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The gut microbiota and microbial metabolites influence the enteric nervous system and the central nervous system via the microbial–gut–brain axis. Increasing body of evidence suggests that disturbances in the metabolism of peripheral branched-chain amino acids (BCAAs) can contribute to the development of neurodegenerative diseases through neuroinflammatory signaling. Preliminary research has shown that longitudinal changes in serum amino acid levels in mouse models of Parkinson’s disease (PD) are negatively correlated with disease progression. Therefore, the aim of the present study was to determine the changes in serum levels of short-chain fatty acids (SCFAs) in a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD after dietary BCAA supplementation. In our research, gas chromatography–mass spectrometry was used to detect serum SCFA concentrations. The data were then analyzed with principal component analysis and orthogonal partial least squares discriminant analysis. Finally, the correlations of serum SCFA levels with gut and motor function in MPTP-induced PD mice were explored. Propionic acid, acetic acid, butyric acid, and isobutyric acid concentrations were elevated in MPTP + H-BCAA mice compared with MPTP mice. Propionic acid concentration was increased the most, while the isovaleric acid concentration was decreased. Propionic acid concentration was positively correlated with fecal weight and water content and negatively correlated with the pole-climbing duration. In conclusion, these results not only suggest that propionic acid may be a potential biomarker for PD, but also indicate the possibility that PD may be treated by altering circulating levels of SCFA.

Abstract Background Chemoresistance is one of the main obstacles to successful cancer therapy and is frequently associated with Multidrug resistance (MDR). Many different mechanisms have been suggested to explain the development of an MDR phenotype in cancer cells. One of the most studied mechanisms is the overexpression of P-glycoprotein (P-gp), which is a product of the MDR1 gene. Tumor cells often acquire the drug-resistance phenotype due to upregulation of the MDR1 gene. Overexpression of MDR1 gene has often been reported in primary gastric adenocarcinoma. Methods This study investigated the role of p38-MAPK signal pathway in vincristine-resistant SGC7901/VCR cells. P-gp and MDR1 RNA were detected by Western blot analysis and RT-PCR amplification. Mitgen-activated protein kinases and function of P-gp were demonstrated by Western blot and FACS Aria cytometer analysis. Ap-1 activity and cell apoptosis were detected by Dual-Luciferase Reporter Assay and annexin V-PI dual staining. Results The vincristine-resistant SGC7901/VCR cells with increased expression of the multidrug-resistance 1 (MDR1) gene were resistant to P-gp-related drug and P-gp-unrelated drugs. Constitutive increases of phosphorylated p38-MAPK and AP-1 activities were also found in the drug-resistant cells. Inhibition of p38-MAPK by SB202190 reduced activator protein-1 (AP-1) activity and MDR1 expression levels and increased the sensitivity of SGC7901/VCR cells to chemotherapy. Conclusion Activation of the p38-MAPK pathway might be responsible for the modulation of P-glycoprotein-mediated and P-glycoprotein-unmediated multidrug resistance in the SGC7901/VCR cell line.

Abstract Background Hepatocellular carcinoma (HCC) is the most invasive and frequently diagnosed malignancy and the second leading cause of cancer death in many regions of Asia. The PI3K/Akt/mTOR signal pathway is involved in multiple cellular functions including proliferation, differentiation, tumorigenesis, and apoptosis. Up-regulation of telomerase activity is thought to be a critical step leading to cell transformation. Methods This study investigated changes in mTOR pathway and telomerase activity in hepatocarcinoma cell line SMMC-7721 treated with chemotherapeutic agent 5-fluorouracil (5-Fu). We detected apoptosis of hepatocarcinoma cells by TUNEL assay. Telomerase activity, hTERT transcription level and p- p70 S6k was demonstrated by the telomeric repeat amplification protocol and silver staining assay, Dual-Luciferase Reporter Assay and Western blot analysis respectively. Results Treating SMMC-7721 cells with 5-Fu leads to apoptosis of the cells, and reduction in telomerase activity, as well as a dramatic reduction in the activated form of p70 S6 kinase, a mTOR substrate. The 5-Fu treatment nearly abolishes transcription of hTERT (the major component of telomerase) mRNA. Treating SMMC-7721 cells with Rapamycin, a specific mTOR inhibitor, significantly reduce hTERT protein level but did not affect hTERT transcription. 5-Fu and rapamycin were synergistic in regards to down-regulation of telomerase activity in hepatocarcinoma cells. Conclusion These results suggest that chemotherapeutic agent 5-Fu may down-regulate telomerase activity at both transcriptional level and PI3K/Akt/mTOR pathway-dependent post-transcriptional level to facilitate hepatocellular carcinoma cell apoptosis.

Extrachromosomal DNA (ecDNA) is a central mechanism for focal oncogene amplification in cancer, occurring in approximately 15% of early-stage cancers and 30% of late-stage cancers. EcDNAs drive tumor formation, evolution, and drug resistance by dynamically modulating oncogene copy-number and rewiring gene-regulatory networks. Elucidating the genomic architecture of ecDNA amplifications is critical for understanding tumor pathology and developing more effective therapies. Paired-end short-read (Illumina) sequencing and mapping have been utilized to represent ecDNA amplifications using a breakpoint graph, where the inferred architecture of ecDNA is encoded as a cycle in the graph. Traversals of breakpoint graph have been used to successfully predict ecDNA presence in cancer samples. However, short-read technologies are intrinsically limited in the identification of breakpoints, phasing together of complex rearrangements and internal duplications, and deconvolution of cell-to-cell heterogeneity of ecDNA structures. Long-read technologies, such as from Oxford Nanopore Technologies, have the potential to improve inference as the longer reads are better at mapping structural variants and are more likely to span rearranged or duplicated regions. Here, we propose CoRAL (Complete Reconstruction of Amplifications with Long reads), for reconstructing ecDNA architectures using long-read data. CoRAL reconstructs likely cyclic architectures using quadratic programming that simultaneously optimizes parsimony of reconstruction, explained copy number, and consistency of long-read mapping. CoRAL substantially improves reconstructions in extensive simulations and 10 datasets from previously-characterized cell lines as compared to previous short and long-read based tools. As long-read usage becomes wide-spread, we anticipate that CoRAL will be a valuable tool for profiling the landscape and evolution of focal amplifications in tumors., (Published by Cold Spring Harbor Laboratory Press.)

Background: The reasonable use of amino acids (AAs) in parenteral nutrition (PN) is very critical to the growth and development of premature infants. However, the appropriate dose of AAs has not been determined. Our study was designed to investigate the clinical effect of two different doses of AAs in PN for low birth weight premature infants., Materials and Methods: This randomized controlled study included 191 preterm infants who admitted to the neonatal intensive care unit of the First Affiliated Hospital of Nanjing Medical University from June 2015 to December 2016 and they were randomly divided into Group 1 ( n = 81) and Group 2 ( n = 110). In Group 1, the starting dose of AAs dose was 1.0-1.5 g/kg/day, which was increased by 0.5 g/kg with the maximum dose at 3.5 g/kg/day. In Group 2, the starting dose of AAs was 1.8-2.5 g/kg/day and was increased by 1.0 g/kg with the maximum dose at 4.0-4.5 g/kg/day. We analyzed the clinical characteristics, body weight, body length, total calorie intake, nonprotein calorie intake, total protein intake, liver and kidney function, and complications of the two groups of preterm infants., Results: The start of enteral feeding and the recovery of birth weight in Group 2 were earlier than those in Group 1 (3.83 ± 3.15 day vs. 5.53 ± 5.63 day, P = 0.016 and 6.36 ± 4.88 day vs. 8.48 ± 9.27 day, P = 0.043, respectively). The duration of PN and the time before total enteral nutrition were shorter in Group 2 than in Group 1 (16.46 ± 10.33 day vs. 21.41 ± 18.00 day, P = 0.029 and 15.47 ± 10.54 day vs. 19.47 ± 14.57 day, P = 0.038; respectively). The duration of mechanical ventilation (1.12 ± 2.62 day vs. 3.31 ± 8.13 day, P = 0.028) in Group 2 was shorter than that in Group 1., Conclusion: High doses of AAs in the early PN for preterm infants facilitate the promotion of early growth and development, advance recovery of birth weight, reduce the duration of PN, and reduce respiratory support without increasing the incidence of complications., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Journal of Research in Medical Sciences.)

Tumor necrosis factor (TNF)-α has been proved as an adjuvant therapy for tumor by FDA. However, the effect of chronic TNF-α expression for tumor is still controversial. In this study, we investigated the effect of low-dose TNF-α on tumor growth. We confirmed that low-dose TNF-α promoted angiogenesis of tumor in vivo, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1α, the transcription factor of VEGF, were both upregulated. Our results suggested that low-dose TNF-α was a powerful activator of angiogenesis in tumor and HIF-1α-VEGF pathway seemed to be the most important molecular mechanism.