Monday, November 2, 2020

Maintaining resting cardiac fibroblasts in vitro by disrupting mechanotransduction

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journal.pone.0241390.g006&size=inline

by George Gilles, Andrew D. McCulloch, Cord H. Brakebusch, Kate M. Herum

Mechanical cues activate cardiac fibroblasts and induce differentiation into myofibroblasts, which are key steps for development of cardiac fibrosis. In vitro, the high stiffness of plastic culturing conditions will also induce these changes. It is therefore challenging to study resting cardiac fibroblasts and their activation in vitro. Here we investigate the extent to which disrupting mechanotransduction by culturing cardiac fibroblasts on soft hydrogels or in the presence of biochemical inhibitors can be used to maintain resting cardiac fibroblasts in vitro. Primary cardiac fibroblasts were isolated from adult mice and cultured on plastic or soft (4.5 kPa) polyacrylamide hydrogels. Myofibroblast marker gene expression and smooth muscle α-actin (SMA) fibers were quantified by real-time PCR and immunostaining, respectively. Myofibroblast differentiation was prevented on soft hydrogels for 9 days, but had occurred after 15 days on hydrogels. Transferring myofibr oblasts to soft hydrogels reduced expression of myofibroblast-associated genes, albeit SMA fibers remained present. Inhibitors of transforming growth factor β receptor I (TGFβRI) and Rho-associated protein kinase (ROCK) were effective in preventing and reversing myofibroblast gene expression. SMA fibers were also reduced by blocker treatment although cell morphology did not change. Reversed cardiac fibroblasts maintained the ability to re-differentiate after the removal of blockers, suggesting that these are functionally similar to resting cardiac fibroblasts. However, actin alpha 2 smooth muscle (Acta2), lysyl oxidase (Lox) and periostin (Postn) were no longer sensitive to substrate stiffness, suggesting that transient treatment with mechanotransduction inhibitors changes the mechanosensitivity of some fibrosis-related genes. In summary, our results bring novel insight regarding the relative importance of specific mechanical signaling pathways in regulating different myofibroblas t-associated genes. Furthermore, combining blocker treatment with the use of soft hydrogels has not been tested previously and revealed that only some genes remain mechano-sensitive after phenotypic reversion. This is important information for researchers using inhibitors to maintain a "resting" cardiac fibroblast phenotype in vitro as well as for our current understanding of mechanosensitive gene regulation.
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A comparison of the corneal biomechanics in pseudoexfoliation glaucoma, primary open-angle glaucoma and healthy controls using Corvis ST

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journal.pone.0241296.t004&size=inline

by Zia Sultan Pradhan, Sujit Deshmukh, Shivani Dixit, Shruthi Sreenivasaiah, Sujani Shroff, Sathi Devi, Carroll A. B. Webers, Harsha Laxmana Rao

Purpose

To compare the corneal biomechanical parameters between pseudoexfoliation glaucoma (PXG), primary open-angle glaucoma (POAG) and healthy controls using Corvis ST.

Methods

A prospective, cross-sectional study was conducted which included 132 treatment-naïve eyes which underwent Corvis ST. The study cohort comprised of 44 eyes with PXG, 42 eyes with POAG and 46 healthy controls. Corneal biomechanical parameters, which included corneal velocities, length of corneal applanated surface, deformation amplitude (DA), peak distance and radius of curvature, were compared between the groups using analysis of variance models.

Results

The 3 groups were demographically similar. The mean IOP was 15.7 ±3 mmHg in the control group, 21.3 ±5 mmHg in the POAG group and 25.8 ±7 mmHg in the PXG group (p Conclusion

Corneal biomechanical parameters measured on Corvis ST are not different between eyes with PXG, POAG and healthy controls after adjusting for IOP.

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Utilizing methylglyoxal and D-lactate in urine to evaluate saikosaponin C treatment in mice with accelerated nephrotoxic serum nephritis

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journal.pone.0241053.g011&size=inline

by Chia-Yu Lin, Jen-Ai Lee, Po-Yeh Lin, Shih-Chun Hua, Pei-Yun Tsai, Bi-Li Chen, Chia-En Lin, Tzong-Huei Lee, Shih‐Ming Chen

The relationship between methylglyoxal (MGO) and D-lactate during saikosaponin C (SSC) treatment of mice with accelerated nephrotoxic serum (NTS) nephritis was investigated. NTS nephritis was induced by administration of anti-basement membrane antibodies to C57BL/6 mice and three dosages of SSC were administered for 14 days. Proteinuria, blood urea nitrogen, serum creatinine, renal histology, urinary MGO and d-lactate changes were examined. Compared to the NTS control group, the middle dosage (10 mg/kg/day) of SSC significantly alleviated the development of nephritis based on urine protein measurements (34.40 ± 6.85 vs. 17.33 ± 4.79 mg/day, pppp
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Relationship between sedentary behaviour and anxiety symptoms among youth in 24 low- and middle-income countries

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journal.pone.0241303.g002&size=inline

by Ming-Hui Wang, Dian-Min Xiao, Ming-Wei Liu, Yuan-An Lu, Qi-Qiang He

Background

Anxiety is burdensome and common in youth. Sedentary behaviour has been identified as potentially modifiable dangerous factors for many diseases. Nevertheless, little is known about the relationship between sedentary behaviour and the risk of anxiety symptoms in youth. Therefore, we aimed to examine the association among youth in 24 low- and middle-income countries (LMICs).

Methods

Data from the Global School-based Student Health Survey (GSHS) were analyzed in 59587 youth aged 12–15 years. Most of the country-wide data were nationally representative. Anxiety symptoms were self-reported. Multivariable logistic regression and meta-analyses of country-wise estimates were conducted.

Results

The prevalence of anxiety symptoms was 10.3%. Countrywide meta-analysis demonstrated that sedentary behaviour of >2 h/day (vs.≤2 h/day) was associated with an increased risk of anxiety symptoms (OR = 1.22; 95% CI = 1.10–1.37).

Conclusions

This study provides multi-national evidence of the dangerous effect of sedentary behaviour against anxiety symptoms among youth in LMICs. Decreasing the level of sedentary behaviour during adolescence could be an important target for reducing the prevalence of anxiety.

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Exposure to small molecule cocktails allows induction of neural crest lineage cells from human adipose-derived mesenchymal stem cells

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journal.pone.0241125.g004&size=inline

by Yuzo Takayama, Yuka Akagi, Yoichiro Shibuya, Yasuyuki S. Kida

Neural crest cells (NCCs) are a promising source for cell therapy and regenerative medicine owing to their multipotency, self-renewability, and capability to secrete various trophic factors. However, isolating NCCs from adult organs is challenging, because NCCs are broadly distributed throughout the body. Hence, we attempted to directly induce NCCs from human adipose-derived mesenchymal stem cells (ADSCs), which can be isolated easily, using small molecule cocktails. We established a controlled induction protocol with two-step application of small molecule cocktails for 6 days. The induction efficiency was evaluated based on mRNA and protein expression of neural crest markers, such as nerve growth factor receptor (NGFR) and sex-determining region Y-box 10 (SOX10). We also found that various trophic factors were significantly upregulated following treatment with the small molecule cocktails. Therefore, we performed global profiling of cell surface makers and identified distinctly upre gulated markers, including the neural crest-specific cell surface markers CD271 and CD57. These results indicate that our chemical treatment can direct human ADSCs to developing into the neural crest lineage. This offers a promising experimental platform to study human NCCs for applications in cell therapy and regenerative medicine.
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Trace metals contamination

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journal.pone.0241320.g001&size=inline

by Mohammed Abdus Salam, Shujit Chandra Paul, Rabiatul Adawiyah M. Mohamad Zain, Snahasish Bhowmik, Mithun Rani Nath, Sadia Afrin Siddiqua, Tutun Das Aka, Muhammad Anwar Iqbal, Wan Rashidah Kadir, Rozita Binti Ahamad, Md. Abdul Khaleque, Aweng Eh Rak, Mohamad Faiz Mohd Amin

The rapid growth of industrial and agricultural activities in Malaysia are leading to the impairment of most of the rivers in recent years through realising various trace metals. This leads to toxicity, particularly when the toxic has entered the food chain. Perak River is one of the most dynamic rivers for the Malaysian population. Therefore, in consideration of the safety issue, this study was conducted to assess the concentration of such metals (Cd, Cu, Zn, Fe, and Pb) in the muscles of most widely consumed fish species (Barbonymus schwanenfeldii, Puntius bulum, Puntius daruphani, Hexanematichthys sagor, Channa striatus, Mystacoleucus marginatus, and Devario regina) from different locations of Perak River, Malaysia by employing inductively coupled plasma optical emission spectroscopy (ICP-OES). Among the trace metals, Fe and Cd were found to be the highest (29.33–148.01 μg/g) and lowest (0.16–0.49 μg/g) concentration in all of the studied species, respectively. Although the estimated daily intakes (μg/kg/day) of Cd (0.65–0.85), Fe (79.27–352.00) and Pb (0.95–12.17) were higher than their reference, the total target hazard quotients values suggested that the local residents would not experience any adverse health effects from its consumption. In contrast, the target cancer risk value suggested that all fish species posed a potential cancer risk due to Cd and cumulative cancer risk values, strongly implying that continuous consumption of studied fish species would cause cancer development to its consumers.
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Novel prognostic biomarkers of pouchitis after ileal pouch-anal anastomosis for ulcerative colitis: Neutrophil-to-lymphocyte ratio

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journal.pone.0241322.g003&size=inline

by Yu Nishida, Shuhei Hosomi, Hirokazu Yamagami, Koji Fujimoto, Rieko Nakata, Shigehiro Itani, Yuji Nadatani, Shusei Fukunaga, Koji Otani, Fumio Tanaka, Yasuaki Nagami, Koichi Taira, Noriko Kamata, Toshio Watanabe, Yasuhito Iseki, Tatsunari Fukuoka, Masatsune Shibutani, Hisashi Nagahara, Satoko Ohfuji, Yasuhiro Fujiwara

Objectives

Pouchitis is a major complication after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis (UC). Although there have been many investigations of the neutrophil-to-lymphocyte ratio (NLR) in various diseases, its role in predicting the development of pouchitis remains unclear. We aimed to evaluate the clinical utility of the NLR for predicting the development of pouchitis after IPAA in UC patients.

Materials and methods

UC patients who underwent IPAA at Osaka City University Hospital between May 2006 and March 2019 were included. The incidence of pouchitis was estimated using the Kaplan-Meier method. Potential preoperative, intraoperative, and postoperative predictors for pouchitis, including various demographic and clinical variables, were analyzed. The combined impact of the NLR and other known prognostic factors were investigated using Cox proportional hazard regression with inverse probability of treatment w eighting (IPTW).

Results

Forty-nine patients with UC who underwent IPAA were included. The median follow-up period was 18.3 months (interquartile range: 10.7–47.2 months). Eighteen patients (36.7%) developed pouchitis. The incidence of pouchitis was 19.2%, 32.6%, and 45.9% at 1, 2, and 5 years, respectively. NLR was significantly associated with the development of pouchitis in the univariate Cox regression analysis (hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.01–1.28; P = 0.03). The NLR cutoff value of 2.15 was predictive of the development of pouchitis according to receiver operating characteristic analysis (specificity: 67.7%, sensitivity: 72.2%). The incidence of pouchitis was significantly lower in the low NLR group than that in the high NLR group (P = 0.01, log-rank test). Cox regression analyses using IPTW also identified NLR as a prognostic factor for the development of pouchitis by statistically adjusting for background factors (HR, 3.60; 95% CI, 1.31 –9.89; P = 0.01).

Conclusions

NLR may be a novel and useful indicator for predicting the development of pouchitis after IPAA in UC and should be introduced in clinical practice.

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Uremic pruritus and long-term morbidities in the dialysis population

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journal.pone.0241088.g003&size=inline

by Sze-Wen Ting, Pei-Chun Fan, Yu-Sheng Lin, Ming-Shyan Lin, Cheng-Chia Lee, George Kuo, Chih-Hsiang Chang

Background

Uremic pruritus (UP) is a multifactorial problem that contributes to low quality of life in dialysis patients. The long-term influences of UP on dialysis patients are still poorly understood. This study aims to elucidate the contribution of UP to long-term outcomes.

Materials and method

We used the Taiwan National Health Insurance Research Database to conduct this study. Patients on chronic dialysis were included and divided into UP and non-UP groups according to the long-term prescription of antihistamine in the absence of other indications. The outcomes include infection-related hospitalization, catheter-related infection, major adverse cardiac and cerebrovascular events (MACCE) and parathyroidectomy.

Results

After propensity score matching, 14,760 patients with UP and 29,520 patients without UP were eligible for analysis. After a mean follow-up of 5 years, we found that infection-related hospitalization, MACCE, catheter-related infection, heart failure and parathyroidectomy were all slightly higher in the UP than non-UP group (hazard ratio: 1.18 [1.16–1.21], 1.05 [1.01–1.09], 1.16 [1.12–1.21], 1.08 [1.01–1.16] and 1.10 [1.01–1.20], respectively). Subgroup analysis revealed that the increased risk of adverse events by UP was generally more apparent in younger patients and patients who underwent peritoneal dialysis.

Conclusion

UP may be significantly associated with an increased risk of long-term morbidities.

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Efficacy of Banxia Xiexin decoction for chronic atrophic gastritis: A systematic review and meta-analysis

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journal.pone.0241202.g012&size=inline

by Yang Cao, Yixin Zheng, Jingbin Niu, Chunmei Zhu, Decai Yang, Fen Rong, Guoping Liu

Background

Banxia Xiexin decoction (BXD), a classical formula of traditional Chinese medicine (TCM), has been wildly used for chronic atrophic gastritis (CAG) patients with the cold-heat complex syndrome in China, and achieved satisfied effects. However, the clinical effects of it remains unclear.

Purpose

The purpose of this article is to evaluate the clinical efficacy and safety of BXD for CAG treatment.

Methods

We searched seven electronic databases including Ovid, Embase, PubMed, Cochrane Library, Wan-fang database, VIP (Chinese Scientific Journals Database) and CNKI (China National Knowledge Infrastructure) from their inception to September 21, 2020. We used Jadad scale and Cochrane Collaboration's risk of bias tool to make evaluation of methodological quality. Revman 5.3 statistical software was used for statistical processing to evaluate the clinical efficacy and safety of BXD.

Results

26 randomized controlled trials (RCTs) totaling 1985 patients were identified for analysis. Meta-analysis showed that BXD treatment was more effective (RR 1.29; 95%CI 1.24, 1.35; P Conclusions

The meta-analysis showed that BXD was more effective and safer for CAG patients than the control group. However, due to limitations of methodological quality and small sample size of the included studies, further standardized research of rigorous design should be needed.

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Metabolomics of primary cutaneous melanoma and matched adjacent extratumoral microenvironment

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journal.pone.0240849.g003&size=inline

by Nicholas J. Taylor, Irina Gaynanova, Steven A. Eschrich, Eric A. Welsh, Timothy J. Garrett, Chris Beecher, Ritin Sharma, John M. Koomen, Keiran S. M. Smalley, Jane L. Messina, Peter A. Kanetsky

Background

Melanoma causes the vast majority of deaths attributable to skin cancer, largely due to its propensity for metastasis. To date, few studies have examined molecular changes between primary cutaneous melanoma and adjacent putatively normal skin. To broaden temporal inferences related to initiation of disease, we performed a metabolomics investigation of primary melanoma and matched extratumoral microenvironment (EM) tissues; and, to make inferences about progressive disease, we also compared unmatched metastatic melanoma tissues to EM tissues.

Methods

Ultra-high performance liquid chromatography—mass spectrometry-based metabolic profiling was performed on frozen human tissues.

Results

We observed 824 metabolites as differentially abundant among 33 matched tissue samples, and 1,118 metabolites as differentially abundant between metastatic melanoma (n = 46) and EM (n = 34) after false discovery rate (FDR) adjustment (p Conclusions

Overall, pathway-bas ed results significantly distinguished melanoma tissues from EM in the metabolism of: ascorbate and aldarate, propanoate, tryptophan, histidine, and pyrimidine. Within pathways, the majority of individual metabolite abundances observed in comparisons of primary melanoma vs. EM and metastatic melanoma vs. EM were directionally consistent. This observed concordance suggests most identified compounds are implicated in the initiation or maintenance of melanoma.

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Full-dose hepatitis B virus vaccination coverage and associated factors among health care workers

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journal.pone.0241226.g004&size=inline

by Nefsu Awoke, Henok Mulgeta, Tsegaye Lolaso, Tiwabwork Tekalign, Serawit Samuel, Mohammed Suleiman Obsa, Robera Olana

Introduction

The hepatitis B vaccine is the backbone of hepatitis B prevention. All health care workers must receive a full-dose (3-dose vaccine series) to achieve >90% protection against hepatitis B virus. There is limited evidence available on vaccination coverage of HBV among health care workers in Ethiopia. Therefore, the objective of this study was to estimate the national full-dose hepatitis B vaccination coverage and the associated factors among health care workers in Ethiopia.

Methods

Studies were retrieved from PubMed, EMBASE, Web of Science, SCOPUS, CINAHL, and Google Scholar by using a combination of search terms with Boolean operators. The quality of each study was evaluated independently by three authors using the modified Newcastle-Ottawa Scale (NOS) for cross-sectional studies. Statistical analyses were performed using STATA™ Version 14 software. Meta-analysis was carried out using a random-effects (DerSimonian and Laird) method. The heterogeneity test w as conducted by using I-squared (I2) statistics. Leave-one-out sensitivity analysis was performed.

Results

A total of 15 articles with 5734 participants were included in this systematic review and meta-analysis. The pooled prevalence of full-dose hepatitis B virus vaccination coverage among health care workers in Ethiopia was 20.04% (95% CI: 13.83, 26.26); I2 = 98.9%). Being male sex (p = 0.002), having work experience of less than 5 years (p p = 0.003), health care providers who received training on infection prevention (p p = 0.001), were factors significantly associated with full-dose hepatitis B virus vaccination.

Conclusion

The national full-dose hepatitis B vaccination coverage among health care workers was low. Training of health care workers in infection prevention, particularly in hepatitis B and testing and providing hepatitis B vaccination for newly recruited staff and every 5 years for those lo ng-term workers were recommended to increase the uptake of the vaccine.

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