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Macrophage cholesterol homeostasis is crucial for health and disease and has been linked to the lipid-peroxidizing enzyme arachidonate 15-lipoxygenase type B (ALOX15B), albeit molecular mechanisms remain obscure. We performed global transcriptome and immunofluorescence analysis in ALOX15B-silenced primary human macrophages and observed a reduction of nuclear sterol regulatory element-binding protein (SREBP) 2, the master transcription factor of cellular cholesterol biosynthesis. Consequently, SREBP2-target gene expression was reduced as were the sterol biosynthetic intermediates desmosterol and lathosterol as well as 25- and 27-hydroxycholesterol. Mechanistically, suppression of ALOX15B reduced lipid peroxidation in primary human macrophages and thereby attenuated activation of mitogen-activated protein kinase ERK1/2, which lowered SREBP2 abundance and activity. Low nuclear SREBP2 rendered both, ALOX15B-silenced and ERK1/2-inhibited macrophages refractory to SREBP2 activation upon blocking the NPC intracellular cholesterol transporter 1. These studies suggest a regulatory mechanism controlling macrophage cholesterol homeostasis based on ALOX15B-mediated lipid peroxidation and concomitant ERK1/2 activation.

Background: HTLV-1 is a worldwide distribution retrovirus with 10–20 million infected individuals. ATLL is an Adult T-cell leukaemia lymphoma caused by aggressive T-cell proliferation that is infected by HTLV-1 and is associated with an inferior prognosis. The exact molecular pathogenesis has yet to be fully understood. CREB, a transcription factor, acts as a molecular switch that controls the expression of numerous genes in response to various extracellular signals. Its activation is primarily mediated through phosphorylation by multiple kinases, including MAPKs. MAPKs, a family of serine/threonine kinases, serve as crucial mediators of intracellular signaling cascades. Method and material: This study investigated, 38 HTLV-I-infected individuals, including 18 HTLV-1 asymptomatic carriers (ACs) and 20 ATLL subjects. mRNA was extracted and converted to cDNA from Peripheral blood mononuclear cells (PBMCs), and then the expression of TAX, HBZ, CREB, and MAPK was analyzed by TaqMan qPCR. The genomic HTLV-1 Proviral loads were examined among the study group. Results: The data analysis showed a significant difference in the mean of CREB expression amongst study groups (ATLL and carriers, (p = 0.002). There is no statistical difference between the MAPK gene expression (p = 0.35). HBZ, TAX, and HTLV-1 proviral load weree significantly higher in ATLL subjects compared to ACs (p = 0.002, 0.000, and 0.000), respectively. Moreover, our results, demonstrated a direct positive correlation among HBZ, CREB, and TAX gene expression in ATLL patients (p = 0.001), whilst between the ACs, TAX gene expression had a positive significant correlation with HBZ and HTLV-1 proviral load (p = 0.007 and p = 0.004, respectively). Conclusion: The present study demonstrated that CREB gene expression was higher in the ATLL group than ACs, while there was no difference for MAPK. Therefore, this pathway may not strongly involve in the activation of CREB. The CREB may be a prognostic factor for the development of HTLV-I-associated diseases and can be used as a monitoring marker for the efficiency of the therapeutic regime and prognosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

BACKGROUND: Mesenchymal stem cells possess characteristics such as rapid renewal, targeted homing, tissue repair, and immune regulation, which provide potential for the treatment of inflammatory diseases. In most inflammatory diseases, interleukin-1β is highly expressed. Both exogenous and endogenous mesenchymal stem cells unavoidably exist in an environment with high interleukin -1β concentration. OBJECTIVE: To study the interaction of interleukin-1β with mesenchymal stem cells in inflammatory environment and the mechanism of its influence on the migration and adhesion of mesenchymal stem cells to provide a theoretical basis for adjusting stem cell therapy strategies. METHODS: The first author searched for studies involving interleukin-1β enhancing migration and adhesion of mesenchymal stem cells by computer on CNKI, WanFang, VIP, PubMed, and Web of Science using search terms “interleukin-1β, mesenchymal stem cell, nuclear factor-κB, MAPK, ERK, p38, migration, adhesion” in Chinese and English. The literature tracing method was also used to search for some of the literature. Finally, 65 articles were included in the review analysis. RESULTS AND CONCLUSION: (1) In the inflammatory environment, interleukin-1β can regulate the migration and adhesion ability of mesenchymal stem cells. This effect may be achieved by recruiting IRAK1 through interleukin-1RI and then activating TAK1 and IKK in turn. After IKK phosphorylation, nuclear factor-κB and ERK signaling pathways are activated or CXCR expression is upregulated through the p38 pathway to promote mesenchymal stem cell migration and adhesion. However, further standardized research needs to be carried out based on the genetic background of mesenchymal stem cells, the dose and processing time of interleukin-1β. (2) In vitro experiments using pre-stimulated mesenchymal stem cells with interleukin-1β can change the survival environment of mesenchymal stem cells and alter their secretion factors to make them develop towards a more anti-inflammatory direction. On the other hand, under the premise of producing higher levels of anti-inflammatory and pro-nutrient factors, extracted mesenchymal stem cell exosomes can exert antiinflammatory effects. (3) It has been observed in various animal disease models that pre-stimulating mesenchymal stem cells with interleukin-1β regulates their immune regulation ability, thereby affecting the development and outcome of inflammation. However, this is limited to preclinical basic research only; further verification on efficacy and safety of stem cell therapy with interleukin-1β pre-treated mesenchymal stem cells is required in clinical settings. [ABSTRACT FROM AUTHOR]

To explore diagnostic and prognostic biomarkers in the progression of oral squamous cell carcinoma (OSCC) and to reveal their regulatory mechanisms in key pathways. A RayBiotech protein chip was used to screen differentially expressed serum proteins in OSCC, oral leukoplakia (OLK), and healthy participants. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to determine the pathways enriched by characteristic differential proteins. Immunohistochemical analysis and western blotting were used to verify the expression of characteristic differential proteins and key regulatory factors in human tissues and in a nude mouse model. Fibroblast growth factor 6 (FGF6) was identified as a key differential protein and was weakly expressed in OSCC tissues. The mitogen-activated protein kinases (MAPK) and PI3K-AKT pathways were identified as key signaling pathways. The results showed that pERK, Cyclin D1, pAKT, and BCL2 were highly expressed in OSCC, Caspase9 was lowly expressed in OSCC. With an increase in FGF6 expression in nude mice, the expression of FGFR4, pERK, Cyclin D1, pAKT, BCL2, GPX4, and ACSL4 increased, and the expression of Caspase9 decreased. FGF6 may change the expression of apoptosis-related proteins and proliferation factors by binding to FGFR4 in the PI3K-AKT/MAPK pathway and may inhibit the ferroptosis of OSCC, thereby possibly participating in the process of inhibiting OSCC. [ABSTRACT FROM AUTHOR]

Summary In Magnaporthe oryzae, the Pmk1 MAP kinase signaling pathway regulates appressorium formation, plant penetration, effector secretion, and invasive growth. While the Mst11‐Mst7‐Pmk1 cascade was characterized two decades ago, knowledge of its signaling in the intracellular network remains limited. In this study, we demonstrate that the endosomal surface scaffolds Pmk1 MAPK signaling and Msb2 activates Ras2 on endosomes in M. oryzae. Protein colocalization demonstrated that Msb2, Ras2, Cap1, Mst50, Mst11, Mst7, and Pmk1 attach to late endosomal membranes. Damage to the endosome–vacuole transport system influences Pmk1 phosphorylation. When Msb2 senses a plant signal, it internalizes and activates Ras2 on endosome membrane surfaces, transmitting the signal to Pmk1 via Mst11 and Mst7. Signal‐sensing and delivery proteins are ubiquitinated and sorted for degradation in late endosomes and vacuoles, terminating signaling. Plant penetration and lowered intracellular turgor are required for the transition from late endosomes to vacuoles in appressoria. Our findings uncover an effective mechanism that scaffolds and controls Pmk1 MAPK signaling through endosomal–vacuolar transport, offering new knowledge for the cytological and molecular mechanisms by which the Pmk1 MAPK pathway modulates development and pathogenicity in M. oryzae. [ABSTRACT FROM AUTHOR]

IKKε is an IκB kinase participating in the control of NF-κB and type I IFN signal pathways in mammals. However, the function of IKKε in regulating immune response is largely unknown in teleost. Herein, an IKKε homologue named AjIKKε was characterized in Japanese eel (Anguilla japonica). AjIKKε has an N-terminal kinase domain, a ubiquitin-like domain, and a coiled coil-containing domain (CC), which is conserved and similar to its counterpart in mammals. Expression analysis showed that AjIKKε could be up-regulated in kidney, spleen, and particularly in liver under the stimulation of poly I:C, LPS, and Aeromonas hydrophila infection. In vitro, the mRNA levels of AjIKKε were significantly provoked in eel liver cells stimulated by LPS and poly I:C, or the different concentrations of A. hydrophila. The overexpression of AjIKKε could not only induce a significantly higher level of promoter activity of human NF-κB, AP-1, and IFN-β in a dose-dependent manner but also upregulate the activation of promoters of Japanese eel cRel, AP1, IL6, IFN4, IRF3, and IRF7 in HEK293 cells. RNAi studies showed that after AjIKKε was knocked down, the expression levels of IL1, IL6, TNFα, c-Jun, IFN2, IFN3, MX1, MX2, and IRF3 genes were significantly down-regulated in liver, spleen, and kidney of Japanese eels. In addition, the mutants of AjIKKε-K39A, AjIKKε-S174A, and AjIKKε-ΔCC failed to activate Japanese eel IFN4, IRF3 and human IFN-β promoters in HEK293 cells. Collectively, these results suggest that AjIKKε may function as a positive regulator of NF-κB, MAPK, and IRF3-mediated type I IFN signaling pathways related to immune response evoked by bacterial and viral infection. [ABSTRACT FROM AUTHOR]

Preeclampsia (preE) is a hypertensive disorder in pregnancies. It is the third leading cause of mortality among pregnant women and fetuses worldwide, and there is much we have yet to learn about its pathophysiology. One complication includes cerebral edema, which causes a breach of the blood–brain barrier (BBB). Urinary marinobufagenin (MBG) is elevated in a preE rat model prior to developing hypertension and proteinuria. We investigated what effect MBG has on the endothelial cell permeability of the BBB. Human brain microvascular endothelial cells (HBMECs) were utilized to examine the permeability caused by MBG. The phosphorylation of ERK1/2, Jnk, p38, and Src was evaluated after the treatment with MBG. Apoptosis was evaluated by examining caspase 3/7. MBG ≥ 1 nM inhibited the proliferation of HBMECs by 46–50%. MBG induced monolayer permeability, causing a decrease in the phosphorylation of ERK1/2 and the activated phosphorylation of Jnk, p38, and Src. MBG increased the caspase 3/7 expression, indicating the activation of apoptosis. Apoptotic signaling or the disruption of endothelia tight junction proteins was not observed when using the p38 inhibitor as a pretreatment in MBG-treated cells. The MBG-induced enhancement of the HBMEC monolayer permeability occurs by the downregulation of ERK1/2, the activation of Jnk, p38, Src, and apoptosis, resulting in the cleavage of tight junction proteins, and are attenuated by p38 inhibition. [ABSTRACT FROM AUTHOR]

AbstractOne of the most common causes of cancer-related death in women worldwide is breast cancer(Edited)Restore original. Factors such as increased expression of HER family members can contribute to its development. Elevated HER3 expression, especially when combined with other tyrosine kinase receptors such as HER2, plays a significant role in activating cancer pathways crucial for cell survival and proliferation in breast cancer. Detecting high HER3 levels is essential for effective cancer treatment. Affibody proteins, a class including antibodies, are utilized to detect elevated HER3 receptor expression due to their specific high binding affinity. Affibodies, a new type of non-immune probe, show promise in therapy, diagnostics, and biotechnology due to their exceptional specificity and high target protein affinity. The innovative design of these recombinant affibodies not only enhances the accuracy of HER3 detection but also facilitates the development of targeted therapeutic strategies. By employing advanced engineering techniques, these affibodies can be optimized for improved stability and binding efficacy, making them ideal candidates for clinical applications. Additionally, the versatility of affibody-based systems allows for potential integration with imaging technologies, enabling real-time monitoring of HER3 expression and therapeutic response. This multifaceted approach could ultimately lead to more personalized treatment options for patients with HER3-positive breast cancers, thereby improving overall patient management and outcomes in this challenging disease landscape. This study presents recombinant affibodies tailored to bind to HER3 for cancer cell identification, along with novel methods for producing a range of affibody molecules. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Syndecan 4 (SDC4), a type I transmembrane proteoglycan, serves as a critical link between chondrocytes and the extracellular matrix. Objective: This study aimed to explore the role of SDC4 in cartilage degeneration of temporomandibular joint osteoathritis (TMJOA). Methods: Condylar chondrocytes were stimulated with varying concentrations of recombinant rat interleukin‐1β (rrIL‐1β) and SDC4 small interfering RNA (si‐SDC4). Anti‐SDC4 ectodomain‐specific antibodies or IgG were intra‐articularly administrated in a TMJOA model rats. SDC4 conditional knockout (SDC4‐cKO) and Sdc4flox/flox mice were induced TMJOA. Cartilage degeneration was assessed using haematoxylin & eosin (H&E) and safranin O (SO) staining. Protein levels of SDC4, matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase with a thrombospondin motifs 5 (ADAMTS5), tumour necrosis factor α (TNFα), type II collagen (Col‐II), aggrecan (ACAN), cleaved caspase 3 (CASP3), Ki67 and related pathways in condylar cartilage were evaluated by immunohistochemical (IHC) staining or western blot assays. Results: SDC4 expression was evidently increased in MIA‐model animals compared to control groups. rrIL‐1β stimulation increased the expression of SDC4, MMP3 and ADAMTS5 expression in chondrocytes, while decreasing the expression of Col‐II. These effects were reversed by si‐SDC4 in vitro. In vivo, SDC4 blockade reduced the death of chondrocytes and the loss of cartilage matrix, which was evidenced by increased expression of Col‐II and ACAN, and a decrease in SDC4, MMP13 and cleaved‐CASP3‐positive cells. Furthermore, the protein levels of ACAN and Ki67 were elevated, and the ERK1/2 and P38 signalling pathways were activated following SDC4 inhibition. Conclusions: SDC4 inhibition significantly ameliorates condylar cartilage degeneration, which was mediated, at least partly, through P38 and ERK1/2 signalling. Inhibition of SDC4 may be of great value for the treatment of TMJOA. [ABSTRACT FROM AUTHOR]

BACKGROUND: Dendrobium officinale flos (DOF), a novel food raw material, is used in Chinese folk medicine to nourish the stomach. However, there is still no available study to evaluate the effects of DOF on animal models of acute gastric injury and its mechanism by modern pharmacological research. RESULTS: Herein, we characterized the major components of an aqueous extract of DOF and assessed its potential ameliorative effects in a rat model of acute gastric mucosal injury. The DOF water extract showed significant protective effects on the gastric mucosa and exhibited excellent antioxidant and anti‐inflammatory activities. Acute gastric injury rat models induced by ethanol (6 mL kg−1) were pretreated with different doses of DOF water extract (50–100 mg kg−1 day−1), and the biological effects of DOF extract in gastric tissues were evaluated. DOF extract alleviated the symptoms of ethanol‐stimulated acute gastric mucosal injury, as evidenced by a significant reduction in gastric injury index and the degree of gastric pathological changes. Additionally, treatment with DOF extract upregulated mucin expression in the gastric mucosa, attenuated oxidative stress, decreased the release of inflammatory mediators (TNF‐α, IL‐6), suppressed the expression of key proinflammatory enzymes (COX‐2 and iNOS), reduced the phosphorylation of p38 MAPK and p65 NF‐κB and increased the level of PGE2 in gastric tissues. CONCLUSION: DOF exerts protective effects against ethanol‐induced acute gastric mucosal injury, mainly by inhibiting inflammation and oxidative stress. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Background/Objectives: Glehnia littoralis is a medicinal plant, but the scientific basis is still unclear. This study thoroughly investigated phenols from Glehnia littoralis extract (GLE) to determine their potential as anti-inflammatory and antioxidant agents. Methods: High-performance liquid chromatography (HPLC) and mass spectrometry (MS) were used to analyze the compounds in GLE. In addition, we performed GLE in vitro in macrophages after lipopolysaccharide (LPS)-induced inflammation. Results: The extract contained eight peaks representing phenolic compounds and one peak representing riboflavin, with the corresponding mass spectrometry data documented. These biologically active compounds were purified by ultrafiltration using LC to determine their ability to target cyclooxygenase-2 (COX-2) and 2,2-diphenyl-1-picrylhydrazyl (DPPH). The results showed that significant compounds were identified, demonstrating a binding affinity for both COX-2 and DPPH. This suggests that the compounds showing excellent binding affinity for COX-2 and DPPH may be the main active ingredients. Vital inflammatory cytokines, including COX-2, inducible nitric oxide synthase (iNOS), mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF-κB), were found to be down-regulated during the treatment. In addition, we revealed that the selected drugs exhibited potent binding capacity to inflammatory factors through molecular docking studies. In addition, we confirmed the presence of phenolic components in GLE extract and verified their possible anti-inflammatory and antioxidant properties. Conclusions: This study provided evidence for an efficient strategy to identify critical active ingredients from various medicinal plants. These data may serve as a baseline for further investigations of applying GLE in the pharmaceutical industry. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Severe COVID-19 is associated with neutrophilic inflammation and immunothrombosis. Several members of the IL-17 cytokine family have been associated with neutrophilic inflammation and activation of the endothelium. Therefore, we investigated whether these cytokines were associated with COVID-19. Methods: We investigated the association between COVID-19 and circulating plasma levels of IL-17 cytokine family members in participants to the Biobanque québécoise de la COVID-19 (BQC19), a prospective observational cohort and an independent cohort from Western University (London, Ontario). We measured the in vitro impact of IL-17F on intercellular adhesion molecule 1 (ICAM-1) cell surface expression and neutrophil adhesion on endothelial cells in culture. The contribution of two Mitogen Activated Protein Kinase (MAPK) pathways was determined using small molecule inhibitors PD184352 (a MKK1/MKK2 inhibitor) and BIRB0796 (a p38 MAPK inhibitor). Results: We found increased IL-17D and IL-17F plasma levels when comparing SARS-CoV-2-positive vs negative hospitalized participants. Moreover, increased plasma levels of IL-17D, IL-17E and IL-17F were noted when comparing severe versus mild COVID-19. IL-17F, but not IL-17A, was significantly elevated in people with COVID-19 compared to healthy controls and with more severe disease. In vitro work on endothelial cells treated with IL-17F for 24h showed an increase cell surface expression of ICAM-1 accompanied by neutrophil adhesion. The introduction of two MAPK inhibitors significantly reduced the binding of neutrophils while also reducing ICAM-1 expression at the surface level of endothelial cells, but not its intracellular expression. Discussion: Overall, these results have identified an association between two cytokines of the IL-17 family (IL-17D and IL-17F) with COVID-19 and disease severity. Considering that IL-17F stimulation promotes neutrophil adhesion to the endothelium in a MAPK-dependent manner, it is attractive to speculate that this pathway may contribute to pathogenic immunothrombosis in concert with other molecular effectors. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a prevalent chronic pulmonary fibrosis disease characterized by alveolar epithelial cell damage, fibroblast proliferation and activation, excessive extracellular matrix deposition, and abnormal epithelial- mesenchymal transition (EMT), resulting in tissue remodeling and irreversible structural distortion. The mortality rate of IPF is very high, with a median survival time of 2-3 years after diagnosis. The exact cause of IPF remains unknown, but increasing evidence supports the central role of epigenetic changes, particularly microRNA (miRNA), in IPF. Approximately 10% of miRNAs in IPF lung tissue exhibit differential expression compared to normal lung tissue. Diverse miRNA phenotypes exert either a pro-fibrotic or anti-fibrotic influence on the progression of IPF. In the context of IPF, epigenetic factors such as DNA methylation and long non-coding RNAs (lncRNAs) regulate differentially expressed miRNAs, which in turn modulate various signaling pathways implicated in this process, including transforming growth factor-β1 (TGF-β1)/ Smad, mitogen-activated protein kinase (MAPK), and phosphatidylinositol-3- kinase/protein kinase B (PI3K/AKT) pathways. Therefore, this review presents the epidemiology of IPF, discusses the multifaceted regulatory roles of miRNAs in IPF, and explores the impact of miRNAs on IPF through various pathways, particularly the TGF-β1/Smad pathway and its constituent structures. Consequently, we investigate the potential for targeting miRNAs as a treatment for IPF, thereby contributing to advancements in IPF research. [ABSTRACT FROM AUTHOR]

Background: Visceral adipose tissue (VAT) abnormalities are directly associated with obesity‐associated disorders. The underlying mechanisms that confer increased pathological risk to VAT in obesity have not been fully described. Methods: A case‐control study was conducted that included 10 women with obesity (36.80 ± 7.39 years, BMI ≥ 30 kg/m2) and 10 women of normal weight (32.70 ± 9.45 years, BMI < 24.9 kg/m2). RNA was extracted from greater omentum biopsies, and, using a DNA microarray, differential transcriptomic expression of VAT in women with obesity was evaluated taking as a reference that of women with normal weight. The differentially expressed genes (DEGs) were classified into functional biological processes and signaling pathways; moreover, the protein–protein interaction (PPI) networks were integrated for a deeper analysis of the pathways and genes involved in the central obesity‐associated disorders. The expression of TNF‐α, MAPK, and AKT proteins was also quantified in VAT. Results: The VAT of women with obesity had 3808 DEGs, mainly associated with the cellular process of inflammation and carbohydrates and lipid metabolism. Overexpressed genes were associated with inflammatory, metabolic, hormonal, neuroendocrine, carcinogenic, and infectious pathways. Cellular processes related to addictive behaviors were notable. MAPK and PI3K‐AKT pathways were overexpressed, and Mapk1 and Akt3 genes were common crossing points among obesity‐associated disorders' pathways. The increased expression of MAPK, AKT, and TNF proteins was confirmed in the VAT of women with obesity. Conclusion: VAT confers a complex and blended pathogenic transcriptomic profile in obese patients, where abnormal processes are mainly controlled by activating intracellular signaling pathways that exhibit a high degree of redundancy. Identifying shared cross points between those pathways could allow specific targeting treatments to exert a widespread effect over multiple pathogenic processes. [ABSTRACT FROM AUTHOR]

Licorice is a therapeutic herb in traditional Chinese herbal medicine. Licorice is considered as an anti‐inflammatory agent due to its suppression and inhibition of inflammatory pathways. Licorice has many bioactive compounds such as glycyrrhetinic acid, glycyrrhizin, liquiritigenin, and isoliquirtigenin which are principally accountable for its therapeutic benefits. These bioactive components reduce inflammation by preventing the activation of important inflammatory pathways including mitogen‐activated protein kinases (MAPKs) and nuclear factor‐kappa B (NF‐κB). As a result of this tumor necrosis factor‐alpha (TNF‐α), interleukin‐1 beta (IL‐1β) and interleukin‐6 (IL‐6) are among the proinflammatory cytokines whose production is inhibited. Components present in licorice inhibit the activation by suppressing the IκBα phosphorylation and degradation. Moreover, licorice compounds also attenuate the MAPK signaling cascades by inhibiting the MAPK kinase phosphorylation and downstream MAPKs such as extracellular signal–regulated kinase (ERK), p38 MAPK, and c‐Jun N‐terminal kinase (JNK). The present review focuses on the current understanding of licorice effect on the NF‐κB and MAPK inflammatory cell signaling pathways at molecular level. Furthermore, emerging evidence suggested that licorice‐derived bioactive compounds may attenuate the molecular mechanism which is associated with inflammation, providing the additional insights into the therapeutic potential. Further studies explained the precise molecular mechanism at the cellular level underlying the licorice anti‐inflammatory effect and potential application in managing inflammatory disorders. In conclusion, licorice has a complex mode of action and is a valuable natural anti‐inflammatory. Its natural origin and effectiveness in clinical applications make it an intriguing topic for additional study. As licorice becomes more widely used in medicine, future research should focus on refining its formulations to optimize therapeutic advantages. [ABSTRACT FROM AUTHOR]

ABSTRACT Fermented and aged mountain‐cultivated ginseng sprouts (FAMCGS) exhibit superior antioxidant and anti‐inflammatory properties compared to mountain‐cultivated ginseng sprouts (MCGS). However, the mechanisms behind these properties of FAMCGSE remain unclear. This study explores the anti‐inflammatory effects of FAMCGS extract (FAMCGSE) on LPS‐stimulated RAW 264.7 macrophages and the underlying mechanisms. The MTT assay confirmed that FAMCGSE (0 to 0.1%) maintained cell viability without inducing morphological changes. Pretreatment with FAMCGSE significantly mitigated LPS‐induced morphological alterations dose‐dependently. RT‐PCR and Western blot analyses showed that FAMCGSE significantly reduced the mRNA and protein levels of proinflammatory mediators such as TNF‐α, IL‐1β, IL‐6, iNOS, and COX‐2. Additionally, FAMCGSE decreased the production of TNF‐α, IL‐1β, IL‐6, nitric oxide, and PGE2 in LPS‐activated RAW264.7 cells. Mechanistically, FAMCGSE inhibited the phosphorylation of mitogen‐activated protein kinases (MAPKs; ERK, p38, and JNK) and prevented the LPS‐induced nuclear translocation of NF‐κB, with effects comparable to compound K (CK) or dexamethasone. Notably, FAMCGSE was particularly effective in inhibiting ERK and JNK activation, with less impact on p38, suggesting a specific inhibitory action on certain MAPK pathways. These findings highlight FAMCGSE's potential as an inhibitor of MAPK and NF‐κB pathways, indicating that FAMCGSE, including its main component CK, may be a promising therapeutic agent for inflammation‐related conditions. [ABSTRACT FROM AUTHOR]

Prolonged use of atypical antipsychotics (AAPs) is commonly associated with increased cardiovascular disease risk. While weight gain and related health issues are generally considered the primary contributors to this risk, direct interference with mitochondrial bioenergetics, particularly in the liver where these drugs are metabolized, is emerging as an additional contributing factor. Here, we compared the effects of two AAPs with disparate metabolic profiles on the response of Fao hepatoma cells to oxidative stress: olanzapine (OLA), which is obesogenic, and aripiprazole (ARI), which is not. Results showed that cells treated with ARI exhibited resistance to H2O2-induced oxidative stress, while OLA treatment had the opposite effect. Despite enhanced survival, ARI-treated cells exhibited higher apoptotic rates than OLA-treated cells when exposed to H2O2. Gene expression analysis of pro- and anti-apoptotic factors revealed that ARI-treated cells had a generally blunted response to H2O2, contrasting with a heightened response in OLA-treated cells. This was further supported by the reduced activation of MAPKs and STAT3 in ARI-treated cells in response to H2O2, whereas OLA pre-treatment enhanced their activation. The loss of stress response in ARI-treated cells was consistent with the observed increase in the mitochondrial production of O2•-, a known desensitizing factor. The physiological relevance of O2•- in ARI-treated cells was demonstrated by the increase in mitophagy flux, likely related to mitochondrial damage. Notably, OLA treatment protected proteasome activity in Fao cells exposed to H2O2, possibly due to the better preservation of stress signaling and mitochondrial function. In conclusion, this study highlights the underlying changes in cell physiology and mitochondrial function by AAPs. ARI de-sensitizes Fao cells to stress signaling, while OLA has the opposite effect. These findings contribute to our understanding of the metabolic risks associated with prolonged AAP use and may inform future therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: The immunoglobulin superfamily protein Trem2 (triggering receptor expressed on myeloid cells 2) is primarily expressed on myeloid cells where it functions to regulate macrophage‐related immune response induction. While macrophages are essential mediators of diabetic wound healing, the specific regulatory role that Trem2 plays in this setting remains to be established. Objective: This study was developed to explore the potential importance of Trem2 signalling in diabetic wound healing and to clarify the underlying mechanisms through which it functions. Methods and results: Following wound induction, diabetic model mice exhibited pronounced upregulation of Trem2 expression, which was primarily evident in macrophages. No cutaneous defects were evident in mice bearing a macrophage‐specific knockout of Trem2 (T2‐cKO), but they induced more pronounced inflammatory responses and failed to effectively repair cutaneous wounds, with lower levels of neovascularization, slower rates of wound closure, decreased collagen deposition following wounding. Mechanistically, we showed that interleukin (IL)‐4 binds directly to Trem2, inactivating MAPK/AP‐1 signalling to suppress the expression of inflammatory and chemoattractant factors. Co‐culture of fibroblasts and macrophages showed that macrophages from T2‐cKO mice suppressed the in vitro activation and proliferation of dermal fibroblasts through upregulation of leukaemia inhibitory factor (Lif). Injecting soluble Trem2 in vivo was also sufficient to significantly curtail inflammatory responses and to promote diabetic wound healing. Conclusions: These analyses offer novel insight into the role of IL‐4/Trem2 signalling as a mediator of myeloid cell‐fibroblast crosstalk that may represent a viable therapeutic target for efforts to enhance diabetic wound healing. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Bufadienolides, specifically bufalin, have garnered attention for their potential therapeutic application in modulating inflammatory pathways. Bufalin is derived from toad venom and exhibits promising anti-inflammatory properties. Its anti-inflammatory effects have been demonstrated by influencing crucial signaling pathways like NF-B, MAPK, and JAK-STAT, resulting in the inhibition of pro-inflammatory substances like cytokines, chemokines, and adhesion molecules. Bufalin blocks inflammasome activation and reduces oxidative stress, hence increasing its anti-inflammatory properties. Bufalin has shown effectiveness in reducing inflammation-related diseases such as cancer, cardiovascular problems, and autoimmune ailments in preclinical investigations. Furthermore, producing new approaches of medication delivery and combining therapies with bufalin shows potential for improving its effectiveness and reducing adverse effects. This review explores the pharmacological effects and mechanistic approaches of bufalin as an anti-inflammatory agent, which further highlights its potential for therapy and offers the basis for further study on its therapeutic application in inflammation-related disorders. [ABSTRACT FROM AUTHOR]

Steroid-induced osteonecrosis of the femoral head (SONFH) is a prevalent form of osteonecrosis in young individuals. More efficacious clinical strategies must be used to prevent and treat this condition. One of the mechanisms through which SONFH operates is the disruption of normal differentiation in bone marrow adipocytes and osteoblasts due to prolonged and extensive use of glucocorticoids (GCs). In vitro, it was observed that atorvastatin (ATO) effectively suppressed the impact of dexamethasone (DEX) on bone marrow mesenchymal stem cells (BMSCs), specifically by augmenting their lipogenic differentiation while impeding their osteogenic differentiation. To investigate the underlying mechanisms further, we conducted transcriptome sequencing of BMSCs subjected to different treatments, leading to the identification of Wnt5a as a crucial gene regulated by ATO. The analyses showed that ATO exhibited the ability to enhance the expression of Wnt5a and modulate the MAPK pathway while regulating the Wnt canonical signaling pathway via the WNT5A/LRP5 pathway. Our experimental findings provide further evidence that the combined treatment of ATO and DEX effectively mitigates the effects of DEX, resulting in the upregulation of osteogenic genes (Runx2, Alpl, Tnfrsf11b, Ctnnb1, Col1a) and the downregulation of adipogenic genes (Pparg, Cebpb, Lpl), meanwhile leading to the upregulation of Wnt5a expression. So, this study offers valuable insights into the potential mechanism by which ATO can be utilized in the prevention of SONFH, thereby holding significant implications for the prevention and treatment of SONFH in clinical settings. [ABSTRACT FROM AUTHOR]

[Display omitted] • Microglia are a major target of PGN in gut microbiota-brain signalling. • Physiological doses of MDP result in long-lasting transcriptional changes in microglial Nod2 signaling, cytokines and chemokines. • Increased TNF-α and CCL5 gene expression is reflected in elevated protein secretion. • In IMG cells MDP signalling via NF-κB is MAPK dependent. • IMG cells show a strong correlation in gene expression to primary microglia, making them a useful in vitro model to study microglia. 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. [ABSTRACT FROM AUTHOR]

Background: The peptidyl-prolyl isomerase (PIN1) plays a vital role in cellular processes, including intracellular signaling and apoptosis. While oxidative stress is considered one of the primary mechanisms of pathogenesis in brain ischemic injury, the precise function of PIN1 in this disease remains to be elucidated. Objective: We constructed a cell-permeable PEP-1–PIN1 fusion protein and investigated PIN1's function in HT-22 hippocampal cells as well as in a brain ischemic injury gerbil model. Methods: Transduction of PEP-1–PIN1 into HT-22 cells and signaling pathways were determined by Western blot analysis. Intracellular reactive oxygen species (ROS) production and DNA damage was confirmed by DCF-DA and TUNEL staining. Cell viability was determined by MTT assay. Protective effects of PEP-1-PIN1 against ischemic injury were examined using immunohistochemistry. Results: PEP-1–PIN1, when transduced into HT-22 hippocampal cells, inhibited cell death in H2O2-treated cells and markedly reduced DNA fragmentation and ROS production. This fusion protein also reduced phosphorylation of mitogen-activated protein kinase (MAPK) and modulated expression levels of apoptosis-signaling proteins in HT-22 cells. Furthermore, PEP-1–PIN1 was distributed in gerbil hippocampus neuronal cells after passing through the blood–brain barrier (BBB) and significantly protected against neuronal cell death and also decreased activation of microglia and astrocytes in an ischemic injury gerbil model. Conclusions: These results indicate that PEP-1–PIN1 can inhibit ischemic brain injury by reducing cellular ROS levels and regulating MAPK and apoptosis-signaling pathways, suggesting that PIN1 plays a protective role in H2O2-treated HT-22 cells and ischemic injury gerbil model. [ABSTRACT FROM AUTHOR]

The overproduction of proinflammatory cytokines triggers a variety of diseases. Protopanaxadiol (PPD) and resveratrol are naturally found in plants such as ginseng and have potential anti-inflammatory properties, and resveratrol- and PPD-enriched rice seeds have been previously successfully generated. Herein, the synergistic anti-inflammatory activities of extracts of these enriched seeds were assessed in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. In comparison with treatment using extract prepared from PPD-producing transgenic rice (DJ-PPD) alone, cotreatment with DJ526 and DJ-PPD (TR_3) markedly enhanced the anti-inflammatory activities at a similar (compared to DJ526) or higher (compared to DJ-PPD) level. Cotreatment with DJ526 and DJ-PPD markedly inhibited the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Thus, DJ526 and DJ-PPD in combination suppressed the expression of phosphorylated (p)-NF-κB p65, p-p38 MAPK, and p-ERK 1/2. Cotreatment with DJ526 and DJ-PPD downregulated the expression of proinflammatory cytokines (IL-1β, IL-6, and TNF-α), LPS receptor (toll-like receptor-4, TLR-4), proinflammatory mediators (nitric oxide and PGE2), and arachidonic acid pathway critical enzyme (COX-2). These findings demonstrate the synergistic potential anti-inflammatory activities of resveratrol- and PPD-enriched rice seed extract. [ABSTRACT FROM AUTHOR]

Background: High GABA levels and its conversion to succinate via the GABA shunt are known to be associated with abiotic and biotic stress tolerance in plants. The exact mode of action is still under debate and it is not yet clear whether GABA is a common component of the plant stress defense process or not. We hypothesized that if it is a common route for stress tolerance, activation of GABA-shunt by a biotic stressor might also function in increased abiotic stress tolerance. To test this, Brassica napus plants treated with Flagellin-22 (Flg-22) were exposed to drought stress and the differences in GABA levels along with GABA-shunt components (biosynthetic and catabolic enzyme activities) in the leaf and root samples were compared. In order to provide a better outlook, MYC2, MPK6 and ZAT12, expression profiles were also analyzed since these genes were recently proposed to function in abiotic and biotic stress tolerance. Results: Briefly, we found that Flg treatment increased drought stress tolerance in B. napus via GABA-shunt and the MAPK cascade was involved while the onset was different between leaves and roots. Flg treatment promoted GABA biosynthesis with increased GABA content and GAD activity in the leaves. Better performance of the Flg treated plants under drought stress might be dependent on the activation of GABA-shunt which provides succinate to TCA since GABA-T and SSADH activities were highly induced in the leaves and roots. In the transcript analysis, Flg + drought stressed groups had higher MYC2 transcript abundances correlated well with the GABA content and GABA-shunt while, MPK6 expression was induced only in the roots of the Flg + drought stressed groups. ZAT12 was also induced both in leaves and roots as a result of Flg-22 treatment. However, correlation with GABA and GABA-shunt could be proposed only in Flg + drought stressed group. Conclusion: We provided solid data on how GABA-shunt and Fgl-22 are interacting against abiotic stress in leaf and root tissues. Fgl-22 induced ETI activated GABA-shunt with a plausible cross talk between MYC2 and ZAT12 transcription factors for drought stress tolerance in B. napus. [ABSTRACT FROM AUTHOR]

The lipogenesis and steroidogenesis of granulosa cells are crucial during follicular development, yet it remains unclear whether dual-specificity phosphatase 8 ( DUSP8 ) is involved. In this study, the specific role of DUSP8 in lipogenesis and steroidogenesis was investigated through culturing chicken granulosa cells in vitro. The results revealed that the expression levels of adipogenic genes were elevated after DUSP8 overexpression and reduced after knockdown. The same was observed for lipid deposition in granulosa cells. Meanwhile, the steroidogenic gene expression and progesterone synthesis were promoted after DUSP8 overexpression and inhibited after knockdown. In addition, we also found that DUSP8 blocked the phosphorylation of extracellular regulatory kinase 1/2 (ERK1/2). Based on the previous results that activated ERK1/2 signaling inhibited lipid deposition and progesterone synthesis in chicken granulosa cells, we demonstrated that DUSP8 promoted lipid deposition and progesterone synthesis through mediating the ERK1/2 signaling pathway. The results will improve our understanding of the molecular regulatory mechanisms regarding lipid metabolism and progesterone synthesis in chicken granulosa cells. • DUSP8 promotes lipid deposition and progesterone synthesis. • DUSP8 inhibits the activation of ERK1/2 signaling pathway. • DUSP8- attenuated ERK1/2 signaling mediates the functions of granulosa cells. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma (GBM) stands as the most prevalent and aggressive form of adult gliomas. Despite the implementation of intensive therapeutic approaches involving surgery, radiation, and chemotherapy, Glioblastoma Stem Cells contribute to tumor recurrence and poor prognosis. The induction of Glioblastoma Stem Cells differentiation by manipulating the transcriptional machinery has emerged as a promising strategy for GBM treatment. Here, we explored an innovative approach by investigating the role of the depolarized resting membrane potential (RMP) observed in patient-derived GBM sphereforming cell (GSCs), which allows them to maintain a stemness profile when they reside in the G0 phase of the cell cycle. Methods: We conducted molecular biology and electrophysiological experiments, both in vitro and in vivo, to examine the functional expression of the voltage-gated sodium channel (Nav) in GSCs, particularly focusing on its cell cycle-dependent functional expression. Nav activity was pharmacologically manipulated, and its effects on GSCs behavior were assessed by live imaging cell cycle analysis, self-renewal assays, and chemosensitivity assays. Mechanistic insights into the role of Nav in regulating GBM stemness were investigated through pathway analysis in vitro and through tumor proliferation assay in vivo. Results: We demonstrated that Nav is functionally expressed by GSCs mainly during the G0 phase of the cell cycle, suggesting its pivotal role in modulating the RMP. The pharmacological blockade of Nav made GBM cells more susceptible to temozolomide (TMZ), a standard drug for this type of tumor, by inducing cell cycle re-entry from G0 phase to G1/S transition. Additionally, inhibition of Nav substantially influenced the self-renewal and multipotency features of GSCs, concomitantly enhancing their degree of differentiation. Finally, our data suggested that Nav positively regulates GBM stemness by depolarizing the RMP and suppressing the ERK signaling pathway. Of note, in vivo proliferation assessment confirmed the increased susceptibility to TMZ following pharmacological blockade of Nav. Conclusions: This insight positions Nav as a promising prognostic biomarker and therapeutic target for GBM patients, particularly in conjunction with temozolomide treatment. [ABSTRACT FROM AUTHOR]

Osteoporosis is a common, mainly middle-aged and elderly metabolic disease. With the increasing aging trend in China, it is of great significance to study the physiological and pathological progress of osteoporosis to prevent the harm caused by osteoporosis and related complications. As a regulatory factor, microRNAs participate in the metabolic regulation of a variety of bone cells, and play a key role in the differentiation and generation of osteoblasts and osteoclasts, which are closely related to osteoporosis, and are considered to be an important factor in the prevention and treatment of osteoporosis. As a classical signaling pathway related to osteoporosis MAPK signaling pathway plays an important role in delaying the progression of osteoporosis. Studies have shown that the regulation of microRNAs by drugs can prevent and cure osteoporosis, and there is a relationship between MAPK signaling pathway and micrornas signaling pathway. Based on the above background this paper discusses the correlation between microRNAs and MAPK signaling pathways, and links them with bone cells closely related to the treatment of osteoporosis, in order to provide more theoretical basis for the related research on the treatment and prevention of osteoporosis. [ABSTRACT FROM AUTHOR]

Microbiotas are complex microbial communities that colonize specific niches in the host and provide essential organismal functions that are important in health and disease. Understanding the ability of each distinct community member to promote or impair host health, alone or in the context of the community, is imperative for understanding how differences in community structure affect host health and vice versa. Recently, a reference 12‐member microbiota for the model organism Caenorhabditis elegans, known as CeMbio, was defined. Here, we show the differential ability of each CeMbio bacterial species to activate innate immunity through the conserved PMK‐1/p38 MAPK, ACh‐WNT, and HLH‐30/TFEB pathways. Although distinct CeMbio members differed in their ability to activate the PMK‐1/p38 pathway, the ability to do so did not correlate with bacterial‐induced lifespan reduction in wild‐type or immunodeficient animals. In contrast, most species activated HLH‐30/TFEB and showed virulence toward hlh‐30‐deficient animals. These results suggest that the microbiota of C. elegans is rife with bacteria that can shorten the host's lifespan if host defense is compromised and that HLH‐30/TFEB is a fundamental and key host protective factor. [ABSTRACT FROM AUTHOR]

Chitosan (CHT) and propolis (P) are natural materials with antiseptic, anti-inflammatory, antimicrobial, and mucoadhesive properties with many applications in orthopaedia dentistry. The objective of this study was to develop a low molecular weight (LMW) and medium molecular weight (MMW) chitosan polymeric system with propolis at different concentrations (0.31%, 0.62%, 1.25%, 2.5%, and 5%) and to evaluate the effect in terms of their cell interaction with dental pulp fibroblasts. FTIR spectra of both molecular weights CHT's films with propolis show increased transmittance bands at 1730–1720 cm−1 and 1460 cm−1, indicating the presence of propolis ethanolic extract in the organic matrix. Contact angles test to determine hydrophobicity CHT films functionalized with propolis exhibit a more hydrophobic surface as propolis concentration increases. Cytotoxicity showed synergy between chitosan and propolis; the highest proliferation was observed in LMW CHT with 0.31% of propolis. Membranes made with CHT of both molecular weights plus propolis in an inflammatory stage (cells previously treated with LPS) can inhibit the expression of NF-k-B, MAPK, and VEGF. A polymeric system based on chitosan/ethanolic extract propolis could be a future alternative treatment for oral ulcers. [ABSTRACT FROM AUTHOR]

Acute pancreatitis remains a serious public health problem, and the burden of acute pancreatitis is increasing. With significant morbidity and serious complications, appropriate and effective therapies are critical. Great progress has been made in understanding the pathophysiology of acute pancreatitis over the past two decades. However, specific drugs targeting key molecules and pathways involved in acute pancreatitis still require further study. Natural compounds extracted from plants have a variety of biological activities and can inhibit inflammation and oxidative stress in acute pancreatitis by blocking several signaling pathways, such as the nuclear factor kappa-B and mitogen-activated protein kinase pathways. In this article, we review the therapeutic effects of various types of phytochemicals on acute pancreatitis and discuss the mechanism of action of these natural compounds in acute pancreatitis, aiming to provide clearer insights into the treatment of acute pancreatitis. [ABSTRACT FROM AUTHOR]

Natural products are favored in the study of skin photodamage protection recently. Isoquercetin, namely 3‐O‐glucoside of quercetin, can be isolated from various plant species. In present research, the protective effect of isoquercitrin on UVB‐induced injury in cells and mice skin were investigated. Our study reveals that 400 μM of isoquercitrin exhibits the best viability on UVB‐irradiated HaCaT cells, and beneficial effects against oxidative stress UVB‐induced in skin tissue by decreasing the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and simultaneously enhancing the activity of superoxide dismutase (SOD). Additionally, isoquercitrin was identified as an anti‐inflammatory agent by reducing the level of COX‐2 by Western blot analysis, and inflammatory cytokines such as IL‐6, IL‐1β, and TNF‐α by ELISA, and UVB‐induced epidermal thickening evidenced by H&E staining. It also effectively prevented UVB‐induced collagen fibers from degradation identified by Masson staining. Isoquercitrin significantly inhibited MAPK pathway by downregulating the levels of AP‐1, MMP‐1, MMP‐3, phospho‐p38, phospho‐JNK, phospho‐ERK, cleaved caspase‐9, cleaved caspase‐3, and JAK2‐STAT3 pathway by western blot analysis. In conclusion, isoquercitrin pretreatment protected mice skin from UVB irradiation‐induced injury effectively, and the underlying mechanism may involve MAPK and JAK2‐STAT3 signaling pathways. [ABSTRACT FROM AUTHOR]

Key Clinical Message: With no family history, and an atypical phenotype, the clinical diagnosing of Noonan syndrome (NS) can be very difficult. The present case emphasized that generalized edema in neonates may be the potential first symptom of NS. Severe generalized edema is a rare pathological condition with high mortality in newborns, in particular the premature infants. It is characterized by the extensive subcutaneous tissue edema and the accumulation of fluid in neonatal body fluid compartments. The etiology and pathogenesis of hydrops in neonates are quite complex. Generally speaking, hydrops can be divided into immune hydrops and non‐immune hydrops according to the etiology. It is still challenging in treating severe neonatal edema. In this study, we presented a preterm newborn with severe generalized edema after birth, which was finally diagnosed with Noonan syndrome (NS). The infant clinically manifested as severe generalized edema alone, without the involvement of multiple organ malformation. Generalized edema in neonates was probably the first symptom of NS. Therefore, differential diagnosis of NS is necessary for infants developing generalized edema. [ABSTRACT FROM AUTHOR]

Purpose: Ulcerative colitis (UC) is a serious health problem with increasing morbidity and prevalence worldwide. The pathogenesis of UC is complex, currently believed to be influenced by genetic factors, dysregulation of the host immune system, imbalance in the intestinal microbiota, and environmental factors. Currently, UC is typically managed using aminosalicylates, immunosuppressants, and biologics as adjunctive therapies, with the risk of relapse and development of drug resistance upon discontinuation. Therefore, further research into the pathogenesis of UC and exploration of potential treatment strategies are necessary to improve the quality of life for affected patients. According to previous studies, Lactobacillus paracasei Jlus66 (Jlus66) reduced inflammation and may help prevent or treat UC. Methods: We used dextran sulfate sodium (DSS) to induce a mouse model of UC to assess the effect of Jlus66 on the progression of colitis. During the experiment, we monitored mouse body weight, food and water consumption, as well as rectal bleeding. Hematoxylin-eosin staining was performed to assess intestinal pathological damage. Protein imprinting and immunohistochemical methods were used to evaluate the protein levels of nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and tight junction (TJ) proteins in intestinal tissues. Fecal microbiota was analyzed based on partial 16S rRNA gene sequencing. Results: Jlus66 supplementation reduced the degree of colon tissue damage, such as colon shortening, fecal occult blood, colon epithelial damage, and weight loss. Supplementation with Jlus66 reduced DSS-induced upregulation of cytokine levels such as TNF-α, IL-1β, and IL-6 (p < 0.05). The NF-κB pathway and MAPK pathway were inhibited, and the expression of TJ proteins (ZO-1, Occludin, and Claudin-3) was upregulated. 16S rRNA sequencing of mouse cecal contents showed that Jlus66 effectively regulated the structure of the intestinal biota. Conclusion: In conclusion, these data indicate that Jlus66 can alter the intestinal biota and slow the progression of UC, providing new insights into potential therapeutic strategies for UC. [ABSTRACT FROM AUTHOR]

MAPK has been reported as a key oncogenic pathway for canine histiocytic sarcoma, which can be pharmacologically targeted with trametinib, a small inhibitor of MEK1/2. Preliminary data showed promising antitumor activity in in vitro and in vivo models and represented a proof of concept to translate the findings from bench to bedside. In this phase I, dose escalating study using a 3 + 3 cohort design, trametinib was evaluated in 18 dogs with cancer. Adverse events were graded according to VCOG‐CTCAE v2. Blood samples and tumour biopsies were collected for pharmacokinetic and pharmacodynamic assessment. Trametinib was well tolerated with a maximum tolerated dose of 0.5 mg/m2/day, PO. Dose‐limiting toxicities included systemic hypertension, proteinuria, lethargy and elevated ALP, and were all Grade 3. The drug exposures increased more than linearly with dose since the elimination of trametinib was saturable. At a dose of 500 μg Q24h (0.5 mg/m2/day in a 30 kg dog), approximately 70% of dogs had an average steady‐state concentration of 10 ng/mL, achieved after approximately 2 weeks. This threshold was associated with clinical efficacy in humans. Target engagement was not observed in biospecimens collected on Days 0 and 7. In conclusion, trametinib was considered safe in dogs with cancer, and the dose of 0.5 mg/m2/day was the recommended dose for phase II studies. [ABSTRACT FROM AUTHOR]

The precise cause of HS/DCS is still unknown. The relatively low incidence in humans urges for an animal model with a high incidence to accelerate knowledge about genetics and optimal treatment of HS/DCS. Namely, until now, the therapies targeting genetic variants are still more experimental and sparsely used, while consensus is missing. In addition, the literature about variants and possible mutation‐targeted therapies in humans and dogs consists mainly of case reports scattered throughout the literature. Therefore, an overview is provided of all currently known genetic variants in humans and dogs with HS/DCS and its subtypes, their possible mutation‐targeted therapies, their efficacy, and a contemplation about the future. Several genetic variants have already been discovered in HS/DCS, of which many are shared between canine and human HS/DCS, but unique variants exist as well. Unfortunately, none of these already found variants seem to be specifically causal for HS/DCS, and the puzzle of its landscape of genetic variation is far from complete. The use of mutation‐targeted therapies, including MAPK‐/MEK‐inhibitors and the future use of PTPN11‐, CDK4/6‐ and PD‐1‐inhibitors, seems to be promising for these specific variants, but clearly, clinical trials are needed to determine optimal inhibitors and standardised protocols for all variants. It can be concluded that molecular analysis for variants and subsequent mutation‐targeted therapy are an essential addition to cancer diagnostics and therapy. A joint effort of humans and dogs in research is urgently needed and will undoubtedly increase knowledge and survival of this devastating disease in dogs and humans. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Fluoride-induced oxidative stress and synaptic dysfunction pose significant threats to neural health. This research investigated the potential ameliorative effects of Strychnos potatorum seed (SPS)-treated water on fluoride-induced neurotoxicity using SK-N-SH cells as an in vitro model system. Methods: To elucidate the underlying molecular mechanisms involved, we focused on the brain-derived neurotrophic factor (BDNF)-TrkB signaling pathway, a crucial modulator of synaptic plasticity, and neuroprotection. Results: Our study revealed that Strychnos potatorum seed water administered for 48 to 96 h improved cell viability, as evidenced by enhanced cell survival rates and preserved cellular architecture, and that SPS-treated water effectively attenuated fluoride-induced oxidative stress, as evidenced by a reduction in reactive oxygen species (ROS). Furthermore, SPS-treated water significantly improved synaptic function, as indicated by enhanced expression of synaptic proteins, including synaptophysin (SYN 1) and postsynaptic density 95 (PSD-95). SPS water upregulated BDNF expression and promoted the activation of its cognate receptor, TrkB, in fluoride-challenged SK-N-SH cells. In addition, SPS-treated water-mediated regulation of the mitogen-activated protein kinase (MAPK) signaling cascade was observed, with increased phosphorylation of extracellular signal-regulated kinase (ERK). Conclusion: These results suggest that SPS-treated water exerts neuroprotective effects against fluoride-induced neurotoxicity by targeting the MAPK-mediated BDNF-TrkB signaling pathway. However, further research is needed to investigate the effectiveness of SPS in vivo and its potential use as a neuroprotective agent. [ABSTRACT FROM AUTHOR]

Ginger (Zingiber officinale Rosc.) is the most widely used medicinal herb of the ancient "Ayurveda" and "Unani" system of medicine due to bioactive compounds present in its rhizomes, i.e., volatile oils (terpenoids), diarylheptanoids (curcuminoids), and gingerols (phenols), which serve as an important panacea for treating arthritis, heart diseases, cancer, diarrhea, and respiratory disorders. It is a vegetatively propagated crop through underground rhizomes and its production is hampered by various soil-borne pathogens which predominantly include Fusarium oxysporum f.sp. zingiberi. During the preceding research, the technique of in vitro mutagenesis and selection was employed in ginger cv. Himgiri for the development of Fusarium tolerant lines, resulting in mutant Himgiri-17.5, which displayed improved accumulation of gingerol and demonstrated enhanced tolerance to Fusarium wilt. The present study reveals the first-ever transcriptome data of in vitro-raised Himgiri-17.5 to unravel the role of gingerol biosynthesis and MAPK-dependent hormonal signaling pathways in imparting tolerance to Fusarium wilt as compared to conventionally propagated Himgiri. Through transcriptome analysis, a total of 13.84 GB data was generated encoding 57,939 genes, out of which 3745 were differentially expressed genes (DEGs) in both the samples with 351 upregulated and 3394 downregulated. The expression patterns of genes in Himgiri-17.5 linked to antioxidant activity and MAPK-dependent hormonal signaling exhibited notable upregulation suggesting their possible participation in mediating plant defense response. Additionally, the investigation provided insights into volatile oil, diarylheptanoids, and gingerol biosynthetic pathway in ginger governed by crucial regulatory genes, namely DCS, CURS2, and ClPKS10. The examination also revealed the presence of 165 upregulated transcription factors primarily belonging to the ERF, bHLH, MYB, NAC, and bZIP families which exhibited a strong correlation with the biosynthesis of gingerol and MAPK-mediated hormonal signaling pathway, contributing to stress tolerance. The discovery of these DEGs related to antioxidant activity, MAPK-mediated hormonal signaling, and the biosynthetic pathway of gingerol holds a promise for the development of improved varieties of ginger through molecular approaches. [ABSTRACT FROM AUTHOR]

In this study, we discovered the mechanisms underlying parecoxib and resveratrol combination's anti-cancer characteristics against human colorectal cancer DLD-1 cells. We studied its anti-proliferation and apoptosis-provoking effect by utilizing cell viability 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, fluorescence microscope, gene overexpression, Western blot, and flow cytometry analyses. Parecoxib enhanced the ability of resveratrol to inhibit cell viability and increase apoptosis. Parecoxib in combination with resveratrol strongly enhanced apoptosis by inhibiting the expression of thioredoxin domain containing 5 (TXNDC5) and Akt phosphorylation. Parecoxib enhanced resveratrol-provoked c-Jun N-terminal kinase (JNK) and p38 phosphorylation. Overexpression of TXNDC5 and repression of JNK and p38 pathways significantly reversed the inhibition of cell viability and stimulation of apoptosis by the parecoxib/resveratrol combination. This study presents evidence that parecoxib enhances the anti-cancer power of resveratrol in DLD-1 colorectal cancer cells via the inhibition of TXNDC5 and Akt signaling and enhancement of JNK/p38 MAPK pathways. Parecoxib may be provided as an efficient drug to sensitize colorectal cancer by resveratrol. [ABSTRACT FROM AUTHOR]

This study aimed to assess the anti-inflammatory properties of a bioactive glutamic-alanine rich glycoprotein (GP) derived from Undaria pinnatifida on both LPS-stimulated RAW264.7 cells, peritoneal macrophages, and mouse models of carrageenan- and xylene-induced inflammation, investigating the underlying molecular mechanisms. In both in-vitro and in-vivo settings, GP was found to reduce the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) while also inhibiting the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in response to lipopolysaccharide (LPS) stimulation. GP treatment significantly impeded the nuclear translocation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway by blocking the phosphorylation of IKKα and IκBα, leading to a reduction in proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Additionally, GP effectively inhibited the activation of mitogen-activated protein kinases (MAPKs), with specific inhibitors of p38 and extra-cellular signal regulated kinase (ERK) enhancing GP's anti-inflammatory efficacy. Notably, GP administration at 10 mg/kg/day (p.o.) markedly reduced carrageenan-induced paw inflammation and xylene-induced ear edema by preventing the infiltration of inflammatory cells into targeted tissues. GP treatment also downregulated key inflammatory markers, including iNOS, COX-2, IκBα, and NF-κB, by suppressing the phosphorylation of p38 and ERK, thereby improving the inflammatory index in both carrageenan- and xylene-induced mouse models. These findings suggest that marine resources, particularly seaweeds like U. pinnatifida, could serve as valuable sources of natural anti-inflammatory proteins for the effective treatment of inflammation and related conditions. [ABSTRACT FROM AUTHOR]

Inflammatory osteolysis is often caused by the excessive activation of osteoclasts stimulated by bacterial products such as lipopolysaccharide. The natural flavonoid trifolirhizin (TRI) has anti‐inflammatory properties; however, its function in inflammatory bone lysis remains unclear. This study aimed to elucidate the potential regulatory mechanisms of TRI in osteoclasts.Tartrate‐resistant acid phosphatase (TRAP) staining, acid secretion assays, podosomal actin belt fluorescence staining, and bone resorption assays were used to investigate the effects of TRI on osteoclast differentiation and bone resorption. A reactive oxygen species (ROS) measurement kit was used to detect the effect of TRI on ROS levels in osteoclasts. The effects of TRI on genes and signaling pathways related to osteoclast differentiation were determined by quantitative polymerase chain reaction (qPCR) and western blotting. A mouse model of lipopolysaccharide‐mediated inflammatory osteolysis was established, and the effects of TRI treatment on bone mass were observed using micro‐CT and histological examination. Mechanistically, TRI reduced ROS production by inhibiting receptor activator of nuclear factor‐κB ligand (RANKL)‐induced activation of the nuclear factor‐κB (NF‐κB) and mitogen‐activated protein kinase (MAPK) signaling pathways, and by upregulating the expression levels of the anti‐ROS enzymes heme oxygenase‐1 (HO‐1) and catalase (CAT), which contributed to the degradation of ROS, ultimately leading to a decrease in osteoclastogenesis. TRI inhibited osteoclast formation and ameliorated lipopolysaccharide (LPS)‐mediated inflammatory osteolysis. Thus, TRI may be a candidate agent for anti‐inflammatory osteolysis. [ABSTRACT FROM AUTHOR]

Longan (Dimocarpus longan Lour.) is an important tropical and subtropical fruit, and most of its cultivars bloom once a year (once-flowering, OF). Dimocarpus longan cv. 'Sijimi' (SJ) is a tropical ecotype variety that blooms several times a year (continuous-flowering, CF) without the need for low-temperature induction. Several studies have focused on the mechanism of continuous flowering in SJ longan; however, none used leaves as research material. As leaves are a key organ in sensing floral-induction signals, we compared gene-expression differences between mature leaves of CF (SJ) and OF (D. longan cv. 'Shixia' (SX) and D. longan cv. 'Chuliang' (CL)) longan by transcriptome sequencing. An average of 47,982,637, 43,833,340 and 54,441,291 clean reads were obtained for SJ, SX and CL respectively, and a total of 6745 differentially expressed genes (DEGs) were detected. Following Metabolic pathways, Plant-pathogen interaction and Biosynthesis of secondary metabolites, most of the other genes were assigned to the KEGG classifications of MAPK signaling pathway- plant, Plant hormone signal transduction, Amino sugar and nucleotide sugar metabolism and Starch and sucrose metabolism. WGCNA analysis clustered genes into 27 modules, among which bisque4 and darkorange2 module genes specifically were expressed at low and high levels in SJ, respectively. Different gene-expression patterns were detected between CF and OF longan in bisque4 and darkorange2 modules, especially the high levels of transcription factor (TF) expression and the large number of gibberellic acid (GA)-signaling-pathway-specific genes expressed at high levels in CF longan (SJ). Floral-induction-gene expression levels in CF longan, such as levels of GA-signaling-related and FT genes, were always high. In CF longan, after vegetative-growth accumulation, flowers could be directly induced, thereby eliminating the need for low-temperature induction. [ABSTRACT FROM AUTHOR]

Repurposing saffron (Crocus sativus) waste presents a sustainable strategy for generating high-value products within the bioeconomy framework. Typically, flower components are discarded after stigma harvest, resulting in significant waste—350 kg of tepals per kilogram of stigmas. This research employed a comprehensive approach, integrating bioactivity studies (in vitro and in silico) with Life Cycle Assessment (LCA) evaluations, to extract and assess bioactive compounds from C. sativus tepals sourced in Tuscany, Italy. Phytochemical characterization using UPLC-MS/MS revealed a high abundance and variety of flavonoids in the hydro-ethanolic extract (CST). The antioxidant capacity was validated through various assays, and the ability to mitigate H2O2-induced oxidative stress and enhance fermentation was demonstrated in Saccharomyces cerevisiae. This study reports that C. sativus tepals extract reduces oxidative stress and boosts ethanol fermentation in yeast, paving the way for applications in the food and biofuels sectors. Further validation in RAW 264.7 macrophages confirmed CST's significant anti-inflammatory effects, indicating its potential for pharmaceutical, cosmeceutical, and nutraceutical applications. In silico studies identified potential targets involved in antioxidant and anti-inflammatory processes, shedding light on possible interaction mechanisms with Kaempferol 3-O-sophoroside (KOS-3), the predominant compound in the extract. The integration of LCA studies highlighted the environmental benefits of this approach. Overall, this research underscores the value of using waste-derived extracts through "green" methodologies, offering a model that may provide significant advantages for further evaluations compared to traditional methodologies and supporting the circular bioeconomy. [ABSTRACT FROM AUTHOR]

Noscapine is widely used to prevent stroke, glioblastoma, and anxiety. The aim of this study was to investigate the anti-neuroinflammatory activity and possible molecular mechanisms of noscapine on lipopolysaccharide (LPS)-induced BV-2 microglia cells. BV2 microglial cells were treated with LPS in the presence and absence of noscapine. In the current study, nitrite, Prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 productions, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA levels, phosphorylation of NF-κB, IκB, ERK, JNK, and p38 proteins were measured. Noscapine treatment triggered a significant reduction on nitrite, PGE2, TNF-α, IL-6, and IL-1β production, iNOS and COX-2 mRNA levels, NF-κB, IκB, ERK, JNK, and p38 phosphorylation in LPS-induced BV-2 microglia cells. The results of this study demonstrate the efficiency of noscapine as a potent anti-inflammatory agent. It can be suggested that noscapine has suppressed LPS‑induced neuroinflammation in BV‑2 microglia cells in the current study, and thus noscapine can be utilized as an efficient anti-neuroinflammatory agent. [ABSTRACT FROM AUTHOR]

Abstract Background HTLV-1 is a worldwide distribution retrovirus with 10–20 million infected individuals. ATLL is an Adult T-cell leukaemia lymphoma caused by aggressive T-cell proliferation that is infected by HTLV-1 and is associated with an inferior prognosis. The exact molecular pathogenesis has yet to be fully understood. CREB, a transcription factor, acts as a molecular switch that controls the expression of numerous genes in response to various extracellular signals. Its activation is primarily mediated through phosphorylation by multiple kinases, including MAPKs. MAPKs, a family of serine/threonine kinases, serve as crucial mediators of intracellular signaling cascades. Method and material This study investigated, 38 HTLV-I-infected individuals, including 18 HTLV-1 asymptomatic carriers (ACs) and 20 ATLL subjects. mRNA was extracted and converted to cDNA from Peripheral blood mononuclear cells (PBMCs), and then the expression of TAX, HBZ, CREB, and MAPK was analyzed by TaqMan qPCR. The genomic HTLV-1 Proviral loads were examined among the study group. Results The data analysis showed a significant difference in the mean of CREB expression amongst study groups (ATLL and carriers, (p = 0.002). There is no statistical difference between the MAPK gene expression (p = 0.35). HBZ, TAX, and HTLV-1 proviral load weree significantly higher in ATLL subjects compared to ACs (p = 0.002, 0.000, and 0.000), respectively. Moreover, our results, demonstrated a direct positive correlation among HBZ, CREB, and TAX gene expression in ATLL patients (p = 0.001), whilst between the ACs, TAX gene expression had a positive significant correlation with HBZ and HTLV-1 proviral load (p = 0.007 and p = 0.004, respectively). Conclusion The present study demonstrated that CREB gene expression was higher in the ATLL group than ACs, while there was no difference for MAPK. Therefore, this pathway may not strongly involve in the activation of CREB. The CREB may be a prognostic factor for the development of HTLV-I-associated diseases and can be used as a monitoring marker for the efficiency of the therapeutic regime and prognosis.

Abstract To explore diagnostic and prognostic biomarkers in the progression of oral squamous cell carcinoma (OSCC) and to reveal their regulatory mechanisms in key pathways. A RayBiotech protein chip was used to screen differentially expressed serum proteins in OSCC, oral leukoplakia (OLK), and healthy participants. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to determine the pathways enriched by characteristic differential proteins. Immunohistochemical analysis and western blotting were used to verify the expression of characteristic differential proteins and key regulatory factors in human tissues and in a nude mouse model. Fibroblast growth factor 6 (FGF6) was identified as a key differential protein and was weakly expressed in OSCC tissues. The mitogen-activated protein kinases (MAPK) and PI3K-AKT pathways were identified as key signaling pathways. The results showed that pERK, Cyclin D1, pAKT, and BCL2 were highly expressed in OSCC, Caspase9 was lowly expressed in OSCC. With an increase in FGF6 expression in nude mice, the expression of FGFR4, pERK, Cyclin D1, pAKT, BCL2, GPX4, and ACSL4 increased, and the expression of Caspase9 decreased. FGF6 may change the expression of apoptosis-related proteins and proliferation factors by binding to FGFR4 in the PI3K-AKT/MAPK pathway and may inhibit the ferroptosis of OSCC, thereby possibly participating in the process of inhibiting OSCC.