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Doxorubicin (Dox) has been limited in clinical application due to its cardiac toxicity that varies with the dose. This study aimed to explore how Rhein modulates Dox-induced myocardial toxicity. The general condition and echocardiographic changes of mice were observed to evaluate cardiac function and structure, with myocardial cell injury and apoptosis checked by TUNEL and HE staining. The ELISA assessed markers of myocardial damage and inflammation. The TCMSP and SwissTargetPrediction databases were used to retrieve Rhein's targets while GeneCards was used to find genes related to Dox-induced myocardial injury. Intersection genes were analyzed by Protein-Protein Interaction Networks. The core network genes underwent GO and KEGG enrichment analysis using R software. Western blot was used to detect protein expression. Compared to the Dox group, there was no remarkable difference in heart mass /body mass ratio in the Rhein+Dox group. However, heart mass/tibia length increased. Mice in the Rhein+Dox group had significantly increased LVEF, LVPWs, and LVFS compared to those in the Dox group. Myocardial cell damage, inflammation, and apoptosis significantly reduced in the Rhein+Dox group compared to the model group. Eleven core network genes were selected. Further, Rhein+Dox group showed significantly downregulated expression of p38/p-p38, HSP90AA1, c-Jun/p-c-Jun, c-Fos/p-c-Fos, Bax, and cleaved-caspase-3/caspase-3 while Bcl-2 expression significantly upregulated compared to the Dox group. The study suggests that Rhein mediates cardioprotection against Dox-induced myocardial injury, at least partly, by influencing multiple core genes in the MAPK signaling pathway to inhibit myocardial cell apoptosis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The primary cilium is a characteristic feature of most non-immune cells and functions as an environmental signal transduction sensor. The defects in primary cilium have profound effects on the developmental program, including the maturation of retinal epithelium. The ciliary length is tightly regulated during ciliogenesis, but the impact of inflammation on ciliary length remains elusive. The current study investigates the outcome of inflammatory stimuli for the primary cilium length in retinal epithelium cells and mouse embryonic fibroblasts. Here, we report that exposure to the pro-inflammatory cytokine TNF-alpha elongates cilia in a mixed-lineage kinase (MLK)-dependent manner. Pro-inflammatory stimuli such as bacterial LPS and interferon-gamma have similar effects on ciliary length. In contrast, febrile condition-mimicking heat stress dramatically reduced the number of ciliated cells regardless of TNF-alpha exposure but did not shorten TNF-induced elongation, suggesting distinct but rapid effects of inflammatory stresses on ciliogenesis., (© 2024 Wiley Periodicals LLC.)

Objective: Der f 2, a major allergen derived from Dermatophagoides farinae , is a leading cause of allergic asthma. IL-6 and GM-CSF play essential roles in the exacerbation of asthma. However, the mechanical act by which Der f 2 mediates the expression of IL-6, IL-8, and GM-CSF in airway epithelial cells remains incompletely elucidated. Herein, we aimed to explore the effect of Der f 2 on IL-6 and GM-CSF expression in the human airway epithelial cell BEAS-2B and A549., Methods: Recombinant Der f 2 (rDf2) was acquired using Pichia pastoris . BEAS-2B and A549 cells were used as cell model. The expression of genes and proteins and the involvement of the signaling cascade were assessed using RT-PCR, quantitative real-time PCR (qPCR), Western blotting, and ELISA, respectively., Results: Our findings showed that rDf2 significantly induced mRNA expression and protein production of IL-6 and GM-CSF in BEAS-2B and A549 cells. In contrast, rDf2 did not influence IL-8 expression or production in both cells. Mechanistic studies revealed that rDf2 triggered activation of the p38 MAPK and JNK. Inhibition of p38, but not JNK, significantly attenuated rDf2-induced IL-6 and GM-CSF expression and production., Conclusion: This study demonstrates that Der f 2 promotes the expression and production of the pro-inflammatory cytokines IL-6 and GM-CSF in airway epithelial cells via activation of the p38 signaling pathway. These findings provide insights into the molecular mechanisms that Der f 2 may exacerbate airway inflammation.

Objective: This study integrates network pharmacology and metabolomics techniques to explore the potential regulatory mechanisms of Res on gouty arthritis (GA)., Methods: Network pharmacology was used to predict the mechanism of Res in regulating GA, and methods such as HE staining, ELISA, immunohistochemistry, Real-time PCR, Western blot, and molecular docking were used to verify the role of NF-κB, MAPK, and JAK/STAT inflammatory signaling pathways in the MSU-induced GA rat model. In addition, non-targeted metabolomics techniques were combined to further investigate the mechanism of Res in treating GA., Results: The results of network pharmacology showed that Res may exert its therapeutic effects through the NF-κB signaling pathway. Animal experiments demonstrated that in the MSU-induced GA rat model, pathological damage, serum biochemical indicators, and levels of inflammatory factors were significantly increased, and the NF-κB signaling pathway was activated. The intervention of Res significantly reduced pathological damage, serum biochemical indicators, levels of inflammatory factors, and the activation of NF-κB, MAPK, and JAK/STAT signaling pathways in the model rats. Metabolomics results showed that Res could improve the metabolic trajectory deviations in serum and joint fluid of GA model rats. Through related metabolic pathway analysis, the most affected metabolic pathways were found to be Sphingolipid metabolism, Glycerophospholipid metabolism, Phenylalanine, tyrosine and tryptophan biosynthesis, Pantothenate and CoA, Citrate cycle (TCA cycle), and Arachidonic acid metabolism., Conclusion: Resveratrol can regulate the biosynthetic pathways of arachidonic acid, phenylalanine, tyrosine, and tryptophan, pantothenic acid and CoA biosynthesis pathways, TCA cycle, and other metabolic pathways, thereby regulating the NF-κB, MAPK, and JAK/STAT3 signaling pathways, and inhibiting the acute inflammatory response during GA attacks, showing characteristics of multi-pathway and multi-target action., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu, Yu, Wang, Jiang, Lu and Liu.)

One of the best antipsychotics for treating schizophrenia and bipolar disorders is olanzapine (OLA). However, its use is restricted owing to unfavorable adverse effects as liver damage, dyslipidemia, and weight gain. The primary objective of the present investigation was to examine the signaling mechanisms that underlie the metabolic disruption generated by OLA. Besides, the potential protective effect of sulforaphane (SFN) and β-sitosterol (βSS) against obesity and metabolic toxicity induced by OLA were inspected as well. A total of five groups of male Wistar rats were established, including the control, OLA, SFN+OLA, βSS+OLA, and the combination + OLA groups. Hepatic histopathology, biochemical analyses, ultimate body weights, liver function, oxidative stress, and pro-inflammatory cytokines were evaluated. In addition to the relative expression of FOXO, the signaling pathways for PI3K/AKT, JAK/STAT3, and MAPK were assessed as well. All biochemical and hepatic histopathological abnormalities caused by OLA were alleviated by SFN and/or βSS. A substantial decrease in systolic blood pressure (SBP), proinflammatory cytokines, serum lipid profile parameters, hepatic MDA, TBIL, AST, and ALT were reduced through SFN or/and βSS. To sum up, the detrimental effects of OLA are mediated by alterations in the Akt/FOXO3a/ATG12, Ras/SOS2/Raf-1/MEK/ERK1/2, and Smad3,4/TGF-β signaling pathways. The administration of SFN and/or βSS has the potential to mitigate the metabolic deficit, biochemical imbalances, hepatic histological abnormalities, and the overall unfavorable consequences induced by OLA by modulating the abovementioned signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Bacterial peptidoglycan (PGN) fragments are commonly studied in the context of bacterial infections. However, PGN fragments recently gained recognition as signalling molecules from the commensal gut microbiota in the healthy host. Here we focus on the minimal bioactive PGN motif muramyl dipeptide (MDP), found in both Gram-positive and Gram-negative commensal bacteria, which signals through the Nod2 receptor. MDP from the gut microbiota translocates to the brain and is associated with changes in neurodevelopment and behaviour, yet there is limited knowledge about the underlying mechanisms. In this study we demonstrate that physiologically relevant doses of MDP induce rapid changes in microglial gene expression and lead to cytokine and chemokine secretion. In immortalised microglial (IMG) cells, C-C Motif Chemokine Ligand 5 (CCL5/RANTES) expression is acutely sensitive to the lowest physiologically prevalent dose (0.1 µg/ml) of MDP. As CCL5 plays an important role in memory formation and synaptic plasticity, microglial CCL5 might be the missing link in elucidating MDP-induced alterations in synaptic gene expression. We observed that a higher physiological dose of MDP elevates the expression of cytokines TNF-α and IL-1β, indicating a transition toward a pro-inflammatory phenotype in IMG cells, which was validated in primary microglial cultures. Furthermore, MDP induces the translocation of NF-κB subunit p65 into the nucleus, which is blocked by MAPK p38 inhibitor SB202190, suggesting that an interplay of both the NF-κB and MAPK pathways is responsible for the MDP-specific microglial phenotype. These findings underscore the significance of different MDP levels in shaping microglial function in the CNS and indicate MDP as a potential mediator for early inflammatory processes in the brain. It also positions microglia as an important target in the gut microbiota-brain-axis pathway through PGN signalling., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Helical growth of the root tip (circumnutation) that permits surface exploration facilitates root penetration into soil. Here, we reveal that rice actin-binding protein RMD aids in root circumnutation, manifested by wavy roots as well as compromised ability to efficiently explore and avoid obstacles in rmd mutants. We demonstrate that root circumnutation defects in rmd depend on brassinosteroid (BR) signaling, which is elevated in mutant roots. Suppressing BR signaling via pharmacological (BR inhibitor) or genetic (knockout of BR biosynthetic or signaling components) manipulation rescues root defects in rmd . We further reveal that mutations in MAPK6 suppress BR signaling and restore normal root circumnutation in rmd , which may be mediated by the interaction between MAPK6, MAPKK4 and BR signaling factor BIM2. Our study thus demonstrates that RMD and MAPK6 control root circumnutation by modulating BR signaling to facilitate early root growth.

Chronic pain has emerged as a significant public health issue, seriously affecting patients' quality of life and psychological well-being, with a lack of effective pharmacological treatments. Numerous studies have indicated that macrophages play a crucial role in inflammatory pain, and targeting neuro-immune interactions for drug development may represent a promising direction for pain management. Chilobrachys jingzhao (C. jingzhao) is used as a folk medicine of the Li nationality with the efficacy of eliminating swelling, detoxicating, and relieving pain, and the related products are widely used in the market. However, the chemical constituents of C. jingzhao have not been reported, and the pharmacodynamic substance and the precise functional mechanism are unrevealed. Here we isolated a cyclic dipeptide, cyclo(L-Pro-L-Trp) (CPT) from C. jingzhao for the first time. CPT remarkably alleviated formalin-induced inflammatory pain and significantly inhibited inflammatory responses. In vivo, CPT attenuated neutrophil infiltration and plantar tissue edema and suppressed the mRNA expression of pro-inflammatory molecules. In vitro, CPT suppressed inflammation triggered by lipopolysaccharide (LPS) in both RAW 264.7 and iBMDM cells, reducing expressions of inducible nitric oxide synthase (iNOS), superoxide, and pro-inflammatory molecules. A mechanistic study revealed that CPT exerted an anti-inflammatory activity by blocking the mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, as well as alleviating the ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6). Our results elucidated the pharmacodynamic material basis of C. jingzhao, and CPT can be a promising lead for alleviating inflammation and inflammatory pain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background/objectives: Gastric cancer (GC) is a globally frequent cancer, in particular leading in mortality caused by digestive tract cancers in China. Vascular endothelial growth factor A (VEGFA) is excessively expressed in cancers including GC; its involvement in GC development, particularly in multidrug resistance (MDR), and the signal route it affects in GC remain unknown. To explore the roles VEGFA plays during progression and MDR formation in GC, we studied its function in a VEGFA-deleted GC cell platform., Methods: We initially assessed the importance of VEGFA in GC and MDR using database analysis. Then, using CCK8, wound healing, transwell, scanning electron microscopy, immunofluorescence, flow cytometry, and other techniques, the alterations in tumor malignancy-connected cell behaviors and microstructures were photographed and evaluated in a VEGFA-gene-deleted GC cell line (VEGFA-/-SGC7901). Finally, the mechanism of VEGFA in GC progression and MDR was examined by Western blot., Results: Database analysis revealed a strong correlation between high VEGFA expression and a poor prognosis for GC. The results showed that VEGFA deletion reduced GC cell proliferation and motility and altered microstructures important for motility, such as the depolymerized cytoskeleton. VEGFA deletion inhibited the growth of pseudopodia/filopodia and suppressed the epithelial-mesenchymal transition (EMT). The occurrence of MDR is induced by overactivation of the MAPK-AKT and TGFβ signaling pathways, while PTEN inhibits these pathways., Conclusions: All findings suggested that VEGFA acts as a cancer enhancer and MDR inducer in GC via the MAPK-AKT/PTEN/TGFβ signal pathway.

Recent studies have revealed that B-subgroup rapidly accelerated fibrosarcoma (RAF) kinases have pivotal roles in hormone signaling and stress responses across a wide range of organisms. In this forum, I explore their evolution and diverse signaling pathways, highlighting the significance of B-RAF kinases in plant growth and plant-environment interactions while discussing open questions for future research., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The aim of this study was to investigate the effects of acupressure bladder meridian (ABM) on anxiety in rats. Chronic stress was induced rats to establish rat anxiety model. Shuttle experiment and open field experiments of were used to measure behaviors. The levels of cytokines in serum and hippocampus of rats were detected. Brain neurotransmitters (dopamine, 5- hydroxy tryptamine, norepinephrine) were detected by Enzyme linked immunosorbent assay (ELISA) kits. Immunohistochemistry and western blotting were used to detect MAPK and BDNF signal pathway in hippocampus of rats. ABM significantly improve behaviors, decreased cytokine levels in serum and hippocampus. ABM restored the changes of neurotransmitters and significantly decreased protein expressions of MAPK signal pathway and increased protein expressions of BDNF signal pathway in hippocampus of rats. The results shown that ABM significantly improved anxiety via inhibition of MAPK signal pathway and increased BDNF signal pathway., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Various extracts are tested for anti-allergic or anti-inflammatory properties on in vitro models. RBL-2H3 cells are widely used in allergic or immunological studies. FCεRI and its downstream signaling cascades, such as MAPK, NF-κB, and JAK/STAT signaling pathways, are important allergic or inflammatory signaling mechanisms in mast and basophil cells. This systematic review aims to study common signaling pathways of the anti-allergic or anti-inflammatory compounds on RBL-2H3 cells. We selected the relevant research articles published after 2015 from the PubMed, Scopus, Science Direct and Web of Science databases. The risk of bias of the studies was assessed based on the modified CONSORT checklist for in vitro studies. The cell lines, treatments, assay, primary findings, and signaling pathways on RBL-2H3 cells were extracted to synthesize the results. Thirty-eight articles were included, and FCεRI and its downstream pathways, such as Lyn, Sky, PLCγ, and MAPK, were commonly studied. Moreover, the JAK/STAT pathway was a potential signaling mechanism in RBL-2H3 cells. However, the findings based on RBL-2H3 cells needed to be tested along with human mast cells to confirm its relevance to human health. In conclusion, a single plant extract may act as an anti-inflammatory reagent in RBL-2H3 cells via multiple signaling pathways besides the MAPK signaling pathway.

Cadmium (Cd +2 ) renders multifarious environmental stresses and highly toxic to nearly all living organisms including plants. Cd causes toxicity by unnecessary augmentation of ROS that targets essential molecules and fundamental processes in plants. In response, plants outfitted a repertory of mechanisms to offset Cd toxicity. The main elements of these are Cd chelation, sequestration into vacuoles, and adjustment of Cd uptake by transporters and escalation of antioxidative mechanism. Signal molecules like phytohormones and reactive oxygen species (ROS) activate the MAPK cascade, the activation of the antioxidant system andsynergistic crosstalk between different signal molecules in order to regulate plant responses to Cd toxicity. Transcription factors like WRKY, MYB, bHLH, bZIP, ERF, NAC etc., located downstream of MAPK, and are key factors in regulating Cd toxicity responses in plants. Apart from this, MAPK and Ca 2+ signaling also have a salient involvement in rectifying Cd stress in plants. This review highlighted the mechanism of Cd uptake, translocation, detoxification and the key role of defense system, MAPKs, Ca 2+ signals and jasmonic acid in retaliating Cd toxicity via synchronous management of various other regulators and signaling components involved under stress condition., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Acute lung injury (ALI) is a severe inflammatory disorder that has a high morbidity and mortality rate. Urolithin A (UA) is reported to have anti-inflammatory and anti-oxidative effects in ALI. However, its molecular mechanisms in ALI remain to be explored. Mice and BEAS-2B cells were administrated with lipopolysaccharide (LPS) to mimic the ALI model in vivo and in vitro. Hematoxylin-eosin (HE) staining was used to detect the pathological injury of lung tissues. The levels of proinflammatory cytokines in bronchoalveolar lavage fluid (BALF) and culture supernatant and the levels of oxidative stress markers in lung tissues were measured using ELISA. DCFH-DA probe was used to assess the reactive oxygen species (ROS) level. TUNEL staining and flow cytometry were performed to determine cell apoptosis. The key targets and pathways were confirmed by immunohistochemistry (IHC) and western blot. UA suppressed the pathologic damage, wet/dry weight ratio, and total protein and inflammatory cells in BALF. UA decreased neutrophil infiltration and proinflammatory cytokines production. UA reduced the level of malondialdehyde (MDA) and increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in pulmonary tissues. UA also inhibited cell apoptosis in lung tissues by decreasing Bax expression and increasing Bcl-2 expression. In addition, UA suppressed LPS-induced inflammatory factor production, ROS level, and cell apoptosis in BEAS-2B. Importantly, UA decreased the expression of HMGB1 in LPS-treated mice and BEAS-2B cells. HMGB1 overexpression greatly abrogated the inhibition of UA on inflammation, ROS, and cell apoptosis in LPS-administrated BEAS-2B. Furthermore, UA treatment suppressed the phosphorylated levels of p38, JNK, ERK, and p65 in LPS-administrated mice and BEAS-2B cells. UA alleviated lung inflammation, oxidative stress, and apoptosis in ALI by targeting HMGB1 to inactivate the MAPK/NF-κB signaling, suggesting the potential of UA to treat ALI., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Glaesserella parasuis is usually a benign swine commensal in the upper respiratory tract, but virulent strains can cause systemic infection characterized by pneumonia, meningitis, and fibrinous polyserositis. The intensive pulmonary inflammatory response following G. parasuis infection is the main cause of lung injury and death in pigs. Vaccination has failed to control the disease due to the lack of extended cross-protection. Accumulating evidence indicates that the heme-binding protein A (HbpA) is a potential virulence determinant and a promising antigen candidate for the development of a broader range of vaccines. However, it is not yet known whether HbpA contributes to G. parasuis virulence or has any potential immune protective effects against G. parasuis. Here, we show that HbpA can induce the transcription and secretion of proinflammatory cytokines (IL-6, TNF-α, and MCP-1) in porcine alveolar macrophages (PAM, 3D4/31). The HbpA protein is recognized by Toll-like receptors 2 and 4 on 3D4/21 macrophages, resulting in the activation of MAP kinase and NF-κB signalling cascades and the transcription and secretion of proinflammatory cytokines. HbpA contributes to virulence and bacterial pulmonary colonization in C57BL/6 mice and plays a role in adhesion to host cells and evasion of the bactericidal effect of pulmonary macrophages. In addition, mice immunized with HbpA were partially protected against challenge by G. parasuis SC1401. The results suggest that HbpA plays an important role in the pathogenesis of disease caused by G. parasuis and lay a foundation for the development of a subunit or chimeric anti-G. parasuis vaccine., (© 2024. The Author(s).)

Background: Chronic atrophic gastritis (CAG) is a global digestive system disease and one of the important causes of gastric cancer. The incidence of CAG has been increasing yearly worldwide., Purpose: This article reviews the latest research on the common causes and future therapeutic targets of CAG as well as the pharmacological effects of corresponding clinical drugs. We provide a detailed theoretical basis for further research on possible methods for the treatment of CAG and reversal of the CAG process., Results: CAG often develops from chronic gastritis, and its main pathological manifestation is atrophy of the gastric mucosa, which can develop into gastric cancer. The drug treatment of CAG can be divided into agents that regulate gastric acid secretion, eradicate Helicobacter. pylori (H. pylori), protect gastric mucous membrane, or inhibit inflammatory factors according to their mechanism of action. Although there are limited specific drugs for the treatment of CAG, progress is being made in defining the pathogenesis and therapeutic targets of the disease. Growing evidence shows that NF-κB, PI3K/AKT, Wnt/ β-catenin, MAPK, Toll-like receptors (TLRs), Hedgehog, and VEGF signaling pathways play an important role in the development of CAG., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Conflict of Interest None., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

In mammals, intrinsic 24 h or circadian rhythms are primarily generated by the suprachiasmatic nuclei (SCN). Rhythmic daily changes in the transcriptome and proteome of SCN cells are controlled by interlocking transcription-translation feedback loops (TTFLs) of core clock genes and their proteins. SCN cells function as autonomous circadian oscillators, which synchronize through intercellular neuropeptide signalling. Physiological and behavioural rhythms can be severely disrupted by genetic modification of a diverse range of genes and proteins in the SCN. With the advent of next generation sequencing, there is unprecedented information on the molecular profile of the SCN and how it is affected by genetically targeted alteration. However, whether the expression of some genes is more readily affected by genetic alteration of the SCN is unclear. Here, using publicly available datasets from recent RNA-seq assessments of the SCN from genetically altered and control mice, we evaluated whether there are commonalities in transcriptome dysregulation. This was completed for four different phases across the 24 h cycle and was augmented by Gene Ontology Molecular Function (GO:MF) and promoter analysis. Common differentially expressed genes (DEGs) and/or enriched GO:MF terms included signalling molecules, their receptors, and core clock components. Finally, examination of the JASPAR database indicated that E-box and CRE elements in the promoter regions of several commonly dysregulated genes. From this analysis, we identify differential expression of genes coding for molecules involved in SCN intra- and intercellular signalling as a potential cause of abnormal circadian rhythms., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Ribosomes mediate protein synthesis, which is one of the most energy-demanding activities within the cell, and mitochondria are one of the main sources generating energy. How mitochondrial morphology and functions are adjusted to cope with ribosomal defects, which can impair protein synthesis and affect cell viability, is poorly understood. Here, we used the fission yeast Schizosaccharomyces Pombe as a model organism to investigate the interplay between ribosome and mitochondria. We found that a ribosomal insult, caused by the absence of Rpl2702, activates a signaling pathway involving Sty1/MAPK and mTOR to modulate mitochondrial morphology and functions. Specifically, we demonstrated that Sty1/MAPK induces mitochondrial fragmentation in a mTOR-independent manner while both Sty1/MAPK and mTOR increases the levels of mitochondrial membrane potential and mitochondrial reactive oxygen species (mROS). Moreover, we demonstrated that Sty1/MAPK acts upstream of Tor1/TORC2 and Tor1/TORC2 and is required to activate Tor2/TORC1. The enhancements of mitochondrial membrane potential and mROS function to promote proliferation of cells bearing ribosomal defects. Hence, our study reveals a previously uncharacterized Sty1/MAPK-mTOR signaling axis that regulates mitochondrial morphology and functions in response to ribosomal insults and provides new insights into the molecular and physiological adaptations of cells to impaired protein synthesis., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Spinal cord injury (SCI) is a serious and disabling central nervous system injury. Its complex pathological mechanism can lead to sensory and motor dysfunction. It has been reported that signaling pathway plays a key role in the pathological process and neuronal recovery mechanism of SCI. Such as PI3K/Akt, MAPK, NF-κB, and Wnt/β-catenin signaling pathways. According to reports, various stimuli and cytokines activate these signaling pathways related to SCI pathology, thereby participating in the regulation of pathological processes such as inflammation response, cell apoptosis, oxidative stress, and glial scar formation after injury. Activation or inhibition of relevant pathways can delay inflammatory response, reduce neuronal apoptosis, prevent glial scar formation, improve the microenvironment after SCI, and promote neural function recovery. Based on the role of signaling pathways in SCI, they may be potential targets for the treatment of SCI. Therefore, understanding the signaling pathway and its inhibitors may be beneficial to the development of SCI therapeutic targets and new drugs. This paper mainly summarizes the pathophysiological process of SCI, the signaling pathways involved in SCI pathogenesis, and the potential role of specific inhibitors/activators in its treatment. In addition, this review also discusses the deficiencies and defects of signaling pathways in SCI research. It is hoped that this study can provide reference for future research on signaling pathways in the pathogenesis of SCI and provide theoretical basis for SCI biotherapy., Competing Interests: Declaration of Competing Interest Yi Ding and Qin Chen are major contributors towards the writing. Yi Ding and Qin Chen conceived and designed the review. All authors read and approved the final manuscript. All authors contributed to the article and approved the submitted version., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Olive is an evergreen tree of Oleaceae Olea with numerous bioactive components. While the anti-inflammatory properties of olive oil and the derivatives are well-documented, there remains a dearth of in-depth researches on the immunosuppressive effects of olive fruit water extract. This study aimed to elucidate the dose-effect relationship and underlying molecular mechanisms of olive fruit extract in mediating anti-inflammatory responses., Methods and Results: The impacts of olive fruit extract on the release of nitric oxide (NO), tumor necrosis factor (TNF-α), interleukins-6 (IL-6) and reactive oxygen species (ROS) were assessed in RAW264.7 cells induced by lipopolysaccharide (LPS). For deeper understanding, the expression of genes encoding inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α and IL-6 was quantitatively tested. Additionally, the expression patterns of MAPK and NF-κB pathways were further observed to analyze the action mechanisms. Results suggested that olive fruit extract (200, 500, 1000 µg/mL) markedly exhibited a dose-dependent reduction in the generation of NO, TNF-α, IL-6 and ROS, as well as the expression of correlative genes studied. The activation of ERK, JNK, p38, IκB-α and p65 were all suppressed when p65 nuclear translocation was further restricted by olive fruit extract in NF-κB and MAPK signal pathways., Conclusions: Olive fruit extract targeted imposing restrictions on the signal transduction of key proteins in NF-κB and MAPK pathways, and thereby lowered the level of inflammatory mediators, which put an enormous hindrance to inflammatory development. Accordingly, it is reasonable to consider olive fruit as a potent ingredient in immunomodulatory products., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Trypanosoma brucei, a causative agent of human and animal trypanosomiasis, regularly switches its major surface antigen to avoid elimination by the immune system. Toll-like receptor 9 (TLR9) is a key modulator for resistance to host-infective trypanosomes; however, the underlying molecular mechanism remains indistinct. Thus, we first approached the issue using Tlr9-mutant mice that render them non-responsive to TLR9 agonists. After infection, T cells in the spleens of Tlr9-mutant mice were analyzed by flow cytometry and a reduction in CD8 + , CD4 + T, and NKT cells was observed in Tlr9-mutant mice compared to WT mice. We further found that the responses of inflammatory cytokines in the sera were reduced in Tlr9-mutant mice after T. brucei infection. The underlying molecular mechanism was that T. b. brucei DNA activated TLR9, which consequently upregulated the expression of p38 and ERK/MAPK, resulting in host resistance to trypanosome infection. In conclusion, these findings provide novel insights into the TLR9-mediated host responses to trypanosome infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: Among numerous constituents of Panax ginseng, a constituent named Ginsenoside Rb1 (G-Rb1) has been studied to diminish inflammation associated with diseases. This study investigated the anti-inflammatory properties of G-Rb1 on human dental pulp cells (hDPCs) exposed to lipopolysaccharide (LPS) and aimed to determine the underlying molecular mechanisms., Methodology: The KEGG pathway analysis was performed after RNA sequencing in G-Rb1- and LPS-treated hDPCs. Reverse-transcription polymerase chain reaction (RT-PCR) and western blot analysis were used for the assessment of cell adhesion molecules and inflammatory cytokines. Statistical analysis was performed with one-way ANOVA and the Student-Newman-Keuls test., Results: G-Rb1 did not exhibit any cytotoxicity within the range of concentrations tested. However, it affected the levels of TNF-α, IL-6 and IL-8, as these showed reduced levels with exposure to LPS. Additionally, less mRNA and protein expressions of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were shown. With the presence of G-Rb1, decreased levels of PI3K/Akt, phosphorylated IκBα and p65 were also observed. Furthermore, phosphorylated ERK and JNK by LPS were diminished within 15, 30 and 60 min of G-Rb1 exposure; however, the expression of non-phosphorylated ERK and JNK remained unchanged., Conclusions: G-Rb1 suppressed the LPS-induced increase of cell adhesion molecules and inflammatory cytokines, while also inhibiting PI3K/Akt, phosphorylation of NF-κB transcription factors, ERK and JNK of MAPK signalling in hDPCs., (© 2024 British Endodontic Society. Published by John Wiley & Sons Ltd.)

Urban Particulate Matter (UPM) induces skin aging and inflammatory responses by regulating skin cells through the transient receptor potential vanilloid 1 (TRPV1). Although oleic acid, an unsaturated free fatty acid (FFA), has some functional activities, its effect on UPM-induced skin damage has not been elucidated. Here, we investigated signaling pathways on how oleic acid is involved in attenuating UPM induced cell damage. UPM treatment increased XRE-promoter luciferase activity and increased translocation of AhR to the nucleus, resulting in the upregulation of CYP1A1 gene. However, oleic acid treatment attenuated the UPM effects on AhR signaling. Furthermore, while UPM induced activation of TRPV1 and MAPKs signaling which activated the downstream molecules NFκB and AP-1, these effects were reduced by cotreatment with oleic acid. UPM-dependent generation of reactive oxygen species (ROS) and reduction of cellular proliferation were also attenuated by the treatment of oleic acid. These data reveal that cell damage induced by UPM treatment occurs through AhR signaling and TRPV1 activation which in turn activates ERK and JNK, ultimately inducing NFκB and AP-1 activation. These effects were reduced by the cotreatment of oleic acid on HaCaT cells. These suggest that oleic acid reduces UPM-induced cell damage through inhibiting both the AhR signaling and activation of TRPV1 and its downstream molecules, leading to a reduction of pro-inflammatory cytokine and recovery of cell proliferation., (© 2024 The Authors. Environmental Toxicology published by Wiley Periodicals LLC.)

Piperine, an active plant alkaloid from black pepper (Piper nigrum ), has several pharmacological effects, namely antioxidant, anti-inflammatory and immunomodulatory effects, which involve inhibiting molecular events associated with various stages of cancer development. The aim of this study was to investigate the molecular mechanisms of action of piperine in relation to its potential anticancer effect on head and neck cancer cells. Parameters related to neoplastic potential and cytokine, protein and gene expression were investigated in head and neck cancer cell lines (HEp-2 and SCC-25) treated with piperine. The results of the tests indicated that piperine modified morphology and inhibited viability and the formation of cell colonies. Piperine promoted genotoxicity by triggering apoptosis and cell cycle arrest in the G2/M and S phases. A decrease in cell migration was also observed, and there was decreased expression of MMP2/9 genes. Piperine also reduced the expression of inflammatory molecules (PTGS2 and PTGER4), regulated the secretion of cytokines (IFN- γ and IL-8) and modulated the expression of ERK and p38. These results suggest that piperine exerts anticancer effects on tumor cells by regulating signaling pathways associated with head and neck cancer.

Traumatic spinal cord injury (SCI) is a life-threatening and life-altering condition that results in debilitating sensorimotor and autonomic impairments. Despite significant advances in the clinical management of traumatic SCI, many patients continue to suffer due to a lack of effective therapies. The initial mechanical injury to the spinal cord results in a series of secondary molecular processes and intracellular signaling cascades in immune, vascular, glial, and neuronal cell populations, which further damage the injured spinal cord. These intracellular cascades present promising translationally relevant targets for therapeutic intervention due to their high ubiquity and conservation across eukaryotic evolution. To date, many therapeutics have shown either direct or indirect involvement of these pathways in improving recovery after SCI. However, the complex, multifaceted, and heterogeneous nature of traumatic SCI requires better elucidation of the underlying secondary intracellular signaling cascades to minimize off-target effects and maximize effectiveness. Recent advances in transcriptional and molecular neuroscience provide a closer characterization of these pathways in the injured spinal cord. This narrative review article aims to survey the MAPK, PI3K-AKT-mTOR, Rho-ROCK, NF-κB, and JAK-STAT signaling cascades, in addition to providing a comprehensive overview of the involvement and therapeutic potential of these secondary intracellular pathways following traumatic SCI.

Epithelial ovarian cancer (EOC) is one of the most aggressive forms of gynaecological malignancies. Survival rates for women diagnosed with OC remain poor as most patients are diagnosed with advanced disease. Debulking surgery and platinum-based therapies are the current mainstay for OC treatment. However, and despite achieving initial remission, a significant portion of patients will relapse because of innate and acquired resistance, at which point the disease is considered incurable. In view of this, novel detection strategies and therapeutic approaches are needed to improve outcomes and survival of OC patients. In this review, we summarize our current knowledge of the genetic landscape and molecular pathways underpinning OC and its many subtypes. By examining therapeutic strategies explored in preclinical and clinical settings, we highlight the importance of decoding how single and convergent genetic alterations co-exist and drive OC progression and resistance to current treatments. We also propose that core signalling pathways such as the PI3K and MAPK pathways play critical roles in the origin of diverse OC subtypes and can become new targets in combination with known DNA damage repair pathways for the development of tailored and more effective anti-cancer treatments.

Hyperoside is a natural flavonol glycoside widely found in plants and has been reported to have a variety of pharmacological effects, including anticancer abilities. In this study, we demonstrated for the first time that hyperoside inhibited the proliferation of bladder cancer cells in vitro and in vivo. Moreover, hyperoside could not only induce cell cycle arrest, but also induce apoptosis of a few bladder cancer cells. Quantitative proteomics, bioinformatics analysis and Western blotting confirmed that hyperoside induced the overexpression of EGFR, Ras and Fas proteins, which affects a variety of synergistic and antagonistic downstream signaling pathways, including MAPKs and Akt, ultimately contributing to its anticancer effects in bladder cancer cells. This study reveals that hyperoside could be a promising therapeutic strategy for the prevention of bladder cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Cells continuously fine-tune signaling pathway proteins to match nutrient and stress levels in their local environment by modifying intracellular proteins with O-linked N-acetylglucosamine (O-GlcNAc) sugars, an essential process for cell survival and growth. The small size of these monosaccharide modifications poses a challenge for functional determination, but the chemistry and biology communities have together created a collection of precision tools to study these dynamic sugars. This review presents the major themes by which O-GlcNAc influences signaling pathway proteins, including G-protein coupled receptors, growth factor signaling, mitogen-activated protein kinase (MAPK) pathways, lipid sensing, and cytokine signaling pathways. Along the way, we describe in detail key chemical biology tools that have been developed and applied to determine specific O-GlcNAc roles in these pathways. These tools include metabolic labeling, O-GlcNAc-enhancing RNA aptamers, fluorescent biosensors, proximity labeling tools, nanobody targeting tools, O-GlcNAc cycling inhibitors, light-activated systems, chemoenzymatic labeling, and nutrient reporter assays. An emergent feature of this signaling pathway meta-analysis is the intricate interplay between O-GlcNAc modifications across different signaling systems, underscoring the importance of O-GlcNAc in regulating cellular processes. We highlight the significance of O-GlcNAc in signaling and the role of chemical and biochemical tools in unraveling distinct glycobiological regulatory mechanisms. Collectively, our field has determined effective strategies to probe O-GlcNAc roles in biology. At the same time, this survey of what we do not yet know presents a clear roadmap for the field to use these powerful chemical tools to explore cross-pathway O-GlcNAc interactions in signaling and other major biological pathways., Competing Interests: Conflict of interest The authors declare no potential conflict of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Muscone is a chemical monomer derived from musk. Although many studies have confirmed the cardioprotective effects of muscone, the effects of muscone on cardiac hypertrophy and its potential mechanisms are unclear.The aim of the present study was to investigate the effect of muscone on angiotensin (Ang) II-induced cardiac hypertrophy., Methods and Results: In the present study, we found for the first time that muscone exerted inhibitory effects on Ang II-induced cardiac hypertrophy and cardiac injury in mice. Cardiac function was analyzed by echocardiography measurement, and the degree of cardiac fibrosis was determined by the quantitative real-time polymerase chain reaction (qRT-PCR), Masson trichrome staining and western blot assay. Secondly, qRT-PCR experiment showed that muscone attenuated cardiac injury by reducing the secretion of pro-inflammatory cytokines and promoting the secretion of anti-inflammatory cytokines. Moreover, western blot analysis found that muscone exerted cardio-protective effects by inhibiting phosphorylation of key proteins in the STAT3, MAPK and TGF-β/SMAD pathways. In addition, CCK-8 and determination of serum biochemical indexes showed that no significant toxicity or side effects of muscone on normal cells and organs., Conclusions: Muscone could attenuate Ang II-induced cardiac hypertrophy, in part, by inhibiting the STAT3, MAPK, and TGF-β/SMAD signaling pathways., (© 2023. The Author(s).)

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and inflammation. The molecular mechanisms underlying OA progression remain incompletely understood. In this study, we investigated the role of STEAP3 (Six Transmembrane Epithelial Antigen of the Prostate 3) in the development of OA. Our results demonstrated that STEAP3 was upregulated in OA cartilage tissues and contributes to the progression of the disease. To elucidate the mechanism, we employed transcriptomic and interaction proteomics analysis, and identified dysregulated genes and pathways associated with STEAP3 overexpression. Specifically, we found that STEAP3 interacted with Rab7A, a protein involved in intracellular trafficking and autophagy, and suppressed its activity. In addition, STEAP3 interacted with activated C kinase 1 (RACK1) and enhanced its activity. Furthermore, our data indicated that the suppression of Rab7A activity by STEAP3 promoted the activation of receptor tyrosine kinases (RTKs) and the promoting effects of RACK1 by STEAP3, both of which in turn activated the MAPK and JAK/STAT signaling pathways. In conclusion, our findings highlighted the role of STEAP3 in promoting OA progression. By inhibiting Rab7A activity and promoting RACK1 activity, STEAP3 enhanced inflammation through the activation of RTKs and subsequent activation of the MAPK and JAK/STAT signaling pathways. Targeting STEAP3 may provide a potential therapeutic strategy for the treatment of OA by modulating these interconnected pathways., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

The response of cells to extracellular signals is mediated by a variety of intracellular signaling pathways that determine stimulus-dependent cell fates. One such pathway is the cJun-N-terminal Kinase (JNK) cascade, which is mainly involved in stress-related processes. The cascade transmits its signals via a sequential activation of protein kinases, organized into three to five tiers. Proper regulation is essential for securing a proper cell fate after stimulation, and the mechanisms that regulate this cascade may involve the following: (1) Activatory or inhibitory phosphorylations, which induce or abolish signal transmission. (2) Regulatory dephosphorylation by various phosphatases. (3) Scaffold proteins that bring distinct components of the cascade in close proximity to each other. (4) Dynamic change of subcellular localization of the cascade's components. (5) Degradation of some of the components. In this review, we cover these regulatory mechanisms and emphasize the mechanism by which the JNK cascade transmits apoptotic signals. We also describe the newly discovered PP2A switch, which is an important mechanism for JNK activation that induces apoptosis downstream of the Gq protein coupled receptors. Since the JNK cascade is involved in many cellular processes that determine cell fate, addressing its regulatory mechanisms might reveal new ways to treat JNK-dependent pathologies.

Background: Ovarian cancer, particularly epithelial ovarian cancer (EOC), is the leading cause of cancer-related mortality among women. Our previous study revealed that high HMGB3 levels are associated with poor prognosis and lymph node metastasis in patients with high-grade serous ovarian carcinoma; however, the role of HMGB3 in EOC proliferation and metastasis remains unknown., Methods: MTT, clonogenic, and EdU assays were used to assess cell proliferation. Transwell assays were performed to detect cell migration and invasion. Signaling pathways involved in HMGB3 function were identified by RNA sequencing (RNA-seq). MAPK/ERK signaling pathway protein levels were evaluated by western blot., Results: HMGB3 knockdown inhibited ovarian cancer cell proliferation and metastasis, whereas HMGB3 overexpression facilitated these processes. RNA-seq showed that HMGB3 participates in regulating stem cell pluripotency and the MAPK signaling pathway. We further proved that HMGB3 promotes ovarian cancer stemness, proliferation, and metastasis through activating the MAPK/ERK signaling pathway. In addition, we demonstrated that HMGB3 promotes tumor growth in a xenograft model via MAPK/ERK signaling., Conclusions: HMGB3 promotes ovarian cancer malignant phenotypes and stemness through the MAPK/ERK signaling pathway. Targeting HMGB3 is a promising strategy for ovarian cancer treatment that may improve the prognosis of women with this disease. Video Abstract., (© 2023. The Author(s).)

RAS/MAPK gene dysfunction underlies various cancers and neurocognitive disorders. Although the roles of RAS/MAPK genes have been well studied in cancer, less is known about their function during neurodevelopment. There are many genes that work in concert to regulate RAS/MAPK signaling, suggesting that if common brain phenotypes could be discovered they could have a broad impact on the many other disorders caused by distinct RAS/MAPK genes. We assessed the cellular and molecular consequences of hyperactivating the RAS/MAPK pathway using two distinct genes in a cell type previously implicated in RAS/MAPK-mediated cognitive changes, cortical GABAergic interneurons. We uncovered some GABAergic core programs that are commonly altered in each of the mutants. Notably, hyperactive RAS/MAPK mutants bias developing cortical interneurons towards those that are somatostatin positive. The increase in somatostatin-positive interneurons could also be prevented by pharmacological inhibition of the core RAS/MAPK signaling pathway. Overall, these findings present new insights into how different RAS/MAPK mutations can converge on GABAergic interneurons, which may be important for other RAS/MAPK genes and related disorders., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Low-intensity pulsed ultrasound (LIPUS), as a safe and potent physical therapy, has been widely used. It has been demonstrated that LIPUS could induce multiple biological effects, such as relieving pain, accelerating tissue repair/regeneration, and alleviating inflammation. A number of in vitro studies have indicated that LIPUS could significantly reduce the expression of proinflammatory cytokines. This anti-inflammatory effect has also been verified in many in vivo researches. However, the molecular mechanisms underlying LIPUS against inflammation are far from fully elucidated and may differ among different tissues and cells. Here, we review the applications of LIPUS against inflammation through different signaling pathways including nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and phosphatidylinositol-3-kinase/serine/threonine kinase (PI3K/Akt), and discuss the underlying mechanisms. The positive effects of LIPUS on exosomes against inflammation and related signaling pathways are also discussed. A systematic overview of recent advances will present a deeper understanding of the molecular mechanisms of LIPUS, thus boosting our ability to optimize this promising anti-inflammatory therapy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Bavachin is a dihydroflavonoid compound isolated from Psoralea corylifolia, and exhibits anti-bacterial, anti-inflammatory, anti-tumor and lipid-lowering activities. Recent attention has gradually drawn on bavachin-induced apoptosis in many human cancer cell lines. However, the anti-cancer effects and related mechanisms in colorectal cancer remain unknown. Here, we investigated the effects of bavachin on colorectal cancer in vivo and in vitro. The results showed that bavachin inhibited the proliferation of human colorectal cancer cells and induce apoptosis. These changes were mediated by activating the MAPK signaling pathway, which significantly up-regulated the expression of Gadd45a. Furthermore, Gadd45a silencing obviously attenuated bavachin-mediated cell apoptosis. Inhibition of the MAPK signaling pathway by JNK/ERK/p38 inhibitors also weakened the up-regulation of Gadd45a by bavachin. The anticancer effect of bavachin was also validated using a mouse xenograft model of human colorectal cancer. In conclusion, these findings suggest that bavachin induces the apoptosis of colorectal cancer cells through activating the MAPK signaling pathway., (Copyright © 2023 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Paracrine signaling is a fundamental process regulating tissue development, repair, and pathogenesis of diseases such as cancer. Herein we describe a method for quantitatively measuring paracrine signaling dynamics, and resultant gene expression changes, in living cells using genetically encoded signaling reporters and fluorescently tagged gene loci. We discuss considerations for selecting paracrine "sender-receiver" cell pairs, appropriate reporters, the use of this system to ask diverse experimental questions and screen drugs blocking intracellular communication, data collection, and the use of computational approaches to model and interpret these experiments., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

Analyses of G-protein-mediated contraction and relaxation of vascular smooth muscle cells (VSMCs) are usually hampered by a rigid growth surface and culture conditions promoting cell proliferation and a less contractile phenotype. Our studies indicated that mouse aortic VSMCs cultured in three-dimensional spheroids acquire a quiescent contractile status while decreasing the baseline G-protein-dependent inositolphosphate formation and increasing the expression of endothelin receptor type A ( Ednra ). Endothelin-1 (ET-1) promoted inositolphosphate formation in VSMC spheroids, but not in VSMCs cultured under standard conditions. To trace ET-1-mediated contraction of VSMC spheroids, we developed an assay by adhering them to collagen hydrogels and recording structural changes by time-lapse microscopy. Under these conditions, mouse and human VSMC spheroids contracted upon treatment with ET-1 and potassium chloride or relaxed in response to caffeine and the prostacyclin analogue Iloprost. ET-1 activated AKT-, MKK1-, and MKK3/6-dependent signaling cascades, which were inhibited by an overexpressing regulator of G-protein signaling 5 ( Rgs5 ) to terminate the activity of Gα subunits. In summary, culture of VSMCs in three-dimensional spheroids lowers baseline G-protein activity and enables analyses of both contraction and relaxation of mouse and human VSMCs. This model serves as a simple and versatile tool for drug testing and investigating G-protein-depending signaling.

Herba Epimedii is a famous herb collected from China and Korea. It has been used for impotency, osteoporosis, and amnestic treatment for thousands of years. Icariin, a typical flavonoid compound isolated from Herba Epimedii, was reported as a potential anti-inflammatory drug. Icariside and icaritin are the two metabolites of icariin. Icariin and its metabolites have been used to treat a wide range of inflammatory diseases, such as atherosclerosis, Alzheimer's disease, depression, osteoarthritis, and asthma. They exert powerful suppression of proinflammatory signaling, such as NF-κB and MAPKs. More importantly, they can upregulate anti-inflammatory signaling, such as GR and Nrf2. In this study, we review the therapeutic effects and mechanisms of icariin and its metabolites in inflammatory diseases and provide novel insights into these potential anti-inflammatory drugs., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Current evidence suggests that bacteria contribute to the development of certain cancers, such as colorectal cancer (CRC), partly by stimulating chronic inflammation. However, little is known about the bacterial impact on molecular pathways in CRC. Recent studies have demonstrated how specific bacteria can influence the major CRC-related pathways, i.e., Wnt, PI3K-Akt, MAPK, TGF-β, EGFR, mTOR, and p53. In order to advance the current understanding and facilitate the choice of pathways to investigate, we have systematically collected and summarized the current knowledge within bacterial altered major pathways in CRC. Several pro-tumorigenic and anti-tumorigenic bacterial species and their respective metabolites interfere with the major signaling pathways addressed in this review. Not surprisingly, some of these studies investigated known CRC drivers, such as Escherichia coli, Fusobacterium nucleatum, and Bacteroides fragilis. Interestingly, some metabolites produced by bacterial species typically considered pathogenic, e.g., Vibrio cholera, displayed anti-tumorigenic activities, emphasizing the caution needed when classifying healthy and unhealthy microorganisms. The results collectively emphasize the complexity of the relationship between the microbiota and the tumorigenesis of CRC, and future studies should verify these findings in more realistic models, such as organoids, which constitute a promising platform. Moreover, future trials should investigate the clinical potential of preventive modulation of the gut microbiota regarding CRC development., (© 2022 Scandinavian Societies for Medical Microbiology and Pathology.)

Psoriasis, a chronic and immune-mediated inflammatory disease, adversely affects patients' lives. We previously prepared selenium-rich yeast peptide fraction (SeP) from selenium-rich yeast protein hydrolysate and found that SeP could effectively alleviate ultraviolet radiation-induced skin damage in mice and inhibited H 2 O 2 -induced cytotoxicity in cultured human epidermal keratinocyte (HaCaT) cells. This study aimed to investigate whether SeP had a protective effect on imiquimod (IMQ)-induced psoriasis-like dermatitis in mice and the underlying mechanisms. Results showed that SeP significantly ameliorated the severity of skin lesion in IMQ-induced psoriasis-like mouse model. Moreover, SeP treatment significantly attenuated the expression of key inflammatory cytokines, including interleukin (IL)-23, IL-17A, and IL-17F, in the dorsal skin of mice. Mechanistically, SeP application not only inhibited the activation of JNK and p38 MAPK, but also the translocation of NF-κB into the nucleus in the dorsal skin. Furthermore, SeP treatment inhibited the levels of inflammatory cytokines and the activation of MAPK and NF-κB signaling induced by lipopolysaccharide in HaCaT cells and macrophage cell line RAW264.7. Overall, our findings showed that SeP alleviated psoriasis-like skin inflammation by inhibiting MAPK and NF-κB signaling pathways, which suggested that SeP would have a potential therapeutic effect against psoriasis.

Background: The population with diabetes mellitus-induced erectile dysfunction is increasing rapidly, but current drugs are not effective in treating erectile dysfunction. Studies of the traditional Chinese medicine extract berberine on diabetes and its complications provide us with new ideas., Objectives: To evaluate the therapeutic effect and potential mechanism of berberine on the erectile function of diabetic rats., Materials and Methods: Fifty male Sprague-Dawley rats were randomly grouped, and 42 rats were injected intraperitoneally with streptozotocin to establish a diabetes model. Erectile dysfunction rats were screened out through the apomorphine test and randomly divided into the diabetes mellitus and berberine groups, and these animals were administered berberine (200 mg/kg/day) and normal saline by gavage for 4 weeks. Primary corpus cavernous smooth muscle cells from healthy rats were cultured and treated with berberine., Results: Fasting blood glucose in the diabetes mellitus group was significantly increased, while berberine showed no significant effect on glucose. Erectile function was obviously impaired in the diabetes mellitus group, and berberine administration partially rescued this impairment. The expression of sphingosine kinase 1, S1PR2, and sphingosine-1-phosphate in the diabetes mellitus group was increased. Berberine partially inhibited the expression of sphingosine kinase 1 and S1PR2, but the decrease in sphingosine-1-phosphate was not significant. Moreover, mitogen-activated protein kinase pathway factor expression was upregulated and eNOS activity was decreased in the diabetes mellitus group. Berberine treatment could partially reverse these alterations. Severe fibrosis and apoptosis were detected in diabetic rats, accompanied by higher expression of TGFβ1, collagen I/IV, Bax/Bcl-2, and caspase 3 than in the other groups. However, supplementation with berberine inhibited the expression of these proteins and attenuated fibrosis and apoptosis., Conclusions: Berberine ameliorated erectile dysfunction in rats with diabetes mellitus, possibly by improving endothelial function and inhibiting apoptosis and fibrosis by suppressing the sphingosine kinase 1/sphingosine-1-phosphate/S1PR2 and mitogen-activated protein kinase pathways., (© 2021 American Society of Andrology and European Academy of Andrology.)

Seneca Valley virus (SVV), a member of the Picornaviridae family, can activate autophagy via the PERK and ATF6 unfolded protein response pathways and facilitate viral replication; however, the precise molecular mechanism that regulates SVV-induced autophagy remains unclear. Here, we revealed that SVV infection inhibited the phosphorylation of mechanistic target of rapamycin kinase (MTOR) and activated phosphorylation of the serine/threonine kinase AKT. We observed that activating AMP-activated protein kinase (AMPK), extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MAPK), and p38 MAPK signaling by SVV infection promoted autophagy induction and viral replication; additionally, the SVV-induced autophagy was independent of the ULK1 complex. We further evaluated the role of viral protein(s) in the AKT-AMPK-MAPK-MTOR pathway during SVV-induced autophagy and found that VP1 induced autophagy, as evidenced by puncta colocalization with microtubule-associated protein 1 light chain 3 (LC3) in the cytoplasm and enhanced LC3-II levels. This might be associated with the interaction of VP1 with sequestosome 1 and promoting its degradation. In addition, the expression of VP1 enhanced AKT phosphorylation and AMPK phosphorylation, while MTOR phosphorylation was inhibited. These results indicate that VP1 induces autophagy by the AKT-AMPK-MTOR pathway. Additionally, expression of VP3 and 3C was found to activate autophagy induction via the ERK1/2 MAPK-MTOR and p38 MAPK-MTOR pathway. Taken together, our data suggest that SVV-induced autophagy has finely tuned molecular mechanisms in which VP1, VP3, and 3C contribute synergistically to the AKT-AMPK-MAPK-MTOR pathway. IMPORTANCE Autophagy is an essential cellular catabolic process to sustain normal physiological processes that are modulated by a variety of signaling pathways. Invading virus is a stimulus to induce autophagy that regulates viral replication. It has been demonstrated that Seneca Valley virus (SVV) induced autophagy via the PERK and ATF6 unfolded protein response pathways. However, the precise signaling pathway involved in autophagy is still poorly understood. In this study, our results demonstrated that viral proteins VP1, VP3, and 3C contribute synergistically to activation of the AKT-AMPK-MAPK-MTOR signaling pathway for SVV-induced autophagy. These findings reveal systemically the finely tuned molecular mechanism of SVV-induced autophagy, thereby facilitating deeper insight into the development of potential control strategies against SVV infection.

Increased intercellular tension is associated with enhanced cell proliferation and tissue growth. Here, we present evidence for a force-transduction mechanism that links mechanical perturbations of epithelial (E)-cadherin (CDH1) receptors to the force-dependent activation of epidermal growth factor receptor (EGFR, ERBB1)-a key regulator of cell proliferation. Here, coimmunoprecipitation studies first show that E-cadherin and EGFR form complexes at the plasma membrane that are disrupted by either epidermal growth factor (EGF) or increased tension on homophilic E-cadherin bonds. Although force on E-cadherin bonds disrupts the complex in the absence of EGF, soluble EGF is required to mechanically activate EGFR at cadherin adhesions. Fully quantified spectral imaging fluorescence resonance energy transfer further revealed that E-cadherin and EGFR directly associate to form a heterotrimeric complex of two cadherins and one EGFR protein. Together, these results support a model in which the tugging forces on homophilic E-cadherin bonds trigger force-activated signaling by releasing EGFR monomers to dimerize, bind EGF ligand, and signal. These findings reveal the initial steps in E-cadherin-mediated force transduction that directly link intercellular force fluctuations to the activation of growth regulatory signaling cascades., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

Staphylococcal enterotoxin A (SEA), the toxin protein secreted by Staphylococcus aureus , can cause staphylococcal food poisoning outbreaks and seriously threaten global public health. However, little is known about the pathogenesis of SEA in staphylococcal foodborne diseases. In this study, the effect of SEA on intestinal barrier injury and NLRP3 inflammasome activation was investigated by exposing BALB/c mice to SEA with increasing doses and a potential toxic mechanism was elucidated. Our findings suggested that SEA exposure provoked villi injury and suppressed the expression of ZO-1 and occludin proteins, thereby inducing intestinal barrier dysfunction and small intestinal injury in mice. Concurrently, SEA significantly up-regulated the expression of NLRP3 inflammasome-associated proteins and triggered the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathways in jejunum tissues. Notably, selective inhibitors of MAPKs and NF-κB p65 ameliorated the activation of NLRP3 inflammasome stimulated by SEA, which further indicated that SEA could activate NLRP3 inflammasome through NF-κB/MAPK pathways. In summary, SEA was first confirmed to induce intestinal barrier dysfunction and activate NLRP3 inflammasome via NF-κB/MAPK signaling pathways. These findings will contribute to a more comprehensive understanding of the pathogenesis of SEA and related drug-screening for the treatment and prevention of bacteriotoxin-caused foodborne diseases via targeting specific pathways.

Cancer begins due to uncontrolled cell division. Cancer cells are insensitive to the signals that control normal cell proliferation. This uncontrolled cell division is due to the accumulation of abnormalities in different factors associated with the cell division, including different cyclins, cell cycle checkpoint inhibitors, and cellular signaling. Cellular signaling pathways are aberrantly activated in cancer mainly due to epigenetic regulation and post-translational regulation. In this chapter, the role of epigenetic regulation in aberrant activation of PI3K/AKT, Ras, Wnt, Hedgehog, Notch, JAK/STAT, and mTOR signaling pathways in cancer progression is discussed. The role of epigenetic regulators in controlling the upstream regulatory proteins and downstream effector proteins responsible for abnormal cellular signaling-mediated cancer progression is covered in this chapter. Similarly, the role of signaling pathways in controlling epigenetic gene regulation-mediated cancer progression is also discussed. We have tried to ascertain the current status of potential epigenetic drugs targeting several epigenetic regulators to prevent different cancers., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Kirsten rat sarcoma 2 viral oncogene homolog ( Kras ) is a proto-oncogene that encodes the small GTPase transductor protein KRAS, which has previously been found to promote cytokine secretion, cell survival, and chemotaxis. However, its effects on preadipocyte differentiation and lipid accumulation are unclear. In this study, the effects of KRAS inhibition on proliferation, autophagy, and adipogenic differentiation as well as its potential mechanisms were analyzed in the 3T3-L1 and C2C12 cell lines. The results showed that KRAS was localized mainly in the nuclei of 3T3-L1 and C2C12 cells. Inhibition of KRAS altered mammalian target of rapamycin ( Mtor ), proliferating cell nuclear antigen ( Pcna ), Myc , peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer binding protein beta ( C/ebp-β ), diacylglycerol O-acyltransferase 1 ( Dgat1 ), and stearoyl-coenzyme A desaturase 1 ( Scd1 ) expression, thereby reducing cell proliferation capacity while inducing autophagy, enhancing differentiation of 3T3-L1 and C2C12 cells into mature adipocytes, and increasing adipogenesis and the capacity to store lipids. Moreover, during differentiation, KRAS inhibition reduced the levels of extracellular regulated protein kinases (ERK), c-Jun N-terminal kinase (JNK), p38, and phosphatidylinositol 3 kinase (PI3K) activation. These results show that KRAS has unique regulatory effects on cell proliferation, autophagy, adipogenic differentiation, and lipid accumulation.

Background: Gastric cancer) GC) is one of the most common cancer with high mortality worldwide. The human Wharton's jelly stem cells (hWJSCs) can inhibit several cancer cells through several molecular pathways. Therefore, the present study aimed to investigate anticancer effects of hWJSCs conditioned medium (hWJSC-CM) and cell-free lysate (hWJSC-CL) against of GC cell line AGS and underlying signaling pathways., Methods: In this study, we evaluated the effects of hWJSC-CM and hWJSC-CL on viability, proliferation, migration, invasion, apoptosis, and MAPK and NF-κB signaling pathways in AGS cells. Moreover, mRNA expression of genes involved in apoptosis (BAX, BCL2, SMAC, and SURVIVIN), as well as expression of proteins involved in NF-κB and MAPK signaling pathways were evaluated., Results: The obtained results showed that the hWJSC-CM and hWJSC-CL decreased viability, migration, and invasion of GC cell line AGS in a concentration and time dependent manner. We observed that the hWJSC-CM and hWJSC-CL induced apoptosis pathway through regulation of apoptosis involved genes mRNA expression. In addition, the hWJSC-CM and hWJSC-CL suppressed NF-κB signaling pathways as well as promoted MAPK signaling pathways., Conclusion: In general, our study suggested that the hWJSC-CM and hWJSC-CL inhibits proliferation and viability of GC cell line AGS through induction of apoptosis, as well as modification of NF-κB and MAPK signaling pathways., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

We performed X-ray diffraction analyses on rat plantaris muscle to determine if there are strain-specific structural changes at the molecular level after eccentric contraction (ECC). ECC was elicited in situ by supramaximal electrical stimulation through the tibial nerve. One hour after a series of ECC sessions, the structural changes that remained in the sarcomere were evaluated using X-ray diffraction. Proteins involved in cell signaling pathways in the muscle were also examined. ECC elicited by 100, 75, and 50 Hz stimulation respectively developed peak tension of 1.34, 1.12 and 0.79 times the isometric maximal tetanus tension. The series of ECC sessions phosphorylated the forkhead box O proteins (FoxO) in a tension-time integral-dependent manner, as well as phosphorylated the mitogen-activated protein kinases (MAPK) and a protein in the mammalian target of rapamycin (mTOR) pathway in a maximal tension dependent manner. Compared to isometric contractions, ECC was more efficient in phosphorylating the signaling proteins. X-ray diffraction revealed that the myofilament lattice was preserved even after intense ECC stimulation at 100 Hz. Additionally, ECC < 75 Hz preserved the molecular alignment of myoproteins along the myofilaments, while 75-Hz stimulation induced a slight but significant decrease in the intensity of meridional troponin reflection at 1/38 nm -1 , and of myosin reflection at 1/14.4 nm -1 . These two reflections demonstrated no appreciable decrease with triple repetitions of the standard series of ECC sessions at 50 Hz, suggesting that the intensity decrease depended on the instantaneous maximal tension development rather than the total load of contraction, and was more likely linked with the phosphorylation of MAPK and mTOR signaling proteins.

Ischemia/reperfusion injury (IRI) in the kidney is the most common cause of acute renal dysfunction through different cell damage mechanisms. This study aimed to investigate, on molecular basics for the first time, the effect of pantoprazole on renal IRI in rats. Different biochemical parameters and oxidative stress markers were assessed. ELISA was used to estimate proinflammatory cytokines. qRT-PCR and western blot were used to investigate the gene and protein expression. Renal histopathological examination was also performed. IRI resulted in tissue damage, elevation of serum levels of creatinine, urea nitrogen, malondialdehyde, TNF-α, IL-6, IL-1β, up-regulation of NF-κB, JNK1/2, ERK1/2, p38, and cleaved caspase-3 proteins. Furthermore, it up-regulated the expression of the Bax gene and down-regulated the expression of the Bcl -2 gene. Treatment of the injured rats with pantoprazole, either single dose or multiple doses, significantly alleviated IRI-induced biochemical and histopathological changes, attenuated the levels of proinflammatory cytokines, down-regulated the expression of NF-κB, JNK1/2, ERK1/2, p38, and cleaved caspase-3 proteins, and the Bax gene, and up-regulated Bcl -2 gene expression. Moreover, treatment with pantoprazole multiple doses has an ameliorative effect that is greater than pantoprazole single-dose. In conclusion, pantoprazole diminished renal IRI via suppression of apoptosis, attenuation of the pro-inflammatory cytokines' levels, and inhibition of the intracellular signaling pathway MAPK (ERK1/2, JNK, p38)-NF-κB.

Colorectal cancer (CRC) is a predominant malignancy worldwide, being the fourth most common cause of mortality and morbidity. The CRC incidence in adolescents, young adults, and adult populations is increasing every year. In the pathogenesis of CRC, various factors are involved including diet, sedentary life, smoking, excessive alcohol consumption, obesity, gut microbiota, diabetes, and genetic mutations. The CRC tumor microenvironment (TME) involves the complex cooperation between tumoral cells with stroma, immune, and endothelial cells. Cytokines and several growth factors (GFs) will sustain CRC cell proliferation, survival, motility, and invasion. Epidermal growth factor receptor (EGFR), Insulin-like growth factor -1 receptor (IGF-1R), and Vascular Endothelial Growth Factor -A (VEGF-A) are overexpressed in various human cancers including CRC. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) and all the three major subfamilies of the mitogen-activated protein kinase (MAPK) signaling pathways may be activated by GFs and will further play key roles in CRC development. The main aim of this review is to present the CRC incidence, risk factors, pathogenesis, and the impact of GFs during its development. Moreover, the article describes the relationship between EGF, IGF, VEGF, GFs inhibitors, PI3K/AKT/mTOR-MAPK signaling pathways, and CRC., Competing Interests: The authors declare no conflict of interest.