Typical Signaling Research Articles

Epigenetic Effects of Natural Products in Inflammatory Diseases: Recent Findings.

Inflammation is an essential step for the etiology of multiple diseases. Clinically, due to the limitations of current drugs for the treatment of inflammatory diseases, such as serious side effects and expensive costs, it is urgent to explore novel mechanisms and medicines. Natural products have received extensive attention recently because of their multi-component and multi-target characteristics. Epigenetic modifications are crucial pathophysiological targets for developing innovative therapies for pharmacological interventions. Investigations examining how natural products improving inflammation through epigenetic modifications are emerging. This review state that natural products relieve inflammation via regulating the gene transcription levels through chromosome structure regulated by histone acetylation levels and the addition or deletion of methyl groups on DNA duplex. They could also exert anti-inflammatory effects by modulating the proteins in typical inflammatory signaling pathways by ubiquitin-related degradation and the effect of glycolysis derived free glycosyls. Studies on epigenetic modifications have the potential to facilitate the development of natural products as therapeutic agents. Future research directed at better understanding of how natural products modulate inflammatory processes through less studied epigenetic modifications including neddylation, SUMOylation, palmitoylation and lactylation, may provide new implications. Meanwhile, higher quality preclinical studies and more powerful clinical evidence are still needed to firmly establish the clinical efficacy of the natural products. Trial Registration: ClinicalTrials.gov Identifier: NCT01764204; ClinicalTrials.gov Identifier: NCT05845931; ClinicalTrials.gov Identifier: NCT04657926; ClinicalTrials.gov Identifier: NCT02330276.

From Classical to Alternative Pathways of 2-Arachidonoylglycerol Synthesis: AlterAGs at the Crossroad of Endocannabinoid and Lysophospholipid Signaling.

2-arachidonoylglycerol (2-AG) is the most abundant endocannabinoid (EC), acting as a full agonist at both CB1 and CB2 cannabinoid receptors. It is synthesized on demand in postsynaptic membranes through the sequential action of phosphoinositide-specific phospholipase Cβ1 (PLCβ1) and diacylglycerol lipase α (DAGLα), contributing to retrograde signaling upon interaction with presynaptic CB1. However, 2-AG production might also involve various combinations of PLC and DAGL isoforms, as well as additional intracellular pathways implying other enzymes and substrates. Three other alternative pathways of 2-AG synthesis rest on the extracellular cleavage of 2-arachidonoyl-lysophospholipids by three different hydrolases: glycerophosphodiesterase 3 (GDE3), lipid phosphate phosphatases (LPPs), and two members of ecto-nucleotide pyrophosphatase/phosphodiesterases (ENPP6-7). We propose the names of AlterAG-1, -2, and -3 for three pathways sharing an ectocellular localization, allowing them to convert extracellular lysophospholipid mediators into 2-AG, thus inducing typical signaling switches between various G-protein-coupled receptors (GPCRs). This implies the critical importance of the regioisomerism of both lysophospholipid (LPLs) and 2-AG, which is the object of deep analysis within this review. The precise functional roles of AlterAGs are still poorly understood and will require gene invalidation approaches, knowing that both 2-AG and its related lysophospholipids are involved in numerous aspects of physiology and pathology, including cancer, inflammation, immune defenses, obesity, bone development, neurodegeneration, or psychiatric disorders.

The Multiple Roles of Lactate in the Skeletal Muscle.

Believed for a long time to be merely a waste product of cell metabolism, lactate is now considered a molecule with several roles, having metabolic and signalling functions together with a new, recently discovered role as an epigenetic modulator. Lactate produced by the skeletal muscle during physical exercise is conducted to the liver, which uses the metabolite as a gluconeogenic precursor, thus generating the well-known "Cori cycle". Moreover, the presence of lactate in the mitochondria associated with the lactate oxidation complex has become increasingly clear over the years. The signalling role of lactate occurs through binding with the GPR81 receptor, which triggers the typical signalling cascade of the G-protein-coupled receptors. Recently, it has been demonstrated that lactate regulates chromatin state and gene transcription by binding to histones. This review aims to describe the different roles of lactate in skeletal muscle, in both healthy and pathological conditions, and to highlight how lactate can influence muscle regeneration by acting directly on satellite cells.

Phenethyl isothiocyanate inhibits the carcinogenic properties of hepatocellular carcinoma Huh7.5.1 cells by activating MAPK/PI3K-Akt/p53 signaling pathways.

Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited effective treatment options. Phenethyl isothiocyanate (PEITC) is a bioactive substance present primarily in the cruciferous vegetables. PEITC has exhibited anti-cancer properties in various cancers, including lung, bile duct, and prostate cancers. It has been demonstrated that PEITC can inhibit the proliferation, invasion, and metastasis of SK-Hep1 cells, while effectively inducing apoptosis and cell cycle arrest in HepG2 cells. However, knowledge of its anti-carcinogenic effects on Huh7.5.1 cells and its underlying mechanism remains elusive. In the present study, we aim to evaluate the anti-carcinogenic effects of PEITC on human HCC Huh7.5.1 cells. MTT assay and colony formation assay was performed to investigate the anti-proliferative effects of PEITC against Huh7.5.1 cells. The pro-apoptosis effects of PEITC were determined by Annexin V-FITC/PI double staining assay by flow cytometry (FCM), mitochondrial transmembrane potential (MMP) measurement, and Caspase-3 activity detection. A DAPI staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay was conducted to estimate the DNA damage in Huh7.5.1 cells induced by PEITC. Cell cycle progression was determined by FCM. Transwell invasion assay and wound healing migration assay were performed to investigate the impact of PEITC on the migration and invasion of Huh7.5.1 cells. In addition, transcriptome sequencing and gene set enrichment analysis (GSEA) were used to explore the potential molecular mechanisms of the inhibitory effects of PEITC on HCC. Quantitative real-time PCR (qRT-PCR) analysis was performed to verify the transcriptome data. MTT assay showed that treatment of Huh7.5.1 cells with PEITC resulted in a dose-dependent decrease in viability, and colony formation assay further confirmed its anti-proliferative effect. Furthermore, we found that PEITC could induce mitochondrial-related apoptotic responses, including a decrease of mitochondrial transmembrane potential, activation of Caspase-3 activity, and generation of intracellular reactive oxygen species. It was also observed that PEITC caused DNA damage and cell cycle arrest in the S-phase in Huh7.5.1 cells. In addition, the inhibitory effect of PEITC on the migration and invasion ability of Huh7.5.1 cells was assessed. Transcriptome sequencing analysis further suggested that PEITC could activate the typical MAPK, PI3K-Akt, and p53 signaling pathways, revealing the potential mechanism of PEITC in inhibiting the carcinogenic properties of Huh7.5.1 cells. PEITC exhibits anti-carcinogenic activities against human HCC Huh7.5.1 cells by activating MAPK/PI3K-Akt/p53 signaling pathways. Our results suggest that PEITC may be useful for the anti-HCC treatment.

Fisetin Alleviates Inflammation and Oxidative Stress in Deep Vein Thrombosis via MAPK and NRF2 Signaling Pathway.

Oxidative stress and inflammation play pivotal roles in the progression of deep vein thrombosis (DVT). Fisetin has demonstrated promising pharmacological features; however, its underlying mechanisms in DVT remain elusive. In our study, we investigated the effects and underlying mechanisms of Fisetin on a DVT mouse model. The protective effects of Fisetin on DVT were evaluated by comparing the size of thrombosis and detecting the mRNA expression levels of pro-inflammatory cytokines. After that, the biological processes were studied via transcriptomics after Fisetin administration. The antioxidant effect was evaluated and explained via NRF2 signaling pathway. Finally, the anti-inflammatory effect was explained according to KEGG analysis and the final mechanism was verified via Western blot. Our results found that the mRNA expression levels of pro-inflammatory cytokines were inhibited by Fisetin. Moreover, transcriptomic studies suggested that MAPK signaling pathway may be associated with the anti-inflammatory activity of Fisetin. Then, we confirmed that Fisetin administration significantly inhibited the activation of typical pro-inflammatory signaling pathways via Western blot. Finally, the results of Western blot showed that Fisetin significantly activated NRF2 signaling pathway and induced the expression of downstream antioxidant enzymes. Our findings suggested that Fisetin exhibits potential therapeutic effects on DVT through its ability to attenuate inflammation and oxidative stress. The underlying mechanism may involve the suppression of MAPK-mediated inflammatory signaling pathway and activation of NRF2-mediated antioxidant signaling pathway.

EPAC inhibitor suppresses angiogenesis and tumor growth of triple-negative breast cancer

AimsExchange protein directly activated by cAMP 1 (EPAC1), a major isoform of guanine nucleotide exchange factors, is highly expressed in vascular endothelia cells and regulates angiogenesis in the retina. High intratumor microvascular densities (MVD) resulting from angiogenesis is responsible for breast cancer development. Downregulation of EPAC1 in tumor cell reduces triple-negative breast cancer (TNBC)-induced angiogenesis. However, whether Epac1 expressed in vascular endothelial cells contributes to angiogenesis and tumor development of TNBC remains elusive. Main methodsWe employed NY0123, a previously identified potent EPAC inhibitor, to explore the anti-angiogenic biological role of EPAC1 in vitro and in vivo through vascular endothelial cells, rat aortic ring, Matrigel plug, and chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) assays, as well as the in vivo xenograft tumor models of TNBC in both chick embryo and mice. Key findingsInhibiting EPAC1 in vascular endothelial cells by NY0123 significantly suppresses angiogenesis and tumor growth of TNBC. In addition, NY0123 possesses a better inhibitory efficacy than ESI-09, a reported specific EPAC inhibitor tool compound. Importantly, inhibiting EPAC1 in vascular endothelia cells regulates the typical angiogenic signaling network, which is associated with not only vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor-2 (VEGFR2) signaling, but also PI3K/AKT, MEK/ERK and Notch pathway. ConclusionsOur findings support that EPAC1 may serve as an effective anti-angiogenic therapeutic target of TNBC, and EPAC inhibitor NY0123 has the therapeutic potential to be developed for the treatment of TNBC.

The Configuration of GRB2 in Protein Interaction and Signal Transduction.

Growth-factor-receptor-binding protein 2 (GRB2) is a non-enzymatic adaptor protein that plays a pivotal role in precisely regulated signaling cascades from cell surface receptors to cellular responses, including signaling transduction and gene expression. GRB2 binds to numerous target molecules, thereby modulating a complex cell signaling network with diverse functions. The structural characteristics of GRB2 are essential for its functionality, as its multiple domains and interaction mechanisms underpin its role in cellular biology. The typical signaling pathway involving GRB2 is initiated by the ligand stimulation to its receptor tyrosine kinases (RTKs). The activation of RTKs leads to the recruitment of GRB2 through its SH2 domain to the phosphorylated tyrosine residues on the receptor. GRB2, in turn, binds to the Son of Sevenless (SOS) protein through its SH3 domain. This binding facilitates the activation of Ras, a small GTPase, which triggers a cascade of downstream signaling events, ultimately leading to cell proliferation, survival, and differentiation. Further research and exploration into the structure and function of GRB2 hold great potential for providing novel insights and strategies to enhance medical approaches for related diseases. In this review, we provide an outline of the proteins that engage with domains of GRB2, along with the function of different GRB2 domains in governing cellular signaling pathways. This furnishes essential points of current studies for the forthcoming advancement of therapeutic medications aimed at GRB2.

A non-canonical Aux/IAA gene MsIAA32 regulates peltate glandular trichome development in spearmint.

Phytohormone auxin controls various aspects of plant growth and development. The typical auxin signalling involves the degradation of canonical Aux/IAA proteins upon auxin perception releasing the auxin response factors (ARF) to activate auxin-regulated gene expression. Extensive research has been pursued in deciphering the role of canonical Aux/IAAs, however, the function of non-canonical Aux/IAA genes remains elusive. Here we identified a non-canonical Aux/IAA gene, MsIAA32 from spearmint (Mentha spicata), which lacks the TIR1-binding domain and shows its involvement in the development of peltate glandular trichomes (PGT), which are the sites for production and storage of commercially important essential oils. Using yeast two-hybrid studies, two canonical Aux/IAAs, MsIAA3, MsIAA4 and an ARF, MsARF3 were identified as the preferred binding partners of MsIAA32. Expression of a R2R3-MYB gene MsMYB36 and a cyclin gene MsCycB2-4 was altered in MsIAA32 suppressed plants indicating that these genes are possible downstream targets of MsIAA32 mediated signalling. Ectopic expression of MsIAA32 in Arabidopsis affected non-glandular trichome formation along with other auxin related developmental traits. Our findings establish the role of non-canonical Aux/IAA mediated auxin signalling in PGT development and reveal species-specific functionalization of Aux/IAAs.

The Molecular Mechanism Underlying the Therapeutic Effect of Dihydromyricetin on Type 2 Diabetes Mellitus Based on Network Pharmacology, Molecular Docking, and Transcriptomics.

Type 2 diabetes mellitus (T2DM) is a chronic and complex disease, and traditional drugs have many side effects. The active compound dihydromyricetin (DHM), derived from natural plants, has been shown in our previous study to possess the potential for reducing blood glucose levels; however, its precise molecular mechanism remains unclear. In the present study, network pharmacology and transcriptomics were performed to screen the molecular targets and signaling pathways of DHM disturbed associated with T2DM, and the results were partially verified by molecular docking, RT-PCR, and Western blotting at in vivo levels. Firstly, the effect of DHM on blood glucose, lipid profile, and liver oxidative stress in db/db mice was explored and the results showed that DHM could reduce blood glucose and improve oxidative stress in the liver. Secondly, GO analysis based on network pharmacology and transcriptomics results showed that DHM mainly played a significant role in anti-inflammatory, antioxidant, and fatty acid metabolism in biological processes, on lipoprotein and respiratory chain on cell components, and on redox-related enzyme activity, iron ion binding, and glutathione transferase on molecular functional processes. KEGG system analysis results showed that the PI3K-Akt signaling pathway, IL17 signaling pathway, HIF signaling pathway, MAPK signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and TNF signaling pathway were typical signaling pathways disturbed by DHM in T2DM. Thirdly, molecular docking results showed that VEGFA, SRC, HIF1A, ESR1, KDR, MMP9, PPARG, and MAPK14 are key target genes, five genes of which were verified by RT-PCR in a dose-dependent manner. Finally, Western blotting results revealed that DHM effectively upregulated the expression of AKT protein and downregulated the expression of MEK protein in the liver of db/db mice. Therefore, our study found that DHM played a therapeutic effect partially by activation of the PI3K/AKT/MAPK signaling pathway. This study establishes the foundation for DHM as a novel therapeutic agent for T2DM. Additionally, it presents a fresh approach to utilizing natural plant extracts for chemoprevention and treatment of T2DM.

USP14 promotes the proliferation of cervical cancer via upregulating β-catenin.

In recent years, the ubiquitin-proteasome system (UPS) has become a hot spot in medical research in cervical cancer (CC) and has received extensive attention. Among them, ubiquitin-specific protease 14 (USP14) is involved in a wide variety of typical cell signaling pathways and is recognized to be involved in the progression of most known tumors. However, the expression and significance of USP14 in CC have not been directly studied. Through database analysis, we found that USP14 was overexpressed in CC, which influenced the FIGO stage and prognosis of CC patients, and it was positively correlated with the expression level of β-catenin. In this study, USP14 promoted the G1-S phase transition of Hela and Siha cells and inhibited cell apoptosis, thereby promoting the proliferation, migration, and invasion of CC cells. In addition, USP14 also significantly promoted the growth of subcutaneous tumor in nude mice. We also found that overexpression of USP14 significantly upregulated β-catenin expression and increased the activity of Wnt/β-catenin signaling pathway. While knockdown of USP14 resulted in the opposite. These results suggest that USP14 may promote the proliferation of CC by up-regulating the expression of β-catenin, contributing to a deeper understanding of the mechanisms of CC and providing a potential therapeutic target.

Atlas of the anatomical localization of atypical chemokine receptors in healthy mice.

Atypical chemokine receptors (ACKRs) scavenge chemokines and can contribute to gradient formation by binding, internalizing, and delivering chemokines for lysosomal degradation. ACKRs do not couple to G-proteins and fail to induce typical signaling induced by chemokine receptors. ACKR3, which binds and scavenges CXCL12 and CXCL11, is known to be expressed in vascular endothelium, where it has immediate access to circulating chemokines. ACKR4, which binds and scavenges CCL19, CCL20, CCL21, CCL22, and CCL25, has also been detected in lymphatic and blood vessels of secondary lymphoid organs, where it clears chemokines to facilitate cell migration. Recently, GPR182, a novel ACKR-like scavenger receptor, has been identified and partially deorphanized. Multiple studies point towards the potential coexpression of these 3 ACKRs, which all interact with homeostatic chemokines, in defined cellular microenvironments of several organs. However, an extensive map of ACKR3, ACKR4, and GPR182 expression in mice has been missing. In order to reliably detect ACKR expression and coexpression, in the absence of specific anti-ACKR antibodies, we generated fluorescent reporter mice, ACKR3GFP/+, ACKR4GFP/+, GPR182mCherry/+, and engineered fluorescently labeled ACKR-selective chimeric chemokines for in vivo uptake. Our study on young healthy mice revealed unique and common expression patterns of ACKRs in primary and secondary lymphoid organs, small intestine, colon, liver, and kidney. Furthermore, using chimeric chemokines, we were able to detect distinct zonal expression and activity of ACKR4 and GPR182 in the liver, which suggests their cooperative relationship. This study provides a broad comparative view and a solid stepping stone for future functional explorations of ACKRs based on the microanatomical localization and distinct and cooperative roles of these powerful chemokine scavengers.

Extracellular RNA in melanoma: Advances, challenges, and opportunities.

Melanoma, a malignant mass lesion that originates in melanocytes and has a high rate of malignancy, metastasis, and mortality, is defined by these characteristics. Malignant melanoma is a kind of highly malignant tumor that produces melanin and has a high mortality rate. Its incidence accounts for 1%-3% of all malignant tumors and shows an obvious upward trend. The discovery of biomolecules for the diagnosis and treatment of malignant melanoma has important application value. So far, the exact molecular mechanism of melanoma development relevant signal pathway still remains unclear. According to previous studies, extracellular RNAs (exRNAs) have been implicated in tumorigenesis and spread of melanoma. They can influence the proliferation, invasion and metastasis of melanoma by controlling the expression of target genes and can also influence tumor progression by participating in signal transduction mechanisms. Therefore, understanding the relationship between exRNA and malignant melanoma and targeting therapy is of positive significance for its prevention and treatment. In this review, we did an analysis of extracellular vesicles of melanoma which focused on the role of exRNAs (lncRNAs, miRNAs, and mRNAs) and identifies several potential therapeutic targets. In addition, we discuss the typical signaling pathways involved in exRNAs, advances in exRNA detection and how they affect the tumor immune microenvironment in melanoma.

Inoculation of ACC deaminase-producing endophytic bacteria down-regulates ethylene-induced pathogenesis-related signaling in red pepper (Capsicum annuum L.) under salt stress.

Pathogenesis-related (PR) signaling plays multiple roles in plant development under abiotic and biotic stress conditions and is regulated by a plethora of plant physiological as well as external factors. Here, our study was conducted to evaluate the role of an ACC deaminase-producing endophytic bacteria in regulating ethylene-induced PR signaling in red pepper plants under salt stress. We also evaluated the efficiency of the bacteria in down-regulating the PR signaling for efficient colonization and persistence in the plant endosphere. We used a characteristic endophyte, Methylobacterium oryzae CBMB20 and its ACC deaminase knockdown mutant (acdS- ). The wild-type M. oryzae CBMB20 was able to decrease ethylene emission by 23% compared to the noninoculated and acdS- M. oryzae CBMB20 inoculated plants under salt stress. The increase in ethylene emission resulted in enhanced hydrogen peroxide concentration, phenylalanine ammonia-lyase activity, β-1,3 glucanase activity, and expression profiles of WRKY, CaPR1, and CaPTI1 genes that are typical salt stress and PR signaling factors. Furthermore, the inoculation of both the bacterial strains had shown induction of PR signaling under normal conditions during the initial inoculation period. However, wild-type M. oryzae CBMB20 was able to down-regulate the ethylene-induced PR signaling under salt stress and enhance plant growth and stress tolerance. Collectively, ACC deaminase-producing endophytic bacteria down-regulate the salt stress-mediated PR signaling in plants by regulating the stress ethylene emission levels and this suggests a new paradigm in efficient colonization and persistence of ACC deaminase-producing endophytic bacteria for better plant growth and productivity.

SAG, a sonic hedgehog signaling agonist, alleviates anxiety behavior in high-fat diet-fed mice

Anxiety is a prevalent and disabling psychiatric disorder. Mitochondrial dysfunction due to the high-fat diet (HFD) was regarded as a risk factor in the pathogenesis of anxiety. The Sonic hedgehog (SHH) pathway was known to improve mitochondrial dysfunction through antioxidant and anti-apoptotic effects on some neurological diseases. Nonetheless, its effect on anxiety has not been well studied. In this study, we aimed to explore whether SHH signaling pathway plays a protective role in anxiety by regulating mitochondrial homeostasis. SAG, a typical SHH signaling agonist, was administered intraperitoneally in HFD-fed mice. HFD-induced anxiety-like behavior in mice was confirmed using the open field and elevated plus maze tests. Immunofluorescence staining and Western blotting assays showed that the SHH signaling was downregulated in the prefrontal cortex neurons from HFD-fed mice. Electron microscopy results showed the mitochondria in the prefrontal cortex of HFD-fed mice were fragmented, which appeared small and spherical, and the area, perimeter and circularity of mitochondria were decreased. Mitofusin2 (Mfn2) and dynamin-related protein 1 (Drp1) were the key proteins involved in mitochondrial division and fusion. SAG treatment could rectify the imbalanced expression of Mfn2 and Drp1 in the prefrontal cortex of the HFD-fed mice, and alleviate the mitochondrial fragmentation. Furthermore, SAG decreased anxiety-like behavior in the HFD-fed mice. These findings suggested that SHH signal was neuroprotective in obesity and SAG relieved anxiety-like behavior through reducing mitochondrial fragmentation.

Novel insights into the mechanism of reactive oxygen species-mediated neurodegeneration.

Neurite degeneration, a major component of many neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, is not part of the typical apoptosis signaling mechanism, but rather it appears that a self-destructive process is in action. Oxidative stress is a well-known inducer of neurodegenerative pathways: neuronal cell death and neurite degeneration. Although oxidative stress exerts cytotoxic effects leading to neuronal loss, the pathogenic mechanisms and precise signaling pathways by which oxidative stress causes neurite degeneration have remained entirely unknown. We previously reported that reactive oxygen species generated by NADPH oxidases induce activation of the E3 ubiquitin ligase ZNRF1 in neurons, which promotes neurite degeneration. In this process, the phosphorylation of an NADPH oxidase subunit p47-phox at the 345th serine residue serves as an important checkpoint to initiate the ZNRF1-dependent neurite degeneration. Evidence provides new insights into the mechanism of reactive oxygen species-mediated neurodegeneration. In this review, we focus specifically on reactive oxygen species-induced neurite degeneration by highlighting a phosphorylation-dependent regulation of the molecular interaction between ZNRF1 and the NADPH oxidase complex.

Stability improvement and the mechanism of a microbial electrolysis cell biocathode for treating wastewater containing sulfate by quorum sensing

The treatment of sulfate-containing wastewater by microbial electrolysis cells (MEC) is a feasible method, but the biocathode suffers from poor microbial stability. The phenomenon of quorum sensing (QS) has offered the opportunity to overcome these weaknesses. Nevertheless, it has not been well evaluated how QS improves microbial stability performance and which enzymes and genes influence microbial activity. In this study, N-butyryl-l-Homoserine lactone (C4-HSL) was added as a typical QS signaling molecule to the biocathode in MEC. Sulfate reduction efficiency, microbial community structure, and related functional genes were analyzed comprehensively. The results showed that the sulfate reduction efficiency and biocathode stability were higher under the regulation of C4-HSL. Results indicated that the number of microorganisms on the electrode surface was more than that of the control group, and the percentage of live cells was 22% higher after the regulation by C4-HSL. In addition, the C4-HSL regulation stimulated the growth of the hydrogen producer (Desulfomicrobium), Homoacetogens (Acetoanaerobium), and part of Anaerobic fermentation bacteria (Macellibacteroides and Lentimicrobium). Metagenomic sequencing elucidated the phenomenon of QS mainly through an exponential increase in autoinducer-producer-related genes and cysteine/methionine metabolism pathways. The regulation by C4-HSL mainly affected genes controlling surface proteins and biofilm formation, which resulted in higher activity and more stability of biofilms. And the relative abundance of functional genes associated with sulfate reduction metabolism was increased, which positively affected the assimilatory sulfate reduction and dissimilatory sulfate reduction pathways. These findings reveal the potential and mechanisms of the QS signaling molecule in enhancing MEC for sulfate-containing wastewater treatment.

Sodium Tanshinone IIA Sulfonate Inhibits Vascular Endothelial Cell Pyroptosis via the AMPK Signaling Pathway in Atherosclerosis.

Atherosclerosis (AS) is the underlying cause of cardiovascular events. Endothelial cell mitochondrial damage and pyroptosis are important factors contributing to AS. Changes in internal mitochondrial conformation and increase in reactive oxygen species (ROS) lead to the disruption of mitochondrial energy metabolism, activation of the NLRP3 inflammasome and pyroptosis, which in turn affect atherogenesis by impairing endothelial function. AMPK is a core player in the regulation of cellular metabolism, not only by regulating mitochondrial homeostasis but also by regulating cellular inflammatory responses. Sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, has significant antioxidant and anti-inflammatory effects, and roles in cardiovascular protection. In this study, we investigated whether STS plays a protective role in AS by regulating endothelial cell mitochondrial function and pyroptosis through an AMPK-dependent mitochondrial pathway. Male ApoE-/- mice and HUVECs were used for the experiments. We found that STS treatment largely abrogated the upregulation of key proteins in aortic vessel wall plaques and typical pyroptosis signaling in ApoE-/- mice fed a western diet, consequently enhancing pAMPK expression, plaque stabilization, and anti-inflammatory responses. Consistently, STS pretreatment inhibited cholesterol crystallization (CC) -induced cell pyroptosis and activated pAMPK expression. In vitro, using HUVECs, we further found that STS treatment ameliorated mitochondrial ROS caused by CC, as evidenced by the finding that STS inhibited mitochondrial damage caused by CC. The improvement of endothelial cell mitochondrial function by STS is blocked by dorsomorphin (AMPK inhibitor). Consistently, the blockade of endothelial cell pyroptosis by STS is disrupted by dorsomorphin. Our results suggest that STS enhances maintenance of mitochondrial homeostasis and inhibits mitochondrial ROS overproduction via AMPK, thereby improving endothelial cell pyroptosis during AS.

Reprogramming of three-dimensional microenvironments for in vitro hair follicle induction.

During embryonic development, reciprocal interactions between epidermal and mesenchymal layers trigger hair follicle morphogenesis. This study revealed that microenvironmental reprogramming via control over these interactions enabled hair follicle induction in vitro. A key approach is to modulate spatial distributions of epithelial and mesenchymal cells in their spontaneous organization. The de novo hair follicles with typical morphological features emerged in aggregates of the two cell types, termed hair follicloids, and hair shafts sprouted with near 100% efficiency in vitro. The hair shaft length reached ~3 mm in culture. Typical trichogenic signaling pathways were up-regulated in hair follicloids. Owing to replication of hair follicle morphogenesis in vitro, melanosome production and transportation were also monitored in the hair bulb region. This in vitro hair follicle model might be valuable for better understanding hair follicle induction, evaluating hair growth and inhibition of hair growth by drugs, and modeling gray hairs in a well-defined environment.

WNT6 participates in the occurrence and development of ovarian cancer by upregulating/activating the typical Wnt pathway and Notch1 signaling pathway

Wnt/β-catenin pathway is associated with the progression of various cancers such as gastric cancer, colorectal cancer, and endometrial cancer. Using the Kaplan-Meier Plotter database, we found that WNT6 was associated with progression-free survival (PFS) outcomes. Immunohistochemical analysis of ovarian cancer samples and normal ovaries showed that the expression of WNT6 protein was significantly increased in ovarian cancer samples. Further, we explored the possible role of WNT6 in the occurrence and development of ovarian cancer. Our results showed that the mRNA and protein expression of WNT6 were significantly higher in CAOV3 and OVCAR3 cells compared with other ovarian cancer cell lines and normal ovarian cell line IOSE-80 as well. The transformation of CAOV3 and OVCAR3 cells with short interfering WNT6 (siWNT6) significantly inhibited their proliferation and lamellipodia formation, causing cell cycle arrest and promoting cell apoptosis. Western blot experiments confirmed that the down-regulation of WNT6 inhibited the expression of β-catenin and Notch1. These results suggest that WNT6 plays an important role in the occurrence and development of ovarian cancer.

Oncogenic signaling pathway dysregulation landscape reveals the role of pathways at multiple omics levels in pan-cancer.

Dysregulation of signaling pathways plays an essential role in cancer. However, there is not a comprehensive understanding on how oncogenic signaling pathways affect the occurrence and development with a common molecular mechanism of pan-cancer. Here, we investigated the oncogenic signaling pathway dysregulation by using multi-omics data on patients from TCGA from a pan-cancer perspective to identify commonalities across different cancer types. First, the pathway dysregulation profile was constructed by integrating typical oncogenic signaling pathways and the gene expression of TCGA samples, and four molecular subtypes with significant phenotypic and clinical differences induced by different oncogenic signaling pathways were identified: TGF-β+ subtype; cell cycle, MYC, and NF2− subtype; cell cycle and TP53+ subtype; and TGF-β and TP53− subtype. Patients in the TGF-β+ subtype have the best prognosis; meanwhile, the TGF-β+ subtype is associated with hypomethylation. Moreover, there is a higher level of immune cell infiltration but a slightly worse survival prognosis in the cell cycle, MYC, and NF2− subtype patients due to the effect of T-cell dysfunction. Then, the prognosis and subtype classifiers constructed by differential genes on a multi-omics level show great performance, indicating that these genes can be considered as biomarkers with potential therapeutic and prognostic significance for cancers. In summary, our study identified four oncogenic signaling pathway–driven patterns presented as molecular subtypes and their related potential prognostic biomarkers by integrating multiple omics data. Our discovery provides a perspective for understanding the role of oncogenic signaling pathways in pan-cancer.