristic-curve analysis was used to determine the optimal baseline anti-HBc/anti-HBs levels for predicting HBV reactivation. RESULTS: HBV reactivation occurred in 24 of the 197 patients enrolled, with an incidence of 11.6/100 person-years. For the 192 patients with enough serum samples for analysis, low anti-HBs (<56.48 mIU/ml) and high anti-HBc (≥6.41 IU/ml) at baseline were significantly associated with high risk of HBV reactivation (hazard ratio [HR] 8.48 and 4.52, respectively; p <0.01). The multivariate analysis indicated that (1) patients with both high anti-HBc and low anti-HBs at baseline (36 of 192 patients) had an HR of 17.29 for HBV reactivation (95% CI 3.92-76.30; p <0.001), and (2) HBV reactivation may be associated with inferior overall survival (HR 2.41; 95% CI 1.15-5.05; p = 0.02). CONCLUSIONS: Baseline anti-HBc/anti-HBs levels may predict HBV reactivation in these patients with lymphoma and help optimize prophylactic antiviral therapy for high-risk patients. LAY SUMMARY: In this study, we identified a subgroup of patients with lymphoma and resolved hepatitis B virus infection that had a high risk of hepatitis B virus reactivation after receiving rituximab-containing chemotherapy. These findings will help optimize a preventive strategy, especially in hepatitis B virus endemic regions with limited healthcare resources. Clinical trial number: NCT 00931229.

The treatment outcome of multiple myeloma patients ineligible for hematopoietic transplantation--a single institutional experience in Taiwan.

Multiple myeloma (MM) is characterized by the neoplastic proliferation of monoclonal plasma cells in the bone marrow and results in complications. In Taiwan, melphalan and several novel agents are used to treat myeloma patients who are not candidate for hematopoietic stem cell transplant (HSCT). This retrospective study aimed to evaluate the characteristics, treatment outcome, and prognostic factors of MM patients who were ineligible for HSCT at our institution from October 2000 until November 2012. A total of 101 MM patients were reviewed. The median age was 71.0 years, and median overall survival (OS) was 22.0 months. Most of patients were diagnosed as IgG-type myeloma (55.4 %). The initial presentations included anemia (89.1 %), skeletal events (49.5 %), severe renal insufficiency (30.7 %), and hypercalcemia (28.7 %). With regard to the frontline therapy, thalidomide/steroid was the most common. Infection was the leading cause of death and adverse effects. Treatment with bortezomib, almost in the second- or third-line setting, was associated with longer median OS (35.5 months) and the median time to progression (TTP) (6.0 months). Bortezomib treatment, chemotherapy, International Staging System (ISS) stage I, and better performance status significantly correlated with survival benefit. In the bortezomib-treated subgroup, better treatment response caused excellent median OS (67.7 months) and also significantly delayed TTP. Therefore, this current analysis concluded a median OS of 22 months in myeloma patients ineligible for HSCT at our institution during the past 10 years. The use of bortezomib with better treatment response also achieved significantly better median OS and TTP.

Effects of paeonol on anti-neuroinflammatory responses in microglial cells.

Increasing studies suggest that inflammatory processes in the central nervous system mediated by microglial activation plays an important role in numerous neurodegenerative diseases. Development of planning for microglial suppression is considered a key strategy in the search for neuroprotection. Paeonol is a major phenolic component of Moutan Cortex, widely used as a nutrient supplement in Chinese medicine. In this study, we investigated the effects of paeonol on microglial cells stimulated by inflammagens. Paeonol significantly inhibited the release of nitric oxide (NO) and the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Treatment with paeonol also reduced reactive oxygen species (ROS) production and inhibited an ATP-induced increased cell migratory activity. Furthermore, the inhibitory effects of neuroinflammation by paeonol were found to be regulated by phosphorylated adenosine monophosphate-activated protein kinase-α (AMPK-α) and glycogen synthase kinase 3 α/ß (GSK 3α/ß). Treatment with AMPK or GSK3 inhibitors reverse the inhibitory effect of neuroinflammation by paeonol in microglial cells. Furthermore, paeonol treatment also showed significant improvement in the rotarod performance and microglial activation in the mouse model as well. The present study is the first to report a novel inhibitory role of paeonol on neuroinflammation, and presents a new candidate agent for the development of therapies for inflammation-related neurodegenerative diseases.

The correlation between a chronic inflammatory marker Tartrate-resistant acid phosphatase 5a with cancer cachexia.

PURPOSE: The mechanism of cancer cachexia remains unclear and inflammatory cytokines may play a role in its development. Interleukin-6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor-α (TNFα) are known to be associated with cancer cachexia. Tartrate-resistant acid phosphatase 5a (TRACP5a) is proposed to be related to chronic inflammation. In this study we hypothesize that TRACP5a is a chronic inflammatory marker that is correlated with cancer cachexia. METHODS: Fifty-five cancer patients with and without cancer cachexia were enrolled from January 2009 to December 2012. Body mass index (BMI) was measured and serum total cholesterol, triglycerides and albumin were examined to evaluate the nutritional status. IL-6, CRP and TRACP5a protein activity were evaluated. RESULTS: Inflammatory markers including IL-6, and CRP were significantly elevated in patients with cancer cachexia (p=0.0075 and 0.0021, respectively). Patients with cachexia also had higher CRP/albumin ratio (p=0.0265). TRACP5a activity, TRACP5a protein and their combinations with albumin were increased in the cancer cachexia groups but without significant difference. There were good correlations between IL-6, CRP, and BMI. Patients with higher TRACP5a activity had shorter survival (p=0.004). CONCLUSION: TRACP5a may be a promising chronic inflammatory marker and may play a prognostic role in cancer cachexia. Further large-scale prospective studies are warranted to confirm its role in the cancer cachexia process.

MicroRNA-224 inhibits progression of human prostate cancer by downregulating TRIB1.

Our previous microarray data showed that microRNA-224 (miR-224) was downregulated in human prostate cancer (PCa) tissues compared with adjacent benign tissues. However, the underlying mechanisms by which miR-224 is involved in PCa remain unclear. In this study, we identified TRIB1 as a target gene of miR-224. Forced expression of miR-224 suppressed PCa cell proliferation, invasion and migration, and promoted cell apoptosis by downregulating TRIB1. Moreover, the expression level of miR-224 in PCa tissues was negatively correlated with that of TRIB1. miR-224 downregulation was frequently found in PCa tissues with metastasis, higher PSA level and clinical stage, whereas TRIB1 upregulation was significantly associated with metastasis. Both miR-224 downregulation and TRIB1 upregulation were significantly associated with poor biochemical recurrence-free survival of patients with PCa. In conclusion, these findings reveal that the aberrant expression of miR-224 and TRIB1 may promote PCa progression and have potentials to serve as novel biomarkers for PCa prognosis.

MicroRNA-30c serves as an independent biochemical recurrence predictor and potential tumor suppressor for prostate cancer.

MicroRNA-30c (miR-30c) acts as a tumor suppressor or a tumor promoter in various human malignancies. However, the involvement of miR-30c in prostate cancer (PCa) is still unclear. The aim of this study was to investigate the molecular function and the clinical significance of miR-30c in PCa. Expression levels of miR-30c in PCa tissues and cells were detected by quantitative real-time-PCR (qRT-PCR). Additionally, the associations of miR-30c expression with clinicopathological features and prognosis in PCa patients were analyzed. The potential role of miR-30c in tumorigenesis of PCa cells was further evaluated by in vitro cell assays. MiR-30c was significantly down-regulated in PCa tissues and cells compared with the corresponding controls (P<0.05). In addition, the downregulation of miR-30c in PCa tissues was significantly associated with higher Gleason score (P=0.009), advanced pathological stage (P=0.016) and biochemical recurrence (P=0.034). Moreover, Kaplan-Meier survival analysis showed that the reduced expression of miR-30c was correlated with shorter biochemical recurrence-free survival (P=0.023). The multivariate analysis also identified miR-30c as an independent prognostic predictor for biochemical recurrence-free survival in patients with PCa. Furthermore, the enforced expression of miR-30c suppressed proliferation, migration and invasion of PCa cells in vitro. Our data indicated the involvement of miR-30c in PCa progression and suggested its potential role as an independent predictor of biochemical recurrence in PCa. On cellular level, miR-30c may function as a tumor suppressor for PCa cells by inhibiting tumor cell proliferation, migration and invasion.