The cryptic metabolites and anti-phytopathogenic activities from Nigrospora lacticolonia and Penicillium rubens uncovered by the synergism with host Paris polyphylla, monoculture, and co-culture.

The synergism of host Paris polyphylla medium, the monoculture, and the coculture led to seventeen new metabolites, including eight sesquiterpenes, 1-7 having uncommon structural motifs compared to similar caryophyllene derivatives, 8 with an unprecedented bicyclic framework, and three xyloketals (13-15) with unprecedented frameworks from Nigrospora lacticolonia; one polyketide, 17 with novel bicyclo [2.2.2] undecane skeleton, and five polyketide-terpenoid hybrids, 20 (one novel sulfated), 21-24 from Penicillium rubens. The structures were determined mainly by the NMR, HRESIMS, ECD calculation, and single-crystal X-ray diffraction. Nine cryptic compounds (2-4, 5, 12-15, 17) were produced by the inductions of host medium and the coculture. The compounds 13 from N. lacticolonia, 24-26, 28, 29, and 31 from P. rubens indicated significant antiphytopathogenic activities against N. lacticolonia with MICs at 2-4 µg/mL. Moreover, compounds 22-26, 28, 29, and 31 from P. rubens showed antifungal activities against P. rubens with MICs at 2-4 µg/mL. The synergistic effects of host medium and the coculture can induce the structural diversity of metabolites.

Erratum: CircZCCHC2 decreases pirarubicin sensitivity and promotes triple-negative breast cancer development via the miR-1200/TPR axis.

[This corrects the article DOI: 10.1016/j.isci.2024.109057.].

CircZCCHC2 decreases pirarubicin sensitivity and promotes triple-negative breast cancer development via the miR-1200/TPR axis.

Triple-negative breast cancer (TNBC) has attracted attention due to its poor prognosis and limited treatment options. The mechanisms underlying the association between circular RNAs (circRNAs) and the occurrence and development of TNBC remain unclear. CircZCCHC2 is observed to be upregulated in TNBC cells, tissues, and plasma exosomes. Knockdown of circZCCHC2 inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition of TNBC cells in vitro and in vivo. Pirarubicin (THP) treatment downregulated circZCCHC2, and circZCCHC2 affected the sensitivity to THP. CircZCCHC2/miR-1200/translocated promoter region, the nuclear basket protein (TPR) pathway was cascaded and verified. It is demonstrated that circZCCHC2 plays a crucial role in the malignant progression of TNBC via the miR-1200/TPR axis, thereby activating the RAS-RAF-MEK-ERK pathway. The present results indicate that circZCCHC2 has the potential to serve as a novel prognostic biomarker for TNBC.

[Retracted] MicroRNA­9 limits hepatic fibrosis by suppressing the activation and proliferation of hepatic stellate cells by directly targeting MRP1/ABCC1.

Following the publication of this article, a concerned reader drew to our attention that in Fig. 5C on p. 1704, showing histological images of mouse livers stained with H&E, unexpected areas of similarity were identified in terms of the staining patterns revealed within the data panels themselves. After having conducted an internal investigation, the Editor of Oncology Reports has reached the conclusion that the overlapping portions of data shown in this figure were unlikely to have arisen by coincidence. Therefore, on the grounds of a lack of confidence in the integrity of these data, the Editor has decided that the article should be retracted from the publication. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive any reply. The Editor apologizes to the readership for any inconvenience caused, and thanks the interested reader for drawing this matter to our attention. [Oncology Reports 37: 1698­1706, 2017; DOI: 10.3892/or.2017.5382].

15-deoxy-Δ12,14-prostaglandin J2 relieved acute liver injury by inhibiting macrophage migration inhibitory factor expression via PPARγ in hepatocyte.

15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) exhibited potential to alleviate liver inflammation in chronic injury but was less studied in acute injury. Acute liver injury was associated with elevated macrophage migration inhibitory factor (MIF) levels in damaged hepatocytes. This study aimed to investigate the regulatory mechanism of hepatocyte-derived MIF by 15d-PGJ2 and its subsequent impact on acute liver injury. In vivo, mouse models were established by carbon tetrachloride (CCl4) intraperitoneal injection, with or without 15d-PGJ2 administration. 15d-PGJ2 treatment reduced the necrotic areas induced by CCl4. In the same mouse model constructed using enhanced green fluorescent protein (EGFP)-labeled bone marrow (BM) chimeric mice, 15d-PGJ2 reduced CCl4 induced BM-derived macrophage (BMM, EGFP+F4/80+) infiltration and inflammatory cytokine expression. Additionally, 15d-PGJ2 down-regulated liver and serum MIF levels; liver MIF expression was positively correlated with BMM percentage and inflammatory cytokine expression. In vitro, 15d-PGJ2 inhibited Mif expression in hepatocytes. In primary hepatocytes, reactive oxygen species inhibitor (NAC) showed no effect on MIF inhibition by 15d-PGJ2; PPARγ inhibitor (GW9662) abolished 15d-PGJ2 suppressed MIF expression and antagonists (troglitazone, ciglitazone) mimicked its function. In Pparg silenced AML12 cells, the suppression of MIF by 15d-PGJ2 was weakened; 15d-PGJ2 promoted PPARγ activation in AML 12 cells and primary hepatocytes. Furthermore, the conditioned medium of recombinant MIF- and lipopolysaccharide-treated AML12 respectively promoted BMM migration and inflammatory cytokine expression. Conditioned medium of 15d-PGJ2- or siMif-treated injured AML12 suppressed these effects. Collectively, 15d-PGJ2 activated PPARγ to suppress MIF expression in injured hepatocytes, reducing BMM infiltration and pro-inflammatory activation, ultimately alleviating acute liver injury.

Single-cell RNA seq identifies Plg-RKT-PLG as signals inducing phenotypic transformation of scar-associated macrophage in liver fibrosis.

Hepatic macrophages play a central role in liver fibrosis. Scar-associated macrophages (SAMs), a recently identified subgroup of macrophages, play an important role in this process. However, the mechanism by which SAMs transform during liver fibrosis is still unclear. In this study, we aimed to characterize SAMs and elucidate the underlying mechanism of SAM transformation. Bile duct ligation (BDL) and carbon tetrachloride (CCl4) were used to induce mouse liver fibrosis. Non-parenchymal cells were isolated from normal/fibrotic livers and were analyzed using single cell RNA sequencing (scRNA-seq) or mass cytometry (CyTOF). The glucan-encapsulated siRNA particles (siRNA-GeRPs) was employed to perform macrophage selective gene knockdown. The results of scRNA-seq and CyTOF revealed that SAMs, which derived from bone marrow-derived macrophages (BMMs), accumulated in mouse fibrotic livers. Further analysis showed that SAMs highly expressed genes related to fibrosis, indicating the pro-fibrotic functions of SAMs. Moreover, plasminogen receptor Plg-RKT was highly expressed by SAMs, suggesting the role of Plg-RKT and plasminogen (PLG) in SAM transformation. In vitro, PLG-treated BMMs transformed into SAMs and expressed SAM functional genes. Knockdown of Plg-RKT blocked the effects of PLG. In vivo, selective knockdown of Plg-RKT in intrahepatic macrophages of BDL- and CCl4-treated mice reduced the number of SAMs and alleviated BDL- and CCl4-induced liver fibrosis, suggesting that Plg-RKT-PLG played an important role in liver fibrosis by mediating SAM transformation. Our findings reveal that SAMs are crucial participants in liver fibrosis. Inhibition of SAM transformation by blocking Plg-RKT might be a potential therapeutic target for liver fibrosis.

Development of a MOF-based SPE method combined with GC-MS for simultaneous determination of alachlor, acetochlor and pretilachlor in field soil.

In this work, a rapid, highly selective, reusable and effective method was developed for simultaneous determination of alachlor, acetochlor and pretilachlor in field soil by GC-MS coupled with MIL-101 based SPE. Main factors affecting the SPE by using MIL-101 were optimized. Moreover, by comparing with the other commercial materials such as C18, PSA and Florisil, the MIL-101(Cr) exhibited excellent adsorption performance, which aimed at amide herbicides. On the other hand, method validation displayed excellent method performance, achieving good linearities with r2 ≥ 0.9921, limits of detection between 0.25-0.45 µg kg-1, enrichment factors ≥ 89, matrix effect in the range of ± 20%, recoveries between 86.3% and 102.4%, and RSD lower than 4.38%. The developed method was successfully applied to the determination of amide herbicides in soil taken from the wheat, corn and soybean field at different depths, where the concentration of alachlor, acetochlor and pretilachlor were in the range of 0.62-8.04 µg kg-1. It was demonstrated that the more depth of soil, the lower of three amide herbicides. This finding could be proposed a novel method to detect the amide herbicides in the agriculture and food industry.

Necroptosis of macrophage is a key pathological feature in biliary atresia via GDCA/S1PR2/ZBP1/p-MLKL axis.

Biliary atresia (BA) is a severe inflammatory and fibrosing neonatal cholangiopathy disease characterized by progressive obstruction of extrahepatic bile ducts, resulting in cholestasis and progressive hepatic failure. Cholestasis may play an important role in the inflammatory and fibrotic pathological processes, but its specific mechanism is still unclear. Necroptosis mediated by Z-DNA-binding protein 1 (ZBP1)/phosphorylated-mixed lineage kinase domain-like pseudokinase (p-MLKL) is a prominent pathogenic factor in inflammatory and fibrotic diseases, but its function in BA remains unclear. Here, we aim to determine the effect of macrophage necroptosis in the BA pathology, and to explore the specific molecular mechanism. We found that necroptosis existed in BA livers, which was occurred in liver macrophages. Furthermore, this process was mediated by ZBP1/p-MLKL, and the upregulated expression of ZBP1 in BA livers was correlated with liver fibrosis and prognosis. Similarly, in the bile duct ligation (BDL) induced mouse cholestatic liver injury model, macrophage necroptosis mediated by ZBP1/p-MLKL was also observed. In vitro, conjugated bile acid-glycodeoxycholate (GDCA) upregulated ZBP1 expression in mouse bone marrow-derived monocyte/macrophages (BMDMs) through sphingosine 1-phosphate receptor 2 (S1PR2), and the induction of ZBP1 was a prerequisite for the enhanced necroptosis. Finally, after selectively knocking down of macrophage S1pr2 in vivo, ZBP1/p-MLKL-mediated necroptosis was decreased, and further collagen deposition was markedly attenuated in BDL mice. Furthermore, macrophage Zbp1 or Mlkl specific knockdown also alleviated BDL-induced liver injury/fibrosis. In conclusion, GDCA/S1PR2/ZBP1/p-MLKL mediated macrophage necroptosis plays vital role in the pathogenesis of BA liver fibrosis, and targeting this process may represent a potential therapeutic strategy for BA.

Food processing industry changes across China regions: The case of flour, rice, oil, and other cereal derivative food.

Faced with the pressure of slowing industrial growth and industrial transformation requirements, it is crucial to analyze the changes and the corresponding driving factors of the food processing industry in China. An analysis using traditional and spatial shift-share models was conducted to decompose the changes in the food processing industry in each region of China from 2009 to 2019 into five effects: national growth effect (NG), industrial mix effect (IM), competitive effect (CE), neighbor-nation competitive effect (NNC), and region-neighbor competitive effect (RNC). Among the five effects from 2009 to 2019, the NG contributed the most to the growth in most regions, indicating that the development of the food processing industry in China was greatly influenced by the industrial base and that China's food processing industry has entered a "growth bottleneck period." During the period 2009-2014 to period 2014-2019, compared to the IM and CE, the influence of spatial spillover effects was stronger and significantly enhanced. Moreover, the IM, CE, NNC, and RNC in most southern regions were stronger than those in most northern regions. Therefore, China's food processing industry needs and is transforming into high-quality development. It is necessary to innovate the mode of development of food processing industry and strengthen interregional exchanges and cooperation.

Immunotherapy for Triple-Negative Breast Cancer: Combination Strategies to Improve Outcome.

Due to the absence of hormone receptor (both estrogen receptors and progesterone receptors) along with human epidermal growth factor receptor 2 (HER-2) amplification, the treatment of triple-negative breast cancer (TNBC) cannot benefit from endocrine or anti-HER-2 therapy. For a long time, chemotherapy was the only systemic treatment for TNBC. Due to the lack of effective treatment options, the prognosis for TNBC is extremely poor. The successful application of immune checkpoint inhibitors (ICIs) launched the era of immunotherapy in TNBC. However, the current findings show modest efficacy of programmed cell death- (ligand) 1 (PD-(L)1) inhibitors monotherapy and only a small proportion of patients can benefit from this approach. Based on the basic principles of immunotherapy and the characteristics of the tumor immune microenvironment (TIME) in TNBC, immune combination therapy is expected to further enhance the efficacy and expand the beneficiary population of patients. Given the diversity of drugs that can be combined, it is important to select effective biomarkers to identify the target population. Moreover, the side effects associated with the combination of multiple drugs should also be considered.

Neuron-Glial Antigen 2 Participates in Liver Fibrosis via Regulating the Differentiation of Bone Marrow Mesenchymal Stem Cell to Myofibroblast.

Neuron-glial antigen 2 (NG2, gene name: Cspg4) has been characterized as an important factor in many diseases. However, the pathophysiological relevance of NG2 in liver disease specifically regarding bone marrow mesenchymal stem cell (BMSC) differentiation to myofibroblast (MF) and the molecular details remain unknown. Human liver tissues were obtained from patients with different chronic liver diseases, and mouse liver injury models were induced by feeding a methionine-choline-deficient and high-fat diet, carbon tetrachloride administration, or bile duct ligation operation. NG2 expression was increased in human and mouse fibrotic liver and positively correlated with MF markers α-smooth muscle actin (αSMA) and other fibrotic markers in the liver. There was a co-localization between NG2 and αSMA, NG2 and EGFP (BMSC-derived MF) in the fibrotic liver determined by immunofluorescence analysis. In vitro, TGFß1-treated BMSC showed a progressive increase in NG2 levels, which were mainly expressed on the membrane surface. Interestingly, there was a translocation of NG2 from the cell membrane into cytoplasm after the transfection of Cspg4 siRNA in TGFß1-treated BMSC. siRNA-mediated inhibition of Cspg4 abrogated the TGFß1-induced BMSC differentiation to MF. Importantly, inhibition of NG2 in vivo significantly attenuated the extent of liver fibrosis in methionine-choline-deficient and high fat (MCDHF) mice, as demonstrated by the decreased mRNA expression of fibrotic parameters, collagen deposition, serum transaminase levels, liver steatosis and inflammation after the administration of Cspg4 siRNA in MCDHF mice. We identify the positive regulation of NG2 in BMSC differentiation to MF during liver fibrosis, which may provide a promising target for the treatment of liver disease.

Nogo-B receptor increases glycolysis and the paclitaxel resistance of estrogen receptor-positive breast cancer via the HIF-1α-dependent pathway.

Chemotherapy can improve the prognosis and overall survival of breast cancer patients, but chemoresistance continues a major problem in clinical. Most breast cancer is estrogen receptor (ER) positive but responds less to neoadjuvant or adjuvant chemotherapy than ER-negative breast cancer. The Nogo-B receptor (NgBR) increases the chemoresistance of ER-positive breast cancer by facilitating oncogene signaling pathways. Here, we further investigated the potential role of NgBR as a novel target to overcome glycolysis-dependent paclitaxel resistance in ER-positive breast cancer. NgBR knockdown inhibited glycolysis and promoted paclitaxel-induced apoptosis by attenuating HIF-1α expression in ER-positive breast cancer cells via NgBR-mediated estrogen receptor alpha (ERα)/hypoxia-inducible factor-1 alpha (HIF-1α) and nuclear factor-kappa B subunit (NF-κB)/HIF-1α signaling pathways. A ChIP assay further confirmed that NgBR overexpression not only facilitates ERα binding to HIF-1α and GLUT1 genes but also promotes HIF-1α binding to GLUT1, HK2, and LDHA genes, which further promotes glycolysis and induces paclitaxel resistance. In conclusion, our study suggests that NgBR expression is essential for maintaining the metabolism and paclitaxel resistance of ER-positive breast cancer, and the NgBR can be a new therapeutic target for improving chemoresistance in ER-positive breast cancer.

circRNAs and their relationship with breast cancer: a review.

BACKGROUND: Recently, an increasing number of studies have been conducted on circular RNAs (circRNAs) that have demonstrated their different roles in a variety of biological processes. Moreover, a large number of circRNAs have been shown to be involved in the occurrence and development of breast cancer (BC). MAIN BODY: Both functional and mechanistic experiments have shown that circular RNAs (circRNAs) can act as competing endogenous RNAs by sponging miRNAs, encoding proteins, and regulating parental genes. In doing so, circRNAs modulate the proliferation, migration, apoptosis, and invasion of BC cells in vitro as well as tumor growth and metastasis in vivo. Moreover, scores of circRNAs have been demonstrated to be related to clinicopathological features, prognosis, and treatment sensitivity in patients with BC; many circRNAs have shown potential as biomarkers for diagnosis, drug sensitivity, and prognosis prediction. Furthermore, researchers have focused on circRNAs as potential therapeutic targets. CONCLUSION: In this review, we briefly summarize the functions and categories of circRNAs, their different roles in BC, and recent research and therapeutic progress related to circRNAs.

The development of epiretinal membrane following rhegmatogenous retinal detachment repair: incidence, risk factors, and outcomes / Desenvolvimento da membrana epirretiniana após reparo do descolamento regmatogênico da retina: incidência, fatores de risco e resultados

ABSTRACT Purpose: To investigate the incidence, risk factors, and visual outcomes of epiretinal membrane development following rhegmatogenous retinal detachment repair. Methods: This was a retrospective study of 309 eyes that underwent initial surgery for primary uncomplicated rhegmatogenous retinal detachment. Examinations were conducted preoperatively and then postoperatively at 1, 3, 6, and 12 months. The study patients were categorized into two groups depending on the presence or absence of the epiretinal membrane. Results: The incidence of postoperative epiretinal membrane was 28.5%; 42.7% of these patients had severe epiretinal membrane development and therefore underwent the epiretinal membrane removal. Logistic regression analyses revealed that giant retinal tears (OR: 2.66; 95% CI: 1.045-6.792, p=0.040) and horseshoe tears (OR: 0.534; 95% CI: 0.295-0.967, p=0.039) were the significant predictors of postoperative epiretinal membrane. Triamcinolone acetonide staining was significantly associated with the prevention of epiretinal membrane (p=0.022). A total of 34 patients showed a better or an equal final best-corrected visual acuity; of which 4 eyes were evaluated at the final follow-up visit and exhibited a reduced best-corrected visual acuity. Conclusion: Our analysis demonstrated that horseshoe tears and giant retinal tears represent the risk factors for the postoperative epiretinal membrane. Triamcinolone acetonide staining had a significant preventive effect on the postoperative epiretinal membrane. Furthermore, a second round of pars plana vitrectomy, including membrane removal, led to a significant improvement in the final best-corrected visual acuity as per the last follow-up examination, albeit the recovery was limited.

RESUMO Objetivos: Investigar a incidência, fatores de risco e desfechos visuais do desenvolvimento da membrana epirretiniana após reparo do descolamento regmatogênico da retina. Métodos: Trata-se de um estudo retrospectivo de 309 olhos submetidos à cirurgia inicial para descolamento regmatogênico da retina primário sem complicações. Os exames foram realizados no pré-operatório aos 1, 3, 6 e 12 meses pós-operatórios. Os pacientes foram divididos em dois grupos, dependendo da presença ou ausência de membrana epirretiniana. Resultados: A incidência de membrana epirretiniana pós-operatória foi de 28,5%; 42,7% desses pacientes apresentaram desenvolvimento grave da membrana epirretiniana e, portanto, foram submetidos à remoção desta membrana. A regressão logística mostrou que as lágrimas retinianas gigantes (RC: 2,66; 95% IC: 1,045 - 6,792, p=0,040) e lágrimas em ferradura (RC: 0,534; 95% IC: 0,295-0,967, p=0,039), foram preditores significativos de membrana epirretiniana pós-operatória. A coloração com acetonida de triancinolona foi significativamente associada à prevenção da membrana epirretiniana (p=0,022). Trinta e quatro pacientes apresentaram acuidade visual melhorada, ou igual, ou acuidade visual final melhor corrigida; 4 olhos foram avaliados na consulta final de acompanhamento e apresentaram redução da acuidade visual melhor corrigida. Conclusão: Nossa análise demonstra que as lágrimas de ferradura e as lágrimas retinianas gigantes representam fatores de risco para a membrana epirretiniana pós-operatória. A coloração com acetonida de triancinolona teve um efeito preventivo significativo na membrana epirretiniana no pós-operatório. Além disso, uma segunda rodada de vitrectomia pars plana, incluindo remoção da membrana, levou a uma melhora significativa da acuidade visual final melhor corrigida na última consulta de acompanhamento, embora a recuperação tenha sido limitada.

Heterogeneity and Function of Kupffer Cells in Liver Injury.

Kupffer cells (KCs) are key regulators of liver immunity composing the principal part of hepatic macrophages even body tissue macrophages. They reside in liver sinusoids towards portal vein. The micro-environment shapes KCs unique immunosuppressive features and functions. KCs express specific surface markers that distinguish from other liver macrophages. By engulfing gut-derived foreign products and apoptotic cells without triggering excessive inflammation, KCs maintain homeostasis of liver and body. Heterogeneity of KCs has been identified in different studies. In terms of the origin, adult KCs are derived from progenitors of both embryo and adult bone marrow. Embryo-derived KCs compose the majority of KCs in healthy and maintain by self-renewal. Bone marrow monocytes replenish massively when embryo-derived KC proliferation are impaired. The phenotype of KCs is also beyond the traditional dogma of M1-M2. Functionally, KCs play central roles in pathogenesis of acute and chronic liver injury. They contribute to each pathological stage of liver disease. By initiating inflammation, regulating fibrosis, cirrhosis and tumor cell proliferation, KCs contribute to the resolution of liver injury and restoration of tissue architecture. The underlying mechanism varied by damage factors and pathology. Understanding the characteristics and functions of KCs may provide opportunities for the therapy of liver injury. Herein, we attempt to afford insights on heterogeneity and functions of KCs in liver injury using the existing findings.

Activated Neutrophils Secrete Chitinase-Like 1 and Attenuate Liver Inflammation by Inhibiting Pro-Inflammatory Macrophage Responses.

Excessive activation and recruitment of neutrophils are generally considered to be associated with pathological aggravation of multiple diseases. However, as the role of neutrophils in tissue injury repair is receiving increasing attention, it is necessary to further explore the beneficial role of activated neutrophils in promoting the resolution of inflammation after injury. In this study, we found that activated neutrophils have a crucial function in suppressing liver inflammation. In methionine-choline-deficient and high-fat (MCDHF) diet induced liver inflammation in mice, tail vein injection of activated neutrophils (A-Neu, stimulated by sphingosine 1-phosphate) inhibited the expressions of pro-inflammatory cytokines in the liver, including C-C chemokine motif ligand 4, tumor necrosis factor and nitric oxide synthase 2, and attenuated liver injury. However, non-activated neutrophils (N-Neu) did not have these effects. In vitro, pro-inflammatory macrophages were co-cultured with N-Neu or A-Neu by transwell, respectively. A-Neu was found to suppress the pro-inflammatory phenotype of macrophages by using RT-qPCR, western blot and cytometric bead array. Microarray analysis showed that there were systematic variations in transcript expression levels between N-Neu and A-Neu. GeneVenn software was used to show the gene expression overlap between GO terms including Regulation of Cell Communication, Cytokine Secretion, Inflammatory Response and Extracellular Space clusters. We identified that Chitinase-like 1 (CHIL1) secreted by S1P activated neutrophils may be an important mediators affecting the pro-inflammatory macrophage responses. In the injured liver of mice induced by MCDHF diet, the expression of Chil1 mRNA increased and was positively correlated with the neutrophil marker Ly6g. Moreover, the secretion of CHIL1 in A-Neu increased significantly. Strikingly, the effect of A-Neu on macrophage response was reproduced by incubating pro-inflammatory macrophages with recombinant CHIL1. A-Neu conditioned medium were incubated with CHIL1 antibody-conjugated protein G beads, magnetically separated to immunodepletion CHIL1 from the A-Neu supernatant, which can partially weaken its inhibitory effect of A-Neu on the production of macrophage pro-inflammatory cytokines. Together, the conclusions indicated that A-Neu could inhibit the pro-inflammatory macrophage responses by secreting CHIL1, thereby effectively inhibiting liver inflammation.

Dual Targeting of Angipoietin-1 and von Willebrand Factor by microRNA-671-5p Attenuates Liver Angiogenesis and Fibrosis.

Angipoietin-1 (Angpt1) and von Willebrand factor (VWF) are two important angiogenic molecules that can drive pathologic angiogenesis and progression of liver fibrosis in our previous study. MicroRNAs (miRs) participate in a variety of physiological and pathological processes, including angiogenesis. However, the critical miRs targeting Angpt1 or VWF and potential molecular mechanism underlying liver fibrosis-associated angiogenesis is not clear yet. Human liver tissues were obtained from patients with different chronic liver diseases. Mouse models of liver fibrosis were induced by injection of CCl4 or bile duct ligation (BDL) operation. MiR-671-5p was predicted to target Angpt1 and VWF from three databases (miRanda, RNA22v2, and miRwalk). MiR-671-5p expression was decreased in the fibrotic liver of human and mice, with a negative correlation with the levels of Angpt1, VWF, sphingosine kinase-1 (SphK1, the rate-limiting enzyme for sphingosine 1-phosphate [S1P] formation), transforming growth factor ß1 (TGFß1), hypoxia inducible factor (Hif)1α, Hif2α, and fibrosis markers. Importantly, miR-671-5p expression was down-regulated in fluorescence-activated cell sorted liver sinusoidal endothelial cells and hepatic stellate cells (HSCs) in CCl4 mice compared with control mice. In vitro miR-671-5p expression was also decreased in S1P-stimulated HSCs and TGFß1-activated liver sinusoidal endothelial cells, negatively correlated with Angpt1 and VWF expression. MiR-671-5p directly targeted Angpt1 and VWF by luciferase reporter assays. In vivo administration of miR-671-5p agomir decreased the messenger RNA and protein levels of Anpgt1 and VWF, and attenuated CCl4 -induced or BDL-induced liver angiogenesis and fibrosis. Conclusion: We identify the negative regulation of miR-671-5p on Angpt1 and VWF and liver fibrosis-associated angiogenesis, which may provide promising targets for the prevention and treatment of liver disease.

Geographic variation in cumulative incidence of private cataract surgery in Australia and its influencing factors: Findings from the 45 and Up Study.

PURPOSE: To investigate the geographic variation in the cumulative incidence of private cataract surgery (PCS) and its association with remoteness, socioeconomic, and private health insurance coverage indexes in a large Australian population. METHODS: A prospective population-based study of 266,896 Australian adults living in New South Wales (NSW) aged 45 years older and over were enrolled in the 45 and Up Study. PCS was identified using Medicare claims data. Participants were assigned to a Statistical Area Level 3 (SA3) based on residential postcode in NSW. Cumulative incidence of PCS (number of surgery per 100,000 population from 2006 to 2016) among 89 SA3s was calculated and standardized to the baseline population. Remoteness and socioeconomic deprivation was derived from Australian Bureau of Statistics (ABS). Private health insurance coverage rates were obtained from the baseline interview. RESULTS: A total of 257,237 participants with complete data were included in the current analysis. During the study period, a total of 67,707 cataract surgeries were performed among 39,744 participants. Cumulative incidence of PCS varied from 14,897 to 37,314 per 100,000 across 89 SA3s. Multivariable adjusted regression models showed that remoteness index and private health insurance coverage rates were independently associated with cumulative incidence of PCS (all P < 0.05), while no significant association between socioeconomic deprivation and cumulative incidence of PCS was observed. Collectively, these three variables explained 52.7% of the geographic variability. CONCLUSIONS: The geographical variation in the cumulative incidence of PCS calls for interventions targeted at individuals living in remote areas to reduce the burden of cataract-related vision impairment.