The differentiation and maturation trajectories of fetal liver stem/progenitor cells (LSPCs) are not fully understood at single-cell resolution, and a priori knowledge of limited biomarkers could ...restrict trajectory tracking.
We employed marker-free single-cell RNA-Seq to characterize comprehensive transcriptional profiles of 507 cells randomly selected from seven stages between embryonic day 11.5 and postnatal day 2.5 during mouse liver development, and also 52 Epcam-positive cholangiocytes from postnatal day 3.25 mouse livers. LSPCs in developing mouse livers were identified via marker-free transcriptomic profiling. Single-cell resolution dynamic developmental trajectories of LSPCs exhibited contiguous but discrete genetic control through transcription factors and signaling pathways. The gene expression profiles of cholangiocytes were more close to that of embryonic day 11.5 rather than other later staged LSPCs, cuing the fate decision stage of LSPCs. Our marker-free approach also allows systematic assessment and prediction of isolation biomarkers for LSPCs.
Our data provide not only a valuable resource but also novel insights into the fate decision and transcriptional control of self-renewal, differentiation and maturation of LSPCs.
The oncogenic mechanisms of overnutrition, a confirmed independent cancer risk factor, remain poorly understood. Herein, we report that enoyl-CoA hydratase-1 (ECHS1), the enzyme involved in the ...oxidation of fatty acids (FAs) and branched-chain amino acids (BCAAs), senses nutrients and promotes mTOR activation and apoptotic resistance. Nutrients-promoted acetylation of lys
of ECHS1 impedes ECHS1 activity by impairing enoyl-CoA binding, promoting ECHS1 degradation and blocking its mitochondrial translocation through inducing ubiquitination. As a result, nutrients induce the accumulation of BCAAs and FAs that activate mTOR signaling and stimulate apoptosis, respectively. The latter was overcome by selection of BCL-2 overexpressing cells under overnutrition conditions. The oncogenic effects of nutrients were reversed by SIRT3, which deacetylates lys
acetylation. Severely decreased ECHS1, accumulation of BCAAs and FAs, activation of mTOR and overexpression of BCL-2 were observed in cancer tissues from metabolic organs. Our results identified ECHS1, a nutrients-sensing protein that transforms nutrient signals into oncogenic signals.Overnutrition has been linked to increased risk of cancer. Here, the authors show that exceeding nutrients suppress Enoyl-CoA hydratase-1 (ECHS1) activity by inducing its acetylation resulting in accumulation of fatty acids and branched-chain amino acids and oncogenic mTOR activation.
The secondary metabolites of marine fungi with rich chemical diversity and biological activity are an important and exciting target for natural product research. This study aimed to investigate the ...fungal community in Quanzhou Bay, Fujian, and identified 28 strains of marine fungi. A total of 28 strains of marine fungi were screened for small-scale fermentation by the OSMAC (One Strain-Many Compounds) strategy, and 77 EtOAc crude extracts were obtained and assayed for cancer cell inhibition rate. A total of six strains of marine fungi (P-WZ-2, P-WZ-3-2, P-WZ-4, P-WZ-5, P56, and P341) with significant changes in cancer cell inhibition induced by the OSMAC strategy were analysed by UPLC-QTOF-MS. The ACD/MS Structure ID Suite software was used to predict the possible structures with inhibitory effects on cancer cells. A total of 23 compounds were identified, of which 10 compounds have been reported to have potential anticancer activity or cytotoxicity. In this study, the OSMAC strategy was combined with an untargeted metabolomics approach based on UPLC-QTOF-MS to efficiently analyse the effect of changes in culture conditions on anticancer potentials and to rapidly find active substances that inhibit cancer cell growth.
The interaction between glomerular endothelial cells (GECs) and glomerular mesangial cells (GMCs) is an essential aspect of diabetic nephropathy (DN). Therefore, understanding how GECs communicate ...with GMCs in the diabetic environment is crucial for the development of new targets for the prevention and treatment of DN. Exosomes, nanometer-sized extracellular membrane vesicles secreted by various cell types, play important roles in cell-to-cell communication via the transfer of mRNA, microRNA and protein. In this study, we demonstrate that high glucose (HG)-treated GECs secrete a higher number of exosomes highly enriched in TGF-β1 mRNA compared with normal glucose (NG)-treated GECs. Exosomes released by HG-treated GECs can promote α-smooth muscle actin (α-SMA) expression, proliferation and extracellular matrix protein overproduction in GMCs through the TGF-β1/Smad3 signaling pathway. Thus, we provide new insights into the pathogenesis of DN that involves intercellular transfer of TGF-β1 mRNA in the GEC-to-GMC direction via exosomes.
Objective
This study was designed to analyze the relationship between tumor metastasis and acute ischemic stroke (AIS) in Chinese cancer patients.
Methods
This retrospective study included 119 cancer ...patients with AIS and 152 cancer patients without AIS. Basic information was collected and tumor metastasis status was determined for all patients.
Results
The whole cohort had a median age of 59 (49–69) years with 150 men (55.4%). There were 98 patients (36.2%) with tumor metastasis. Patients with AIS had significantly more males, tumor metastasis, lung cancer, hypertension, diabetes mellitus, higher age, D-dimer, international normalized ratio, prothrombin time, prothrombin activity, and thrombin time, while they had significantly lower levels of hemoglobin, red blood cells, and hematocrit. In multivariate logistic regression analysis, AIS was significantly and positively associated with age, tumor metastasis, D-dimer, and thrombin time. In multivariate Cox regression analysis, tumor metastasis, AIS, D-dimer, thrombin time, and fibrinogen were significantly and positively associated with worse prognosis.
Conclusions
This study demonstrates that tumor metastasis was positively and independently associated with AIS in Chinese cancer patients, suggesting that tumor metastasis has a significant relationship with the development of AIS. Additionally, tumor metastasis and AIS had negative independent effects on the prognosis of patients.
Scope
Quercetin (QU) is one of the most abundant flavonoids in plants and has attracted the attention of researchers because of its remarkable antirheumatoid arthritis (RA) effects and extremely low ...adverse reactions. However, the underlying mechanism needs further study.
Methods and results
Flow cytometry, immunofluorescence, enzyme linked immunosorbent assay （ELISA）, and quantitative real‐time polymerase chain reaction （qRT‐PCR） reveal the obvious inhibitory effects of QU on Th17 cell differentiation in arthritic mice. More importantly, QU markedly limits the development of Th17 cell polarization, which is virtually compromised by the treatment with peroxisome proliferator activated receptor γ (PPARγ) inhibitor GW9662 and knockdown of PPARγ. Additionally, molecular dynamics simulation and immunofluorescence exhibit QU directly binds to PPARγ and increases PPARγ nuclear translocation. Besides, QU confers its moderation effect on suppressor of cytokine signaling protein (SOCS3)/signal transducer and activator of transcription 3 (STAT3) axis partially depending on PPARγ. Furthermore, coimmunoprecipitation shows QU redistributes the corepressor silencing mediator for retinoid and thyroid‐hormone receptors (SMRT) from PPARγ to STAT3. Finally, the inhibition of Th17 response and the antiarthritic effect of QU are nullified by GW9662 treatment in arthritic mice.
Conclusion
QU targets PPARγ and consequently inhibits Th17 cell differentiation by dual inhibitory activity of STAT3 to exert antiarthritic effect. The findings facilitate its development and put forth a stage for uncovering the mechanism of other naturally occurring compounds with chemical structures similar to QU.
Quercetin is commonly found in foods with anti‐arthritic effects. In this work, authors try to explore the underlying mechanism of quercetin on rheumatoid arthritis. The research finds that quercetin could up‐regulate the expression of suppressors of cytokine signaling 3 (SCOS3) by directly activating peroxisome proliferator activated receptor γ (PPARγ), and further impede Th17 cell differentiation to alleviate arthritis.
Neoadjuvant therapy has become the standard of care for locally advanced mid-low rectal cancer. Pathological complete response (pCR) can be achieved in 12%e38% of patients. Patients with pCR have the ...most favorable long-term outcomes. Intensifying neoadjuvant therapy and extending the interval between termination of neoadjuvant treatment and surgery may in-crease the pCR rate. Growing evidence has raised the issue of whether local excision or observation rather than radical surgery is an alternative for patients who achieve a clinical complete response after neoadjuvant therapy. Herein, we highlight many of the advances and resultant controversies that are likely to dominate the research agenda for pCR of rectal cancer in the modern era.
Background AT-533 is a novel heat shock protein 90 inhibitor that exerting anti-inflammatory, antiviral, and antitumor efficacy. Furthermore, the gel made of AT-533 as raw material named AT-533 gel ...has the function of repairing keratitis and dermatitis caused by herpes virus infection. However, the acute safety evaluation of AT-533 and AT-533 gel has not been conducted. Methods and results Herein, we performed acute toxicological studies of AT-533 and AT-533 gel in Sprague-Dawley rats. Fifteen-day acute toxicity study of AT-533 was conducted in both male and female Sprague-Dawley rats at doses of 5, 50, 250 and 500 mg/kg and AT-533 gel at 5 g/kg in the study. During experiment, food consumption and mortality were observed and body weight, hematology, serum biochemistry and histopathological assessment of rats were carried out. No abnormal changes were observed in rats percutaneously treated with AT-533 at 5 mg/kg and 50 mg/kg and AT-533 gel. However, loss of appetite and body weight, adverse reactions, toxicologically relevant alterations in hematology and biochemistry were found in rats percutaneously treated with AT-533 at 250 mg/kg and 500 mg/kg during 15-day acute dermic toxicity study. Conclusions The aforementioned results suggested that the LD.sub.50 of AT-533 is 228.382 mg/kg and the LD.sub.50 of AT-533 gel is greater than 5 g/kg. These findings indicated that AT-533 is non-toxic in rats when the dose less than 50 mg/kg and AT-533 gel can be considered a gel with no toxicity at doses less than 5 g/kg. Keywords: AT-533, AT-533 gel, Acute toxicity, Sprague-Dawley rats
Angiogenic factor with G-patch and FHA domains 1 (AGGF1) exhibits a dynamic distribution from the nucleus to the cytoplasm in endothelial cells during angiogenesis, but the biological significance ...and underlying mechanism of this nucleocytoplasmic transport remains unknown. Here, we demonstrate that the dynamic distribution is essential for AGGF1 to execute its angiogenic function. To search the structural bases for this nucleocytoplasmic transport, we characterized three potential nuclear localization regions, one potential nuclear export region, forkhead-associated (FHA), and G-patch domains to determine their effects on nucleocytoplasmic transport and angiogenesis, and we show that AGGF1 remains intact during the dynamic subcellular distribution and the region from 260 to 288 amino acids acts as a signal for its nuclear localization. The distribution of AGGF1 in cytoplasm needs both FHA domain and 14-3-3α/β. Binding of AGGF1 via FHA domain to 14-3-3α/β is required to complete the transport. Thus, we for the first time established structural bases for the nucleocytoplasmic transport of AGGF1 and revealed that the FHA domain of AGGF1 is essential for its nucleocytoplasmic transport and angiogenesis.
The electrochemical corrosion behavior of the dental Ti50Zr alloy with and without nanocrystalline (TiZr)N coating was comparatively investigated in artificial saliva solutions with different pH ...values and fluoride ion concentrations. The chemical stability of the passive films on the coated and non-coated Ti50Zr alloy was evaluated by calculating passive film thickness. The chemical compositions and valence structures of the passive films were analyzed by X-ray photoelectron spectroscopy (XPS). The results show that the (TiZr)N-coated alloy displays distinctly decreased corrosion rate and increased impedance compared with Ti50Zr alloy in non-fluoridated and fluoridated acidic solutions. Particularly, in the solution of pH = 3.9 and 0.15% NaF-containing, the corrosion protection efficiency of (TiZr)N coating reaches 90%. The excellent corrosion resistance of the coated alloy is attributed to that the nanocrystallines in (TiZr)N coating decreases micropores and crack defects, which strongly impedes the corrosive ions diffusion and electrode process at Ti substrate/coating interface. Meanwhile, (TiZr)N coating shows good passivation behavior in acidic solution and active–passive transition behavior in fluoridated acidic solution. The coated Ti50Zr alloy with high chemical stability has potential application prospect for dental implants.
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