Search

Objective: Bacterial translocation across the gut barrier has been implicated in the pathogenesis of systemic lupus erythematosus (SLE), though underlying mechanisms remain unclear. This study aimed to investigate the role of translocated bacteria in the context of molecular mimicry by utilizing lupus model mice and blood samples from untreated SLE patients., Methods: Bacterial translocation was evaluated using nonselective cultured mesenteric lymph nodes (MLNs) from B6SKG mice, a lupus model characterized by impaired TCR signalling and gut dysbiosis. The relationships of detected pathobionts with autoantibody production were examined using in vivo experiments, enzyme-linked immunosorbent assay, immunoblotting, and epitope mapping., Results: Culture-based bacterial profiling in MLNs demonstrated that Lactobacillus murinus was enriched in B6SKG mice with elevated anti-dsDNA IgG levels. Subcutaneous injection of heat-killed L. murinus induced anti-dsDNA IgG production without altering T- or B cell subset composition. Immunoblotting and mass spectrometry analysis identified a peptide ATP-binding cassette (ABC) transporter as a molecular mimicry antigen, with its cross-reactivity in lupus mice confirmed by serological assays and in vivo immunization. The L. murinus ABC transporter exhibited surface epitopes that were cross-reactive with sera from lupus mice and patients. The ABC transporter from R. gnavus, known for its pathogenic role in lupus patients, had a similar epitope sequence to that of the L. murinus ABC transporter and reacted with lupus sera., Conclusion: ABC transporters from gut bacteria can serve as cross-reactive antigens that may promote anti-dsDNA antibody production in genetically susceptible mice. These findings underscore the role of commensal-derived molecular mimicry and bacterial translocation in lupus pathogenesis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The intricate interplay between cellular senescence and alterations in the gut microbiome emerges as a pivotal axis in the aging process, increasingly recognized for its contribution to systemic inflammation, physiological decline, and predisposition to age-associated diseases. Cellular senescence, characterized by a cessation of cell division in response to various stressors, induces morphological and functional changes within tissues. The complexity and heterogeneity of senescent cells, alongside the secretion of senescence-associated secretory phenotype, exacerbate the aging process through pro-inflammatory pathways and influence the microenvironment and immune system. Concurrently, aging-associated changes in gut microbiome diversity and composition contribute to dysbiosis, further exacerbating systemic inflammation and undermining the integrity of various bodily functions. This review encapsulates the burgeoning research on the reciprocal relationship between cellular senescence and gut dysbiosis, highlighting their collective impact on age-related musculoskeletal diseases, including osteoporosis, sarcopenia, and osteoarthritis. It also explores the potential of modulating the gut microbiome and targeting cellular senescence as innovative strategies for healthy aging and mitigating the progression of aging-related conditions. By exploring targeted interventions, including the development of senotherapeutic drugs and probiotic therapies, this review aims to shed light on novel therapeutic avenues. These strategies leverage the connection between cellular senescence and gut microbiome alterations to advance aging research and development of interventions aimed at extending health span and improving the quality of life in the older population., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Hepatocellular carcinoma (HCC) is associated with increased soluble CD40 levels. This study aimed to investigate CD40's role in liver tumor progression. CD40 levels were examined in HCC patient tissues and various HCC cell lines, and their interaction with CD4 + T cells was studied. RNA sequencing analysis was performed to explore the mechanisms of CD40 induction. Poorly differentiated HCC tumor tissues exhibited high membrane-bound CD40 expression, in contrast to nontumor areas. Poorly differentiated HCC cell lines showed high expression of membrane-bound CD40 with low CD40 promoter methylation, which was the opposite of that observed in the well-differentiated HCC cell lines. Solely modulating CD40 expression in HCC cells exerted no direct consequences on cell growth or appearance. Interestingly, the human hepatoma cell line HLF co-cultured with activated (CD40 ligand + ) CD4 + T cells had increased CD40 levels and a modest 3.2% dead cells. The percentage of dead cells increased to 10.9% and underwent preneutralizing CD40 condition, whereas preblocking both CD40 and integrin α5β1 concomitantly caused only 1.9% cell death. RNA sequencing of co-cultured HLFs with activated CD4 + T cells revealed the up-regulation of interferon and immune-response pathways. Increased interferon-γ levels in the activated T-cell media stimulated the Janus kinase/signal transducer and activator of transcription 3 pathway, resulting in increased CD40 expression in HLF. Collectively, CD40 expression in poorly differentiated HCC cells prevented cell death by interacting with CD40 ligand in activated T cells. Targeting CD40 may represent a promising anticancer therapy., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The incidence of oral cancer has recently been increasing worldwide, particularly among young individuals and women. The primary risk factors for head and neck cancers, including oral and pharyngeal cancers, are smoking, alcohol consumption, poor oral hygiene, and repeated exposure to mechanical stimuli. However, approximately one-third of the patients with oral and pharyngeal cancers are neither smokers nor drinkers, which points to the existence of other mechanisms. Recently, human microbes have been linked to various diseases, including cancer. Oral pathogens, especially periodontal pathobionts, are reported to play a role in the development of colon and other types of cancer. In this study, we employed a series of bioinformatics analyses to pinpoint Fusobacterium nucleatum as the predominant oral bacterial species in oral and pharyngeal cancer tissue samples. We successfully isolated Fn. polymorphum from the saliva of patients with oral cancer and demonstrated that Fn. polymorphum indeed promoted oral squamous cell carcinoma development by activating YAP in a mouse tongue cancer model. Our research offers scientific evidence for the role of the oral microbiome in oral cancer progression and provides insights that would help in devising preventative strategies against oral cancer, potentially by altering oral bacterial profiles.

Fatty acids play various physiological roles owing to their diverse structural characteristics, such as hydrocarbon chain length (HCL) and degree of saturation (DS). Although the distribution of fatty acids in biological tissues is associated with lipid metabolism, in situ imaging tools are still lacking for HCL and DS. Here, we introduce a framework of near-infrared (1000-1400 nm) hyperspectral label-free imaging with machine learning analysis of the fatty acid HCL and DS distribution in the liver at each pixel, in addition to the previously reported total lipid content. The training data of 16 typical fatty acids were obtained by gas chromatography from liver samples of mice fed with various diets. A two-dimensional mapping of these two parameters was successfully performed. Furthermore, the HCL/DS plot exhibited characteristic clustering among the different diet groups. Visualization of fatty acid distribution would provide insights for revealing the pathophysiological conditions of liver diseases and metabolism., (© 2023. The Author(s).)

The naked mole rat (NMR) is the longest-lived rodent, resistant to multiple age-related diseases including neurodegeneration. However, the mechanisms underlying the NMR's resistance to neurodegenerative diseases remain elusive. Here, we isolated oligodendrocyte progenitor cells (OPCs) from NMRs and compared their transcriptome with that of other mammals. Extracellular matrix (ECM) genes best distinguish OPCs of long- and short-lived species. Notably, expression levels of CD44, an ECM-binding protein that has been suggested to contribute to NMR longevity by mediating the effect of hyaluronan (HA), are not only high in OPCs of long-lived species but also positively correlate with longevity in multiple cell types/tissues. We found that CD44 localizes to the endoplasmic reticulum (ER) and enhances basal ATF6 activity. CD44 modifies proteome and membrane properties of the ER and enhances ER stress resistance in a manner dependent on unfolded protein response regulators without the requirement of HA. HA-independent role of CD44 in proteostasis regulation may contribute to mammalian longevity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The gut and the liver are anatomically and physiologically connected, and this connection is called the "gut-liver axis," which exerts various influences on liver physiology and pathology. The gut microbiota has been recognized to trigger innate immunity and modulate the liver immune microenvironment. Gut microbiota influences the physiological processes in the host, such as metabolism, by acting on various signaling receptors and transcription factors through their metabolites and related molecules. The gut microbiota has also been increasingly recognized to modulate the efficacy of immune checkpoint inhibitors. In this review, we discuss recent updates on gut microbiota-associated mechanisms in the pathogenesis of chronic liver diseases such as NAFLD and NASH, as well as liver cancer, in light of the gut-liver axis. We particularly focus on gut microbial metabolites and components that are associated with these liver diseases. We also discuss the role of gut microbiota in modulating the response to immunotherapy in liver diseases., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Although molecular features underlying aging and species maximum lifespan (MLS) have been comprehensively studied by transcriptome analyses, the actual impact of transcriptome on aging and MLS remains elusive. Here, we found that transcriptional signatures that are associated with mammalian MLS exhibited significant similarity to those of aging. Moreover, transcriptional signatures of longer MLS and aging both exhibited significant similarity to that of longer-lived mouse strains, suggesting that gene expression patterns associated with species MLS contribute to extended lifespan even within a species and that aging-related gene expression changes overall represent adaptations that extend lifespan rather than deterioration. Finally, we found evidence of co-evolution of MLS and promoter sequences of MLS-associated genes, highlighting the evolutionary contribution of specific transcription factor binding motifs such as that of E2F1 in shaping MLS-associated gene expression signature. Our results highlight the importance of focusing on adaptive aspects of aging transcriptome and demonstrate that cross-species genomics can be a powerful approach for understanding adaptive aging transcriptome., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The elucidation of the mechanisms of ageing and the identification of methods to control it have long been anticipated. Recently, two factors associated with ageing-the accumulation of senescent cells and the change in the composition of gut microbiota-have been shown to play key roles in ageing. However, little is known about how these phenomena occur and are related during ageing. Here we show that the persistent presence of commensal bacteria gradually induces cellular senescence in gut germinal centre B cells. Importantly, this reduces both the production and diversity of immunoglobulin A (IgA) antibodies that target gut bacteria, thereby changing the composition of gut microbiota in aged mice. These results have revealed the existence of IgA-mediated crosstalk between the gut microbiota and cellular senescence and thus extend our understanding of the mechanism of gut microbiota changes with age, opening up possibilities for their control., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Aims: Cell-cell interactions between hepatocytes (Hep) and other liver cells are key to maintaining liver homeostasis. Cytoglobin (CYGB), expressed exclusively by hepatic stellate cells (HSC), is essential in mitigating mitochondrial oxidative stress. CYGB absence causes Hep dysfunction and evokes hepatocarcinogenesis through an elusive mechanism. CYGB deficiency is speculated to hinder nitric oxide dioxygenase (NOD) activity, resulting in the elevated formation and release of nitric oxide (NO). Hence, we hypothesized that NO accumulation induced by the loss of NOD activity in CYGB-deficient HSC could adversely affect mitochondrial function in Hep, leading to disease progression. Results: NO, a membrane-permeable gas metabolite overproduced by CYGB-deficient HSC, diffuses into the neighboring Hep to reversibly inhibit cytochrome c oxidase (CcO), resulting in the suppression of respiratory function in an electron transport chain (ETC). The binding of NO to CcO is proved using purified CcO fractions from Cygb knockout ( Cygb - / - ) mouse liver mitochondria. Its inhibitory action toward CcO-specific activity is fully reversed by the external administration of oxyhemoglobin chasing away the bound NO. Thus, these findings indicate that the attenuation of respiratory function in ETC causes liver damage through the formation of excessive reactive oxygen species. Treating Cygb -/- mice with an NO synthase inhibitor successfully relieved NO-induced inhibition of CcO activity in vivo . Innovation and Conclusion: Our findings provide a biochemical link between CYGB-absence in HSC and neighboring Hep dysfunction; mechanistically the absence of CYGB in HSC causes mitochondrial dysfunction of Hep via the inhibition of CcO activity by HSC-derived NO. Antioxid. Redox Signal. 38, 463-479.

Cellular senescence refers to a state of irreversible cell cycle arrest that can be induced by various cellular stresses and is known to play a pivotal role in tumour suppression. While senescence-associated growth arrest can inhibit the proliferation of cancer-prone cells, the altered secretory profile of senescent cells, termed the senescence-associated secretory phenotype, can contribute to the microenvironment that promotes tumour development. Although the senescence-associated secretory phenotype and its effects on tumorigenesis are both highly context dependent, mechanisms underlying such diversity are becoming better understood, thereby allowing the creation of new strategies to effectively target the senescence-associated secretory phenotype and senescent cells for cancer therapy. In this review, we discuss the current knowledge on cellular senescence and the senescence-associated secretory phenotype to develop a structural understanding of their roles in the tumour microenvironment and provide perspectives for future research, including the possibility of senotherapy for the treatment of cancer., (© 2022 Federation of European Biochemical Societies.)

While topical corticosteroid (TCS) treatment is widely used for many skin diseases, it can trigger adverse side effects, and some of such effects can last for a long time after stopping the treatment. However, molecular changes induced by TCS treatment remain largely unexplored, although transient changes in histology and some major ECM components have been documented. Here, we investigated transcriptomic and proteomic changes induced by fluocinolone acetonide (FA) treatment in the mouse skin by conducting RNA-Seq and quantitative proteomics. Chronic FA treatment affected the expression of 4229 genes, where downregulated genes were involved in cell-cycle progression and ECM organization, and upregulated genes were involved in lipid metabolism. The effects of FA on transcriptome and histology of the skin largely returned to normal by two weeks after the treatment. Only a fraction of transcriptomic changes were reflected by proteomic changes, and the expression of 46 proteins was affected one day after chronic FA treatment. A comparable number of proteins were differentially expressed between control and FA-treated skin samples even at 15 and 30 days after stopping chronic FA treatment. Interestingly, proteins affected during and after chronic FA treatment were largely different. Our results provide fundamental information of molecular changes induced by FA treatment in the skin.

Factors affecting the probability of hepatocellular carcinoma (HCC) development even after sustained virological response (SVR) following anti-hepatitis C virus (HCV) therapy remain unelucidated. This study characterized the role of 16 soluble (s) immune checkpoint proteins in 168 HCV-SVR patients, with 47 developing HCC at the study end point. At baseline, high concentrations of 10 immune checkpoint proteins were found in the sera of the HCC group. At the study end point, levels of sCD27, sCD28, sCD40, and sCD86 in the HCC group, which were depleted following SVR, returned to higher levels than those in the non-HCC group. More importantly, patients with baseline levels of sCD27 ≥ 4104 pg/mL, sCD28 ≥ 1530 pg/mL, and sCD40 ≥ 688 pg/mL predicted a significantly greater HCC cumulative rate. Although sCD27 was elevated in patient sera, its membrane-bound form, mCD27, accumulated in the tumor and peritumor area, mainly localized in T cells. Interestingly, T-cell activation time dependently induced sCD27. Furthermore, CD70, the ligand of CD27, was robustly expressed in HCC area in which CD70 promoter methylation analysis indicated the hypomethylation compared with the nontumor pairs. Recombinant human CD27 treatment induced the proliferation of CD70-bearing HepG2 cells via the mitogen-activated protein kinase (MEK)-extracellular signal-regulated kinase pathway, but not NF-κB or p38 pathway. In conclusion, these data indicate that baseline sCD27, sCD28, and sCD40 levels could be used as HCC prognostic markers in HCV-SVR patients. sCD27 likely promotes HepG2 cell growth via the CD27-CD70 axis., (Copyright © 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Intracellular gap (iGap) formation in liver sinusoidal endothelial cells (LSECs) is caused by the destruction of fenestrae and appears under pathological conditions; nevertheless, their role in metastasis of cancer cells to the liver remained unexplored. We elucidated that hepatotoxin-damaged and fibrotic livers gave rise to LSECs-iGap formation, which was positively correlated with increased numbers of metastatic liver foci after intrasplenic injection of Hepa1-6 cells. Hepa1-6 cells induced interleukin-23-dependent tumor necrosis factor-α (TNF-α) secretion by LSECs and triggered LSECs-iGap formation, toward which their processes protruded to transmigrate into the liver parenchyma. TNF-α triggered depolymerization of F-actin and induced matrix metalloproteinase 9 (MMP9), intracellular adhesion molecule 1, and CXCL expression in LSECs. Blocking MMP9 activity by doxycycline or an MMP2/9 inhibitor eliminated LSECs-iGap formation and attenuated liver metastasis of Hepa1-6 cells. Overall, this study revealed that cancer cells induced LSEC-iGap formation via proinflammatory paracrine mechanisms and proposed MMP9 as a favorable target for blocking cancer cell metastasis to the liver.

More than 500 species of microbiota reside in the human intestine and coexist with humans, their host. Gut microbial metabolites and components are absorbed from the intestine and influence cells in the liver, including hepatocytes and stromal cells, such as liver sinusoidal endothelial cells, hepatic stellate cells, Kupffer cells, natural killer (NK) cells, NK T cells and other immune cells. This gut-originated axis to the liver is called the "gut-liver axis", which underscores the importance of the link between the gut and the liver. In this review, we discuss the gut microbial components and metabolites that affect cells in the liver, particularly in association with immune cells, and the related responses. We also highlight the mechanisms underlying gut microbiota-mediated liver carcinogenesis and discuss cancer prevention, including the recently clarified modulation of immune checkpoint inhibitor efficacy by the gut microbiota., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The senescence-associated secretory phenotype (SASP), where senescent cells produce a variety of secreted proteins including inflammatory cytokines, chemokines, matrix remodelling factors, growth factors and so on, plays pivotal but varying roles in the tumour microenvironment. The effects of SASP on the surrounding microenvironment depend on the cell type and process of cellular senescence induction, which is often associated with innate immunity. Via SASP-mediated paracrine effects, senescent cells can remodel the surrounding tissues by modulating the character of adjacent cells, such as stromal, immune cells, as well as cancer cells. The SASP is associated with both tumour-suppressive and tumour-promoting effects, as observed in senescence surveillance effects (tumour-suppressive) and suppression of anti-tumour immunity in most senescent cancer-associated fibroblasts and senescent T cells (tumour-promoting). In this review, we discuss the features and roles of senescent cells in tumour microenvironment with emphasis on their context-dependency that determines whether they promote or suppress cancer development. Potential usage of recently developed drugs that suppress the SASP (senomorphics) or selectively kill senescence cells (senolytics) in cancer therapy are also discussed., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Accumulating evidence indicates that alterations of gut microbiota are associated with colorectal cancer (CRC). Therefore, the use of gut microbiota for the diagnosis of CRC has received attention. Recently, several studies have been conducted to detect the differences in the gut microbiota between healthy individuals and CRC patients using machine learning-based gut bacterial DNA meta-sequencing analysis, and to use this information for the development of CRC diagnostic model. However, to date, most studies had small sample sizes and/or only cross-validated using the training dataset that was used to create the diagnostic model, rather than validated using an independent test dataset. Since machine learning-based diagnostic models cause overfitting if the sample size is small and/or an independent test dataset is not used for validation, the reliability of these diagnostic models needs to be interpreted with caution. To circumvent these problems, here we have established a new machine learning-based CRC diagnostic model using the gut microbiota as an indicator. Validation using independent test datasets showed that the true positive rate of our CRC diagnostic model increased substantially as CRC progressed from Stage I to more than 60% for CRC patients more advanced than Stage II when the false positive rate was set around 8%. Moreover, there was no statistically significant difference in the true positive rate between samples collected in different cities or in any part of the colorectum. These results reveal the possibility of the practical application of gut microbiota-based CRC screening tests., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Hepatic encephalopathy (HE) is the neuropsychiatric complication of liver cirrhosis (LC). The influence of gut microbiota on HE pathogenesis has been suggested but not precisely elucidated. Here, we investigate how the gut microbial profile changed in patients with HE to clarify the functional gut microbial species associated with HE. We focused on their responses to rifaximin (RFX), a nonabsorbable antibiotic used in HE therapy. Feces samples were collected from patients with decompensated LC (all HE), patients with compensated LC, and healthy controls, and fecal gut microbial profiles were compared using 16S ribosomal RNA gene amplicon and metagenomic sequencing. The linear discriminant analysis effect size was used to identify specific species. Urease-positive Streptococcus salivarius, which can produce ammonia, was identified as the most significantly abundant gut microbiota in the HE group, and its ability to elevate the levels of blood ammonia as well as brain glutamine was experimentally verified in mice. Urease-negative Ruminococcus gnavus was also identified as a significantly abundant species in patients with RFX-nonresponsive HE after RFX administration. Interestingly, R. gnavus enhanced urease activity of recombinant urease itself, implying that R. gnavus could amplify ammonia production of surrounding urease-positive microbiota. Furthermore, the sensitivity of S. salivarius and R. gnavus to RFX depended on conjugated secondary bile acid levels, suggesting a therapeutic potential of the combined use of secondary bile acid levels with RFX for enhancing the efficacy of RFX. This study identified specific gut bacterial species abundant in patients with HE and verified their functions linked to HE pathophysiology. Targeting these bacteria could be a potentially effective strategy to treat HE., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Long-term senescent cells exhibit a secretome termed the senescence-associated secretory phenotype (SASP). Although the mechanisms of SASP factor induction have been intensively studied, the release mechanism and how SASP factors influence tumorigenesis in the biological context remain unclear. In this study, using a mouse model of obesity-induced hepatocellular carcinoma (HCC), we identified the release mechanism of SASP factors, which include interleukin-1β (IL-1β)- and IL-1β-dependent IL-33, from senescent hepatic stellate cells (HSCs) via gasdermin D (GSDMD) amino-terminal-mediated pore. We found that IL-33 was highly induced in senescent HSCs in an IL-1β-dependent manner in the tumor microenvironment. The release of both IL-33 and IL-1β was triggered by lipoteichoic acid (LTA), a cell wall component of gut microbiota that was transferred and accumulated in the liver tissue of high-fat diet-fed mice, and the release of these factors was mediated through cell membrane pores formed by the GSDMD amino terminus, which was cleaved by LTA-induced caspase-11. We demonstrated that IL-33 release from HSCs promoted HCC development via the activation of ST2-positive T reg cells in the liver tumor microenvironment. The accumulation of GSDMD amino terminus was also detected in HSCs from human NASH-associated HCC patients, suggesting that similar mechanism could be involved in a certain type of human HCC. These results uncover a release mechanism for SASP factors from sensitized senescent HSCs in the tumor microenvironment, thereby facilitating obesity-associated HCC progression. Furthermore, our findings highlight the therapeutic potential of inhibitors of GSDMD-mediated pore formation for HCC treatment.