Tat-NTS peptide protects neurons against cerebral ischemia-reperfusion injury via ANXA1 SUMOylation in microglia.

Rationale: Recent studies indicate that microglial activation and the resulting inflammatory response could be potential targets of adjuvant therapy for ischemic stroke. Many studies have emphasized a well-established function of Annexin-A1 (ANXA1) in the immune system, including the regulation of microglial activation. Nevertheless, few therapeutic interventions targeting ANXA1 in microglia for ischemic stroke have been conducted. In the present study, Tat-NTS, a small peptide developed to prevent ANXA1 from entering the nucleus, was utilized. We discovered the underlying mechanism that Tat-NTS peptide targets microglial ANXA1 to protect against ischemic brain injury. Methods: Preclinical studies of ischemic stroke were performed using an oxygen-glucose deprivation and reperfusion (OGD/R) cell model in vitro and the middle cerebral artery occlusion (MCAO) animal model of ischemic stroke in vivo. Confocal imaging and 3D reconstruction analyses for detecting the protein expression and subcellular localization of microglia in vivo. Co-immunoprecipitation (Co-IP), immunoblotting, ELISA, quantitative real-time PCR (qRT-PCR), Luciferase reporter assay for determining the precise molecular mechanism. Measurement on the cytotoxicity of Tat-NTS peptide for microglia was assessed by CCK-8 and LDH assay. TUNEL staining was used to detect the microglia conditioned medium-mediated neuronal apoptosis. Adeno-associated viruses (AAVs) were injected into the cerebral cortex, striatum and hippocampal CA1 region of adult male Cx3cr1-Cre mice, to further verify the neurofunctional outcome and mechanism of Tat-NTS peptide by TTC staining, the modified Neurological Severity Score (mNSS) test, the open field test (OFT), the novel object recognition task (NORT), the Morris water maze (MWM) test, the long-term potentiation (LTP) and the Transmission electron microscopy (TEM). Results: It was observed that administration of Tat-NTS led to a shift of subcellular localization of ANXA1 in microglia from the nucleus to the cytoplasm in response to ischemic injury. Notably, this shift was accompanied by an increase in ANXA1 SUMOylation in microglia and a transformation of microglia towards an anti-inflammatory phenotype. We confirmed that Tat-NTS-induced ANXA1 SUMOylation in microglia mediated IKKα degradation via NBR1-dependent selective autophagy, then blocking the activation of the NF-κB pathway. As a result, the expression and release of the pro-inflammatory factors IL-1ß and TNF-α were reduced in both in vitro and in vivo experiments. Furthermore, we found that Tat-NTS peptide's protective effect on microglia relieved ischemic neuron apoptosis. Finally, we demonstrated that Tat-NTS peptide administration, through induction of ANXA1 SUMOylation in microglia, reduced infarct volume, improved neurological function and facilitated behavioral recovery in MCAO mice. Conclusions: Our study provides evidence for a novel mechanism of Tat-NTS peptide in regulating microglial ANXA1 function and its substantial neuroprotective effect on neurons with ischemic injuries. These findings suggest that Tat-NTS peptides have a high potential for clinical application and may be a promising therapeutic candidate for treating cerebral ischemia.

Crucial roles of sorbitol metabolism and energy status in the chilling tolerance of yellow peach.

In this study, we compared sorbitol metabolism, energy metabolism, and CI development in yellow peach fruit at 1 °C (less susceptible to CI) and 8 °C (more susceptible to CI) storage to elucidate potential connections between them. The results indicated that storage at 1 °C effectively maintained the textural quality of yellow peach fruit and delayed the onset of CI by 12 days compared to 8 °C. This positive effect might be attributable to 1 °C storage maintaining higher sorbitol content throughout the storage duration, thus sustaining the higher adenosine triphosphate (ATP) level and energy charge. The regulation of sorbitol accumulation by 1 °C storage was closely linked to the metabolic activity of sorbitol, which stimulated sorbitol synthesis by enhancing sorbitol-6-phosphate dehydrogenase (S6PDH) activity after 12 days while suppressing sorbitol degradation via decreased sorbitol oxidase (SOX) and NAD+-sorbitol dehydrogenase (NAD+-SDH) activities before 24 days. In addition, the notable up-regulation in the NAD+-SDH activity in the late storage period promoted the conversion of sorbitol to fructose and glucose under 1 °C storage, thereby providing ample energy substrate for ATP generation. Moreover, sorbitol acts as a vital signaling molecule, and substantially up-regulated expressions of sorbitol transporters genes (PpeSOT3, PpeSOT5, and PpeSOT7) were observed in fruit stored at 1 °C, which might promote sorbitol transport and improve cold tolerance in peach fruit. Taken together, these findings suggested that 1 °C storage delayed CI by enhancing sorbitol metabolism and transporter activity, promoting sorbitol accumulation, and finally elevating the energy status in yellow peach fruit.

Chronic Splenic Melioidosis in a Patient with Fever of Unknown Origin Diagnosed by Metagenomics Next-Generation Sequencing: An Emerging Cause and Literature Review.

Introduction: Human melioidosis is an emerging infectious disease in tropical areas of China, and chronic melioidosis can be a rare cause of fever of unknown origin (FUO). Timely diagnosis may improve the prognosis of melioidosis. Case Presentation: We report a case of melioidosis with splenic abscesses caused by Burkholderia pseudomallei in a 57-year-old man, who presented with FUO. Positron emission tomography/computed tomography (PET/CT) revealed multiple hypermetabolic lesions in the spleen. The spleen biopsy was conducted and metagenomics next-generation sequencing (mNGS) of the spleen specimen identified the presence of B. pseudomallei, confirming the diagnosis of melioidosis. Antimicrobial treatment was initiated with intravenous meropenem, followed by oral faropenem. During the follow-up, the patient was in good condition except having a low-grade fever occasionally. A splenectomy was performed, and subsequent culture and mNGS of the spleen pus were both positive for B. pseudomallei. Histopathological characteristics of chronic splenic melioidosis were noted. Conclusion: Melioidosis is a serious endemic disease, and it is critical to raise awareness about this disease.

Early prediction of the failure of methotrexate treatment by Days 1-4 serum ß-hCG change and 48-hour pre-treatment increment inß-hCG.

To determine whether the change of serum ß-hCG levels between Days 1 and 4 and 48-h pre-treatment increment in ß-hCG can early predict treatment failure of single-dose methotrexate (MTX) in tubal ectopic pregnancies (EP), a retrospective study of 1120 ectopic pregnancies treated with a regimen of a single dose of MTX was conducted in the Department of Obstetrics and Gynaecology, Shanghai First Maternity and Infant Hospital. Treatment failure was defined by an obligation to proceed to surgery or have an additional doses of methotrexate.1350 files were reviewed, with 1120 included for final analysis .64% (722/1120) had ß-hCG levels increase on Day 4 after MTX treatment, while 36% (398/1120) had ß-hCG levels fall. In this cohort, the treatment failure rate with a single dose of MTX was 15.7% (113/722), and the significant features in the logistic regression model of diagnosing the results of MTX treatment were the ratio of Day 1 to Day 48-h pre-treatment ß-hCG values (Odds Ratio (OR) 1.221, 95% Confidence interval (CI) 1.159-1.294), the ratio of Day 4 to Day 1 ß-hCG serum values (OR 1.098, 95% CI 1.014-1.226), and ß-hCG values on Day 1 (OR 1.070, 95% CI 1.016-1.156). The decision tree model was developed by using increment of ß-hCG in 48 h before treatment > =19%, the ratio of Day 4 to Day 1 ß-hCG serum values > =36%, and ß-hCG values on Day 1> =728 mIU/L to predict the failure of MTX treatment. The diagnostic accuracy, sensitivity and specificity in the test group were 97.22%, 100%, and 96.9%, respectively.IMPACT STATEMENTWhat is already known on this subject? A decrease of 15% ß-hCG levels between Days 4 and 7 is a common protocol for predicting the success of a single-dose methotrexate therapy of an ectopic pregnancy.What do the results of this study add? This clinical study offers the cut-off values points for prediction of single-dose methotrexate treatment failure.What are the implications of these findings for clinical practice and/or further research? We identified the importance of ß-hCG increase between Days 1 and 4 and ß-hCG increment in 48 h pre-treatment for predicting the failure of single-dose methotrexate therapy. It can be used to aid the clinician to optimise the selection of the most appropriate treatment methods during a follow-up evaluation after MTX treatment.

Evaluation of pretreatment and early treatment changes in serum ß-hCG with methotrexate.

BACKGROUND: Serum beta-human chorionic gonadotropin (ß-hCG) is an important biomarker for the detection of ectopic pregnancies (EPs). The ß-hCG levels between days 1 and 4 after methotrexate (MTX) treatment as an indicator of the success of the MTX in EP have been the focus of research. OBJECTIVES: To determine whether the change in the ß-hCG levels at day 1 and 4 and pretreatment at 48-hour increments can predict early treatment failure of single-dose MTX in EP. MATERIAL AND METHODS: This was a retrospective study of 1120 EPs treated with a single dose of MTX. Treatment failure was defined as an obligation to proceed to surgery or the need for additional doses of MTX. RESULTS: A total 722 out of 1120 EPs had an increase in ß-hCG on day 4 after MTX treatment. The logistic regression analysis indicated that 3 dependents were significantly associated with treatment failure: 1) a pretreatment 48-hour increase in ß-hCG (odds ratio (OR): 1.249, 95% confidence interval (95% CI): 1.008-2.049, p < 0.001); 2) a change in ß-hCG between day 1 and 4 (OR: 1.384, 95% CI: 1.097-2.198, p < 0.001); and 3) a history of EP (OR: 1.208, 95% CI: 1.041- 2.011, p < 0.001). The optimal cutoff point for the prediction of treatment failure was an increase of more than 19% in the 48 h before the treatment, and an increase of more than 36% between day 1 and day 4 in ß-hCG concentrations. Patients with an increase in ß-hCG levels of less than 36% on day 4 experienced MTX treatment failure in 4.2% (n = 25), compared to 74.5% (n = 88) of the patients with an increase above 36%. CONCLUSIONS: A serum ß-hCG increase of more than 36% on day 4 after the administration of MTX alongside a more than 19% increase in ß-hCG concentration 48 h before the MTX treatment may predict the early failure of medical treatment for an EP.

Effects of compound training on motricity among basketball players / Efeitos de treinamento composto sobre a motricidade entre jogadores de basquete / Efectos del entrenamiento compuesto en la motricidad de jugadores de baloncesto

ABSTRACT Introduction: In kinematics, one can measure the strength of movement ability by the time it takes to move a certain distance and the speed of movement of a person by the speed of displacement. Objective: To study the effect of compound training on the mobility of basketball players. Methods: A comparative experimental study was carried out on the sensitivity of basketball players, lasting 8 weeks. There were 30 basketball-playing volunteers randomly divided into two groups, while the control group performed routine activities. The control group implemented a training protocol composed of a ladder and ropes allied to conventional training. Results: After the experiment, the technical level of motricity in the control group and the experimental group showed differences over the result before the experiment (P<0.05), and the experimental group showed a very significant difference (P<0.01), improving their performance after the experiment. There are significant differences in the effects of different sensitivity training methods, the experimental group using rope ladder training methods greatly improved their foot agility and motor skill. Conclusion: Composite training involving a ladder and rope has a superior effect on the development of motor skill, ability, and foot agility in basketball players. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução: Na cinemática, pode-se medir a força de capacidade de movimentação pelo tempo que se leva para mover a uma certa distância e a velocidade de movimentação de uma pessoa pela velocidade de deslocamento. Objetivo: Estudar o efeito do treinamento composto sobre a mobilidade dos jogadores de basquetebol. Métodos: Efetuou-se um estudo experimental comparativo sobre a sensibilidade de jogadores de basquetebol com duração de 8 semanas. Foram 30 voluntários praticantes de basquete divididos aleatoriamente em dois grupos, enquanto o controle realizava as atividades rotineiras, ao grupo controle foi implementado um protocolo de treinamento composto por escada e cordas aliado ao treino convencional. Resultados: Após o experimento, o nível técnico da motricidade no grupo controle e no grupo experimental apresentou diferenças sobre o resultado prévio ao experimento (P<0,05), o grupo experimental mostrou uma diferença muito significativa (P<0,01), melhorando sua performance após o experimento. Há diferenças significativas nos efeitos dos diferentes métodos de treinamento de sensibilidade, o grupo experimental usando métodos de treinamento com escada de corda melhorou muito a agilidade dos pés e a sua habilidade motora. Conclusão: O treinamento composto envolvendo escada e corda tem um efeito superior no desenvolvimento da motricidade, habilidade e agilidade nos pés dos jogadores de basquete. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción: En cinemática, se puede medir la fuerza de la capacidad de movimiento por el tiempo que se tarda en desplazarse una determinada distancia y la velocidad de movimiento de una persona por la velocidad de desplazamiento. Objetivo: Estudiar el efecto del entrenamiento compuesto sobre la movilidad de los jugadores de baloncesto. Métodos: Se realizó un estudio experimental comparativo sobre la sensibilidad de los jugadores de baloncesto con una duración de 8 semanas. Fueron 30 voluntarios jugadores de baloncesto divididos aleatoriamente en dos grupos, mientras que el de control realizó actividades rutinarias, al grupo de control se le aplicó un protocolo de entrenamiento compuesto por escalera y cuerdas aliadas al entrenamiento convencional. Resultados: Después del experimento, el nivel técnico de motricidad en el grupo de control y en el grupo experimental mostró diferencias respecto al resultado anterior al experimento (P<0,05), el grupo experimental mostró una diferencia muy significativa (P<0,01), mejorando su rendimiento después del experimento. Existen diferencias significativas en los efectos de los distintos métodos de entrenamiento de la sensibilidad, el grupo experimental que utilizó métodos de entrenamiento de la escalera de cuerda mejoró enormemente su agilidad del pie y su habilidad motriz. Conclusión: El entrenamiento compuesto con escalera y cuerda tiene un efecto superior en el desarrollo de la motricidad, la habilidad y la agilidad del pie en los jugadores de baloncesto. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

Use of period analysis to timely assess 5-year relative survival for breast cancer patients from Taizhou, Eastern China.

Objectives: While timely assessment of long-term survival for patients with breast cancer is essential for evaluation on early detection and screening programs, those data are extremely scant in China. We aimed to derive most up-to-date survival estimates and to predict future survival using the cancer registry data from Taizhou city, Eastern China. Methods: Patients diagnosed with breast cancer during 2004-2018 from four cancer registries with high-quality data from Taizhou, Eastern China were included. Period analysis was used to calculate 5-year relative survival (RS) for the overall population and according to the stratification factors sex, age at diagnosis and geographic region. We further predict the upcoming 5-year RS during 2019-2023, using continuous data from three 5-year periods (2004-2008, 2009-2013 and 2014-2018) and a model-based period approach. Results: Overall 6159 patients diagnosed with breast cancer during 2004-2018 were enrolled. The 5-year RS for breast cancer in 2014-2018 reached 88.8%, while women were higher compared to men (90.5% versus 83.7%) and urban areas were higher compared to rural areas (91.9% versus 86.7%). Additionally, we found a clear gradient by age at diagnosis, ranging from 94.8% for age<45 years to 83.3% for age>74 years. Projected overall 5-year RS for the upcoming 2019-2023 could reach 91.5% (84.8% for men and 93.5% for women). Conclusions: We provided, for first time in China, using period analysis, most up-to-date 5-year RS (88.8%) for patients with breast cancer from Taizhou, Eastern China. We also demonstrate the 5-year RS has improved greatly over last 15 years, which has important implications for timely evaluation of early detection and screening programs.

Multiple Strikes Achieve Remarkable Tumor-Inhibition Efficiency via Multi-mechanism Combination.

Breast cancer treatment has been challenging all the time because cancer cells have multiple signaling pathways; so, breast cancer still remains a threat to the lives and health of many patients. While common single drug therapies inhibit only one pathway, the combination of multiple mechanisms offers the potential to simultaneously suppress multiple targets and pathways to kill cancer cells more effectively. It is reported that autophagy caused by autophagy inducers and apoptosis caused by some chemotherapeutic drugs can promote ferroptosis to some extent; herein, we combined these three pathways and constructed a multifunctional dual-responsive release nanosystem of Rap@mFe3O4-DOX-HA that achieved the ferroptosis-autophagy-apoptosis synergistic effect for cancer treatment. Mesoporous Fe3O4 (mFe3O4) was set as the carrier and can also release Fe ions for ferroptosis, the autophagy inducer rapamycin (Rap) was wrapped in the carrier to trigger autophagy, and the chemotherapeutic drug doxorubicin (DOX) was used as the apoptosis inducer. At the tumor site, the prepared Rap@mFe3O4-DOX-HA nanoparticles split and released DOX/Rap in response to H+/GSH. From in vivo and in vitro studies, it was found that Rap@mFe3O4-DOX-HA nanoparticles effectively inhibited the migration of 4T1 cells, furthermore, they struck cancer cells through multiple pathways and greatly improved the anti-tumor effect. Therefore, the strategy of multi-mechanism combination achieved a therapeutic effect of 1 + 1 > 2.

Controlled atmosphere storage alleviates internal browning in flat peach fruit by regulating energy and sugar metabolisms.

Flat peach fruit are cold-sensitive and vulnerable to chilling injury (CI), particularly internal browning (IB) during cold storage, which limits the consumer acceptance and market value of the fruit. Controlled atmosphere (CA) has been used to alleviate IB in fruit. However, the mechanisms of CA on IB in peach remains unknown. This study investigated the effects of CA (3-3.5% Oxygen, 3-3.5% Carbon dioxide, and 93-94% nitrogen) treatment on IB development, sugar metabolism, and energy metabolism in cold-stored (1 ± 0.5 °C) peach. The CA treatment effectively inhibited the development of IB and markedly inhibited the reduction of sugar contents and energy charge. The protein expression of the V-type proton ATPase subunit was significantly inhibited by the CA treatment, accompanied by higher adenosine triphosphate (ATP) content, and energy charge than the control fruit. Notably, the expressions of the pyruvate kinase family of proteins, pyruvate decarboxylases, and sucrose synthase were induced by CA treatment that had complex protein interactions with the ATPase and the energy metabolism pathway. These results indicated that CA treatment enhanced the chilling tolerance attributed to maintaining higher levels of energy status and sugar contents by regulating the expression of key proteins involved in energy metabolism during cold storage and shelf life. Taken together, our study can provide theoretical support for the research and development of fresh-keeping and cold-chain logistics technology.

In ovo exposure to cadmium causes right ventricle hyperplasia due to cell proliferation of cardiomyocytes.

Cadmium (Cd) is an environmental and occupational pollutant inhaled through smoking or ingested through contaminated food. Yet, little is known about its teratogenicity. In this study, the effects of Cd on embryonic heart development were investigated by exposing Cd to chicken embryos in ovo. Fertilized eggs were treated with Cd at Hamburger-Hamilton Stage (HH)16 and collected at HH35 for histological evaluation of the heart. Cd treatment of 100 µM at HH16 increased embryo mortality at HH35. Specific structural heart defects were not observed in any Cd treatment group, but the relative myocardial tissue area of the right ventricle was increased with Cd exposure. When the HH31 hearts were stained with p-H3S10, the right ventricle had an increased number of cells undergoing proliferation, which was associated with upregulation of Cdk1, Cdk6, CycA, CycD, and CycE detected by qPCR. These findings suggest that Cd exposure from HH16 upregulates proliferation genes and drives overgrowth of the right ventricle. These results grant further attention to Cd teratogenicity on embryonic heart development. Such morphological changes in the heart can potentially affect cardiac function and increase the risk for future cardiovascular diseases, such as heart failure.

DECR1 directly activates HSL to promote lipolysis in cervical cancer cells.

Fatty acids have a high turnover rate in cancer cells to supply energy for tumor growth and proliferation. Lipolysis is particularly important for the regulation of fatty acid homeostasis and in the maintenance of cancer cells. In the current study, we explored how 2,4-Dienoyl-CoA reductase (DECR1), a short-chain dehydrogenase/reductase associated with mitochondrial and cytoplasmic compartments, promotes cancer cell growth. We report that DECR1 overexpression significantly reduced the triglyceride (TAG) content in HeLa cells; conversely, DECR1 silencing increased intracellular TAG content. Subsequently, our experiments demonstrate that DECR1 promotes lipolysis via effects on hormone sensitive lipase (HSL). The direct interaction of DECR1 with HSL increases HSL phosphorylation and activity, facilitating the translocation of HSL to lipid droplets. The ensuing enhancement of lipolysis thus increases the release of free fatty acids. Downstream effects include the promotion of cervical cancer cell migration and growth, associated with the enhanced levels of p62 protein. In summary, high levels of DECR1 serves to enhance lipolysis and the release of fatty acid energy stores to support cervical cancer cell growth.

A comparative UPLC-Q-TOF/MS-based metabolomics approach for distinguishing peach (Prunus persica (L.) Batsch) fruit cultivars with varying antioxidant activity.

Peaches (Prunus persica (L.) Batsch) are nutritionally and economically important and they are one of the most popular fruits consumed worldwide. Understanding metabolite-caused bioactivity differences among cultivars is essential for designing a peach with enhanced nutritional traits. In this study, we report an untargeted UPLC-Q-TOF/MS-based metabolomics approach for comprehensively discriminating between peaches with different antioxidant activities. Mature fruit from 40 peach cultivars were distinguished using principal component analysis and orthogonal partial least squares discrimination analysis. Seventeen differential metabolites were tentatively identified between peach cultivars with high and low antioxidant potency composite indices, and eight metabolites, including procyanidin C1, procyanidin trimer isomer 1, procyanidin trimer isomer 2, procyanidin B1, procyanidin B2, procyanidin B3, prunus inhibitor b, and phloridzin, were identified as marker compounds responsible for the discrimination of the cultivars base on potential antioxidant activity. Our study highlights the essence and predictive power of metabolomics for detecting small differences and for identifying potential marker metabolites based on their levels and composition in plants exhibiting varying bioactivities. Overall, the variations in the metabolites in peach pulp reflected the diversity in the peach germplasm, and these eight compounds are good candidate markers for future genetic breeding of peach fruit with enhanced antioxidant activity.

PFKFB3, a key glucose metabolic enzyme regulated by pathogen recognition receptor TLR4 in liver cells.

AIMS: Toll-like receptor 4 (TLR4) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB3) are involved in the progress of inflammation and glucose metabolism. Here, we aimed to assess the relationship between TLR4 and PFKFB3 in liver cells. METHODS: We detected the expression of TLR4 and PFKFB3 in both normal liver cell lines and liver cancer cell lines. Then, a small interfering RNA (siRNA) was used to knock down the expression of TLR4 and analyze the expression of PFKFB3 in the HL-7702 cell line. Further, following stimulation of the HL-7702 cell line with free fatty acids (FFA) or insulin, we observed the expression of TLR4 and PFKFB3, respectively. RESULTS: Knocking down siRNA-mediated TLR4 significantly reduced PFKFB3 expression at the mRNA and protein level. Furthermore, activating TLR4 with FFA dramatically increased PFKFB3 expression. Insulin increased the expression of TLR4 and PFKFB3, which could be inhibited by TLR siRNA. CONCLUSION: These findings suggest that PFKFB3 expression is regulated via the TLR4-PFKFB3 axis, which might be a bridge linking fat and glucose metabolism.

Mild Acid-Responsive "Nanoenzyme Capsule" Remodeling of the Tumor Microenvironment to Increase Tumor Penetration.

Dense extracellular matrix (ECM) severely impedes the spread of drugs in solid tumors and induces hypoxia, reducing chemotherapy efficiency. Different proteolytic enzymes, such as collagenase (Col) or bromelain, can directly attach to the surface of nanoparticles and improve their diffusion, but the method of ligation may also impair the enzymatic activity due to conformational changes or blockage of the active site. Herein, a "nanoenzyme capsule" was constructed by combining collagenase nanocapsules (Col-nc) with heavy-chain ferritin (HFn) nanocages encapsulating the chemotherapy drug doxorubicin (DOX) to enhance tumor penetration of the nanoparticles by hydrolyzing collagen from the ECM. Col-nc could protect the activity of the enzyme before reaching the site of action while being degraded under mildly acidic conditions in tumors, and the released proteolytic enzyme could digest collagen. In addition, HFn as a carrier could effectively load DOX and had a self-targeting ability, enabling the nanoparticles to internalize into cancer cells more effectively. From in vivo and in vitro studies, we found that collagen was effectively degraded by Col-nc/HFn(DOX) to increase the accumulation and penetration of nanoparticles in the solid tumor site and could alleviate hypoxia inside the tumor to enhance the antitumor effects of DOX. Therefore, the strategy of increasing nanoparticle penetration in this system is expected to provide a potential approach for the clinical treatment of solid tumors.

Influence of physical activity at a young age and lifetime physical activity on the risks of 3 obesity-related cancers: systematic review and meta-analysis of observational studies.

CONTEXT: Excess weight has been linked to increased risks of 13 types of cancers. Physical activity is a non-nutritional modifiable lifestyle factor that is not only crucial for weight control but is also known to regulate hormones and metabolic pathways that may contribute to carcinogenesis. There is solid evidence that being physically active during middle and late adulthood lowers the risks of 3 obesity-related cancers, namely breast cancer, colon cancer, and endometrial cancer. However, the associations between physical activity at a young age (childhood, adolescence, and young adulthood; age 5 to ≤30 yr) and lifetime physical activity and the risks of breast cancer, colon cancer, and endometrial cancer are less defined. OBJECTIVE: The present systematic review and meta-analysis of observational studies was performed in accordance with the MOOSE guidelines to determine whether physical activity at a young age and lifetime physical activity may lower the risks of breast cancer, colon cancer, and endometrial cancer. DATA SOURCES: The PubMed and Web of Science databases were searched for relevant observational studies published from inception to July 2018. STUDY SELECTION: Observational studies (prospective cohort, case-cohort, nested case-control, historical cohort, and case-control) were considered relevant if they investigated the association between physical activity at a young age or lifetime physical activity and the risks of developing selected cancers. DATA EXTRACTION: A random-effects meta-analysis was performed to generate the summary relative risk (RR) with 95%CI for the highest vs the lowest category of physical activity of any type. RESULTS: Eighty publications were included in the present meta-analysis. Higher physical activity at a young age was associated with lower risks of breast cancer (RR 0.81, 95%CI 0.76, 0.87) and colon cancer (RR 0.67, 95%CI 0.50, 0.88). Similarly, lifetime physical activity was inversely associated with the risks of breast cancer (RR 0.79, 95%CI 0.72, 0.86) and colon cancer (RR 0.75, 95%CI 0.69, 0.82). For breast cancer, menopausal status did not appear to modify the observed inverse association. The benefit with respect to endometrial cancer risk reduction was only observed with higher lifetime physical activity (RR 0.77, 95%CI 0.67, 0.88), not with higher physical activity at a young age (RR 0.89, 95%CI 0.73, 1.07). CONCLUSIONS: Being physically active over a lifetime, starting from early childhood, may lower the risks of developing breast cancer, colon cancer, and endometrial cancer.

A traceable nanoplatform for enhanced chemo-photodynamic therapy by reducing oxygen consumption.

Tumor hypoxia impedes the efficiencies of oxygen-dependent photodynamic therapy (PDT) and chemotherapy. Herein, we design a traceable nanoplatform (DOX/Met/BSA-HA-CDs) by reducing oxygen (O2) consumption to overcome the hypoxia-caused cancer therapy. Carbon dots (CDs) are used not only as a PDT agent but also applied for in vivo traceable imaging. Metformin (Met), a potent antihyperglycemic agent, to improve tumor oxygenation and enhance the efficiencies of hypoxia-caused cancer therapy. In the hypoxic tumor microenvironment, Met was released more rapidly than DOX, which is advantageous for improving hypoxic cancer to exert a better therapeutic efficiency. Ex vivo immunofluorescence staining revealed that the DOX/Met/BSA-HA-CDs nanoparticles greatly reduce O2 consumption in tumor site. Followed by in vivo synergistic treatment achieved considerably enhanced cancer therapeutic efficiency. This system holds great clinical promise as a traceable imaging approach to guide the improvement of PDT and chemotherapy efficiencies through utilizing a simple, safe method improved hypoxic tumor microenvironment.

Interferon-based treatment is superior to nucleos(t)ide analog in reducing HBV-related hepatocellular carcinoma for chronic hepatitis B patients at high risk.

BACKGROUND: The effect of nucleos(t)ide analogs (NAs) versus interferon (IFN) on the occurrence of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) is controversial. We assessed whether antiviral strategy affected HCC development in CHB patients at different HCC risks. METHODS: 1112 CHB patients with antiviral therapy were included in this retrospective study. Patients treated with NAs only were classified into NAs group (n = 682) while those received IFN treatment with or without NAs were defined as IFN group (n = 430). Propensity score matching (PSM) was applied to minimize baseline differences. RESULTS: Totally, 31 patients developed HCC during follow-up (median 5.41 years). The cumulative HCC incidence at 10 years was significantly lower in the IFN group than NAs group (2.7% vs 8.0%, p < 0.001). Similar results were obtained in the PSM-cohort. Patients with IFN-based treatment were less likely to develop HCC than those with NAs (Hazard ratio = 0.15; 95% CI 0.04-0.66; p = 0.012). Subgroup analyses demonstrated that this superiority of IFN in reducing HCC development was obvious in patients at high- but not low-risk of HCC. CONCLUSIONS: Reduction of HCC development was more significant in CHB patients at higher HCC risk with IFN-based therapy than NAs treatment.

S100A11 protects against neuronal cell apoptosis induced by cerebral ischemia via inhibiting the nuclear translocation of annexin A1.

The subcellular location of annexin A1 (ANXA1) determines the ultimate fate of neurons after ischemic stroke. ANXA1 nuclear translocation is involved in neuronal apoptosis after cerebral ischemia, and extracellular ANXA1 is also associated with regulation of inflammatory responses. As the factors and mechanism that influence ANXA1 subcellular translocation remain unclear, studies aiming to determine and clarify the role of ANXA1 as a cell fate 'regulator' within cells are critically needed. In this study, we found that intracerebroventricular injection of the recombinant adenovirus vector Ad-S100A11 (carrying S100A11) strongly improved cognitive function and induced robust neuroprotective effects after ischemic stroke in vivo. Furthermore, upregulation of S100A11 protected against neuronal apoptosis induced by oxygen-glucose deprivation and reoxygenation (OGD/R) in vitro. Surprisingly, S100A11 overexpression markedly decreased ANXA1 nuclear translocation and subsequently alleviated OGD/R-induced neuronal apoptosis. Notably, S100A11 exerted its neuroprotective effect by directly binding ANXA1. Importantly, S100A11 directly interacted with ANXA1 through the nuclear translocation signal (NTS) of ANXA1, which is essential for ANXA1 to import into the nucleus. Consistent with our previous studies, ANXA1 nuclear translocation after OGD/R promoted p53 transcriptional activity, induced mRNA expression of the pro-apoptotic Bid gene, and activated the caspase-3 apoptotic pathway, which was almost completely reversed by S100A11 overexpression. Thus, S100A11 protects against cell apoptosis by inhibiting OGD/R-induced ANXA1 nuclear translocation. This study provides a novel mechanism whereby S100A11 protects against neuronal cells apoptosis, suggesting the potential for a previously unidentified treatment strategy in minimizing apoptosis after ischemic stroke.

Genetic variations of NTCP are associated with susceptibility to HBV infection and related hepatocellular carcinoma.

Sodium taurocholate cotransporting polypeptide (NTCP), encoded by gene SLC10A1, is a receptor for hepatitis B virus (HBV). The aim of the current study was to investigate the role of NTCP polymorphisms in HBV susceptibility, cirrhosis and hepatocarcinogenesis. A total 1221 cases [including 866 chronic hepatitis B (CHB), 238 liver cirrhosis (LC), 117 hepatocellular carcinoma (HCC) patients] and 1232 healthy controls (HCs) were recruited, and 6 single nucleotide polymorphisms (SNPs) were genotyped. Meta-analysis was executed among 14591 CHBs and 12396 HCs to determine the association between NTCP polymorphisms and HBV infection, cirrhosis or hepatocarcinogenesis. The frequency of rs2296651-GA was inversely correlated with CHB, LC or HCC patients [adjusted OR(95%CI)=0.16(0.11-0.23), p<0.001; 0.34(0.21-0.55), p=0.001; or 0.46(0.25-0.83), p=0.008], respectively, compared with HCs. Meta-analysis also showed that NTCP rs2296651-GA was inversely associated with HBV infection [OR(95%CI)=0.532(0.287-0.986), p=0.028, codominant] or HBV-related HCC [OR(95%CI)=0.701(0.564-0.872), p=0.001, recessive]. Furthermore, the frequency of rs943277-GA was positively correlated with HBV infection [adjusted OR(95%CI)=2.42(1.05-5.54), p=0.032, codominant]. Our data suggest that NTCP mutants contribute to the susceptibility of HBV infection or HBV-related HCC.

Anti-obesity effect of a traditional Chinese dietary habit-blending lard with vegetable oil while cooking.

Obesity, which is associated with dietary habits, has become a global social problem and causes many metabolic diseases. In China, both percentages of adult obesity and overweight are far lower compared to western countries. It was designed to increase the two levels of daily intake in human, namely 3.8% and 6.5%, which are recommendatory intake (25 g/d) and Chinese citizens' practical intake (41.4 g/d), respectively. The mice were respectively fed with feeds added with soybean oil, lard or the oil blended by both for 12 weeks. In the mice fed with diet containing 3.8% of the three oils or 6.5% blended oil, their body weight, body fat rate, cross-sectional area of adipocytes, adipogenesis and lipogenesis in adipose were decreased, whereas hydrolysis of triglyserides in adipose was increased. This study demonstrated that the oil mixture containing lard and soybean oil had a remarkable anti-obesity effect. It suggests that the traditional Chinese dietary habits using oils blended with lard and soybean oil, might be one of the factors of lower percentages of overweight and obesity in China, and that the increasing of dietary oil intake and the changing of its component resulted in the increasing of obesity rate in China over the past decades.