EP300-mediated H3 acetylation elevates MTHFD2 expression to reduce mitochondrial dysfunction in lipopolysaccharide-induced tubular epithelial cells.

Sepsis represents an organ dysfunction resulting from the host's maladjusted response to infection, and can give rise to acute kidney injury (AKI), which significantly increase the morbidity and mortality of septic patients. This study strived for identifying a novel therapeutic strategy for patients with sepsis-induced AKI (SI-AKI). Rat tubular epithelial NRK-52E cells were subjected to lipopolysaccharide (LPS) exposure for induction of in-vitro SI-AKI. The expressions of E1A binding protein p300 (EP300) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in NRK-52E cells were assessed by western blot and qRT-PCR, and their interaction was explored by chromatin immunoprecipitation performed with antibody for H3K27 acetylation (H3K27ac). The effect of them on SI-AKI-associated mitochondrial dysfunction of tubular epithelial cells was investigated using transfection, MTT assay, TUNEL staining, 2',7'-Dichlorodihydrofluorescein diacetate probe assay, Mitosox assay, and JC-1 staining. MTHFD2 and EP300 were upregulated by LPS exposure in NRK-52E cells. LPS increased the acetylation of H3 histone in the MTHFD2 promoter region, and EP300 suppressed the effect of LPS. EP300 ablation inhibited the expression of MTHFD2. MTHFD2 overexpression antagonized LPS-induced viability reduction, apoptosis promotion, reactive oxygen species overproduction, and mitochondrial membrane potential collapse of NRK-52E cells. By contrast, MTHFD2 knockdown and EP300 ablation brought about opposite consequences. Furthermore, MTHFD2 overexpress and EP300 ablation counteracted each other's effect in LPS-exposed NRK-52E cells. EP300-mediated H3 acetylation elevates MTHFD2 expression to reduce mitochondrial dysfunction of tubular epithelial cells in SI-AKI.

Formation of active inclusion bodies induced by hydrophobic self-assembling peptide GFIL8.

BACKGROUND: In the last few decades, several groups have observed that proteins expressed as inclusion bodies (IBs) in bacteria could still be biologically active when terminally fused to an appropriate aggregation-prone partner such as pyruvate oxidase from Paenibacillus polymyxa (PoxB). More recently, we have demonstrated that three amphipathic self-assembling peptides, an alpha helical peptide 18A, a beta-strand peptide ELK16, and a surfactant-like peptide L6KD, have properties that induce target proteins into active IBs. We have developed an efficient protein expression and purification approach for these active IBs by introducing a self-cleavable intein molecule. RESULTS: In this study, the self-assembling peptide GFIL8 (GFILGFIL) with only hydrophobic residues was analyzed, and this peptide effectively induced the formation of cytoplasmic IBs in Escherichia coli when terminally attached to lipase A and amadoriase II. The protein aggregates in cells were confirmed by transmission electron microscopy analysis and retained ~50% of their specific activities relative to the native counterparts. We constructed an expression and separation coupled tag (ESCT) by incorporating an intein molecule, the Mxe GyrA intein. Soluble target proteins were successfully released from active IBs upon cleavage of the intein between the GFIL8 tag and the target protein, which was mediated by dithiothreitol. A variant of GFIL8, GFIL16 (GFILGFILGFILGFIL), improved the ESCT scheme by efficiently eliminating interference from the soluble intein-GFIL8 molecule. The yields of target proteins at the laboratory scale were 3.0-7.5 µg/mg wet cell pellet, which is comparable to the yields from similar ESCT constructs using 18A, ELK16, or the elastin-like peptide tag scheme. CONCLUSIONS: The all-hydrophobic self-assembling peptide GFIL8 induced the formation of active IBs in E. coli when terminally attached to target proteins. GFIL8 and its variant GFIL16 can act as a "pull-down" tag to produce purified soluble proteins with reasonable quantity and purity from active aggregates. Owing to the structural simplicity, strong hydrophobicity, and high aggregating efficiency, these peptides can be further explored for enzyme production and immobilization.

Association between RC/HDL-C ratio and risk of non-alcoholic fatty liver disease in the United States.

Background: The occurrence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. The link between serum remnant cholesterol (RC) to high-density lipoprotein cholesterol (HDL-C) ratio and NAFLD remains unclear. Therefore, we sought to clarify the relationship between the RC/HDL-C ratio and the NAFLD. Methods: Data for our cross-sectional study came from the 2017-2018 National Health and Nutrition Examination Survey (NHANES) with 2,269 participants. Associations between RC/HDL-C levels and the prevalence of NAFLD and hepatic fibrosis were evaluated using adjusted multivariate logistic regression analyses. A generalized additive model examined the non-linear relationship between RC/HDL-C and the probability of developing NAFLD. Results: Among 2,269 participants, 893 (39.36%) were diagnosed with NAFLD. In each of the three models, RC/HDL-C and NAFLD had a strong positive statistical relationship: model 1 (OR = 9.294, 95%CI: 6.785, 12.731), model 2 (OR = 7.450, 95%CI: 5.401, 10.278), and model 3 (OR = 2.734, 95%CI: 1.895, 3.944). In addition, the subgroup analysis by gender and BMI suggested that RC/HDL-C showed a positive correlation with NAFLD. The RC/HDL-C ratio was positively correlated with the degree of liver steatosis. There was an inverted U-shaped connection between the prevalence of NAFLD and RC/HDL-C, with an inflection point of 0.619 for all participants and 0.690 for men. Receiver operating characteristic (ROC) analysis showed that the predictive value of RC/HDL-C for NAFLD (area under the curve: 0.7139; 95%CI: 0.6923, 0.7354; P < 0.001), was better than traditional lipid parameters. Conclusion: Increased RC/HDL-C levels are independently associated with an increased risk of NAFLD and the severity of liver steatosis in the American population. In addition, the RC/HDL-C ratio can be used as a simple and effective non-invasive biomarker to identify individuals with a high risk of NAFLD.

Differences in global, regional, and national time trends in disability-adjusted life years for atrial fibrillation and flutter, 1990-2019: an age-period-cohort analysis from the 2019 global burden of disease study.

Background: Atrial fibrillation and flutter, collectively referred to as AF/AFL, pose substantial public health challenges across nations of different economic statuses. Abjective: This research is intended to assess the discrepancies in global, regional, and national trends in DALYs for atrial fibrillation and flutter throughout 1990 and 2019. Methods: The GBD 2019 report included statistics on AF/AFL. An age-period-cohort (APC) model was used to calculate the changes in DALYs from ages 30 to 34 years up to 95 + years. The model calculated both net drifts and local drifts in DALYs. In addition, we analysed the relative risks for certain time periods and birth cohorts from 1990 to 2019 in order to assess their impact. In order to measure the changes over time in the age-standardized rate (ASR) of DALYs caused by AF/AFL, we calculated the average annual percentage changes (AAPCs) based on age, gender, socio-demographic index (SDI), and location. This approach enables us to analyse the impact of age, period, and cohort on trends in DALYs, which may uncover disparities in the management of AF/AFL. Results: The global number of DALYs cases was 8,393,635 [95% uncertainty interval (UI): 6,693,987 to 10,541,461], indicating a 121.6% rise (95% UI: 111.5 to 132.0) compared to 1990. From 1990 to 2019, the worldwide ASR of DALYs decreased by 2.61% (95% UI -6.9 to 1.3). However, the other SDI quintiles, except for high SDI and high-middle SDI, had an increase. During the last three decades, high-income nations in the Asia Pacific region had the most significant reduction in ASR of DALYs, whereas Central Asia experienced the highest rise (with a net drift of -0.9% [95% Confidence Interval (CI): -1.0 to -0.9] and 0.6% [95% CI: 0.5 to 0.7], respectively). Approximately 50% of the burden of AF/AFL has been transferred from areas with high and high-middle SDI to those with lower SDI. There was an inverse relationship between the AAPC and the SDI. In addition, men and older individuals were shown to have a greater burden of AF/AFL DALYs. Conclusion: The findings of this research demonstrate that the worldwide impact of AF/AFL remains significant and increasing, with the burden differing depending on SDI. The exhaustive and comparable estimates provided by these results may contribute to international efforts to attain equitable AF/AFL control.

Association between oral microbial nitrate metabolism and poor prognosis in acute ischemic stroke patients with a history of hypertension.

Background: Oral microbes mediate the production of nitric oxide (NO) through the denitrification pathway. This study aimed to investigate the association between oral microbial nitrate metabolism and prognosis in acute ischemic stroke (AIS) patients. Methods: This prospective, observational, single-center cohort study included 124 AIS patients admitted within 24 hours of symptom onset, with 24-hour ambulatory blood pressure data. Oral swabs were collected within 24 hours. Hypertensive AIS patients were stratified by the coefficient of variation (CV) of 24-hour systolic blood pressure. Microbial composition was analyzed using LEfSe and PICRUSt2 for bacterial and functional pathway identification. Results: Significant differences in oral microbiota composition were observed between hypertensive AIS patients with varying CVs. Lower CV groups showed enrichment of nitrate-reducing bacteria and "Denitrification, nitrate => nitrogen" pathways. The TAX score of oral nitrate-reducing bacteria, derived from LASSO modeling, independently correlated with 90-day modified Rankin Scale scores, serving as an independent risk factor for poor prognosis. Mediation analyses suggested indirect that the TAX score not only directly influences outcomes but also indirectly affects them by modulating 24-hour systolic blood pressure CV. Conclusions: AIS patients with comorbid hypertension and higher systolic blood pressure CV exhibited reduced oral nitrate-reducing bacteria, potentially worsening outcomes.

Modeling the air pollutant concentration near a cement plant co-processing wastes.

In this study, for the first time, we conducted full life-cycle studies on pollutants in a cement plant co-processing hazardous waste (HW) via the combined use of thermodynamic equilibrium calculations and the American Meteorological Society/Environmental Protection Regulatory Model. Results showed that the potential toxic elements (PTEs) can be classified into three categories: (1) non-volatized elements, Co; (2) semi-volatized elements, Cr and Ni; and (3) volatized elements, Cd, Pb and As. Besides, the spatial distributions of pollutants were strongly influenced by the prevalent wind direction and the size of the particulate matter they were absorbed on. The highest concentrations of most pollutants tended to be centralized at a distance in the range of 400 to 800 m away from the cement plant. Finally, validated results indicated that there is good agreement between the simulated and observed concentrations in this study. These findings can facilitate and assist local government authorities and policy makers with the management of urban air quality.

Effectiveness of Common Fabrics to Block Aqueous Aerosols of Virus-like Nanoparticles.

Layered systems of commonly available fabric materials can be used by the public and healthcare providers in face masks to reduce the risk of inhaling viruses with protection that is about equivalent to or better than the filtration and adsorption offered by 5-layer N95 respirators. Over 70 different common fabric combinations and masks were evaluated under steady-state, forced convection air flux with pulsed aerosols that simulate forceful respiration. The aerosols contain fluorescent virus-like nanoparticles to track transmission through materials that greatly assist the accuracy of detection, thus avoiding artifacts including pore flooding and the loss of aerosol due to evaporation and droplet breakup. Effective materials comprise both absorbent, hydrophilic layers and barrier, hydrophobic layers. Although the hydrophobic layers can adhere virus-like nanoparticles, they may also repel droplets from adjacent absorbent layers and prevent wicking transport across the fabric system. Effective designs are noted with absorbent layers comprising terry cloth towel, quilting cotton, and flannel. Effective designs are noted with barrier layers comprising nonwoven polypropylene, polyester, and polyaramid.

Whole slide imaging of circulating tumor cells captured on a capillary microchannel device.

Liquid biopsy with circulating tumor cells (CTCs) can aid in cancer detection at early stages and determine whether a certain treatment is effective or not. However, existing CTC techniques focus on one or two aspects of CTC management including sampling, enrichment, enumeration, and treatment selection. This paper reports an integrated capillary microchannel device that allows efficient capturing of CTCs with a wide microchannel, rapid enumeration of captured CTCs with whole slide cell imaging, and in situ drug testing with captured CTCs. Blood is drawn into the microchannel whose height is appropriate to the diameter of cancer cells, while its width is a thousand times larger than the diameter of cancer cells. The inner bottom surface of the microchannel is modified with long chain polymers that have cell adhesive ends to efficiently capture CTCs from blood. With this design, cells including CTCs are forced to move through the polymer coated microchannel, and the chance of cell adhesive ends interacting with specific antigens overexpressed on surfaces of cancer cells is significantly enhanced without a channel blockage issue. Captured CTCs are enumerated with a whole slide imaging platform via dual LED autofocusing technology then exposed to anti-cancer drugs, followed by live/dead assay and fluorescence imaging. Given its straightforward, easy and powerless operation, this device with whole slide imaging will be useful for cancer diagnosis, prognosis and point-of-care treatments.

Tumor targeted, stealthy and degradable bismuth nanoparticles for enhanced X-ray radiation therapy of breast cancer.

Nanoparticles of heavy elements can be used as radiosensitizers to enhance X-ray radiation therapy, but a major roadblock in translating nanoparticle radiosensitizers into clinical practice of cancer treatment is related to the non-degradable nature of the nanoparticles, which can cause accumulation inside body and long-term toxicity. This paper reports the use of a folate-inserted, red blood cell membrane-modified bismuth (i.e., F-RBC bismuth) nanoparticles in X-ray radiation therapy for breast cancer, where cell membrane coating provides long blood circulation time, folate acts as tumor targeting agent, X-ray and bismuth nanoparticles interaction generates more free radicals for cancer cells damage, and physiological condition helps dissolve bismuth nanoparticles after treatment. Significant tumor inhibition and improved survival ratio in mice was confirmed when F-RBC bismuth nanoparticles were used to sensitize X-ray radiation. In vivo bio-distribution and histological analysis indicated F-RBC bismuth nanoparticles were excreted from animal body after 15 days and no evident damage or inflammatory was observed in major organs. Cell membrane modification and dissolution of bismuth nanoparticles in body allow the fine tune of the circulation, radiation enhancement and body clearance in such a way that treatment effect can be maximized and long term toxicity can be minimized.