Caveolin-1-ACE2 axis modulates xenobiotic metabolism-linked chemoresistance in ovarian clear cell carcinoma.

Among epithelial ovarian cancers, ovarian clear cell carcinoma (OCCC) remains markedly resistant to platinum-based chemotherapy, leading to poor clinical outcomes. In response to xenobiotic insults, caveolar platforms play crucial roles in modulating stress signaling responses in cancer cells. It has been hypothesized that caveolin-1 (Cav-1), a main component of the lipid raft, may regulate the response to platinum-based treatment in OCCC. The clinical transcriptomic evaluation demonstrated that high Cav-1 expression was positively associated with a favorable prognosis in patients with ovarian cancer. Cav-1 overexpression enhanced sensitivity to cisplatin (CDDP) treatment, whereas Cav-1 deficiency promoted chemoresistance in OCCC cells. Mechanistically, although Cav-1 counteracted angiotensin-converting enzyme 2 (ACE2) expression, ACE2 positively facilitated resistance to CDDP in OCCC cells. Furthermore, ACE2 restricted aryl hydrocarbon receptor expression and subsequent transcription of drug-metabolizing enzymes. Of note, ACE2 positively regulated the expression of the platinum-clearing enzyme CYP3A4. These findings suggest that the Cav-1-ACE2 axis modulates xenobiotic metabolism-linked chemoresistance in OCCC, predicting potential roles for the stress sentinel networks in oncogenic processes.

Fish Collagen Peptides Protect against Cisplatin-Induced Cytotoxicity and Oxidative Injury by Inhibiting MAPK Signaling Pathways in Mouse Thymic Epithelial Cells.

Thymic epithelial cells (TECs) account for the most abundant and dominant stromal component of the thymus, where T cells mature. Oxidative- or cytotoxic-stress associated injury in TECs, a significant and common problem in many clinical settings, may cause a compromised thymopoietic capacity of TECs, resulting in clinically significant immune deficiency disorders or impairment in the adaptive immune response in the body. The present study demonstrated that fish collagen peptides (FCP) increase cell viability, reduce intracellular levels of reactive oxygen species (ROS), and impede apoptosis by repressing the expression of Bax and Bad and the release of cytochrome c, and by upregulating the expression of Bcl-2 and Bcl-xL in cisplatin-treated TECs. These inhibitory effects of FCP on TEC damage occur via the suppression of ROS generation and MAPK (p38 MAPK, JNK, and ERK) activity. Taken together, our data suggest that FCP can be used as a promising protective agent against cytotoxic insults- or ROS-mediated TEC injury. Furthermore, our findings provide new insights into a therapeutic approach for the future application of FCP in the prevention and treatment of various types of oxidative- or cytotoxic stress-related cell injury in TECs as well as age-related or acute thymus involution.

MicroRNA target-based network predicts androgen receptor-linked mycotoxin stress.

Stress-responsive microRNAs (miRNAs) contribute to the regulation of cellular homeostasis or pathological processes, including carcinogenesis, by reprogramming target gene expression following human exposure to environmental or dietary xenobiotics. Herein, we predicted the targets of carcinogenic mycotoxin-responsive miRNAs and analyzed their association with disease and functionality. miRNA target-derived prediction indicated potent associations of oncogenic mycotoxin exposure with metabolism- or hormone-related diseases, including sex hormone-linked cancers. Mechanistically, the signaling network evaluation suggested androgen receptor (AR)-linked signaling as a common pivotal cluster associated with metabolism- or hormone-related tumorigenesis in response to aflatoxin B1 and ochratoxin A co-exposure. Particularly, high levels of AR and AR-linked genes for the retinol and xenobiotic metabolic enzymes were positively associated with attenuated disease biomarkers and good prognosis in patients with liver or kidney cancers. Moreover, AR-linked signaling was protective against OTA-induced genetic insults in human hepatocytes whereas it was positively involved in AFB1-induced genotoxic actions. Collectively, miRNA target network-based predictions provide novel clinical insights into the progression or intervention against malignant adverse outcomes of human exposure to environmental oncogenic insults.

Di-(2-ethylhexyl) Phthalate Triggers Proliferation, Migration, Stemness, and Epithelial-Mesenchymal Transition in Human Endometrial and Endometriotic Epithelial Cells via the Transforming Growth Factor-ß/Smad Signaling Pathway.

Di-(2-ethylhexyl) phthalate (DEHP) is a frequently used plasticizer that may be linked to the development of endometriosis, a common gynecological disorder with a profound impact on quality of life. Despite its prevalence, vital access to treatment has often been hampered by a lack of understanding of its pathogenesis as well as reliable disease models. Recently, epithelial-mesenchymal transition (EMT) has been suggested to have a significant role in endometriosis pathophysiology. In this study, we found that DEHP treatment enhanced proliferation, migration, and inflammatory responses, along with EMT and stemness induction in human endometrial and endometriotic cells. The selective transforming growth factor-ß (TGF-ß) receptor type 1/2 inhibitor LY2109761 reversed the DEHP-induced cell proliferation and migration enhancement as well as the increased expression of crucial molecules involved in inflammation, EMT, and stemness, indicating that DEHP-triggered phenomena occur via the TGF-ß/Smad signaling pathway. Our study clearly defines the role of DEHP in the etiology and pathophysiological mechanisms of endometriosis and establishes an efficient disease model for endometriosis using a biomimetic 3D cell culture technique. Altogether, our data provide novel etiological and mechanistic insights into the role of DEHP in endometriosis pathogenesis, opening avenues for developing novel preventive and therapeutic strategies for endometriosis.

Ribosome Inactivation Leads to Attenuation of Intestinal Polymeric Ig Receptor Expression via Differential Regulation of Human Antigen R.

The polymeric IgR (pIgR) is a central component in the transport of IgA across enterocytes and thereby plays a crucial role in the defense against enteropathogens and in the regulation of circulating IgA levels. The present study was performed to address the novel regulation of pIgR expression in intestinal epithelia undergoing ribosome inactivation. Insults to mucosa that led to ribosome inactivation attenuated pIgR expression in enterocytes. However, IFN regulatory factor-1 (IRF-1) as a central transcription factor of pIgR induction was superinduced by ribosome inactivation in the presence of IFN-γ as a result of mRNA stabilization by the RNA-binding protein HuR. Another important transcription factor for pIgR expression, NF-κB, was marginally involved in suppression of pIgR by ribosome inactivation. In contrast to a positive contribution of HuR in early induction of IRF-1 expression, extended exposure to ribosome inactivation caused nuclear entrapment of HuR, resulting in destabilization of late-phase-induced pIgR mRNA. These HuR-linked differential regulations of pIgR and of IRF-1 led to a reduced mucosal secretion of IgA and, paradoxically, an induction of IRF-1-activated target genes, including colitis-associated IL-7. Therefore, these events can account for ribosome inactivation-related mucosal disorders and provide new insight into interventions for HuR-linked pathogenesis in diverse mucosa-associated diseases, including inflammatory bowel disease and IgA nephritis.

Early Epithelial Restitution by Nonsteroidal Anti-Inflammatory Drug-Activated Gene 1 Counteracts Intestinal Ulcerative Injuries.

In response to ulcerative mucosal injuries, intestinal epithelial restitution is a critical event in the early defense against harmful attacks by luminal Ags. Based on the assumption that epithelial NAG-1 is an endogenous regulator of ulcerative stress-induced injuries, the expression and functions of NAG-1 were investigated. Genetic ablation of NAG-1 decreased survival of mice with dextran sodium sulfate-induced intestinal ulcer and histologically delayed the epithelial restitution, confirming early protective roles of NAG-1 in ulcerative insults. Moreover, enhanced expression of NAG-1 during the wound-healing process was associated with epithelial cell migration and spreading. In response to ulcerative injury, RhoA GTPase, a cytoskeleton modulator, mediated epithelial restitution via enhanced motility. RhoA expression was prominently elevated in the restituting epithelia cells around the insulted wound bed and was attenuated by NAG-1 deficiency. Pharmacological intervention with RhoA thus attenuated NAG-1-mediated epithelial cell migration during epithelial restitution. Taken together, epithelial restitution was promoted by enhanced NAG-1 expression and subsequent enterocyte locomotion during the early wound-healing process, suggesting clinical usefulness of NAG-1 as a novel endogenous muco-protective factor or an indicator of therapeutic efficacy against the ulcerative gastrointestinal diseases, including inflammatory bowel disease.

Non-mutagenic Suppression of Enterocyte Ferroportin 1 by Chemical Ribosomal Inactivation via p38 Mitogen-activated Protein Kinase (MAPK)-mediated Regulation: EVIDENCE FOR ENVIRONMENTAL HEMOCHROMATOSIS.

Iron transfer across the basolateral membrane of an enterocyte into the circulation is the rate-limiting step in iron absorption and is regulated by various pathophysiological factors. Ferroportin (FPN), the only known mammalian iron exporter, transports iron from the basolateral surface of enterocytes, macrophages, and hepatocytes into the blood. Patients with genetic mutations in FPN or repeated blood transfusion develop hemochromatosis. In this study, non-mutagenic ribosomal inactivation was assessed as an etiological factor of FPN-associated hemochromatosis in enterocytes. Non-mutagenic chemical ribosomal inactivation disrupted iron homeostasis by regulating expression of the iron exporter FPN-1, leading to intracellular accumulation in enterocytes. Mechanistically, a xenobiotic insult stimulated the intracellular sentinel p38 MAPK signaling pathway, which was positively involved in FPN-1 suppression by ribosomal dysfunction. Moreover, ribosomal inactivation-induced iron accumulation in Caenorhabditis elegans as a simplified in vivo model for gut nutrition uptake was dependent on SEK-1, a p38 kinase activator, leading to suppression of FPN-1.1 expression and iron accumulation. In terms of gene regulation, ribosomal stress-activated p38 signaling down-regulated NRF2 and NF-κB, both of which were positive transcriptional regulators of FPN-1 transcription. This study provides molecular evidence for the modulation of iron bioavailability by ribosomal dysfunction as a potent etiological factor of non-mutagenic environmental hemochromatosis in the gut-to-blood axis.

Acquisition of Chemoresistance and Other Malignancy-related Features of Colorectal Cancer Cells Are Incremented by Ribosome-inactivating Stress.

Colorectal cancer (CRC) as an environmental disease is largely influenced by accumulated epithelial stress from diverse environmental causes. We are exposed to ribosome-related insults, including ribosome-inactivating stress (RIS), from the environment, dietary factors, and medicines, but their physiological impacts on the chemotherapy of CRC are not yet understood. Here we revealed the effects of RIS on chemosensitivity and other malignancy-related properties of CRC cells. First, RIS led to bidirectional inhibition of p53-macrophage inhibitory cytokine 1 (MIC-1)-mediated death responses in response to anticancer drugs by either enhancing ATF3-linked antiapoptotic signaling or intrinsically inhibiting MIC-1 and p53 expression, regardless of ATF3. Second, RIS enhanced the epithelial-mesenchymal transition and biogenesis of cancer stem-like cells in an ATF3-dependent manner. These findings indicate that gastrointestinal exposure to RIS interferes with the efficacy of chemotherapeutics, mechanistically implying that ATF3-linked malignancy and chemoresistance can be novel therapeutic targets for the treatment of environmentally aggravated cancers.

Epithelial Cholesterol Deficiency Attenuates Human Antigen R-linked Pro-inflammatory Stimulation via an SREBP2-linked Circuit.

Patients with chronic intestinal ulcerative diseases, such as inflammatory bowel disease, tend to exhibit abnormal lipid profiles, which may affect the gut epithelial integrity. We hypothesized that epithelial cholesterol depletion may trigger inflammation-checking machinery via cholesterol sentinel signaling molecules whose disruption in patients may aggravate inflammation and disease progression. In the present study, sterol regulatory element-binding protein 2 (SREBP2) as the cholesterol sentinel was assessed for its involvement in the epithelial inflammatory responses in cholesterol-depleted enterocytes. Patients and experimental animals with intestinal ulcerative injuries showed suppression in epithelial SREBP2. Moreover, SREBP2-deficient enterocytes showed enhanced pro-inflammatory signals in response to inflammatory insults, indicating regulatory roles of SREBP2 in gut epithelial inflammation. However, epithelial cholesterol depletion transiently induced pro-inflammatory chemokine expression regardless of the well known pro-inflammatory nuclear factor-κB signals. In contrast, cholesterol depletion also exerts regulatory actions to maintain epithelial homeostasis against excessive inflammation via SREBP2-associated signals in a negative feedback loop. Mechanistically, SREBP2 and its induced target EGR-1 were positively involved in induction of peroxisome proliferator-activated receptor γ (PPARγ), a representative anti-inflammatory transcription factor. As a crucial target of the SREBP2-EGR-1-PPARγ-associated signaling pathways, the mRNA stabilizer, human antigen R (HuR) was retained in nuclei, leading to reduced stability of pro-inflammatory chemokine transcripts. This mechanistic investigation provides clinical insights into protective roles of the epithelial cholesterol deficiency against excessive inflammatory responses via the SREBP2-HuR circuit, although the deficiency triggers transient pro-inflammatory signals.

NSAID-activated gene 1 and its implications for mucosal integrity and intervention beyond NSAIDs.

In spite of the beneficial actions of non-steroid anti-inflammatory drugs (NSAIDs) in epithelial inflammation and cancers, their use is limited because of their cyclooxygenase-dependent or independent gastrointestinal toxicity. As an eicosanoid-independent mediator, NSAID-activated gene 1 (NAG-1) has been assessed for its involvement in cellular integrity and pathogenesis in mucosal inflammation and carcinogenesis. At the cellular levels, NAG-1 is involved in the cell growth regulation (cell death, cell cycle arrest, or proliferation) in epithelial and mesenchymal tissues. Moreover, NAG-1 can modulate inflammatory responses in either direct or indirect manner, which ultimately affects fibrogenic and tumorigenic processes in various disease states. Finally, NAG-1 has been assessed for its contribution to cellular behavior, such as the mobility of epithelial and malignant cells in response to the external insults or oncogenic stimulation in the mucosa. This review on the "Yin-Yang" nature of NAG-1-mediated responses provides comprehensive insights into therapeutic and diagnostic interventions for mucosal health and integrity in the human body.

Activating transcription factor 3-mediated chemo-intervention with cancer chemokines in a noncanonical pathway under endoplasmic reticulum stress.

The cell-protective features of the endoplasmic reticulum (ER) stress response are chronically activated in vigorously growing malignant tumor cells, which provide cellular growth advantages over the adverse microenvironment including chemotherapy. As an intervention with ER stress responses in the intestinal cancer cells, preventive exposure to flavone apigenin potentiated superinduction of a regulatory transcription factor, activating transcription factor 3 (ATF3), which is also known to be an integral player coordinating ER stress response-related gene expression. ATF3 superinduction was due to increased turnover of ATF3 transcript via stabilization with HuR protein in the cancer cells under ER stress. Moreover, enhanced ATF3 caused inhibitory action against ER stress-induced cancer chemokines that are potent mediators determining the survival and metastatic potential of epithelial cancer cells. Although enhanced ATF3 was a negative regulator of the well known proinflammatory transcription factor NF-κB, blocking of NF-κB signaling did not affect ER stress-induced chemokine expression. Instead, immediately expressed transcription factor early growth response protein 1 (EGR-1) was positively involved in cancer chemokine induction by ER stressors. ER stress-induced EGR-1 and subsequent chemokine production were repressed by ATF3. Mechanistically, ATF3 directly interacted with and recruited HDAC1 protein, which led to epigenetic suppression of EGR-1 expression and subsequent chemokine production. Conclusively, superinduced ATF3 attenuated ER stress-induced cancer chemokine expression by epigenetically interfering with induction of EGR-1, a transcriptional modulator crucial to cancer chemokine production. Thus, these results suggest a potent therapeutic intervention of ER stress response-related cancer-favoring events by ATF3.

SOCS3 regulates BAFF in human enterocytes under ribosomal stress.

Although the activation of B cells in the gastrointestinal tract is of great importance in the context of immunity to pathogens and mucosal inflammatory diseases, little is known about the mechanisms responsible for the local activation of B cells in the subepithelial area of the intestine. Epithelium-derived BAFF is the major modulator of B cell development and Ig class switching. The present study was performed to address the molecular mechanism of BAFF expression in gut epithelial cells in the presence of proinflammatory stimuli. Inflammation-induced BAFF expression in mucosal epithelial cells might be responsible for diverse mucosa-associated diseases linked to intestinal inflammation and autoimmunity. Although BAFF was marginally expressed in unstimulated epithelial cells, BAFF mRNA was significantly upregulated by proinflammatory IFN-γ. Furthermore, IFN-γ triggered JAK/STAT1 signals via the cytokine receptor, which contributed to epithelial BAFF upregulation. In terms of signaling intervention, ribosomal insult attenuated IFN-γ-activated JAK/STAT signal transduction and subsequent BAFF induction in gut epithelial cells. Ribosomal insults led to the superinduction of SOCS3 by enhancing its mRNA stability via HuR RNA-binding protein. Upregulated SOCS3 then contributed to the blocking of the JAK/STAT-linked signal, which mediated BAFF suppression by ribosomal stress. All of these findings show that ribosomal stress-induced SOCS3 plays a novel regulatory role in epithelial BAFF production, suggesting that epithelial ribosomal dysfunction in association with SOCS3 may be a promising therapeutic point in BAFF-associated human mucosal diseases.

Novel regulatory action of ribosomal inactivation on epithelial Nod2-linked proinflammatory signals in two convergent ATF3-associated pathways.

In response to excessive nucleotide-binding oligomerization domain-containing protein 2 (Nod2) stimulation caused by mucosal bacterial components, gut epithelia need to activate regulatory machinery to maintain epithelial homeostasis. Activating transcription factor 3 (ATF3) is a representative regulator in the negative feedback loop that modulates TLR-associated inflammatory responses. In the current study, the regulatory effects of ribosomal stress-induced ATF3 on Nod2-stimulated proinflammatory signals were assessed. Ribosomal inactivation caused persistent ATF3 expression that in turn suppressed proinflammatory chemokine production facilitated by Nod2. Decreased chemokine production was due to attenuation of Nod2-activated NF-κB and early growth response protein 1 (EGR-1) signals by ATF3. However, the underlying molecular mechanisms involve two convergent regulatory pathways. Although ATF3 induced by ribosomal inactivation regulated Nod2-induced EGR-1 expression epigenetically through the recruitment of histone deacetylase 1, NF-κB regulation was associated with posttranscriptional regulation by ATF3 rather than epigenetic modification. ATF3 induced by ribosomal inactivation led to the destabilization of p65 mRNA caused by nuclear entrapment of transcript-stabilizing human Ag R protein via direct interaction with ATF3. These findings demonstrate that ribosomal stress-induced ATF3 is a critical regulator in the convergent pathways between EGR-1 and NF-κB, which contributes to the suppression of Nod2-activated proinflammatory gene expression.

Ribosomal alteration-derived signals for cytokine induction in mucosal and systemic inflammation: noncanonical pathways by ribosomal inactivation.

Ribosomal inactivation damages 28S ribosomal RNA by interfering with its functioning during gene translation, leading to stress responses linked to a variety of inflammatory disease processes. Although the primary effect of ribosomal inactivation in cells is the functional inhibition of global protein synthesis, early responsive gene products including proinflammatory cytokines are exclusively induced by toxic stress in highly dividing tissues such as lymphoid tissue and epithelia. In the present study, ribosomal inactivation-related modulation of cytokine production was reviewed in leukocyte and epithelial pathogenesis models to characterize mechanistic evidence of ribosome-derived cytokine induction and its implications for potent therapeutic targets of mucosal and systemic inflammatory illness, particularly those triggered by organellar dysfunctions.

Gut ribotoxic stress responses facilitate dyslipidemia via metabolic reprogramming: an environmental health prediction.

Rationale: The gut and its accessory organ, the liver, are crucial determinants of metabolic homeostasis via the regulation of circulating lipids for cardiovascular health. In response to environmental insults, cells undergo diverse adaptation or pathophysiological processes via stress-responsive eukaryotic initiation factor 2 alpha (eIF2α) kinase signaling and subsequent cellular reprogramming. We noted that patients with inflammatory gut distress display enhanced levels of ribosomal stress-responsive eIF2α kinase, which is notably associated with lipid metabolic process genes. Based on an assumption that eukaryotic ribosomes are a promising stress-responsive module for molecular reprogramming, chemical ribosome-inactivating stressors (RIS) were assessed for their involvement in enterohepatic lipid regulation. Methods: Experimental assessment was based on prediction using the clinical transcriptome and single-cell RNA-sequencing analysis of inflammatory bowel diseases and obesity. The prediction was verified using RIS exposure models of mice, gut organoids, and intestinal cells. The lipidomic profiling was performed to address RIS-induced intracellular fat alterations. Biochemical processes of the mechanisms were evaluated using RT-PCR, western blot analysis, luciferase reporter assays, and confocal microscopy of genetically ablated or chemically inhibited mice, organoids, and cells. Results: Chemical RIS including deoxynivalenol promoted enterohepatic lipid sequestration while lowering blood LDL cholesterol in normal and diet-induced obese mice. Although ribosomal stress caused extensive alterations in cellular lipids and metabolic genes, the cholesterol import-associated pathway was notably modulated. In particular, ribosomal stress enhanced gut levels of the low-density lipoprotein receptor (LDLR) via both transcriptional and post-transcriptional regulation. Subsequently, LDLR facilitated enterohepatic cholesterol accumulation, leading to dyslipidemia in response to ribosomal stress. Moreover, genetic features of stress-responsive LDLR modulators were consistently proven in the inflammation- and obesity-associated gut model. Conclusion: The elucidated ribosome-linked gut lipid regulation provides predictive insights into stress-responsive metabolic rewiring in chronic human diseases as an environmental health prediction.

Two in-and-out modulation strategies for endoplasmic reticulum stress-linked gene expression of pro-apoptotic macrophage-inhibitory cytokine 1.

Excessive and persistent insults during endoplasmic reticulum (ER) stress lead to apoptotic cell death that is implicated in a range of chronic inflammatory diseases and cancers. Macrophage inhibitory cytokine 1 (MIC-1), a member of the transforming growth factor-ß superfamily, is diversely linked to the pathogenesis of cancer. To investigate the precise molecular mechanisms of MIC-1 gene regulation, ER stress and its related signals were studied in human colon cancer cells. Functionally, MIC-1 played pivotal roles in ER stress-linked apoptotic death, which was also influenced by C/EBP homologous protein, a well known apoptotic mediator of ER stress. ER stress enhanced MIC-1 mRNA stability instead of transcriptional activation, and there were two mechanistic translocations critical for mRNA stabilization. First, C/EBP homologous protein triggered protein kinase C-linked cytosolic translocation of the HuR/ELAVL1 (Elav-like RNA-binding protein 1) RNA-binding protein, which bound to and stabilized MIC-1 transcript. As the second critical in-and-out regulation, ER stress-activated ERK1/2 signals contributed to enhanced stabilization of MIC-1 transcript by controlling the extended holding of the nucleated mRNA in the stress granules fusing with the mRNA-decaying processing body. We propose that these two sequential in-and-out modulations can account for stabilized transcription and subsequent translation of pro-apoptotic MIC-1 gene in human cancer cells under ER stress.

Prolonged NF-κB activation by a macrophage inhibitory cytokine 1-linked signal in enteropathogenic Escherichia coli-infected epithelial cells.

Intestinal epithelial activation of nuclear factor kappa B (NF-κB) exerts both detrimental and beneficial functions in response to various luminal insults, including ones associated with mucosa-associated pathogens. Gastrointestinal infection with enteropathogenic Escherichia coli (EPEC) causes severe injuries in epithelial integrity and leads to watery diarrhea. The present study was conducted to investigate the prolonged epithelial responses to persistent EPEC infection via NF-κB activation. EPEC infection led to sustained activation of NF-κB signal in mouse intestinal epithelial cells in vivo and in vitro, which was positively associated with a type III secretion system, whereas early NF-κB is regulated. Moreover, prolonged NF-κB activation was found to be a part of macrophage inhibitory cytokine 1 (MIC-1)-mediated signaling activation, a novel link between NF-κB signaling and infection-associated epithelial stress. EPEC infection induced gene expression of MIC-1, a member of the transforming growth factor ß (TGF-ß) superfamily, which then activated TGF-ß-activated kinase 1 and consequently led to NF-κB activation. Functionally, both EPEC-induced MIC-1 and NF-κB signaling mediated epithelial survival by enhancing the expression of cyclin D1, a target of NF-κB. In summary, the results of the present study suggest that MIC-1 serves as a mediator of prolonged NF-κB activation, which is critical in maintaining gut epithelial integrity in response to infection-induced injuries.

Integrated stress response-altered pro-inflammatory signals in mucosal immune-related cells.

Various cells are associated with the integrated stress response (ISR) that leads to translation arrest via phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Pathogenic insults or nutritional imbalance in the mucosal tissues including the intestinal, airway, and genitourinary epithelia can cause ISRs, which have been linked to different mucosal inflammatory responses and subsequent systemic diseases. In particular, translational arrest caused by the early recognition of luminal microbes as well as nutritional status allows the human body to mount appropriate responses and maintain homeostasis both at the cellular and systemic levels. However, an over- or reduced ISR can create pathogenic conditions such as inflammation and carcinogenesis. This present review explores the association between eIF2α kinase-linked pathways and mucosal or systemic pro-inflammatory signals activated by xenobiotic insults (such as ones caused by microbes or nutritional abnormalities). Understanding ISR-modulated cellular alterations will provide progressive insights into approaches for treating human mucosal inflammatory and metabolic disorders.

Gut distress and intervention via communications of SARS-CoV-2 with mucosal exposome.

Acute coronavirus disease 2019 (COVID-19) has been associated with prevalent gastrointestinal distress, characterized by fecal shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA or persistent antigen presence in the gut. Using a meta-analysis, the present review addressed gastrointestinal symptoms, such as nausea, vomiting, abdominal pain, and diarrhea. Despite limited data on the gut-lung axis, viral transmission to the gut and its influence on gut mucosa and microbial community were found to be associated by means of various biochemical mechanisms. Notably, the prolonged presence of viral antigens and disrupted mucosal immunity may increase gut microbial and inflammatory risks, leading to acute pathological outcomes or post-acute COVID-19 symptoms. Patients with COVID-19 exhibit lower bacterial diversity and a higher relative abundance of opportunistic pathogens in their gut microbiota than healthy controls. Considering the dysbiotic changes during infection, remodeling or supplementation with beneficial microbial communities may counteract adverse outcomes in the gut and other organs in patients with COVID-19. Moreover, nutritional status, such as vitamin D deficiency, has been associated with disease severity in patients with COVID-19 via the regulation of the gut microbial community and host immunity. The nutritional and microbiological interventions improve the gut exposome including the host immunity, gut microbiota, and nutritional status, contributing to defense against acute or post-acute COVID-19 in the gut-lung axis.

Xenobiotic-induced ribosomal stress compromises dysbiotic gut barrier aging: A one health perspective.

Upon exposure to internal or environmental insults, ribosomes stand sentinel. In particular, stress-driven dysregulation of ribosomal homeostasis is a potent trigger of adverse outcomes in mammalians. The present study assessed whether the ribosomal insult affects the aging process via the regulation of sentinel organs such as the gut. Analyses of the human aging dataset demonstrated that elevated features of ribosomal stress are inversely linked to barrier maintenance biomarkers during the aging process. Ribosome-insulted worms displayed reduced lifespan, which was associated with the disruption of gut barriers. Mechanistically, ribosomal stress-activated Sek-1/p38 signaling, a central platform of ribosomal stress responses, counteracted the gut barrier deterioration through the maintenance of the gut barrier, which was consistent with the results in a murine insult model. However, since the gut-protective p38 signaling was attenuated with aging, the ribosomal stress-induced distress was exacerbated in the gut epithelia and mucosa of the aged animals, subsequently leading to increased bacterial exposure. Moreover, the bacterial community-based evaluation predicted concomitant increases in the abundance of mucosal sugar utilizers and mucin metabolic enzymes in response to ribosomal insult in the aged host. All of the present evidence on ribosomal insulting against the gut barrier integrity from worms to mammals provides new insights into organelle-associated translational modulation of biological longevity in a one health perspective.