A novel long non-coding RNA linc-93.2 participates in bisphenol induced oxidative stress and macrophage polarization in red common carp (Cyprinus carpio).

Previous studies show that bisphenol A (BPA) and its analogs induce oxidative stress and promote inflammatory response. However, the key molecules in regulating this process remain unclear. Here, we report significant inductive effects of BPA and bisphenol AF (BPAF) on a newly found long non-coding RNA linc-93.2 accompanied by oxidative stress and activation of pro-inflammatory pathways in treated fish and fish primary macrophages. Silencing linc-93.2 in fish primary macrophages in vitro or fish in vivo significantly promotes the expression of anti-oxidative stress-related genes and anti-inflammatory cytokines. This inhibition of pro-inflammatory cytokine expression, showing cell status disruption towards to M2 polarization. Followed by exposure to BPA or BPAF, silencing linc-93.2 in vitro or in vivo significantly attenuates the increased production of reactive oxygen species and malondialdehyde level aroused by bisphenol treatment, possibly owing to the enhancement of total antioxidant capacity observed in cells and tissue after linc-93.2 knockdown. RNA-sequencing further revealed regulation of nuclear factor-kappa b (NF-κB) in linc-93.2's downstream network, combining with our previous observation on the upstream regulation of linc-93.2 via NF-κB, which together suggest a critical role of linc-93.2 in promoting NF-κB positive feedback loop that may be an important molecular event initiating the immunotoxicity of bisphenols.

Computational identification of mitochondrial dysfunction biomarkers in severe SARS-CoV-2 infection: Facilitating therapeutic applications of phytomedicine.

BACKGROUND: Currently, SARS-CoV-2 has not disappeared and continues to prevail worldwide, with the ongoing risk of mutations and the potential for severe COVID-19. The impairment of monocyte mitochondrial function caused by SARS-CoV-2, leading to a metabolic and immune dysregulation, is a crucial factor in the development of severe COVID-19. PURPOSE: Discover effective phytomedicines based on mitochondrial-related biomarkers in severe SARS-CoV-2 infection. METHODS: Firstly, differential gene analysis and gene set enrichment analysis (GSEA) were conducted on monocytes datasets to identify genes and pathways distinguishing severe patients from uninfected individuals. Then, GO and KEGG enrichment analysis on the differentially expressed genes (DEGs) obtained. Take the DEGs and intersect them with the MitoCarta 3.0 gene set to obtain the differentially expressed mitochondrial-related genes (DE-MRGs). Subsequently, machine learning algorithms were employed to screen potential mitochondrial dysfunction biomarkers for severe COVID-19 based on score values. ROC curves were then plotted to assess the distinguish capability of the biomarkers, followed by validation using two additional independent datasets. Next, the effects of the identified biomarkers on metabolic pathways and immune cells were explored through Gene Set Variation Analysis (GSVA) and CIBERSORT. Finally, potential nature products for severe COVID-19 were screened from the expression profile dataset based on dysregulated mitochondrial-related genes, followed by in vitro experimental validation. RESULTS: There are 1812 DEGs and 17 dysregulated mitochondrial processes between severe COVID-19 patients and uninfected individuals. A total of 77 DE-MRGs were identified, and the potential biomarkers were identified as RECQL4, PYCR1, PIF1, POLQ, and GLDC. In both the training and validation sets, the area under the ROC curve (AUC) for these five biomarkers was greater than 0.9. And they did not show significant changes in mild to moderate patients (p > 0.05), indicating their ability to effectively distinguish severe COVID-19. These biomarkers exhibit a highly significant correlation with the dysregulated metabolic processes (p < 0.05) and immune cell imbalance (p < 0.05) in severe patients, as demonstrated by GSVA and CIBERSORT algorithms. Curcumin has the highest score in the predictive model based on transcriptomic data from 496 natural compounds (p = 0.02; ES = 0.90). Pre-treatment with curcumin for 8 h has been shown to alleviate mitochondrial membrane potential damage caused by the SARS-CoV-2 S1 protein (p < 0.05) and reduce elevated levels of reactive oxygen species (ROS) (p < 0.01). CONCLUSION: The results of this study indicate a significant correlation between severe SARS-CoV-2 infection and mitochondrial dysfunction. The proposed mitochondrial dysfunction biomarkers identified in this study are associated with the disease progression, metabolic and immune changes in severe SARS-CoV-2 infected patients. Curcumin has a potential role in preventing severe COVID-19 by protecting mitochondrial function. Our findings provide new strategies for predicting the prognosis and enabling early intervention in SARS-CoV-2 infection.

Mechanism of skin whitening through San-Bai decoction-induced tyrosinase inhibition and discovery of natural products targeting tyrosinase.

Melanin deposition is the main cause of skin darkening, which can lead to severe physical and psychological distress, necessitating the development of approaches for preserving skin health and fairness. Tyrosinase (TYR) is the rate-limiting enzyme in melanin synthesis, and its activity directly determines the degree of melanin accumulation in the skin, which in turn affects skin color. Currently, TYR inhibitors derived from natural products are widely used for skin whitening. San-Bai decoction (SBD) is effective for skin whitening and softening, but its mechanism of action, efficacy and high efficiency TYR inhibitors for skin whitening remain poorly understood. Here, we employed systems biology and network pharmacology to analyze the active compounds and targets of SBD, using the follow databases: TCMIP, TCMID, and BATMAN-TCM. Construct a molecular network centered on the regulation of TYR by SBD in skin whitening, using STRING database and cytoscape. Enrichment analysis using KOBAS database and ClusterProfiler. Virtual screening of candidate TYR inhibitors using Molecular Operating Environment software and Amber 18 software. SBD may act through tyrosine metabolism, melanogenesis, and other signaling pathways to regulate TYR activity and inhibit melanogenesis. We identified TYR and ESR1 as possible key targets for the whitening effect of SBD and screened out pentagalloylglucose, 1,3,6-tri-O-galloyl-beta-D-glucose, 1,2,4,6-tetragalloylglucose, and liquiritigenin 4',7-diglucoside as inhibitors of TYR, in addition to glycyrrhizic acid, pachymic acid methyl ester, nicotiflorin, gamma-sitosterol, and isoliensinine as inhibitors of ESR1. We also performed virtual drug screening of a library of natural small-molecule compounds (19,505 in total) and screened out lycopsamine, 2-phenylethyl b-D-glucopyranoside, and 6-beta-hydroxyhyoscyamine as inhibitors of TYR. We identified natural compounds with the potential for skin whitening through inhibition of TYR, thus advancing research on SBD and its applications.

Cultivation-dependent and cultivation-independent investigation of O-methylated pollutant-producing bacteria in three drinking water treatment plants.

O-methylated pollutants (OMPs) are emerging contaminants in drinking water and mainly produced through bacterial O-methylation. However, the information of OMP-producing bacteria (OMPPB) in drinking water treatment plant (DWTP) is largely unknown so far. In this study, the OMPPB in water samples from three DWTPs (XL, JX and NX) were investigated by using cultivation-dependent and cultivation-independent technologies. Four OMPs were detected and their odor and toxicity risks were assessed. Formation potentials (FPs) of 2,4,6-trichloanisole, 2,3,6-trichloanisole, 2,4,6-tribromoanisole, pentachloroanisole and diclofenac methyl ester were determined in water samples and their values shifted significantly among DWTPs. A most probable number (MPN) method was established to quantify OMPPB numbers and the relationships between total haloanisole FPs (HAFPs) (y) and OMPPB numbers (x) in three DWTPs could be described by the following functions: y = 0.496×0.373 (XL), y = 0.041×0.465 (JX) and y = 0.218×0.237 (NX). Several genera like Bacillus, Ralstonia, Brevundimonas, etc. were newly found OMPPB among the cultivable bacteria, and their OMP products were evaluated in terms of quantity and environment risks (odor, toxicity and bioaccumulation). High-throughput sequencing revealed treatment process was the main driving factor to shape the OMPPB community structures and Mantel test showed HAFP profile was significantly influenced by Mycobacterium and Pelomonas. PICURSt2 analysis discovered four phenolic O-methyltransferases (OMTs) and four carboxylic OMTs which might be responsible for OMP formation. Several strategies were recommended to assess risk and control contamination brought by OMPPB in DWTPs.

Mycobacterial PPE13 activates inflammasome by interacting with the NATCH and LRR domains of NLRP3.

Pathogenic mycobacteria, such as Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium marinum, can trigger NLRP3 inflammasome activation leading to maturation and secretion of interleukin 1ß (IL-1ß). However, the mycobacterial factors involved in the activation of NLRP3 inflammasome are not fully understood. Here, we identified that the PPE family protein PPE13 was responsible for the induction of IL-1ß secretion in a NLRP3 inflammasome-dependent manner. We found that the recombinant Mycobacterium smegmatis expressing PPE13 activates NLRP3 inflammasome, thereby inducing caspase-1 cleavage and IL-1ß secretion in J774A.1, BMDMs, and THP-1 macrophages. To examine whether this inflammasome activation was triggered by PPE13 rather than components of M. smegmatis, PPE13 was introduced into the aforementioned macrophages by lentivirus as a delivery vector. Similarly, this led to the activation of NLRP3 inflammasome, indicating that PPE13 is a direct activator of NLRP3 cascade. We further demonstrated that the NLRP3 complex activated the inflammasome cascade, and the assembly of this complex was facilitated by PPE13 through interacting with the LRR and NATCH domains of NLRP3. Finally, we found that all PPE13 proteins isolated from M. tuberculosis, M. bovis, and M. marinum can activate NLRP3 inflammasome through binding to NLRP3, which requires C-terminal repetitive MPTR domain of PPE13. Thus, we, for the first time, revealed that PPE13 triggers the inflammasome-response by interacting with the MPTR domain of PPE13 and the LRR and NATCH domains of NLRP3. These findings provide a novel perspective on the function of PPE proteins in the immune system during mycobacteria invasion.

Direct Z-scheme La1-xCexMnO3 catalyst for photothermal degradation of toluene.

A series of Ce-doped LaMnO3 (La1-xCexMnO3) were prepared and were tested for gaseous toluene oxidation in order to investigate the effect of cerium doping in LaMnO3 on activity under photothermal conditions. It was found that the activity and CO2 yield of the catalyst can be effectively increased when x = 0.25. A group of characterization is used to characterize the morphology, composition, and physical properties of the as-prepared catalysts. Results show that the Ce-doped LaMnO3 can form coexistence of La1-xCexMnO3 and CeO2, the reaction of CeO2/La1-xCexMnO3 under photothermal conditions follows the Mars-van Krevelen redox cycle mechanism, and the prepared CeO2/La1-xCexMnO3 can form a highly efficient Z-scheme heterojunction, which can enhance the electrons transfer speed of the catalyst. Moreover, in the photothermal catalytic degradation, lattice oxygen is the most important active substance, a small amount of cerium doping can increase the lattice oxygen content of perovskite and increase the activity of the reaction.