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Mitochondria affect cellular functions alone or in cooperation with other cellular organelles. Recent research has demonstrated the close relationship of mitochondria with the endoplasmic reticulum (ER), both at the physical and the functional level. In an effort to define the combined effect of mitochondrial dysfunction (MD) and ER stress in the proinflammatory activities of macrophages, the human macrophage-like monocytic leukemia cell line THP-1 was treated with mitochondrial electron transport chain (ETC) blockers, and changes in the cellular responses upon stimulation by interferon (IFN)-[gamma] were analyzed. Inducing mitochondrial dysfunction (MD) with ETC blockers resulted in suppression of IFN-induced activation of JAK1 and STAT1/3, as well as the expression of STAT1-regulated genes. In addition, experiments utilizing pharmacological modulators of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and liver kinase B1 (LKBl)-deficient HeLa cells demonstrated that these suppressive effects are mediated by the LKB1-AMPK pathway. Treatment with pharmacological inhibitors of ER stress sensors failed to affect these processes, thus indicating that involvement of ER stress is not required. These results indicate that MD, induced by blocking the ETC, affects IFN-induced activation of JAK-STAT and associated inflammatory changes in THP-1 cells through the LKB1-AMPK pathway independently of ER stress. Key words: macrophage, inflammation, mitochondrial dysfunction, ER stress, JAK-STAT, AMPK. Les mitochondries affectent les fonctions cellulaires, seules ou en coopération avec d'autres organites cellulaires. La recherche récente a démontré une étroite relation entre la mitochondrie et le réticulum endoplasmique (RE), tant sur le plan physique que fonctionnel. Dans le but de définir les effets combinés de la dysfonction mitochondriale (DM) et du stress du RE sur les activités proinflammatoires des macrophages, la lignée cellulaire monocytique humaine de type macrophage THP-1 a été traitée avec des bloqueurs de la chaîne de transport d'électrons (CTE), et les changements des réponses cellulaires en réponse à une stimulation par l'interféron (IFN)-_ ont été analysés. L'induction de la dysfonction mitochondriale par les bloqueurs de la CTE donnait lieu à la suppression de l'activation de JAK1 et de STAT1/3 induite par l'IFN, de même que de l'expression des gènes régulés par STAT1. De plus, des expériences réalisées avec des modulateurs pharmacologiques de la protéine kinase activée par l'adénosine 5=-monophosphate (AMP) (AMPK) et des cellules HeLa déficientes en kinase B1 du foie (LKB1) ont démontré que ces effets suppresseurs sont médiés par la voie LKB1-AMPK. Un traitement avec des inhibiteurs pharmacologiques de détecteurs du stress du RE n'affectait pas ces processus, indiquant alors que l'implication du stress du RE n'est pas requise. Ces résultats indiquent que la dysfonction mitochondriale induite par le blocage de la CTE affecte l'activation de JAK-STAT induite par l'IFN et les changements inflammatoires associés chez les cellules THP1 par l'intermédiaire de la voie LKB1-AMPK de manière indépendante du stress du RE. [Traduit par la Rédaction] Mots-clés : macrophage, inflammation, dysfonction mitochondriale, stress du RE, JAK-STAT, AMPK., Introduction Mitochondria generate ATP by oxidative phosphorylation. This involves a redox reaction whereby electrons are transferred by the electron transport chain (ETC). Electrons are donated by nicotinamide adenine dinucleotide (NADH) [...]

Purpose: Psoriasis is a common and well-studied autoimmune skin disease, which is characterized by plaques. The formation of psoriasis plaques occurs through the hyperproliferation and abnormal differentiation of keratinocytes, infiltration of numerous immune cells into the dermis, increased subepidermal angiogenesis, and various autoimmune-associated cytokines and chemokines. According to previous research, Lin28 regulates the let-7 family, and let-7b is associated with psoriasis. However, the link between Lin28 and psoriasis is unclear. In this study, an association was identified between Lin28a and psoriasis progression, which promoted the pathological characteristic of psoriasis in epidermal keratinocytes. Patients and Methods: This study aims to investigate the role of Lin28a and its underlying mechanism in psoriasis through in vivo and in vitro models, which include the Lin28a-overexpressing transgenic (TG) mice and Lin28a-overexpressing human keratinocyte (HaCaT) cell lines, respectively. Results: In vivo and in vitro results revealed that overexpression of Lin28a downregulated microRNA let-7 expression levels and caused hyperproliferation and abnormal differentiation in keratinocytes. In imiquimod (IMQ)-induced psoriasis-like inflammation, Lin28a overexpressing transgenic (TG) mice exhibited more severe symptoms of psoriasis. Conclusion: Mechanistically, Lin28a exacerbated psoriasis-like inflammation through the activation of the extracellular-signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 signaling (STAT 3) by targeting proinflammatory cytokine interleukin-6 (IL-6). [ABSTRACT FROM AUTHOR]

The functional and physical interaction between mitochondria and the endoplasmic reticulum (ER) has been the subject of intense study. To test the effect of this interaction on macrophage inflammatory activation, the human macrophage‐like monocytic leukemia cell line THP‐1 was treated with oligomycin, rotenone, or sodium azide, which induce mitochondrial dysfunction (MD) by blocking the electron transport chain (ETC). MD induced by these agents triggered activation of various sensors and markers of ER stress. This linkage affected macrophage function since LPS‐induced expression of IL‐23 was enhanced by the MD inducers, and this enhancing effect was abolished by inhibition of pancreatic endoplasmic reticulum kinase (PERK) activity. This MD‐mediated ER stress may be universal since it was observed in human embryonic kidney HEK293 cells and colon cancer SW480 cells. On the other hand, MD regulated LPS‐induced activation of the AKT/GSK3β/β‐catenin pathway in a manner not affected by inhibition of PERK or inositol‐requiring enzyme 1α (IRE1α) activities. These results indicate that the occurrence of MD can lead to ER stress and these two events, separately or in combination, can affect various cellular processes. [ABSTRACT FROM AUTHOR]

The tumor necrosis factor (TNF) superfamily (TNFSF) is a protein superfamily of type II transmembrane proteins commonly containing the TNF homology domain. The superfamily contains more than 20 protein members, which can be released from the cell membrane by proteolytic cleavage. Members of the TNFSF function as cytokines and regulate diverse biological processes, including immune responses, proliferation, differentiation, apoptosis, and embryogenesis, by binding to TNFSF receptors. Many TNFSF proteins are also known to be responsible for the regulation of innate immunity and inflammation. Both receptor-mediated forward signaling and ligand-mediated reverse signaling play important roles in these processes. In this review, we discuss the functional expression and roles of various reverse signaling molecules and pathways of TNFSF members in macrophages and microglia in the central nervous system (CNS). A thorough understanding of the roles of TNFSF ligands and receptors in the activation of macrophages and microglia may improve the treatment of inflammatory diseases in the brain and periphery. In particular, TNFSF reverse signaling in microglia can be exploited to gain further insights into the functions of the neuroimmune interface in physiological and pathological processes in the CNS. [ABSTRACT FROM AUTHOR]

Bitter gourd is the fruit of a tropical vine in Asia, Africa, and South America where it is commonly used in traditional medicine. Our study tested the effects of a fermented extract of the bitter gourd on the inflammatory activities of the human monocytic leukemia cell line, THP-1. Treatment with the extract resulted in the suppression of phagocytic as well as lipopolysaccharide (LPS)-induced adhesion activity. Interestingly, the LPS-induced expression of matrix metalloproteinase-9 (MMP-9) and tumor necrosis factor-α (TNF-α) was suppressed by the extract while the expression of Interleukin-8 (IL-8) was upregulated. The extract inhibited the LPS-induced activation of p38 mitogen-activated protein kinase (MAPKs) and nuclear factor-κB (NF-κB), both of which are well known to be required for the expression of MMP-9 and TNF-α. In contrast, the expression of interferon regulatory factor (IRF) 1, a transcription factor involved in the expression of IL-8, but not TNF-α, was enhanced by the extract. Suppression of IRF-1 expression resulted in the elimination of the extract's interleukin-8 (IL-8) enhancing effect. These results indicate that the fermented bitter gourd extract has general anti-inflammatory effects, with a differential effect on the expression of cytokines through modulation of NF-κB and IRF-1 activities. [ABSTRACT FROM AUTHOR]

Lymphotoxin-beta receptor (LTβR), a receptor for LIGHT and LTα 1 β 2 , is expressed on the epithelial, stromal, and myeloid cells. LTβR is known to affect the lymphoid organ development and immune homeostasis. However, its role in macrophage function has not been sufficiently elucidated. The effect of LTβR stimulation in the inflammatory activation of macrophages was investigated by treating the human macrophage-like cell line THP-1 with LTβR-specific monoclonal antibody. Interestingly, combined treatment with anti-LTβR antibody and LPS caused the synergistic induction of IL-8 expression at the transcriptional level. Analysis indicated that nuclear factor (NF)-κB activity was enhanced via the mitogen-activated protein kinase (MAPK) and glycogen synthase kinase (GSK)-3β/cAMP response element binding protein (CREB) pathways. In addition, LTβR stimulation induced the expression of interferon regulatory factor (IRF)-1, one of the major transcription factors of IL-8 gene. Down-regulation of IRF-1 expression reduced the enhancing effect caused by LTβR stimulation. This indicates that the LTβR stimulation enhances the LPS-induced expression of IL-8 via the combined action of NF-κB and IRF-1. [ABSTRACT FROM AUTHOR]

Highlights: [•] LIGHT-mediated signaling was analyzed in human macrophage cell line THP-1. [•] LIGHT triggering induced expression of MMP-9 and IL-8. [•] LIGHT triggering suppressed phagocytic activity of THP-1 cells. [•] ERK/PI3K/NF-κB mediated in the signaling induced by LIGHT. [Copyright &y& Elsevier]

The effect of glucose-dependent insulinotropic polypeptide (GIP) on cells under oxidative stress induced by glutamate, a neurotransmitter, and the underlying molecular mechanisms were assessed in the present study. We found that in the pre-treatment of HT-22 cells with glutamate in a dose-dependent manner, intracellular ROS were excessively generated, and additional cell damage occurred in the form of lipid peroxidation. The neurotoxicity caused by excessive glutamate was found to be ferroptosis and not apoptosis. Other factors (GPx-4, Nrf2, Nox1 and Hspb1) involved in ferroptosis were also identified. In other words, it was confirmed that GIP increased the activity of sub-signalling molecules in the process of suppressing ferroptosis as an antioxidant and maintained a stable cell cycle even under glutamate-induced neurotoxicity. At the same time, in HT-22 cells exposed to ferroptosis as a result of excessive glutamate accumulation, GIP sustained cell viability by activating the mitogen-activated protein kinase (MAPK) signalling pathway. These results suggest that the overexpression of the GIP gene increases cell viability by regulating mechanisms related to cytotoxicity and reactive oxygen species production in hippocampal neuronal cell lines. [ABSTRACT FROM AUTHOR]

Oral cancer (OC) has been attracted research attention in recent years as result of its high morbidity and mortality. Costunolide (CTD) possesses potential anticancer and bioactive abilities that have been confirmed in several types of cancers. However, its effects on oral cancer remain unclear. This study investigated the potential anticancer ability and underlying mechanisms of CTD in OC in vivo and in vitro. Cell viability and anchorage-independent colony formation assays were performed to examine the antigrowth effects of CTD on OC cells; assessments for migration and invasion of OC cells were conducted by transwell; Cell cycle and apoptosis were investigated by flow cytometry and verified by immunoblotting. The results revealed that CTD suppressed the proliferation, migration and invasion of oral cancer cells effectively and induced cell cycle arrest and apoptosis; regarding the mechanism, CTD bound to AKT directly by binding assay and repressed AKT activities through kinase assay, which thereby downregulating the downstream of AKT. Furthermore, CTD remarkably promotes the generation of reactive oxygen species by flow cytometry assay, leading to cell apoptosis. Notably, CTD strongly suppresses cell-derived xenograft OC tumor growth in an in vivo mouse model. In conclusion, our results suggested that costunolide might prevent progression of OC and promise to be a novel AKT inhibitor. [ABSTRACT FROM AUTHOR]

Cellular response to stimulation is mediated by meshwork of signaling pathways that may share common signaling adaptors. Here, we present data demonstrating that signaling pathways initiated from the membrane-bound form of B-cell activating factor (BAFF) can crosstalk with lipopolysaccharide (LPS)-induced signaling for synergistic expression of proinflammatory mediators in the human macrophage-like cell line THP-1. Co-treatment of the cells with BAFF-specific monoclonal antibody and LPS resulted in enhanced mitogen-activated protein kinase (MAPK)/mitogen- and stress-activated protein kinase (MSK)-mediated phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 subunit (Ser276), which then interacts with CREB binding protein (CBP) for subsequent acetylation. Simultaneously, the phosphorylation of cyclic AMP-response element binding protein (CREB) was enhanced through the combined action of phosphatidylinositol-3-kinase (PI3K)/AKT and MAPK/MSK pathways, and the resulting phospho-CREB interacted with the NF-κB/CBP complex. Transfection of CREB-specific siRNA inhibited the BAFF-mediated enhancing effect indicating that the formation of the CREB/NF-κB/CBP complex is required for the synergistic induction of the proinflammatory genes. These findings indicate that BAFF-mediated reverse signaling can modulate LPS-induced inflammatory activation through regulation of NF-κB and CREB activity and point out the necessity to re-evaluate the role of BAFF in diseases where its expression is high in macrophages. [ABSTRACT FROM AUTHOR]

Glucose-dependent insulinotropic polypeptide (GIP), a 42-aminoacid hormone, exerts multifaceted effects in physiology, most notably in metabolism, obesity, and inflammation. Its significance extends to neuroprotection, promoting neuronal proliferation, maintaining physiological homeostasis, and inhibiting cell death, all of which play a crucial role in the context of neurodegenerative diseases. Through intricate signaling pathways involving its cognate receptor (GIPR), a member of the G protein-coupled receptors, GIP maintains cellular homeostasis and regulates a defense system against ferroptosis, an essential process in aging. Our study, utilizing GIP-overexpressing mice and in vitro cell model, elucidates the pivotal role of GIP in preserving neuronal integrity and combating age-related damage, primarily through the Epac/Rap1 pathway. These findings shed light on the potential of GIP as a therapeutic target for the pathogenesis of ferroptosis in neurodegenerative diseases and aging. [BMB Reports 2024; 57(9): 417-423].

Background/aim: Skin wound healing is a physiological process restoring the structural and functional integrity of injured skin. During this process, wound management preventing bacterial infection and complications is important for the regeneration of skin layers and adnexa, as well as the protective function of the skin. Therefore, the development of an effective ointment to promote wound healing without complications is beneficial., Materials and Methods: This study developed Raepenol™ cream, comprising a base cream and natural compounds including paeonol, D-panthenol and extract of Centella asiatica, and assessed its therapeutic effect in wound healing. A rat model of skin wound healing and a mouse model of imiquimod-induced pruritus were employed. The effect of Raepenol™ cream was evaluated by wound size and histological analysis, including the integrity of skin structures and inflammatory response., Results: Raepenol™ cream treatment effectively restored the structural integrity of the skin in rats, including wound closure, regeneration of skin adnexa, and reconstitution of collagen, comparable to commercial ointment. Additionally, Raepenol™ cream significantly suppressed pruritus by inhibiting mast cell infiltration or retention in the inflammatory site of mouse ears., Conclusion: Raepenol™ cream effectively promoted wound healing and relieved pruritus in animal models. These results suggest that it could be a promising option for wound care and pruritus relief, offering potential advantages over current ointments., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Inflammatory bowel disease (IBD) is characterized by dysregulated immune responses and a multifactorial etiology. While imatinib has demonstrated efficacy in the treatment of immune-related diseases, its potential effects in IBD treatment remain underexplored., Materials and Methods: This study aimed to investigate the therapeutic effects of imatinib in colitis treatment. A dextran sulfate sodium (DSS)-induced colitis model was used to mimic IBD in mice. Imatinib was administered orally to mice simultaneously with DSS treatment. The effects of imatinib on DSS-induced colitis were evaluated by analyzing colitis-related pathology, including the disease activity index (DAI), histological lesions, inflammatory markers, and tight junction integrity. Additionally, western blot analysis and quantitative real-time polymerase chain reaction were used to assess inflammatory markers, tight-junction proteins, and cell death., Results: In the DSS-induced colitis model, imatinib treatment exerted protective effects by attenuating weight loss, restoring colon length, reducing spleen weight, and improving the DAI score and histological lesions. Additionally, imatinib reduced the level of proinflammatory cytokines, including TNF-α, IL-6, and IL-1β. Furthermore, imatinib treatment restored tight-junction integrity and decreased the expression of apoptosis marker proteins., Conclusion: Overall, imatinib treatment significantly alleviated the symptoms of DSS-induced colitis by influencing the expression of proinflammatory cytokines, tight junction proteins, and apoptotic markers in mice. These findings highlight imatinib as a potential therapeutic candidate for IBD., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: [6]-Gingerol, a compound extracted from ginger, has been studied for its therapeutic potential in various types of cancers. However, its effects on oral cancer remain largely unknown. Here, we aimed to investigate the potential anticancer activity and underlying mechanisms of [6]-gingerol in oral cancer cells., Materials and Methods: We analyzed the antigrowth effects of [6]-gingerol in oral cancer cell lines by cell proliferation, colony formation, migration, and invasion assays. We detected cell cycle and apoptosis with flow cytometry and further explored the mechanisms of action by immunoblotting., Results: [6]-Gingerol significantly inhibited oral cancer cell growth by inducing apoptosis and cell cycle G2/M phase arrest. [6]-Gingerol also inhibited oral cancer cell migration and invasion by up-regulating E-cadherin and down-regulating N-cadherin and vimentin. Moreover, [6]-gingerol induced the activation of AMPK and suppressed the AKT/mTOR signaling pathway in YD10B and Ca9-22 cells., Conclusion: [6]-Gingerol exerts anticancer activity by activating AMPK and suppressing the AKT/mTOR signaling pathway in oral cancer cells. Our findings highlight the potential of [6]-gingerol as a therapeutic drug for oral cancer treatment., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

LETM1 domain-containing protein 1 (LETMD1), also known as HCCR-1, is a mitochondrial protein and is known to regulate p53 and STAT3 activities in cancer cells. In this study, we present, for the first time (to our knowledge), data indicating that LETMD1 suppresses multiple immune responses in monocyte/macrophage lineage cells and mouse primary macrophages. Attenuation of LETMD1 expression with specific small interfering RNA and short hairpin RNA constructs enhanced LPS-induced expressions of inflammatory mediators in macrophages. In addition, LETMD1 attenuation caused potentiation of phagocytosis as well as migration in a macrophage-like cell line, U937. These enhancing effects were associated with altered activation of signaling adaptors (such as NF-κB, MAPKs, p53, and JAK-STAT) involved in TLR4 signaling. Especially, LETMD1 selectively regulated TLR4-induced NF-κB activation via MyD88 but not via TIR-domain-containing adapter-inducing IFN-β (TRIF). Attenuation of LETMD1 expression caused mitochondrial hyperpolarization and subsequent decrease in ATP production and increase in mitochondrial/cellular reactive oxygen species (ROS) and intracellular calcium levels. LETMD1 attenuation also enhanced LPS-induced expression of NADPH oxidase (NOX) 2, the main producer of cellular ROS in phagocytes, through augmenting IFN regulatory factor 1. Accordingly, treatment with ROS scavenger, NOX2 suppressing agents, or calcium chelators resulted in suppression of LPS-induced cytokine production as well as NF-κB activation in cells with LETMD1 attenuation. These findings reveal a previously unknown function of LETMD1 and provide evidences showing LETMD1 negatively regulates macrophage functions by modulating mitochondrial function, subsequent ROS generation, and NF-κB activation., (Copyright © 2020 by The American Association of Immunologists, Inc.)