Nanocarrier of Pin1 inhibitor based on supercritical fluid technology inhibits cancer metastasis by blocking multiple signaling pathways.

Cancer metastasis is the primary cause of all cancer-related deaths due to the lack of effective targeted drugs that simultaneously block multiple signaling pathways that drive the dissemination and growth of cancer cells. The unique proline isomerase Pin1 activates numerous cancer pathways, but its role in cancer metastasis and the inhibitory efficacy of Pin1 inhibitors on cancer metastasis are unknown. Moreover, the applicability of Pin1 inhibitor-all-trans retinoic acid (ATRA) is limited due to its several drawbacks. Herein, uniform ATRA-loaded polylactic acid-polyethylene glycol block copolymer nanoparticles (ATRA-NPs) with high encapsulation efficiency, good cellular uptake, excellent controlled release performance and pharmacokinetics are developed using supercritical carbon dioxide processing combined with an optimized design. ATRA-NPs exhibited excellent biosafety and significant inhibition on the growth and metastasis of hepatocellular carcinoma. Pin1 played a key role in cancer metastasis and was the main target of ATRA-NPs. ATRA-NPs exerted their potent anti-metastatic effect by inhibiting Pin1 and then simultaneously blocking multiple signaling pathways and cancer epithelial-mesenchymal progression. Since ATRA-NPs could effectively couple the inhibition of cancer cell dissemination with cancer growth, it provided a novel therapeutic strategy for efficiently inhibiting cancer metastasis.

The Supportive Role of International Government Funds on the Progress of Sepsis Research During the Past Decade (2010-2019): A Narrative Review.

This narrative review aimed to clarify the characteristics of international government support for sepsis research, trends in published literature on sepsis, and potential contributions of government-source grants to progress in sepsis research between fiscal years 2010 and 2019. The data in this study were collected from the National Institutes of Health (NIH, https://projectreporter.nih.gov/reporter.cfm/) of the United States of America (USA), National Natural Science Foundation of China (NSFC, https://isisn.nsfc.gov.cn/egrantweb/), and Japan Society for the Promotion of Science (JSPS, https://kaken.nii.ac.jp/). All sepsis-related projects approved by the NIH, NSFC, and JSPS were retrieved by searching the project titles, abstracts, and key words for "sepsis," "septic shock," or "sepsis inflammatory response syndrome" between 2010 and 2019. Representative sepsis-related studies published between Jan 2010 and Aug 2020 by the first/corresponding authors from these countries were obtained by searching the PubMed database using Medical Subject Heading terms for "sepsis" in representative journals, including Nature, Cell, Science, The Lancet, New England Journal of medicine (New Engl J Med), The Journal of American Medical Association (JAMA), Critical Care Medicine (CCM), Intensive Care Medicine (ICM), Chest, Annals of Emergency Medicine (Ann Emerg Med), and American Thoracic Society journals (ATS). The total/annual institutional budgets, major funding mechanisms and schemes, superior institutions and individual principal investigators, and published original research articles in the field of sepsis in the USA, China, and Japan during the past decade were investigated. The national supporting schemes of the NIH, NSFC, and JSPS were similar. Support from these institutions is quite important for the development of the field of "sepsis" which was acknowledged in 57-64% of original research articles published in CCM. For the future development of precision medicine in sepsis, more government funding support is necessary.

Dec2 inhibits macrophage pyroptosis to promote periodontal homeostasis.

PURPOSE: Macrophages play crucial roles as early responders to bacterial pathogens and promote/ or impede chronic inflammation in various tissues. Periodontal macrophage-induced pyroptosis results in physiological and pathological inflammatory responses. The transcription factor Dec2 is involved in regulating immune function and inflammatory processes. To characterize the potential unknown role of Dec2 in the innate immune system, we sought to elucidate the mechanism that may alleviate macrophage pyroptosis in periodontal inflammation. METHODS: Porphyromonas gingivalis lipopolysaccharide (LPS) was used to induce pyroptosis in RAW 264.7 macrophages. Subsequently, we established an LPS-stimulated Dec2 overexpression cellular model in macrophages. Human chronic periodontitis tissues were employed to evaluate potential changes in inflammatory marker expression and pyroptosis. Finally, the effects of Dec2 deficiency on inflammation and pyroptosis were characterized in a P. gingivalis-treated experimental periodontitis Dec2-knockout mouse model. RESULTS: Macrophages treated with LPS revealed significantly increased messenger RNA expression levels of Dec2 and interleukin (IL)-1ß. Dec2 overexpression reduced IL-1ß expression in macrophages treated with LPS. Overexpression of Dec2 also repressed the cleavage of gasdermin D (GSDMD), and the expression of caspase-11 was concurrently reduced in macrophages treated with LPS. Human chronic periodontitis tissues showed significantly higher gingival inflammation and pyroptosis-related protein expression than non-periodontitis tissues. In vivo, P. gingivalis-challenged mice exhibited a significant augmentation of F4/80, tumor necrosis factor-α, and IL-1ß. Dec2 deficiency markedly induced GSDMD expression in the periodontal ligament of P. gingivalis-challenged mice. CONCLUSIONS: Our findings indicate that Dec2 deficiency exacerbated P. gingivalis LPS-induced periodontal inflammation and GSDMD-mediated pyroptosis. Collectively, our results present novel insights into the molecular functions of macrophage pyroptosis and document an unforeseen role of Dec2 in pyroptosis.

A deficiency of Dec2 triggers periodontal inflammation and pyroptosis.

BACKGROUND AND OBJECTIVES: Periodontal pathogens initiate various diseases and induce inflammatory host responses. The activation of inflammasomes triggers caspase-1 and interleukin (IL)-1ß-mediated pyroptosis via gasdermin D (GSDMD). Differentiated embryo chondrocyte 2 (Dec2) is a transcription repressor that controls the expression of genes involved in innate immune and inflammatory responses. However, the effects of Dec2 on inflammasome-induced pyroptosis in periodontal tissues remain elusive. This study aimed to characterize the activation of Dec2 inflammasomes that contribute to P. gingivalis lipopolysaccharide (LPS)-induced pyroptosis and its functional and regulatory importance in periodontal inflammation. MATERIALS AND METHODS: Human gingival fibroblasts (HGFs) and human periodontal ligament fibroblasts (HPDLFs) were stimulated with P. gingivalis LPS in vitro. An experimental periodontitis mouse model (wild-type (WT) and Dec2KO) was established to profile periodontal pyroptosis. RESULTS: The results demonstrate that P. gingivalis LPS activates caspase-1, caspase-11, and NF-κB in HGFs and in HPDLFs. siRNA knockdown of Dec2 stimulated the induction and further upregulated LPS-induced pyroptosis in HGFs and HPDLFs, resulting in the release of IL-1ß. Further, a deficiency of Dec2 alleviated periodontal pyroptosis via the transcriptional induction of GSDMD. In addition, P. gingivalis-induced IL-1ß expression and Dec2-deficient mice subsequently increased the inflammatory effect of P. gingivalis in HGFs and in HPDLFs, confirming the importance of Dec2 in the activation of inflammasomes and the regulation of pyroptosis. CONCLUSION: Our results demonstrate that Dec2 alleviates periodontal pyroptosis by regulating the expression of NF-κB, caspase-1 and GSDMD, suggesting that Dec2 is a crucial component of inflammasome activation and subsequent pyroptosis.

Loss of Dec1 prevents autophagy in inflamed periodontal ligament fibroblast.

Periodontal ligament fibroblasts (PDLFs) are integral to the homeostasis of periodontal tissue. The transcription factor Dec1 functions to modulate Porphyromonas gingivalis-induced periodontal inflammation. Here, we aimed to characterize the Dec1-mediated autophagy in PDLFs under inflammatory conditions. Human PDLFs were subjected to an inflammatory environment using P. gingivalis Lipopolysaccaride (LPS) along with Dec1 siRNA in vitro. Quantitative real-time polymerase chain reaction and Western blot analyses were used to evaluate the expression levels of autophagy-related genes and their upstream AKT/mTOR signaling pathways. An experimental P. gingivalis-treated Dec1 knockout (Dec1KO) mouse model was used to confirm the expression of autophagy in PDLFs in vivo. Treatment with P. gingivalis LPS induced the expression of ATG5, Beclin1 and microtubule-associated protein 1 light chain 3 (LC3) and elevated the expression of pro-inflammatory cytokine IL-1ß and Dec1 in human PDLFs. Knockdown of Dec1 partly reversed the detrimental influences of LPS on these autophagy markers in human PDLFs. The inhibition of autophagy with Dec1 siRNA suppressed the inflammatory effect of AKT/mTOR signaling pathways following treatment with P. gingivalis LPS. P. gingivalis-treated Dec1KO mice partly reduced autophagy expression. These findings suggest that a Dec1 deficiency can modulate the interaction between autophagy and inflammation in PDLFs.

MicroRNA-21 facilitates osteoblast activity.

MicroRNAs are emerging as critical post-transcriptional modulators in bone remodeling, regulating the functions of osteoblasts and osteoclasts. Intercellular crosstalk between osteoblasts and osteoclasts is mediated by miR-21 that controls the bone homeostasis response, providing potential targets for the maintenance of osteoblast function. The aim of this study was to investigate the effects of miR-21 on osteoblast function, and to explore the underlying mechanism. Increased alkaline phosphatase (ALP) activity and accelerated matrix mineralization was observed in mouse pre-osteoblast MC3T3-E1 cells compared with the non-induction (control) group. MiR-21 positively regulates osteogenic differentiation and mineralization by facilitating the expression of key osteogenic factors (ALP, Runx2, Osteopontin (OPN), Osterix (OSX) and Mef2c) in MC3T3-E1 cells. Furthermore, a deficiency of miR-21 suppresses the expression of those factors at both the mRNA and protein levels, indicating that miR-21 is a positive regulator of osteoblastic differentiation. H-E staining, Azan staining, Masson's Trichrome staining and Toluidine blue staining were performed in jaw and femur tissues of miR-21 knockout (miR-21KO) and wild-type (WT) mice. Immunohistochemical staining revealed substantially lower levels of ALP, Runx2 and OSX expression in jaw and femur tissues of miR-21KO mice. A similar trend was observed in femur tissues using quantitative real-time (RT) PCR. A total of 17 osteogenesis-related mRNAs were found to be differentially expressed in miR-21KO femur tissues using Mouse Gene Expression Microarray analysis. GeneSpring and Ingenuity Pathway Analysis revealed several potential target genes that are involved in bone remodeling, such as IL-1ß and HIF-1α. Several important pathways were determined to be facilitators of miR-21, which provides a reliable reference for future studies to elucidate the biological mechanisms of osteoblast function. Taken together, these results lead us to hypothesize a potential role for miR-21 in regulating osteoblast function, thus representing a potential biomarker of osteogenesis.

Dec2 attenuates autophagy in inflamed periodontal tissues.

INTRODUCTION: Transcriptional regulation of autophagy depends on the transcription factors coordinated inflammatory feedback mechanism. Here, we provide a comprehensive functional characterization of periodontal ligament fibroblasts (PDLFs) treated with Porphyromonas gingivalis lipopolysaccharide (LPS), aiming to reveal previously unappreciated biological changes and to investigate how a transcription factor differentiated embryonic chondrocytes 2 (Dec2)-deficient environment influences the function of autophagy in nflamed human PDLFs. METHODS: A Dec2-deficient (Dec2KO) experimental periodontal inflammation mouse model and treatment with P. gingivalis LPS were employed to examine the role of autophagy in PDLFs using hematoxylin and eosin staining and immunohistochemistry in vivo. A Dec2 small interfering RNA (siRNA) was used to modulate autophagy, and the effect of autophagy on the Dec2 pathway was explored using real-time polymerase chain reaction and western blot analysis in vitro. RESULTS: LPS-treated human PDLFs (HPDLFs) induced autophagy, as demonstrated by the enhanced levels of microtubule-associated protein 1 light chain 3-II (LC3-II) and the induction of ATG5, Beclin1, and Dec2. Compared with a scrambled siRNA, a Dec2 siRNA triggered the detrimental influences of LPS and markedly enhanced autophagy expression in inflamed HPDLFs. The expression of phosphorylated ERK was increased and levels of phosphorylated mammalian target of rapamycin (mTOR) were decreased after exposure to LPS in Dec2 siRNA transfected HPDLFs. The Dec2KO model exhibited that P. gingivalis in Dec2 deficient conditions increases the inflammation of PDLFs by regulating autophagy. CONCLUSIONS: These results demonstrate that a Dec2 deficiency can alleviate LPS-induced inflammation via the ERK/mTOR signaling pathway by regulating autophagy, conceivably delivering a novel approach for the detection of periodontal treatments.

[Analysis of projects funded by NSFC in field of efficacy material base of traditional Chinese medicine].

This paper introduces the application and financing of programs of efficacy material base of traditional Chinese medicine funded by the National Natural Science Foundation of China(NSFC), the Youth Science Fund and the Regional Science Fund from 2016 to 2019, and conducts analysis and summary in terms of research objects and analysis methods, with the aim to provide reference for applicants for programs of efficacy material base of traditional Chinese medicine.

[Analysis on projects of ethnomedicine and ethnopharmacology funded by National Natural Science Foundation of China from 1986-2018].

Through summarizing the applications and funding for research related to ethnomedicine and ethnopharmacology in the department of Health Sciences of the National Natural Science Foundation of China( NSFC) from 1986 to 2018,and analyzing the categories,numbers,funds and research contents of all funded projects including Mongolian,Uygur,Tibetan,Zhuang,Miao,the study is aimed to provide certain reference for the declaration of ethnic medicine project. The results showed that the national medicine project application numbers and the amount of funding growth after 2011 have increased significantly,but the overall level of research remained to be further promoted,and the lack of suitable for the study of ethnic medicine features and ways,has yet to mainland medical universities and research institutions to give more attention and jointly promote the development of basic research in the field of ethnic medicine.

[Overview of research projects funding in traditional Chinese medicine oncology field supported by National Natural Science Foundation of China].

In this paper, the funding situation of traditional Chinese medicine oncology research projects supported by National Natural Science Fund from 1986-2016 was reviewed. The characteristics of funded projects were summarized from funding amount, funding expenses, funding category, and the main research contents of projects, etc. At the same time, the main problems in the projects were analyzed in this paper, in order to provide reference for the relevant fund applicants.

[Analysis of projects funded by NSFC in field of Chinese material medica resource in recent three years].

The paper reviewed the sponsorship and final reports of projects focus on Science of Chinese materia medica resource in Medical Science Department, National Natural Science Foundation of China. The applicant and supportive organizations were analyzed. The progress and results of some projects were summarized by research fields including formation mechanism of Dao-di herbs, research of plant taxonomy, breeding and cultivation of medical plants, ecological and environmental adaptability of Chinese materia medica resource, quality assessment of Chinese materia medica resource, and biosynthesis and regulation of active compounds. In addition, the potential problems and the most and least focused areas in the application were summarized for reference.

[Analysis of different mutations in regulatory sequence of prolactin gene during the formation of 17 beta-estradiol-induced prolactinoma in eutopic and ectopic pituitary of rats].

OBJECTIVE: To analyze different mutations in regulatory sequence of prolactin (PRL) gene during the formation of 17 beta-estradiol (E2 ) -induced prolactinoma in eutopic and ectopic pituitary of rats. METHODS: Male Sprague-Dawley rats transplanted with an isologaus pituitary under renal capsule were treated with subcutaneous implantation of an empty or E2-laden silastic capsule. Reverse transcription-polymerase chain reaction was employed to evaluate the expression of PRL mRNA in pituitary glands, and DNA sequencing was used to analyze the mutation in regulatory sequence of PRL gene. RESULTS: After treated with E2 for 120 days, both the eutopic and ectopic pituitaries were three times more heavier than those from control group (P < 0. 01) , and the body weight of rats was decreased to 42. 90% of the control group (P < 0 01 ). The PRL mRNA expressions in glands from the eutopic and ectopic pituitaries 120 days after treated with E2 were much more than those in untreated pituitary glands (P <0. 01). DNA sequencing showed seven mutations in the regulatory sequence of PRL gene in the eutopic pituitaries 120 days after treated with E2 , while the mutation in the ectopic pituitaries was decreased. CONCLUSIONS: Prolactinomas can be induced by chronic treatment with E2 in both the eutopic and the ectopic pituitaries transplanted under renal capsule distant from the hypothalamus. Different mechanisms exist in the formation of eutopic and ectopic prolactinomas.