👤 Wenjing Gao

Manganese (Mn) is an essential micronutrient. However, it is well established that Mn overexposure causes nervous system diseases. In contrast, there are few reports on the effects of Mn exposure on glomerular endothelium. In the present study, the potential effects of Mn exposure on glomerular endothelium were evaluated. Sprague Dawley rats were used as a model of Mn overexposure by intraperitoneal injection of MnCl Show less

Kinesin superfamily protein 3C (KIF3C), a motor protein of the kinesin superfamily, is expressed in the central nervous system (CNS). Recently, several studies have suggested that KIF3C may act as a potential therapeutic target in solid tumors. However, the exact function and possible mechanism of the motor protein KIF3C in glioma remain unclear. In this study, a variety of tests including CCK-8, migration, invasion, and flow cytometry assays, and western blot were conducted to explore the role of KIF3C in glioma cell lines (U87 and U251). We found that overexpression of KIF3C in glioma cell lines promoted cell proliferation, migration, and invasion and suppressed apoptosis, while silencing of KIF3C reversed these effects. Ectopic KIF3C also increased the expression of N-cadherin, vimentin, snail, and slug to promote the epithelial-mesenchymal transition (EMT). Mechanistically, overexpression of KIF3C increased the levels of phosphatidylinositol 3-kinase (PI3K) and phosphorylated protein kinase B (p-AKT). These responses were reversed by KIF3C downregulation or AKT inhibition. Our results indicate that KIF3C promotes proliferation, migration, and invasion and inhibits apoptosis in glioma cells, possibly by activating the PI3K/AKT pathway Show less

RNF8 (ring finger protein 8), a RING finger E3 ligase best characterized for its role in DNA repair and sperm formation via ubiquitination, has been found to promote tumor metastasis in breast cancer recently. However, whether RNF8 also plays a role in other types of cancer, especially in lung cancer, remains unknown. We show here that RNF8 expression levels are markedly increased in human lung cancer tissues and negatively correlated with the survival time of patients. Overexpression of RNF8 promotes the EMT process and migration ability of lung cancer cells, while knockdown of RNF8 demonstrates the opposite effects. In addition, overexpression of RNF8 activates the PI3K/Akt signaling pathway, knockdown of RNF8 by siRNA inhibits this activation, and pharmacologic inhibition of PI3K/Akt in RNF8-overexpressing cells also reduces the expression of EMT markers and the ability of migration. Furthermore, RNF8 is found to directly interact with Slug and promoted the K63-Ub of Slug, and knockdown of Slug disrupts RNF8-dependent EMT in A549 cells, whereas overexpression of Slug rescues RNF8-dependent MET in H1299 cells, and depletion of RNF8 expression by shRNA inhibits metastasis of lung cancer cells Show less

Prostate cancer (PCa) is the second leading cause of cancer-associated mortality in men. Speckle-type pox virus and zinc finger protein (SPOP), the most frequently mutated gene in PCa, functions as a tumor suppressor via degradation of cancer-promoting substrates. However, its upstream regulation in PCa metastasis remains poorly determined. Here, in a Snail-induced metastatic PCa model, we observed an accelerated degradation of SPOP protein in cells, which is crucial for the PCa migration and activation of the AKT signaling pathway. Mechanistically, we demonstrated that binding to Snail promoted SPOP ubiquitination and degradation. Moreover, the bric-a-brac/tramtrack/broad complex (BTB) domain of SPOP is turned out to be essential for Snail-mediated SPOP degradation. Thus, our findings reveal a post-translational level regulation of SPOP expression that facilitates the metastasis of PCa cells. Show less

The metastasis of cervical cancer has always been a clinical challenge. We investigated the effects of low-dose naltrexone (LDN) on the epithelial mesenchymal transition of cervical cancer cells in vitro as well as its influence on macrophage polarization and associated cytokines in vivo. The results suggested that LDN supressed the proliferation, migration and invasion abilities and promote their apoptosis in Hela cells, whereas the opioid growth factor receptor (OGFr) silenced significantly reversed these effects in vitro. Knockdown the expression of OGFr, the inhibitory of LDN on EMT was weakened. LDN could inhibit cervical cancer progression in nude mice. In additon, LDN indirectly reduced the number of tumor-associated macrophages (TAMs), mainly M2 macrophages, and decreased expression of anti-inflammatory factor IL-10 in the serum of nude mice. These findings demonstrate that LDN could be a potential treatment for cervical cancer. Show less

Amplification of chromosome 7q21-7q31 is associated with tumor recurrence and multidrug resistance, and several genes in this region are powerful drivers of hepatocellular carcinoma (HCC). We aimed to investigate the key circular RNAs (circRNAs) in this region that regulate the initiation and development of HCC. We used qRT-PCR to assess the expression of 43 putative circRNAs in this chromosomal region in human HCC and matched nontumor tissues. In addition, we used cultured HCC cells to modify circRNA expression and assessed the effects in several cell-based assays as well as gene expression analyses via RNA-seq. Modified cells were implanted into immunocompetent mice to assess the effects on tumor development. We performed additional experiments to determine the mechanism of action of these effects. circMET (hsa_circ₀₀₈₂₀₀₂₎ was overexpressed in HCC tumors, and circMET expression was associated with survival and recurrence in HCC patients. By modifying the expression of circMET in HCC cells in vitro, we found that circMET overexpression promoted HCC development by inducing an epithelial to mesenchymal transition and enhancing the immunosuppressive tumor microenvironment. Mechanistically, circMET induced this microenvironment through the miR-30-5p/Snail/ dipeptidyl peptidase 4(DPP4)/CXCL10 axis. In addition, the combination of the DPP4 inhibitor sitagliptin and anti-PD1 antibody improved antitumor immunity in immunocompetent mice. Clinically, HCC tissues from diabetic patients receiving sitagliptin showed higher CD8 circMET is an onco-circRNA that induces HCC development and immune tolerance via the Snail/DPP4/CXCL10 axis. Furthermore, sitagliptin may enhance the efficacy of anti-PD1 therapy in a subgroup of patients with HCC. Show less

Reprogramming of the tumor immune microenvironment is a salient feature during metastasis in LUAD. miR-24-3p and KLF8, which are key regulators of the tumor immune microenvironment, had been proved to show metastasis-promoting property in LUAD. However, whether miR-24-3p could regulate LUAD metastasis by targeting KLF8 remains unclear. This study explored the functions and mechanisms of miR-24-3p/KLF8 signaling in advanced LUAD. The expression level of miR-24-3p and KLF8 were tested in LUAD patients, and the corelation of miR-24-3p and KLF8 was evaluated. The interaction of miR-24-3p and KLF8 was demonstrated by luciferase reporter activity assay, Show less

Gastric cancer is an important health problem, being the fifth most common cancer and the third leading cause of cancer-related death worldwide. Aberrant protein translation contributes to the oncogenesis and development of cancers, and upregulation of translation initiation factor eIF4A1 has been observed in several kinds of malignancies. However, the role of eIF4A1 in gastric cancer progression remains unclear. In this study, we found that the expression of eIF4A1, a component of translation initiation complex, was increased in gastric cancer. High expression of eIF4A1 was positively associated with poor tumor differentiation, late T stage, lymph node metastasis, advanced TNM stage, and poor prognosis in patients with gastric cancer. Overexpression of eIF4A1 promoted the migration and invasion of gastric cancer cells in vitro and enhanced tumor metastasis in nude mice model. Mechanism studies revealed that eIF4A1 induced epithelial-to-mesenchymal transition (EMT) of gastric cancer cells through driving the translation of SNAI1 mRNA. Together, these findings indicate that eIF4A1 promotes EMT and metastasis of gastric cancer and suggest that eIF4A1 is a potential target for the adjuvant therapy for gastric cancer patients. Show less

Ovarian cancer is prone to chemoresistance, leading to poor outcomes in patients. MicroRNA 1301 plays a regulatory role in multiple tumors. However, whether microRNA 1301 regulates cisplatin resistance in ovarian cancer cells remains unclear. The ovarian cancer SKOV3 cell line and the human ovarian cancer cisplatin-resistant strain cell SKOV3/DDP were cultured in vitro and microRNA1301 expression was analyzed by Real time PCR. MicroRNA1301 mimics and microRNA 1301 were transfected into SKOV3/DDP, respectively followed by analysis of cell proliferation by MTT assay, cell invasion, expression of autophagy genes ATG5 and Beclin1 and EMT-related transcription factors Snail and Slug by Real time PCR, expression of NF-κB and E-cadherin and N-cadherin by Western blot. MicroRNA 1301 expression was significantly increased in SKOV3/DDP cells compared with that in SKOV3 cells (p<0.05). MicroRNA1301 mimics transfection into SKOV3/DDP up-regulated microRNA1301 expression, promoted cell proliferation, and invasion, inhibited ATG5 and Beclin1 expression, and promoted Snail and Slug expression, decreased E-cadherin expression and increased N-cadherin and NF-κB expression, compared with the control group, the differences were statistically significant (p<0.05). MicroRNA1301 inhibitor transfection into SKOV3/DDP cells could down-regulate the expression of microRNA1301 and significantly reversed the above changes. Compared with the control group, differences were statistically significant (p<0.05). Targeting microRNA1301 can inhibit the proliferation of cisplatin-resistant cells and the development of EMT in human ovarian cancer cells by inhibiting the NF-κB signaling pathway, thereby inhibiting the occurrence and development of drug-resistant ovarian cancer. Show less

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is an oncogenic long noncoding RNA that has been found to promote carcinogenesis and metastasis in many tumors. However, the underlying role of MALAT1 in the progression and metastasis of hepatocellular carcinoma (HCC) remains unclear. In this study, aberrantly elevated levels of MALAT1 were detected in both HCC specimens and cell lines. We found that knockdown of MALAT1 caused retardation in proliferation, migration, and invasion both in vivo and in vitro. Mechanistic investigations showed that Snail family transcriptional repressor 1 (SNAI1) is a direct target of microRNA (miR)-22 and that MALAT1 modulates SNAI1 expression by acting as a competing endogenous RNA for miR-22. Inhibition of miR-22 restored SNAI1 expression suppressed by MALAT1 knockdown. Furthermore, MALAT1 facilitated the enrichment of enhancer of zeste homolog 2 (EZH2) at the promoter region of miR-22 and E-cadherin, which was repressed by MALAT1 knockdown. Cooperating with EZH2, MALAT1 positively regulated SNAI1 by repressing miR-22 and inhibiting E-cadherin expression, playing a vital role in epithelial to mesenchymal transition. In conclusion, our results reveal a mechanism by which MALAT1 promotes HCC progression and provides a potential target for HCC therapy. Show less

Dihydroartemisinin (DHA) is currently considered as the promising cancer therapeutic drug. In this study, we aimed to investigate the anti-proliferative and anti-metastasis effects of DHA. Utilizing breast cancer cells MCF-7, MDA-MB-231 and BT549, cell proliferation, migration and invasion were detected. RT-qPCR was performed to detect CIZ1, TGF-β1 and Snail expression, and the interactions of these related molecules were analyzed by GeneMANIA database. Western blot detected CIZ1, TGF-β1/Smads signaling and Snail expression in DHA-treated cells, in TGFβ1-induced cells with enhanced metastatic capacity, and in cells treated with DHA plus TGFβ1/TGFβ1 inhibitor SD-208. Results indicated DHA inhibited breast cancer cell proliferation and migration, with more potent effects compared with that of artemisinin. RT-qPCR and Western blot showed DHA inhibited CIZ1, TGF-β1 and Snail expression, and these molecules were shown to have protein-protein interactions by bioinformatics. Furthermore, TGFβ1-treatment enhanced MCF-7 migration and invasion, and CIZ1, TGF-β1/Smads signaling and snail activities; DHA, SD-208, combination of DHA and SD-208 reversed these conditions, preliminarily proving the cascade regulation between TGF-β1 signaling and CIZ1. MCF-7 xenografts model demonstrated the inhibition of DHA on tumor burden, and its mechanisms and well-tolerance in vivo; combination of DHA and SD-208 tried by us for the first time showed better treatment effects, but possible liver impairment made its use still keep cautious. DHA treatment inhibits the proliferation and metastasis of breast cancer, through suppressing TGF-β1/Smad signaling and CIZ1, suggesting the promising potential of DHA as a well-tolerated antitumor TGF-β1 pathway inhibitor. Show less

Succinate dehydrogenase (SDH) deficiency is associated with gastrointestinal stromal tumor (GIST) oncogenesis, but the underlying molecular mechanism remains to be further investigated. Here, we show that succinate accumulation induced by SDHB loss of function increased the expression of zinc finger protein 148 (ZNF148, also named ZBP-89) in GIST cells. Meanwhile, ZNF148 is found to be phosphorylated by ERK at Ser306, and this phosphorylation results in ZNF148 binding to Forkhead box M1 (FOXM1). Through the complex formation at the promoter, ZNF148 facilitates Histone H3 acetylation and FOXM1-mediated Snail transcription, which eventually promotes cell invasion and tumor growth. The clinical analysis indicates that SDHB deficiency is associated with elevated ZNF148 levels, and ZNF148-S306 phosphorylation level displays a positive correlation with poor prognosis in GIST patients. These findings illustrate an unidentified molecular mechanism underlying FOXM1-regulated gene transcription related to GIST cell invasion, which highlights the physiological effects of SDHB deficiency on the invasiveness of GIST. Show less

Breast cancer is one of the most common types of cancer in women. Although the mortality rate of breast cancer has fallen over the past 10 years, effective treatments that reduce the occurrence of breast cancer metastasis remain lacking. In this study, we explored the role of receptor for hyaluronan mediated motility (RHAMM) and the associated signaling pathway in cell migration in luminal A breast cancer. We first examined RHAMM expression levels using human breast tissue microarray and patient breast tissues. We then studied the role of RHAMM in migration in luminal A breast cancer using loss-of-function and gain-of-function strategies in in vitro models and confirmed these findings in an in vivo model. Finally, we investigated signaling molecules that play a role in cell migration using western blot. Our results demonstrated the following: (a) RHAMM shows high expression levels in malignant breast tissue, (b) RHAMM shows low expression levels in luminal A breast cancer compared to other subtypes of breast cancer, (c) RHAMM inhibits cell migration in luminal A breast cancer, and (d) RHAMM inhibits cell migration via the AKT/GSK3β/Snail axis in luminal A breast cancer. This study demonstrates a novel role of RHAMM in cell migration in luminal A breast cancer and suggests that therapeutic strategies involving RHAMM should be considered for various subtypes of breast cancer. Show less

The opacity of the lens capsule after cataract surgery is caused by epithelial‑to‑mesenchymal transition (EMT) of lens epithelial cells. Snail family transcriptional repressor 1 (SNAI1) is a transcriptional repressor that recruits multiple chromatin enzymes including lysine‑specific histone demethylase 1A, histone deacetylase (HDAC) 1/2, polycomb repressive complex 2, euchromatic histone lysine methyltransferase 2 and suppressor of variegation 3‑9 homolog 1 to the E‑cadherin promoter, thereby suppressing E‑cadherin expression. However, the functional relationship between SNAI1 and HDAC in the induction of EMT in human lens epithelial cells (HLECs) is still unclear. Therefore, the objective of the present study was to explore the possible functional relationship between SNAI1 and HDAC1 in the induction of EMT in HLECs. In the present study, SNAI1 was found to be increased in HLECs during transforming growth factor‑β2 (TGF‑β2)‑induced EMT. Knockdown of SNAI1 by siRNA reversed TGF‑β2‑induced downregulation of E‑cadherin and upregulation of α‑Smooth Muscle Actin. Furthermore, SNAI1 was found to be associated with HDAC1 in the E‑cadherin promoter in TGF‑β2‑treated HLECs. Inhibition of HDAC by trichostatin A and suberoylanilide hydroxamic acid could prevent TGF‑β2‑induced EMT in HLECs. Collectively, SNAI1 interacted with HDAC1 to repress E‑cadherin in the TGF‑β2‑induced EMT in HLECs, suggesting that HDAC inhibitors may have potential therapeutic value for the prevention of EMT in HLECs. Show less

Highly expressed G protein-coupled receptor 81 (GPR81), a receptor for lactate, is emerging as a critical regulator of tumor growth and metastasis. However, the mechanistic basis for its highly expression in cancer cells remains elusive. Here we report that tumor-derived lactate transcriptionally regulates GPR81 expression. We demonstrated that the transcriptional response of GPR81 to lactate is mediated by Signal transducer and activator of transcription 3 (STAT3). Mechanistically, lactate upregulates transcriptional factor Snail and induces the assembly of Snail/EZH2/STAT3 complex. Within this ternary complex, STAT3 activity is strongly enhanced. Consequently, the activated STAT3 by lactate directly binds GPR81promoter and activates its expression. These findings shed light on the transcriptional mechanism by which GPR81 expression is regulated in cancer cells, and provides mechanistic insight into how aberrant signaling and continually high lactate levels due to metabolic switch may yield a feed-forward/self-enabling loop to promote tumor progression. Show less

Prostate cancer is the most common malignancy in men in developed countries. Overexpression of enhancer of zeste homolog 2 (EZH2), the major histone H3 lysine 27 methyltransferase, has been connected to prostate cancer malignancy. However, its downstream genes and pathways have not been well established. Here, we show tumor suppressor Hepatocyte Nuclear Factor 1β (HNF1B) as a direct downstream target of EZH2. EZH2 binds HNF1B locus and suppresses HNF1B expression in prostate cancer cell lines, which is further supported by the reverse correlation between EZH2 and HNF1B expression in clinical samples. Consistently, restored HNF1B expression significantly suppresses EZH2-mediated overgrowth and EMT processes, including migration and invasion of prostate cancer cell lines. Mechanistically, we find that HNF1B primarily binds the promoters of thousands of target genes, and differentially regulates the expression of 876 genes. We also identify RBBP7/RbAP46 as a HNF1B interacting protein which is required for HNF1B-mediated repression of SLUG expression and EMT process. Importantly, we find that higher HNF1B expression strongly predicts better prognosis of prostate cancer, alone or together with lower EZH2 expression. Taken together, we have established a previously underappreciated axis of EZH2-HNF1B-SLUG in prostate cancer, and also provide evidence supporting HNF1B as a potential prognosis marker for metastatic prostate cancer. Show less

It is critical to identify patients with stage II and III colorectal cancer (CRC) who will benefit from adjuvant chemotherapy (ACT) after curative surgery, while the only use of clinical factors is insufficient to predict this beneficial effect. In this study, we performed genetic algorithm (GA) to select ACT candidate genes, and built a predictive model of support vector machine (SVM) using gene expression profiles from the Gene Expression Omnibus database. The model contained four ACT candidate genes (EDEM1, MVD, SEMA5B, and WWP2) and TNM stage (stage II or III). After using Subpopulation Treatment Effect Pattern Plot to determine the optimal cutoff value of predictive scores, the validated patients from The Cancer Genome Atlas database can be divided into the predictive ACT-benefit/-futile groups. Patients in the predictive ACT-benefit group with 5-fluorouracil (5-Fu)-based ACT had significantly longer relapse-free survival (RFS) compared to those without ACT (P = .015); However, the difference in RFS in the predictive ACT-futile group was insignificant (P = .596). The multivariable analysis found that the predictive groups were significantly associated with the effect of ACT (P Show less

The epithelial-mesenchymal transition (EMT) process is a key priming activity of fibroblasts in pulmonary fibrosis during silicosis. Ets-like protein-1 (Elk-1) is a critical modulator that promotes functional changes in cells, and the effects are mediated by oxidative stress (OS). However, whether ELK-1 is involved in EMT of silicosis remains unclear. In addition, researchers have found that Elk-1 is involved in the expression of the gene zc3h12a, which encodes the protein MCPIP1, and MCPIP1 is a member of the zinc finger Cys-Cys-Cys-His (CCCH)-type protein family. A previous study from our lab showed that ZC3H4, which is also a member of the CCCH-type protein family, critically affected the regulation of EMT during silicosis. However, it has not yet been elucidated if ELK-1 acts at the promoter for zc3h4 to increase its expression in a mechanism that is similar to that of the zc3h12a gene and whether such regulation ultimately controls EMT. Therefore, we explored the correlation between ELK-1 and ZC3H4 expression and tested the underlying mechanisms affecting ELK-1 activation induced by silica. Our study identifies that SiO Show less

Ubiquitin chain specificity has been described for some deubiquitinases (DUBs) but lacks a comprehensive profiling in vivo. We used quantitative proteomics to compare the seven lysine-linked ubiquitin chains between wild-type yeast and its 20 DUB-deletion strains, which may reflect the linkage specificity of DUBs in vivo. Utilizing the specificity and ubiquitination heterogeneity, we developed a method termed DUB-mediated identification of linkage-specific ubiquitinated substrates (DILUS) to screen the ubiquitinated lysine residues on substrates modified with certain chains and regulated by specific DUB. Then we were able to identify 166 Ubp2-regulating substrates with 244 sites potentially modified with K63-linked chains. Among these substrates, we further demonstrated that cyclophilin A (Cpr1) modified with K63-linked chain on K151 site was regulated by Ubp2 and mediated the nuclear translocation of zinc finger protein Zpr1. The K48-linked chains at non-K151 sites of Cpr1 were mainly regulated by Ubp3 and served as canonical signals for proteasome-mediated degradation. Show less

Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone of energy balance. Here, we aimed to identify a physiological signal that arises from excess caloric intake and negatively controls hypothalamic leptin action. We found that deficiency of the gastric inhibitory polypeptide receptor (Gipr) for the gut-derived incretin hormone GIP protected against diet-induced neural leptin resistance. Furthermore, a centrally administered antibody that neutralizes GIPR had remarkable antiobesity effects in diet-induced obese mice, including reduced body weight and adiposity, and a decreased hypothalamic level of SOCS3, an inhibitor of leptin actions. In contrast, centrally administered GIP diminished hypothalamic sensitivity to leptin and increased hypothalamic levels of Socs3. Finally, we show that GIP increased the active form of the small GTPase Rap1 in the brain and that its activation was required for the central actions of GIP. Altogether, our results identify GIPR/Rap1 signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions. Show less

Genetic studies based on single-nucleotide polymorphisms have provided valuable insights into the genetic architecture of complex diseases. However, a large fraction of heritability for most of these diseases remains unexplained, and the impact of small insertions and deletions (InDels) has been neglected. We performed a comprehensive screen on the exome sequence data of 1,326 genes using the SOAP-PopIndel method for InDels in 32,043 Chinese Han individuals and identified 29 unreported InDels within 25 susceptibility genes associated with psoriasis. Specifically, we identified 12 common, 9 low-frequency, and 8 rare InDels that explained approximately 1.29% of the heritability of psoriasis. Further analyses identified KIAA0319, RELN, NCAPG, ABO, AADACL2, LMAN1, FLG, HERC5, CCDC66, LEKR1, AFF3, ABCG2, ANXA7, SYTL2,GIPR, METTL1, and FYCO1 as unreported genes for psoriasis. In addition, identified InDels were associated with the following reported genes: IFIH1, ERAP1, ERAP2, LNPEP, UBLCP1, and STAT3; unreported independent associations for exonic InDels were found within GJB2 and ZNF816A. Our study enriched the genetic basis and pathogenesis of psoriasis and highlighted the non-negligible impact of InDels on complex human diseases. Show less

The present study aimed to identify the molecular markers for genes that influence intramuscular fat content (IFC), but not average backfat thickness (ABT). A total of 330 Suhuai pigs were slaughtered, and measurements of IFC and ABT were obtained. Phenotypic and genetic correlations between IFC and ABT were calculated. Thirteen single nucleotide polymorphisms (SNPs) among 12 candidate genes for IFC were analyzed, including Show less

Neuropeptide Y (NPY) is the most powerful central neuropeptide implicated in feeding regulation via its receptors. Understanding the role of NPY system is critical to elucidate animal feeding regulation. Unlike mammal, the possible mechanisms of NPY system in the food intake of teleost fish are mostly unknown. Therefore, we investigated the regulatory mechanism of NPY and NPY receptors in Siberian sturgeon. In this study, we cloned the cDNA encoding NPY, and assessed the effects of different energy status on npy mRNAs abundance. The expression of npy was decreased in the brain after feeding 1 and 3 h. Besides, the expression of npy was increased after fasting within 15 days, while exhibiting significant decrease after refeeding. In order to further characterize the role of NPY receptor in fish, we performed acute intraperitoneal (i.p.) injection of NPY Y1 and Y2 receptor agonists, which is [Leu 31, Pro 34] NPY and NPY13-36 respectively. The results showed that the food intake of Siberian sturgeon was increased within 30 mins after injection of both Y1 and Y2 receptor agonist. To explore the relationship between NPY, NPY receptors and another appetite peptides, we examined the level of npy, cocaine- and amphetamine-regulated transcript (cart) and melanocortin-4 receptor (mc4r) by injected Y1 and Y2 receptor agonist. The results suggested that cart expression was regulated by NPY which acts on Y1 receptor or Y2 receptor. While mc4r expression just was mediated by NPY and Y1 receptor. Show less

Fat mass and obesity-associated (FTO) and melanocortin 4 receptor (MC4R) genes associated with obesity have been identified through Genome-wide Association Studies. However, no multiple loci interaction studies have been conducted in the Chinese population. This study investigated whether the combined effects of FTO and MC4R increase the risk of obesity in children and adolescents living in Northwest China. A total of 370 subjects (170 overweight/obese and 200 normal BMI subjects according to the Working Group on Obesity in China criteria) were enrolled using the random sampling method. FTO rs9939609 and rs9935401 and MC4R rs12970134 and rs17782313 interactions were analysed through generalized multifactor dimensionality reduction, and logistic regression models were used to calculate the risk of the relationship between genotypes and obesity. Generalized multifactor dimensionality reduction analysis showed a significant gene-gene interaction among FTO rs9939609/MC4R rs12970134/MC4R rs17782313, with a score of 10/10 for the cross-validation consistency and 9 for the sign test (p=0.011). A 2.453-fold increased risk of obesity was observed in individuals carrying the genotypes of FTO rs9939609 TA/AA, MC4R rs12970134 GA/AA, and MC4R rs17782313 TC/CC (adjusted for age, sex, and ethnicity; 95% CI=1.12-5.37, p=0.025). Our results suggested that FTO rs9939609, MC4R rs12970134, and MC4R rs17782313 are strongly associated with obesity. The combined effects were highly significant on obesity in children and adolescents living in Northwest China. Show less

Being a hydroxylated metabolite of aflatoxin B1 (AFB1) and the most threatening aspect of AFB1 contamination, aflatoxin M1 (AFM1) can lead to hepatotoxicity and hepato-carcinogenicity, and possess intestinal cytotoxicity. However, little is known about the potential mechanisms of the extrahepatic effect. The aim of this study was to investigate intestinal dysfunction induced by AFM1 via transcriptome analysis. Gene expression profiling was analyzed to comparatively characterize the differentially expressed genes (DEGs) after differentiated Caco-2 cells were exposed to different concentrations of AFM1 for 48 h. A total of 165 DEGs were significantly clustered into two down-regulated patterns. Protein-protein interaction (PPI) network analysis based on Search Tool for Retrieval of Interacting Genes (STRING)suggested that 23 key enzymes mainly participated in the regulation of the cell cycle. Q-PCR analysis was performed to validate that key 12 genes (BUB1, BUB1B, MAD2L1, CCNA2, RB1, CDK1, ANAPC4, ATM, KITLG, PRKAA2, SIRT1, and SOS1) were involved. This study firstly revealed that the toxicity of AFM1 to intestinal functions may be partly due to the occurrence of cell cycle arrest, which is linked to changes in CDK1, SOS1/Akt, and AMPK signaling molecules. Show less

Danshen (Salvia miltiorrhiza) and prednisone are extensively applied in the treatment of kidney disease. Salvianolic acid A (SAA), the major biologically active component of Danshen, which has various biological effects. Our previous findings have demonstrated the renoprotective effect of SAA in various kidney disease rodent models. Here, we explore the therapeutic potential and possible mechanisms of SAA in combination with low-dose prednisone in adriamycin (ADR)-induced minimal change disease (MCD) rat model and mouse podocyte injury cell model. SAA was injected via tail vein at 10 mg/kg/day and prednisone at 5 mg/kg/day via gavage. Each drug was administered daily alone or in combination for 3 weeks. Combination therapy showed significant therapeutic efficacy as manifested by relieved urinary proteins, improved blood biochemical indicators including serum total protein, albumin, triglyceride, cholesterol, the indices of renal function i.e. blood urea nitrogen and serum creatinine levels, and ameliorated pathological lesions. Particularly, co-administration showed a significant anti-proteinuria effect in MCD rats. Further studies suggested that co-administration effectively ameliorated the podocyte injury as indicated by the reduction of podocyte foot processes fusion, up-regulation of synaptopodin and down-regulation of desmin. These beneficial effects are accompanied by activation of the Nrf2/HO-1 and PPARγ/Angptl4 pathways in vivo, and the effect of SAA on PPARγ/Angptl4 is also demonstrated in vitro. These findings suggested that SAA exerted podocyte-protection against MCD injury through PPARγ/Angptl4 and Nrf2/HO-1 pathways, and combined with low-dose prednisone possessed a significant anti-proteinuria and therapeutic effects in MCD rats. Show less

The role of Tibet kefir milk (TKM) feeding on fat deposition was investigated in high-fat diet (HFD)-fed human flora-associated (HFA) rats. TKM feeding reduced abdominal fat mass from 33.9 g to 24.0 g and serum triglyceride (TG) from 0.75 mmol/L to 0.47 mmol/L, and caused lipoprotein lipase (LPL) to decrease from 395.8 ± 36.0 ng/L to 362.3 ± 64.4 ng/L in fat and increase from 287.3 ± 40.8 ng/L to 329.8 ± 48.5 ng/L and 312.5 ± 22.0 to 375.1 ± 30.8 ng/L in liver and serum, respectively. Likewise, TMK feeding down-regulated Lpl gene expression in fat and Angptl4 (angiopoietin-like protein-4, also known as fasting-induced adipose factor) gene expression in liver, and up-regulated Angptl4 gene expression in fat. Sequence analysis showed that the Firmicutes/Bacteroidetes proportion and Verrucomicrobia at the phylum level, Akkermansia, Escherichia and Oscillospira at the genus level, as well as Escherichia coli at the species level were positively regulated by TKM. The results indicated that TKM decreased abdominal fat deposition and serum TG by regulating Lpl and Angptl4 at the transcriptional level. The microbiota groups mentioned above were regulated by TKM at the same time and may be the potential intervention targets to reduce fat deposition. Show less

Chronic HBV infection (CHB) can lead to acute-on-chronic liver failure (HBV-ACLF) characterized by high mortality. This study aimed to reveal ACLF-related proteomic alterations, from which protein based diagnostic and prognostic scores for HBV-ACLF were developed. Show less

Cell division cycle 20 (CDC20) is frequently overexpressed in malignant tumours and involved in the differentiation process of hematopoietic stem cells. However, the role of CDC20 in prostate cancer stem-like cells (CSCs) remains poorly understood. The expression of CDC20, CD44, β-catenin were examined in prostate cancer specimens by immunohistochemistry assay, the role of CDC20 on the stem-like properties of prostate CSCs was accessed by real-time quantitive PCR, spheroid formation, in vitro and in vivo limiting dilution assay. CDC20 was associated with malignant progression of prostate cancer, the patients with both high expression CDC20 and CD44 or β-catenin were associated with more aggressive clinicopathological features and poor prognosis. CDC20 was usually enriched in CD44 Our results indicated that CDC20 maintains the self-renewal ability of CD44 Show less