Integration of network pharmacology and transcriptomics to explore the mechanism of isoliquiritigenin in treating heart failure induced by myocardial infarction.

BACKGROUND: The inflammatory response and myocardial remodeling play critical roles in the progression of heart failure (HF) following myocardial infarction (MI). Isoliquiritigenin (ISL) possesses anti-inflammatory properties and has been investigated in cardiovascular diseases such as atherosclerosis. However, the effects and mechanism of ISL on MI-induced HF remain unclear. This research aimed to explore the effects and mechanism of ISL in the treatment of HF on the basis of network pharmacology, transcriptomics, and experimental verification. METHODS AND RESULTS: We established an MI-induced HF mouse model in which ISL was administered via gavage for 28 days. Ultrasonic cardiogram data were collected from the mice, and pathological staining was conducted. Then, network pharmacology and molecular docking were performed. Transcriptomic analysis was also conducted on mouse myocardial tissue. Ultimately, we integrated transcriptomic data and network pharmacology to reveal the underlying mechanism, with the results verified through in vivo experiments. Our experiments indicated that ISL improved cardiac function, preserved myocardial structure, inhibited collagen fiber accumulation, reduced inflammatory factor secretion, and mitigated myocardial cell apoptosis in mice with MI-induced HF. A combination of transcriptomics and network pharmacology analysis revealed that core targets of ISL related to HF were significantly enriched in the Tumor Necrosis Factor (TNF) signaling pathway. Molecular docking validation demonstrated that ISL shows strong binding to these core targets. Additionally, in vivo experiments verified that ISL protects against HF post-MI by inhibiting the TNF signaling pathway. CONCLUSION: We clarified the anti-inflammatory and antimyocardial remodeling mechanisms of ISL in the treatment of HF post-MI, which involves the TNF signaling pathway.

cGAS-STING, inflammasomes and pyroptosis: an overview of crosstalk mechanism of activation and regulation.

BACKGROUND: Intracellular DNA-sensing pathway cGAS-STING, inflammasomes and pyroptosis act as critical natural immune signaling axes for microbial infection, chronic inflammation, cancer progression and organ degeneration, but the mechanism and regulation of the crosstalk network remain unclear. Cellular stress disrupts mitochondrial homeostasis, facilitates the opening of mitochondrial permeability transition pore and the leakage of mitochondrial DNA to cell membrane, triggers inflammatory responses by activating cGAS-STING signaling, and subsequently induces inflammasomes activation and the onset of pyroptosis. Meanwhile, the inflammasome-associated protein caspase-1, Gasdermin D, the CARD domain of ASC and the potassium channel are involved in regulating cGAS-STING pathway. Importantly, this crosstalk network has a cascade amplification effect that exacerbates the immuno-inflammatory response, worsening the pathological process of inflammatory and autoimmune diseases. Given the importance of this crosstalk network of cGAS-STING, inflammasomes and pyroptosis in the regulation of innate immunity, it is emerging as a new avenue to explore the mechanisms of multiple disease pathogenesis. Therefore, efforts to define strategies to selectively modulate cGAS-STING, inflammasomes and pyroptosis in different disease settings have been or are ongoing. In this review, we will describe how this mechanistic understanding is driving possible therapeutics targeting this crosstalk network, focusing on the interacting or regulatory proteins, pathways, and a regulatory mitochondrial hub between cGAS-STING, inflammasomes, and pyroptosis. SHORT CONCLUSION: This review aims to provide insight into the critical roles and regulatory mechanisms of the crosstalk network of cGAS-STING, inflammasomes and pyroptosis, and to highlight some promising directions for future research and intervention.

Berberine Ameliorates High-fat-induced Insulin Resistance in HepG2 Cells by Modulating PPARs Signaling Pathway.

BACKGROUND: Berberine (BBR), also known as berberine hydrochloride, was isolated from the rhizomes of the Coptis chinensis. Studies have reported that BBR plays an important role in glycolipid metabolism, including insulin (IR). The targets, and molecular mechanisms of BBR against hyperlipid-induced IR is worthy to be further studied. MATERIAL AND METHODS: The related targets of BBR were identified via Pharmmapper database and relevant targets of diabetes were obtained through GeneCards and Online Mendelian Inheritance in Man (OMIM) database. The common targets were employed with the STRING database and visualized with the protein-protein interactions (PPI) network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed to explore the biological progress and pathways. In vitro, human hepatocellular carcinomas (HepG2) cell was used as experimental cell line, and an insulin resistant HepG2 cell model (IR-HepG2) was constructed using free fatty acid induction. After intervention with BBR, glucose consumption and uptake in HepG2 cells were observed. Molecular docking was used to test the interaction between BBR and key targets, and real-time fluorescence quantitative PCR was used to detect the regulatory effect of BBR on related targets. RESULTS: 262 overlapped targets were extracted from BBR and diabetes. In the KEGG enrichment analysis, the peroxisome proliferator activated receptor (PPAR) signaling pathway was included. In vitro experiments, BBR can significantly increase sugar consumption and uptake in IR HepG2 cells, while PPAR inhibitors can weaken the effect of BBR on IR-HepG2. CONCLUSION: The PPAR signaling pathway is one of the important pathways for BBR to improve high-fat-induced insulin resistance in HepG2 cells.

A review on micro- and nanoplastics in humans: Implication for their translocation of barriers and potential health effects.

As emerging contaminants, micro- and nanoplastics (MNPs) can absorb and leach various toxic chemicals and ultimately endanger the health of the ecological environment and humans. With extensive research on MNPs, knowledge about MNPs in humans, especially their translocation of barriers and potential health effects, is of utmost importance. In this review, we collected literature published from 2000 to 2023, focusing on MNPs on their occurrence in humans, penetrating characteristics in the placental, blood-brain, and blood-testis barriers, and exposure effects on mammalian health. The characteristics and distributions of MNPs in human samples were analyzed, and the results demonstrated that MNPs were ubiquitous in most human samples, except for kidneys and cerebrospinal fluid. In addition, the phenomenon of MNPs crossing barriers and their underlying mechanisms were discussed. We also summarized the potential factors that may affect the barrier crossing and health effects of MNPs, including characteristics of MNPs, exposure doses, administration routes, exposure durations, co-exposure to other pollutants, and genetic predisposition. Exposure to MNPs may cause cytotoxicity, neurotoxicity, and developmental and reproductive toxicity in mammals. People are encouraged to reduce their exposure to MNPs to prevent these adverse health effects. Finally, we discussed the shortcomings of current research on MNPs in humans, providing a valuable reference for understanding and evaluating the potential health risks from MNP exposure in mammals, including humans.

Identification of Dalbergiae Odoriferae Lignum active ingredients and potential mechanisms in the treatment of adriamycin-induced cardiotoxicity based on network pharmacology and experimental verification.

The purpose of this study is to investigate the ingredients and mechanisms through which Dalbergiae Odoriferae Lignum (DOL) reduces adriamycin-induced cardiotoxicity. DOL's ingredients and drug targets were acquired from Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), and adriamycin-induced cardiotoxicity disease targets were gathered from GeneCards and National Center for Biotechnology Information (NCBI). The therapeutic targets of DOL against adriamycin-induced cardiotoxicity were identified by intersecting drug and disease targets. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) were conducted using R. Subsequently, core targets were determined and used for molecular docking with DOL ingredients. In vitro and in vivo experiments validated DOL's primary ingredients against adriamycin-induced cardiotoxicity efficacy. Western blot and immunohistochemistry verified its impact on target protein. After intersecting 530 drug targets and 51 disease targets, 19 therapeutic targets for DOL alleviated adriamycin-induced cardiotoxicity were received. Molecular docking demonstrated that DOL primary ingredient formononetin had a robust binding affinity for nitric oxide synthase 3 (NOS3). Experimental results showed that formononetin effectively mitigated adriamycin-induced cardiotoxicity. Additionally, western blot and immunohistochemistry showed that formononetin improved NOS3 expression. The network pharmacology and experimentation suggest that the primary ingredient of DOL, formononetin, may target NOS3 to act as a therapeutic agent for adriamycin-induced cardiotoxicity.

Exposure to per- and polyfluoroalkyl substances in lung cancer patients and their associations with clinical health indicators.

Per- and polyfluoroalkyl substances (PFASs) have potential carcinogenicity, immunotoxicity, and hepatotoxicity. Research has been conducted on PFAS exposure in people to discuss their potential health effects, excluding lung cancer. In this study, we recruited participants (n = 282) with lung cancer from Heilongjiang Province, northeast China. The PFAS concentrations were measured in their serum to fill the data gap of exposure, and relationships were explored in levels between PFASs and clinical indicators of tumor, immune and liver function. Ten PFASs were found in over 80 % of samples and their total concentrations were 5.27-152 ng/mL, with the highest level for perfluorooctanesulfonate (median: 12.4 ng/mL). Long-chain PFASs were the main congeners and their median concentration (20.5 ng/mL) was nearly three times to that of short-chain PFASs (7.61 ng/mL). Significantly higher concentrations of perfluorobutanoic acid, perfluorononanoic acid and perfluorohexanesulfonate were found in males than in females (p < 0.05). Serum levels of neuro-specific enolase were positively associated with perfluoropentanoic acid in all participants and were negatively associated with perfluorononanesulfonate in females (p < 0.05, multiple linear regression models). Exposure to PFAS mixture was significantly positively associated with the lymphocytic absolute value (difference: 0.224, 95% CI: 0.018, 0.470; p < 0.05, quantile g-computation models) and serum total bilirubin (difference: 2.177, 95% CI: 0.0335, 4.33; p < 0.05). Moreover, PFAS exposure can affect γ-glutamyl transpeptidase through several immune markers (p < 0.05, mediating test). Our results suggest that exposure to certain PFASs could interfere with clinical indicators in lung cancer patients. To our knowledge, this is the first study to detect serum PFAS occurrence and check their associations with clinical indicators in lung cancer patients.

Triclosan in paired-maternal and cord blood, and their relationships with congenital heart disease of baby.

Prenatal triclosan (TCS) exposure has been reported to be associated with various birth outcomes and thyroid function, while the study of TCS exposure for congenital heart disease (CHD) patients is limited. In the present study, paired mother-fetus blood samples from CHD and healthy participants were collected to measure TCS exposure levels, and then check their relationship. Coupled with the concentrations of thyroid function biomarkers [free thyroxine (FT4), free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), and thyroid antibodies (TgAb)] in maternal blood, we aimed to investigate whether the hormone-disrupting properties of TCS will affect its association with CHD. Our results indicated that the maternal TCS concentrations in the CHD group (median 0.31 ng/mL) were significantly lower than those in the control group (0.48 ng/mL, Mann Whitney U test, p = 0.01). Higher interquartile of TCS levels in maternal blood was associated with decrease odds of CHD (adjusted OR = 0.61, 95%CI: 0.41-0.91, p = 0.02). Maternal blood TCS higher than the cut-off value (25th quantile, 0.17 ng/mL) was significantly negatively associated with CHD risk (adjusted OR = 0.24, 95%CI: 0.09-0.62, p < 0.01). Besides, none of the thyroid biomarkers were significantly associated with maternal TCS exposure. However, maternal FT4 concentrations were positively correlated with TCS transplacental transfer rate and cord blood TCS levels (general linear regression, both p < 0.01). The results of molecular docking and dynamics simulation suggested that these correlations might be related to the transthyretin, a thyroid hormone-binding protein involved in the placental thyroid hormone transport system. Overall, our findings indicated that at normal exposure levels, the increase of maternal blood TCS concentration may have an inverse association with CHD, which merits further investigation.

Long-term stability of several endocrine disruptors in the first morning urine samples and their associations with lifestyle characteristics.

Parabens, triclosan (TCS), bisphenols, benzophenones, and phthalates are typical endocrine disruptors (EDs) with short half-lives in the human body. The concentration levels of those EDs in a spot urine sample are frequently used in exposure assessment studies, and the reproducibility of urinary levels of these nonpersistent EDs should be considered. In the present study, we consecutively collected 45-day first morning void (FMV) urine samples, as well as daily questionnaires, in six recruited participants and measured the urinary concentrations of six parabens, TCS, nine bisphenols, five benzophenones, and ten phthalate metabolites by using high-performance liquid chromatography-tandem mass spectrometry. MeP, EtP, PrP, TCS, BPA, BPS, BPF, and most phthalate metabolites were frequently detected (over 62 % of samples). The intraclass correlation coefficients (ICCs) for ED concentrations in FMV urine samples ranged from fair to excellent for MeP (0.683), EtP (0.702), BPA (0.505), BPS (0.908), BPF (0.887), BP-3 (0.712), mMP (0.661), mEP (0.523), mBP (0.500), miBP (0.724), mBzP (0.961) and all metabolites of DEHP (0.867-0.957), whereas they were low for PrP (0.321) and TCS (0.306). After creatinine adjustment, the values of ICCs for most target EDs were increased with mild to significant improvement. The stability of ED concentrations was affected by daily diet (MeP, TCS, BPA, mMP, miBP, mBP and mBzP), food containers (PrP and mECPP), use of personal care products (HMWP metabolites), pharmaceuticals (EtP) and recorded activities (BPS, mEHP, mBzP, mEHHP and mEOHP), as confirmed by a general linear mixed model. Furthermore, extending the FMV sampling period improved the probability of acceptable reproducibility (ICCs > 0.40) of MeP, EtP, BP-3 and mEP concentrations. For BPS, BPF and HMWP metabolite concentrations showed high probabilities (>80 %) of acceptable reproducibility in the last three days, and the increasing sample size slowly improved the ability to discriminate the subjects. The results were exactly the opposite for BPA concentrations.