Publications by authors named "Yakun Wang"

62 Publications

Reducing embryonic mtDNA copy number alters epigenetic profile of key hepatic lipolytic genes and causes abnormal lipid accumulation in adult mice.

FEBS J 2021 Jul 14. Epub 2021 Jul 14.

Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100193, China.

Adverse fetal environment, in particular a shortage or excess of nutrients, is associated with increased risks of metabolic diseases later in life. However, the molecular mechanisms underlying this developmental origin of adult diseases remain unclear. Here, we directly tested the role of mitochondrial stress in mediating fetal programming in mice by enzymatically depleting mitochondrial DNA (mtDNA) in zygotes. mtDNA-targeted plasmid microinjection is used to reduce embryonic mtDNA copy number directly, followed by embryo transfer. Mice with reduced zygote mtDNA copy number were born morphologically normal and showed no accelerated body weight gain. However, at five-month of age these mice showed markedly increased hepatic lipidosis and became glucose intolerant. Hepatic mRNA and protein expression of peroxisome proliferator-activated receptor α (Pparα), a key transcriptional regulator of lipid metabolism, were significantly decreased as a result of increased DNA methylation in its proximal regulatory region. These results indicate that perturbation of mitochondrial function around the periconceptional period causes hypermethylation and thus suppressed expression of PPARα in fetal liver, leading to impaired hepatic lipid metabolism. Our findings provide the first direct evidence that mitochondrial stress mediates epigenetic changes associated with fetal programming of adult diseases in a mammalian system.
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http://dx.doi.org/10.1111/febs.16121DOI Listing
July 2021

Synergistic Effect of Surface Chemistry and Surface Topography Gradient on Osteogenic/Adipogenic Differentiation of hMSCs.

ACS Appl Mater Interfaces 2021 Jul 22;13(26):30306-30316. Epub 2021 Jun 22.

Unit of STEM, University of South Australia, Mawson Lakes 5095, Australia.

Much attention has been paid to understanding the individual effects of surface chemistry or topography on cell behavior. However, the synergistic influence of both surface chemistry and surface topography on differentiation of human mesenchymal stem cells (hMSCs) should also be addressed. Here, gold nanoparticles were immobilized in an increasing number density manner to achieve a surface topography gradient; a thin film rich in amine (-NH) or methyl (-CH) chemical groups was plasma-polymerized to adjust the surface chemistry of the outermost layer (ppAA and ppOD, respectively). hMSCs were cultured on these model substrates with defined surface chemistry and surface topography gradient. The morphology and focal adhesion (FA) formation of hMSCs were first examined. hMSC differentiation was then co-induced in osteogenic and adipogenic medium, as well as in the presence of extracellular-signal-regulated kinase1/2 (ERK1/2) and RhoA/Rho-associated protein kinase (ROCK) inhibitors. The results show that the introduction of nanotopography could enhance FA formation and osteogenesis but inhibited adipogenesis on both ppAA and ppOD surfaces, indicating that the surface chemistry could regulate hMSC differentiation, in a surface topography-dependent manner. RhoA/ROCK and ERK1/2 signaling pathways may participate in this process. This study demonstrated that surface chemistry and surface topography can jointly affect cell morphology, FA formation, and thus osteogenic/adipogenic differentiation of hMSCs. These findings highlight the importance of the synergistic effect of different material properties on regulation of cell response, which has important implications in designing functional biomaterials.
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http://dx.doi.org/10.1021/acsami.1c03915DOI Listing
July 2021

Vasa expression is associated with sex differentiation in the Asian yellow pond turtle, Mauremys mutica.

J Exp Zool B Mol Dev Evol 2021 Jul 8;336(5):431-442. Epub 2021 Jun 8.

Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation of Ministry of Agriculture and Rural Affairs, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China.

Vasa, one of the best-studied germ cell markers plays a critical role in germ cell development and differentiation in animals. Vasa deficiency would lead to male-specific sterility in most vertebrates, but female sterility in the fly. However, the role of the vasa gene involved in germ cell differentiation is largely elusive. Here, we first characterized the expression profile of vasa products in the Asian yellow pond turtle by quantitative reverse-transcription polymerase chain reaction and fluorescence immunostaining. The results showed that vasa messenger RNA (mRNA) is initially detected in embryos at stage 16, and then dramatically increased in embryos at stage 19. In particular, like the sex-related genes, vasa mRNA exhibited differential expression in embryos between the male-producing temperature (MPT, 25°C) and the female-producing temperature (FPT, 33°C), whereas there was no difference in methylation levels of vasa promoter detected between FPT and MPT. In contrast, in the adult Asian yellow pond, the level of vasa mRNA was much higher in the testis than ovary. Moreover, the immunostaining on testicular sections and cells showed that Vasa protein was exclusively expressed in germ cells: Weak but detectable in spermatogonia, highest in spermatocytes, moderate and concentrated in chromatid bodies in spermatids and spermatozoa, and bare in somatic cells. The expression profile of Vasa protein is similar in turtle species studied so far but distinct from those in fish species in this study. The findings of this study would provide new insights into our understanding of the conservation and divergence of the vasa gene, even other germ cell genes across phyla.
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http://dx.doi.org/10.1002/jez.b.23064DOI Listing
July 2021

A mitochondria-targeted thiazoleorange-based photothermal agent for enhanced photothermal therapy for tumors.

Bioorg Chem 2021 Aug 30;113:104954. Epub 2021 Apr 30.

Allan H. Conney Laboratory for Anticancer Research, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China; School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China. Electronic address:

Organic small molecules with near-infrared (NIR) absorption hold great promise as the phototheranostic agents for clinical translation by virtue of their inherent merits such as well-defined chemical structure, high purity and good reproducibility. Probes that happen to be based on cyanine dyes exhibit strong NIR-absorbing and efficient photothermal conversion, representing a new class of photothermal agents (PAs) for photothermal therapy (PTT), and taking into account the heat susceptibility of Mitochondria (Mito), we designed and prepared a mitochondria-targeted organic small molecule (Mito-BWQ) based on thiazole orange maternal unit that can effectively kill tumor cells through the hyperpyrexia generated in the lesions under exogenous laser irradiation. The Confocal laser scanning microscope was employed to determine the preferential targeting of Mito-BWQ to the mitochondria of MCF-7 cells and U87 cells. When subjected to 600 nm laser radiation, Mito-BWQ produced an increase in temperature in test systems and this increase was dependent on both the laser power and probe concentration. In vitro tests, cytotoxicity was observed when cells were incubated with Mito-BWQ and exposed to laser irradiation. The PTT in vivo also showed that Mito-BWQ performed remarkably in tumor inhibition. This study thus provides a vital starting point for the creation of thiazole orange-based PTT formulations and promotes further advances in the field of PAs-based anticancer research and therapy.
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http://dx.doi.org/10.1016/j.bioorg.2021.104954DOI Listing
August 2021

Asymmetric α-electrophilic difluoromethylation of β-keto esters by phase transfer catalysis.

Org Biomol Chem 2021 Jun;19(21):4788-4795

School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China.

An efficient and enantioselective α-electrophilic difluoromethylation of β-keto esters has been achieved by phase-transfer catalysis. This procedure is applicable to different kinds of β-keto esters with a series of cinchona-derived C-2' aryl-substituted phase-transfer catalysts. The reaction gives the corresponding products in good enantioselectivities (up to 83% ee) and yields (up to 92%) with high C/O regioselectivities (up to 98 : 2). Moreover, the C/O selectivity of β-keto esters could be easily reversed and controlled. This asymmetric difluoromethylation provided a novel and efficient way for introducing chiral C-CF2H groups.
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http://dx.doi.org/10.1039/d1ob00511aDOI Listing
June 2021

Phase I study of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors.

Gastric Cancer 2021 Jul 4;24(4):913-925. Epub 2021 May 4.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Hai-Dian District, Fu-Cheng Road 52, Beijing, 100142, China.

Purpose: RC48 contains the novel humanized anti-HER2 antibody hertuzumab conjugated to MMAE via a cleavable linker. A phase I study was initiated to evaluate the toxicity, MTD, PK, and antitumor activity of RC48 in patients with HER2-overexpressing locally advanced or metastatic solid carcinomas, particularly gastric cancer.

Patients And Methods: This was a 2-part phase I study. Successive cohorts of patients received escalating doses of RC48 (0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, and 3.0 mg/kg). Dose expansion proceeded at the dose of 2.0 mg/kg Q2W. The efficacy and safety set included all patients who received at least one dose of RC48.

Results: Fifty-seven patients were enrolled, the MTD was unavailable due to termination of 3.0 mg/kg cohort; 2.5 mg/kg Q2W was declared the RP2D. RC48 was well tolerated, the most frequent grade 3 or worse TRAEs included neutropenia (19.3%), leukopenia (17.5%), hypoesthesia (14.0%), and increased conjugated blood bilirubin (8.8%). Four deaths occurred during the whole study, three of which were believed to be related to RC48. Overall, ORR and DCR were 21.0% (12/57) and 49.1% (28/57). Notably, patients who were HER2 IHC2+/FISH- responded similarly to those who were IHC2+/FISH+ and IHC3+, with ORRs of 35.7% (5/14), 20% (2/10), and 13.6% (3/22), respectively. In patients who were pretreated with HER2-targeted drugs, RC48 also showed promising efficacy, with ORR of 15.0% (3/20) and DCR of 45.0% (9/20).

Conclusion: RC48 was well tolerated and showed promising antitumor activity in HER2-positive solid tumors, including gastric cancer with HER2 IHC 2+/FISH- status.

Clinical Trial Information: NCT02881190.
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http://dx.doi.org/10.1007/s10120-021-01168-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205919PMC
July 2021

The role of Eimeria tenella EtCab protein in the attachment and invasion of host cells.

Vet Parasitol 2021 Apr 18;292:109415. Epub 2021 Mar 18.

Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian City, Shandong Province, China; Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian City, Shandong Province, China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, Taian City, Shandong Province, China. Electronic address:

Calcium-binding proteins (CaBPs) containing the specific calcium-binding motif (EF-hand) play a crucial role in important physiological events such as secretion, storage and signal transduction of cells. Recently, CaBPs have been found to be associated with host cell invasions in some parasites. In this study, an Eimeria tenella membrane-associated calcium-binding protein (EtCab) was cloned and its expression at different developmental stages, adhesive functions and host cell invasion in vitro were investigated. The results of the sequence analysis showed that EtCab contains six EF-hand motifs and the HDEL ER-retention signal belonging to the CREC (45 kDa calcium-binding protein, reticulocalbin, ER calcium-binding protein of 55 kDa, and calumenin) family. An indirect immunofluorescence assay (IFA) using specific polyclonal antibodies under permeabilized and nonpermeabilized conditions labeled EtCab on the surface of sporozoites. Quantitative real-time PCR and western blotting indicated that EtCab was highly transcribed and expressed in sporozoites. The attachment assay using a yeast surface display model showed that the adherence rates of EtCab expressed on the surfaces of yeasts to host cells were 2.5-fold greater than the control. Invasion inhibition assays revealed that specific polyclonal antibodies against EtCab significantly reduced the invasion rate of sporozoites on host cells compared to the control group (P < 0.01). These results suggest that EtCab plays an important role in the attachment and invasion of E. tenella to host cells.
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http://dx.doi.org/10.1016/j.vetpar.2021.109415DOI Listing
April 2021

Printable and Stretchable Giant Magnetoresistive Sensors for Highly Compliant and Skin-Conformal Electronics.

Adv Mater 2021 Mar 2;33(12):e2005521. Epub 2021 Feb 2.

Institute of Ion Beam Physics and Materials Research, Helmholtz-Zentrum Dresden-Rossendorf e.V., Bautzner Landstrasse 400, Dresden, 01328, Germany.

Highly compliant electronics, naturally conforming to human skin, represent a paradigm shift in the interplay with the surroundings. Solution-processable printing technologies are yet to be developed to comply with requirements to mechanical conformability of on-skin appliances. Here, it is demonstrated that high-performance spintronic elements can be printed on ultrathin 3 µm thick polymeric foils enabling the mechanically imperceptible printed magnetoelectronics, which can adapt to the periodic buckling surface to be biaxially stretched over 100%. They constitute the first example of printed and stretchable giant magnetoresistive sensors, revealing 2 orders of magnitude improvements in mechanical stability and sensitivity at small magnetic fields, compared to the state-of-the-art printed magnetoelectronics. The key enabler of this performance enhancement is the use of elastomeric triblock copolymers as a binder for the magnetosensitive paste. Even when bent to a radius of 16 µm, the sensors printed on ultrathin foils remain intact and possess unmatched sensitivity for printed magnetoelectronics of 3 T in a low magnetic field of 0.88 mT. The compliant printed sensors can be used as components of on-skin interactive electronics as it is demonstrated with a touchless control of virtual objects including zooming in and out of interactive maps and scrolling through electronic documents.
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http://dx.doi.org/10.1002/adma.202005521DOI Listing
March 2021

Reproductive performance is associated with seasonal plasma reproductive hormone levels, steroidogenic enzymes and sex hormone receptor expression levels in cultured Asian yellow pond turtles (Mauremys mutica).

Comp Biochem Physiol B Biochem Mol Biol 2021 Jun-Jul;254:110566. Epub 2021 Jan 27.

Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture and Rural Affairs, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, Guangdong 510380, PR China. Electronic address:

In order to understand the endocrine mechanism associated with fecundity of seasonally breeding animals, we investigated the plasma reproductive hormones levels and detected the differences in steroidogenic enzymes and sex hormone receptor mRNA levels in female Mauremys mutica. These turtles were divided into higher fecundity (HF) group than those in lower fecundity (LF) group based on paternity identification in our previous research. The plasma estrogen (E2), testosterone (T) and progesterone (P4) levels were significantly higher in pre-breeding season (PBS) than those in non-breeding season (NBS) and were markedly higher in the HF group than those in LF group. In the hypothalamus, there was significantly higher mRNA abundance of P450-cholesterol side-chain cleavage enzyme (P450Scc) encoded by Cyp11α1, aromatase (Cyp19α1) and 5-reductase (5α-R), but significantly lower mRNA levels of follicular stimulating hormone receptor (FSHR) and progesterone receptor (PR) detected in PBS than those in NBS. The pituitary steroidogenic acute regulatory protein (StAR), cytochrome P450-17alpha-hydroxylase (Cyp17α1), 3-hydroxy-steroid dehydrogenase (3βHSD), 17-hydroxy-steroid dehydrogenase 3 (17βHSD3), Cyp19α1, 5α-R, FSHR, estrogen receptor 1 (ESR1), androgen receptor (AR) and PR transcriptional levels in HF group were up-regulated significantly compared with the LF group. In the ovary, Cyp17α1 and 17βHSD3 transcriptional levels were markedly higher in PBS than those in NBS. We detected significantly increased expression levels of all steroidogenic enzymes, but notably lower mRNA levels of FSHR and PR in uterus during the PBS, and the HF group has significantly higher expression levels of StAR, Cyp17α1, 5α-R and AR than LF group. Our work reveals seasonal variations in hormone regulation as well as gene regulation in turtles, providing reliable information to understand the mechanisms underlying the different reproductive capacity of reptiles.
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http://dx.doi.org/10.1016/j.cbpb.2021.110566DOI Listing
July 2021

Overexpression of NNT-AS1 Activates TGF- Signaling to Decrease Tumor CD4 Lymphocyte Infiltration in Hepatocellular Carcinoma.

Biomed Res Int 2020 23;2020:8216541. Epub 2020 Dec 23.

Medical Research Center, Beijing Chao-yang Hospital, Capital Medical University, China.

Nicotinamide nucleotide transhydrogenase-antisense RNA1 (NNT-AS1) is a long noncoding RNA (lncRNA) that has been shown to be overexpressed in hepatocellular carcinoma (HCC). However, the molecular mechanism involving NNT-AS1 in HCC remains to be extensively investigated. The activation of TGF- signaling inhibits tumor-infiltrating lymphocytes (TILs) and results in tumor immune evasion. We thus planned to explore the mechanism by which NNT-AS1 activates the TGF- signaling pathway and inhibits TILs in HCC. High levels of NNT-AS1 were detected in HCC tissues by both RNAscope and real-time quantitative PCR (RT-qPCR) assays. The levels of proteins involved in TGF- signaling and those of CD4 T lymphocytes were quantified by immunohistochemistry (IHC). HCC cell lines (HepG2 and Huh7) were used to explore the effects of NNT-AS1 on TGF- signaling activation. In these analyses, RNAscope detection demonstrated that NNT-AS1 levels were significantly increased in HCC cancer tissues ( = 0.0001). In addition, the elevated NNT-AS1 levels in cancer tissue were further confirmed by RT-qPCR analysis of HCC cancer tissues ( = 64) and normal tissues ( = 26) ( = 0.0003). Importantly, the overall survival time of HCC patients who exhibited higher levels of NNT-AS1 expression was significantly shorter than that of HCC patients who had lower levels of NNT-AS1 expression ( = 0.0402). Further mechanistic investigation indicated that NNT-AS1 inhibition significantly decreased the levels of TGF-, TGFBR1, and SMAD5 in HCC cells. In HCC tissues, IHC detection showed that relatively high NNT-AS1 levels were associated with a reduction in infiltrated CD4 lymphocyte numbers. In conclusion, this research identifies a novel mechanism by which NNT-AS1 impairs CD4 T cell infiltration via activation of the TGF- signaling pathway in HCC.
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http://dx.doi.org/10.1155/2020/8216541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775131PMC
May 2021

Contribution of retrotrapezoid nucleus neurons to CO -amplified cardiorespiratory activity in spontaneously hypertensive rats.

J Physiol 2021 02 5;599(4):1115-1130. Epub 2021 Jan 5.

Department of Physiology, Hebei Medical University, Shijiazhuang, Hebei, 050017, China.

Key Points: This study demonstrates that both CO -induced respiratory and cardiovascular responses are augmented in spontaneously hypertensive rats (SHRs). Genetic ablation of the retrotrapezoid nucleus (RTN) neurons depresses enhanced hypercapnic ventilatory response and eliminates CO -stimulated increase in arterial pressure and heart rate in SHRs. SHRs have a high protein level of pH-sensitive channels in the RTN, including the TASK-2 channel, Kv12.1 channel and acid-sensing ion channel 3. The inhibition of putative TASK-2 channel activity by clofilium diminishes amplified hypercapnic ventilatory and cardiovascular responses, and reduces the number of CO -activated RTN neurons in SHRs. These results indicate that RTN neurons contribute to enhanced CO -stimulated respiratory and cardiovascular responses in SHRs.

Abstract: The respiratory regulation of cardiovascular activity is essential for maintaining an efficient ventilation and perfusion ratio. Activation of central respiratory chemoreceptors not only elicits a ventilatory response but also regulates sympathetic nerve activity and arterial blood pressure (ABP). The retrotrapezoid nucleus (RTN) is the most completely characterized cluster of central respiratory chemoreceptors. We hypothesize that RTN neurons contribute to augmented CO -stimulated respiratory and cardiovascular responses in adult spontaneously hypertensive rats (SHRs). Our findings indicate that SHRs exhibit more enhanced hypercapnic cardiorespiratory responses than age-matched normotensive Wistar-Kyoto rats. Genetic ablation of RTN neurons notably depresses an enhanced hypercapnic ventilatory response (HCVR) and eliminates a CO -stimulated greater increase in ABP and heart rate in SHRs. In addition, SHRs have a higher protein level of pH-sensitive channels in the RTN, including TASK-2 channels, Kv12.1 channels and acid-sensing ion channel 3. Administration of clofilium (i.p.), an unselective inhibitor of TASK-2 channels, not only significantly reduces the enhanced HCVR but also inhibits CO -amplified increases in ABP and heart rate in SHRs. Moreover, clofilium significantly decreases the number of CO -activated RTN neurons in SHRs. Taken together, we suggest that RTN neurons play an important role in enhanced hypercapnic ventilatory and cardiovascular responses in SHRs and the putative mechanism involved is associated with TASK-2 channel activity in the RTN.
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http://dx.doi.org/10.1113/JP280246DOI Listing
February 2021

Gut microbiota-mediated xanthine metabolism is associated with resistance to high-fat diet-induced obesity.

J Nutr Biochem 2021 02 23;88:108533. Epub 2020 Oct 23.

College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China. Electronic address:

Resistance to high-fat diet-induced obesity (DIR) has been observed in mice fed a high-fat diet and may provide a potential approach for anti-obesity drug discovery. However, the metabolic status, gut microbiota composition, and its associations with DIR are still unclear. Here, ultraperformance liquid chromatography-tandem mass spectrometry-based urinary metabolomic and 16S rRNA gene sequencing-based fecal microbiome analyses were conducted to investigate the relationship between metabolic profile, gut microbiota composition, and body weight of C57BL/6J mice on chow or a high-fat diet for 8 weeks. PICRUSt analysis of 16S rRNA gene sequences predicted the functional metagenomes of gut bacteria. The results demonstrated that feeding a high-fat diet increased body weight and fasting blood glucose of high-fat diet-induced obesity (DIO) mice and altered the host-microbial co-metabolism and gut microbiota composition. In DIR mice, high-fat diet did not increase body weight while fasting blood glucose was increased significantly compared to chow fed mice. In DIR mice, the urinary metabolic pattern was shifted to a distinct direction compared to DIO mice, which was mainly contributed by xanthine. Moreover, high-fat diet caused gut microbiota dysbiosis in both DIO and DIR mice, but in DIR mice, the abundance of Bifidobacteriaceae, Roseburia, and Escherichia was not affected compared to mice fed a chow diet, which played an important role in the pathway coverage of FormylTHF biosynthesis I. Meanwhile, xanthine and pathway coverage of FormylTHF biosynthesis I showed significant positive correlations with mouse body weight. These findings suggest that gut microbiota-mediated xanthine metabolism correlates with resistance to high-fat DIO.
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http://dx.doi.org/10.1016/j.jnutbio.2020.108533DOI Listing
February 2021

LINC00052 ameliorates acute kidney injury by sponging miR-532-3p and activating the Wnt signaling pathway.

Aging (Albany NY) 2020 11 24;13(1):340-350. Epub 2020 Nov 24.

Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Qingpu 201700, Shanghai, P.R. China.

Acute kidney injury (AKI) is a complex renal disease. Long non-coding RNAs (lncRNAs) have frequently been associated with AKI. In the present study, we aimed to investigate the molecular mechanism(s) of LINC00052 in AKI. We found that LINC00052 expression was significantly decreased in AKI patient serum. In addition, in a hypoxic AKI cell model, LINC00052 expression was strongly elevated. In an I/R-triggered AKI rat model, the expression of TNF-α, IL-6 and IL-1β mRNA was strongly elevated. Moreover, we predicted miR-532-3p to be targeted by LINC00052 in AKI. Overexpression of LINC00052 increased hypoxia-induced inhibition of NRK-52E cell proliferation and reversed hypoxia-triggered apoptosis. Furthermore, we found that induction of TNF-α, IL-6 and IL-1β was repressed by overexpression of LINC00052. LINC00052 decreased hypoxia-induced ROS and MDA accumulation and increased SOD activity. Decreased levels of c-myc and cyclin D1 were observed in renal tissues of AKI rats. Lastly, Wnt/β-catenin signaling was inactivated in NRK-52E cells experiencing hypoxia, and LINC00052 upregulation reactivated Wnt/β-catenin signaling by sponging miR-532-3p. Taken together, these results suggest that LINC00052 ameliorates AKI by sponging miR-532-3p and activating Wnt signaling.
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http://dx.doi.org/10.18632/aging.104152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835036PMC
November 2020

Alterations of gut microbiome in patients with type 2 diabetes mellitus who had undergone cholecystectomy.

Am J Physiol Endocrinol Metab 2021 01 9;320(1):E113-E121. Epub 2020 Nov 9.

Department of Pharmacy, The Third Affiliated Hospital of Soochow University, Changzhou, China.

Patients with type 2 diabetes mellitus (T2DM) have a high risk of developing cholecystic disease. The gut microbiota has been shown to be strongly associated with cholecystectomy and T2DM pathogenesis. However, alterations of the gut microbiome in patients with T2DM who had undergone cholecystectomy remain unexplored. In this study, the gut microbiomes of 14 long-term patients with T2DM who had undergone cholecystectomy (T2DIIC group) and 21 age- and/or sex-matched subjects with new-onset (T2DI group) and long-term (T2DII group) T2DM without cholecystectomy were assessed using 16S rRNA gene sequencing of stool samples. It was found that cholecystectomy could alleviate the decrease in Pielou's evenness and the increase in the relative abundances of the Firmicutes phylum and genus in long-term patients with T2DM compared with T2DII subjects. Moreover, cholecystectomy also significantly increased the relative abundance of the Fusobacteria phylum, as well as that of the and genera. Interestingly, the T2DIIC and T2DI groups showed higher similarities than the T2DII group with respect to patterns of gut microbiota composition and predicted gut metagenomes. In summary, cholecystectomy could partially alleviate long-term diabetes-induced dysbiosis of the gut microbiota composition and function, but alterations in T2DM patient health warrant further study. The gut microbiome of long-term T2DM patients who had undergone cholecystectomy and age- and/or sex-matched subjects of new-onset and long-term T2DM without cholecystectomy was assessed using 16S rRNA gene sequencing in stool samples. The findings suggest that, cholecystectomy could partially alleviate long-term diabetes-induced dysbiosis of gut microbiome composition and function.
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http://dx.doi.org/10.1152/ajpendo.00471.2020DOI Listing
January 2021

Quantification of circadian rhythm in mitochondrial DNA copy number in whole blood, and identification of factors that influence it.

Cell Mol Biol (Noisy-le-grand) 2020 Jul 31;66(5):179-184. Epub 2020 Jul 31.

Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, China.

Mitochondrial DNA (mtDNA), the genetic material in mitochondria, encodes key genes related to the respiratory chain and ATP production. To accurate quantification mtDNA content in whole blood is important for various disease states. Absolute quantitative Real-time PCR and platelet contamination erase method were used for mtDNA copy number analysis in whole blood. In the quantitative study of mtDNA content, it was found that whole blood mtDNA copy number showed a fluctuating rhythm during a 24-h period due to dynamic changes in white blood cells combined with platelets. However, when isolated white blood cells were used, or absolute whole blood mtDNA was calculated, the circadian rhythm pattern of mtDNA disappeared. In this study, a feasible method that can accurately quantify mitochondrial DNA in small blood samples was established, and it was found that two factors which greatly influenced mtDNA copy number were sampling time and platelets in blood.
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July 2020

Circ_LARP4 regulates high glucose-induced cell proliferation, apoptosis, and fibrosis in mouse mesangial cells.

Gene 2021 Jan 3;765:145114. Epub 2020 Sep 3.

Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University. 1158 Gongyuan East Road, Qingpu District, Shanghai 201700, PR China. Electronic address:

The current study aimed to investigate the role and underlying mechanisms of circ_LARP4 in diabetic nephropathy (DN). Here, mouse mesangial cells (SV40-MES13) were cultured with 30 mM glucose to establish a DN cellular model. The qRT-PCR results indicated that circ_LARP4 expression was downregulated in the DN cellular model compared to that in the control cells. As determined by an MTT assay, circ_LARP4 overexpression via the circ_LARP4 overexpression (OE) plasmids inhibited the cell proliferation rate. As determined by an Annexin V/PI kit and flow cytometry, circ_LARP4 overexpression increased the cell apoptosis rate. As measured by Western blot, circ_LARP4 overexpression enhanced BAX expression but reduced Bcl-2 expression, also suggesting an enhancement of cell apoptosis. Moreover, regarding cell fibrosis, circ_LARP4 overexpression reduced the mRNA levels of fibrosis markers, including fibronectin, collagen I and collagen IV. Interestingly, miR-424 was found to be reduced in the DN cellular model after transfection with the circ_LARP4 OE plasmids. In addition, restoration of miR-424 expression with the miR-424 mimics reversed the negative effects of circ_LARP4 overexpression on cell proliferation and fibrosis. In conclusion, circ_LARP4 was lower in the DN cellular model than in normal cells, and circ_LARP4 overexpression resulted in decreased cell proliferation and cell fibrosis but increased cell apoptosis in the DN cellular model by sponging miR-424.
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http://dx.doi.org/10.1016/j.gene.2020.145114DOI Listing
January 2021

BBB-penetrating codelivery liposomes treat brain metastasis of non-small cell lung cancer with EGFR mutation.

Theranostics 2020 15;10(14):6122-6135. Epub 2020 May 15.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China.

EGFR TKI therapy has become a first-line regimen for non-small cell lung cancer (NSCLC) patients with EGRF mutations. However, there are two big challenges against effective therapy--the secondary EGFR mutation-associated TKI resistance and brain metastasis (BMs) of lung cancer. The BMs is a major cause of death for advanced NSCLC patients, and the treatment of BMs with TKI resistance remains difficult. Tumor-associated macrophages (TAM) is a promising drug target for inhibiting tumor growth, overcoming drug resistance, and anti-metastasis. TAM also plays an essential role in regulating tumor microenvironment. We developed a dual-targeting liposomal system with modification of anti-PD-L1 nanobody and transferrin receptor (TfR)-binding peptide T12 for codelivery of simvastatin/gefitinib to treat BMs of NSCLC. The dual-targeting liposomes could efficiently penetrate the blood-brain barrier (BBB) and enter the BMs, acting on TAM repolarization and reversal of EGFR-associated drug resistance. The treatment mechanisms were related to the elevating ROS and the suppression of the EGFR/Akt/Erk signaling pathway. The dual-targeting liposomal codelivery system offers a promising strategy for treating the advanced EGFR NSCLC patients with BMs.
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http://dx.doi.org/10.7150/thno.42234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255027PMC
May 2021

Respiratory Control by Phox2b-expressing Neurons in a Locus Coeruleus-preBötzinger Complex Circuit.

Neurosci Bull 2021 Jan 28;37(1):31-44. Epub 2020 May 28.

Department of Physiology, Hebei Medical University, Shijiazhuang, 050017, China.

The locus coeruleus (LC) has been implicated in the control of breathing. Congenital central hypoventilation syndrome results from mutation of the paired-like homeobox 2b (Phox2b) gene that is expressed in LC neurons. The present study was designed to address whether stimulation of Phox2b-expressing LC (Phox2b) neurons affects breathing and to reveal the putative circuit mechanism. A Cre-dependent viral vector encoding a Gq-coupled human M3 muscarinic receptor (hM3Dq) was delivered into the LC of Phox2b-Cre mice. The hM3Dq-transduced neurons were pharmacologically activated while respiratory function was measured by plethysmography. We demonstrated that selective stimulation of Phox2b neurons significantly increased basal ventilation in conscious mice. Genetic ablation of these neurons markedly impaired hypercapnic ventilatory responses. Moreover, stimulation of Phox2b neurons enhanced the activity of preBötzinger complex neurons. Finally, axons of Phox2b neurons projected to the preBötzinger complex. Collectively, Phox2b neurons contribute to the control of breathing most likely via an LC-preBötzinger complex circuit.
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http://dx.doi.org/10.1007/s12264-020-00519-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811975PMC
January 2021

Using Reduced Amino Acid Alphabet and Biological Properties to Analyze and Predict Animal Neurotoxin Protein.

Curr Drug Metab 2020 ;21(10):810-817

College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China.

Aims: Because of the high affinity of these animal neurotoxin proteins for some special target site, they were usually used as pharmacological tools and therapeutic agents in medicine to gain deep insights into the function of the nervous system.

Background And Objective: The animal neurotoxin proteins are one of the most common functional groups among the animal toxin proteins. Thus, it was very important to characterize and predict the animal neurotoxin proteins.

Methods: In this study, the differences between the animal neurotoxin proteins and non-toxin proteins were analyzed.

Result: Significant differences were found between them. In addition, the support vector machine was proposed to predict the animal neurotoxin proteins. The predictive results of our classifier achieved the overall accuracy of 96.46%. Furthermore, the random forest and k-nearest neighbors were applied to predict the animal neurotoxin proteins.

Conclusion: The compared results indicated that the predictive performances of our classifier were better than other two algorithms.
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http://dx.doi.org/10.2174/1389200221666200520090555DOI Listing
January 2020

Comparative transcriptome analysis reveals the sexual dimorphic expression profiles of mRNAs and non-coding RNAs in the Asian yellow pond turtle (Meauremys mutica).

Gene 2020 Aug 7;750:144756. Epub 2020 May 7.

Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation of Ministry of Agriculture, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China. Electronic address:

Noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs), circular RNAs (circRNAs) and microRNAs (miRNAs) have been extensively studied in biological processes such as disease development, cell proliferation but remained unclear in sex differentiation in organisms. In this study, the transcriptome profiles were comparatively analyzed between male and female gonads in Mauremys mutica. A total of 8237 differentially expressed genes (DEGs), 9573 DE lncRNAs, 84 DE circRNAs and 665 DE miRNAs were identified between male and female gonads. Through gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) of the DE RNAs, it was revealed that the DE mRNAs were majorly involved in GO terms, such as 'reproduction', 'reproductive process' and the pathways of 'focal adhesion' and 'oocyte meiosis'. In addition, a co-expression network showed that the expression of gametogenesis and sex differentiation related genes, including dmrt3a, tdrd7, sox14, etc were closely associated with the levels of their corresponding ncRNAs. Intriguingly, the dmrt1 circRNA and its target mRNA were detected upregulated both in adult testis and male producing temperature (MPT) embryos. Our findings demonstrated the sexually dimorphic expression profiles of mRNAs and ncRNAs in turtle gonads, which will provide the index to find out the molecular mechanisms behind the sex differentiation in turtles, even in other environmental sex determination (ESD) species.
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http://dx.doi.org/10.1016/j.gene.2020.144756DOI Listing
August 2020

Characterization of the relationship between FLI1 and immune infiltrate level in tumour immune microenvironment for breast cancer.

J Cell Mol Med 2020 05 5;24(10):5501-5514. Epub 2020 Apr 5.

College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.

Breast cancer is the most common cancer and the leading cause of cancer death among women in the world. Tumour-infiltrating lymphocytes were defined as the white blood cells left in the vasculature and localized in tumours. Recently, tumour-infiltrating lymphocytes were found to be associated with good prognosis and response to immunotherapy in tumours. In this study, to examine the influence of FLI1 in immune system in breast cancer, we interrogated the relationship between the FLI1 expression levels with infiltration levels of 28 immune cell types. By splitting the breast cancer samples into high and low expression FLI1 subtypes, we found that the high expression FLI1 subtype was enriched in many immune cell types, and the up-regulated differentially expressed genes between them were enriched in immune system processes, immune-related KEGG pathways and biological processes. In addition, many important immune-related features were found to be positively correlated with the FLI1 expression level. Furthermore, we found that the FLI1 was correlated with the immune-related genes. Our findings may provide useful help for recognizing the relationship between tumour immune microenvironment and FLI1, and may unravel clinical outcomes and immunotherapy utility for FLI1 in breast cancer.
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http://dx.doi.org/10.1111/jcmm.15205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214163PMC
May 2020

Response to "Comments on 'Zhang et al: Clinical trial analysis of 2019-nCoV therapy registered in China'".

J Med Virol 2020 07 25;92(7):713. Epub 2020 Apr 25.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, People's Republic of China.

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http://dx.doi.org/10.1002/jmv.25803DOI Listing
July 2020

Cosmc Disruption-Mediated Aberrant O-glycosylation Suppresses Breast Cancer Cell Growth via Impairment of CD44.

Cancer Manag Res 2020 22;12:511-522. Epub 2020 Jan 22.

Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, People's Republic of China.

Background: Breast cancer remains the most lethal malignancy in women worldwide. Aberrant O-glycosylation is closely related to many human diseases, including breast carcinoma; however, its precise role in cancer development is insufficiently understood. Cosmc is an endoplasmic reticulum-localized chaperone that regulates the O-glycosylation of proteins. Cosmc dysfunction results in inactive T-synthase and expression of truncated O-glycans such as Tn antigen. Here we investigated the impact of Cosmc disruption-mediated aberrant O-glycosylation on breast cancer cell development through in vitro and in vivo experiments.

Materials And Methods: We deleted the Cosmc gene in two breast cancer cell lines (MCF7, T47D) using the CRISPR/Cas-9 system and then measured the expression levels of Tn antigen. The proliferation of Tn-positive cells was examined by RTCA, colony formation and in vivo experiments. The effects of Cosmc deficiency on glycoprotein CD44 and MAPK pathway were also determined.

Results: Both in vitro and in vivo studies showed that Cosmc deficiency markedly suppressed breast cancer cell growth compared with the corresponding controls. Mechanistically, Cosmc disruption impaired the protein expression of CD44 and the associated MAPK signaling pathway; the latter plays a crucial role in cell proliferation. Reconstitution of CD44 substantially reversed the observed alterations, confirming that CD44 requires normal O-glycosylation for its proper expression and activation of the related signaling pathway.

Conclusion: This study showed that Cosmc deficiency-mediated aberrant O-glycosylation suppressed breast cancer cell growth, which was likely mediated by the impairment of CD44 expression.
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http://dx.doi.org/10.2147/CMAR.S234735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986418PMC
January 2020

Clinical trial analysis of 2019-nCoV therapy registered in China.

J Med Virol 2020 06 5;92(6):540-545. Epub 2020 Mar 5.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China.

So far, there is a lack of effective drugs for the new coronavirus pneumonia. With more and more patients diagnosed, China has carried out more than 100 clinical studies of new coronavirus infection, including antiviral drugs, antimalarial drugs, glucocorticoids, plasma therapy, virus vaccine, and other Western drugs, while Chinese medicine research accounted for half of the studies. Most of the trials were initiated by investigators and the study period would last for 1 to 11 months. The primary endpoints included symptom improvement and virus nucleic acid turning negative, but the optimal endpoint has not been determined. Although the final results of studies will take a long time to complete, the interim research data may provide some help for the current urgent demand for drug treatment. Compared with that of during SARS period in 2003, China has the stronger capability to carry out clinical trials of new drugs in emergency period.
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http://dx.doi.org/10.1002/jmv.25733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228274PMC
June 2020

YARS as an oncogenic protein that promotes gastric cancer progression through activating PI3K-Akt signaling.

J Cancer Res Clin Oncol 2020 Feb 8;146(2):329-342. Epub 2020 Jan 8.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China.

Purpose: Members of the aaRS (aminoacyl-tRNA synthetase) family are proteins controlling the aminoacylation process, in which YARS (tyrosyl-tRNA synthetase) catalyzes the binding of tyrosine to its cognate tRNA and plays an important role in basic biosynthesis. Several studies have demonstrated the association between YARS mutation and certain developmental abnormalities/diseases, yet YARS's linkage with cancer remains uncategorized. In this study, by combining in silico, in vitro, and in vivo studies, we explored the expressions and functions of YARS in gastric cancer (GC).

Methods: We evaluated YARS's distribution in tumor and paired normal tissues/specimens of GC by referring to large cohort online datasets and patient-derived tissue specimens. YARS-related changes were assessed by phenotypical/molecular experiments and RNA-sequencing analysis in GC cell lines harboring YARS knockdown or overexpression.

Results: Both the transcript and protein levels of YARS were evidently higher in gastric cancer tissues than in paired normal tissues. YARS knockdown induced repressed proliferation and invasiveness, as well as enhanced apoptosis in GC cell lines, while abnormally upregulating YARS expression promoted gastric cancer growth in vivo. We inferred based on RNA-sequencing that YARS modulates multiple cancerous signaling pathways and proved through cellular experiments that YARS promoted GC progression, as well as homologous recombination by activating PI3K-Akt signaling.

Conclusions: By revealing the existence of a YARS-PI3K-Akt signaling axis in gastric cancer, we discovered that tRNA synthetase YARS is a novel tumorigenic factor, characterized by its upregulation in tumor-derived specimens, as well as its functions in promoting gastric cancer progression.
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http://dx.doi.org/10.1007/s00432-019-03115-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985085PMC
February 2020

Cosmc overexpression enhances malignancies in human colon cancer.

J Cell Mol Med 2020 01 21;24(1):362-370. Epub 2019 Oct 21.

Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.

Cosmc is known as a T-synthase-specific molecular chaperone that plays a crucial role in the process of O-glycosylation. Cosmc dysfunction leads to inactive T-synthase and results in aberrant O-glycosylation, which is associated with various tumour malignancies. However, it is unclear whether Cosmc has some other functions beyond its involvement in O-glycosylation. In this study, we aimed to investigate the functional role of Cosmc in human colorectal cancer (CRC). We first assessed the expression levels of Cosmc in human CRC specimens and then forcedly expressed Cosmc in human CRC cell lines (HCT116, SW480) to examine its impact on cellular behaviours. The mechanisms for aberrant expression of Cosmc in CRC tissues and the altered behaviours of tumour cells were explored. It showed that the mRNA and protein levels of Cosmc were markedly elevated in human CRC specimens relative to normal colorectal tissues. The occurrence of endoplasmic reticulum (ER) stress may largely contribute to the increased Cosmc expression in cancer tissue and cells. Cosmc overexpression in CRC cells significantly promoted cell migration and invasion, which could be attributed to the activation of the epithelial-mesenchymal transition (EMT) pathway rather than aberrant O-glycosylation. These data indicate that Cosmc expression was elevated in human CRC possibly caused by ER stress, which further enhanced malignancies through the activation of EMT but independently of aberrant O-glycosylation.
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http://dx.doi.org/10.1111/jcmm.14740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933370PMC
January 2020

FAM83H-AS1 is upregulated and predicts poor prognosis in colon cancer.

Biomed Pharmacother 2019 Oct 19;118:109342. Epub 2019 Aug 19.

Department of Cellular and Molecular Biology, Beijing Chest Hospital, Capital Medical University & Beijing Tuberculosis and Thoracic Tumor Research Institute, China.

Long noncoding RNAs (LncRNAs) have been proven to participate in many principal pathways during colonic mucosa tumourigenesis. FAM83H-AS1 has been identified as one of the LncRNAs that is dysregulated in multi-type cancers. Here, our purpose was to determine the expression pattern and clinical significance of FAM83H-AS1 and further analyse its prognostic value in colon cancer. FAM83H-AS1 expression was examined in 90 patients with colon cancer by RNAscope in situhybridization, and the expression levels were analysed with the overall survival (OS) rates for patients with colon cancer. TCGA datasets derived from colon cancer (COAD) were used to further validate the main findings. We demonstrated that the expression of FAM83H-AS1 was significantly higher in cancer tissues than in paired normal mucosa from colon cancer patients (P < 0.001). The prognostic analysis indicated that the OS rates for colon cancer patients with high levels of FAM83H-AS1 were significantly lower than those for patients with low levels of FAM83H-AS1 (P = 0.013). The higher levels of FAM83H-AS1 were found to be associated with a lower expression of SMAD1/5/9, which is involved in TGF-β signalling in colon cancer tissues (P = 0.0174). In HCT116 and SW480 cell lines, the down regulation of FAM83H-AS1 promoted the expression of SMAD1. Our investigations suggest that the upregulation of FAM83H-AS1 serves as a promising predictor and might be conducive for clinicians to estimate OS time. FAM83H-AS1 might serve as an inhibitor of TGF-β signalling.
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http://dx.doi.org/10.1016/j.biopha.2019.109342DOI Listing
October 2019

Long non-coding RNA MEG3 promotes fibrosis and inflammatory response in diabetic nephropathy via miR-181a/Egr-1/TLR4 axis.

Aging (Albany NY) 2019 06;11(11):3716-3730

Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Qingpu District, Shanghai 201700, P.R. China.

Long non-coding RNAs (lncRNAs) play vital roles in diabetic nephropathy (DN). This research aimed to study the potential role and underlying molecular mechanisms of long non-coding RNA MEG3 in DN. We found that MEG3 was upregulated in DN in vivo and in vitro and could enhance cell fibrosis and inflammatory response in DN. MEG3 functioned as an endogenous sponge for miR-181a in mesangial cells (MCs) via direct targeting and in an Ago2-dependent manner. MiR-181a inhibition promoted MC fibrosis and inflammatory response. In addition, Egr-1 was confirmed as a target gene of miR-181a. Further investigations verified that MEG3 promotes fibrosis and inflammatory response via the miR-181a/Egr-1/TLR4 axis in vitro and in vivo. These results provide new insights into the regulation between MEG3 and the miR-181a/Egr-1/TLR4 signaling pathway during DN progression.
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http://dx.doi.org/10.18632/aging.102011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594792PMC
June 2019

Identification of SNPs and copy number variations in mitochondrial genes related to the reproductive capacity of the cultured Asian yellow pond turtle (Mauremys mutica).

Anim Reprod Sci 2019 Jun 24;205:78-87. Epub 2019 Apr 24.

College of Life Science, Nanchang University, Jiangxi, Nanchang 330031, China; Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation of Ministry of Agriculture and Rural Affairs, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangdong, Guangzhou 510380, China. Electronic address:

Mitochondria function as an energy transfer organelle for cell metabolism with the energy being used for processes such as reproduction. To investigate whether mutations and copy number variations in mitochondrial genes are related to the reproductive capacity of the Asian yellow pond turtle, Mauremys mutica, there was exploration of the distribution frequency of 129 Single Nucleotide Polymorphism loci of six mitochondrial genes, ND1, ND2, COX2, ND4, Cytb andD-loop, of turtles from a relatively greater and lesser fecundity group by direct sequencing. The validation results for five candidate SNP loci in 83 female turtles indicated that only three SNP loci (C119T, A320G and A417C) in ND1 were positively correlated with reproductive capacity in M. mutica (P < 0.05). In addition, by constructing linear regression equations of the copy numbers of ND1, ND4, Cytb, D-loop, COX3, and ATP6 (log10 transformed) genes and the mean offspring number of different female turtles during a 4-year period, the copy numbers of ND4 and ATP6 (log10 transformed) genes were positively correlated (P < 0.05) with the fecundity of female turtles. Results from the present study may provide useful genetic markers for breeding M. mutica with greater reproductive capacity.
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http://dx.doi.org/10.1016/j.anireprosci.2019.04.006DOI Listing
June 2019

Hepatoid adenocarcinoma of the stomach: a unique subgroup with distinct clinicopathological and molecular features.

Gastric Cancer 2019 11 15;22(6):1183-1192. Epub 2019 Apr 15.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Fucheng Road 52, Haidian District, Beijing, 100142, China.

Objectives: Hepatoid adenocarcinoma of the stomach (HAS) is characterized by histological resemblance to hepatocellular carcinoma and a poor prognosis. The aim of this study is to elucidate the clinicopathological and molecular characteristics of HAS.

Methods: Forty-two patients with HAS who received gastrectomy were enrolled in this study. Based on a panel of 483 cancer-related genes, targeted sequencing of 24 HAS and 22 clinical parameter-matched common gastric cancer (CGC) samples was performed. Prognostic factors for overall survival (OS) and disease-free survival (DFS) were analysed with the Kaplan-Meier method.

Results: The most frequently mutated gene in both HAS and CGC was TP53, with a mutation rate of 30%. Additionally, CEBPA, RPTOR, WISP3, MARK1, and CD3EAP were identified as genes with high-frequency mutations in HAS (10-20%). Copy number gains (CNGs) at 20q11.21-13.12 occurred frequently in HAS, nearly 50% of HAS tumours harboured at least one gene with a CNG at 20q11.21-13.12. This CNG tended to be related to more adverse biobehaviour, including poorer differentiation, greater vascular and nerve invasion, and greater liver metastasis. Pathway enrichment analysis revealed that the HIF-1 signalling pathway and signalling pathways regulating stem cell pluripotency were specifically enriched in HAS. The survival analysis showed that a preoperative serum AFP level ≥ 500 ng/ml was significantly associated with poorer OS (p = 0.007) and tended to be associated with poorer DFS (p = 0.05).

Conclusion: CNGs at 20q11.21-13.12 happened frequently in HAS and tended to be related to more adverse biobehaviour. The preoperative serum AFP level was a sensitive prognostic biomarker for DFS and OS.
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http://dx.doi.org/10.1007/s10120-019-00965-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811386PMC
November 2019