A novel neuroprotective peptide YVYAETY identified and screened from Flammulina velutipes protein hydrolysates attenuates scopolamine-induced cognitive impairment in mice.

Flammulina velutipes protein hydrolysates are known for their abundant amino acids and excellent developmental values. This study aimed to identify and screen neuroprotective peptides from F. velutipes protein hydrolysates in vitro and validate the protective effects of YVYAETY on memory impairment in scopolamine-induced mice. The F. velutipes protein was hydrolyzed by simulated gastrointestinal digestion, followed by purification through ultrafiltration and gel chromatography. The fraction exhibiting the strongest neuroprotective activity was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The main identified peptides (SDLKPADF, WNDHYY, YVYAETY, and WFHPLF) effectively mitigated excessive ROS production by increasing SOD and GSH-px activities while inhibiting cell apoptosis and mitochondrial membrane potential (MMP) collapse against oxidative stress in Aß25-35-induced HT22 cells. By molecular docking, the interaction between peptides and the active site of the Keap1-Kelch domain reveals their capacity to regulate the Keap1/Nrf2/HO-1 pathway. In vitro, the peptide YVYAETY had the best effect and can be further validated in vivo. The behavioral tests showed that YVYAETY improved scopolamine-induced cognitive impairment in mice. YVYAETY also alleviated neuron damage including neuron vacuolation and pyknotic nuclei in the hippocampus. Furthermore, it significantly inhibited oxidative stress and suppressed the activation of the Nrf2 pathway. Therefore, this study revealed that YVYAETY had the potential to serve as a novel neuroprotective agent.

Aucubin inhibits hepatic stellate cell activation through stimulating Nrf2/Smad7 axis.

AIM: Liver fibrosis may develop into end-stage liver disease if left unprevented. The study is attempting to identify a compound to ameliorate liver fibrosis progression with high efficiency and low toxicity, as well as to analyze its potential molecular mechanism. METHODS: The drug screening was performed using human hepatic stellate cell line LX-2 for identifying the compound as collagen I inhibitor. Primary Human hepatic stellate cells and LX-2 cell line were used to detect the antifibrotic function activity and molecular mechanism analysis in vitro. The CCl4-induced mouse experimental model was used to measure the amelioration in liver fibrosis. RESULTS: This study identified Aucubin, a natural compound, as a candidate for anti-liver fibrosis. Besides, Aucubin could inhibit the collagen I and α-SMA expressions in LX-2 cells and primary human hepatic stellate cells, as well as the cell proliferation. In terms of mechanism, Aucubin could upregulate Smad7 in hepatic stellate cells in a dose-dependent manner and block TGF-ß signaling. We also found that Nrf2 might be a direct target for the action of Aucubin, whose activation was necessary for Smad7 upregulation. In an in-vivo mouse model, Aucubin efficiency ameliorated the progression of CCl4-induced liver fibrosis, and reduced the hepatic levels of collagen deposition, transaminase and inflammatory cytokines. CONCLUSION: Capable of inhibiting the activation of hepatic stellate cells in vitro and in vivo, Aucubin may be a potential therapeutic candidate for liver fibrosis, which is dependent on the suppression of TGF-ß signaling through stimulating Nrf2/Smad7 axis.

Parallel Genome-Wide CRISPR Screens to Identify State-Dependent Self-Renewal Regulators of Mouse Embryonic Stem Cells.

The pluripotency of embryonic stem cells (ESCs) is more accurately viewed as a continuous developmental process rather than a fixed state. However, the factors that play general or state-specific roles in regulating self-renewal in different pluripotency states remain poorly defined. In this study, parallel genome-wide CRISPR/Cas9 knockout (KO) screens were applied in ESCs cultured in the serum plus LIF (SL) and in the 2i plus LIF (2iL) conditions. The candidate genes were classified into seven groups based on their positive or negative effects on self-renewal, and whether this effect was general or state-specific for ESCs under SL and 2iL culture conditions. We characterized the expression and function of genes in these seven groups. The loss of function of novel pluripotent candidate genes Usp28, Zfp598, and Zfp296 was further evaluated in mouse ESCs. Consistent with our screen, the knockout of Usp28 promotes the proliferation of SL-ESCs and 2iL-ESCs, whereas Zfp598 is indispensable for the self-renewal of ESCs under both culture conditions. The cell phenotypes of Zfp296 KO ESCs under SL and 2iL culture conditions were different. Our work provided a valuable resource for dissecting the molecular regulation of ESC self-renewal in different pluripotency states.

Multi-omics profiling of primary hepatic stellate cells from advanced liver fibrosis patients reveals distinctive molecular signatures.

BACKGROUND AND AIM: Hepatic fibrosis is a common pathogenic outcome of almost all chronic liver diseases and a growing public health problem globally. However, the key genes or proteins driving liver fibrosis and cirrhosis are not well understood. We aimed to identify novel hepatic fibrosis genes of human primary hepatic stellate cells (HSCs). METHODS: Human primary HSCs were isolated from surgically resected advanced fibrosis liver tissues (n = 6) and surgical resection of normal liver tissue around hemangioma (n = 5). Differences in the expression levels of mRNA and proteins from HSCs in advanced fibrosis group and the control group were analyzed using RNA sequencing and mass spectrometry as transcriptomic and proteomic approaches. The obtained biomarkers were further validated through real-time quantitative polymerase chain reaction (RT-qPCR), immunofluorescence, and Western blot. RESULTS: A total of 2156 transcripts and 711 proteins were found to be differently expressed between the advanced fibrosis group and the control group patients. The Venn diagram shows that a total of 96 upregulated molecules are overlapped in both the transcriptomic and proteomic datasets. Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes analysis indicated that those overlapped genes were mainly involved in wound healing, cell adhesion regulation, and actin binding, which reflects the major biological conversions in liver cirrhosis process. Pyruvate kinase M2 and EH domain-containing 2 were identified as potential new markers for advanced liver cirrhosis, which have been validated in primary human HSCs and in vitro cellular hepatic fibrosis model Lieming Xu-2 (LX-2) cells. CONCLUSIONS: Our results revealed the major transcriptomic and proteomic changes during liver cirrhosis process and identified new biomarkers and potential therapeutic targets for advanced liver fibrosis.

No evidence for a causal link between Helicobacter pylori infection and nonalcoholic fatty liver disease: A bidirectional Mendelian randomization study.

Although clinical studies have shown the possible relationship between Helicobacter pylori (H. pylori) infection and the development of nonalcoholic fatty liver disease (NAFLD), their causal relationship is still unknown. This bidirectional Mendelian randomization (MR) study aimed to investigate the causal link between H. pylori infection and NAFLD. Two previously reported genetic variants SNPs rs10004195 and rs368433 were used as the instrumental variables (IVs) of H. pylori infection. The genetic variants of NAFLD were extracted from the largest genome-wide association study (GWAS) summary data with 1,483 cases and 17,781 controls. The exposure and outcome data were obtained from the publicly available GWAS dataset. Then, a bidirectional MR was carried out to evaluate the causal relationship between H. pylori infection and NAFLD. In addition, the GWAS data were also collected to explore the causal relationship between H. pylori infection and relevant clinical traits of NAFLD, including triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting blood glucose (FBG), and body mass index (BMI). Genetically predicted H. pylori infection showed no association with NAFLD both in FinnGen GWAS (OR, 1.048; 95% CI, 0.778-1.411; value of p = 0.759) and the GWAS conducted by Anstee (OR, 0.775; 95% CI, 0.475-1.265; value of p = 0.308). An inverse MR showed no causal effect of NAFLD on H. pylori infection (OR,0.978;95% CI, 0.909-1.052; value of p = 0.543). No significant associations were observed between H. pylori infection and the levels of triglycerides, LDL-C, HDL-C, or FBG, while H. pylori infection was associated with an increase in BMI. These results indicated that there was no genetic evidence for a causal link between H. pylori and NAFLD, suggesting that the eradication or prevention of H. pylori infection might not benefit NAFLD and vice versa.

Sixteen-Week Vitamin D3 Supplementation Increases Peripheral T Cells in Overweight Black Individuals: Post hoc Analysis of a Randomized, Double-Blinded, Placebo-Controlled Trial.

Background: Vitamin D is considered to modulate T-cell function, which has been implicated in the treatment of inflammatory conditions. However, there is limited knowledge on the effects of vitamin D and its influences on circulating T-cell profiles in humans, particularly in overweight Black individuals who are more likely to be vitamin D insufficient (serum 25(OH)D concentrations of ≤20 ng/mL). Thus, this study tested the hypothesis that vitamin D supplementation modulates T-cell composition, which is in a dose-dependent manner. Methods: A 16-week randomized, double-blinded, placebo-controlled trial of vitamin D3 supplementation was undertaken in 70 overweight/obese Black people (mean age = 26 years, 82% female) with 25 hydroxyvitamin D ≤ 20 ng/mL at baseline. Subjects were randomly assigned a supervised monthly oral vitamin D3 equivalent to approximately 600 IU/day (n = 17), 2000 IU/day (n = 18), 4000 IU/day (n = 18), or a placebo (n = 17). Fresh peripheral whole blood was collected and CD3+, CD4+ and CD8+ cell counts and percentages were determined by flow cytometry at baseline and at 16 weeks, among 56 subjects who were included in the analyses. Results: A statistically significant increase in CD3+% in the 2000 IU/day vitamin D3 supplementation group, and increases in CD4+% in the 2000 IU/day and 4000 IU/day vitamin D3 supplementation groups were observed (p-values < 0.05) from the changes in baseline to 16 weeks. Further adjustments for age, sex and BMI showed that 2000 IU/day vitamin D3 supplementation increased in CD3+ count, CD3%, CD4 count, and CD4%, as compared to the placebo group (p-values < 0.05). Moreover, the highest serum 25(OH)D quantile group had the highest CD3% and CD4%. Conclusions: Sixteen-week vitamin D3 supplementation increases peripheral blood T-cell numbers and percentages in overweight/obese Black patients with vitamin D insufficiency. This resulting shift in circulating T-cell composition, particularly the increase in T helper cells (CD4+ cells), suggests that vitamin D supplementation may improve immune function in Black individuals.

Magnesium Intake, C-Reactive Protein, and Muscle Mass in Adolescents.

Background: Adult studies have suggested that magnesium intake may regulate C-reactive protein (CRP) and muscle mass, known risk factors for cardiometabolic diseases. Given the large deficiencies in magnesium intake in adolescents, we aimed to investigate sex and race differences in dietary magnesium intake and test the hypothesis that lower magnesium intake is associated with higher CRP and lower muscle mass. Methods: A total of 766 black and white adolescents, 14 to 18 years old (51% black; 50% female) were previously recruited. Diet was assessed with four to seven independent 24-h recalls. Body composition was measured by dual-energy X-ray absorptiometry. High-sensitivity CRP (hs-CRP), leptin, resistin, and adiponectin were measured using fasting blood samples by ELISA. Results: There were sex and race differences in the daily consumption of magnesium. The average daily magnesium intakes were 200.66 ± 7.09 mg and 205.03 ± 7.05 mg for males and females, respectively, far below the recommended amounts of 410 mg for males and 360 mg for females. White subjects (217.95 ± 6.81 mg/day) consumed more than black subjects (187.75 ± 6.92 mg/day). Almost none of the adolescents met the recommendations. Adjusted multiple linear regressions revealed that lower magnesium intake was associated with higher hs-CRP and lower fat-free mass (FFM) (p-values < 0.05). Higher hs-CRP was associated with lower FFM. Moreover, an interaction between magnesium intake and hs-CRP on FFM was identified (p-value < 0.05). Lower magnesium intake amplified the inverse relationships between hs-CRP and FFM (p-values < 0.05). Conclusion: Magnesium consumption in our adolescents was far below daily recommended levels with male and black subjects consuming less than female and white subjects. Lower magnesium intake was associated with higher CRP and lower muscle mass. Low magnesium intake may also augment the inverse relationship between CRP and FFM.

Identification of Immune Microenvironment Changes and the Expression of Immune-Related Genes in Liver Cirrhosis.

Liver inflammation and the immune response have been recognized as critical contributors to cirrhosis pathogenesis. Immunity-related genes (IRGs) play an essential role in immune cell infiltration and immune reactions; however, the changes in the immune microenvironment and the expression of IRGs involved in cirrhosis remain unclear. CD45+ liver cell single-cell RNA (scRNA) sequencing data (GSE136103) from patients with cirrhosis were analyzed. The clusters were identified as known cell types through marker genes according to previous studies. GO and KEGG analyses among differentially expressed genes (DEGs) were performed. DEGs were screened to identify IRGs based on the ImmPort database. The protein-protein interaction (PPI) network of IRGs was generated using the STRING database. IRGs activity was calculated using the AUCell package. RNA microarray expression data (GSE45050) of cirrhosis were analyzed to confirm common IRGs and IRGs activity. Relevant regulatory transcription factors (TFs) were identified from the Human TFDB database. A total of ten clusters were obtained. CD8+ T cells and NK cells were significantly decreased in patients with cirrhosis, while CD4+ T memory cells were increased. Enrichment analyses showed that the DEGs focused on the regulation of immune cell activation and differentiation, NK-cell mediated cytotoxicity, and antigen processing and presentation. Four common TFs, IRF8, NR4A2, IKZF3, and REL were expressed in both the NK cluster and the DEGs of liver tissues. In conclusion, we proposed that the reduction of the CD8+ T cell cluster and NK cells, as well as the infiltration of CD4+ memory T cells, contributed to immune microenvironment changes in cirrhosis. IRF8, NR4A2, IKZF3, and REL may be involved in the transcriptional regulation of NK cells in liver fibrosis. The identified DEGs, IRGs, and pathways may serve critical roles in the development and progression of liver fibrosis.

The assessment of mesenchymal stem cells therapy in acute on chronic liver failure and chronic liver disease: a systematic review and meta-analysis of randomized controlled clinical trials.

BACKGROUND: Mesenchymal stem cells (MSCs) therapy is showing potential therapeutic effects on liver function improvement in patients with chronic liver disease; however, the consensus on efficacy and safety of MSCs has not been reached. METHODS: We performed this systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of MSCs therapy for patients with chronic liver disease. A detailed search of the Cochrane Library, MEDLINE, Web of Science, and EMBASE databases was conducted to find studies published prior to September 15, 2021. The outcome measures were survival rate, model of end-stage liver disease (MELD) score, albumin, total bilirubin, coagulation function, and aminotransferase. RESULTS: A literature search resulted in 892 citations. Of these, 12 studies met the inclusion criteria. It was found that compared with conventional treatment, MSCs therapy was associated with improved liver function including the MELD score, albumin levels, and coagulation function. However, it had no obvious beneficial effects on survival rate and aminotransferase levels. Subgroup analyses indicated that MSCs therapy had therapeutic effects on patients with both acute on chronic liver failure (ACLF) and cirrhosis. BM-MSCs and UC-MSCs treatment had similar efficacy to improve liver function. The effectiveness varied slightly between the peripheral intravenous injection and hepatic arterial injection. Five studies reported that the only adverse event of the MSCs therapy was fever, and no serious adverse events and side effects were reported. Analysis on clinical symptoms showed that encephalopathy and gastrointestinal hemorrhage events were reduced after MSCs therapy. CONCLUSIONS: In conclusion, this study suggested that MSCs therapy could be a potential therapeutic alternative for patients with chronic liver disease in clinical practice.

A New Index Developed for Fast Diagnosis of Meteorological Roles in Ground-Level Ozone Variations.

China experienced worsening ground-level ozone (O3) pollution from 2013 to 2019. In this study, meteorological parameters, including surface temperature (T 2 ), solar radiation (SW), and wind speed (WS), were classified into two aspects, (1) Photochemical Reaction Condition (PRC = T 2 × SW) and (2) Physical Dispersion Capacity (PDC = WS). In this way, a Meteorology Synthetic Index (MSI = PRC/PDC) was developed for the quantification of meteorology-induced ground-level O3 pollution. The positive linear relationship between the 90th percentile of MDA8 (maximum daily 8-h average) O3 concentration and MSI determined that the contribution of meteorological changes to ground-level O-3 varied on a latitudinal gradient, decreasing from ∼40% in southern China to 10%-20% in northern China. Favorable photochemical reaction conditions were more important for ground-level O3 pollution. This study proposes a universally applicable index for fast diagnosis of meteorological roles in ground-level O3 variability, which enables the assessment of the observed effects of precursor emissions reductions that can be used for designing future control policies. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available in the online version of this article at 10.1007/s00376-021-1257-x.

A novel insulin delivery system by ß cells encapsulated in microcapsules.

Introduction: Diabetes is a growing epidemic worldwide and requires effective clinical therapies. In recent years, ß-cell transplantation has emerged as a promising treatment for diabetes, and an encapsulation approach has been proposed to ameliorate this treatment. Methods: Microfluidic technology had been used to generate microcapsules using a porous sodium alginate shell and a core containing ß cells. The microcapsules were transplanted into diabetic mice and the therapeutic effect was measured. Results: Porous hydrogel shell allows exchange of small molecules of nutrients while protecting beta cells from immune rejection, while the core ensures high activity of the encapsulated cells. The glucose control effect of the microcapsules were more durable and better than conventional methods. Discussion: We believe that this system, which is composed of biocompatible porous hydrogel shell and enables highly activity of encapsulated ß cells, can enhance therapeutic efficacy and has promising clinical applications.

Efficacy of Various Facial Protective Equipment for Infection Control in a Healthcare Setting.

INTRODUCTION: The coronavirus 2019 (COVID-19) pandemic has reinforced the importance of facial protection against droplet transmission of diseases. Healthcare workers wear personal protection equipment (PPE), including face shields and masks. Plastic face shields may have advantages over regular medical masks. Although many designs of face shields exist, there is a paucity of evidence regarding the efficacy of shield designs against droplet transmissions. There is even less published evidence comparing various face shields. Due to the urgency of the pandemic and the health and safety of healthcare workers, we aimed to study the efficacy of various face shields against droplet transmission. METHODS: We simulated droplet transmission via coughing using a heavy-duty chemical spray bottle filled with fluorescein. A standard-adult sized mannequin head was used. The mannequin head wore various face shields and was positioned to face the spray bottle at either a 0°, 45°, or 90° angle. The spray bottle was positioned at and sprayed from 30 centimeters (cm), 60 cm, or 90 cm away from the head. These steps were repeated for all face shields used. Control was a mannequin that wore no PPE. A basic mask was also tested. We collected data for particle count, total area of particle distribution, average particle size, and percentage area covered by particles. We analyzed percent covered by particles using a repeated measures mixed-model regression with Tukey-Kramer pairwise comparison. RESULTS: We used least square means to estimate the percentage area covered by particles. Wearing PPE regardless of the design reduced particle transmission to the mannequin compared to the control. The LCG mask had the lowest square means of 0.06 of all face-shield designs analyzed. Tukey-Kramer pairwise comparison showed that all PPEs had a decrease in particle contamination compared to the control. LCG shield was found to have the least contamination compared to all other masks (P < 0.05). CONCLUSION: Results suggest the importance of wearing a protective covering against droplet transmission. The LCG shield was found to decrease facial contamination by droplets the most of any tested protective equipment.

The role of dendritic cells derived osteoclasts in bone destruction diseases.

The bone is previously considered as a dominant organ involved in the processes of locomotion. However, in the past two decades, a large number of studies have suggested that the skeletal system closely coordinated with the immune system so as to result in the emerging area of 'osteoimmunology'. In the evolution of many kinds of bone destruction-related diseases, osteoclasts could differentiate from dendritic cells, which contributed to increased expression of osteoclast-related membrane receptors and relatively higher activity of bone destruction, inducing severe bone destruction under inflammatory conditions. Numerous factors could influence the interaction between osteoclasts and dendritic cells, contributing to the pathogenesis of several bone diseases in the context of inflammation, including both immunocytes and a large number of cytokines. In addition, the products of osteoclasts released from bone destruction area serve as important signals for the differentiation and activation of immature dendritic cells. Therefore, the border between the dendritic cell-related immune response and osteoclast-related bone destruction has gradually unravelled. Dendritic cells and osteoclasts cooperate with each other to mediate bone destruction and bone remodelling under inflammatory conditions. In this review, we will pay attention to the interactions between dendritic cells and osteoclasts in physiological and pathological conditions to further understand the skeletal system and identify potential new therapeutic targets for the future by summarizing their significant roles and molecular mechanisms in bone destruction.

Handgrip and sex-specific cardiometabolic risk factors in Hispanic/Latino migrant farmworkers.

Studies have suggested that handgrip strength might be a marker for cardiometabolic risk (CMR), but it has not been studied in Hispanic/Latino farmworker population. This study aimed to characterize absolute and relative handgrip strength in Hispanic/Latino farmworkers, and investigate the sex-specific association between handgrip strength and CMR factors. CMR factors and seated isometric absolute (the sum of both hands) and relative (absolute handgrip strength divided by body mass index) handgrip strengths were collected in 173 Hispanic/Latino farmworkers (mean age 35.1 ± 0.7 years; 49% female). The absolute and the relative handgrip strengths were 89.2 ± 1.8 kg, 3.3 ± 0.1 kg among males, and 56.5 ± 1.9 kg, 1.9 ± 0.1 kg among females, respectively. Age was correlated with absolute (r = - 0.17, p = 0.03) and relative handgrip strengths (r = - 0.28, p < 0.01). In males, absolute handgrip was related to triglycerides (r = - 0.25, p < 0.05), whereas relative handgrip was related to waist circumference (r = - 0.32, p < 0.01), waist/hip circumference ratio (r = - 0.36, p < 0.01), high-density lipoprotein (r = 0.24, p < 0.05), and triglycerides (r = - 0.35, p < 0.01). In females, absolute handgrip was related to fasting plasma glucose (r = - 0.28, p = 0.03), whereas relative handgrip was related to waist circumference (r = - 0.38, p < 0.01) and fasting plasma glucose (r = - 0.22, p < 0.05). Males had lower absolute handgrip strength when their triglycerides levels were at risk (p = 0.021), and lower relative handgrip strength when their plasma glucose (p = 0.034) and triglycerides (p = 0.002) levels were at risk. Females had lower relative handgrip strength when their plasma glucose (p = 0.001) and blood pressure (p = 0.004) were at risk. This study suggests that handgrip strength may be associated with sex-specific CMR factors in a Hispanic/Latino farmworker population.

A selected small molecule prevents inflammatory osteolysis through restraining osteoclastogenesis by modulating PTEN activity.

BACKGROUND: Inflammatory osteolysis is a severe infectious bone disorder that occurs during orthopaedic surgery and is caused by disruptions in the dynamic balance of bone matrix homeostasis, which makes this condition a burden on surgical procedures. Developing novel therapeutic drugs about inhibiting excessive osteoclastogenesis acts as an efficient approach to preventing inflammatory bone destruction. METHODS: To study this, we explored the potential effects and mechanisms of compound 17 on inflammatory osteolysis in vitro. Meanwhile, a lipopolysaccharide (LPS)-induced calvarial osteolysis mouse model was used to evaluate the protective effect of compound 17 on inflammatory bone destruction in vivo. RESULTS: In our study, we found that compound 17 could inhibit osteoclast (OC) differentiation and bone resorption during RANKL and LPS stimulation in a time- and dose-dependent manner, while compounds 5 and 13 did not have the same effects. Mechanistically, compound 17 promoted phosphatase and tensin homologue (PTEN) activity by reducing PTEN ubiquitination, thereby restraining the RANKL-induced NF-κB pathway, resulting in the inhibition of the expression of osteoclastogenesis-related genes and the formation of the NLRP3 inflammasome. Additionally, we also investigated whether compound 17 could negatively modulate macrophage polarization and repolarization due to its anti-inflammatory effects. Moreover, compound 17 also plays an important role in osteoblast differentiation and mineralization. In vivo experiments showed that compound 17 could effectively protect mice from LPS-induced inflammatory bone destruction by inhibiting osteoclastogenesis and inflammation. CONCLUSIONS: Taken together, these results show that compound 17 might play protective role in inflammatory bone destruction through inhibiting osteoclastogenesis and inflammation. These findings imply a possible role of compound 17 in inflammatory osteolysis-related diseases.

Tumour dormancy in inflammatory microenvironment: A promising therapeutic strategy for cancer-related bone metastasis.

Cancer metastasis is a unique feature of malignant tumours. Even bone can become a common colonization site due to the tendency of solid tumours, including breast cancer (BCa) and prostate cancer (PCa), to metastasize to bone. Currently, a previous concept in tumour metabolism called tumour dormancy may be a promising target for antitumour treatment. When disseminated tumour cells (DTCs) metastasize to the bone microenvironment, they form a flexible regulatory network called the "bone-tumour-inflammation network". In this network, bone turnover as well as metabolism, tumour progression, angiogenesis and inflammatory responses are highly unified and coordinated, and a slight shift in this balance can result in the disruption of the microenvironment, uncontrolled inflammatory responses and excessive tumour growth. The purpose of this review is to highlight the regulatory effect of the "bone-tumour-inflammation network" in tumour dormancy. Osteoblast-secreted factors, bone turnover and macrophages are emphasized and occupy in the main part of the review. In addition, the prospective clinical application of tumour dormancy is also discussed, which shows the direction of future research.

Dendritic cells-derived interferon-λ1 ameliorated inflammatory bone destruction through inhibiting osteoclastogenesis.

Bone infection contributing to inflammatory osteolysis is common in orthopedic surgery. The dynamic balance between bone formation and bone resorption is destroyed due to excessive osteoclast fusion and differentiation, which results in severe bone matrix loss. Many therapeutic approaches that restrain osteoclast formation and function act as efficient ways to prevent inflammatory bone erosion. We have demonstrated for the first time that dendritic cells-derived interferon-λ1 (IFN-λ1) inhibited inflammatory bone destruction in vivo and explored its underlying mechanisms on osteoclast formation in vitro. We found that IFN-λ1 was highly expressed in infectious bone tissue compared with that of non-infectious bone tissue. Additionally, dendritic cells marker genes such as CD80, CD86, and CD1a were higher expressed in infectious bone tissue than that of non-infectious bone tissue. Dendritic cells that were pretreated with LPS showed high expression of IFN-λ1. Moreover, conditioned medium of LPS-pretreated dendritic cells significantly inhibited osteoclast differentiation, as determined by TRAP staining assay. This suppressive effect was reversed by adding an IFN-λ1 monoclonal antibody. It was also investigated whether exogenous IFN-λ1 restrained osteoclastogenesis, bone resorption, F-actin ring formation, osteoclast-specific gene expression, release of pro-inflammatory cytokines, and translocation of p65 and NFATc1 by preventing the NF-κB signaling pathway and NLRP3 inflammasome formation, as well as by inducing the JAK-STAT signaling pathways in vitro. In vivo study indicated that IFN-λ1 prevents lipopolysaccharide (LPS)-induced inflammatory bone destruction by inhibiting excessive osteoclast fusion and bone resorption activity. In conclusion, our findings confirmed that dendritic cells-derived IFN-λ1 could attenuate osteoclast formation and bone resorptive activity in vitro and in vivo. These novel findings pave the way for the use of exogenous IFN-λ1 as a potential therapeutic treatment for excessive osteoclast-related diseases, such as inflammatory osteolysis, by regulating osteoclastogenesis to maintain the dynamic balance between bone formation and bone resorption.

Sphingosine-1-phosphate (S1P) receptors: Promising drug targets for treating bone-related diseases.

Sphingosine-1-phosphate (S1P) is a natural bioactive lipid molecule and a common first or second messenger in the cardiovascular and immune systems. By binding with its receptors, S1P can serve as mediator of signalling during cell migration, differentiation, proliferation and apoptosis. Although the predominant role of S1P in bone regeneration has been noted in many studies, this role is not as well-known as its roles in the cardiovascular and immune systems. In this review, we summarize previous research on the role of S1P receptors (S1PRs) in osteoblasts and osteoclasts. In addition, S1P is regarded as a bridge between bone resorption and formation, which brings hope to patients with bone-related diseases. Finally, we discuss S1P and its receptors as therapeutic targets for treating osteoporosis, inflammatory osteolysis and bone metastasis based on the biological effects of S1P in osteoclastic/osteoblastic cells, immune cells and tumour cells.

P2X7 receptor acts as an efficient drug target in regulating bone metabolism system.

Skeletal system is a highly dynamic system going through continuous resorption and reconstruction to maintain homeostasis, which is influenced by numerous factors. Once the balance is disrupted, various kinds of bone diseases may occur such as osteoporosis. It has been well known that ATP (adenosine triphosphate), an important signaling molecule, is important in maintaining the dynamic balance of bone matrix. ATP mainly functions through P2X receptors, a kind of ATP receptors expressed by various kinds of bone cells to regulate the whole network of skeleton system. Among P2X receptors, P2X7 plays a crucial role in bone since P2X7 is widely expressed by bone cells and the mutation of P2X7 receptor is associated with kinds of bone diseases. It's acknowledged that P2X7 acts as a potential therapeutic target for clinical treatment of bone-related diseases but further investigations are needed for the practical application. However, since P2X7 has a complicated effect in many aspects, the exact role of P2X7 in skeleton system is ambiguous. This review discusses the function of P2X7 in bone and other cells and their general effect on skeleton system, especially focusing on the possible clinical application for bone diseases.

Multiple fingerprint and fingerprint-activity relationship for quality assessment of polysaccharides from Flammulina velutipes.

Polysaccharides are known as one of the most important bioactive compounds in Flammulina velutipes. However, there is no accurate and comprehensive assessment method to evaluate and authenticate F. velutipes polysaccharides (FVPs) from different sources. In this study, a multiple fingerprint analysis method including scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FT-IR), and high-performance liquid chromatography (HPLC) was established. The inhibitory activities of FVPs against HepG2 were measured and introduced into multiple linear regression (MLR) analysis to investigate fingerprint-activity relationship. The principal component analysis (PCA) scores showed that the polysaccharides extracted from 20 batches of different F. velutipes were highly similar, and substandard samples could be distinguished from the authentic polysaccharides clearly. The glucuronic acid could be considered as a marker for discrimination of white and yellow F. velutipes polysaccharides in HPLC fingerprints. Moreover, the HPLC fingerprint-growth inhibitory activity relationship illuminated that monosaccharides composition played an important role on the HepG2 growth inhibitory activity, and activity-associated markers (mannose, rhamnose, xylose, and galactose) were chosen to assess FVPs from different sources. The suggested HPLC fingerprint-activity relationship method provides an integrated strategy for the quality control of F. velutipes and its related products.