Modified citrus pectin inhibits breast cancer development in mice by targeting tumor-associated macrophage survival and polarization in hypoxic microenvironment.

Large amounts of tumor-associated macrophages (TAM), which are predominately localized in hypoxia area of the tumor tissue, are associated with the malignant progression of the tumor. In the present study, we investigated the inhibitory effects of modified citrus pectin (MCP), a natural dietary polysaccharide, on the survival and polarization of TAM in relation to its inhibition on the growth and migration of breast cancer. M2 macrophages polarized from human monocyte THP-1 were chosen as a model for TAM. We showed that MCP (0.06%-1%) concentration-dependently suppressed the survival of TAM through inhibiting glucose uptake with a greater extent in hypoxia than in normoxia. Furthermore, MCP treatment decreased ROS level in TAM through its reducibility and inhibiting galectin-3 expression, leading to inhibition of glucose transporter-1 expression and glucose uptake. In addition, MCP suppressed M2-like polarization via inhibiting STAT3 phosphorylation. Moreover, the tumor-promoting effect of TAM could be restrained by MCP treatment as shown in human breast cancer MDA-MB-231 cells in vitro and in mouse breast cancer 4T1-luc orthotopic and metastasis models. In both tumor tissue and lung tissue of the mouse tumor models, the number of TAM was significantly decreased after MCP treatment. Taken together, MCP may be a promising agent for targeting TAM in tumor hypoxic microenvironment for breast cancer treatment.

Overexpression of miR-150 Inhibits the NF-κB Signal Pathway in Intervertebral Disc Degeneration through Targeting P2X7.

OBJECTIVE: To elaborate the mechanism of miR-150 in the regulation of the NF-κB signal pathway in intervertebral disc degeneration (IDD) by targeting P2X7. METHODS: The degenerative and normal intervertebral disc tissues were collected to detect the expressions of miR-150 and P2X7. Nucleus pulposus cells were transfected and divided into different groups. Cell apoptosis was determined by flow cytometry and TUNEL staining. The expressions of IL-6, TNF-α, MMP-3, MMP-13, Cox-2, iNOS, collagen II and aggrecan, as well as NF-κB-associated proteins were measured by qRT-PCR and Western blotting. Furthermore, IDD rat models were established to validate the role of miR-150 in vivo. RESULTS: miR-150 was down-regulated but P2X7 was up-regulated in the degenerative intravertebral disc tissues. The apoptosis of nucleus pulposus cells in the IL-1ß-induced group with the transfection of miR-150 mimic and siP2X7 was significantly decreased, with reduced levels of IL-6, TNF-α, MMP-3, MMP-13, Cox-2 and iNOS, increased levels of collagen II and aggrecan, as well as decreased P2X7, p-p65/p65 and cleaved caspase-3. However, the above factors showed an opposite tendency after treatment with miR-150 inhibitor. Furthermore, the P2X7 siRNA transfection could reverse the effects caused by miR-150 inhibitor. Simultaneously, pcDNA P2X7 transfection also inhibited the function of miR-150 mimic in IL-1ß-induced nucleus pulposus cells. In vivoexperiments further verified the protective role of miR-150 in IDD rats. CONCLUSION: miR-150 may alleviate the degeneration of the intervertebral disc partially since it could restrict the NF-κB pathway by targeting P2X7, and thereby inhibiting IL-1ß-induced matrix catabolism, inflammatory responses and apoptosis of the nucleus pulposus cells.

Antineoplastic activity of linear leucine homodipeptides and their potential mechanisms of action.

Galaxamide is a rare cyclic homopentapeptide composed of three leucines and two N-methyl leucines isolated from marine algae Galaxaura filamentosa. The strong antitumor activity of this compound makes it a promising candidate for tumor therapy. The synthesis of galaxamide, however, is a complex process, and it has poor water solubility. On the basis of its special chemical composition, we designed a series of linear leucine homopeptides. Among seven dipeptide derivatives, five compounds with terminal protection groups and methyl substitution of the hydrogen in the amido group showed remarkable inhibitory effects against various cancer cells. N-tertbutyl-D-leucine-N-methyl-D-leucinebenzyl (A7), the only stereomer condensed by two D-leucines, showed the highest antineoplastic activity. A7-treated cells showed cell cycle arrest and morphological changes typical of cells undergoing apoptosis. The population of Annexin-V positive/propidium iodide-negative cells also increased, indicating the induction of early apoptosis. A7 promoted the cleavage of caspase-9 and caspase-3, as well as increased intracellular Ca levels and decreased the mitochondrial membrane potential. Collectively, certain linear leucine dipeptides derived from cyclic pentapeptide are able to inhibit tumor cell proliferation through cell cycle arrest and apoptosis induction. The N-methyl group in the side chain and the D/L conformation of the amino-acid residue are critical for their activity.

[Effects of single heat stress treatment on spermatogenic cells in mice].

OBJECTIVE: To investigate the effects of single heat stress treatment on spermatogenic cells in mice. METHODS: We randomly divided 36 C57 male mice into a control and a heat stress treatment group and submerged the lower part of the torso in water at 25 °C and 43 °C, respectively, both for 15 minutes. At 1, 7, and 14 days after treatment, we obtained the testicular organ indexes, observed the changes in testicular morphology by HE staining, and determined the location and expression levels of the promyelocytic leukemia zinc finger (PLZF) and synaptonemal comlex protein-3 (SCP-3) in the testis tissue by immunohistochemistry and Western blot. RESULTS: The testicular organ index was significantly lower in the heat stress treatment than in the control group (P < 0.05). Compared with the controls, the heat shock-treated mice showed loosely arranged spermatogenic cells scattered in the seminiferous tubules at 1 day after heat stress treatment, atrophied, loosely arranged and obviously reduced number of spermatogenic cells at 7 days, and relatively closely arranged seminiferous tubules and increased number and layers of spermatogenic cells at 14 days. The number of SCP-3 labelled spermatocytes obviously decreased in the heat stress-treated animals at 1 and 7 days and began to increase at 14 days. The PLZF protein expression was significantly reduced in the heat stress treatment group at 1 day as compared with that in the control (0.19 ± 0.12 vs 0.64 ± 0.03, P < 0.01), but elevated to 0.77 ± 0.02 at 7 and 14 days, even remarkably higher than in the control animals (P < 0.01). CONCLUSION: Heat stress treatment can induce short-term dyszoospermia in mice, which can be recovered with the prolonged time after treatment.

[Depressive Symptoms in the Mid- and Old-aged People in China].

OBJECTIVES: To determine the prevalence and determinants of depressive symptoms in the mid- and old-aged people in China. METHODS: Data were extracted from the 2013 China Health and Retirement Longitudinal Study (CHARLS),which containthe Center Epidemiologic Studies-Depression scale(CES-D). Binary logistic regression models were developed to identify factors associated with the prevalence of depression symptoms. These included socio-economic status of the respondents (gender, age, education),health-related factors (chronic diseases, disability, accident injury, and fall in recent two years),and family events over the past two years (deaths of a parent, spouse or child). RESULTS: About 31.9% of respondents had depressive symptoms, with a mean CES-D score of 8.0±4.9.Women and those who were younger than 75 years, widowed, resided in a rural area, had low levels of education, and suffered from multiple chronic conditions were more likely to have depressive symptoms than the others. CONCLUSIONS: High prevalence of depressive symptoms in the mid- and old-aged population in China is evident, which is associated with the health and socio-economic status of the population.

RBRDetector: improved prediction of binding residues on RNA-binding protein structures using complementary feature- and template-based strategies.

Computational prediction of RNA-binding residues is helpful in uncovering the mechanisms underlying protein-RNA interactions. Traditional algorithms individually applied feature- or template-based prediction strategy to recognize these crucial residues, which could restrict their predictive power. To improve RNA-binding residue prediction, herein we propose the first integrative algorithm termed RBRDetector (RNA-Binding Residue Detector) by combining these two strategies. We developed a feature-based approach that is an ensemble learning predictor comprising multiple structure-based classifiers, in which well-defined evolutionary and structural features in conjunction with sequential or structural microenvironment were used as the inputs of support vector machines. Meanwhile, we constructed a template-based predictor to recognize the putative RNA-binding regions by structurally aligning the query protein to the RNA-binding proteins with known structures. The final RBRDetector algorithm is an ingenious fusion of our feature- and template-based approaches based on a piecewise function. By validating our predictors with diverse types of structural data, including bound and unbound structures, native and simulated structures, and protein structures binding to different RNA functional groups, we consistently demonstrated that RBRDetector not only had clear advantages over its component methods, but also significantly outperformed the current state-of-the-art algorithms. Nevertheless, the major limitation of our algorithm is that it performed relatively well on DNA-binding proteins and thus incorrectly predicted the DNA-binding regions as RNA-binding interfaces. Finally, we implemented the RBRDetector algorithm as a user-friendly web server, which is freely accessible at http://ibi.hzau.edu.cn/rbrdetector.

Immunomodulation of adipose-derived mesenchymal stem cells on peripheral blood mononuclear cells in colorectal cancer patients with COVID-19.

BACKGROUND: Accumulating evidence has shown that adipose tissue-derived mesenchymal stem cells (ADSCs) are an effective therapeutic approach for managing coronavirus disease 2019 (COVID-19); however, further elucidation is required to determine their underlying immunomodulatory effect on the mRNA expression of T helper cell-related transcription factors (TFs) and cytokine release in peripheral blood mononuclear cells (PBMCs). AIM: To investigate the impact of ADSCs on the mRNA expression of TFs and cytokine release in PBMCs from colorectal cancer (CRC) patients with severe COVID-19 (CRC+ patients). METHODS: PBMCs from CRC+ patients (PBMCs-C+) and age-matched CRC patients (PBMCs-C) were stimulated and cultured in the presence/absence of ADSCs. The mRNA levels of T-box TF TBX21 (T-bet), GATA binding protein 3 (GATA-3), RAR-related orphan receptor C (RORC), and forkhead box P3 (FoxP3) in the PBMCs were determined by reverse transcriptase-polymerase chain reaction. Culture supernatants were evaluated for levels of interferon gamma (IFN-γ), interleukin 4 (IL-4), IL-17A, and transforming growth factor beta 1 (TGF-ß1) using an enzyme-linked immunosorbent assay. RESULTS: Compared with PBMCs-C, PBMCs-C+ exhibited higher mRNA levels of T-bet and RORC, and increased levels of IFN-γ and IL-17A. Additionally, a significant decrease in FoxP3 mRNA and TGF-ß1, as well as an increase in T-bet/GATA-3, RORC/FoxP3, IFN-γ/IL-4, and IL-17A/TGF-ß1 ratios were observed in PBMCs-C+. Furthermore, ADSCs significantly induced a functional regulatory T cell (Treg) subset, as evidenced by an increase in FoxP3 mRNA and TGF-ß1 release levels. This was accompanied by a significant decrease in the mRNA levels of T-bet and RORC, release of IFN-γ and IL-17A, and T-bet/GATA-3, RORC/FoxP3, IFN-γ/IL-4, and IL-17A/TGF-ß1 ratios, compared with the PBMCs-C+alone. CONCLUSION: The present in vitro studies showed that ADSCs contributed to the immunosuppressive effects on PBMCs-C+, favoring Treg responses. Thus, ADSC-based cell therapy could be a beneficial approach for patients with severe COVID-19 who fail to respond to conventional therapies.

[Effects of Different Forms of Nitrogen Addition on Soil Physical and Chemical Properties and Microbial Community Structure of Perennial Alpine Cultivated Grassland].

This study aimed to investigate the impact of different nitrogen forms on soil physicochemical properties and microbial community structure in perennial alpine cultivated grasslands, in order to provide scientific basis for developing nitrogen addition strategies for perennial alpine cultivated grasslands. In June 2022, a 4-year-old Qinghai grassland mixed with Poa pratensis Qinghai and Festuca sinensis Qinghai was established at the Bakatai Farm in Gonghe County, Hainan Tibetan Autonomous Prefecture, Qinghai Province. The study was conducted without fertilization as a control (CK), and three different forms of nitrogen treatments were set up, namely, U:urea (amide nitrogen), A:ammonium sulfate (ammonium nitrogen), and N:calcium nitrate (nitrate nitrogen); the nitrogen application rate for each treatment was 67.5 kg·(hm2·a)-1, and the composition and diversity of soil nutrients and microbial communities under different treatments were analyzed. The results showed that the input of exogenous ammonium nitrogen significantly increased NH4+-N content, AP content, and EC; amide nitrogen input significantly increased SOC content and TN content; and nitrate nitrogen input significantly increased NO3--N content, AN content, and TC content. Exogenous nitrogen input changed the structure of soil bacterial and fungal communities, as well as the relative abundance of dominant phyla and genera, but it did not significantly affect the alpha diversity of bacterial and fungal communities. Principal coordinate analysis (PCoA) showed that different forms of nitrogen addition had a significant impact on the Beta diversity of bacterial communities, whereas the impact on fungal communities was not significant. Redundancy analysis (RDA) indicated that nitrogen addition mainly changed the composition and structure of microbial communities through soil ammonium nitrogen. Overall, ammonium nitrogen fertilizer should be given priority in the soil remediation process of perennial cultivated grasslands in the Qinghai Tibet Plateau.

Effects of yak and Tibetan sheep grazing on soil arthropods community in an alpine meadow on the Qinghai-Tibet Plateau, China.

We investigated the responses of community structure of soil arthropods to yak and Tibetan sheep grazing based on a manipulated grazing experiment at the alpine meadow livestock Adaptive Management Platform, which locates in Haiyan County, Qinghai Province. The results showed that the obtained soil arthropods belonged to 26 families, 8 orders, and 4 classes, with Acaroidae and Oribatida as the dominant groups. Yak and Tibetan sheep grazing decreased the abundance but increased Shannon index, Margalef index and Pielou index of soil arthropods. Yak grazing significantly increased the quantity of the predatory soil arthropod groups. Yak and Tibetan sheep gra-zing significantly increased the quantity of the detritivore soil arthropod groups, but did not affect the quantity of the omnivorous and phytophagous soil arthropod groups. Yak and Tibetan sheep grazing significantly reduced the abundance of soil mites. Soil bulk density, available potassium, and available nitrogen were the main abiotic factors affecting soil arthropods community composition.

Grazing practices affect phyllosphere and rhizosphere bacterial communities of Kobresia humilis by altering their network stability.

The primary utilization strategy for meadow grasslands on the Qinghai-Tibet Plateau (QTP) is livestock grazing. This practice is considered as one of the major drivers of plant-associated bacterial community construction and changes in soil properties. The species of Kobresia humilis is considered as the most dominant one in grasslands. However, how different grazing practices affect the phyllosphere and rhizosphere bacterial communities of K. humilis is unknown. To address this issue, the effects of the grazing enclosure (GE), single-species grazing (YG and SG, representing yak only and sheep only, respectively), and different ratios of grazing (ratio of yak to sheep is 1:2, 1:4, and 1:6, represented by MG1:2, MG1:4, and MG1:6, respectively) on the dominant plant of K. humilis, it's phyllosphere and rhizosphere bacteria, and soil properties were investigated using artificially controlled grazing and grazing enclosure. Our data showed that grazing enclosure enhanced vegetation coverage, and rhizosphere bacterial richness and diversity, while reduced plant number and bacterial network stability of K. humilis. The NO3--N, K+, and Cl- concentrations were lower under grazing compared to GE. SG reduced the concentration of NH4+-N, TN, K+, and Na+ compared to YG. Moderate grazing intensity had a lower relative abundance of the r-strategists (Bacteroidota and Gammaproteobacteria) with higher bacterial network stability. Yak and sheep grazing showed reversed impacts on the bacterial network stability between the phyllosphere and rhizosphere of K. humilis. Proteobacteria and Actinobacteriota were identified in the molecular ecological network analysis as keystone taxa in the phyllosphere and rhizosphere networks, respectively, under all treatments. This study explained why sheep grazing has more adverse effects on grazing-tolerant grass species, K. humilis, than yak grazing, and will contribute to a better understanding of the impacts of different grazing practices and grazing enclosure on alpine grassland ecosystems on the QTP.

Synthesis and biological evaluation of novel potent angiotensin II receptor antagonists with anti-hypertension effect.

A series of novel angiotensin II type 1 receptor antagonists were prepared. Radioligand binding assay suggested that compounds 1b and 1c could be recognized by the AT(1) receptor with an IC(50) value of 1.6 ± 0.09 nM and 2.64 ± 0.7 nM, respectively. In vivo anti-hypertension experiments showed that compounds (1a, 1b, 1c, 1e) elicited a significant decrease in SBP and DBP of spontaneous hypertensive rats (SHRs). The antihypertensive effects maintained for 10 h, which indicated that these compounds had a favorable blood pressure-lowering effect. Acute toxicity testing suggested that the LD(50) value of compound 1b was 2316.8 mg/kg which was lower than valsartan (LD(50)=307.50 mg/kg) but higher than losartan (LD(50)=2248 mg/kg). So they could be considered as novel anti-hypertension candidates and deserved for further investigation.

[Effects of livestock grazing on the C:N:P stoichiometry in global grassland ecosystems: A meta analysis]. / æ”¾ç‰§å¯¹å ¨çƒè‰åœ°ç”Ÿæ€ç³»ç»Ÿç¢³æ°®ç£·åŒ–å­¦è®¡é‡ç‰¹å¾å½±å“çš„Meta分析.

In order to clarify the influence of livestock grazing managements on C:N:P stoichiometry of grassland ecosystem and improve grassland management ability at global scale, 83 Chinese and English papers were selected for meta-analysis in this study. We explored the effects of grazing herbivore assemblage (sheep alone, cattle alone, and mixed cattle and sheep) and grazing intensity (light grazing, moderate grazing and heavy grazing) on leaf, litter, root and soil C, N and P stoichiometry of grassland ecosystems. The results showed that grazing significantly decreased C content, C/N and C/P, and increased N, P content and N/P in leaf and litter. C content, N content, C/P and N/P were significantly reduced, and P content and C/N were increased in root and soil. Leaf and litter stoichiometry were more sensitive to cattle and sheep grazing alone, while root and soil stoichiometry were more sensitive to mixed grazing. Heavy grazing had a greater impact on the stoichiometry of grassland ecosystems. Grazing reduced soil N content and increased P content, indicating that grazing had different pathways of influence on grassland N and P content. Further research on the mechanisms of N and P content changes in response to unbalanced grazing activities and the incorporation of the effects of grazing herbivore assemblage and intensity into models for predicting and managing grassland ecosystems could effectively improve grassland ecosystem management.

DSC2 Suppresses the Metastasis of Gastric Cancer through Inhibiting the BRD4/Snail Signaling Pathway and the Transcriptional Activity of ß-Catenin.

Downregulated DSC2 involved in the metastasis of cancers. Unfortunately, its role on the development of gastric cancer (GC) and the potential mechanisms remain unclear. Bioinformatics analysis, Western blot, qRT-PCR, and immunohistochemistry were performed to detect the DSC2 levels of human GC and normal stomach tissues. The role of DSC2 and the downstream signaling in gastric carcinogenesis were explored by using GC specimens, GC cells with different DSC2 expression, inhibitors, and mouse metastasis models. We found that the level of DSC2 decreased significantly in GC tissues and cells. Recovered DSC2 inhibited the invasion and migration of GC cells both in culture and in xenografts. Mechanistically, DSC2 could not only decrease Snail level and nuclear BRD4 level by forming DSC2/BRD4, but also inhibit nuclear translocation of ß-catenin. We concluded that DSC2 inhibited the metastasis of GC, and the underlying mechanisms were closely related to the regulation on nuclear translocation of BRD4 and ß-catenin. Our results suggest that DSC2 may serve as a novel therapeutic target for GC.

Circulating galectin-3 promotes tumor-endothelium-adhesion by upregulating ICAM-1 in endothelium-derived extracellular vesicles.

The adhesion of tumor cells to vascular endothelial cells is an important process of tumor metastasis. Studies have shown that tumor could educate vascular endothelial cells to promote tumor metastasis through many ways. However, the effect of tumor cells on the functions of vascular endothelial cells-derived extracellular vesicles (H-EVs) and the mechanisms underlying their effects in tumor-endothelium adhesion in metastasis remain mysterious. In this study, we found that H-EVs promoted the adhesion of triple negative breast cancer cell to endothelial cells and cirGal-3 enhanced the adhesion-promoting effects of H-EVs. The underlying mechanism was related to the upregulation of glycolysis in endothelial cells induced by cirGal-3 which led to the increase of the ICAM-1 expression and its transmission to MDA-MB-231 cells by H-EVs. Targeting of cirGal-3 or glycolysis of vascular endothelium in breast cancer therefore represents a promising therapeutic strategy to reduce metastasis.

[Toxic effects of sublethal acetochlor with sublethal doses on earthworms in soil using multi-endpoints system]. / äºšè‡´æ­»å‰‚é‡ä¹™è‰èƒºå¯¹èš¯èš“çš„æ¯’æ€§æ•ˆåº”åŠæ•æ„Ÿç”Ÿç‰©æ ‡è®°ç‰©.

In this study, we examined the toxic effect of sublethal doses of acetochlor (1, 2, 4, 8 mg·kg-1) on earthworms by exogenous addition. The growth inhibition rate, cytochrome P450 isozymes (CYP1A2, 2C9 and 3A4) activities and the metabolomics were analyzed after seven days of exposure, to infer the toxicity threshold of acetochlor, screen the sensitive biomarkers from the levels of the individual, detoxified enzymes and small molecular metabolites, and elucidate the underlying toxicity mechanism. The results showed that CYP1A2, 2C9 and 3A4 activities were all significantly inhibited, and that the levels of ten metabolites (fructose-6-diphosphate, cytosine monophosphate, uridine monophosphate, adenosine monophosphate, adenosine, xanthine, fumaric acid, dihydroxyglutaric acid, ornithine and 16-hydroxyeicosatetraenoic acid) were significantly decreased by acetochlor exposure. The levels of six metabolites (adenosine succinic acid, succinic acid, arginine, tryptophan, asparagine and phenylalanine) were significantly increased when earthworms being exposed to 2-8 mg·kg-1 acetochlor. Acetochlor exposure caused oxidative damage to earthworms, weakened the glycolysis, disturbed the tricarboxylic acid cycle, disordered the purine and pyrimidine metabolism, and impaired the amino acids metabolism. Compared with the end point at individual level, the above 16 small molecule metabolites and CYP isozymes activities were more sensitive to acetochlor exposure. It was thus recommended that CYP isozymes (1A2, 2C9, and 3A4) activities and small molecular metabolites could be used as a set of biomarkers to diagnose the acetochlor pollution, given their high sensitivity and accuracy.

Bioinformatics analysis and identification of genes and molecular pathways involved in Parkinson's disease in patients with mutations in the glucocerebrosidase gene.

Glucocerebrosidase (GBA) mutations occur frequently in Parkinson's disease (PD) patients. This study aims to identify potential crucial genes and pathways associated with GBA mutations in patients with PD and to further analyze new molecular mechanisms related to the occurrence of gene mutations from the perspective of bioinformatics. Gene expression profiles of datasets GSE53424 and GSE99142 were acquired from the Gene Expression Ominibus database. Differentially expressed genes (DEGs) were detected, using the 'limma' package in R, comparing IDI-PD 1 (idiopathic PD patients) and GBA-PD 1 [PD patients with heterozygous GBA mutations (GBA N370S)] group samples. The functions of top modules were assessed using the DAVID, whereas gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. Protein-protein interaction networks were assembled with Cytoscape software and separated into subnetworks using the Molecular Complex Detection Algorithm. Data from GSE53424 and GSE99142 were also extracted to verify our findings. There were 283 DEGs identified in PD patients heterozygous for GBA mutations. Module analysis revealed that GBA mutations in PD patients were associated with significant pathways, including Calcium signaling pathway, Rap1 signaling pathway and Cytokine-cytokine receptor interaction. Hub genes of the two modules were corticotropin-releasing hormone (CRH) and Melatonin receptor 1B (MTNR1B). The expression of CRH was downregulated, whereas that of MTNR1B was upregulated in PD patients with GBA mutations. The expression of CRH and MTNR1B has diagnostic value for PD patients with heterozygous GBA mutations. Novel DEGs and pathways identified herein might provide new insights into the underlying molecular mechanisms of heterozygous GBA mutations in PD patients.

Combination treatment strategies with a focus on rosiglitazone and adriamycin for insulin resistant liver cancer.

Insulin resistance promotes the occurrence of liver cancer and decreases its chemosensitivity. Rosiglitazone (ROSI), a thiazolidinedione insulin sensitiser, could be used for diabetes with insulin resistance and has been reported to show anticancer effects on human malignant cells. In this paper, we investigated the combination of ROSI and chemotherapeutics on the growth and metastasis of insulin-resistant hepatoma. In vitro assay, ROSI significantly enhanced the inhibitory effects of adriamycin (ADR) on the proliferation, autophagy and migration of insulin-resistant hepatoma HepG2/IR cells via downregulation of EGFR/ERK and AKT/mTOR signalling pathway. In addition, ROSI promoted the apoptosis of HepG2/IR cells induced by ADR. In vivo assay, high fat and glucose diet and streptozotocin (STZ) induced insulin resistance in mice by increasing the body weight, fasting blood glucose (FBG) level, oral glucose tolerance, fasting insulin level and insulin resistance index. Both the growth of mouse liver cancer hepatoma H22 cells and serum FBG level in insulin resistant mice were significantly inhibited by combination of ROSI and ADR. Thus, ROSI and ADR in combination showed a stronger anti-tumour effect in insulin resistant hepatoma cells accompanying with glucose reduction and might represent an effective therapeutic strategy for liver cancer accompanied with insulin resistant diabetes.

Studies on preparation and photodynamic mechanism of chlorin P6-13,15-N-(cyclohexyl)cycloimide (Chlorin-H) and its antitumor effect for photodynamic therapy in vitro and in vivo.

Photodynamic therapy (PDT) represents a promising method for treatment of cancerous tumors. The chemical and physical properties of used photosensitizer play key roles in the treatment efficacy. In this study, a novel photosensitizer, Chlorin-H [-13,15-N-(cyclohexyl)cycloimide] which displayed a characteristic long wavelength absorption peak at 698nm was synthesized. Following flash photolysis with 355nm laser, Chlorin-H is potent to react with O(2) and then produce (1)O(2). This finding indicates that Chlorin-H takes its effects through type II mechanism in PDT. Generally, Chlorin-H is localized in mitochondria and nucleus of cell. After light irradiation with 698nm laser, it can kill many types of cell, inhibit cell proliferation and colony formation, suppress cancer cell invasiveness and trigger apoptosis via the mitochondrial pathway in A549 cells in vitro. In addition, Chlorin-H-PDT can destroy A549 tumor in nude mice and a necrotic scab was formed eventually. The expression levels of many genes which regulated cell growth and apoptosis were determined by RT-PCR following Chlorin-H-PDT. The results showed that it either increased or decrease. Among which, the expression level of TNFSF13, a member of tumor necrosis factor superfamily, increased significantly. Silencing of TNFSF13 caused by RNA interference decreased the susceptibility of A549 cells to Chlorin-H-PDT. In general, Chlorin-H is an effective antitumor photosensitizer in vitro and in vivo and is worthy of further study as a new drug candidate. TNFSF13 will be an important molecular target for the discovery of new photosensitizers.

Exosomal microRNAs-mediated intercellular communication and exosome-based cancer treatment.

Exosomes are extracellular vesicles with a diameter of about 30 to 100 nm, which play a crucial role in intercellular communication. Compared with normal cells, the release rate of tumor-derived exosomes (TDEs) significantly increased, and exosomal contents, especially microRNAs (miRNAs), greatly changed. TDEs contribute to the proliferation, metastasis and resistance of tumor cells, regulate immune response and tumor autophagy, and mediate tumor-stroma communication. In addition, exosomes may be involved in tumor complications. In view of the role of exosomes in intercellular communication, exosomes have been developed as tumor biomarkers, therapeutic targets, and drug delivery systems for tumor diagnosis, prognosis and treatment. Despite the many advantages of exosomes, there are many challenges in exosomal development and application, such as incomprehensive understanding of biological functions, safety and specificity for therapeutic use. This article reviews the biogenesis of TDEs and focuses on the role of exosomal miRNAs in intercellular communication and exosome-based treatment for cancer.

Topographic distribution features of the choroidal and retinal nerve fiber layer thickness in Chinese school-aged children.

AIM: To explore the topographic distribution features of choroidal thickness (CT) and retinal nerve fiber layer thickness (RNFLT), and determine the relationship between CT and ocular parameters in school-aged children. METHODS: The healthy school-aged children with low ametropia or emmetropia in Wenzhou were recruited for this cross-sectional study. With high-density optical coherence tomography (HD-OCT) combined with MATLAB software, the CT and RNFLT values in the macular area were measured at different locations and compared. Statistical analyses were performed to evaluate the correlation between CT and ophthalmic parameters, such as spherical equivalent (SE) and the axial length (AL). RESULTS: A total of 279 school-aged children with 8.00±1.35 years of mean age (range, 6-10y) were included. The mean AL was 23.66±0.86 mm. The mean CT in CT-C (264.31±48.93 µm) was thicker than that in CT-N1 (249.54±50.52 µm), and the average CT in the parafoveal region was also thicker than that in CT-N2 (235.65±50.63 µm). The subfoveal CT also varied substantially across refractive errors (P<0.001), and those with myopia (250.59±47.01 µm) exhibited a thinner choroid compared with those with emmetropia (278.74±48.06 µm). CT negatively correlated with AL (y=-21.72x+779.17; R 2=0.1458), and positively correlated with SE (y=15.76x+271.9; R 2=0.0727, OD; y=18.31x+269.8; R 2=0.1007, OS). The average RNFLT was thickest in the peripapillary region (236.35±19.03 µm), the mean RNFLT-S (131.10±15.16 µm) was thicker than the RNFLT-I (128.20±16.59 µm), and the mean RNFLT-T (76.54±11.99 µm) was thicker than the RNFLT-N (64.28±8.55 µm). The variations in the RNFLT between quadrants did differ between those with myopia and emmetropia (P<0.05). CONCLUSION: We establish demographic information for the choroid and RNFLT. These findings provide information that should be considered in future analyses of the CT and RNFLT in OCT studies in school-aged children.