Predicting mitophagy-related genes and unveiling liver endothelial cell heterogeneity in hepatic ischemia-reperfusion injury.

Background: Hepatic Ischemia-Reperfusion Injury (HIRI) is a major complication in liver transplants and surgeries, significantly affecting postoperative outcomes. The role of mitophagy, essential for removing dysfunctional mitochondria and maintaining cellular balance, remains unclear in HIRI. Methods: To unravel the role of mitophagy-related genes (MRGs) in HIRI, we assembled a comprehensive dataset comprising 44 HIRI samples alongside 44 normal control samples from the Gene Expression Omnibus (GEO) database for this analysis. Using Random Forests and Support Vector Machines - Recursive Feature Elimination (SVM-RFE), we pinpointed eight pivotal genes and developed a logistic regression model based on these findings. Further, we employed consensus cluster analysis for classifying HIRI patients according to their MRG expression profiles and conducted weighted gene co-expression network analysis (WGCNA) to identify clusters of genes that exhibit high correlation within different modules. Additionally, we conducted single-cell RNA sequencing data analysis to explore insights into the behavior of MRGs within the HIRI. Results: We identified eight key genes (FUNDC1, VDAC1, MFN2, PINK1, CSNK2A2, ULK1, UBC, MAP1LC3B) with distinct expressions between HIRI and controls, confirmed by PCR validation. Our diagnostic model, based on these genes, accurately predicted HIRI outcomes. Analysis revealed a strong positive correlation of these genes with monocytic lineage and a negative correlation with B and T cells. HIRI patients were divided into three subclusters based on MRG profiles, with WGCNA uncovering highly correlated gene modules. Single-cell analysis identified two types of endothelial cells with different MRG scores, indicating their varied roles in HIRI. Conclusions: Our study highlights the critical role of MRGs in HIRI and the heterogeneity of endothelial cells. We identified the macrophage migration inhibitory factor (MIF) and cGAS-STING (GAS) pathways as regulators of mitophagy's impact on HIRI. These findings advance our understanding of mitophagy in HIRI and set the stage for future research and therapeutic developments.

Multiomics Sequencing and AlphaFold2 Analysis of the Stereoselective Behavior of Mefentrifluconazole for Bioactivity Improvement and Risk Reduction.

As the first isopropanol chiral triazole fungicide, mefentrifluconazole has broad prospects for application. In this study, the stereoselective stability, bioactivity, fate, and biotoxicity were systematically investigated. Our results indicated that the stability of mefentrifluconazole enantiomers differed between environmental media, and they were stable in water and sediment in the dark. The bactericidal activity of R-mefentrifluconazole against the four target pathogens was 4.6-43 times higher than that of S-mefentrifluconazole. In the water-sediment system, S-mefentrifluconazole dissipated faster than R-mefentrifluconazole in water; however, its accumulation capacity was higher than that of R-mefentrifluconazole in sediment and zebrafish. S-Mefentrifluconazole induced more differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) in zebrafish than did R-mefentrifluconazole. Multiomics sequencing results showed that S-mefentrifluconazole enhanced the antioxidant, detoxification, immune, and metabolic functions of zebrafish by interacting with related proteins. Based on AlphaFold2 modeling and molecular docking, mefentrifluconazole enantiomers had different binding modes with key target proteins in pathogens and zebrafish, which may be the main reason for the stereoselective differences in bioactivity and biotoxicity. Based on its excellent bioactivity and low biotoxicity, the R-enantiomer can be developed to improve the bioactivity and reduce the risk of mefentrifluconazole.

Household polluting cooking fuels and adverse birth outcomes: An updated systematic review and meta-analysis.

Background and aim: The current study aimed to clarify the association between household polluting cooking fuels and adverse birth outcomes using previously published articles. Methods: In this systematic review and meta-analysis, a systematic literature search in PubMed, Embase, Web of Science, and Scopus databases were undertaken for relevant studies that had been published from inception to 16 January 2023. We calculated the overall odds ratio (OR) and 95% confidence interval (CI) for adverse birth outcomes [low birth weight (LBW), small for gestational age (SGA), stillbirth, and preterm birth (PTB)] associated with polluting cooking fuels (biomass, coal, and kerosene). Subgroup analysis and meta-regression were also conducted. Results: We included 16 cross-sectional, five case-control, and 11 cohort studies in the review. Polluting cooking fuels were found to be associated with LBW (OR: 1.37, 95% CI: 1.24, 1.52), SGA (OR: 1.48, 95% CI: 1.13, 1.94), stillbirth (OR: 1.38, 95% CI: 1.23, 1.55), and PTB (OR: 1.27, 95% CI: 1.19, 1.36). The results of most of the subgroup analyses were consistent with the main results. In the meta-regression of LBW, study design (cohort study: P < 0.01; cross-sectional study: P < 0.01) and sample size (≥ 1000: P < 0.01) were the covariates associated with heterogeneity. Cooking fuel types (mixed fuel: P < 0.05) were the potentially heterogeneous source in the SGA analysis. Conclusion: The use of household polluting cooking fuels could be associated with LBW, SGA, stillbirth, and PTB. The limited literature, observational study design, exposure and outcome assessment, and residual confounding suggest that further strong epidemiological evidence with improved and standardized data was required to assess health risks from particular fuels and technologies utilized.

The fate, acute, and subchronic risks of dinotefuran in the water-sediment system: A systematic analysis at the enantiomer level.

Environmental risks associated with neonicotinoid insecticides have attracted considerable attention. This study systematically investigated the stereoselective behavior of dinotefuran in a water-sediment system. The results showed that S-dinotefuran accumulated more easily in sediment and zebrafish. Although dinotefuran enantiomers and metabolites present a low risk to aquatic organisms, the risk of dinotefuran enantiomers to sediment organisms should be considered. Additionally, S-dinotefuran induced more remarkable oxidative damage in zebrafish than that of R-dinotefuran. Nevertheless, R-dinotefuran remarkably activated antioxidant and detoxifying enzymes. Multi-omics analyses revealed that S-dinotefuran induced more differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) in zebrafish. In particular, S-dinotefuran inhibited the expression of ribosome- and proteasome-related genes and proteins, affecting the synthesis and degradation of proteins in zebrafish. R-dinotefuran remarkably activated peroxisome-related genes and proteins, thereby enhancing antioxidant and detoxification abilities of zebrafish. The stereoselective interactions between dinotefuran enantiomers and key DEPs were elucidated using AlphaFold2 modeling and molecular docking techniques, which may serve as the main reason for stereoselective subchronic toxicity. The present study is beneficial for the correct use of dinotefuran and provides an effective means for elucidating the mechanism of the stereoselective behavior of chiral compounds.

Association between handgrip strength and metabolic syndrome: A meta-analysis and systematic review.

Background: Although muscle strength has been reported to be associated with metabolic syndrome (MetS), the association is still controversial. Therefore, the purpose of this meta-analysis was to identify the association between handgrip strength (HGS) and MetS. Methods: Original research studies involving HGS and MetS from database inception to 20 May 2022 were selected from PubMed, Web of Science, Embase, China National Knowledge Infrastructure, Wanfang databases, and Chinese Biomedical Document Service System. The odds ratios (ORs) with 95% confidence intervals (CIs) of MetS for HGS were calculated using a random-effects model. A dose-response analysis was performed. Subgroup analysis and meta-regression were also conducted. Results: Thirty effect sizes (reported in 19 articles) with a total of 43,396 participants were included in this meta-analysis. All studies were considered to be of moderate-to-good quality. An inverse association between HGS (low vs. high) with MetS was shown (OR: 2.59, 95% CI: 2.06-3.25). Subgroup analyses demonstrated the pooled ORs of relative HGS (HGS/weight), relative HGS (HGS/BMI), and absolute HGS were 2.97 (95% CI: 2.37-3.71), 2.47 (95% CI: 1.08-5.63), and 1.34 (95% CI: 1.06-1.68), respectively. Dose-response analysis revealed a significant linear dose-response relationship between relative HGS (HGS/weight) and MetS in observational studies (0.1 HGS/weight: OR, 0.68; 95% CI: 0.62-0.75). Univariate meta-regression analysis indicated that country status, measuring tools of HGS, components of MetS, and diagnosed criteria of MetS explained 16.7%, 26.2%, 30.1%, and 42.3% of the tau-squared in the meta-regression, respectively. Conclusion: The results of the current meta-analysis indicated that lower HGS is associated with a higher risk of MetS. A linear dose-response association between lower relative HGS (HGS/weight) and increased prevalence of MetS was found. Accordingly, a lower HGS is a significant predictor of MetS. Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42021276730].

Systematic evaluation of chiral fungicide penflufen for the bioactivity improvement and input reduction using alphafold2 models and transcriptome sequencing.

Traditional risk assessment of pesticide concludes at the racemic level, which is often incomprehensive. In this study, systematic studies on environmental stability, bioactivity, and ecotoxicological effects of fungicide penflufen were carried out at the enantiomeric level. The single-enantiomer of penflufen was successfully separated and prepared, and their stability was verified in different environmental matrices. Meanwhile, bioactivity test indicated that S-(+)-penflufen had increased bioactivity with its bioactivities against Rhizoctonia solani, Fusarium oxysporum, and Fusarium moniliforme being factors of 7.8, 1.8, and 4.7, respectively greater than those of R-(-)-penflufen. Molecular docking results showed the strong hydrogen bond interactions with Leu300, enantiomer-specific hydrophobic interactions with Cys299, Arg91, and His93, and the greater binding energy between S-(+)-penflufen and succinate dehydrogenase of Rhizoctonia solani caused the selective bioactivity. Additionally, two enantiomers showed low acute toxicity whereas selective sub-chronic toxicity to earthworms. In sub-chronic toxicity test, the accumulated enantiomers caused abnormalities in intestinal tract structure, enzyme activities, and gene expression of earthworms, especially in the S-(+)-penflufen treatment. The selective interactions between penflufen enantiomers and key proteins were elucidated using molecular docking, which may be the main reason of stereoselective subchronic toxicity. S-(+)-penflufen has high bioactivity and low acute risk, it has great potential for development.

Assessing the bioavailability and biotoxicity of spiromesifen and its main metabolite spiromesifen-enol (M01) reveals the defense mechanisms of earthworms (Eisenia fetida).

As a promising acaricide and potentially hazardous material, the defense mechanisms of non-target organisms to its exposure are unknown. This study investigates the bioavailability and biotoxicity of spiromesifen and spiromesifen-enol (M01), its main metabolite, in Eisenia fetida. The results showed that M01 was more persistent in the soil environment and E. fetida than spiromesifen. Transcriptome analysis indicated that the spiromesifen- and M01-induced differentially expressed genes (DEGs) were mainly enriched in lysosomal and phagosomal pathways. Analysis of the key common DEGs showed that both spiromesifen and M01 significantly influenced the lysosomes, phagosomes, antioxidant systems, and detoxification systems. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) showed that spiromesifen and M01 damaged E. fetida epidermis and enhanced lysosomal and phagosomal activities. Significant oxidative stress effects were observed at the end of exposure. The hydroxyl free radical (·OH-) content and neutral red retention time (NRRT) could serve as sensitive early biomarkers to predict their pollution. These results revealed the synergistic effects of the epidermis, lysosomes, phagosomes, antioxidant systems, and detoxification system in resisting spiromesifen- and M01-induced damage, which could contribute to the defense mechanisms of non-target organisms against these pollutants.

Earthworms accelerated the degradation of the highly toxic acetochlor S-enantiomer by stimulating soil microbiota in repeatedly treated soils.

This study investigated the effects of earthworms on the enantioselective degradation of chloroacetamide herbicide acetochlor with soil microorganisms in repeatedly treated soils. The S-enantiomer degraded more slowly and exerted stronger inhibition on soil microbial functions than the R-enantiomer in single soil system. A synergistic effect was observed between soil microorganisms and earthworms that accelerated the degradation of both the enantiomers, particularly the highly toxic S-enantiomer, which resulted in the preferential degradation of S-enantiomer in soil-earthworm system. Earthworms stimulated five potential indigenous degraders (i.e. Lysobacter, Kaistobacter, Flavobacterium, Arenimonas, and Aquicell), induced two new potential degraders (i.e. Aeromonas and Algoriphagus), and also significantly strengthened the correlations among these seven dominant potential degraders and other microorganisms. Notably, the relative abundances of Flavobacterium and Aeromonas in soil treated with earthworms for S-enantiomer were higher than those for R-enantiomer. Furthermore, earthworms significantly stimulated overall soil microbial activity and improved three microbial metabolic pathways, and xenobiotics biodegradation and metabolism, signal transduction, cell motility, particularly for the S-enantiomer treatment with earthworms, which alleviated the strong inhibition of S-enantiomer on microbial community functions. This study confirmed that earthworms accelerated the degradation of the highly toxic acetochlor S-enantiomer in soil, providing a potential approach in chloroacetamide herbicide-polluted soil remediation.

Enantioselective bioaccumulation and detoxification mechanisms of earthworms (Eisenia fetida) exposed to mandipropamid.

As a novel chiral amide fungicide, the enantioselective behaviors of mandipropamid in the soil environment are unclear. Furthermore, there is a need to understand the stress response mechanisms of soil organisms exposed to mandipropamid isomers. Therefore, the selective bioaccumulation of mandipropamid isomers and detoxification mechanisms of earthworms (Eisenia fetida) were investigated in this study. Our results suggested that the enantioselective bioaccumulation of mandipropamid in earthworms occurred with the preferential enrichment of S-(+)-isomer. The activities of detoxification enzymes, such as cytochrome P450 (CYP450), glutathione-S-transferases (GST), and carboxylesterase (CarE), changed significantly upon exposure to S-(+)- and R-(-)-mandipropamid (particularly for CYP450 and GST). A transcriptome analysis revealed that more differentially expressed genes (DEGs) were observed under S-(+)-isomer exposure (15,798) than those under R-(-)-isomer exposure (12,222), as compared to the control group. These DEGs were mainly enriched in bile secretion and thyroid hormone signaling pathways, which were related to the detoxification process in earthworms. Moreover, the 20 DEGs, which exhibited the most profound changes (such as CYP2 and CYP3A4) in these pathways, were screened, clustered, and observed to be mainly involved in regulating the detoxification function of earthworm cells. These results indicated that detoxification systems played an essential role in the stress response to mandipropamid exposure. Additionally, earthworms were more sensitive to the stress induced by S-(+)-mandipropamid than that induced by R-(-)-mandipropamid. This is the first study to elucidate the mandipropamid detoxification mechanism of earthworms at the enantiomer level, which can be beneficial for remediating chiral pollutants.

Simultaneous Determination of the Residues of Isopyrazam Isomers and Their Metabolites in Soil and Tomatoes by Ultraperformance Liquid Chromatography-Tandem Mass Spectrometry.

An effective and sensitive method for the determination of isopyrazam (IZM) isomers (syn-IZM and anti-IZM) and their metabolites (syn545364 and syn545449) in tomato and soil by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed in the present study. The method showed excellent linearities (R2 = 0.999) at 0.005-5 mg/L. The recoveries were 92.0-107%, and the relative standard deviation (RSD) values were lower than 9.40% in tomato and soil matrices at 0.01, 0.1, and 10 mg/kg. The limits of detection (LODs) of the four compounds ranged from 6.88 × 10-5 to 2.70 × 10-4 mg/kg, while the limits of quantification (LOQs) ranged from 2.20 × 10-4 to 9.20 × 10-4 mg/kg. The storage stability test results showed that syn-IZM, anti-IZM, syn545449, and syn545364 were stable in tomato at -20 °C within 36 weeks, and the maximum degradation rates were 16.0, 12.0, 7.10, and 12.0%, respectively. The field dissipation test results showed that the half-lives of syn-IZM in tomato and soil were 2.60-10.2 and 13.6-33.0 days, respectively, while the half-lives of anti-IZM in soil were 21.7-46.2 days, and no residues of anti-IZM were detected in tomato. The terminal residue test results showed that the residue of syn-IZM and anti-IZM in tomato ranged from <0.0100-0.490 to <0.0100-0.0850 mg/kg. The present results showed that anti-IZM degraded faster than syn-IZM in tomato and soil, and had a lower residue level in tomato.

Er-Xian Decoction, a traditional Chinese herbal formula, intervening early in hypothalamic-pituitary axis of male rats with delayed puberty.

BACKGROUND: Er-Xian Decoction (EXD) is one of the traditional Chinese medicine (TCM) with unique effect on osteoporosis, menopausal syndrome and delayed puberty in China for many years. OBJECTIVE: We aim to evaluate the potential activity of starting hypothalamic-pituitary-testicular (HPT) axis of male rats with delayed puberty. MATERIALS AND METHODS: Delayed puberty model of male Sprague-Dawley (SD) rats were established with soy isoflavones (90 mg·kg(-1)) and were treated by EXD extract at doses of 5, 10 g·kg(-1) or Testosterone undecanoate (TU) for 8 weeks. Body weight, body length, testis weight, T, E2 and luteinizing hormone (LH) in serum, gonadotropin releasing hormone (GnRH) in hypothalamus, follicle stimulating hormone (FSH) and LH in pituitary gland were determined by ELISA. Immunohistochemistry was used to detect LH in pituitary gland. RESULTS: Soy isoflavones could significantly decrease body weight, body length, testicular organ coefficient T in serum, GnRH in hypothalamus, FSH and LH in pituitary gland. Both of EXD and TU could improve the condition. E2 and LH in serum of all groups were non-significance of difference (P > 0.05). The immunohistochemical results were well consistent with LH in pituitary gland. CONCLUSION: The results of the present research indicate that EXD extract is effective to start the HPT axis in puberty and can significantly improve sexual developmental inhibition caused by soy isoflavones.

An improved workflow for identifying ubiquitin/ubiquitin-like protein conjugation sites from tandem mass spectra.

The identification of ubiquitin (Ub) and Ub-like protein (Ubl) conjugation sites is important in understanding their roles in biological pathway regulations. However, unambiguously and sensitively identifying Ub/Ubl conjugation sites through high-throughput MS remains challenging. We introduce an improved workflow for identifying Ub/Ubl conjugation sites based on the ChopNSpice and X!Tandem software. ChopNSpice is modified to generate Ub/Ubl conjugation peptides in the form of a cross-link. A combinatorial FASTA database can be acquired using the modified ChopNSpice (MchopNSpice). The modified X!Tandem (UblSearch) introduces a new fragmentation model for the Ub/Ubl conjugation peptides to match unambiguously the MS/MS spectra with linear peptides or Ub/Ubl conjugation peptides using the combinatorial FASTA database. The novel workflow exhibited better performance in analyzing an Ub and Ubl spectral library and a large-scale Trypanosoma cruzi small Ub-related modifier dataset compared with the original ChopNSpice method. The proposed workflow is more suitable for processing large-scale MS datasets of Ub/Ubl modification. MchopNSpice and UblSearch are freely available under the GNU General Public License v3.0 at http://sourceforge.net/projects/maublsearch.