Hexavalent chromium exposure induces lung injury via activation of NLRP3 and AIM2 inflammasomes in rats.

Hexavalent chromium (Cr(VI)) has been identified as a Class I human carcinogen, but its carcinogenic mechanism is currently unclear. There is still a lack of understanding of its associations with early pulmonary inflammatory damages. Inflammation is an important stage before the occurrence of tumors, and under the long-term stimulation of inflammation, it can promote the development of tumors. In this study, the aim is to explore the effect of Cr(VI) exposure on pulmonary inflammation and its relationship with the mechanism of inflammation cancer transformation. We established a Cr(VI) exposure model in SD rats using tracheal instillation of potassium dichromate solution, and collected samples at the time of cessation of exposure and 14 days after cessation of exposure. Analyzing the experimental results, it was found that the lung index increased after exposure to Cr(VI), promoting the occurrence of apoptosis in lung tissue cells and exacerbating lung tissue damage. The damage situation improved after exposure termination; Inductively coupled plasma mass (ICPRQ) spectrometer detection found that the exposed group had significantly increased levels of blood chromium, blood manganese, blood copper, blood arsenic, urine chromium, urine copper, and urine lead; After two weeks of repair, blood chromium and blood manganese levels were significantly lower than those in the same dose group of the exposure group, while blood copper levels were significantly higher than those in the same dose group of the exposure group. There was no significant difference in blood arsenic levels between the exposure group and the exposure group. Urine chromium and urine lead levels were significantly lower than those in the same dose group of the exposure group, while urine copper levels only increased. At the same time, it was found that Cr(VI) exposure caused disruption of oxidative stress levels in rat lung tissues. After 14-day exposure, Cr(VI) significantly decreased and oxidative stress levels significantly decreased. Further investigation revealed that Cr(VI) induces activation of inflammasomes NLRP3, AIM2, and their signaling pathways in lung inflammatory injuries, but this condition persists even after cessation of exposure. The study suggested that in hexavalent chromium induced lung tissue injuries in rats, NLRP3 and AIM2 inflammasomes and their signaling pathways activation. Furthermore, the characteristic of sustained activation after cessation of exposure was also indicated. These results provide new ideas and references for further elucidating the mechanisms of Cr(VI), lung inflammation and inflammation cancer transformation.

Identification and functional analysis of the Dof transcription factor genes in sugar beet.

In this study, members of the BvDof transcription factor family were identified in the beet genome data (Beta vulgaris L.) Through systematic analysis, 22 BvDof family genes were found in the beet genome, and they were divided into nine groups by phylogenetic analysis. Fifteen members of the BvERF family were involved in the transition to rapid root tuber growth. There was a tandem replication during the generation of the Dof gene family in sugar beet. Bv1_zfms, Bv_ofna, Bv5_racn, and Bv6_augo may be involved in the regulation of secondary cambium development in the beet root tuber. Bv9_nood, Bv1_zfms, and Bv6_cdca may be related to the growth rate of root tubers. The results provide a reference for further elucidating the molecular mechanism of the BvDof transcription factor, which regulates the development of beet root tubers.

Mechanisms of the NAD+ salvage pathway in enhancing skeletal muscle function.

Nicotinamide adenine dinucleotide (NAD+) is crucial for cellular energy production, serving as a coenzyme in oxidation-reduction reactions. It also supports enzymes involved in processes such as DNA repair, aging, and immune responses. Lower NAD+ levels have been associated with various diseases, highlighting the importance of replenishing NAD+. Nicotinamide phosphoribosyltransferase (NAMPT) plays a critical role in the NAD+ salvage pathway, which helps sustain NAD+ levels, particularly in high-energy tissues like skeletal muscle.This review explores how the NAMPT-driven NAD+ salvage pathway influences skeletal muscle health and functionality in aging, type 2 diabetes mellitus (T2DM), and skeletal muscle injury. The review offers insights into enhancing the salvage pathway through exercise and NAD+ boosters as strategies to improve muscle performance. The findings suggest significant potential for using this pathway in the diagnosis, monitoring, and treatment of skeletal muscle conditions.

A spray-induced gene silencing strategy for Spodoptera frugiperda oviposition inhibition using nanomaterial-encapsulated dsEcR.

Although RNAi-based pest management holds great potential as an alternative to traditional chemical control, its efficiency is restricted by dsRNA instability and limited cellular uptake. Using nanomaterials to facilitate dsRNA delivery has shown promise in solving these challenges. In this study, we firstly used RNAi to investigate the role of the juvenile hormone and ecdysteroid signaling pathways genes in reproduction of Spodoptera frugiperda, the fall armyworm. Females in knocked-down treatments of any of the Met, EcR, and USP genes had greatly reduced fertility with the most pronounced inhibitory effects on oviposition observed following EcR knockdown, and thus the dsEcR could be a candidate target for RNAi-based oviposition inhibitory agency. Then a combinatorial spray-induced and nanocarrier-delivered gene silencing (SI-NDGS) approach that targeted EcR was conducted. At 72 h post-spay, the transcript levels of EcR and the oviposition were successfully reduced and inhibited. These findings support the groundwork for further developing novel RNAi-based pest management strategies for S. frugiperda.

GPR158 in pyramidal neurons mediates social novelty behavior via modulating synaptic transmission in male mice.

Impairment in social communication skills is a hallmark feature of autism spectrum disorder (ASD). The role of G-protein-coupled receptor 158 (GPR158) in ASD remains largely unexplored. In this study, we observed that both constitutive and cell-/tissue-specific knockouts of Gpr158 in pyramidal neurons or the medial prefrontal cortex (mPFC) result in impaired novelty preference, while sociability remains unaffected in male mice. Notably, the loss of GPR158 leads to a significant decline in excitatory synaptic transmission, characterized by a reduction in glutamate vesicles, as well as the expression and phosphorylation of GluN2B in the mPFC. We successfully rescue the phenotype of social novelty deficits either by reintroducing GPR158 in the mPFC of Gpr158 deficient mice or by chemogenetic activation of pyramidal neurons where Gpr158 is specifically ablated. Our findings indicate that GPR158 in pyramidal neurons plays a specific role in modulating social novelty and may represent a potential target for treating social disorders.

Composite microarc oxidation coatings containing Cu on titanium alloy.

A soft and hard composite MAO coating was prepared by adding Cu particles to an alkaline phosphate-borate electrolyte to modify the MAO coating on titanium alloy. The effects of Cu particles on the thickness, structural features, and friction characteristics of the MAO coating were investigated. The MAO coating formed in Cu particle-free electrolyte mainly comprised rutile and anatase TiO2. Cu and CuO were detected in the oxide coatings obtained in the electrolyte with Cu particles. The hardness of the coating prepared in the base electrolyte was approximately 420 HV, whereas that obtained in the electrolyte containing 2 g L-1 Cu particles increased to 470 HV. While the friction coefficient of the base MAO coating exhibited significant fluctuations, the friction coefficient of the MAO coating containing Cu particles remained relatively stable. The MAO coating formed in the electrolyte containing 2 g L-1 Cu particles demonstrated superior frictional performance, exhibiting a value approximately 3.6 times higher than the base coating. Cu particles enter the MAO coating through electrophoresis, mechanical agitation, and micro-melt adsorption to improve the compactness of the coating. Due to the excellent plasticity of Cu, the friction properties of Cu-containing MAO coating were enhanced.

Comprehensive analysis of GINS subunit expression, prognostic value, and immune infiltration in clear cell renal cell carcinoma.

Background: In recent decades, there has been increasing evidence that Go-Ichi-Nii-San (GINS) subunits play an important role in the development and progression of various tumors. However, little research has been conducted on the role of GINS subunits in clear cell renal cell carcinoma (ccRCC). This study sought to explore the differential expression, prognosis, and immunological significance of GINS subunits in ccRCC. Methods: We used various analysis packages of R (version 3.6.3), the University of ALabama at Birmingham CANcer (UALCAN) data analysis portal, the Cancer Cell Line Encyclopedia (CCLE), the cBio Cancer Genomics Portal (cBioPortal), and the Tumor Immune Estimation Resource (TIMER) to study the gene expression, promoter methylation level, gene mutations, prognostic and diagnostic value, immune infiltration, pathway enrichment, and other aspects of the GINS subunits. Next, the genes related to the GINS subunits were analyzed using the STRING and GeneMANIA platforms, and the correlation between GINS subunits and the functions involved were investigated. Results: The expression level of GINS1/2/3/4 was significantly higher in ccRCC tumor tissues than normal tissues, and was significantly related to tumor grade and stage. The expression of GINS1/2/4 may be related to the methylation degree of the promoter region. The prognostic and diagnostic analyses showed that the increased expression of GINS1 was associated with various poor prognoses and had diagnostic value. The GINS subunit mutation also significantly affected the clinical prognosis of ccRCC patients. Finally, the correlation analysis of the immune infiltration level, co-expression, and enrichment of related genes indicated that GINS subunit expression was associated with different levels of ccRCC immune infiltration. Conclusions: The analysis results showed that the differential expression of GINS subunits in ccRCC, which had prognostic and diagnostic value, was correlated with clinicopathological stage, immune infiltration, and other related aspects. GINS1 may serve as a new potential prognostic biomarker for ccRCC patients and be used to guide treatment.

Influence of Water and Fertilizer Reduction on Respiratory Metabolism in Sugar Beet Taproot (Beta vulgaris L.).

Inner Mongolia, a major region in China for growing sugar beet, faces challenges caused by unscientific water and fertilizer management. This mismanagement restricts the improvement of sugar beet yield and quality and exacerbates water waste and environmental pollution. This study aims to evaluate the effects of reduced water and fertilizer on the growth and physiological metabolism of sugar beet taproot. Field experiments were conducted in Ulanqab, Inner Mongolia, in 2022 and 2023, using a split-plot design with three levels each of fertilization and irrigation. The study analyzed the effects of reduced water and fertilizer treatments on fresh taproot weight, respiration rate, energy metabolism, respiratory enzyme activity, and gene expression in sugar beet taproot. It was found that a 10% reduction in fertilizer significantly increased the beet taproot fresh weight. Further research revealed that during the rapid leaf growth phase and the taproot and sugar growth period, a 10% reduction in fertilizer upregulated HK and IDH gene expression and downregulated G6PDH gene expression in the beet taproot. This increased HK and IDH activities, decreased G6PDH activity, enhanced the activity of the EMP-TCA pathway, and inhibited the PPP. Taproot weight was positively correlated with the respiration rate, ATP content, EC, and ATPase, HK, and IDH activities, thereby increasing the taproot growth rate and taproot fresh weight, with an average increase of 4.0% over two years. These findings introduce a novel method for optimizing fertilizer use, particularly beneficial in water-scarce regions. Implementing this strategy could help farmers in western Inner Mongolia and similar areas improve crop yield and sustainability. This study offers new insights into resource-efficient agricultural practices, highlighting the importance of customized fertilization strategies tailored to local environmental conditions.

Low-dose hexavalent chromium induces mitophagy in rat liver via the AMPK-related PINK1/Parkin signaling pathway.

Hexavalent chromium (Cr(VI)) is a hazardous metallic compound commonly used in industrial processes. The liver, responsible for metabolism and detoxification, is the main target organ of Cr(VI). Toxicity experiments were performed to investigate the impacts of low-dose exposure to Cr(VI) on rat livers. It was revealed that exposure of 0.05 mg/kg potassium dichromate (K2Cr2O7) and 0.25 mg/kg K2Cr2O7 notably increased malondialdehyde (MDA) levels and the expressions of P-AMPK, P-ULK, PINK1, P-Parkin, and LC3II/LC3I, and significantly reduced SOD activity and P-mTOR and P62 expression levels in liver. Electron microscopy showed that CR(VI) exposure significantly increased mitophagy and the destruction of mitochondrial structure. This study simulates the respiratory exposure mode of CR(VI) workers through intratracheal instillation of CR(VI) in rats. It confirms that autophagy in hepatocytes is induced by low concentrations of CR(VI) and suggest that the liver damage caused by CR(VI) may be associated with the AMPK-related PINK/Parkin signaling pathway.

Repair of spinal cord injury by bone marrow mesenchymal stem cell-derived exosomes: a systematic review and meta-analysis based on rat models.

Objective: This study aims to systematically evaluate the efficacy of bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exo) in improving spinal cord injury (SCI) to mitigate the risk of translational discrepancies from animal experiments to clinical applications. Methods: We conducted a comprehensive literature search up to March 2024 using PubMed, Embase, Web of Science, and Scopus databases. Two researchers independently screened the literature, extracted data, and assessed the quality of the studies. Data analysis was performed using STATA16 software. Results: A total of 30 studies were included. The results indicated that BMSCs-Exo significantly improved the BBB score in SCI rats (WMD = 3.47, 95% CI [3.31, 3.63]), inhibited the expression of the pro-inflammatory cytokine TNF-α (SMD = -3.12, 95% CI [-3.57, -2.67]), and promoted the expression of anti-inflammatory cytokines IL-10 (SMD = 2.76, 95% CI [1.88, 3.63]) and TGF-ß (SMD = 3.89, 95% CI [3.02, 4.76]). Additionally, BMSCs-Exo significantly reduced apoptosis levels (SMD = -4.52, 95% CI [-5.14, -3.89]), promoted the expression of axonal regeneration markers NeuN cells/field (SMD = 3.54, 95% CI [2.65, 4.42]), NF200 (SMD = 4.88, 95% CI [3.70, 6.05]), and the number of Nissl bodies (SMD = 1.89, 95% CI [1.13, 2.65]), and decreased the expression of astrogliosis marker GFAP (SMD = -5.15, 95% CI [-6.47, -3.82]). The heterogeneity among studies was primarily due to variations in BMSCs-Exo transplantation doses, with efficacy increasing with higher doses. Conclusion: BMSCs-Exo significantly improved motor function in SCI rats by modulating inflammatory responses, reducing apoptosis, inhibiting astrogliosis, and promoting axonal regeneration. However, the presence of selection, performance, and detection biases in current animal experiments may undermine the quality of evidence in this study.

Impact of the gut microbiome on response and toxicity to chemotherapy in advanced esophageal cancer.

Objective: To identify the gut bacteria associated with chemotherapeutic outcomes, t characterized the gut microbiota in patients with esophageal squamous cell carcinoma (ESCC) in this prospective study. Design: Thirty-one patients with ESCC were enrolled. Chemotherapy was performed with paclitaxel and cisplatin (TP). Fecal samples were collected before and after treatment and analyzed using 16S rRNA sequencing. Results: The species with differences in baseline abundance between partial response (PR) and non-PR groups was identified as Bacteroides plebeius (P = 0.043). The baseline abundance of B. plebeius was higher in the responder (R, PR + stable disease (SD)) group (P = 0.045) than in the non-responder (NR). The abundance of B. ovatus was identified as a predictor for distinguishing patients with PR from those without PR (sensitivity, 83.3 %; specificity, 69.6 %). The abundance of B. plebeius was positively associated with the response to PR + SD (R) in predicting responders in the receiver operating characteristic (ROC) curve analysis (area under the ROC curve = 0.865, P = 0.041). The abundance of B. plebeius and B.uniform was a predictor of grade (G) 3-4 chemotherapy toxicities. The sensitivity and specificity of the established multi-analyte microbial predictive model demonstrated a better predictive ability than a single parameter (B. uniform or B. plebeius). Conclusion: The abundance of gut microbiota B. plebeius and B. ovatus are associated with the efficacy of TP chemotherapy in patients with ESCC. The abundance of B. plebeius and B.uniform may related to the toxicity of TP chemotherapy.

Development of a marker recyclable CRISPR/Cas9 system for scarless and multigene editing in Fusarium fujikuroi.

Iterative metabolic engineering of Fusarium fujikuroi has traditionally been hampered by its low homologous recombination efficiency and scarcity of genetic markers. Thus, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (Cas9) system has emerged as a promising tool for precise genome editing in this organism. Some integrated CRISPR/Cas9 strategies have been used to engineer F. fujikuroi to improve GA3 production capabilities, but low editing efficiency and possible genomic instability became the major obstacle. Herein, we developed a marker recyclable CRISPR/Cas9 system for scarless and multigene editing in F. fujikuroi. This system, based on an autonomously replicating sequence, demonstrated the capability of a single plasmid harboring all editing components to achieve 100%, 75%, and 37.5% editing efficiency for single, double, and triple gene targets, respectively. Remarkably, even with a reduction in homologous arms to 50 bp, we achieved a 12.5% gene editing efficiency. By employing this system, we successfully achieved multicopy integration of the truncated 3-hydroxy-3-methyl glutaryl coenzyme A reductase gene (tHMGR), leading to enhanced GA3 production. A key advantage of our plasmid-based gene editing approach was the ability to recycle selective markers through a simplified protoplast preparation and recovery process, which eliminated the need for additional genetic markers. These findings demonstrated that the single-plasmid CRISPR/Cas9 system enables rapid and precise multiple gene deletions/integrations, laying a solid foundation for future metabolic engineering efforts aimed at industrial GA3 production.

Ultra-rapid development of 'solid' aerobic granular sludge by stable transition/filling of inoculated 'hollow' mycelial pellets in hypersaline wastewater.

To overcome the long start-up period in cultivating aerobic granular sludge (AGS) under hypersaline environment, mycelial pellets (MPs) of halotolerant fungus Cladosporium tenuissimum NCSL-XY8 were inoculated to try to realize the ultra-rapid development of salt-tolerant AGS by stable transition of 'hollow' MPs into 'solid' AGS without apparent fragmentation. The granules directly met the standard of AGS after inoculating MPs (Day 0), and it basically satisfied relatively strict standards of AGS (SVI30 < 50 mL/g, D50 > 300 µm, D10 > 200 µm and SVI30/SVI5 > 0.9) under anaerobic/aerobic mode during whole cultivation processes. Microstructure of the granular cross section clarified that MPs with hollow/loose inner layer transitioned into solid/dense AGS under anaerobic/aerobic mode within 7 days, while formed skin-like floating pieces and unstable double-layer hollow granules under aerobic mode. Organics removal reached relatively stable within 13 days under anaerobic/aerobic mode, 6 days faster than aerobic mode. This study provided a strategy for ultra-rapid and stable development of AGS, which showed the shortest granulation period in various AGS-cultivation strategies.

Aqueous humor proteomics analyzed by bioinformatics and machine learning in PDR cases versus controls.

BACKGROUND: To comprehend the complexities of pathophysiological mechanisms and molecular events that contribute to proliferative diabetic retinopathy (PDR) and evaluate the diagnostic value of aqueous humor (AH) in monitoring the onset of PDR. METHODS: A cohort containing 16 PDR and 10 cataract patients and another validation cohort containing 8 PDR and 4 cataract patients were studied. AH was collected and subjected to proteomics analyses. Bioinformatics analysis and a machine learning-based pipeline called inference of biomolecular combinations with minimal bias were used to explore the functional relevance, hub proteins, and biomarkers. RESULTS: Deep profiling of AH proteomes revealed several insights. First, the combination of SIAE, SEMA7A, GNS, and IGKV3D-15 and the combination of ATP6AP1, SPARCL1, and SERPINA7 could serve as surrogate protein biomarkers for monitoring PDR progression. Second, ALB, FN1, ACTB, SERPINA1, C3, and VTN acted as hub proteins in the profiling of AH proteomes. SERPINA1 was the protein with the highest correlation coefficient not only for BCVA but also for the duration of diabetes. Third, "Complement and coagulation cascades" was an important pathway for PDR development. CONCLUSIONS: AH proteomics provides stable and accurate biomarkers for early warning and diagnosis of PDR. This study provides a deep understanding of the molecular mechanisms of PDR and a rich resource for optimizing PDR management.

Mfn2 regulates mitochondria and mitochondria-associated endoplasmic reticulum membrane function in neurodegeneration induced by repeated sevoflurane exposure.

Repeated sevoflurane exposure in neonatal mice can leads to neuronal apoptosis and mitochondrial dysfunction. The mitochondria are responsible for energy production to maintain homeostasis in the central nervous system. The mitochondria-associated endoplasmic reticulum membrane (MAM) is located between the mitochondria and endoplasmic reticulum (ER), and it is critical for mitochondrial function and cell survival. MAM malfunction contributes to neurodegeneration, however, whether it is involved in sevoflurane-induced neurotoxicity remains unknown. Our study demonstrated that repeated sevoflurane exposure induced mitochondrial dysfunction and dampened the MAM structure. The upregulated ER-mitochondria tethering enhanced Ca2+ transition from the cytosol to the mitochondria. Overload of mitochondrial Ca2+ contributed to opening of the mitochondrial permeability transition pore (mPTP), which caused neuronal apoptosis. Mitofusin 2(Mfn2), a key regulator of ER-mitochondria contacts, was found to be suppressed after repeated sevoflurane exposure, while restoration of Mfn2 expression alleviated cognitive dysfunction due to repeated sevoflurane exposure in the adult mice. These evidences suggest that sevoflurane-induced MAM malfunction is vulnerable to Mfn2 suppression, and the enhanced ER-mitochondria contacts promotes mitochondrial Ca2+ overload, contributing to mPTP opening and neuronal apoptosis. This paper sheds light on a novel mechanism of sevoflurane-induced neurotoxicity. Furthermore, targeting Mfn2-mediated regulation of the MAM structure and mitochondrial function may provide a therapeutic advantage in sevoflurane-induced neurodegeneration.

Genomic and T cell repertoire biomarkers associated with malignant mesothelioma survival.

BACKGROUND: Malignant mesothelioma (MM) is an exceedingly rare tumor with poor prognosis due to the limited availability of effective treatment. Immunotherapy has emerged as a novel treatment approach for MM, but less than 40% of the patients benefit from it. Thus, it is necessary to identify accurate and effective biomarkers that can predict the overall survival (OS) and immunotherapy efficacy for MM. METHODS: DNA sequencing was used to identify the genomic landscape based on the data from 86 Chinese patients. T cell receptor (TCR) sequencing was used to characterize MM TCR repertoires of 28 patients between October 2016 and April 2023. RESULTS: Patients with TP53, NF2, or CDKN2A variants at the genomic level, as well as those exhibiting lower Shannon index (<6.637), lower evenness (<0.028), or higher clonality (≥0.194) according to baseline tumor tissue TCR indexes, demonstrated poorer OS. Furthermore, patients with TP53, CDKN2A, or CDKN2B variants and those with a lower evenness (<0.030) in baseline tumor tissue showed worse immunotherapy efficacy. The present study is the first to identify five special TCR Vß-Jß rearrangements associated with MM immunotherapy efficacy. CONCLUSIONS: The present study reported the largest-scale genomic landscape and TCR repertoire of MM in Chinese patients and identified genomic and TCR biomarkers for the prognosis and immunotherapy efficacy in MM. The study results might provide new insights for prospective MM trials using specific genes, TCR indexes, and TCR clones as biomarkers and offer a reference for future antitumor drugs based on TCR-specific clones.

ALS-linked C9orf72 dipeptide repeats inhibit starvation-induced autophagy through modulating BCL2-BECN1 interaction.

Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative disorders. The GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72 (C9orf72) is the most genetic cause of both ALS and FTD. According to the previous studies, GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation, which produces dipeptide repeat (DPR) proteins. Although there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD, whether these DPRs can affect autophagy remains unclear. In the present study, we find that poly-GR and poly-PR, two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies, strongly inhibit starvation-induced autophagy. Moreover, our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation, therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in cells. Importantly, our study not only highlights the role of C9orf72 DPR in autophagy dysfunction, but also provides novel insight that pharmacological intervention of autophagy using SW063058, a small molecule compound that can disrupt the interaction between BECN1 and BCL2, may reduce C9orf72 DPR-induced neurotoxicity.

Apigenin intervenes in liver fibrosis by regulating PKM2-HIF-1α mediated oxidative stress.

Apigenin (API) is a natural flavonoid compound with antioxidant, anti fibrotic, anti-inflammatory and other effects, but there is limited research on the effect of API on liver fibrosis. This study aims to explore the effect and potential mechanism of API on liver fibrosis induced by CCl4 in mice. The results indicate that API reduces oxidative stress levels, inhibits hepatic stellate cell (HSC) activation, and exerts anti liver fibrosis effects by regulating the PKM2-HIF-1α pathway. We observed that API alleviated liver tissue pathological damage and collagen deposition in CCl4 induced mouse liver fibrosis model, promoting the recovery of liver function in mice with liver fibrosis. In addition, the API inhibits the transition of Pyruvate kinase isozyme type M2 (PKM2) from dimer to tetramer formation by regulating the EGFR-MEK1/2-ERK1/2 pathway, thereby preventing dimer from entering the nucleus and blocking PKM2-HIF-1α access. This change leads to a decrease in malondialdehyde (MDA) and Catalase (CAT) levels and an increase in glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) levels, as well as total antioxidant capacity (T-AOC) in the liver of liver fibrosis mice. At the same time, API downregulated the expression of α-smooth muscle actin (α-SMA), Vimentin and Desmin in the liver tissue of mice with liver fibrosis, inhibited the activation of HSC, and reduced collagen deposition. These results indicate that API can inhibit HSC activation and alleviate CCl4 induced liver fibrosis by inhibiting the PKM2-HIF-1α pathway and reducing oxidative stress, laying an important foundation for the development and clinical application of API as a novel drug for treating liver fibrosis.

Calcitonin gene-related peptide: a possible biomarker in migraine patients with patent foramen ovale.

BACKGROUND: Serum CGRP has been found to increase during migraine attack. However, whether CGRP can identify MA with PFO subtypes in MA remains unknown. This study aimed to investigate the differential expression of calcitonin gene-related peptide (CGRP) between migraine (MA) patients with and without patent foramen ovale (PFO), and to evaluate the predictive value of CGRP for MA with PFO. METHODS: A total of 153 patients with MA, 51 patients with PFO and 102 patients without. Venous blood was drawn and HIT-6 score was calculated during the onset of MA, and blood routine, inflammatory indexes and serum CGRP were detected. The differences in serum markers and HIT-6 scores were compared between the two groups, and the risk factors of MA with PFO were determined by univariate and multivariate logistics regression. Furthermore, the correlation between CGRP level with right-to-left shunt (RLS) grades and headache impact test-6 (HIT-6) score in MA patients with PFO were assessed. Independent risk factors were screened out by multivariate Logistic regression analysis. We used the receiver operating characteristic (ROC) curve to analyze the diagnostic value of these risk factors in MA complicated with PFO. RESULTS: The serum CGRP level and HIT-6 scores in the MA with PFO group were significantly higher than those in the MA group (P < 0.001). Multivariate regression analysis showed that CGRP was an independent risk factor for MA with PFO (OR = 1.698, 95% CI = 1.325-2.179, P < 0.001). CGRP values ​​increased with the increase of RLS grade(Spearmen rho = 0.703, P < 0.001). Furthermore, a positive correlation between CGRP and HIT-6 scores was found (Spearmen rho = 0.227; P = 0.016). ROC curve showed that the optimal cut-off value for diagnosing MA with PFO was 79 pg/mL, the area under the curve (AUC) for predicting MA with PFO was 0.845, with 72.55% sensitivity and 78.43% specificity. CONCLUSIONS: MA patients with PFO have higher serum CGRP level. elevated CGRP concentration was associated with higher RLS grade and increased HIT-6 score. Higher serum CGRP level has certain clinical value in predicting PFO in MA patients. TRIAL REGISTRATION: This study was approved by the Ethics Committee of Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine (Ethics batch number: 20,201,215,005).