Mechanism of neoagarotetraose protects against intense exercise-induced liver injury based on molecular ecological network analysis

Here we have explored the effect of neoagarotetraose (NAT) on liver injury caused by intense exercise. Our results showed that NAT treatment obviously decreased liver weight (p < 0.01), improved the liver morphological structure, decreased ALT level (p < 0.05) and endotoxin (LPS) (p < 0.01). In addition, NAT could regulate bile acid profiles in feces and serum of mice, which indicated the potential of liver function, suggesting that NAT was effective to relieve intense exercise-induced liver injury. NAT could regulate the expression of colon genes. NAT tended to alter the microbial composition of mice under intense exercise. We uncovered the network interactions between liver traits and microbial communities in NAT treatment mice. Interestingly, our data indicated that intense exercise-induced liver injury may be related to Clostridiales. In summary, these results demonstrated that NAT relieved liver injury induced by intense exercise may be related to gut microbiota.     

MiR-130b increases fibrosis of HMC cells by regulating the TGF-β1 pathway in diabetic nephropathy

Basement membrane thickening, glomerular hypertrophy, and deposition of multiple extracellular matrix characterize the pathological basis of diabetic nephropathy (DN), a condition which ultimately leads to glomerular and renal interstitial fibrosis. Here, we identified a novel microRNA, miR-130b, and investigated its role and therapeutic efficacy in alleviating DN. Introduction of miR-130b dramatically increased cell growth and fibrosis in DN cells. We found that transforming growth factor (TGF)-β1 was a functional target of miR-130b in human glomerular mesangial cells (HMCs) and overexpression of miR-130b increased expressions of the downstream signaling molecules of TGF-β1, t-Smad2/3, p-Smad2/3, and SMAD4. An ectopic application of miR-130b increased messenger RNA and protein expressions of collagen type I (colI), colIV, and fibronectin, whose expression levels were correlated with the expression of miR-130b. Taken together, the findings of this study reveal that miR-130b in HMC cells plays an important role in fibrosis regulation and may thus be involved with the pathogenesis of DN. Therefore, miR-130b may serve as a novel therapeutic target for the prevention and the treatment of DN.     

Investigation of the molecular interactions of triclocarban with human serum albumin using multispectroscopies and molecular modeling

Triclocarban (TCC), as a broad spectrum antibacterial agent widely used in personal care products, has recently been recognized as environmental pollutant with the potential of adversely affecting wildlife and human health. However, the behavior of TCC in blood circulatory system and the potential toxicity of TCC at the molecular level have been poorly investigated. In this study, the effect of TCC on human serum albumin (HSA) and the binding mechanism of TCC to HSA were examined using spectroscopic techniques and molecular modeling methods. The fluorescence results suggested that the fluorescence of HSA was quenched by TCC through a static quenching mechanism and nonradiation energy transfer, and TCC was bound to HSA with moderately strong binding affinity via hydrophobic interaction based on the analysis of the thermodynamic parameters. The site marker competitive experiments revealed that TCC bound into subdomain IIA (site I) of HSA. In addition, the results obtained from the circular dichroism, Fourier transform infrared (FT-IR), 8-anilino-1-naphthalenesulfonic acid fluorescence, synchronous fluorescence, three-dimensional fluorescence spectra and dynamic light scattering suggested the change in the microenvironment and conformation of HSA during the binding reaction. Finally, the best binding mode of TCC and specific interaction of TCC with amino acid residues were determined using molecular docking and molecular dynamics simulations. In a word, the present studies can provide a way to help us well understand the transport, distribution and toxicity effect of TCC when it diffused in the human body.

Communicated by Ramaswamy H. Sarma     

Egg investment in response to helper presence in cooperatively breeding Tibetan ground tits

Life‐history theory predicts a trade‐off between current and future reproduction to maximize lifetime fitness. In cooperatively breeding species, where offspring care is shared between breeders and helpers, helper presence may influence the female breeders’ egg investment, and consequently, survival and future reproductive success. For example, female breeders may reduce egg investment in response to helper presence if this reduction is compensated by helpers during provisioning. Alternatively, female breeders may increase egg investment in response to helper presence if helpers allow the breeders to raise more or higher quality offspring successfully. In the facultatively cooperative‐breeding Tibetan ground tit Pseudopodoces humilis, previous studies found that helpers improve total nestling provisioning rates and fledgling recruitment, but have no apparent effects on the number and body mass of fledglings produced, while breeders with helpers show reduced provisioning rates and higher survival. Here, we investigated whether some of these effects may be explained by female breeders reducing their investment in eggs in response to helper presence. In addition, we investigated whether egg investment is associated with the female breeder's future fitness. Our results showed that helper presence had no effect on the female breeders’ egg investment, and that egg investment was not associated with breeder survival and reproductive success. Our findings suggest that the responses of breeders to helping should be investigated throughout the breeding cycle, because the conclusions regarding the breeders’ adjustment of reproductive investment in response to being helped may depend on which stage of the breeding cycle is considered.     

CSN5 promotes the invasion and metastasis of pancreatic cancer by stabilization of FOXM1

COP9 signalosome subunit 5 (CSN5) has been involved in the progression of diverse human cancers. MMP2 plays an important role in the metastasis of cancer cells. However, the roles and relationship of in pancreatic cancer (PC) is still unknown. Here, our data shown that both CSN5 and MMP2 were significantly upregulated in PC compared with the corresponding adjacent tissues, where a positive correlation in their expression and associated malignant characteristics were found. Further, silencing of CSN5 expression markedly inhibited PC invasion and metastasis in vitro and in vivo, accompanied by decreased MMP2 expression. Moreover, the anti-metastasis role of CSN5 silence was reversed by MMP2 overexpression, whereas knockdown of MMP2 decreased PC metastasis driven by upregulation of CSN5. Further investigation revealed that CSN5 regulated MMP2 expression via activation of FOXM1 in PC cells. Mechanistically, CSN5 directly bound FOXM1 and decreased its ubiquitination to enhance the protein stability of FOXM1. Taken together, the results indicate that CSN5 can contribute to PC invasion and metastasis through activation of FOXM1/MMP2 axis.     

PVT1 (rs13281615) and miR-146a (rs2910164) polymorphisms affect the prognosis of colon cancer by regulating COX2 expression and cell apoptosis

In this study, we aimed to investigate the potential correlation between rs13281615/rs2910164 polymorphisms and the prognosis of colon cancer (CC). Taqman was utilized to genotype the rs13281615/rs2910164 polymorphisms in recruited subjects. Kaplan–Meier survival curves were calculated to study the prognostic values of different genotypes of rs13281615/rs2910164 polymorphisms. Real-time polymerase chain reaction, enzyme-linked immunosorbent assay, immunohistochemistry, and terminal deoxynucleotidyl transferase dUTP nick-end labeling assays were conducted to establish a potential signaling pathway underlying the role of rs13281615/rs2910164 polymorphisms, whereas bioinformatics analysis and luciferase reporter assays were performed to identify plasmacytoma variant translocation 1 (PVT1) and cyclooxygenase-2 (COX2) as targets of microRNA-146a (miR-146a). No significant difference was observed in respect to clinical characteristics among subjects with different genotypes. However, patients genotyped as GG/CC + GC showed the lowest chance of survival, whereas patients of GA + AA/GG genotype showed the highest chance of survival. Moreover, the relative expressions of PVT1, prostaglandin E2 (PGE2), and COX2 were the lowest and the relative expression of miR-146a was the highest in GA + AA/GG subjects, validating the roles of PVT1, miR-146a, and COX2 in CC. In addition, both PVT1 and COX2 were identified as virtual targets of miR-146a, and the luciferase activities of cells cotransfected with wild-type PVT1/COX2 and miR-146a mimics were significantly reduced. Moreover, the presence of PVT1 decreased the level of miR-146a whereas increasing the messenger RNA and protein levels of COX2, thus establishing a PVT1/miR-146a/COX2 signaling pathway underlying the pathogenesis of CC. The presence of rs13281615 G > A polymorphism on PVT1 and the rs2910164 C > G polymorphism on miR-146a contributes to a favorable prognosis in CC patients via modulating the activity of the PVT1/miR-146a/COX2 signaling pathway.     

Retracted: Prelamin A overexpression promotes detrusor calcification/aging in urinary incontinence via prelamin A accumulation

Urinary incontinence (UI) is known as a distressing condition particularly among older adults, and negatively associated with health-related quality of life in both males and females. Prelamin A accumulation has been found in all progeroid laminopathies and is obviously linked to cell and organism aging. Therefore, this study was expected to investigate the effect of prelamin A on detrusor on UI. Prelamin A expression in clinical and animal samples was detected. To investigate the degree of prelamin A accumulation and detrusor calcification/aging, the detrusor cells were subcultured separately into low and high passage. The low-passage subculture cells were treated with transfection of overexpressed prelamin A plasmid, and transfection of overexpressed prelamin A plasmid and application of farnesyl transferase inhibitor (FTIs) H-9279, respectively. Zmpste24, Icmt and lamin A/C expression were detected to explore how prelamin A affected detrusor calcification/aging. Prelamin A was overexpressed in aged detrusor cells, indicating prelamin A expression was positively related to the age of subjects. The degree of prelamin A accumulation and detrusor calcification/aging was higher in aged rats and high passage subculture cells. Zmpste24, Icmt and lamin A/C were poorly expressed in cells transfected with overexpressed prelamin A, as well as cell proliferation activity decreased and calcium deposition and apoptotic rate increased. Furthermore, we also found that the effect of overexpressed prelamin A was lost when cells were treated with H-9279. These findings provide evidence that prelamin A overexpression impairs degradation of its farnesylated form, thus causing prelamin A accumulation which induces detrusor calcification/aging in UI.     

KPC1 alleviates hypoxia/reoxygenation-induced apoptosis in rat cardiomyocyte cells though BAX degradation

Bax triggers cell apoptosis by permeabilizing the outer mitochondrial membrane, leading to membrane potential loss and cytochrome c release. However, it is unclear if proteasomal degradation of Bax is involved in the apoptotic process, especially in heart ischemia-reperfusion (I/R)-induced injury. In the present study, KPC1 expression was heightened in left ventricular cardiomyocytes of patients with coronary heart disease (CHD), in I/R-myocardium in vivo and in hypoxia and reoxygenation (H/R)-induced cardiomyocytes in vitro. Overexpression of KPC1 reduced infarction size and cell apoptosis in I/R rat hearts. Similarly, the forced expression of KPC1 restored mitochondrial membrane potential (MMP) and cytochrome c release driven by H/R in H9c2 cells, whereas reducing cell apoptosis, and knockdown of KPC1 by short-hairpin RNA (shRNA) deteriorated cell apoptosis induced by H/R. Mechanistically, forced expression of KPC1 promoted Bax protein degradation, which was abolished by proteasome inhibitor MG132, suggesting that KPC1 promoted proteasomal degradation of Bax. Furthermore, KPC1 prevented basal and apoptotic stress-induced Bax translocation to mitochondria. Bax can be a novel target for the antiapoptotic effects of KPC1 on I/R-induced cardiomyocyte apoptosis and render mechanistic penetration into at least a subset of the mitochondrial effects of KPC1.     

Calcium-activated nucleotidase 1 silencing inhibits proliferation,migration, and invasion in human clear cell renal cell carcinoma

Calcium-activated nucleotidase 1 (CANT1, belongs to the apyrase family, is widely expressed in various organs. However, the biological function of CANT1 remains poorly explored. In this study, we aimed to investigate the expression profile and functions of CANT1 in clear cell renal cell carcinoma (ccRCC). Our data show that the protein level of CANT1 was significantly higher in tumor tissues than in adjacent normal tissues. CANT1 silencing suppressed cell proliferation, migration, and invasion obviously in 769-P and 786-O cells, arrested cell cycle in S phase and promoted apoptosis in 769-P cells. In conclusion, the present study shows the different expression mode of CANT1 in human ccRCC tumor tissue and adjacent normal tissue, denotes the function of CANT1 in ccRCC cells and provides potential molecular mechanisms and pathways of CANT1 antitumor function in ccRCC.