Leptin attenuates the osteogenic induction potential of BMP9 by increasing ß-catenin malonylation modification via Sirt5 down-regulation.

BMP9 has demonstrated significant osteogenic potential. In this study, we investigated the effect of Leptin on BMP9-induced osteogenic differentiation. Firstly, we found Leptin was decreased during BMP9-induced osteogenic differentiation and serum Leptin concentrations were increased in the ovariectomized (OVX) rats. Both in vitro and in vivo, exogenous expression of Leptin inhibited the process of osteogenic differentiation, whereas silencing Leptin enhanced. Exogenous Leptin could increase the malonylation of ß-catenin. However, BMP9 could increase the level of Sirt5 and subsequently decrease the malonylation of ß-catenin; the BMP9-induced osteogenic differentiation was inhibited by silencing Sirt5. These data suggested that Leptin can inhibit the BMP9-induced osteogenic differentiation, which may be mediated through reducing the activity of Wnt/ß-catenin signalling via down-regulating Sirt5 to increase the malonylation level of ß-catenin partly.

Succession changes of microbial community for inferring the time since deposition of saliva.

Saliva is a common biological examination material at crime scenes and has high application value in forensic case investigations. It can reflect the suspect's time of crime at the scene and provide evidence of the suspect's criminal facts. Even though many researchers have proposed their experimental protocols for estimating the time since deposition (TsD) of saliva, there is still a relative lack of research on the use of microorganisms to estimate TsD. In the current study, the succession change of microbial community in saliva with different TsD values was explored to discern the microbial markers related to TsD of saliva. We gathered saliva samples from six unrelated healthy Han individuals living in Guizhou, China and exposed these samples to indoor conditions at six time points (0, 1, 3, 7, 15, and 28 days). Temporal changes of microbial compositions in these samples were investigated by 16S rRNA sequencing (V3-V4 regions). By assessing temporal variation patterns of microbial abundance at the genus level, four bacteria (Brucella, Prevotella, Pseudomonas, and Fusobacterium) were observed to show good time dependence in these samples. In addition, the hierarchical clustering and principal co-ordinates analysis results revealed that these saliva samples could be classified into t-short (≤7 days) and t-long (>7 days) groups. In the end, the random forest model was developed to predict the TsD of these samples. For the model, the root mean square error, R2, and mean absolute error between predicted and actual TsD values were 1.5213, 0.9851, and 1.1969, respectively. To sum up, we identified TsD-related microbial markers in saliva samples, which could be viewed as valuable markers for inferring the TsD of saliva.

Salivary metabolites are promising noninvasive biomarkers of drug-induced liver injury.

BACKGROUND: Drug-induced liver injury (DILI) is one of the most common adverse events of medication use, and its incidence is increasing. However, early detection of DILI is a crucial challenge due to a lack of biomarkers and noninvasive tests. AIM: To identify salivary metabolic biomarkers of DILI for the future development of noninvasive diagnostic tools. METHODS: Saliva samples from 31 DILI patients and 35 healthy controls (HCs) were subjected to untargeted metabolomics using ultrahigh-pressure liquid chromatography coupled with tandem mass spectrometry. Subsequent analyses, including partial least squares-discriminant analysis modeling, t tests and weighted metabolite coexpression network analysis (WMCNA), were conducted to identify key differentially expressed metabolites (DEMs) and metabolite sets. Furthermore, we utilized least absolute shrinkage and selection operato and random fores analyses for biomarker prediction. The use of each metabolite and metabolite set to detect DILI was evaluated with area under the receiver operating characteristic curves. RESULTS: We found 247 differentially expressed salivary metabolites between the DILI group and the HC group. Using WMCNA, we identified a set of 8 DEMs closely related to liver injury for further prediction testing. Interestingly, the distinct separation of DILI patients and HCs was achieved with five metabolites, namely, 12-hydroxydodecanoic acid, 3-hydroxydecanoic acid, tetradecanedioic acid, hypoxanthine, and inosine (area under the curve: 0.733-1). CONCLUSION: Salivary metabolomics revealed previously unreported metabolic alterations and diagnostic biomarkers in the saliva of DILI patients. Our study may provide a potentially feasible and noninvasive diagnostic method for DILI, but further validation is needed.

New indole derivatives from endophytic fungus Colletotruchum sp. HK-08 originated from leaves of Nerium indicum.

Objective: To study secondary metabolites from endophytic fungus Colletotruchum sp. HK-08 originated from the leaves of Nerium indicum. Methods: The compounds were isolated by various column chromatographic techniques, and their structures were elucidated by spectroscopic techniques [high resolution electrospray ionization mass spectroscopy (HRESIMS), one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance spectroscopy (NMR)], as well as comparison with literature data. The Ellman method was used to determine the acetylcholinesterase (AChE) inhibitory activity. Results: Four indole derivatives were identified from Colletotruchum sp. HK-08, including 6'-hydroxymonaspiloindole (1), 2-(2-oxoindolin-3-yl)ethyl 2-(4-hydroxyphenyl) acetate (2), 2-(2-oxoindolin-3-yl)ethyl 2-(2-hydroxyphenyl)acetate (3), and monaspiloindole (4). Compound 4 presented weak AChE inhibitory activity with IC50 value of (69.30 ± 6.27) µmol/L [tacrine as the positive control, with IC50 value of (0.61 ± 0.07) µmol/L]. Conclusion: Compounds 1-3 were new compounds, and compound 4 had weak AChE inhibitory activity.

Probucol mitigates high-fat diet-induced cognitive and social impairments by regulating brain redox and insulin resistance.

Probucol has been utilized as a cholesterol-lowering drug with antioxidative properties. However, the impact and fundamental mechanisms of probucol in obesity-related cognitive decline are unclear. In this study, male C57BL/6J mice were allocated to a normal chow diet (NCD) group or a high-fat diet (HFD) group, followed by administration of probucol to half of the mice on the HFD regimen. Subsequently, the mice were subjected to a series of behavioral assessments, alongside the measurement of metabolic and redox parameters. Notably, probucol treatment effectively alleviates cognitive and social impairments induced by HFD in mice, while exhibiting no discernible influence on mood-related behaviors. Notably, the beneficial effects of probucol arise independently of rectifying obesity or restoring systemic glucose and lipid homeostasis, as evidenced by the lack of changes in body weight, serum cholesterol levels, blood glucose, hyperinsulinemia, systemic insulin resistance, and oxidative stress. Instead, probucol could regulate the levels of nitric oxide and superoxide-generating proteins, and it could specifically alleviate HFD-induced hippocampal insulin resistance. These findings shed light on the potential role of probucol in modulating obesity-related cognitive decline and urge reevaluation of the underlying mechanisms by which probucol exerts its beneficial effects.

Antibiotic exposure alters the honeybee gut microbiota and may interfere with the honeybee behavioral caste transition.

Behavioral division is essential for the sustainability and reproduction of honeybee populations. While accumulating evidence has documented that antibiotic exposure interferes with bee behavioral divisions, how the gut microbiome, host physiology, and genetic regulation are implicated in this process remains understudied. Here, by constructing single-cohort colonies, we validated that the gut microbiota varied in composition between age-matched nurse and forager bees. Perturbing the gut microbiota with a low dose of antibiotic retained the gut bacterial size, but the structure of the microbial community continuously diverged from the control group after antibiotic treatment. Fewer foragers were observed in the antibiotic groups in the field experiment. A combinatorial effect of decreased gut metabolic gene repertoires, reduced brain neurotransmitter titers, and downregulated brain immune genes could potentially be related to behavioral tasks transition delay. This work indicates that the disturbance to both the gut microbiome and host physiologies after antibiotic exposure may have implications on social behavior development, highlighting the need for further research focusing on antibiotic pollution threatening the honeybee population's health.

Multifunctional DNA Nanoflower Applied for High Specific Photodynamic Cancer Therapy in vivo.

Photodynamic therapy (PDT) is a newly emerged strategy for disease treatment. One challenge of the application of PDT drugs is the side-effect caused by the non-specificity of the photosensitive molecules. Most of the photosensitizers may invade not only the pathogenic cells but also the normal cells. In recent, people tried to use special cargoes to deliver the drugs into target cells. DNA nanoflowers (NFs) are a kind of newly-emerged nanomaterial which constructed through DNA rolling cycle amplification (RCA) reaction. It is reported that the DNA NFs were suitable materials which have been widely applied as nanocargos for drug delivery in cancer chemotherapeutic treatment. In this paper, we have introduced a new multifunctional DNA NF which could be prepared through an one-pot RCA reaction. This proposed DNA NF contained a versatile AS1411 G-quadruplex moiety, which plays key roles not only for specific recognition of cancer cells but also for near-infrared ray based photodynamic therapy when conjugating with a special porphyrin molecule. We demonstrated that the DNA NF showed good selectivity toward cancer cells, leading to highly efficient photo-induced cytotoxicity. Moreover, the in vivo experiment results suggested this DNA NF is a promising nanomaterial for clinical PDT.

Recent advances in potential therapeutic targets of ferroptosis­associated pathways for the treatment of stroke (Review).

Stroke is a severe neurological disease that is associated with high rates of morbidity and mortality, and the underlying pathological processes are complex. Ferroptosis fulfills a significant role in the progression and treatment of stroke. It is well established that ferroptosis is a type of programmed cell death that is distinct from other forms or types of cell death. The process of ferroptosis involves multiple signaling pathways and regulatory mechanisms that interact with mechanisms inherent to stroke development. Inducers and inhibitors of ferroptosis have been shown to exert a role in the onset of this cell death process. Furthermore, it has been shown that interfering with ferroptosis affects the occurrence of stroke, indicating that targeting ferroptosis may offer a promising therapeutic approach for treating patients of stroke. Hence, the present review aimed to summarize the latest progress that has been made in terms of using therapeutic interventions for ferroptosis as treatment targets in cases of stroke. It provides an overview of the relevant pathways and molecular mechanisms that have been investigated in recent years, highlighting the roles of inducers and inhibitors of ferroptosis in stroke. Additionally, the intervention potential of various types of Traditional Chinese Medicine is also summarized. In conclusion, the present review provides a comprehensive overview of the potential therapeutic targets afforded by ferroptosis­associated pathways in stroke, offering new insights into how ferroptosis may be exploited in the treatment of stroke.

Identification of the mutual gliding locus as a factor for gut colonization in non-native bee hosts using the ARTP mutagenesis.

BACKGROUND: The gut microbiota and their hosts profoundly affect each other's physiology and evolution. Identifying host-selected traits is crucial to understanding the processes that govern the evolving interactions between animals and symbiotic microbes. Current experimental approaches mainly focus on the model bacteria, like hypermutating Escherichia coli or the evolutionary changes of wild stains by host transmissions. A method called atmospheric and room temperature plasma (ARTP) may overcome the bottleneck of low spontaneous mutation rates while maintaining mild conditions for the gut bacteria. RESULTS: We established an experimental symbiotic system with gnotobiotic bee models to unravel the molecular mechanisms promoting host colonization. By in vivo serial passage, we tracked the genetic changes of ARTP-treated Snodgrassella strains from Bombus terrestris in the non-native honeybee host. We observed that passaged isolates showing genetic changes in the mutual gliding locus have a competitive advantage in the non-native host. Specifically, alleles in the orphan mglB, the GTPase activating protein, promoted colonization potentially by altering the type IV pili-dependent motility of the cells. Finally, competition assays confirmed that the mutations out-competed the ancestral strain in the non-native honeybee gut but not in the native host. CONCLUSIONS: Using the ARTP mutagenesis to generate a mutation library of gut symbionts, we explored the potential genetic mechanisms for improved gut colonization in non-native hosts. Our findings demonstrate the implication of the cell mutual-gliding motility in host association and provide an experimental system for future study on host-microbe interactions. Video Abstract.

PVALB Was Identified as an Independent Prognostic Factor for HCC Closely Related to Immunity, and Its Absence Accelerates Tumor Progression by Regulating NK Cell Infiltration.

Purpose: Hepatocellular carcinoma is the most common primary liver cancer, with poor prognosis. Complex immune microenvironment of the liver is linked to the development of HCC. PVALB is a calcium-binding protein which has been described as a cancer suppressor gene in thyroid cancer and glioma. Nevertheless, the role of PVALB in HCC is unknown. Materials and Methods: We obtained data from TCGA and GSE54236 datasets. MCP-counter, WGCNA and LASSO model were applied to identify PVALB. With UALCAN, MethSurv, and other websites, we probed the expression, methylation and survival of PVALB. LinkedOmics and GSEA were adopted for functional analysis, while TIMER, TISIDB, Kaplan-Meier plotter, TIDE databases were utilized to evaluate the relevance of PVALB to the tumor immune microenvironment and predict immunotherapy efficacy. TargetScan, DIANA, LncRNASNP2 databases and relevant experiments were employed to construct ceRNA network. Finally, molecular docking and drug sensitivity of PVALB were characterized by GeneMANIA, CTD, and so on. Results: PVALB was recognized as a gene associated with HCC and NK cell. Its expression was down-regulated in HCC tissue, which lead to adverse prognosis. Besides, the hypomethylation of PVALB was related to its reduced expression. Notably, PVALB was tightly linked to immune, and its reduced expression attenuated the anticancer effect of NK cells via the Fas/FasL pathway, leading to a adverse outcome. The lnc-YY1AP1-3/hsa-miR-6735-5p/PVALB axis may regulate the PVALB expression. Finally, we found immunotherapy might be a viable treatment option. Conclusion: In a word, PVALB is a prognostic indicator, whose low expression facilitates HCC progression by impacting NK cell infiltration.

An oncolytic HSV-1 armed with Visfatin enhances antitumor effects by remodeling tumor microenvironment against murine pancreatic cancer.

Oncolytic viruses (OVs) have shown potential in converting a "cold" tumor into a "hot" one and exhibit effectiveness in various cancer types. However, only a subset of patients respond to oncolytic virotherapy. It is important to understand the resistance mechanisms to OV treatment in pancreatic ductal adenocarcinoma (PDAC) to engineer oncolytic viruses. In this study, we used transcriptome RNA sequencing (RNA-seq) to identify Visfatin, which was highly expressed in the responsive tumors following OV treatment. To explore the antitumor efficacy, we modified OV-mVisfatin, which effectively inhibited tumor growth. For the first time, we revealed that Visfatin promoted the antitumor efficacy of OV by remodeling the tumor microenvironment, which involved enhancing CD8+ T cell and DC cell infiltration and activation, repolarizing macrophages towards the M1-like phenotype, and decreasing Treg cells using single-cell RNA sequencing (scRNA-seq) and flow cytometry. Furthermore, PD-1 blockade significantly enhanced OV-mVisfatin antitumor efficacy, offering a promising new therapeutic strategy for PDAC.

Experience in improving treatment outcomes for childhood acute lymphoblastic leukemia: real-world results for a province in China, 2011-2020.

The present study aimed to investigate the real-world results of childhood acute lymphoblastic leukemia (cALL) cases in Fujian, China. The clinical data of 1414 patients with newly diagnosed cALL in Fujian were retrospectively analyzed. Patients were treated according to the Chinese Children Leukemia Group 2008 protocol (CCLG-ALL 2008 group) or Chinese Children's Cancer Group 2015 protocol (CCCG-ALL 2015 group). Cumulative incidence of treatment abandonment (TA) at 5 years was 4.2% ± 0.6% and significantly associated with treatment period and risk stratification. The 5-OS and EFS were significantly higher in the CCCG-ALL 2015 group than in the CCLG-ALL 2008 group. Patients treated with CCCG-ALL 2015 from Fujian Medical Union Hospital had a significantly higher 4-year OS and EFS than did those from the other four hospitals. Real-world TA of cALL greatly decreased, and its long-term survival significantly increased in Fujian, which may be related to optimizing programs, multi-center collaboration, and improving treatment compliance.

Covalent organic frameworks derived Single-Atom cobalt catalysts for boosting oxygen reduction reaction in rechargeable Zn-Air batteries.

The design and development of high-performance and long-life Pt-free catalysts for the oxygen reduction reaction (ORR) is of great important with respect to metal-air batteries and fuel cells. Herein, a new low-cost covalent organic frameworks (COFs)-derived CoNC single-atoms catalyst (SAC) is fabricated and compared with the engineered nanoparticle (NP) counterpart for ORR activity. The ORR performance of the SAC catalyst (CoSA@NC) surpasses the NP counterpart (CoNP-NC) under the same operation condition. CoSA@NC also achieves improved long-term durability and better methanol tolerance compared with the Pt/C. The zinc-air battery assembled by the CoSA@NC cathode delivers a higher power density and energy density than that of commercial Pt/C catalyst. Molecular dynamics (MD) is performed to explain the spontaneous evolution from clusters to single-atom metal configuration and density functional theory (DFT) calculations find that CoSA@NC possesses lower d-band center, resulting in weaker interaction between the surface and the O-containing intermediates. Consequently, the reductive desorption of OH*, the rate-determine step, is further accelerated.

A meta-analysis of MRI radiomics-based diagnosis for BI-RADS 4 breast lesions.

OBJECTIVE: The aim of this study is to conduct a systematic evaluation of the diagnostic efficacy of Breast Imaging Reporting and Data System (BI-RADS) 4 benign and malignant breast lesions using magnetic resonance imaging (MRI) radiomics. METHODS: A systematic search identified relevant studies. Eligible studies were screened, assessed for quality, and analyzed for diagnostic accuracy. Subgroup and sensitivity analyses explored heterogeneity, while publication bias, clinical relevance and threshold effect were evaluated. RESULTS: This study analyzed a total of 11 studies involving 1,915 lesions in 1,893 patients with BI-RADS 4 classification. The results showed that the combined sensitivity and specificity of MRI radiomics for diagnosing BI-RADS 4 lesions were 0.88 (95% CI 0.83-0.92) and 0.79 (95% CI 0.72-0.84). The positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were 4.2 (95% CI 3.1-5.7), 0.15 (95% CI: 0.10-0.22), and 29.0 (95% CI 15-55). The summary receiver operating characteristic (SROC) analysis yielded an area under the curve (AUC) of 0.90 (95% CI 0.87-0.92), indicating good diagnostic performance. The study found no significant threshold effect or publication bias, and heterogeneity among studies was attributed to various factors like feature selection algorithm, radiomics algorithms, etc. Overall, the results suggest that MRI radiomics has the potential to improve the diagnostic accuracy of BI-RADS 4 lesions and enhance patient outcomes. CONCLUSION: MRI-based radiomics is highly effective in diagnosing BI-RADS 4 benign and malignant breast lesions, enabling improving patients' medical outcomes and quality of life.

Association of poly(rC)-binding protein-2 with sideroflexin-3 through TOM20 as an iron entry pathway to mitochondria.

Iron is essential for all the lives and mitochondria integrate iron into heme and Fe-S clusters for diverse use as cofactors. Here, we screened mitochondrial proteins in KU812 human chronic myelogenous leukemia cells by glutathione S-transferase pulldown assay with PCBP2 to identify mitochondrial receptors for PCBP2, a major cytosolic Fe(II) chaperone. LC-MS analyses identified TOM20, sideroflexin-3 (SFXN3), SFXN1 and TOM70 in the affinity-score sequence. Stimulated emission depletion microscopy and proteinase-K digestion of mitochondria in HeLa cells revealed that TOM20 is located in the outer membrane of mitochondria whereas SFXN3 is located in the inner membrane. Although direct association was not observed between PCBP2 and SFXN3 with co-immunoprecipitation, proximity ligation assay demonstrated proximal localization of PCBP2 with TOM20 and there was a direct binding between TOM20 and SFXN3. Single knockdown either of PCBP2 and SFXN3 in K562 leukemia cells significantly decreased mitochondrial catalytic Fe(II) and mitochondrial maximal respiration. SFXN3 but not MFRN1 knockout (KO) in mouse embryonic fibroblasts decreased FBXL5 and heme oxygenase-1 (HO-1) but increased transferrin uptake and induced ferritin, indicating that mitochondrial iron entry through SFXN3 is distinct. MFRN1 KO revealed more intense mitochondrial Fe(II) deficiency than SFXN3 KO. Insufficient mitochondrial heme synthesis was evident under iron overload both with SFXN3 and MFRN KO, which was partially reversed by HO-1 inhibitor. Conversely, SFXN3 overexpression caused cytosolic iron deficiency with mitochondrial excess Fe(II), which further sensitized HeLa cells to RSL3-induced ferroptosis. In conclusion, we discovered a novel pathway of iron entry into mitochondria from cytosol through PCBP2-TOM20-SFXN3 axis.

Advancing brain-inspired computing with hybrid neural networks.

Brain-inspired computing, drawing inspiration from the fundamental structure and information-processing mechanisms of the human brain, has gained significant momentum in recent years. It has emerged as a research paradigm centered on brain-computer dual-driven and multi-network integration. One noteworthy instance of this paradigm is the hybrid neural network (HNN), which integrates computer-science-oriented artificial neural networks (ANNs) with neuroscience-oriented spiking neural networks (SNNs). HNNs exhibit distinct advantages in various intelligent tasks, including perception, cognition and learning. This paper presents a comprehensive review of HNNs with an emphasis on their origin, concepts, biological perspective, construction framework and supporting systems. Furthermore, insights and suggestions for potential research directions are provided aiming to propel the advancement of the HNN paradigm.

Clinical manifestation, lifestyle, and treatment patterns of chronic erosive gastritis: A multicenter real-world study in China.

BACKGROUND: Although chronic erosive gastritis (CEG) is common, its clinical characteristics have not been fully elucidated. The lack of consensus regarding its treatment has resulted in varied treatment regimens. AIM: To explore the clinical characteristics, treatment patterns, and short-term outcomes in CEG patients in China. METHODS: We recruited patients with chronic non-atrophic or mild-to-moderate atrophic gastritis with erosion based on endoscopy and pathology. Patients and treating physicians completed a questionnaire regarding history, endoscopic findings, and treatment plans as well as a follow-up questionnaire to investigate changes in symptoms after 4 wk of treatment. RESULTS: Three thousand five hundred sixty-three patients from 42 centers across 24 cities in China were included. Epigastric pain (68.0%), abdominal distension (62.6%), and postprandial fullness (47.5%) were the most common presenting symptoms. Gastritis was classified as chronic non-atrophic in 69.9% of patients. Among those with erosive lesions, 72.1% of patients had lesions in the antrum, 51.0% had multiple lesions, and 67.3% had superficial flat lesions. In patients with epigastric pain, the combination of a mucosal protective agent (MPA) and proton pump inhibitor was more effective. For those with postprandial fullness, acid regurgitation, early satiety, or nausea, a MPA appeared more promising. CONCLUSION: CEG is a multifactorial disease which is common in Asian patients and has non-specific symptoms. Gastroscopy may play a major role in its detection and diagnosis. Treatment should be individualized based on symptom profile.

A review on recent taxonomic updates of gut bacteria associated with social bees, with a curated genomic reference database.

Honeybees and bumblebees play a crucial role as essential pollinators. The special gut microbiome of social bees is a key factor in determining the overall fitness and health of the host. Although bees harbor relatively simple microbial communities at the genus level, recent studies have unveiled significant genetic divergence and variations in gene content within each bacterial genus. However, a comprehensive and refined genomics-based taxonomic database specific to social bee gut microbiomes remains lacking. Here, we first provided an overview of the current knowledge on the distribution and function of social bee gut bacteria, as well as the factors that influence the gut population dynamics. We then consolidated all available genomes of the gut bacteria of social bees and refined the species-level taxonomy, by constructing a maximum-likelihood core genome phylogeny and calculating genome-wide pairwise average nucleotide identity. On the basis of the refined species taxonomy, we constructed a curated genomic reference database, named the bee gut microbe genome sequence database (BGM-GDb). To evaluate the species-profiling performance of the curated BGM-GDb, we retrieved a series of bee gut metagenomic data and inferred the species-level composition using metagenomic intra-species diversity analysis system (MIDAS), and then compared the results with those obtained from a prebuilt MIDAS database. We found that compared with the default database, the BGM-GDb excelled in aligned read counts and bacterial richness. Overall, this high-resolution and precise genomic reference database will facilitate research in understanding the gut community structure of social bees.

Multiomics Analysis of PCB126's Effect on a Mouse Chronic-Binge Alcohol Feeding Model.

BACKGROUND: Environmental pollutants, including polychlorinated biphenyls (PCBs) have been implicated in the pathogenesis of liver disease. Our group recently demonstrated that PCB126 promoted steatosis, hepatomegaly, and modulated intermediary metabolism in a rodent model of alcohol-associated liver disease (ALD). OBJECTIVE: To better understand how PCB126 promoted ALD in our previous model, the current study adopts multiple omics approaches to elucidate potential mechanistic hypotheses. METHODS: Briefly, male C57BL/6J mice were exposed to 0.2mg/kg polychlorinated biphenyl (PCB) 126 or corn oil vehicle prior to ethanol (EtOH) or control diet feeding in the chronic-binge alcohol feeding model. Liver tissues were collected and prepared for mRNA sequencing, phosphoproteomics, and inductively coupled plasma mass spectrometry for metals quantification. RESULTS: Principal component analysis showed that PCB126 uniquely modified the transcriptome in EtOH-fed mice. EtOH feeding alone resulted in >4,000 differentially expressed genes (DEGs), and PCB126 exposure resulted in more DEGs in the EtOH-fed group (907 DEGs) in comparison with the pair-fed group (503 DEGs). Top 20 significant gene ontology (GO) biological processes included "peptidyl tyrosine modifications," whereas top 25 significantly decreasing GO molecular functions included "metal/ion/zinc binding." Quantitative, label-free phosphoproteomics and western blot analysis revealed no major significant PCB126 effects on total phosphorylated tyrosine residues in EtOH-fed mice. Quantified hepatic essential metal levels were primarily significantly lower in EtOH-fed mice. PCB126-exposed mice had significantly lower magnesium, cobalt, and zinc levels in EtOH-fed mice. DISCUSSION: Previous work has demonstrated that PCB126 is a modifying factor in metabolic dysfunction-associated steatotic liver disease (MASLD), and our current work suggests that pollutants also modify ALD. PCB126 may, in part, be contributing to the malnutrition aspect of ALD, where metal deficiency is known to contribute and worsen prognosis. https://doi.org/10.1289/EHP14132.

Optogenetic Stimulation of the Cardiac Vagus Nerve to Promote Heart Regenerative Repair after Myocardial Infarction.

Background: It had been shown that selective cardiac vagal activation holds great potential for heart regeneration. Optogenetics has clinical translation potential as a novel means of modulating targeted neurons. This study aimed to investigate whether cardiac vagal activation via optogenetics could improve heart regenerative repair after myocardial infarction (MI) and to identify the underlying mechanism. Methods: We used an adeno-associated virus (AAV) as the vector to deliver ChR2, a light-sensitive protein, to the left nodose ganglion (LNG). To assess the effects of the cardiac vagus nerve on cardiomyocyte (CM) proliferation and myocardial regeneration in vivo, the light-emitting diode illumination (470 nm) was applied for optogenetic stimulation to perform the gain-of-function experiment and the vagotomy was used as a loss-of-function assay. Finally, sequencing data and molecular biology experiments were analyzed to determine the possible mechanisms by which the cardiac vagus nerve affects myocardial regenerative repair after MI. Results: Absence of cardiac surface vagus nerve after MI was more common in adult hearts with low proliferative capacity, causing a poor prognosis. Gain- and loss-of-function experiments further demonstrated that optogenetic stimulation of the cardiac vagus nerve positively regulated cardiomyocyte (CM) proliferation and myocardial regeneration in vivo. More importantly, optogenetic stimulation attenuated ventricular remodeling and improved cardiac function after MI. Further analysis of sequencing results and flow cytometry revealed that cardiac vagal stimulation activated the IL-10/STAT3 pathway and promoted the polarization of cardiac macrophages to the M2 type, resulting in beneficial cardiac regenerative repair after MI. Conclusions: Targeting the cardiac vagus nerve by optogenetic stimulation induced macrophage M2 polarization by activating the IL-10/STAT3 signaling pathway, which obviously optimized the regenerative microenvironment and then improved cardiac function after MI.