Public participation and outgoing audit of natural resources: Evidence from tripartite evolutionary game in China.

Public participation is essential to the success of ecological civilization. Whether public participation can effectively play a role in the outgoing audit of natural resources (OANR) is an important issue that remains to be explored. This paper uses the tripartite evolutionary game to explore the mechanism of the audit subjects, the leading cadres, and the public in the OANR. The research finds that there is a two-way linkage relationship between the audit subjects and the leading cadres. The audit subjects and the leading cadres affect the behavior strategies of the public in the indirect way and direct way, respectively. However, the public lacks the path to directly affect the other two subjects. The tripartite ideal audit model of "the audit subjects conduct due diligence audits, leading cadres perform duties, the public participate" cannot be realized. The external effect of the public's strategic choice is not enough to make the profit or loss of leading cadres change structurally and then change their behaviors. This paper demonstrates the reasons why the public cannot effectively participate in the OANR at the current stage from three aspects, which are the interpretation of the equations for replication dynamics, the particularity of the audit system, and the effectiveness of public participation. Three suggestions are put forward which are encouraging citizens' indirect participation in the OANR, disclosing information about the OANR, and improving citizens' awareness of the OANR. This paper has important guiding significance for other developing countries to promote public participation in natural resource auditing.

ATM/IKK alpha axis regulates the crosstalk between autophagy and apoptosis in selenite-treated Jurkat cells.

Selenium is an essential trace element. High dosage of selenite exhibits a great potential in treating leukemia. Previous study discovered selenite could promote leukemia cells apoptosis through inducing DNA damage and cell cycle arrest, while the switch mechanisms of these events and autophagy were still unclear. Current study discovered selenite promoted autophagy and apoptosis of leukemia Jurkat cells. In this process, DNA damage related ATM/IKK alpha axis was activated. This axis could stabilize pro-apoptotic P73, and promote autophagy through regulating NF-kappaB signaling pathway. Moreover, survivin-2B was also confirmed to be necessary for the ATM-induced nuclear location of IKK alpha, and therefore stood at the node position of apoptosis and autophagy cascades inside Jurkat cells. Finally, our in vivo experiments proved that selenite exhibited some anti-tumor effects on Jurkat cells-bearing mice. Moreover, alterations of ATM and IKK alpha expression observed in vivo were similar to that identified in vitro. Therefore, our findings had fully confirmed survivin-2B dependent activation of ATM/IKK alpha axis might be another crosstalk between autophagy and apoptosis of selenite-treated leukemia cells.

Berberine Suppresses Lung Metastasis of Cancer via Inhibiting Endothelial Transforming Growth Factor Beta Receptor 1.

This study investigated the effects of berberine (BBR) on pancreatic cancer (PC) lung metastasis and explored the underlying mechanisms, using a BALB/C-nu/nu nude mouse model injected with PC cells (AsPC-1). Intragastric administration of BBR dose-dependently improves survival of mice intravenously injected with AsPC-1 cells, and reduces lung metastasis. Especially, BBR significantly reduces lung infiltration of circulating tumor cells (CTCs) 24 h after AsPC-1 cells injection. In vitro, tumor cells (TCs) trigger endothelial barrier disruption and promote trans-endothelial migration of CFSE-labeled TCs. BBR treatment effectively ameliorates TC-induced endothelial disruption, an effect that is diminished by inhibiting transforming growth factor-ß receptor 1 (TGFBR1). Blocking TGFBR1 blunts the anti-metastatic effect of BBR in vivo. Mechanistically, BBR binds to the intercellular portion of TGFBR1, suppresses its enzyme activities, and protects endothelial barrier disruption by TCs which express higher levels of TGF-ß1. Hence, BBR might be a promising drug for reducing PC lung metastasis in clinical practice.

T-cell receptor repertoire analysis for the diagnosis and treatment of solid tumor: A methodology and clinical applications.

T cells, which are involved in adaptive immunity, are essential in the elimination of tumor cells. Mature T cells can specifically recognize the antigen on the major histocompatibility complex (MHC) molecule through T-cell receptors (TCR). The unique rearrangement mechanisms during T-cell maturation provide great diversity to TCR, ensuring specific recognition between T cells and antigens. Thus, TCR repertoire analysis occupied an important position in T-cell regarding research. Nowadays, next-generation sequencing technology allows the simultaneous detection of TCR sequences with high throughput, and several evaluation indexes facilitate the measure of TCR repertoire. Based on this new methodology, discoveries are made across a range of tumor types. Results have shed light on the TCR repertoire differences between cancer patients and healthy control as well as between individual's lesions, paracancer, and peripheral blood samples. The potential of TCR repertoire as a biomarker for immunotherapy efficacy is also widely studied as TCR repertoire represents different baseline within individuals and shows dynamic change during treatment. Accurate delineation of the T-cell repertoire can further the understanding of the immune system response to tumorigenesis. Still, existing researches are insufficient to clarify the specific clinical implications of TCR dynamic change and the definite role of TCR repertoire diversity during the treatment process. The results of some studies are even contrary. In this article, we reviewed TCR rearrangement mechanisms and analysis methods. Recent progress of TCR sequencing technology in tumor research is also discussed. In conclusion, intensive studies over an extended range of cancer types and a broadened group of subjects should be carried to solidify the TCR repertoire's position as an immunotherapy biomarker.

2-methylbenzoyl berbamine, a multi-targeted inhibitor, suppresses the growth of human osteosarcoma through disabling NF-κB, ERK and AKT signaling networks.

Osteosarcoma is the most common malignant bone tumor in children and young adults, and it has a survival rate of only 60% with current cytotoxic chemotherapy combined with aggressive surgery. The aim of this study was to evaluate the therapeutic efficacy of the berbamine derivative 2-methylbenzoyl berbamine (BBD24) for osteosarcoma in vitro and in vivo. We used human osteosarcoma cell lines, primary osteosarcoma cells and mouse models to evaluate the inhibitory effects of BBD24 on osteosarcoma and to determine the molecular mechanism. Our results showed that BBD24 inhibited the growth of the human osteosarcoma cell lines HOS and MG63 in a time- and dose-dependent manner. BBD24 also exhibited significant inhibitory effects on primary osteosarcoma cells. In contrast, BBD24 did not affect normal blood cells under the same conditions. Treatment with BBD24 induced apoptosis, necrosis and autophagy in osteosarcoma cells. Western blot analysis revealed that BBD24 activated the caspase-dependent pathway and downregulated the NF-kB, AKT, and ERK pathways. Finally, BBD24 treatment induced a significant inhibitory effect on the growth of osteosarcoma in nude mice. Our findings indicate that BBD24 is a multitarget inhibitor and may represent a new type of anticancer agent for osteosarcoma treatment.

Loss of TIMP3 expression induces inflammation, matrix degradation, and vascular ingrowth in nucleus pulposus: A new mechanism of intervertebral disc degeneration.

Low back pain (LBP) is one of the most common complains in orthopedic outpatient department and intervertebral disc degeneration (IDD) is one of the most important reasons of LBP. The mechanisms of IDD contain a complex biochemical cascade which includes inflammation, vascular ingrowth, and results in degradation of matrix. In our study, we used both in vitro and in vivo models to investigate the relation between tissue inhibitor of metalloproteinase-3 (TIMP3) expression and IDD. Loss of TIMP3 expression was found in degenerative intervertebral disc (IVD), this change of expression was closely related with the dephosphorylation of smad2/3. Overexpression of TIMP3 significantly inhibited the release of TNF-α and matrix degradation induced by Lipopolysaccharide. Vascular ingrowth was also suppressed by TIMP3 in the in vitro and in vivo models. Further, animal experiments confirmed that the degeneration of IVD was reduced after overexpression of TIMP3 in nucleus pulposus. Taken together, our results indicated TIMP-3 might play an important role in the pathogenesis of IDD and therefore be a potential therapeutic target in the future.

Ependyma-expressed CCN1 restricts the size of the neural stem cell pool in the adult ventricular-subventricular zone.

Adult neural stem cells (NSCs) reside in specialized niches, which hold a balanced number of NSCs, their progeny, and other cells. How niche capacity is regulated to contain a specific number of NSCs remains unclear. Here, we show that ependyma-derived matricellular protein CCN1 (cellular communication network factor 1) negatively regulates niche capacity and NSC number in the adult ventricular-subventricular zone (V-SVZ). Adult ependyma-specific deletion of Ccn1 transiently enhanced NSC proliferation and reduced neuronal differentiation in mice, increasing the numbers of NSCs and NSC units. Although proliferation of NSCs and neurogenesis seen in Ccn1 knockout mice eventually returned to normal, the expanded NSC pool was maintained in the V-SVZ until old age. Inhibition of EGFR signaling prevented expansion of the NSC population observed in CCN1 deficient mice. Thus, ependyma-derived CCN1 restricts NSC expansion in the adult brain to maintain the proper niche capacity of the V-SVZ.

Nitric oxide, a communicator between tumor cells and endothelial cells, mediates the anti-tumor effects of Marsdenia Tenacissima Extract (MTE).

ETHNOPHARMACOLOGICAL RELEVANCE: Marsdenia tenacissima (Roxb.) Wight & Arn is a well-known traditional Chinese medicine for treating cancer. The anti-tumor effects of the water soluble component of M. tenacissima (MTE, M. Tenacissima Extract) have been intensely studied. However, the roles of microenvironmental cells in mediating the anti-tumor actions of MTE remain to be defined. AIM OF THE STUDY: To determine the roles of nitric oxide (NO) released by endothelial cells (ECs), an important component of tumor microenvironment, in regulating the anti-cancer effects of MTE, and to explore the underlying mechanisms. MATERIALS AND METHODS: Co-culture system of ECs and A549 non-small cell lung cancer (NSCLC) cells was established for determining the interactions of ECs and lung cancer cells. Nitro-L-arginine methyl ester hydrochloride (L-NAME) was used to inhibit the production of NO. Cell viability was examined using cell counting kit 8 and 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay. NO assay and Western blot were used to determine the involved signaling pathway. Primary lung microenvironmental cells (PLMCs) were cultured to examine the roles of NO released from the lung microenvironment in regulating the anti-cancer effects of MTE. A subcutaneous xenograft model was established to determine the involvement of NO in effects of MTE against NSCLCs in vivo. RESULTS: In the co-culture system of ECs and A549 NSCLC cells, MTE (30 mg/mL) treatment reduced viability of lung cancer cells. However, when L-NAME (a nitric oxide synthase (NOS) inhibitor, 300 µM) was introduced into the co-culture system, the NSCLC-inhibiting effects of MTE were significantly suppressed. By contrast, addition of L-NAME (300 µM) did not affect the anti-cancer efficiency of MTE when ECs were not present. Mechanistically, MTE enhanced endothelial production of NO via stimulating PKA-endothelial nitric oxide synthase (eNOS) signaling. Elevated levels of NO inhibited proliferation and promoted apoptosis of the A549 NSCLC cells. Importantly, PKA-eNOS-NO signaling was effective in mediating the anti-cancer effects of MTE, when lung cancer cells were co-cultured with PLMCs. Finally, oral administration of MTE to the subcutaneous xenograft mice significantly suppressed tumor growth, while elevated NO productions. Plasma NO was also revealed to be negatively correlated with the tumor weight. CONCLUSIONS: ECs significantly contributed to anti-cancer effects of MTE by elevating production of NO, in a PKA-dependent manner. The present study revealed a novel anti-cancer mechanism of MTE through regulating the function of ECs, an important component of tumor microenvironment.

High-mobility group nucleosomal binding domain 2 protects against microcephaly by maintaining global chromatin accessibility during corticogenesis.

The surface area of the human cerebral cortex undergoes dramatic expansion during late fetal development, leading to cortical folding, an evolutionary feature not present in rodents. Microcephaly is a neurodevelopmental disorder defined by an abnormally small brain, and many gene mutations have been found to be associated with primary microcephaly. However, mouse models generated by ablating primary microcephaly-associated genes often fail to recapitulate the severe loss of cortical surface area observed in individuals with this pathology. Here, we show that a mouse model with deficient expression of high-mobility group nucleosomal binding domain 2 (HMGN2) manifests microcephaly with reduced cortical surface area and almost normal radial corticogenesis, with a pattern of incomplete penetrance. We revealed that altered cleavage plane and mitotic delay of ventricular radial glia may explain the rising ratio of intermediate progenitor cells to radial glia and the displacement of neural progenitor cells in microcephalic mutant mice. These led to decreased self-renewal of the radial glia and reduction in lateral expansion. Furthermore, we found that HMGN2 protected corticogenesis by maintaining global chromatin accessibility mainly at promoter regions, thereby ensuring the correct regulation of the transcriptome. Our findings underscore the importance of the regulation of chromatin structure in cortical development and highlight a mouse model with critical insights into the etiology of microcephaly.

Identification and characterization of Populus microRNAs in response to plant growth-promoting endophytic Streptomyces sp. SSD49.

Endophytic Streptomyces sp. SSD49 inhibited eight pathogens, including the human opportunistic pathogenic microorganisms, the plant pathogenic fungi and bacteria. The growth of soybeans, tomatoes, peppers and Populus tomentosa seedings inoculated with SSD49 are remarkably promoted. Here, we constructed two P. tomentosa seedling microRNA (miRNA) libraries inoculated with (PS30d) and without SSD49 (PC30d) to explore the molecular regulatory roles in the plant response to the beneficial bacteria. Totals of 314 known and 144 novel miRNAs were identified, among which 27 known and 11 novel miRNA had significantly different expression. The targets of up-regulated miR160, miR156, ptc114 and down-regulated miR319 and other differential expressed miRNAs primarily regulated genes encoding transcription factors (auxin response factor, small auxin-up RNA, and GRAS proteins), disease resistance proteins, phytohormone oxidase, and response regulators, which could promote plant growth, influence disease resistance and miRNA biosynthesis in P. tomentosa. This is the first report on the genome-wide identification of biocontrol endophytic Streptomyces inoculation-responsive miRNAs using small RNA sequencing in P. tomentosa and these findings provide new insight into understanding the biocontrol effects of endophytic Streptomyces.

Marsdenia tenacissima extract dilated small mesenteric arteries via stimulating endothelial nitric oxide synthase and inhibiting calcium influx.

ETHNOPHARMACOLOGICAL RELEVANCE: Marsdenia tenacissima is a traditional Chinese medicine that is known to be effective in combating cancer as well as reducing blood pressure. The efficacy and mechanisms of Marsdenia tenacissima in treating cancer have been well described. However, the potential vasoactivities of Marsdenia tenacissima remain poorly known. AIM OF THE STUDY: To determine the vasoactive effects of the water-soluble part of marsdenia tenacissima in mesenteric resistance arteries of the mice, and to explore the underlying mechanisms. MATERIALS AND METHODS: Isometric vessel tension study was used to examine the effects of marsdenia tenacissima extract (MTE) on vasodilation of the mesenteric arteries of mice. KCl, phenylephrine (PE) and 9,11-Dideoxy-11α,9α-epoxymethanoprostaglandin F2α (U46619) were used as vasoconstrictors. Y27632, Nitro-L-arginine methyl ester hydrochloride (L-NAME) and indomethacin were used to explore the underlying mechanisms for the vasoactivities of MTE. Western blot and nitric oxide (NO) assay were used to evaluate the effects of MTE on the activities of endothelial nitric oxide synthase (eNOS). RESULTS: MTE (5-50 mg/mL), but not vehicle, dose-dependently relaxed the mesenteric arteries constricted with KCl, PE or U46619, in which relaxations to KCl were more pronounced than that to PE or U46619. Pre-incubation of the vessels with MTE (40 mg/mL) reduced the vasoconstrictions caused by calcium influx. Decreasing calcium sensitivity by inhibition of Rho kinase (ROCK) significantly augmented the vasorelaxation of MTE. While, inhibition of endothelial cells by pre-incubation with L-NAME (300 µM) and indomethacin (10 µM) or denudating endothelial cells attenuated vasorelaxations of MTE to KCl, and with a larger potency, to U46619. In both human umbilical vein endothelial cells (HUVECs) and human heart microvascular endothelial cells (HMECs), the phosphorylations of eNOS and the production of NO were significantly enhanced after treatment of MTE for 2, 5, 10, 30 min. CONCLUSIONS: MTE, the water-soluble part of marsdenia tenacissima, was effective in relaxing mesenteric resistance arteries via inhibiting calcium influx and stimulating eNOS activities.

Fusion between tumor cells enhances melanoma metastatic potential.

PURPOSE: Malignant melanoma, characterized by early distant metastasis to the lungs and brain, is a leading cause of mortality related to skin cancer. Cell fusion and the subsequent aneuploidy, commonly observed in melanoma, are associated with poor prognosis. However, the pathological consequences of cell fusion in melanoma remain unknown. Therefore, the present study aims to investigate the pathological consequences of cell fusion in melanoma and the mechanism of melanoma metastasis. METHODS: Phytohemagglutinin-polyethylene glycol (PHA-PEG) fusion method was developed for the fusion of tumor cells. Melanoma cells were fused through the improved PHA-PEG fusion method and obtained by fluorescence-activated cell sorting. DNA content was analyzed through flow cytometry. Cell proliferation rate was detected by cell culture in vitro, and the cell number was counted daily. To detect the tumor growth rate in vivo, cells were injected subcutaneously and the tumor volumes were measured using a vernier caliper. To analyze the tumor metastatic potential, cells were injected intravenously, and the collected lung-metastasis samples were weighed by an electronic balance and the surface nodules were counted. RESULTS: We established an improved phytohemagglutinin-polyethylene glycol fusion method and successfully obtained stable melanoma tumor-tumor cell fusion hybrids. Cell size, DNA content, and chromosome numbers of the fusion hybrids were approximately twice those of the parents. The metastatic potential of the fusion hybrids was dramatically enhanced, in contrast to their proliferation rate. Their metastasis was specific to the lungs. CONCLUSIONS: We developed a highly efficient cell fusion method that can be applied in many fields, particularly cancer research. Our study has proven that tumor-tumor cell fusion hybrids in melanoma can acquire enhanced and specific metastatic potential. Thus, blockage of cell fusion may be a new strategy for melanoma metastasis therapy.