ABCC4 suppresses glioblastoma progression and recurrence by restraining cGMP-PKG signalling.

BACKGROUND: Cyclic nucleotides are critical mediators of cellular signalling in glioblastoma. However, the clinical relevance and mechanisms of regulating cyclic nucleotides in glioblastoma progression and recurrence have yet to be thoroughly explored. METHODS: In silico, mRNA, and protein level analyses identified the primary regulator of cyclic nucleotides in recurrent human glioblastoma. Lentiviral and pharmacological manipulations examined the functional impact of cyclic nucleotide signalling in human glioma cell lines and primary glioblastoma cells. An orthotopic xenograft mice model coupled with aspirin hydrogels verified the in vivo outcome of targeting cyclic nucleotide signalling. RESULTS: Elevated intracellular levels of cGMP, instead of cAMP, due to a lower substrate efflux from ATP-binding cassette sub-family C member 4 (ABCC4) is engaged in the recurrence of glioblastoma. ABCC4 gene expression is negatively associated with recurrence and overall survival outcomes in glioblastoma specimens. ABCC4 loss-of-function activates cGMP-PKG signalling, promoting malignancy in glioblastoma cells and xenografts. Hydrogels loaded with aspirin, inhibiting glioblastoma progression partly by upregulating ABCC4 expressions, augment the efficacy of standard-of-care therapies in orthotopic glioblastoma xenografts. CONCLUSION: ABCC4, repressing the cGMP-PKG signalling pathway, is a tumour suppressor in glioblastoma progression and recurrence. Aspirin hydrogels impede glioblastoma progression through ABCC4 restoration and constitute a viable translational approach.

Pyramiding BPH genes in rice maintains resistance against the brown planthopper under climate change.

BACKGROUND: Nilaparvata lugens (brown planthopper; BPH) is a significant rice pest in Asia, causing substantial yield losses. Pyramiding BPH resistance genes with diverse resistance traits into rice cultivars is an effective strategy for pest management. However, the response of pyramiding combinations to environmental changes remains unclear. To address this knowledge gap, we investigated three pyramiding rice lines (BPH2 + 32, BPH9 + 32, and BPH18 + 32) in the context of varying climate change conditions, ensuring sufficient N. lugens-rice interactions. Thus, we set three environmental conditions [30/25 °C (day/night) with 500 ppm CO2 concentration, 32/27 °C (day/night) with 600 ppm CO2 concentration, and 35/30 °C (day/night) with 1000 ppm CO2 concentration]. RESULTS: All three pyramiding rice lines maintained the insect resistant ability under the three environmental settings. In particular, the BPH18 + 32 rice line exhibited stronger antibiotic and antixenosis effects against N. lugens. In addition, BPH18 + 32 rice line had better shoot resilience under N. lugens infestation, whereas the performance of the other two selected pyramiding rice lines varied. Thus, although BPH2, BPH9, and BPH18 represent three alleles at the same locus, their resistance levels against N. lugens may vary under distinct climate change scenarios, as evidenced by the performance of N. lugens on the three pyramiding rice lines. CONCLUSION: Our findings indicate that all three tested pyramiding rice lines maintained their insect resistance in the face of diverse climate change scenarios. However, these lines exhibited varied repellent responses and resilience capacities in response to climate change. Thus, the combination of pyramiding genes needs to be considered for future breeding programs. © 2023 Society of Chemical Industry.

Cellular and exosomal GPx1 are essential for controlling hydrogen peroxide balance and alleviating oxidative stress in hypoxic glioblastoma.

Tumor hypoxia promotes malignant progression and therapeutic resistance in glioblastoma partly by increasing the production of hydrogen peroxide (H2O2), a type of reactive oxygen species critical for cell metabolic responses due to its additional role as a second messenger. However, the catabolic pathways that prevent H2O2 overload and subsequent tumor cell damage in hypoxic glioblastoma remain unclear. Herein, we present a hypoxia-coordinated H2O2 regulatory mechanism whereby excess H2O2 in glioblastoma induced by hypoxia is diminished by glutathione peroxidase 1 (GPx1), an antioxidant enzyme detoxifying H2O2, via the binding of hypoxia-inducible factor-1α (HIF-1α) to GPx1 promoter. Depletion of GPx1 results in H2O2 overload and apoptosis in glioblastoma cells, as well as growth inhibition in glioblastoma xenografts. Moreover, tumor hypoxia increases exosomal GPx1 expression, which assists glioblastoma and endothelial cells in countering H2O2 or radiation-induced apoptosis in vitro and in vivo. Clinical data explorations further demonstrate that GPx1 expression was positively correlated with tumor grade and expression of HIF-1α, HIF-1α target genes, and exosomal marker genes; by contrast, it was inversely correlated with the overall survival outcome in human glioblastoma specimens. Our analyses validate that the redox balance of H2O2 within hypoxic glioblastoma is clinically relevant and could be maintained by HIF-1α-promoted or exosome-related GPx1.

Hypoxia-induced CXC chemokine ligand 14 expression drives protumorigenic effects through activation of insulin-like growth factor-1 receptor signaling in glioblastoma.

Hypoxic tumor microenvironment (HTM) promotes a more aggressive and malignant state in glioblastoma. However, little is known about the role and mechanism of CXC chemokine ligand 14 (CXCL14) in HTM-mediated glioblastoma progression. In this study, we report that CXCL14 expression correlated with poor outcomes, tumor grade, and hypoxia-inducible factor (HIF) expression in patients with glioblastoma. CXCL14 was upregulated in tumor cells within the hypoxic areas of glioblastoma. Hypoxia induced HIF-dependent expression of CXCL14, which promoted glioblastoma tumorigenicity and invasiveness in vitro and in vivo. Moreover, CXCL14 gain-of-function in glioblastoma cells activated insulin-like growth factor-1 receptor (IGF-1R) signal transduction to regulate the growth, invasiveness, and neurosphere formation of glioblastoma. Finally, systemic delivery of CXCL14 siRNA nanoparticles (NPs) with polysorbate 80 coating significantly suppressed tumor growth in vivo and extended the survival time in patient-derived glioblastoma xenografts. Together, these findings suggest that HIF-dependent CXCL14 expression contributes to HTM-promoted glioblastoma tumorigenicity and invasiveness through activation of the IGF-1R signaling pathway. CXCL14 siRNA NPs as an oligonucleotide drug can inhibit glioblastoma progression and constitute a translational path for the clinical treatment of glioblastoma patients.

Haloperidol Instigates Endometrial Carcinogenesis and Cancer Progression by the NF-κB/CSF-1 Signaling Cascade.

Haloperidol is a routine drug for schizophrenia and palliative care of cancer; it also has antitumor effects in several types of cancer. However, the role of haloperidol in endometrial cancer (EC) development is still unclear. Here, we show that chronic haloperidol treatment in clinically relevant doses induced endometrial hyperplasia in normal mice and promoted tumor growth and malignancy in mice with orthotopic EC. The pharmacokinetic study indicated that haloperidol highly accumulated in the uterus of mice. In vitro studies revealed that haloperidol stimulated the cellular transformation of human endometrial epithelial cells (HECCs) and promoted the proliferation, migration, and invasion of human endometrial carcinoma cells (HECCs) by activating nuclear factor kappa B (NF-κB) and its downstream signaling target, colony-stimulating factor 1 (CSF-1). Gain of function of CSF-1 promotes the cellular transformation of HEECs and the malignant progression of HECCs. Moreover, blockade of CSF-1 inhibited haloperidol-promoted EC progression in vitro and in vivo. A population-based cohort study of EC patients further demonstrated that the use of haloperidol was associated with increased EC-specific mortality. Collectively, these findings indicate that clinical use of haloperidol could potentially be harmful to female patients with EC.

T Cells Mediate Kidney Tubular Injury via Impaired PDHA1 and Autophagy in Type 1 Diabetes.

CONTEXT: Nephropathy is a severe complication of type 1 diabetes (T1DM). However, the interaction between the PDHA1-regulated mechanism and CD4+ T cells in the early stage of kidney tubular injury remains unknown. OBJECTIVE: To evaluate the role of PDHA1 in the regulation of tubular cells and CD4+ T cells and further to study its interaction in tubular cell injury in T1DM. METHODS: Plasma and total RNA were collected from T cells of T1DM patients (n = 35) and healthy donors (n = 33) and evaluated for neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1, PDHA1, and biomarkers of CD4+ T cells including T helper 1 cells (Th1) and regulatory T cells (Treg) markers. HK-2 cells cocultured with CD4+ T cells from T1DM patients or healthy donors (HDs) to evaluate the interaction with CD4+ T cells. RESULTS: Increased PDHA1 gene expression levels in CD4+ T cells were positively associated with the plasma level of NGAL in T1DM patients and HDs. Our data demonstrated that the Th1/Treg subsets skewed Th1 in T1DM. Knockdown of PDHA1 in kidney tubular cells decreased ATP/ROS production, NAD/NADH ratio, mitochondrial respiration, and cell apoptosis. Furthermore, PDHA1 depletion induced impaired autophagic flux. Coculture of tubular cells and T1DM T cells showed impaired CPT1A, upregulated FASN, and induced kidney injury. CONCLUSION: Our findings indicate that Th1 cells induced tubular cell injury through dysregulated metabolic reprogramming and autophagy, thereby indicating a new therapeutic approach for kidney tubular injury in T1DM.

Integrative taxonomy of the leaf-beetle genus Gonioctena Chevrolat, 1836 in Taiwan (Coleoptera, Chrysomelidae, Chrysomelinae, Gonioctenini) reveals new synonymies and one new species.

Taiwanese species of Gonioctena are revised based on morphological, molecular, and ecological information. Gonioctenasubgeminata (Chen, 1934), G.tredecimmaculata (Jacoby, 1888), G.kamikawai (Chûjô, 1958), and G.osawai Kimoto, 1996 are redescribed. The study confirms that Phytodectatredecimmaculatusvar.taiwanensis Achard, 1924 should be considered a junior synonym of G.tredecimmaculata (Jacoby, 1888), along with two new junior synonyms, G.ohmomoiCho et al. 2016 (syn. nov.) and G.riyuetanensisCho et al. 2016 (syn. nov.). Phytodecta (Asiphytodecta) issikii Chûjô, 1958 (syn. nov.) is treated as a junior synonym of Gonioctenascutellaris Baly, 1862, which is removed from synonym with G.fulva (Motschulsky, 1861) (stat. rev.) and redescribed. Gonioctenathoracica Baly, 1862 (syn. nov.), G.dichroa Fairmaire, 1888 (syn. nov.), and G.foochowensis Gruev, 1989 (syn. nov.) are proposed as junior synonyms of G.scutellaris Baly, 1862. A new species, G.liui sp. nov., is described and differentiated ecologically from G.scutellaris. Gonioctenanigroplagiata Baly, 1862 is newly recorded from Matsu Islands and redescribed. Host plants and biological information are provided for all Taiwanese species. Lectotypes are designated for G.scutellaris Baly, 1862, G.thoracica Baly, 1862, and G.nigroplagata Baly, 1862.

Paired-like homeodomain 2B contributes to tumour progression and anti-autophagy in human lung cancer.

Paired-like homeodomain transcription factor 2 (PITX2) is well known to play an essential role in normal embryonic development. Emerging evidence suggests that PITX2 may be involved in human tumorigenesis, but the role of PITX2 in tumour progression remains largely unclear. The expression levels of PITX2 in lung cancer cells were determined by qRT-PCR and Western blot analyses. Gain- and loss-of-function experiments were conducted to investigate the biological roles of PITX2 in the phenotype of lung cancer cells. Immunofluorescence staining and transmission electron microscopy were used to observe autophagy. The expression level and clinical significance of PITX2 were determined in a Taiwanese cohort and the Gene Expression Omnibus (GEO) database, respectively. Here, we show that PITX2B is the most abundant isoform of the bicoid homeodomain family in lung cancer cells. The enforced expression of PITX2B promoted lung cancer tumorigenesis and progression in vitro and in vivo. The mechanistic analysis revealed that the nuclear localization of PITX2B is correlated with its oncogenic functions and two important nuclear localization signals. In addition, PITX2B knockdown in lung cancer cells caused a marked increase in autophagy and apoptosis, suggesting that PITX2B plays an important role in lung cancer cell survival. Moreover, a high expression of PITX2B was associated with a poor overall survival (P<0.05) in both Taiwanese non-small-cell lung cancer patients and GEO lung cancer cohorts. These results provide new insight into the contribution of PITX2B to lung cancer progression, implicate PITX2B as an important component of cell survival signals and further establish PITX2B as a therapeutic target for lung cancer treatment.

Gain of CXCR7 function with mesenchymal stem cell therapy ameliorates experimental arthritis via enhancing tissue regeneration and immunomodulation.

BACKGROUND: The major barriers to mesenchymal stem cell (MSC) therapy in rheumatoid arthritis (RA) are a low extent of tissue regeneration and insufficient immunomodulation after cell transplantation. In addition, the role of C-X-C chemokine receptor type 7 (CXCR7) and its mechanism of action in MSC-mediated osteogenic or chondrogenic differentiation and immunomodulation are unclear. METHODS: Gain of CXCR7 function on human MSCs was carried out by lentiviral vector-mediated CXCR7 overexpression or CXCR7 agonist, TC14012. These cells were determined the role and potential mechanisms for CXCR7-regulated MSC differentiation and immunomodulation using cellular and molecular assays. The therapeutic benefits in RA were investigated in rats with collagen-induced arthritis (CIA). RESULTS: CXCR7 was upregulated in MSCs during the induction of osteogenic or chondrogenic differentiation. Blockage of CXCR7 function inhibited osteogenic or chondrogenic differentiation of MSCs whereas gain of CXCR7 function had the opposite effects. Besides, MSCs with CXCR7 gain-of-function facilitated macrophage apoptosis and regulatory T cell differentiation in a co-culture system. Gain of CXCR7 function also promoted the production of anti-inflammatory soluble factors. A gene expression profiling assay and signaling reporter assays revealed that CXCR7 could regulate several candidate genes related to the PPAR, WNT, Hedgehog or Notch pathways, and their signaling activities, which are known to control cell differentiation and immunomodulation. Finally, MSCs with CXCR7 gain-of-function significantly reduced the articular index scores, ankle circumference, radiographic scores, histologic scores, and inflammation in rats with CIA compared with control MSCs. CONCLUSIONS: CXCR7 promotes the osteogenic and chondrogenic differentiation of MSCs and MSC-mediated immunomodulation by regulating several signaling pathways and anti-inflammatory soluble factors. MSCs with CXCR7 gain-of-function significantly ameliorate arthritic symptoms in a CIA model.

The origin and past demography of murine astrovirus 1 in laboratory mice.

Astroviruses are non-enveloped, positive-sense, ssRNA viruses and often associated with gastrointestinal diseases. Murine astrovirus (MuAstV) was first confirmed in a laboratory mouse colony in 2011. Although infected mice do not present significant clinical symptoms, the virus might interfere with research results. A recent surveillance has shown that MuAstV is highly prevalent in laboratory mice. The aims of the present study were to identify and characterize MuAstV strains as well as to investigate the prevalence rate of viral RNA in laboratory mice in Taiwan, and to estimate the origin and past population demography of MuAstVs. Based on molecular surveillance, MuAstV RNA was detected in 45.7 % of laboratory mice (48/105) from seven of nine colonies. Three fully sequenced MuAstV strains, MuAstV TW1, TW2 and TW3, exhibited 89.1-94.4 % and 89.1-90.0 % nucleotide identities with the reference strains MuAstV STL1 and STL2, respectively. Phylogenetic analyses of the partial regions of the RNA-dependent RNA polymerase (RdRp) and capsid protein (CP) genes of 18 Taiwan strains along with other astroviruses revealed that there are three distinct lineages of mouse astrovirus, MuAstV1, MuAstV2 and mouse astrovirus JF755422. The mutation rates of MuAstV1 were 2.6×10-4 and 6.2×10-4 substitutions/site/year for the RdRp and CP regions, respectively. Based on the above molecular clock, the colonization of MuAstV1 in laboratory mice was between 1897 and 1912, in good agreement with the establishment of 'modern' laboratory mouse facilities. Since its initial infection, the population size of MuAstV1 has increased 15-60-fold, probably consistent with the increased use of laboratory mice. In conclusion, MuAstV1 has been associated with modern laboratory mice since the beginning, and its influence on research results may require further investigation.

Population Monitoring, Egg Parasitoids, and Genetic Structure of the Invasive Litchi Stink Bug, Tessaratoma papillosa in Taiwan.

Here we assessed population dynamics, natural enemy fauna (with emphasis on egg parasitoid), and population genetic structure (based on mitochondrial DNA) of the invasive litchi stink bug (LSB), Tessaratoma papillosa in Taiwan. Our major findings include: (1) fluctuations of LSB in numbers of adults, mating pairs, and egg masses over a 2-year period in Taiwan generally resemble those in the native populations; (2) Anastatus dexingensis and A. fulloi are among the most dominant LSB egg parasitoids, with the former consistently outnumbering the latter throughout Taiwan; (3) the presence of two genetically distinct clades suggests LSB in Taiwan most likely derived from multiple invasions. All these data practically improve our understanding of this invasive insect pest, particularly its ecological and genetic characteristics in the introduced area, which represents critical baseline information for the design of future integrated pest management strategies.

The origin and underlying driving forces of the SARS-CoV-2 outbreak.

BACKGROUND: SARS-CoV-2 began spreading in December 2019 and has since become a pandemic that has impacted many aspects of human society. Several issues concerning the origin, time of introduction to humans, evolutionary patterns, and underlying force driving the SARS-CoV-2 outbreak remain unclear. METHOD: Genetic variation in 137 SARS-CoV-2 genomes and related coronaviruses as of 2/23/2020 was analyzed. RESULT: After correcting for mutational bias, the excess of low frequency mutations on both synonymous and nonsynonymous sites was revealed which is consistent with the recent outbreak of the virus. In contrast to adaptive evolution previously reported for SARS-CoV during its brief epidemic in 2003, our analysis of SARS-CoV-2 genomes shows signs of relaxation. The sequence similarity in the spike receptor binding domain between SARS-CoV-2 and a sequence from pangolin is probably due to an ancient intergenomic introgression that occurred approximately 40 years ago. The current outbreak of SARS-CoV-2 was estimated to have originated on 12/11/2019 (95% HPD 11/13/2019-12/23/2019). The effective population size of the virus showed an approximately 20-fold increase from the onset of the outbreak to the lockdown of Wuhan (1/23/2020) and ceased to increase afterwards, demonstrating the effectiveness of social distancing in preventing its spread. Two mutations, 84S in orf8 protein and 251 V in orf3 protein, occurred coincidentally with human intervention. The former first appeared on 1/5/2020 and plateaued around 1/23/2020. The latter rapidly increased in frequency after 1/23/2020. Thus, the roles of these mutations on infectivity need to be elucidated. Genetic diversity of SARS-CoV-2 collected from China is two times higher than those derived from the rest of the world. A network analysis found that haplotypes collected from Wuhan were interior and had more mutational connections, both of which are consistent with the observation that the SARS-CoV-2 outbreak originated in China. CONCLUSION: SARS-CoV-2 might have cryptically circulated within humans for years before being discovered. Data from the early outbreak and hospital archives are needed to trace its evolutionary path and determine the critical steps required for effective spreading.

Atypical chemokine receptor ACKR3/CXCR7 controls postnatal vasculogenesis and arterial specification by mesenchymal stem cells via Notch signaling.

Mesenchymal stem cells (MSCs) are known to play a role in postnatal vasculogenesis and hold great promise for vascular regeneration. However, the mechanisms by which the endothelial differentiation and specification of MSCs remain unclear. We examined the potential role and molecular mechanisms of atypical chemokine receptor ACKR3/CXCR7 in MSC-mediated endothelial cell differentiation and specification. Here, we showed that vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) activate CXCR7 expression on MSCs through PDGF receptors, PDGFRα and PDGFRß-mediated phosphoinositide 3-kinase (PI3K)/Akt signaling. Genetic and pharmacologic blockage of CXCR7 on MSCs suppressed the VEGF or stromal cell-derived factor 1 (SDF)-1-induced the capacity for vasculogenesis in vitro and in vivo. Moreover, CXCR7 gain of function markedly promoted vasculogenesis by MSCs in vitro and in vivo and induced endothelial differentiation along the arterial endothelial cell lineage via upregulation of Notch signaling. However, blockade of Notch signaling inhibited CXCR7-induced vasculogensis by MSCs. These results indicate CXCR7 is a critical regulator of MSC-mediated postnatal vasculogenesis and arterial specification via Notch signaling.

Anticancer effects of epigallocatechin-3-gallate nanoemulsion on lung cancer cells through the activation of AMP-activated protein kinase signaling pathway.

Epigallocatechin-3-gallate (EGCG), a green tea-derived polyphenol, exhibits antitumor activities. An EGCG nanoemulsion (nano-EGCG) was prepared to improve the stability and reduce the side effects of EGCG for treatment of human lung cancer cells, and the antitumor effects were studied. The possible molecular mechanism underlying its antitumor effects on cultured human lung cancer cells was also elucidated. The antitumor effects of EGCG and nano-EGCG were determined using methylthiazolyldiphenyl-tetrazolium bromide (MTT), colony formation, migration, and invasion assays. In addition, changes in the AMP-activated protein kinase (AMPK) signaling pathway were investigated using Western blot analyses. AMPK inhibitors were used to determine the roles of the AMPK signaling pathway involved in the molecular mechanism of the nano-EGCG. Our results showed that both EGCG and nano-EGCG inhibited the growth of H1299 lung cancer cells, with half-maximal inhibitory concentrations of 36.03 and 4.71 µM, respectively. Additionally, nano-EGCG effectively suppressed lung cancer cell colony formation, migration, and invasion in a dose-dependent manner. Nano-EGCG may inhibit lung cancer cell invasion through matrix metalloproteinase (MMP)-2- and MMP-9-independent mechanisms. Furthermore, the expression of several key regulatory proteins in the AMPK signaling pathway was modulated by nano-EGCG. Nano-EGCG may inhibit lung cancer cell proliferation, colony formation, migration, and invasion through the activation of AMPK signaling pathways. This novel mechanism of nano-EGCG suggests its application in lung cancer prevention and treatment. Our results provide an experimental foundation for further research on its potential activities and effects in vivo.

A rapid insect species identification system using mini-barcode pyrosequencing.

BACKGROUND: Rapid and accurate species identification is not only important for biodiversity studies and pest quarantine and management, but in some cases may also influence the results of international trade negotiations. In this study, we developed a rapid species identification system for insects. RESULTS: A universal DNA mini-barcode primer pair was designed to target ∼ 120 bp of the mitochondrial 16S rDNA gene. This primer set can amplify the targeted region from all 300 species of 26 insect orders tested as well as other classes of Arthropoda. Although we found no within-species variation in this region, it provided enough information to separate closely related species or species complexes, in particular Thrips spp. and Bemisia spp. By combining a quick DNA extraction method with pyrosequencing, we were able to generate DNA sequences and complete species identification within 5 h. CONCLUSION: Mini-barcode pyrosequencing of 16S rDNA coupled with the GenBank database provides a rapid, accurate, and efficient species identification system. This system is therefore useful for biodiversity discovery, forensic identification, and quarantine control and management. © 2019 Society of Chemical Industry.

RGS4 deficit in prefrontal cortex contributes to the behaviors related to schizophrenia via system xc--mediated glutamatergic dysfunction in mice.

Rationale: Although molecular investigations of regulator of G-protein signaling 4 (RGS4) alterations in schizophrenia patients yielded partially inconsistent findings, the previous studies suggested that RGS4 is both a positional and functional candidate gene for schizophrenia and is significantly decreased in the prefrontal cortex. However, the exact role of RGS4 in the pathophysiology of schizophrenia is unclear. Moreover, a whole genome transcription profile study showed the possibility of RGS4-regulated expression of SLC7A11(xCT), a component of cysteine/glutamate transporter or system xc-. We hypothesized that system xc- is a therapeutic target of RGS4 deficit-mediated schizophrenia. Methods: Pharmacological and genetic manipulation of RGS4 in organotypic brain slice cultures were used as an ex vivo model to investigate its role in system xc- and glutamatergic function. Lentiviral-based mouse models with RGS4 deficit in the prefrontal cortex and treatment with system xc- activator, N-acetyl cysteine (NAC), were utilized to observe their impacts on glutamatergic function and schizophrenic behaviors. Results: Genetic and pharmacological inhibition of RGS4 resulted in a significant decrease in SLC7A11 (xCT) expression and hypofunction of system xc- and reduced glutamatergic function in organotypic brain slice cultures. However, NAC restored the dysregulation of RGS4-mediated functional deficits of glutamate. Moreover, knockdown of RGS4 specifically in the prefrontal cortex caused mice to exhibit behaviors related to schizophrenia such as increased stereotypy, impaired prepulse inhibition, deficits in social interactions, working memory, and nesting behavior, while enhancing sensitivity to the locomotor stimulatory effect of MK-801. These mice displayed glutamatergic dysfunction in the prefrontal cortex, which may have contributed to the behavioral deficits. RGS4 knockdown mice that received NAC treatment had improved glutamatergic dysfunction and schizophrenia behaviors. Conclusion: Our results suggest that RGS4 deficit induces dysregulation and dysfunction of system xc-, which further results in functional deficits of the glutamatergic system and subsequently to schizophrenia-related behavioral phenotypes. Activation of system xc- offers a promising strategy to treat RGS4 deficit-mediated schizophrenia.

Antioxidant property of Taraxacum formosanum Kitam and its antitumor activity in non-small-cell lung cancer cells.

BACKGROUND: Non-small-cell lung cancer (NSCLC) is known to exhibit resistance to various therapeutic agents and become progressively incurable. Taraxacum formosanum is a medicinal Chinese herb that has been clinically used in Taiwan. However, the investigations of the effects of whole plant on lung cancer are limited. PURPOSE: This study evaluated the in vitro antioxidant, antiproliferative, and antimigration effects of the ethanol extract of T. formosanum (ETF). The possible molecular mechanism underlying its antitumor effects on cultured human NSCLC cell lines was also elucidated. METHODS: The antioxidant effects of the ETF were determined using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and Trolox equivalent antioxidant capacity (TEAC) assays, and its antiproliferative and antimigration effects were determined using trypan blue exclusion and wound healing assays, respectively. In addition, changes in the mitogen-activated protein kinase (MAPK) signaling pathway were investigated using Western blot analyses. Various inhibitors were used to determine the roles of the MAPK signaling pathway involved in the molecular mechanism of the ETF. RESULTS: Our results showed that the ETF exhibited strong reducing power, a high Trolox equivalent antioxidant capacity (TEAC) value, and potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging and Fe+2-chelating abilities. The ETF also exerted antiproliferative and antimigration effects on NSCLC cells in a dose-dependent manner. These effects may be mediated by the inhibitory effects of the ETF on the activation of extracellular signal-regulated kinase. CONCLUSIONS: This study performed the first pharmacological exploration of T. formosanum. Our results demonstrated the antioxidant and antitumor effects of the ETF on NSCLC cell lines, indicating their potential preventive and therapeutic values for lung cancer.

Combination of fucoidan-based magnetic nanoparticles and immunomodulators enhances tumour-localized immunotherapy.

Checkpoint immunotherapy that inhibits tumour immune evasion has demonstrated significant clinical success. However, the therapeutic response is limited to certain patient populations, and immunotoxicity as well as autoimmunity have compromised the therapeutic benefits. Here, we report on an inherently therapeutic fucoidan-dextran-based magnetic nanomedicine (IO@FuDex3) conjugated with a checkpoint inhibitor (anti-PD-L1) and T-cell activators (anti-CD3 and anti-CD28). IO@FuDex3 can repair the immunosuppressive tumour microenvironment by reinvigorating tumour-infiltrating lymphocytes, while targeting the nanomedicine via magnetic navigation to the tumour to minimize off-target effects. Treatment that combines IO@FuDex3 and magnetic navigation reduces the occurrence of adverse events and extends the median survival from 32 to 63 days with less than 1 per cent dose compared with soluble anti-PD-L1. Thus, we demonstrate the potential of integrating anti-PD-L1 and T-cell activators as a form of inherently therapeutic nanomedicine to augment the therapeutic index of combination checkpoint immunotherapy.

Potential role of CBX7 in regulating pluripotency of adult human pluripotent-like olfactory stem cells in stroke model.

The adult olfactory mucosa, a highly regenerative tissue with unique life-long neurogenesis ability, is thought to harbor a naïve yet tightly controlled stem cell population. It will provide unique benefits in various stem cell-based therapies, such as stroke treatment. Here, we identified a subpopulation of adult pluripotent-like olfactory stem cells (APOSCs), which were modulated by an epigenetic repressor of CBX7. APOSCs form a floating sphere, express pluripotency markers Nanog, Oct-4, Sox-2, and SSEA-4 and show alkaline phosphatase activity. In addition, APOSCs display self-renewal and a pluripotent potential to differentiate into all three germ layers. Moreover, APOSCs coexpress pluripotency markers with CBX7. Within their natural niche, APOSCs from CBX7+/+ mice responded promptly to either spontaneous or injury-induced tissue regeneration. However, APOSCs from CBX7-/- mice manifested an impaired self-renewal and differentiation potential. Similarly, in vitro-cultivated CBX7-/- APOSCs underwent premature senescence, whereas CBX7+/+ APOSCs still actively divided, indicating that CBX7 is required for the self-renewal of APOSCs. Intracerebral implantation of APOSCs improved the stroke-mediated neurological dysfunction in rodents. These findings indicate that CBX7 plays a critical role in the regenerative properties of APOSCs and indicate the safety and feasibility of implantation of autologous APOSCs in stroke treatment.

Critical involvement of atypical chemokine receptor CXCR7 in allergic airway inflammation.

Trafficking and recruitment of immune cells to the site of inflammation with spatial and temporal synchronization is crucial for the development of allergic airway inflammation. Particularly, chemokines are known to be key players in these processes. Previous studies revealed that the CXCL12/CXCR4 axis plays an important role in regulating allergic airway inflammation. However, the role of CXCR7, a recently discovered second receptor for CXCL12, in regulating airway inflammation has not been explored. Initially, CXCR7 was considered as a decoy receptor; however, numerous subsequent studies revealed that engagement of CXCR7 triggered its own signalling or modulated CXCR4-mediated signalling. In the present study, we detected the expression of CXCR7 in airway epithelial cells. Use of a lentiviral delivery system to knock down the expression of CXCR7 in the lung of sensitized mice abrogated the cardinal features of asthma, indicating that CXCR7 plays a role in regulating allergic airway inflammation. The activation of mitogen-activated protein kinase and Akt signalling in response to CXCL12 in the mouse epithelial cell line MLE-12 was reduced when CXCR7 expression was knocked down. However, either knockdown or overexpression of CXCR7 in MLE-12 did not affect CXCL12-mediated calcium influx, indicating that CXCR7 does not modulate CXCR4-mediated signalling, and that it functions as a signalling receptor rather than a decoy receptor. Finally, we found that the expression of chemokine CCL2 is regulated by CXCR7/CXCL12-mediated signalling through ß-arrestin in airway epithelial cells. Hence, regulating the expression of CCL2 in airway epithelial cells may be one mechanism by which CXCR7 participates in regulating allergic airway inflammation.