Safety and efficacy of sequential treatments for postmenopausal osteoporosis: a network meta-analysis of randomised controlled trials.

Background: The sequential anti-osteoporotic treatment for women with postmenopausal osteoporosis (PMO) is important, but the order in which different types of drugs are used is confusing and controversial. Therefore, we performed a network meta-analysis to compare the efficacy and safety of available sequential treatments to explore the most efficacious strategy for long-term management of osteoporosis. Methods: In this network meta-analysis, we searched the PubMed, EMBASE, Web of Science, the Cochrane Library, and ClinicalTrials.gov from inception to September 19, 2023 to identify randomised controlled trials comparing sequential treatments for women with PMO. The identified trials were screened by reading the title and abstract, and only randomised clinical trials involving sequential anti-osteoporotic treatments and reported relevant outcomes for PMO were included. The main outcomes included vertebral fracture risk, the percentage change in bone mineral density (BMD) in different body parts, and all safety indicators in the stage after switching treatment. A frequentist network meta-analysis was performed using the multivariate random effects method and evaluated using the surface under the cumulative ranking curve (SUCRA). Certainty of evidence was assessed using the Confidence in the Network Meta-Analysis (CINeMA) framework. This study is registered with PROSPERO: CRD42022360236. Findings: A total of 19 trials comprising 18,416 participants were included in the study. Five different sequential treatments were investigated as the main interventions and compared to the corresponding control groups. The intervention groups in this study comprised the following treatment switch protocols: switching from an anabolic agent (AB) to an anti-resorptive agent (AR) (ABtAR), transitioning from one AR to another AR (ARtAAR), shifting from an AR to an AB (ARtAB), switching from an AB to a combined treatment of AB and AR (ABtC), and transitioning from an AR to a combined treatment (ARtC). A significant reduction in the incidence of vertebral fractures was observed in ARtC, ABtAR and ARtAB in the second stage, and ARtC had the lowest incidence with 81.5% SUCRA. ARtAAR and ABtAR were two effective strategies for preventing fractures and improving BMD in other body parts. Especially, ARtAAR could improve total hip BMD with the highest 96.1% SUCRA, and ABtAR could decrease the risk of total fractures with the highest 94.3% SUCRA. Almost no difference was observed in safety outcomes in other comparisons. Interpretation: Our findings suggested that the ARtAAR and ABtAR strategy are the effective and safe sequential treatment for preventing fracture and improving BMD for PMO. ARtC is more effective in preventing vertebral fractures. Funding: The National Natural Science Foundation of China (82170900, 81970762), the Hunan Administration of Traditional Chinese Medicine, and the Hunan Province High-level Health Talents "225" Project.

Persistent and Severe Viral Replication in PBMCs with Moderate Immunosuppression Served an Alternative Novel Pathogenic Mechanism for Canine Morbillivirus.

Measles virus and canine distemper virus (CDV) cause lethal infections in their respective hosts characterized by severe immunosuppression. To furtherly acknowledge the attenuated mechanisms of the regionally ongoing epidemic CDV isolates and provide novel perspectives for designing new vaccines and therapeutic drugs, a recombinant CDV rHBF-vacH was employed with a vaccine hemagglutinin (H) gene replacement by reverse genetics based on an infectious cDNA clone for the CDV wild-type HBF-1 strain. Interestingly, unlike previously published reports that a vaccine H protein completely changed a pathogenic wild-type CDV variant to be avirulent, rHBF-vacH was only partially attenuated by alleviating the degree of viral immunosuppression, and still caused 66.7% lethality in ferrets with a prolonged period of disease. Further comparisons of pathogenic mechanisms proved that the weaker but necessary invasions into peripheral blood mononuclear cells (PBMCs) of rHBF-vacH, and subsequently persistent viral replications in PBMCs and multiple organs, together contributed to its 66.7% mortality. In addition, despite significantly higher titers than the parent viruses, rHBF-vacH would not be a suitable candidate for a live vaccine, with great invasion and infection potentials of PBMCs from 16 tested kinds of host species. Altogether, sustained and severe viral replication in PBMCs with moderate immunosuppression was first proven to be an alternative novel pathogenic mechanism for CDV, which might help us to understand possible reasons for CDV fatal infections among domestic dogs and the highly susceptible wild species during natural transmission. IMPORTANCE Despite widespread vaccine campaigns for domestic dogs, CDV remained an important infectious disease in vaccinated carnivores and wild species. In recent years, the regionally ongoing epidemic CDV isolates have emphasized conservation threats to, and potentially disastrous epidemics in, endangered species worldwide. However, little is known about how to deal with the CDV variants constantly regional epidemic. In this study, we employed a recombinant CDV rHBF-vacH with a vaccine H gene replacement in a CDV wild-type HBF-1 context to attenuate the epidemic CDV variant to design a new vaccine candidate. Interestingly, rHBF-vacH was only partially attenuated by alleviating the degree of viral immunosuppression, and still caused 66.7% lethality in ferrets by weaker but necessary invasions into PBMCs, and subsequently persistent and severe viral replications in PBMCs. Significantly higher virus titers of rHBF-vacH in vitro might indicate the rapid cell-to-cell spreads in vivo that indirectly contribute to fatal infections of rHBF-vacH in ferrets.

Design and Preparation of NiFe2O4@FeOOH Composite Electrocatalyst for Highly Efficient and Stable Oxygen Evolution Reaction.

Rational design and constructing earth-abundant electrocatalysts for efficient electrocatalytic water splitting is a crucial challenge. Herein, we report a simple and efficient one-step electrochemical synthetic route of the NiFe2O4@FeOOH composite electrocatalyst for the oxygen evolution reaction. The unique morphology of the NiFe2O4 nanoflowers loaded on FeOOH nanosheets allows more active sites to be exposed and promote charge transfer as well as gas release, and the resulting electrode enables a current density of 10 mA cm-2 at a low overpotential of 255 mV with outstanding stability at a current density of 100 mA cm-2 for 300 h.

Geniposide inhibits SphK1 membrane targeting to restore macrophage polarization balance in collagen-induced arthritis mice.

Imbalance of macrophage polarization plays a critical role in the progression of rheumatoid arthritis (RA). Geniposide (GE) has been shown to exert anti-inflammatory effects. However, the effect of GE on macrophage polarization remains unclear. Here, we investigated the regulation of GE on the imbalance of macrophage polarization in RA and how it functions. We established a mouse model of collagen-induced arthritis (CIA) and isolated bone marrow-derived macrophages (BMDMs). The results confirmed that pro-inflammatory M1 macrophages were dominant in CIA mice, but the polarization imbalance of macrophages was restored to a certain extent after GE treatment. Furthermore, the membrane targeting of sphingosine kinase 1 (SphK1) was increased in BMDMs of CIA mice, as manifested by increased membrane and cytoplasmic expression of p-SphK1 and high secretion level of sphingosine-1-phosphate (S1P). RAW264.7 cells were stimulated with lipopolysaccharide (LPS)-interferon (IFN)-γ or interleukin (IL)-4 to induce M1 or M2 phenotype, respectively, to revalidate the results obtained in BMDMs. The results again observed SphK1 membrane targeting in LPS-IFN-γ-stimulated RAW264.7 cells. Selective inhibition of SphK1 by PF543 or inhibition of the S1P receptors by FTY720 both restored the proportion of M1 and M2 macrophages in LPS-IFN-γ-stimulated RAW264.7 cells, confirming that SphK1 membrane targeting mediated a proportional imbalance in M1 and M2 macrophage polarization. In addition, GE inhibited SphK1 membrane targeting and kinase activity. Taken together, results confirmed that the inhibition of SphK1 membrane targeting by GE was responsible for restoring the polarization balance of macrophages in CIA mice.

Metabonomic analysis of abnormal sphingolipid metabolism in rheumatoid arthritis synovial fibroblasts in hypoxia microenvironment and intervention of geniposide.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by a joint hypoxia microenvironment. Our previous untargeted metabolomics study found that sphingolipid (SPL) metabolism was abnormal in the joint synovial fluid samples from adjuvant arthritis (AA) rats. Geniposide (GE), an iridoid glycoside component of the dried fruit of Gardenia jasminoides Ellis, is commonly used for RA treatment in many Asian countries. At present, the mechanism of GE in the treatment of RA, especially in the joint hypoxia microenvironment, is not entirely clear from the perspective of SPL metabolism. The purpose of this research was to explore the potential mechanism of abnormal SPL metabolism in RA joint hypoxia microenvironment and the intervention effect of GE, through the untargeted metabolic analysis based on the ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Arthritis index, foot swelling and histopathology were used to assess whether the AA rat model was successfully established. The SPLs extracts collected from AA rats' synovial tissue, serum and rheumatoid arthritis synovial fibroblasts (RASFs, MH7A cells, hypoxia/normoxia culture) were analyzed by metabolomics and lipdomics approach based on UPLC-Q-TOF/MS, to identify potential biomarkers associated with disorders of GE regulated RA sphingolipid metabolism. As a result, 11 sphingolipid metabolites related to RA were screened and identified. Except for galactosylceramide (d18:1/20:0), GE could recover the change levels of the above 10 sphingolipid biomarkers in varying degrees. Western blotting results showed that the changes in ceramide (Cer) level regulated by GE were related to the down-regulation of acid-sphingomyelinase (A-SMase) expression in synovial tissue of AA rats. To sum up, this research examined the mechanism of GE in the treatment of RA from the perspective of SPL metabolism and provided a new strategy for the screening of biomarkers for clinical diagnosis of RA.

Interaction between Gelatin and Mulberry Leaf Polysaccharides in Miscible System: Physicochemical Characteristics and Rheological Behavior.

In this study, the miscible system was formed by mixing gelatin (G) with mulberry leaf polysaccharides (MLPs) continuously extracted with a hot buffer (HBSS), a chelating agent (CHSS), a dilute alkali (DASS), and a concentrated alkali (CASS), and the zeta potential, turbidity, particle size, distribution, and rheological properties of the miscible systems were evaluated. Under acidic conditions, the miscible systems of four polysaccharides and gelatin were in a clear state; under alkaline conditions, G-HBSS and G-CHSS were clarified, and G-DASS and G-CASS changed from clarification to turbidity. The zeta potential changed from positive to negative with the increase in pH. When the pH was at 7, it increased with the increase in polysaccharide concentration but was still negative. The four miscible systems all showed polydispersity. The particle sizes of G-HBSS and G-CHSS decreased with the increase in pH, while the particle sizes of G-DASS and G-CASS were increased. The four miscible systems showed "shear thinning" behavior, and the addition of gelatin reduced the apparent viscosity of the four polysaccharide solutions. G-CHSS was highly stable, and G-CASS was more suitable as a stabilizer in the freezing process.

Geniposide alleviates VEGF-induced angiogenesis by inhibiting VEGFR2/PKC/ERK1/2-mediated SphK1 translocation.

BACKGROUND: Rheumatoid arthritis (RA) is an angiogenesis-dependent disease caused by the imbalance of pro- and anti-angiogenic factors. More effective strategies to block synovial angiogenesis in RA should be studied. Geniposide (GE), a natural product isolated from the fruit of Gardenia jasminoides Ellis (GJ), is reported to have anti-inflammatory, anti-angiogenic and other pharmacological effects. However, the underlying mechanism through which GE affects synovial angiogenesis in RA remains unclear. PURPOSE: In this research, we aimed to elucidate the effect and potential mechanisms of GE on angiogenesis in RA. MATERIALS AND METHODS: Synovial angiogenesis in patients with RA and a rat model of adjuvant arthritis (AA) was detected by hematoxylin and eosin (HE) staining, immunohistochemistry (IHC), and western blottiing. The biological functions of vascular endothelial cells (VECs) and sphingosine kinase 1 (SphK1) translocation were checked by CCK-8, EdU, Transwell, tube formation, co-immunoprecipitation assays, and laser scanning confocal microscopy. The effect of the SphK1 gene on angiogenesis was assessed by transfection of SphK1-siRNA in cells and mices. The effect of GE on VEGF-induced angiogenesis was measured by Matrigel plug assay in a mouse model of AA. RESULTS: GE effectively inhibited synovial angiogenesis and alleviated the disease process. SphK1, as a new regulatory molecule, has a potentially important relationship in regulating VEGF/VEGFR2 and S1P/S1PR1 signals. SphK1 translocation was activated via the VEGFR2/PKC/ERK1/2 pathway and was closely linked to the biological function of VECs. GE significantly reduced SphK1 translocation, thereby ameliorating the abnormal biological function of VECs. Furthermore, after transfection of SphK1 siRNA in VECs and C57BL/6 mice, silencing SphK1 caused effectively attenuation of VEGF-induced VEC biological functions and angiogenesis. In vivo, the Matrigel plug experiment indicated that GE significantly inhibited pericyte coverage, basement membrane formation, vascular permeability, and fibrinogen deposition. CONCLUSIONS: Our findings suggest that GE inhibited VEGF-induced VEC biological functions and angiogenesis by reducing SphK1 translocation. Generally, studies have revealed that GE down-regulated VEGFR2/PKC/ERK1/2-mediated SphK1 translocation and inhibited S1P/S1PR1 signaling activation, thereby alleviating VEGF-stimulated angiogenesis. The above evidences indicated that angiogenesis inhibition may provide a new direction for RA treatment.

Long noncoding RNA CA3-AS1 suppresses gastric cancer migration and invasion by sponging miR-93-5p and targeting BTG3.

The long noncoding RNAs (lncRNAs) are a class of noncoding RNAs that are broadly expressed in various biological cells and function in regulating gene expression. However, the function of lncRNAs and the role of lncRNAs in gastric cancer remain to be determined. Herein, the function of lncRNA CA3-AS1 was investigated in gastric cancer. Firstly, we found that the expression level of CA3-AS1 was decreased in gastric cancer cell lines and tissues. Then, CA3-AS1 overexpression inhibited the gastric cancer cells migration and invasion and knockdown of CA3-AS1 enhanced the gastric cancer cells migration and invasion. Moreover, FISH assays and qPCR results revealed that CA3-AS1 was mainly expressed in the cytoplasm of gastric cancer cells. Then, the relationship between CA3-AS1 and miR-93-5p was explored. Luciferase reporter assays results showed that miR-93-5p was a direct target of CA3-AS1 in SGC-7901 and BCG-823. Furthermore, BTG3 was identified as a direct target gene of miR-93-5p. Restore experiments showed that CA3-AS1 upregulated the expression level of BTG3 and inhibited the gastric cancer cells invasion by sponging miR-93-5p. Finally, we found that CA3-AS1 inhibited the metastasis ability of gastric cancer cells in vivo. Above results suggested that CA3-AS1 acted as anti-oncogene in gastric cancer and might become a vital target for clinical treatment.

Highly Efficient Oxygen Evolution Reaction Enabled by Phosphorus Doping of the Fe Electronic Structure in Iron-Nickel Selenide Nanosheets.

The electronic structure of active sites is critically important for electrochemical reactions. Here, the authors report a facile approach to independently regulate the electronic structure of Fe in Ni0.75 Fe0.25 Se2 by P doping. The resulting electrode exhibits superior catalytic performance for the oxygen evolution reaction (OER) showing a low overpotential (238 mV at 100 mA cm-2 , 185 mV at 10 mA cm-2 ) and an impressive durability in an alkaline medium. Additionally, the mass activity of 328.19 A g-1 and turnover frequency (TOF) of 0.18 s-1 at an overpotential of 500 mV are obtained for P─Ni0.75 Fe0.25 Se2 which is much higher than that of Ni0.75 Fe0.25 Se2 and RuO2 . This work presents a new strategy for the rational design of efficient electrocatalysts for OER.

Geniposide downregulates the VEGF/SphK1/S1P pathway and alleviates angiogenesis in rheumatoid arthritis in vivo and in vitro.

The VEGF/SphK1/S1P pathway is closely related to angiogenesis in rheumatoid arthritis (RA), but the precise underlying mechanisms are unclear at present. Here, we explored the involvement of the VEGF/SphK1/S1P cascade in RA models and determined the effects of GE intervention. Our results showed abnormal expression of proteins related to this pathway in RA synovial tissue. Treatment with GE effectively regulated the signal axis, inhibited angiogenesis, and alleviated RA symptoms. In vitro, TNF-ɑ enhanced the VEGF/SphK1/S1P pathway in a co-culture model of fibroblast-like synoviocytes (FLS) and vascular endothelial cells (VEC). GE induced downregulation of VEGF in FLS, restored the dynamic balance of pro-/antiangiogenic factors, and suppressed SphK1/S1P signaling in VEC, resulting in lower proliferation activity, migration ability, tube formation ability, and S1P secretion ability of VEC cells. Additionally, SphK1-specific small interfering RNA (siRNA) blocked the VEGF/SphK1/S1P cascade, which can effectively alleviate the stimulatory effect of FLS on VEC and further enhanced the therapeutic effect of GE. Taken together, our results demonstrate that GE suppresses the VEGF/SphK1/S1P pathway and alleviates the stimulation of VEC by FLS, thereby preventing angiogenesis and promoting therapeutic effects against RA.

Analysis on asymptotic stabilization of eco-compensation program for forest ecotourism stakeholders.

Nowadays, many countries in the world have paid attention to the issue of improving the eco-compensation program for their forest ecotourism systems aiming to successfully drive forest ecosystem protection. However, an operable eco-compensation mechanism must give a fair and balanced consideration to each involved party's pursuits which naturally encompass benefits and responsibilities. In this study, based on the evolutionary game theory, we developed a set of mathematical models to evaluate the attitudes and preferences toward the eco-compensation programs in which the three primary stakeholders are involved including farmers, local government, and business groups in order to investigate whether the stakeholders' asymptotic stabilization strategy can be discovered. In addition, the simulation analysis shows the sensitivity characteristics and evolution process of stakeholders influenced by multiple influencing factors. The results show that the threshold effect of these factors turns out to be an important basis in formulating sustainable development schemes for the eco-compensation program in the forest ecotourism system. Furthermore, the simulation analysis also shows that the initial state of stakeholders affects the rate of convergence to the asymptotic stability. Accordingly, we put forward the three-stage strategy and address policy implications on the operable eco-compensation program development of the forest ecotourism system.

[Construction and identification of an infectious clone for CDV-3 strain of canine distemper virus].

In order to establish an infectious clone for CDV-3, a commercial vaccine strain of canine distemper virus for mink, to provide reference for the studies of pathogenesis and novel vaccine development of CDV. Thirteen pairs of primers were used to amplify the full-length genome of CDV-3 strain. Five long fragments were obtained based on single restriction site analysis of the whole genome of CDV-3 by RT-PCR. Five fragments were successively inserted into the multiple clone sites in the modified eukaryotic vector of pcDNA3.2 by restriction enzymes and splicing. Meanwhile, the hammerhead ribozyme and hepatitis delta virus ribozyme sequences were added to the beginning of F1 fragment and the ending of F5 fragment, respectively. Then, the full-length cDNA recombinant plasmid of CDV-3 was obtained and named as pcDNA3.2-CDV-3. In addition, three helper plasmids, expressing the N protein, P protein and L protein of the CDV-3 strain respectively, were constructed. The 293T cells were transfected with the full-length cDNA recombinant plasmid and three helper plasmids by Lipofectamine™ 2000. At 3 days post transfection, the supernatant was added to the monolayer of Vero cells to observe the typical syncytium of CDV. Indirect immunofluorescence and artificial label identification of recombinant virus rCDV-3 were conducted after the occurrence of lesions. Finally, the growth characteristics of wtCDV-3 and rCDV-3 were compared after passaging of rCDV-3. The identification of the full-length cDNA recombinant plasmid and three helper plasmids by restriction enzyme digestion and sequencing were consistent with expected. The Vero cells infected with the recombinant rCDV-3 showed typical syncytic. The identification of indirect immunofluorescence and labeled marker, and observation under electron microscope proved that the rCDV-3 was indeed rescued from the recombinant plasmid of pcDNA3.2-CDV-3. In comparison of the virus titers of wtCDV-3, rCDV-3 replicated massively and rapidly and reached the maximize virus titer of 107·667 TCID50/mL within 36 h post infection (p.i.) in Vero cells, while wtCDV-3 grew gradually to 106·667 TCID50/mL at 72 h p.i. in Vero cells. This reverse genetic system of CDV-3 strain has been established successfully, to provide reference for the studies of pathogenesis and novel vaccine development of CDV.

Anti-Inflammatory Effect of Geniposide on Regulating the Functions of Rheumatoid Arthritis Synovial Fibroblasts via Inhibiting Sphingosine-1-Phosphate Receptors1/3 Coupling Gαi/Gαs Conversion.

The activated Gα protein subunit (Gαs) and the inhibitory Gα protein subunit (Gαi) are involved in the signal transduction of G protein coupled receptors (GPCRs). Moreover, the conversion of Gαi/Gαs can couple with sphingosine-1-phosphate receptors (S1PRs) and have a critical role in rheumatoid arthritis (RA). Through binding to S1PRs, sphingosine-1-phosphate (S1P) leads to activation of the pro-inflammatory signaling in rheumatoid arthritis synovial fibroblasts (RASFs). Geniposide (GE) can alleviate RASFs dysfunctions to against RA. However, its underlying mechanism of action in RA has not been elucidated so far. This study aimed to investigate whether GE could regulate the biological functions of MH7A cells by inhibiting S1PR1/3 coupling Gαi/Gαs conversion. We use RASFs cell line, namely MH7A cells, which were obtained from the patient with RA and considered to be the main effector cells in RA. The cells were stimulated with S1P (5 µmol/L) and then were treated with or without different inhibitors: Gαi inhibitor pertussis toxin (0.1 µg/mL), S1PR1/3 inhibitor VPC 23019 (5 µmol/L), Gαs activator cholera toxin (1 µg/mL) and GE (25, 50, and 100 µmol/L) for 24 h. The results showed that GE may inhibit the abnormal proliferation, migration and invasion by inhibiting the S1P-S1PR1/3 signaling pathway and activating Gαs or inhibiting Gαi protein in MH7A cells. Additionally, GE could inhibit the release of inflammatory factors and suppress the expression of cAMP, which is the key factor of the conversion of Gαi and Gαs. GE could also restore the dynamic balance of Gαi and Gαs by suppressing S1PR1/3 and inhibiting Gαi/Gαs conversion, in a manner, we demonstrated that GE inhibited the activation of Gα downstream ERK protein as well. Taken together, our results indicated that down-regulation of S1PR1/3-Gαi/Gαs conversion may play a critical role in the effects of GE on RA and GE could be an effective therapeutic agent for RA.

Anticancerous potential of polysaccharides sequentially extracted from Polygonatum cyrtonema Hua in Human cervical cancer Hela cells.

The anticancerous effects of PCHPs (HBSS, CHSS, DASS, and CASS) were investigated on Human cervical cancer Hela cells proliferation inhibition, cytotoxicity, caspase-3 activity, cell cycle, and apoptosis. The inhibition rate was expressed as CASS > HBSS > CHSS > DASS, with the maximum inhibition of 74.453 ± 3.399%. Cell cytotoxicity was observed (CASS > CHSS > HBSS > DASS) with the maximum cell death rate of 82.472 ± 3.488%. The caspase-3 activity was induced by CASS > HBSS > DASS > CHSS, with the maximum multiple of 2.954 ± 0.103. CASS induced cell cycle block at the G2/M phase by elevating mRNA expression of CyclinD1, p21, p53 and Wee1, and lowering the expression of Survivin, CHK2, Wee1, CyclinB1, and CDK-1. CASS enhanced the mRNA expression of DR3, DR5, FasL, FADD, PARP, TNF- α, TNF- R1, TRDAA, caspases-8, caspases-10 and the protein expression of FasL and caspases-8, -10 in the death receptor pathway; while, lowered the mRNA expression of antiapoptotic genes (Bcl - 2 and Bcl-xL) and the protein expression of Bcl - 2. The mRNA expression of apoptosis genes (Bak, Cytc, Puma, and caspases-3, -7, -9) and the protein expression of caspases-3, -9 of mitochondria pathway was up regulated which led to cell apoptosis.

Supporting Sustainable Development of Water Resources: A Social Welfare Maximization Game Model.

Water can carry a boat but can also overturn it (human societal sustainable development). Governments faced aquatic ecosystem restoration and preservation challenges following the establishment of the United Nations Sustainable Development Goals. This paper proposes a social welfare maximization game model to analyze the dominant strategy equilibrium of enterprise-1 and enterprise-2 based on welfare maximization under the total sewage emission control policy. Under the aforementioned control policy, a stricter total sewage emission control of an enterprise corresponds to a lower enterprise output and a higher output of a competing enterprise; that is, the profit transfer effect occurs. When the government implements a relatively strict total sewage emission control policy for an enterprise, it is beneficial to reduce the amount of sewage emission from an enterprise but has no impact on the amount of sewage emission from a competing enterprise; however, the amount of sewage reduction of both enterprises will increase. If the government does not provide capital and technical support to enterprise-2, then enterprise-1 and enterprise-2 should implement total quantity control policies with different rigor degrees to avoid the one-size-fits-all phenomenon. To maximize social welfare, the government should adjust the total sewage emission control policy in time according to sewage stock changes and focus more on enterprises with insufficient capital and poor technical skills and provide financial and technical support.

Long noncoding RNA DGCR5 represses hepatocellular carcinoma progression by inactivating Wnt signaling pathway.

Increasing studies have indicated that long noncoding RNAs (lncRNAs) exert important roles in hepatocellular carcinoma (HCC). Therefore, it is of great significance to identify the dysregulated lncRNAs in HCC. According to the previous reports, it has been suggested that DiGeorge syndrome critical region gene 5 (DGCR5) might participate in HCC and can serve as potential biomarker for HCC. In our current study, we concentrated on the biological function and roles of lncRNA-DGCR5 in HCC. It was indicated that DGCR5 was decreased in HCC tissues and HCC cells including HepG2, Hep3B, MHCC-97L, SNU-449, and SNU-182 cells compared with the normal human liver cell line LO2. Overexpression of DGCR5 was able to restrain HCC growth, migration, and invasion capacity in HepG2 and SNU-449 cells. In addition, whether lncRNA-DGCR5 can regulate Wnt/ß-catenin pathway during HCC progression is unclear. In our study, it was found that upregulation of DGCR5 inactivated Wnt signaling pathway through inhibiting ß-catenin, cyclin D1 and increasing GSK-3ß levels. Subsequently, in vivo tumor xenografts were established using HepG2 cells to investigate the function of DGCR5 in HCC development. Inconsistent with the in vitro findings, increase of DGCR5 dramatically suppressed HCC tumor progression in vivo. Taken these together, it was uncovered in our research that DGCR5 could play tumor suppressive role by targeting Wnt signaling in HCC progression.

LINC01433 promotes hepatocellular carcinoma progression via modulating the miR-1301/STAT3 axis.

Long noncoding RNAs (lncRNAs) have been demonstrated to play significant roles in hepatocellular carcinoma (HCC) tumor progression. LINC01433 has been implicated in the progression of lung cancer. However, its biological role in HCC remains poorly understood. In our current study, we focused on the detailed mechanism of LINC01433 in HCC development. First, it was exhibited that LINC01433 was remarkably elevated in HCC cells, which indicated that LINC01433 was involved in HCC. Then, knockdown of LINC01433 was able to restrain HCC cell proliferation and cell colony formation and greatly induced cell apoptosis. On the contrary, overexpression of LINC01433 promoted HCC cell proliferation, increased cell colony formation, and enhanced cell invasion capacity. Subsequently, we found that miR-1301 was remarkably decreased in HCC cells, and it can serve as a target of LINC01433 according to bioinformatics analysis. In addition, the binding correlation between them was validated by performing RNA pull-down experiments and RIP assay. Moreover, STAT3 was predicted and validated as a target of miR-1301, and it was shown that miR-1301 mimics significantly suppressed STAT3 in HCC cells. Finally, in vivo models were established, and the results demonstrated that silencing of LINC01433 could repress HCC development through modulating miR-1301 and STAT3. Taken together, these results indicated in our study that LINC01433 participated in HCC progression through modulating the miR-1301/STAT3 axis and it might act as a novel biomarker in HCC diagnosis and treatment.

LINC00857 contributes to hepatocellular carcinoma malignancy via enhancing epithelial-mesenchymal transition.

Hepatocellular carcinoma (HCC) remains the fifth most frequent cancer with high mortality rate worldwide. However, the underlying molecular mechanisms of HCC progression are still barely known. Long noncoding RNAs (lncRNAs) have been recognized as significant therapeutic targets for HCC. Recently, the biological role of LINC00857 in several cancer types has been reported. Our present study was aimed to investigate the role of LINC00857 in HCC progression. We observed that LINC00857 was overexpressed in HCC cell lines (Huh7, Hep3B, HepG2, MHCC-97H, and SNU449). Knockdown of LINC00857 significantly repressed Hep-3B and SNU449 cell proliferation and inhibited the HCC cell colony formation. In addition, cell apoptosis was induced by the silence of LINC00857 and cell cycle progression was blocked in G1 phase. Besides these, downregulation of LINC00857 was able to restrain HCC cell migration and invasion capacity via enhancing epithelial-mesenchymal transition (EMT) process. As displayed, E-cadherin protein expression was increased by LINC00857 silence, while N-cadherin protein level was repressed by LV-shLINC00857 in HCC cells. Finally, the in vivo assays were used and the data indicated that LINC00857 could also obviously suppress the HCC tumor growth in vivo. In conclusion, our study revealed that LINC00857 might provide a novel perspective for the HCC treatment.

LINC01133 aggravates the progression of hepatocellular carcinoma by activating the PI3K/AKT pathway.

LncRNAs exhibit crucial roles in various pathological diseases, including hepatocellular carcinoma (HCC). Therefore, it is significant to recognize the dysregulated lncRNAs in HCC progression. Recently, LINC01133 has been identified in several tumors. However, the biological role of LINC01133 in HCC remains poorly understood. Currently, we focused on the function of LINC01133 in HCC development. We observed that LINC01133 was significantly increased in HCC cells including HepG2, Hep3B, MHCC-97L, SK-Hep-1, and MHCC-97H cells compared with the normal human liver cell line HL-7702. In addition, PI3K/AKT signaling was highly activated in HCC cells. Knockdown of LINC01133 was able to inhibit HCC cell proliferation, cell colony formation, cell apoptosis, and blocked cell cycle arrest in the G1 phase. For another, downregulation of LINC01133 repressed HCC cell migration and invasion. Subsequently, the PI3K/AKT signaling pathway was strongly suppressed by silence of LINC01133 in Hep3B and HepG2 cells. Then, in vivo tumor xenografts models were established using Hep3B cells to explore the function of LINC01133 in HCC progression. Consistently, our study indicated that knockdown of LINC01133 dramatically repressed HCC tumor progression through targeting the PI3K/AKT pathway in vivo. Taken these together, we revealed that LINC01133 contributed to HCC progression by activating the PI3K/AKT pathway.

miR-130b participates in wear particle-induced inflammation and osteolysis via FOXF2/NF-κB pathway.

OBJECTIVE: To reveal other miR-130b-mediated signaling pathway in the involvement of wear particle-induced inflammation and osteolysis. MATERIALS AND METHODS: Particle-induced osteolysis (PIO) mice model was established. Secretion levels of TNF-α, IL-1ß, IL-6, and IL-10 were measured by ELISA. miR-130b and forkhead box F2 (FOXF2) mRNA were detected by qRT-PCR. Protein levels of FOXF2, phosphorylation-p65 (p-p65), and p-IκB were observed by Western blot. Luciferase reporter assay was performed to confirm the regulation of miR-130b on FOXF2. RESULTS: Compared with normal mice, secretion levels of TNF-α, IL-1ß, and IL-6 in PIO mice were significantly up-regulated and IL-10 was significantly down-regulated; miR-130b and p-p65 expressions were up-regulated and FOXF2 expression was down-regulated. In addition, the trends of miR-130b, FOXF2, and p-p65 expressions in Co-Cr-Mo treated Raw264.7 cells were the same as that in PIO mice. After transfection with miR-130b inhibitor, secretion levels of TNF-α, IL-1ß, and IL-6 in Raw264.7 cells were significantly decreased and secretion level of IL-10 was significantly increased. We also proved FOXF2 was a target of miR-130b, and FOXF2 siRNA increased secretion levels of TNF-α, IL-1ß, and IL-6 and decreased secretion level of IL-10. Finally, we found nuclear factor-kappa B (NF-κB) inhibitor BAY 11-7082 further decreased secretion levels of TNF-α, IL-1ß, and IL-6 and increased IL-10 level. CONCLUSION: The role of miR-130b/FOXF2/NF-κB pathway in PIO was firstly revealed, which provided new targets for the treatment of periprosthetic osteolysis.