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Iturin A is a biosurfactant with various applications, and its low synthesis capability limits its production and application development. Fatty acids play a critical role in cellular metabolism and target product syntheses, and the relationship between fatty acid supplies and iturin A synthesis is unclear. In this study, we attempted to increase iturin A production via strengthening fatty acid synthesis pathways in Bacillus amyloliquefaciens . First, acetyl-CoA carboxylase AccAD and ACP S-malonyltransferase fabD were overexpressed via promoter replacement, and iturin A yield was increased to 1.36 g/L by 2.78-fold in the resultant strain HZ-ADF1. Then, soluble acyl-ACP thioesterase derived from Escherichia coli showed the best performance for iturin A synthesis, as compared to those derived from B. amyloliquefaciens and Corynebacterium glutamicum , the introduction of which in HZ-ADF1 further led to a 57.35% increase of iturin A yield, reaching 2.14 g/L. Finally, long-chain fatty acid-CoA ligase LcfA was overexpressed in HZ-ADFT to attain the final strain HZ-ADFTL2, and iturin A yield reached 2.96 g/L, increasing by 6.59-fold, and the contents of fatty acids were enhanced significantly in HZ-ADFTL2, as compared to the original strain HZ-12. Taken together, our results implied that strengthening fatty acid supplies was an efficient approach for iturin A production, and this research provided a promising strain for industrial production of iturin A.

As a kind of biosurfactants, iturin A has attracted people’s wide attentions due to their features of biodegradability, environmentally friendly, etc.; however, high production cost limited its extensive application, and the aim of this research wants to improve iturin A production in Bacillus amyloliquefaciens . Firstly, dual promoter was applied to strengthen iturin A synthetase expression, and its yield was increased to 1.25 g/L. Subsequently, original 5′-UTRs of downstream genes ( ituA , ituB , and ituC ) in iturin A synthetase cluster were optimized, which significantly increased mRNA secondary stability, and iturin A yield produced by resultant strain HZ-T3 reached 2.32 g/L. Secondly, synthetic pathway of α-glucosidase inhibitor 1-deoxynojirimycin was blocked to improve substrate corn starch utilization, and iturin A yield was increased by 34.91% to 3.13 g/L. Thirdly, efficient precursor (fatty acids, Ser, and Pro) supplies were proven as the critical role in iturin A synthesis, and 5.52 g/L iturin A was attained by resultant strain, through overexpressing yngH , serC , and introducing ocD . Meanwhile, genes responsible for poly-γ-glutamic acid, extracellular polysaccharide, and surfactin syntheses were deleted, which led to a 30.98% increase of iturin A yield. Finally, lipopeptide transporters were screened, and iturin A yield was increased by 17.98% in SwrC overexpression strain, reached 8.53 g/L, which is the highest yield of iturin A ever reported. This study laid a foundation for industrial production and application development of iturin A, and provided the guidance of metabolic engineering breeding for efficient production of other metabolites synthesized by non-ribosomal peptide synthetase. Key points • Optimizing 5′-UTR is an effective tactics to regulate synthetase cluster expression. • Blocking 1-DNJ synthesis benefited corn starch utilization and iturin A production. • The iturin A yield attained in this work was the highest yield reported so far.

The evidence for association between Epstein-Barr virus (EBV) infection and risk of oral squamous cell carcinoma (OSCC) is inconsistent in the literature. Therefore, this meta-analysis was conducted to clarify this association. A literature search was conducted in electronic databases for English- and Chinese-language publications until March 31, 2017 to include eligible case-control studies. The pooled odds ratio (OR) and 95% confidence interval (95% CI) were estimated to determine the association between EBV infection and OSCC risk using a fixed- or random-effects model based on heterogeneity. Publication bias was assessed using funnel plot analysis. A total of 13 case-control studies with 686 OSCC patients and 433 controls were included based on predetermined inclusion and exclusion criteria. The pooled OR with 95% CI between EBV infection and OSCC risk was 5.03 (1.80-14.01) with significant heterogeneity observed (I2 = 87%). The subgroup analysis indicates that the year of publication, study location, economic level, sample size, tissue type, detection method and marker, control type, and language might explain potential sources of heterogeneity. Publication bias was not observed, and sensitivity analysis showed stable results. The results of the current meta-analysis suggest that EBV infection is statistically associated with increased risk of OSCC. However, additional high-quality studies with larger sample sizes are needed to further confirm the relationship between EBV and OSCC.

[This corrects the article DOI: 10.1371/journal.pone.0186860.].

Tetramethylpyrazine (TMP), a bioactive compound isolated from the Chinese herb, Ligusticum wallichii Franchat, has been reported to play a protective role in cardiac diseases. However, the cellular and molecular mechanisms behind the protective effects of TMP on the heart remain to be elucidated. In this study, we aimed to determine the effects of TMP on angiotensin II (Ang II)-induced hypertrophy in neonatal rat cardiomyocytes and its possible mechanisms of action. In addition, we investigated whether TMP regulates tumor necrosis factor-α (TNF-α) secretion and expression. We found that TMP significantly inhibited the Ang II-induced hypertrophic growth of neonatal cardiomyocytes, as evidenced by the decrease in [3H]leucine incorporation and β-myosin heavy chain (β-MHC) mRNA expression. TMP inhibited Ang II-stimulated TNF-α protein secretion and mRNA expression in the cardiomyocytes. Further experiments revealed that Ang II increased the level of the phosphorylated form of the transcription factor, nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), as well as NF-κB-DNA binding activity in the cardiomyocytes; treatment with TMP significantly inhibited the Ang II-induced activation of NF-κB. Furthermore, the inhibition of NF-κB by the specific inhibitor, pyrrolidine dithiocarbamate (PDTC), markedly attenuated the Ang II-induced increase in [3H]leucine incorporation, β-MHC mRNA expression and TNF-α protein secretion. Our findings suggest that TMP inhibits Ang II-induced cardiomyocyte hypertrophy and TNF-α production through the suppression of the NF-κB pathway, which may provide new insight into the mechanisms underlying the protective effects of TMP in heart diseases.

The cardiac L-type Ca 2+ channel current ( I Ca,L ) plays an important role in controlling both cardiac excitability and excitation–contraction coupling and is involved in the electrical remodeling during postnatal heart development and cardiac hypertrophy. However, the possible role of endothelin-1 (ET-1) in the electrical remodeling of postnatal and diseased hearts remains unclear. Therefore, the present study was designed to investigate the transcriptional regulation of I Ca,L mediated by ET-1 in neonatal rat ventricular myocytes using the whole-cell patch-clamp technique, quantitative RT-PCR and Western blotting. Furthermore, we determined whether the extracellular signal–regulated kinase 1/2 (ERK1/2) pathway is involved. ET-1 increased I Ca,L density without altering its voltage dependence of activation and inactivation. In line with the absence of functional changes, ET-1 increased L-type Ca 2+ channel pore-forming α 1C -subunit mRNA and protein levels without affecting the mRNA expression of auxiliary β- and α 2 /δ-subunits. Furthermore, an actinomycin D chase experiment revealed that ET-1 did not alter α 1C -subunit mRNA stability. These effects of ET-1 were inhibited by the ET A receptor antagonist BQ-123 but not the ET B receptor antagonist BQ-788. Moreover, the effects of ET-1 on I Ca,L and α 1C -subunit expression were abolished by the ERK1/2 inhibitor (PD98059) but not by the p38 MAPK inhibitor (SB203580) or the c-Jun N-terminal kinase inhibitor (SP600125). These findings indicate that ET-1 increased the transcription of L-type Ca 2+ channel in cardiomyocytes via activation of ERK1/2 through the ET A receptor, which may contribute to the electrical remodeling of heart during postnatal development and cardiac hypertrophy.

The cardiac L-type Ca^sup 2+^ channel current (I ^sub Ca,L^) plays an important role in controlling both cardiac excitability and excitationâ[euro]\"contraction coupling and is involved in the electrical remodeling during postnatal heart development and cardiac hypertrophy. However, the possible role of endothelin-1 (ET-1) in the electrical remodeling of postnatal and diseased hearts remains unclear. Therefore, the present study was designed to investigate the transcriptional regulation of I ^sub Ca,L^ mediated by ET-1 in neonatal rat ventricular myocytes using the whole-cell patch-clamp technique, quantitative RT-PCR and Western blotting. Furthermore, we determined whether the extracellular signalâ[euro]\"regulated kinase 1/2 (ERK1/2) pathway is involved. ET-1 increased I ^sub Ca,L^ density without altering its voltage dependence of activation and inactivation. In line with the absence of functional changes, ET-1 increased L-type Ca^sup 2+^ channel pore-forming [alpha]^sub 1C^-subunit mRNA and protein levels without affecting the mRNA expression of auxiliary [beta]- and [alpha]^sub 2^/δ-subunits. Furthermore, an actinomycin D chase experiment revealed that ET-1 did not alter [alpha]^sub 1C^-subunit mRNA stability. These effects of ET-1 were inhibited by the ET^sub A^ receptor antagonist BQ-123 but not the ET^sub B^ receptor antagonist BQ-788. Moreover, the effects of ET-1 on I ^sub Ca,L^ and [alpha]^sub 1C^-subunit expression were abolished by the ERK1/2 inhibitor (PD98059) but not by the p38 MAPK inhibitor (SB203580) or the c-Jun N-terminal kinase inhibitor (SP600125). These findings indicate that ET-1 increased the transcription of L-type Ca^sup 2+^ channel in cardiomyocytes via activation of ERK1/2 through the ET^sub A^ receptor, which may contribute to the electrical remodeling of heart during postnatal development and cardiac hypertrophy.[PUBLICATION ABSTRACT]