Tumor microenvironments are strongly related to tumor development, and immune-infiltrating cells and immune-related molecules are potential prognostic markers. However, the shortcomings of traditional Show more
Tumor microenvironments are strongly related to tumor development, and immune-infiltrating cells and immune-related molecules are potential prognostic markers. However, the shortcomings of traditional measurement methods limit the accurate evaluation of various components in tumor microenvironments. With the rapid advancement of Next-Generation RNA Sequencing technology, dedicated and in-depth analyses of immune filtration within the tumor microenvironment has been achieved. In this study, we combined the bioinformatics analysis methods ESTIMATE, CIBERSORT, and ssGSEA to characterize the immune infiltration of sarcomas and to identify specific immunomodulators of different pathological subtypes. We further extracted a functional enrichment of significant immune-related genes related to improved prognosis, including NR1H3, VAMP5, GIMAP2, GBP2, HLA-E and CRIP1. Overall, the immune microenvironment is an important prognostic determinant of sarcomas and may be a potential resource for developing effective immunotherapy. Show less
Atherosclerosis (AS) is the killer of human health and longevity, which is majorly caused by oxidized lipoproteins that attack macrophages in the endarterium. The Shen-Hong-Tong-Luo (SHTL) formula has Show more
Atherosclerosis (AS) is the killer of human health and longevity, which is majorly caused by oxidized lipoproteins that attack macrophages in the endarterium. The Shen-Hong-Tong-Luo (SHTL) formula has shown great clinical efficacy and vascular protective effect for over 30 years in China, to attenuate AS progression. However, its pharmacological mechanism needs more investigation. In this study, we first investigated the chemical composition of SHTL by fingerprint analysis using high-performance liquid chromatography. In primary mouse peritoneal macrophages induced by lipopolysaccharide (LPS), we found that SHTL pretreatment suppressed reactive oxygen species accumulation and reversed the increases of the inflammatory factors, TNF- Show less
Atherosclerosis (AS) is the most common cardiovascular disease, and reverse cholesterol transport (RCT) plays an important role in maintaining cholesterol homeostasis. Both endoplasmic reticulum (ER) Show more
Atherosclerosis (AS) is the most common cardiovascular disease, and reverse cholesterol transport (RCT) plays an important role in maintaining cholesterol homeostasis. Both endoplasmic reticulum (ER) stress and LXRα can affect the metabolism of cholesterol. However, whether ER stress can modulate cholesterol metabolism by LXRα in hepatocytes and macrophages remains unclear. Therefore, in this study, we aimed to explore the relationship between ER stress induced by tunicamycin and LXRα in hepatocytes and macrophages and clarify their possible mechanisms and roles in AS. C57BL/6 mice and Huh-7 and THP-1 cells were treated with tunicamycin and LXR-623 (an agonist of LXRα) alone or in combination. Tunicamycin-induced ER stress caused liver injury; promoted the accumulation of cholesterol and triglycerides; inhibited the expression of LXRα, ABCA1 and ABCG1 in the livers of mice, thus reducing serum high-density lipoprotein (HDL)-C, low-density lipoprotein (LDL)-C, total cholesterol and triglyceride levels; however, LXR-623 could attenuate ER stress and reverse these changes. We also obtained the same results in Huh-7 and THP-1 cells. ER stress induced by tunicamycin could clearly be reversed by activating LXRα because it promoted cholesterol efflux by enhancing the expression of ABCA1 and ABCG1 in hepatocytes and macrophages, contributing to attenuation of the development of AS. Show less
Silicosis, a severe and irreversible form of pulmonary fibrosis (PF) caused by long-term exposure to dust particles in production environments, is the biggest occupational health concern in China and Show more
Silicosis, a severe and irreversible form of pulmonary fibrosis (PF) caused by long-term exposure to dust particles in production environments, is the biggest occupational health concern in China and most low-income countries. The transdifferentiation of pulmonary fibroblasts is the terminal event in silicosis, and specific transcription factors (TFs) play a crucial role in this condition. However, the relationship between TF-mediated regulation and silicosis remains unknown. We performed a transcriptomic analysis to elucidate this relationship, and our results revealed that two TFs, EGR2 and BHLHE40, were upregulated and five, i.e., TBX2, NR1H3 (LXRα), NR2F1, PPARG (PPARγ), and EPAS1, were downregulated in activated fibroblasts. Notably, PPARγ and LXRα expression was also decreased in an experimental mouse model of silicosis. The mechanism underlying these changes may involve TGF-β1 secretion from silica-exposed alveolar macrophages, causing PPARγ and LXRα downregulation, which in turn would result in aberrant α-SMA transcription. Our results suggest that LXRα is a potential target for the prevention of silicosis and PF. Show less
Psoriasis is an immune-mediated chronic inflammatory skin disease. Keratinocyte hyperproliferation has been regarded as a significant event in psoriasis pathogenesis. Considering the vital role of miR Show more
Psoriasis is an immune-mediated chronic inflammatory skin disease. Keratinocyte hyperproliferation has been regarded as a significant event in psoriasis pathogenesis. Considering the vital role of miRNA-mediated mRNA repression in psoriasis pathogenesis, in the present study, we attempted to investigate the mechanism of keratinocyte overproliferation from the point of miRNA-mRNA regulation. Both online microarray expression profiles and experimental results indicated that the expression of LXR-α and PPAR-γ was downregulated in psoriasis lesion skin. LXR-α or PPAR-γ overexpression alone was sufficient to inhibit keratinocyte proliferation, decrease KRT5 and KRT14 protein levels and increase KRT1 and KRT10 protein levels. miR-203 negatively regulated LXR-α and PPAR-γ expression through direct targeting. miR-203 inhibition exerted the opposite effects to LXR-α or PPAR-γ overexpression on HaCaT cells. More importantly, LXR-α or PPAR-γ overexpression could markedly remarkably attenuate the effects of miR-203 overexpression in keratinocytes, indicating that miR-203 promotes keratinocyte proliferation by targeting LXR-α and PPAR-γ. In conclusion, the miR-203-LXR-α/PPAR-γ axis modulates the proliferation of keratinocytes and might be a novel target for psoriasis treatment, which needs further in vivo investigation. Show less
Osteoarthritis (OA) is the most common joint disease that characterized by the degradation of articular cartilage. In this study, we aimed to investigate the anti-inflammatory activity of dioscin on I Show more
Osteoarthritis (OA) is the most common joint disease that characterized by the degradation of articular cartilage. In this study, we aimed to investigate the anti-inflammatory activity of dioscin on IL-1β-stimulated human osteoarthritis chondrocytes. The production of PGE2 and NO was measured in this study. MMP1 and MMP3 were detected by ELISA. The expression of LXRα and NF-κB were tested by western blot analysis. Treatment of dioscin suppressed the production of PGE2 and NO, as well as the expression of COX-2 and iNOS (their key regulatory genes). Dioscin also attenuated the secretion of MMP1 and MMP3. Furthermore, dioscin inhibited the phosphorylation of NF-κB p65 and IκBα induced by IL-1β. The degradation of IκBα induced by IL-1β was also suppressed by dioscin. Dioscin increased the expression of LXRα and pretreatment of GGPP, the LXRα inhibitor, blocked the anti-inflammatory effects of dioscin. In conclusion, this study indicated that dioscin-mediated anti-inflammatory effect may be involved in the activation of LXRα. Show less
Increased cholesterol efflux from macrophage foam cells in the subendothelial space confers protection against atherosclerosis. Soraphen A, a myxobacterial macrolactone, is an inhibitor of acetyl coen Show more
Increased cholesterol efflux from macrophage foam cells in the subendothelial space confers protection against atherosclerosis. Soraphen A, a myxobacterial macrolactone, is an inhibitor of acetyl coenzyme A carboxylases (ACC), which control fatty acid synthesis and oxidation. To assess a potential direct link between macrophage cholesterol efflux and ACC inhibition, we examined [ Show less
Recent studies have demonstrated that commercially available lipid-lowering drugs cause various side effects; therefore, searching for anti-hyperlipidaemic compounds with lower toxicity is a research Show more
Recent studies have demonstrated that commercially available lipid-lowering drugs cause various side effects; therefore, searching for anti-hyperlipidaemic compounds with lower toxicity is a research hotspot. This study was designed to investigate whether the marine-derived compound, 5-hydroxy-3-methoxy-5-methyl-4-butylfuran-2(5H)-one, has an anti-hyperlipidaemic activity, and the potential underlying mechanism in vitro. Results showed that the furanone had weaker cytotoxicity compared to positive control drugs. In RAW 264.7 cells, the furanone significantly lowered ox-LDL-induced lipid accumulation (~50%), and its triglyceride (TG)-lowering effect was greater than that of liver X receptor (LXR) agonist T0901317. In addition, it significantly elevated the protein levels of peroxisome proliferator-activated receptors (PPARα) and ATP-binding cassette (ABC) transporters, which could be partially inhibited by LXR antagonists, GSK2033 and SR9243. In HepG2 cells, it significantly decreased oleic acid-induced lipid accumulation, enhanced the protein levels of low-density lipoprotein receptor (LDLR), ABCG5, ABCG8 and PPARα, and reduced the expression of sterol regulatory element-binding protein 2 (~32%). PPARα antagonists, GW6471 and MK886, could significantly inhibit the furanone-induced lipid-lowering effect. Furthermore, the furanone showed a significantly lower activity on the activation of the expression of lipogenic genes compared to T0901317. Taken together, the furanone exhibited a weak cytotoxicity but had powerful TC- and TG-lowering effects most likely through targeting LXRα and PPARα, respectively. These findings indicate that the furanone has a potential application for the treatment of dyslipidaemia. Show less
Selenium (Se) is an essential trace element for living organisms and plays diverse biological roles. Endometritis is a common reproductive disorder in dairy cows, causing huge economic losses. In this Show more
Selenium (Se) is an essential trace element for living organisms and plays diverse biological roles. Endometritis is a common reproductive disorder in dairy cows, causing huge economic losses. In this study, we explored the effects of Se on lipopolysaccharide (LPS)-induced endometritis in mice and expounded its underlying mechanism of action. We validated the anti-inflammatory effects of Se in vivo by establishing a mouse model of endometriosis induced by LPS. Se significantly reversed the LPS-induced uterine histopathological changes, MPO activity and inflammatory cytokine levels in vivo. Simultaneously, TLR4 and its downstream signaling pathways, lipid rafts and cholesterol levels in the tissues were also attenuated by Se under LPS stimulation. In addition, the molecular mechanism of the Se anti-inflammatory effect was clarified in mouse endometrial epithelial cells. Se inhibited TLR4-mediated NF-κB and IRF3 signal transduction pathways to reduce the production of inflammatory factors. We found that Se promoted the consumption of cholesterol to suppress the lipid rafts coming into being and inhibited the TLR4 positioning to the lipid raft to prevent the inflammatory response caused by LPS. Meanwhile, Se activated the LxRα-ABCA1 pathway to cause the outflow of cholesterol in cells. The anti-inflammatory effect of Se was disrupted by silencing LxRα. In conclusion, Se exerted anti-inflammatory effects most likely by the LxRα-ABCA1 pathway activation, which inhibited lipid rafts by depleting cholesterol and ultimately impeded the migration of TLR4 to lipid rafts. Show less
Bisphenol A (BPA) and its replacement analog, bisphenol S (BPS), have been proposed as environmental obesogen to disrupt the lipid metabolism through regulating peroxisome proliferator-activated recep Show more
Bisphenol A (BPA) and its replacement analog, bisphenol S (BPS), have been proposed as environmental obesogen to disrupt the lipid metabolism through regulating peroxisome proliferator-activated receptor gamma (PPARγ) receptor. However, there is a dearth of information on whether this biological effect can occur in human macrophage, a cell type which closely interacts with adipocytes and hepatocytes to control lipid metabolism. Here, we for the first time investigate the activity of BPA and BPS on PPARγ pathway in human macrophages. The results demonstrated that BPA and BPS served as activators of PPARγ in human macrophage cell line, and significantly induced the expression of lipid metabolism-related genes, including fatty acid binding protein 4 (FABP4), cluster of differentiation 36 (CD36) and nuclear receptor subfamily 1 group H member 3 (NR Show less
Angiopoietin-1 (Ang-1), a secreted protein, mainly regulates angiogenesis. Ang-1 has been shown to promote the development of atherosclerosis, whereas little is known about its effects on lipid metabo Show more
Angiopoietin-1 (Ang-1), a secreted protein, mainly regulates angiogenesis. Ang-1 has been shown to promote the development of atherosclerosis, whereas little is known about its effects on lipid metabolism and inflammation in this process. Ang-1 was transfected into ApoE Our data showed that Ang-1 augmented atherosclerotic plaques formation and inhibited cholesterol efflux. The binding of Ang-1 to Tie2 resulted in downregulation of LXRα, ABCA1 and ABCG1 expression via inhibiting the translocation of TFE3 into nucleus. In addition, Ang-1 decreased serum HDL-C levels and reduced reverse cholesterol transport (RCT) in ApoE-/- mice. Furthermore, Ang-1 induced lipid accumulation followed by increasing TNF-α, IL-6, IL-1β，and MCP-1 produced by MPMs, as well as inducing M1 phenotype macrophage marker iNOS and CD86 expression in aorta of ApoE Ang-1 has an adverse effect on cholesterol efflux by decreasing the expression of ABCA1 and ABCG1 via Tie2/TFE3/LXRα pathway, thereby promoting inflammation and accelerating atherosclerosis progression. Show less
Neurexins (NRXNs) are cell-adhesion molecules important in the formation and remodeling of neural circuits. It has been shown that aversive environmental stimuli can affect the expression pattern of N Show more
Neurexins (NRXNs) are cell-adhesion molecules important in the formation and remodeling of neural circuits. It has been shown that aversive environmental stimuli can affect the expression pattern of Neurexin genes (Nrxns) impacting the regulation of synaptic strength. Accumulated evidence suggests that, after chronic exposure to psychological stress, the triggered changes in gene expression and splicing patterns of Nrxns may be involved in aversive conditioning. Previously, we have demonstrated that a novel treatment using dietary phytochemicals can modulate the response to chronic variable stress (CVS) in mice. Here, we aimed to further investigate the long-term plasticity changes after CVS by focusing on the regulation of NRXNs at synapses. We found that CVS differentially triggers the region-specific gene expression of Nrxns in mice Nucleus Accumbens (NAc) and Hippocampus (HIPP). The prophylactic treatment with the combination of two phytochemicals dihydrocaffeic acid (DHCA) and Malvidin-3-O-glucoside (Mal-gluc) differentially modulated the stress-induced effects on Nrxn1 and 3 mRNA expression in these brain areas and promoted the alternative splicing of Nrxn3 in HIPP. Overall, our data supports the prophylactic effect of dietary phytochemicals in the restoration of stress-induced plasticity changes in mouse brain. By intervening in activity-dependent plasticity at synapses, these compounds may attenuate the effects of chronic aversive conditioning. We propose that an early therapeutic intervention may help with disorders of negative affect, such as depression or post-traumatic stress disorder. Our future studies will address how DHCA/Mal-gluc might serve as a potential complement for current therapies in depression and other mood disorders. Show less
The existence of cancer stem cells (CSCs) accounts for hepatocellular carcinoma (HCC) treatment resistance, relapse, and metastasis. Although the elimination of cancer stem cells is crucial for cancer Show more
The existence of cancer stem cells (CSCs) accounts for hepatocellular carcinoma (HCC) treatment resistance, relapse, and metastasis. Although the elimination of cancer stem cells is crucial for cancer treatment, strategies for their elimination are limited. Here, we report that a remarkable increase in PIK3C3 was detected in HCC tissues and liver CSCs. Upregulated PIK3C3 facilitated liver CSC expansion in HCC cells; RNA interference-mediated silencing of PIK3C3 had an opposite effect. Furthermore, PIK3C3 inhibition by inhibitors effectively eliminated liver CSCs and inhibited the growth of tumors in vivo. The phosphoinositide 3-kinase (PI3K) pathway is considered an important hallmark of cancer. One of our recent studies found that prolonged inhibition by inhibitors of class I PI3K induces liver CSCs expansion. To our surprise, PIK3C3 inhibition blocked the expansion of CSCs induced by PI3K inhibitor; moreover, treatment with the combination of PIK3C3 inhibitor and PI3K inhibitor in maximal suppresses the expansion of liver CSCs of tumors in mice. Mechanistically, inhibition of PIK3C3 inhibit the activation of SGK3, a CSCs promoter, induced by PI3K inhibitor. We also show that PIK3C3 inhibitor suppresses liver CSCs by activation of the AMP-activated kinase (AMPK). Although PIK3C3 plays a critical role in autophagy, we find that PIK3C3 regulates liver CSCs independent of the autophagy process. These findings uncover the effective suppression of liver CSCs by targeting PIK3C3, and targeting PIK3C3 in combination with PI3K inhibitor inhibits the expansion of liver CSCs efficiently, which is an attractive therapeutic regimen for the treatment of HCC. Show less
Xiaobo Wang, Min Gu, Yongjian Ju+1 more · 2020 · Medical science monitor : international medical journal of experimental and clinical research · added 2026-04-24
BACKGROUND Esophageal squamous cell carcinoma (ESCC), a major histological subtype of esophageal cancer, is a common cause of tumor-related deaths in the world. Due to the lack of understanding of the Show more
BACKGROUND Esophageal squamous cell carcinoma (ESCC), a major histological subtype of esophageal cancer, is a common cause of tumor-related deaths in the world. Due to the lack of understanding of the pathogenesis of ESCC, its clinical treatment is still a big challenge. In the present study, we aimed to identify an ESCC-related gene in the GEO dataset, and to explore its function and mechanism in ESCC. MATERIAL AND METHODS The GSE dataset (GSE100492) consisting of 10 samples was analyzed using GEO2R for identifying the differentially expressed genes between ESCC and normal samples. Expression levels of mRNA and miRNA in ESCC tissues and cells were detected via quantitative real-time polymerase chain reaction. Protein expression was analyzed by western blot. Cell proliferation viability was determined through MTT and colony formation. Cell distribution and apoptosis was detected by flow cytometry. MiRNA target prediction was analyzed by bioinformatics. The interplay between miR-340-5p and PIK3C3 was validated by dual-luciferase reporter assay. RESULTS PIK3C3 was lowly expressed in ESCC tissue and indicated a poor prognosis in patents. Overexpression of PIK3C3 in vitro repressed cell proliferation of KYSE-150 and TE-12 cells. Moreover, PIK3C3 overexpression was demonstrated to enhance the sensitivity of KYSE-150 and TE-12 cells to irradiation. In addition, miR-340-5p was revealed to directly bind and negatively modulate PIK3C3 expression in ESCC. Blockage of miR-340-5p promoted ESCC cell proliferation, while rescue of PIK3C3 reversed this effect. MiR-340-5p was highly expressed in ESCC tissue and it exhibited a negative correlation with PIK3C3 expression. CONCLUSIONS MiR-340-5p functioned as an oncogene of ESCC by directly binding and repressing the expression of PIK3C3. Show less
Arsenic poisoning and induced potential lesion is a global concern. However, the exact mechanisms underlying its toxicity especially in male reproductive system still remain unclear. Hence, this study Show more
Arsenic poisoning and induced potential lesion is a global concern. However, the exact mechanisms underlying its toxicity especially in male reproductive system still remain unclear. Hence, this study aimed to explore the roles of mTOR and Beclin1-Vps34/PI3K complex during As-induced-toxicity using Rapamycin (mTOR inhibitor), Beclin1 siRNA and 3-methyladenine (3-MA, Vps34/PI3K inhibitor) in testicular stromal cells. For this, mouse testis Leydig Tumor Cell lines (MLTC-1) were challenged with As Show less
Deoxynivalenol (DON) is a major mycotoxin from the trichothecene family of mycotoxins produced by Fusarium fungi. It can cause a variety of adverse effects on human and farm animal health. Here, we de Show more
Deoxynivalenol (DON) is a major mycotoxin from the trichothecene family of mycotoxins produced by Fusarium fungi. It can cause a variety of adverse effects on human and farm animal health. Here, we determined the effect of DON on the Class III phosphatidylinositol 3-kinase (PIK3C3)/beclin 1/B cell lymphoma-2 (Bcl-2) pathway in PC12 cells and the relationship between autophagy and apoptosis. The effects of DON were evaluated based on the apoptosis ratio; the typical indicators of autophagy, including cellular morphology, acridine orange- and monodansylcadaverine-labeled vacuoles, green fluorescent protein-microtubule associated protein 1 light chain 3 (LC3) localization, and LC3 immunofluorescence; and the expression of key autophagy-related genes and proteins, that is, PIK3C3, beclin 1, Bcl-2, LC3, and p62. The relationship between autophagy and apoptosis was analyzed by western blot analysis and flow cytometry. DON-induced PC12 cell morphological changes and autophagy significantly. PIK3C3, beclin 1, and LC3 increased in tandem with the DON concentration used; Bcl-2 and p62 expression decreased as DON concentrations increased. Moreover, the PIK3C3/beclin 1/Bcl-2 signaling pathway played a role in DON-induced autophagy. Our findings suggest that DON can induce autophagy by activating the PIK3C3/beclin 1/Bcl-2 signaling pathway and that autophagy may play a positive role in reducing DON-induced apoptosis. Show less
Hyperketonemia is a metabolic disease in dairy cows, associated with negative nutrition balance (NNB) induced by low dry matter intake (DMI) and increased nutrient requirements. Hyperketonemia could i Show more
Hyperketonemia is a metabolic disease in dairy cows, associated with negative nutrition balance (NNB) induced by low dry matter intake (DMI) and increased nutrient requirements. Hyperketonemia could induce metabolic stress, which might indirectly affect mammary tissue. Autophagy is a highly conserved physiological process that results in the turnover of intracellular material, and is involved in maintaining cellular homeostasis under the challenge of metabolic stress induced by NNB. The aim of this study was to investigate the autophagy status and autophagy-related pathways AMP-activated kinase α (AMPKα) and mechanistic target of rapamycin (mTOR) in the mammary glands of dairy cows with hyperketonemia. Cows with hyperketonemia [CWH, n = 10, blood β-hydroxybutyrate (BHB) concentration 1.2 to 3.0 mmol/L] and cows without hyperketonemia (CWOH, n = 10, BHB < 1.2 mmol/L) from 3 to 12 DIM were randomly selected from the herd. The mammary tissue and blood samples were collected from these cows between 0630 and 0800 h, before feeding, at 3 to 12 d in milk. Serum concentrations of glucose, BHB, and fatty acids were determined using an autoanalyzer with commercial kits between 0630 and 0800 h, before feeding. Concentrations of fatty acids, BHB (median and interquartile range: CWH, 2.44 and 1.3, 2.82 mM; CWOH, 0.49 and 0.41, 0.57 mM), and milk fat were greater in CWH. The DMI, glucose concentration, milk production, and milk protein levels were lower in CWH. The mRNA abundance of autophagosome formation-related gene, beclin 1 (BECN1), phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3), autophagy-related gene (ATG) 5, ATG7, ATG12, microtubule-associated protein 1 light chain 3 (MAP1LC3, also called LC3) and sequestosome-1 (SQSTM1, also called p62) were greater in the mammary glands of CWH. The protein abundance of LC3-II and phosphorylation level of Unc-51-like kinase 1 (ULK1) were greater in CWH, but the total ubiquitinated proteins and protein abundance of p62 were lower. Transmission electron microscopy showed an increased number of autophagosomes in the mammary glands of CWH. Furthermore, the phosphorylation of AMPKα was greater, but the phosphorylation of mTOR was lower in the mammary glands of CWH. These results indicate that activity of mTOR pathways and autophagy activity, and upregulation of AMPKα, may be response mechanisms to mitigate metabolic stress induced by hyperketonemia in the mammary glands of dairy cows. Show less
Macroautophagy/autophagy plays key roles in development, oncogenesis, and cardiovascular and metabolic diseases. Autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1) is e Show more
Macroautophagy/autophagy plays key roles in development, oncogenesis, and cardiovascular and metabolic diseases. Autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1) is essential for autophagosome formation. However, the regulation of this complex formation requires further investigation. Here, we discovered that STYK1 (serine/threonine/tyrosine kinase 1), a member of the receptor tyrosine kinases (RTKs) family, is a new upstream regulator of autophagy. We discovered that STYK1 facilitated autophagosome formation in human cells and zebrafish, which was characterized by elevated LC3-II and lowered SQSTM1/p62 levels and increased puncta formation by several marker proteins, such as ATG14, WIPI1, and ZFYVE1. Moreover, we observed that STYK1 directly binds to the PtdIns3K-C1 complex as a homodimer. The binding with this complex was promoted by Tyr191 phosphorylation, by means of which the kinase activity of STYK1 was elevated. We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. Furthermore, we found that STYK1 preferentially facilitated the assembly of the PtdIns3K-C1 complex and was required for PtdIns3K-C1 complex kinase activity. Taken together, our findings provide new insights into autophagy induction and reveal evidence of novel crosstalk between the components of RTK signaling and autophagy. Show less
Diabetes is a recognized high-risk factor for the development of atherosclerosis, in which macroautophagy/autophagy is emerging to play essential roles. The retention of low-density lipoprotein (LDL) Show more
Diabetes is a recognized high-risk factor for the development of atherosclerosis, in which macroautophagy/autophagy is emerging to play essential roles. The retention of low-density lipoprotein (LDL) particles in subendothelial space following transcytosis across the endothelium is the initial step of atherosclerosis. Here, we identified that high glucose could promote atherosclerosis by stimulating transcytosis of LDL. By inhibiting AMPK-MTOR-PIK3C3 pathway, high glucose suppresses the CAV-CAVIN-LC3B-mediated autophagic degradation of CAV1; therefore, more CAV1 is accumulated in the cytosol and utilized to form more caveolae in the cell membrane and facilitates the LDL transcytosis across endothelial cells. For a proof of concept, higher levels of lipids were accumulated in the subendothelial space of umbilical venous walls from pregnant women with gestational diabetes mellitus (GDM), compared to those of pregnant women without GDM. Our results reveal that high glucose stimulates LDL transcytosis by a novel CAV1-CAVIN1-LC3B signaling-mediated autophagic degradation pathway. 3-MA: 3-methyladenine; ACTB: actin beta; AMPK: AMP-activated protein kinase; Bafi: bafilomycin A Show less
Macroautophagy/autophagy is an evolutionarily conserved intracellular process that recycles and degrades intracellular components to sustain homeostasis in response to deficiency of nutrients or growt Show more
Macroautophagy/autophagy is an evolutionarily conserved intracellular process that recycles and degrades intracellular components to sustain homeostasis in response to deficiency of nutrients or growth factors. PAQR3 is a newly discovered tumor suppressor that also regulates autophagy induced by nutrient starvation via AMPK and MTORC1 signaling pathways. In this study, we investigated whether PAQR3 modulates EGFR-mediated autophagy and whether such regulation is associated with the tumor suppressive activity of PAQR3. PAQR3 is able to inhibit the AKT: thymoma viral proto-oncogene; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG14: autophagy related 14; BCL2: B cell leukemia/lymphoma 2; BECN1: beclin 1; CCK-8: cell counting kit-8; CQ: chloroquine diphosphate; DMEM: Dulbecco's modified Eagle's medium; EdU: 5-ethynyl-2'-deoxyuridine; EGFR: epidermal growth factor receptor; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; IgG: Immunoglobulin G; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTT: thiazolyl blue tetrazolium bromide; NSCLC: Non-small cell lung cancer; MAP2K/MEK: mitogen-activated protein kinase kinase; MAPK/ERK: mitogen-activated protein kinase; PAQR3: progestin and adipoQ receptor family member 3; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15: phosphoinositide-3-kinase regulatory subunit 4; PRKAA/AMPK: protein kinase, AMP-activated alpha catalytic; RUBCN: rubicon autophagy regulator; RPS6: ribosomal protein S6; RAS: Ras proto-oncogene; RAF: Raf proto-oncogene; TKI: tyrosine kinase inhibitor; TUBA4A: tubulin alpha 4a; UVRAG: UV radiation resistance associated. Show less
Macroautophagy/autophagy is an essential cellular response in the fight against intracellular pathogens. Although some viruses can escape from or utilize autophagy to ensure their own replication, the Show more
Macroautophagy/autophagy is an essential cellular response in the fight against intracellular pathogens. Although some viruses can escape from or utilize autophagy to ensure their own replication, the responses of autophagy pathways to viral invasion remain poorly documented. Here, we show that peste des petits ruminants virus (PPRV) infection induces successive autophagic signalling in host cells via distinct and uncoupled molecular pathways. Immediately upon invasion, PPRV induced a first transient wave of autophagy via a mechanism involving the cellular pathogen receptor NECTIN4 and an AKT-MTOR-dependent pathway. Autophagic detection showed that early PPRV infection not only increased the amounts of autophagosomes and LC3-II but also downregulated the phosphorylation of AKT-MTOR. Subsequently, we found that the binding of viral protein H to NECTIN4 ultimately induced a wave of autophagy and inactivated the AKT-MTOR pathway, which is a critical step for the control of infection. Soon after infection, new autophagic signalling was initiated that required viral replication and protein expression. Interestingly, expression of IRGM and HSPA1A was significantly upregulated following PPRV replication. Strikingly, knockdown of IRGM and HSPA1A expression using small interfering RNAs impaired the PPRV-induced second autophagic wave and viral particle production. Moreover, IRGM-interacting PPRV-C and HSPA1A-interacting PPRV-N expression was sufficient to induce autophagy through an IRGM-HSPA1A-dependent pathway. Importantly, syncytia formation could facilitate sustained autophagy and the replication of PPRV. Overall, our work reveals distinct molecular pathways underlying the induction of self-beneficial sustained autophagy by attenuated PPRV, which will contribute to improving the use of vaccines for therapy. Show less
Impaired macroautophagy/autophagy is involved in the pathogenesis of hepatic fibrosis. However, how aberrant autophagy promotes fibrosis is far from understood. Here, we aimed to define a previously u Show more
Impaired macroautophagy/autophagy is involved in the pathogenesis of hepatic fibrosis. However, how aberrant autophagy promotes fibrosis is far from understood. Here, we aimed to define a previously unrevealed pro-fibrotic mechanism for the stress protein TRIB3 (tribbles pseudokinase 3)-mediated autophagy dysfunction. Human fibrotic liver tissues were obtained from patients with cirrhosis who underwent an open surgical repair process. The functional implications of TRIB3 were evaluated in mouse models of hepatic fibrosis induced by bile duct ligation (BDL) or thioacetamide (TAA) injection. Human fibrotic liver tissues expressed higher levels of TRIB3 and selective autophagic receptor SQSTM1/p62 (sequestosome 1) than nonfibrotic tissues and the elevated expression of TRIB3 and SQSTM1 was positively correlated in the fibrotic tissues. Silencing Show less
GBM (glioblastoma multiforme) is the most common and aggressive brain tumor with no curative options available. Therefore, it is imperative to develop novel potent therapeutic drugs for GBM treatment. Show more
GBM (glioblastoma multiforme) is the most common and aggressive brain tumor with no curative options available. Therefore, it is imperative to develop novel potent therapeutic drugs for GBM treatment. Here, we show that regorafenib, an oral multi-kinase inhibitor, exhibits superior therapeutic efficacy over temozolomide, the first-line chemotherapeutic agent for GBM treatment both Show less
Long non-coding RNAs (lncRNAs) function as a class of significant mediators in prostate cancer (PCa), and this study mainly discussed the molecular mechanism of lncRNA growth arrest-specific 5 (GAS5) Show more
Long non-coding RNAs (lncRNAs) function as a class of significant mediators in prostate cancer (PCa), and this study mainly discussed the molecular mechanism of lncRNA growth arrest-specific 5 (GAS5) in PCa progression and radiosensitivity. GAS5 and microRNA-320a (miR-320a) levels were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability and migration were severally examined through 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT) and transwell assays. PCa cells were treated with X-ray irradiation. Cell survival and apoptosis rate were assayed using colony formation assay and flow cytometry, respectively. The apoptosis-related protein and Rab GTPase 21 ( GAS5 was down-regulated in PCa tissues and cells. GAS5 overexpression suppressed cell viability and migration while facilitated radiosensitivity of PCa cells. GAS5 was a molecular sponge of miR-320a. The effects of GAS5 up-regulation on PCa cells were accomplished by sponging miR-320a. MiR-320a targeted Collectively, GAS5 restrained tumor development and expedited the radiosensitivity in PCa by the miR-320a/ Show less
Enterovirus A71 (EVA71) and Coxsackievirus A10 (CVA10) are representative types of Enterovirus A. Dependent on the host cell types, the EVA71 entry may utilize clathrin-, caveola-, and endophilin-A2-m Show more
Enterovirus A71 (EVA71) and Coxsackievirus A10 (CVA10) are representative types of Enterovirus A. Dependent on the host cell types, the EVA71 entry may utilize clathrin-, caveola-, and endophilin-A2-mediated endocytosis. However, the cell-entry and intracellular trafficking pathways of CVA10, using KREMEN1 as its receptor, are unclear. Here, we tested the relevant mechanisms through RNA interference (RNAi) and chemical inhibitors. We found that endocytosis of EVA71 and CVA10 in rhabdomyosarcoma (RD) cells engaged multiple pathways, and both viruses required Rac1. Interestingly, while CDC42 and Pak1 participated in EVA71 infection, PI3K played a role in CVA10 infection. The functions of Rab proteins in intracellular trafficking of CVA10 and EVA71 were examined by RNAi. Knockdown of Rab5 and Rab21 significantly reduced CVA10 infectivity, while knockdown of Rab5, Rab7 and Rab9 reduced EVA71 infectivity. Confocal microscopy confirmed the colocalization of CVA10 virions with Rab5 or Rab21, and colocalization of EVA71 virions with Rab5 or Rab7. Additionally, we observed that both CVA10 and EVA71 infections were inhibited by endosome acidification inhibitors, bafilomycin-A1 and NH Show less
Early detection is essential to improve the survival and life quality of lung cancer (LC) patients. Changes of peripheral blood DNA methylation could be associated with malignancy but were mostly stud Show more
Early detection is essential to improve the survival and life quality of lung cancer (LC) patients. Changes of peripheral blood DNA methylation could be associated with malignancy but were mostly studied in Caucasians. Here, in a Chinese population, we performed mass spectrometry assays to investigate the association between very early stage LC and methylation levels of RAPSN in the peripheral blood by a case-control cohort using of 221 LC patients (93.2% LC at stage I) and 285 unrelated cancer free control individuals. The odds ratios (ORs) of all CpG sites were evaluated for their risk to LC using inter-quartile analyses by logistic regression. In general, we observed an association between very early LC and decreased methylation of RAPSN_CpG₁.15 and RAPSN_CpG₃.4 (referring to Q4, OR range from 1.64 to 1.81, Our study reveals an association between RAPSN hypomethylation in peripheral blood and LC and suggests the occurrence of altered blood-based methylation at the early stage of cancer. Show less