Vascular modulation through exercise improves chemotherapy efficacy in Ewing sarcoma

Recent studies in mouse models of cancer have shown that exercise improves tumor vascular function, thereby improving chemotherapy delivery and efficacy. However, the mechanisms underlying this improvement remain unclear and the effect of exercise on Ewing sarcoma (ES), a pediatric bone and soft tissue cancer, is unknown. The effect of exercise on tumor vascular hyperpermeability, which inversely correlates with drug delivery to the tumor, has also not been evaluated. We hypothesized that exercise improves chemotherapy efficacy by enhancing its delivery through improving tumor vascular permeability. We treated ES‐bearing mice with doxorubicin with or without moderate treadmill exercise. Exercise did not significantly alter ES tumor vessel morphology. However, compared to control mice, tumors of exercised mice had significantly reduced hyperpermeability, significantly decreased hypoxia, and higher doxorubicin penetration. Compared to doxorubicin alone, doxorubicin plus exercise inhibited tumor growth more efficiently. We evaluated endothelial cell sphingosine‐1‐phosphate receptors 1 and 2 (S1PR1 and S1PR2) as potential mediators of the improved vascular permeability and increased function afforded by exercise. Relative to tumors from control mice, vessels in tumors from exercised mice had increased S1PR1 and decreased S1PR2 expression. Our results support a model in which exercise remodels ES vasculature to reduce vessel hyperpermeability, potentially via modulation of S1PR1 and S1PR2, thereby improving doxorubicin delivery and inhibiting tumor growth more than doxorubicin alone does. Our data suggest moderate aerobic exercise should be tested in clinical trials as a potentially useful adjuvant to standard chemotherapy for patients with ES.     

PRRSV Induces HMGB1 Phosphorylation at Threonine-51 Residue to Enhance Its Secretion

Porcine reproductive and respiratory syndrome virus (PRRSV) induces secretion of high mobility group box 1 (HMGB1) to mediate inflammatory response that is involved in the pulmonary injury of infected pigs. Our previous study indicates that protein kinase C-delta (PKC-delta) is essential for HMGB1 secretion in PRRSV-infected cells. However, the underlying mechanism in HMGB1 secretion induced by PRRSV infection is still unclear. Here, we discovered that the phosphorylation level of HMGB1 in threonine residues increased in PRRSV-infected cells. A site-directed mutagenesis study showed that HMGB1 phosphorylation at threonine-51 was associated with HMGB1 secretion induced by PRRSV infection. Co-immunoprecipitation (co-IP) of HMGB1 failed to precipitate PKC-delta, but interestingly, mass spectrometry analysis of the HMGB1 co-IP product showed that PRRSV infection enhanced HMGB1 binding to ribosomal protein S3 (RPS3), which has various extra-ribosomal functions. The silencing of RPS3 by siRNA blocked HMGB1 secretion induced by PRRSV infection. Moreover, the phosphorylation of HMGB1 at threonine-51 was correlated with the interaction between HMGB1 and RPS3. In vivo, PRRSV infection also increased RPS3 levels and nuclear accumulation in pulmonary alveolar macrophages. These results demonstrate that PRRSV may induce HMGB1 phosphorylation at threonine-51 and increase its interaction with RPS3 to enhance HMGB1 secretion. This finding provides insights into the pathogenesis of PRRSV infection.     

The Role of the Graphene Oxide (GO) and Reduced Graphene Oxide (RGO) Intermediate Layer in CZTSSe Thin-Film Solar Cells

Cu₂ZnSn(S,Se)₄ (CZTSSe) solar cells with low cost and eco-friendly characteristics are attractive as future sources of electricity generation, but low conversion efficiency remains an issue. To improve conversion efficiency, a method of inserting intermediate layers between the CZTSSe absorber film and the Mo back contact is used to suppress the formation of MoSe₂ and decomposition of CZTSSe. Among the candidates for the intermediate layer, graphene oxide (GO) and reduced GO have excellent properties, including high-charge mobility and low processing cost. Depending on the type of GO, the solar cell parameters, such as fill factor (FF), were enhanced. Thus, the conversion efficiency of 6.3% was achieved using the chemically reduced GO intermediate layer with significantly improved FF.     

Atorvastatin Reduces Circulating S100A12 Levels in Patients with Carotid Atherosclerotic Plaques - A Link with Plaque Inflammation

Aims: Inflammation is involved in various processes of atherosclerosis development. Serum C-reactive protein (CRP) levels, a predictor for cardiovascular risk, are reportedly reduced by statins. However, several studies have demonstrated that CRP is a bystander during atherogenesis. While S100A12 has been focused on as an inflammatory molecule, it remains unclear whether statins affect circulating S100A12 levels. Here, we investigated whether atorvastatin treatment affected S100A12 and which biomarkers were correlated with changes in arterial inflammation. Methods: We performed a prospective, randomized open-labeled trial on whether atorvastatin affected arterial (carotid and thoracic aorta) inflammation using¹⁸fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT) and inflammatory markers. Thirty-one statin-naïve patients with carotid atherosclerotic plaques were randomized to either a group receiving dietary management (n=15) or one receiving atorvastatin (10mg/day,n=16) for 12weeks.¹⁸F-FDG-PET/CT and flow-mediated vasodilation (FMD) were performed, the latter to evaluate endothelial function. Results: Atorvastatin, but not the diet-only treatment, significantly reduced LDL-cholesterol (LDL-C, -43%), serum CRP (-37%) and S100A12 levels (-28%) and improved FMD (+38%).¹⁸F-FDG-PET/CT demonstrated that atorvastatin, but not the diet-only treatment, significantly reduced accumulation of¹⁸F-FDG in the carotid artery and thoracic aorta. A multivariate analysis revealed that reduction in CRP, S100A12, LDL-C, oxidized-LDL, and increase in FMD were significantly associated with reduced arterial inflammation in the thoracic aorta, but not in the carotid artery. Conclusions: Atorvastatin treatment reduced S100A12/CRP levels, and the changes in these circulating markers mirrored the improvement in arterial inflammation. Our observations suggest that S100A12 may be an emerging therapeutic target for atherosclerosis.     

Evaluation of the Immunogenicity in Mice Orally Immunized with Recombinant Lactobacillus casei Expressing Porcine Epidemic Diarrhea Virus S1 Protein

Porcine epidemic diarrhea (PED), characterized by diarrhea, vomiting, and dehydration, is an acute enteric infectious disease of pigs. The disease is caused by porcine epidemic diarrhea virus (PEDV), which infects the intestinal mucosal surface. Therefore, mucosal immunization through the oral route is an effective method of immunization. Lactic acid bacteria, which are acid resistant and bile-salt resistant and improve mucosal immunity, are ideal carriers for oral vaccines. The S1 glycoprotein of PEDV mediates binding of the virus with cell receptors and induces neutralizing antibodies against the virus. Therefore, we reversely screened the recombinant strain pPG-SD-S1/Δupp ATCC 393 expressing PEDV S1 glycoprotein by Lactobacillus casei deficient in upp genotype (Δupp ATCC 393). Mice were orally immunized three times with the recombinant bacteria that had been identified for expression, and the changes of anti-PEDV IgG and secreted immunoglobulin A levels were observed over 70 days. The results indicated that the antibody levels notably increased after oral administration of recombinant bacteria. The detection of extracellular cytokines on the 42nd day after immunization indicated high levels of humoral and cellular immune responses in mice. The above results demonstrate that pPG-SD-S1/Δupp ATCC 393 has great potential as an oral vaccine against PEDV.     

Dietary Vitamin B1 Intake Influences Gut Microbial Community and the Consequent Production of Short-Chain Fatty Acids

The gut microbiota is closely related to good health; thus, there have been extensive efforts dedicated to improving health by controlling the gut microbial environment. Probiotics and prebiotics are being developed to support a healthier intestinal environment. However, much work remains to be performed to provide effective solutions to overcome individual differences in the gut microbial community. This study examined the importance of nutrients, other than dietary fiber, on the survival of gut bacteria in high-health-conscious populations. We found that vitamin B1, which is an essential nutrient for humans, had a significant effect on the survival and competition of bacteria in the symbiotic gut microbiota. In particular, sufficient dietary vitamin B1 intake affects the relative abundance of Ruminococcaceae, and these bacteria have proven to require dietary vitamin B1 because they lack the de novo vitamin B1 synthetic pathway. Moreover, we demonstrated that vitamin B1 is involved in the production of butyrate, along with the amount of acetate in the intestinal environment. We established the causality of possible associations and obtained mechanical insight, through in vivo murine experiments and in silico pathway analyses. These findings serve as a reference to support the development of methods to establish optimal intestinal environment conditions for healthy lifestyles.     

Deacetylation of 4-(5-acetylamino-2-furyl)thiazole and formation of 1-(4-thiazolyl)-3-cyano-1-propanone by rat liver tissues

The reductive metabolism of the rat carcinogen 4-(5-nitro-2furyl)thiazole (NFT) to 1-4-thiazolyl)-3-cyano-1-propanone (TCP) is reported. Formation of TCP from NFT involved furan ring fission. This could have occurred through involvement of either aminofuran or N-hydroxylaminofuran as precursors. To examine if 4-(5-amino-2-furyl)thiazole is a precursor for TCP, a stable model compound, 4-(5-acetylamino-2-furyl)thiazole (AAFT), was prepared and subjected to enzymatic deacetylation, using rat liver tissue homogenates. AAFT was synthesized by catalytic hydrogenation of NFT with 5% palladium on activated carbon, followed by acetylation with acetic anhydride. AAFT, a white crystalline powder, melted at 168–170°, had an extinction coefficient of 17.9 mM^?1 cm^?1 at 293 nm in ethyl acetate, and exhibited spectroscopic and mass spectral characteristics consistent with the assigned structure. Incubation with rat liver 10,000 g supernatant preparations resulted in the biotransformation of AAFT as evidenced by a decrease in absorption at 290 nm. Incubation of ¹⁴C-labeled AAFT followed by extraction with chloroform-diethyl ether (1:1) resulted in the recovery of a major portion (56%) of the radioactivity in the organic phase when the label was at the 2-position of the thiazole ring, while the major amount (82%) of radioactivity was recovered in the aqueous phase when the 1-¹⁴C-acetyl group was labeled. The radioactivity from the aqueous phase was extractable into the organic phase following acidification to pH 1, an observation consistent with deacetylation. Furthermore, the deacetylation product exhibited a mass spectrum, and retention times in gas and high pressure liquid chromatography, similar to those of synthetic TCP. These data establish 4-(5-amino-2-furyl)thiazole, derived from AAFT by deacetylation, as a precursor for TCP.     

A novel compound RS-0466 reverses beta-amyloid-induced cytotoxicity through the Akt signaling pathway in vitro

In order to determine whether 5-[bis(carboxymethyl) amino]-2-carboxy4-cyano-3-thiopheneacetic acid distrontium salt (S12911-2) inhibits bone resorption by acting on the differentiation and/or function of osteoclasts, its effects were assessed on the 1,25-dihydroxyvitamin D(3)-induced expression of carbonic anhydrase II and vitronectin receptor in chicken bone marrow cells, and on the resorbing activity of authentic rat osteoclasts cultured on bone slices. S12911-2 dose-dependently inhibited, after a 6-day exposure, the expression of carbonic anhydrase II and vitronectin receptor in stimulated osteoclasts (46% and 40%, respectively, at 10(-3) M Sr(2+), P<0.05). A pre-incubation of bone slices with S12911-2 induced a dose-dependent inhibition of bone resorbing activity from 32% at 10(-4) M Sr(2+) to 66% at 10(-3) M Sr(2+) (P<0.05 in each case). A continuous incubation (10(-3) M Sr(2+)) induced a greater inhibition of bone resorbing activity (73%, P<0.05). The inhibition of bone resorption obtained specifically with S12911-2 is related to an inhibition of the differentiation and resorbing activity of the osteoclasts.     

荞麦花叶提取物对S180荷瘤小鼠的辅助治疗作用

目的:研究荞麦花叶提取物(extraction of buckwheat flower and leaf,EBFL)对肿瘤的辅助治疗作用,并探讨其可能的机制。方法:建立小鼠S180肿瘤模型;分别ig荞麦花叶提取物200,400 mg.kg-1及与环磷酰胺(CTX)联合给药14 d,实验重复3次。测定荷瘤小鼠的生存期、肿瘤抑制率、白细胞计数、胸腺指数、脾指数,同时测定荷瘤小鼠血清中白细胞介素-2(IL-2),肿瘤坏死因子-α(TNF-α)水平。结果:与模型组相比,EBFL对肿瘤抑制作用不明显,但可使荷瘤小鼠生存期明显延长,25 d生存率以CTX+EBFL-H组最高(35%),其次是EBFL-H(25%)和EBFL-L(20%);与CTX阳性对照组比较,EBFL能明显抑制CTX所致白细胞数量减少及免疫器官指数降低(P<0.05,P<0.01);EBFL可提高IL-2水平,但对TNF-α水平无影响。结论:EBFL可改善荷瘤小鼠生存质量,延长生存期,减轻CTX的毒性,其机制可能是通过提高机体免疫力实现的。     

NSE和S-100在先天性胆管扩张症发病机制中的协同作用

目的 探讨神经细胞特异性烯醇化酶(NSE)和S-100蛋白在先天性胆管扩张症(CBD)发病中的作用及临床意义。方法 2007～2009年连续CBD患儿36例,均行囊肿和胆囊切除、肝门空肠吻合术,切取囊肿远、近端囊壁和胆囊壁为实验组。选取非正常怀孕或因其母亲特殊原因需终止妊娠胎儿15例的肝外胆管和胆囊为对照组。每组标本分别固定、包埋,免疫组织化学染色检测对比其NSE和S-100表达,比较其染色结果和分布特点,并对囊肿直径和胆道不同部位NSE和S-100的表达进行相关分析。结果 NSE和S-100在囊肿远端表达(1.86±1.29,1.81±1.04)均弱于囊肿近端表达(3.61±1.92,3.58±1.95)(P＜0.05);囊肿远端与胆囊(3.42±1.99,3.72±2.08)间差异有统计学意义(P＜0.05),囊肿近端与胆囊间差异无统计学意义(P＞0.05)。胎儿胆管(4.86±2.97,5.14±2.73)和胎儿胆囊(3.71±2.14,4.00±1.63)间NSE和S-100差异无统计学意义(P＞0.05)。组间比较,囊肿远端与胎儿胆管、胆囊间NSE和S-100差异均有统计学意义(P＜0.05);囊肿近端与胎儿胆管、胆囊间差异无统计学意义(P＜0.05);两组胆囊间差异无统计学意义(P＞0.05)。囊肿直径和胆道不同部位NSE和S-100的表达均呈负相关(P＜0.05)。结论 胆道远端神经节细胞和神经纤维的发育和分布受限与CBD发病关系密切,与其囊肿大小呈负相关;NSE与S-100表达在CBD发病中协同互补,可为CBD术中囊肿切除范围的正确判断提供理论依据。