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Syringic acid (SA), a naturally occurring phenolic substance present in many edible plants and fruits, has been shown to have potential in immunoenhancement applications. In this study, we investigated the immunomodulatory effects of SA in mitigating cyclophosphamide (CYP)-induced immunosuppression in BALB/c mice using doxycycline as a positive control. SA administration prevented immune organ atrophy and morphological changes in the thymus, spleen, and bone marrow induced by CYP treatment in mice while also showing a dose-dependent enhancement of thymus and spleen indices compared to mice treated with CYP alone. Furthermore, SA improved thymocyte and splenocyte proliferation and exhibited significant antioxidant activity by reducing the elevated levels of malondialdehyde induced by CYP treatment. SA treatment effectively restored white blood cell (WBC) and lymphocyte counts to normal levels in CYP-treated animals, and the protective effects of CYP on immunological tissues were confirmed through histopathological examination. Moreover, SA treatment upregulated the expression of IL-6, IL-7, IL-15, and FoxN1. Finally, molecular docking studies revealed that binding energy values predicted minor inhibition potential toward IL-6, IL-7, FoxN1, IL-15, STAT3, STAT5, and JAK3. Overall, our findings suggest that SA treatment has the potential to reduce CYP-induced immunosuppression and may have applications as an immunologic adjuvant or functional food additive in chemotherapy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hepatic stellate cells (HSCs) are pericytes of the liver responsible for liver fibrosis and cirrhosis, which are the end stages of chronic liver diseases. TGF-β activates HSCs, leading to the differentiation of myofibroblasts in the process of liver fibrosis. While the heterogeneity of HSCs is appreciated in the fibrotic liver, it remains elusive which HSC subsets mainly contribute to fibrosis. Here, we show that the expression of the pericyte marker FoxD1 specifically marks a subset of HSCs in FoxD1-fate tracer mice. HSCs fate-mapped by FoxD1 were preferentially localized in the portal and peripheral areas of both the homeostatic and fibrotic liver induced by carbon tetrachloride. Furthermore, the deletion of Cbfβ, which is necessary for TGF-β signaling, in FoxD1-expressing cells ameliorated liver fibrosis. Thus, we identified an HSC subset that preferentially responds to liver injuries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The establishment and maintenance of a successful pregnancy rely heavily on maternal-fetal immune tolerance. Inflammatory and immune mechanisms during pregnancy bear a resemblance to those observed in tumor progression, with Treg cells exhibiting similar immunoregulatory functions in both contexts. Interferon regulatory factor 1 (IRF1) is implicated in modulating the immune milieu within tumors and influencing regulatory T (Treg) cell differentiation. However, the precise association between IRF1 and the onset of preeclampsia (PE) remains unclear. In our investigation, we identified trophoblasts as a significant source of IRF1 expression at the maternal-fetal interface through immunofluorescence analysis. Moreover, heightened levels of IRF1 expression were detected in both placental tissues and peripheral blood samples obtained from PE patients, concomitant with an imbalance in the Th17/Treg ratio. In the peripheral circulation, a notable inverse correlation was observed between IRF1 mRNA levels and Foxp3 mRNA, a transcription factor specific to Treg cells. IRF1 mRNA expression showed a positive association with systolic blood pressure and a negative association with serum albumin levels. Furthermore, co-culturing naïve T cells with supernatants from HTR-8/SV neo cells overexpressing IRF1 resulted in diminished differentiation of T cells into Treg cells. In summary, our study indicates elevated IRF1 expression in the peripheral blood and trophoblast cells of PE patients. Elevated IRF1 in trophoblast cells hinders the differentiation of maternal Treg cells, disrupting maternal-fetal immune tolerance and contributing to PE pathogenesis. Additionally, IRF1 expression correlates with disease severity, suggesting its potential as a novel sensitive target in PE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Motile cilia are crucial for maintaining healthy bodily functions by facilitating fluid transport and removing foreign substances or debris from the body. The dysfunction of motile cilia leads to ciliopathy. In particular, damage to the motile cilia of the airways can cause or worsen respiratory disease, making it an attractive target for therapeutic interventions. However, there are no treatments to induce motile ciliogenesis. Forkhead box transcription factor J1 (FOXJ1), the master regulator, has been implicated in motile cilia formation. Mice lacking the Foxj1 gene show loss of axoneme, a key component of cilia, that further highlights the importance of FOXJ1 in motile cilia formation. This prompted us to identify new small molecules that could induce motile ciliogenesis. A phenotype-based high-throughput screening (HTS) in a Tg(foxj1a:eGFP) zebrafish model was performed and a novel hit compound was identified. Among the synthesized compounds, compound 16c effectively enhanced motile ciliogenesis in a transgenic zebrafish model. To further test the efficacy of compound 16c on a mammalian airway system consisting of multiciliated cells (MCCs), ex vivo mice tracheal epithelial cell culture was adopted under an air-liquid interface system (ALI). Compound 16c significantly increased the number of MCCs by enhancing motile ciliogenesis. In addition, compound 16c exhibited good liver microsomal stability, in vivo PK profiles with AUC, and oral bioavailability. There was no significant inhibition of CYP and hERG, and no cell cytotoxicity was shown. In an elastase-induced COPD (chronic obstructive pulmonary disease) mouse model, compound 16c effectively prevented the development and onset of COPD. Taken together, compound 16c has great promise as a therapeutic agent for treating and alleviating motile ciliopathies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Aging triggers physiological changes in organisms that are tightly linked to metabolic changes. Senolytics targeting many fundamental aging processes are currently being developed. However, the host metabolic response to natural senescence and the molecular mechanism underlying the antiaging benefits of senolytics remain poorly understood. In this study, we investigated metabolic changes during natural senescence based on the Caenorhabditis elegans model and pinpointed potential biomarkers linked to the benefits of senolytics. These results suggest that age-dependent metabolic changes during natural aging occur in C elegans. Betaine was identified as a crucial metabolite in the natural aging process. We explored the metabolic effects of aging interventions by administering 3 antiaging drugs-metformin, quercetin, and minocycline-to nematodes. Notably, betaine expression significantly increased under the 3 antiaging drug treatments. Our findings demonstrated that betaine supplementation extends lifespan, primarily through pathways associated with the forkhead box transcription factor (FoxO) signaling pathway, the p38-mitogen-activated protein kinase (MAPK) signaling pathway, autophagy, the longevity regulating pathway, and the target of rapamycin (mTOR) signaling pathway. In addition, autophagy and free radicals are altered in betaine-treated nematodes. Overall, we found that betaine is a critical metabolite during natural aging and that senolytics extend the lifespan of nematodes by increasing betaine levels and promoting autophagy and antioxidant activity. This finding suggests that betaine could be a novel therapeutic target for promoting longevity., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Detection of critical colonization is gaining importance in wound management, but its pathophysiology remains unclear. We previously clarified that a dysbiotic wound microbiota differing from skin commensal microbiota may be involved in critical colonization and that such wounds contain fewer Forkhead box protein P3 (FOXP3)-positive cells in the tissue. However, it is not clear whether FOXP3-positive cells contribute to the development of critical colonization. Here, we examined whether inhibition of FOXP3-positive cell could induce critical colonization when the commensal microbiota was present in the wounds., Methods: Sprague-Dawley rats were administered FK506 or vehicle to inhibit differentiation into FOXP3-positive cells. Full-thickness wounds were made on the dorsal skin and inoculated with bacterial solution (dysbiosis group) or Luria-Bertani medium (commensal group). A bacterial solution was prepared by anaerobically culturing bacteria from the skin of donor rats on an artificial dermis in Luria-Bertani medium for 72 hours. Tissues were collected on day 4 postwounding for histological evaluation., Results: After microbiota transplantation, excessive inflammation occurred in the FK506 + commensal group. In contrast, wounds with transplanted dysbiotic microbiota showed the same level of neutrophil infiltration, regardless of FK506 administration. Furthermore, the wound area was larger in the FK506 + commensal group than in the vehicle + commensal group on day 4 postwounding ( P = 0.01). This area was also significantly larger in both the vehicle + dysbiosis ( P = 0.01) and FK506 + dysbiosis groups ( P = 0.03) than in the vehicle + commensal group., Conclusions: This study has shown that dysbiosis may be at least related to developing critical colonization, and the results suggest that FOXP3-positive cells are involved in this process. Our study may contribute to establishing new interventions that prevent critical colonization by correcting wound microbiota., Competing Interests: Conflicts of interest and sources of funding: T.M. and S.K. are members of the Department of Skincare Science, which receives financial support from Saraya Co, Ltd., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: HER2(+) gastric cancer (GC) can benefit from trastuzumab. However, the impact of additional trastuzumab in preoperative treatment on immune cells remains largely unknown., Methods: In cohort I, immune cells were detected by immunohistochemistry in 1321 patients. Then 88 HER2(+) patients received preoperative therapy were collected as cohort II. Immune cell profiles and changes were analyzed in paired pre- and post-operative specimens using multiple immunohistochemistry staining., Results: In the treatment-naive GC patients (n = 1002), CD3+ and CD8+ T cell infiltration was significantly lower in the HER2(+) GC patients together with higher FoxP3+ T cells compared with HER2(-). However, FoxP3+ T and CD20+ B cell infiltration was significantly higher in HER2(+) GC after neoadjuvant chemotherapy (n = 319). The trastuzumab-exposed group had higher CD8+ T and lower FoxP3+ T cell infiltration and CD8+ T cell was even more significant in responders. Additionally, tertiary lymphoid structure (TLS) density increased in invasion margin of residual tumors. Patients with lower TLS in the tumor core or lower FoxP3+ T cells had better overall survival in the trastuzumab-exposed group., Conclusion: Addition of trastuzumab modulates the immune microenvironment, suggesting the potential mechanism of the favorable outcome of anti-HER2 therapy and providing a theoretical rationale for the combinational immunotherapy in resectable HER2(+) GC patients., (© 2024. The Author(s).)

A multifaceted approach in treating Alzheimer's disease (AD), a neurodegenerative condition that poses health risks in the aging population is explored in this investigation via encapsulating Piper betle essential oil (PBEO) in chitosan nanoparticles (ChNPs) to improve solubility and efficacy of PBEO. PBEO-ChNPs mitigated AD-like features more effectively than free PBEO by delaying paralysis progression and reducing serotonin hypersensitivity, ROS levels, Aβ deposits, and neurotoxic Aβ-oligomers in the Caenorhabditis elegans AD model. PBEO-ChNPs significantly improved lifespan, neuronal health, healthspan, cognitive function, and reversed deficits in chemotaxis and reproduction. PBEO-ChNPs also induced stress response genes daf-16, sod-3, and hsp-16.2. The participation of the DAF-16 pathway in reducing Aβ-induced toxicity was confirmed by daf-16 RNAi treatment, and upregulation of autophagy genes leg-1, unc-51, and bec-1 was noted. This study is the first to demonstrate an alternative biopolymeric nanoformulation with natural PBEO and chitosan, in mitigating AD and its associated symptoms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Regulatory T (Treg) cells play a central role in immune homeostasis. Forkhead box P3 (Foxp3), a hallmark molecule in Treg cells, is a vital transcription factor for their development and function. Studies have shown that degradation of the Foxp3 could provide therapeutic benefits in achieving effective anti-tumor immunity. In this study, we designed three PROTAC molecules, P60-L1-VHL, P60-L2-VHL, and P60-L3-VHL, based on a 15-mer peptide inhibitor of Foxp3 (P60), and explored their potential in regulating Foxp3 expression and function. Our data show that, among these molecules, P60-L3-VHL can inhibit the expression and nuclear localization of Foxp3 in HEK 293 T and HeLa cells, respectively. Meanwhile, use of proteasome inhibitor in P60-L3-VHL treated cells revealed an increased Foxp3 expression, indicating that P60-L3-VHL mediates the inhibition of Foxp3 through its degradation in the proteasome pathway. We further substantiate that P60-L3-VHL reduces the differentiation and Foxp3 expression in the in-vitro activated Treg cells. Overall, our findings suggest that P60-L3-VHL inhibits the differentiation of Treg cells by degrading the Foxp3, which may have potential implications in cancer immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Punica granatum L., commonly known as pomegranate, is renowned for its health benefits, primarily associated with the consumption of its fruit and seeds. However, its non-edible parts, including leaves, have been used in traditional medicine as a remedy with anti-inflammatory and anti-diabetic properties. Considering the abundance of bioactive compounds, predominantly flavonols, flavones, and tannins P. granatum leaf (PGL) extract holds potential as health-promoting agent. Yet, its effect on longevity and healthspan remains largely unexplored., Purpose: Our study aims to explore the potential of PGL extract to enhance healthspan and ameliorate age-related frailty in Caenorhabditis elegans. Additionally, we seek to elucidate its effect on the molecular signaling networks associated with stress resistance and longevity., Methods: After characterizing the extract metabolite profile by NMR spectroscopy, phenotypic and stress analyses were performed. In order to establish the molecular mechanism of action, the involvement of signaling pathways key to longevity were investigated by means of real-time quantitative PCR (RT-qPCR) and the use of transgenic strains (MIR13, MAH240, LD1, and OH16024). In addition, the effect of PGL on metabolism and lipid accumulation, as well as mitochondrial homeostasis, was examined., Results: The PGL extract supplementation significantly enhanced stress resistance and extended the lifespan of C. elegans. Additionally, it improved locomotion, as well as metabolic and mitochondrial functions, indicating an overall improvement in health. The molecular mechanisms highlight the coordinated regulation of stress response, metabolic homeostasis, and longevity signaling pathways. Specifically, our results demonstrate the essential roles of HLH-30/TFEB, in conjunction with DAF-16/FOXO and SKN-1/NRF2, as mediators of the PGL extract effect on healthspan., Conclusion: Our findings emphasize the potential of PGL extract to ameliorate age-related decline, induce longevity and further enhance healthspan. Given the diverse effects on the molecular network associated with stress-adaptations, longevity and metabolic control, PGL extract might become a promising natural product with a particular importance to the field of gerontology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background: Psoriasis is an immune-mediated inflammatory skin disorder with a multifaceted pathogenesis. Immune dysregulation and immune cell dysfunction are among the mechanisms involved. TEA domain family member 4 (TEAD4) is suggested to play a role in psoriasis development. TEAD4 expression in keratinocytes may have a chemotactic effect and could disturb the function of FOXP3-positive T lymphocytes. This study aimed to evaluate the expressions of TEAD4 and FOXP3 in lesional, nonlesional psoriatic, and healthy skin and assess the clinical impact of their expression., Methods: This case-control study included 32 cases with psoriasis vulgaris and 32 control groups. Hematoxylin and eosin-stained slides were examined to evaluate the histopathological findings. Moreover, other sections were immunohistochemically stained with FOXP3 and TEAD4., Results: FOXP3 was expressed in inflammatory cells in 56.5, 37.5, and 12.5% of lesional, nonlesional, and healthy skin, whereas it was entirely negative in the keratinocytes. TEAD4 was expressed in keratinocytes in 93.7 and 46.9% of lesional and nonlesional skin, while negative in healthy skin. Significant differences were observed between their lesional, nonlesional, and healthy skin expressions. Furthermore, FOXP3 expression in lesional skin was significantly associated with early onset (P = 0.016), low PASI score (P = 0.002), mild psoriasis (P = 0.007), and axial affection (P = 0.022), while TEAD4 expression was associated with progressive course (P = 0.032), high PASI score (P = 0.002), severe psoriasis (P = 0.001), severe inflammation (P = 0.001), and progressive course (P = 0.017)., Conclusion: TEAD4 expression was higher in lesional than nonlesional skin and absent in healthy skin, suggesting a role in psoriasis development. TEAD4 expression was also associated with severe and progressive psoriasis. This may be mediated by the downregulation of FOXP3 and dysfunction of Treg cells. TEAD4 could serve as a promising therapeutic target in psoriasis., (© 2024 the International Society of Dermatology.)

Background: Zoledronic acid (ZOL) is a type of bisphosphonate with good therapeutic effects on orthopaedic diseases. However, the pharmacological functions of ZOL on steroid-induced avascular necrosis of femoral head (SANFH) and the underlying mechanism remain unclear, which deserve further research., Methods: SANFH models both in vivo and in vitro were established by dexamethasone (Dex) stimulation. Osteoclastogenesis was examined by TRAP staining. Immunofluorescence was employed to examine autophagy marker (LC3) level. Cell apoptosis was analyzed by TUNEL staining. The interaction between Foxhead box D3 protein (FOXD3) and Annexin A2 (ANXA2) promoter was analyzed using ChIP and dual luciferase reporter gene assays., Results: Dex aggravated osteoclastogenesis and induced osteoclast differentiation and autophagy in vitro, which was abrogated by ZOL treatment. PI3K inhibitor LY294002 abolished the inhibitory effect of ZOL on Dex-induced osteoclast differentiation and autophagy. FOXD3 overexpression neutralized the downregulation effects of ZOL on Dex-induced osteoclasts by transcriptionally activating ANXA2. ANXA2 knockdown reversed the effect of FOXD3 overexpression on ZOL-mediated biological effects in Dex-treated osteoclasts. In addition, ZOL improved SANFH symptoms in rats., Conclusion: ZOL alleviated SANFH through regulating FOXD3 mediated ANXA2 transcriptional activity and then promoting PI3K/AKT/mTOR pathway, revealing that FOXD3 might be a target for ZOL in SANFH treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Regulatory T (Treg) cells are essential for immune tolerance of embryo implantation, and insufficient Treg cells provokes early pregnancy loss. An abortion-prone mouse model was used to evaluate IL-2 complexed with JES6-1 anti-IL-2 antibody (IL-2/JES6-1) to boost uterine Treg cells and improve reproductive success. IL-2/JES6-1, but not IL-2/IgG, administered in periconception to CBA/J females mated with DBA/2 males elicited a greater than twofold increase in the proportion of CD4 + T cells expressing forkhead box P3 (FOXP3), and an increased ratio of FOXP3 + Treg cells/FOXP3 - T conventional cells in the uterus and its draining lymph nodes at embryo implantation that was sustained into midgestation. An attenuated phenotype was evident in both thymic-derived and peripheral Treg cells with elevated cytotoxic T-lymphocyte antigen-4, CD25, and FOXP3 indicating improved suppressive function, as well as increased proliferative marker Ki-67. IL-2/JES6-1 treatment reduced fetal loss from 31% to 10%, accompanied by a 6% reduction in late gestation fetal weight, despite comparable placental size and architecture. Similar effects of IL-2/JES6-1 on Treg cells and fetal growth were seen in CBA/J females with healthy pregnancies sired by BALB/c males. These findings show that expanding the uterine Treg cell pool through targeting IL-2 signaling is a strategy worthy of further investigation for mitigating risk of immune-mediated fetal loss., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. All rights reserved.)

Alkylation repair homolog protein 5 (ALKBH5) is reported to participate in infantile hemangioma (IH) progression. However, the underlying mechanism of ALKBH5 in IH remains unclear. Using qRT-PCR and Western blotting, ALKBH5, forkhead box F1 (FOXF1) and hexokinase 2 (HK-2) expressions in IH tissues and IH-derived endothelial cells XPTS-1 were assessed. The Me-RIP assay was used to analyze FOXF1 m 6 A level. CCK8, colony formation, flow cytometry and transwell assays were employed to determine IH cell viability, proliferation, apoptosis, migration and invasion. The interactions between YTH (YT521-B homology) domain 2 (YTHDF2), FOXF1 and HK-2 were analyzed by RIP, dual luciferase reporter gene assay and/or ChIP assay. The in vivo IH growth was evaluated in immunocompromised mice. FOXF1 was overexpressed in IH tissues, and its silencing inhibited IH cell proliferation, migration and invasion whereas promoting cell apoptosis in vitro. ALKBH5 upregulation facilitated FOXF1 mRNA stability and expression in IH cells in a m 6 A-YTHDF2-dependent manner. FOXF1 downregulation reversed the impact of ALKBH5 upregulation on IH cellular phenotypes. It also turned out that FOXF1 positively regulated HK-2 expression in IH cells through interacting with the HK-2 promoter. HK-2 upregulation abolished FOXF1 knockdown's inhibition on IH cell aggressive behaviors. ALKBH5 or FOXF1 silencing suppressed IH tumor development via HK-2 signaling in immunocompromised mice. ALKBH5 promoted FOXF1 expression m 6 A-YTHDF2 dependently, which in turn elevated HK-2 expression, thereby accelerating IH development., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Autologous therapeutic tumor-infiltrating lymphocyte (TIL) therapy is a promising strategy to enhance antitumor immunity. Optimization of ex vivo TIL expansion could expand current immunotherapy options. Previous attempts to generate TIL in renal cell carcinoma (RCC) have been technically challenging. We applied a second-generation manufacturing process, currently used to generate the melanoma TIL product lifileucel, in RCC. Resected primary and metastatic RCC samples were processed using the Gen 2 manufacturing process comprising of pre-Rapid Expansion Protocol (pre-REP) and REP steps. We assessed REP TILs for viability and performed phenotypic and functional characterization. We correlated the tumor immune microenvironment (TIME) with successful TIL expansion. Eight of 11 RCC samples underwent successful REP. Three failed cases demonstrated low CD8/FoxP3 ratio and high expression of PD-1 within FoxP3 cells. Expression of exhaustion markers differed between the TIME and expanded TILs; the latter had a TIM3-high/PD-1-low phenotype but retained functional capacity comparable to lifileucel. The Gen 2 manufacturing process used for lifileucel successfully expanded functional TILs from RCC samples, enabling further study in a clinical trial. TIME features such as low CD8/FoxP3 ratio and high PD-1 expression within FoxP3 cells warrant study as potential biomarkers of successful TIL expansion., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Oclacitinib (OCL), a Janus kinase inhibitor, is a novel immunomodulatory/immunosuppressive agent which is an approved as the first-line treatment for atopic dermatitis (AD) in dogs. The aim of the study was to investigate the effects of OCL on CD4 + and CD8 + T cells and their selected subsets under clinical conditions, i.e. in dogs suffering from AD, in terms of both safety and immune mechanisms underlying its therapeutic actions. Eight dogs were treated for 28 days with OCL at the recommended dose. Blood samples were taken at day 0, 7, 14 and 28., Results: The study showed that the mean percentage and absolute count of CD4 + and CD8 + T cells on the 14th and 28th day of the treatment with OCL did not differ from the corresponding baseline values, i.e. those before the treatment. On the 7th day of the treatment, the mean absolute count of CD4 + T cells and the mean percentage and absolute count of CD8 + T cells were significantly increased. The research found that on the 14th day of the treatment, the mean percentage and absolute count of CD25 + CD4 + and CD25 + CD8 + T cells were significantly decreased; the reduction in the percentage of CD25 + CD4 + T cells persisted on 28th day of the treatment. A two-week treatment with OCL resulted in an increase in the mean percentage of Foxp3 + CD4 + T cells, and this effect was sustained at the last time point. The treatment with OCL decreased the eosinophil level but does not affect the absolute counts of basophils, monocytes and neutrophils., Conclusions: The findings of the study strongly suggest that: (a) in terms of the impact of OCL on the number of PB CD4 + and CD8 + T cells, monthly treatment with the drug should be considered as a relatively safe; (b) the eosinophil-reducing effect and the down-regulation of the AD up-regulated CD25 expression on CD4 + Teff cells may constitute significant elements of the mechanism of action underlying the therapeutic effects of the drug in the treatment of canine AD; (c) the generation of inducible Foxp3-expressing CD4 + regulatory T cells - resulting in the shift of the CD4 + Treg cell (i.e. Foxp3 + CD4 + )/activated Teff (i.e. CD25 + CD4 + ) cell balance toward an increased proportion of Treg cells - may be considered as additional mechanism involved in producing the immunomodulatory/immunosuppressive properties of OCL., (© 2024. The Author(s).)

Autoimmune diseases (ADs) are among the most significant health complications, with their incidence rising in recent years. Type 1 diabetes (T1D), an AD, targets the insulin-producing β cells in the pancreas, leading to chronic insulin deficiency in genetically susceptible individuals. Regulatory immune cells, particularly T-cells (Tregs), have been shown to play a crucial role in the pathogenesis of diabetes by modulating immune responses. In diabetic patients, Tregs often exhibit diminished effectiveness due to various factors, such as instability in forkhead box P3 (Foxp3) expression or abnormal production of the proinflammatory cytokine interferon-gamma (IFN-γ) by autoreactive T-cells. Consequently, Tregs represent a potential therapeutic target for diabetes treatment. Building on the successful clinical outcomes of chimeric antigen receptor (CAR) T-cell therapy in cancer treatment, particularly in leukemias, the concept of designing and utilizing CAR Tregs for ADs has emerged. This review summarizes the findings on Treg targeting in T1D and discusses the benefits and limitations of this treatment approach for patients suffering from T1D., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Dendritic cells (DCs) are crucial for initiating protective immune responses and have also been implicated in the generation and regulation of Foxp3 + regulatory T cells (Treg cells). Here, we show that in the lamina propria of the small intestine, the alternative NF-κB family member RelB is necessary for the differentiation of cryptopatch and isolated lymphoid follicle-associated DCs (CIA-DCs). Moreover, single-cell RNA sequencing reveals a RelB-dependent signature in migratory DCs in mesenteric lymph nodes favoring DC-Treg cell interaction including elevated expression and release of the chemokine CCL22 from RelB-deficient conventional DCs (cDCs). In line with the key role of CCL22 to facilitate DC-Treg cell interaction, RelB-deficient DCs have a selective advantage to interact with Treg cells in an antigen-specific manner. In addition, DC-specific RelB knockout animals show increased total Foxp3 + Treg cell numbers irrespective of inflammatory status. Consequently, DC-specific RelB knockout animals fail to mount protective Th2-dominated immune responses in the intestine after infection with Heligmosomoides polygyrus bakeri. Thus, RelB expression in cDCs acts as a rheostat to establish a tolerogenic set point that is maintained even during strong type 2 immune conditions and thereby is a key regulator of intestinal homeostasis., (© 2024. The Author(s).)

Kaposi's sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus that can cause several cancers, such as Kaposi sarcoma and primary effusion lymphoma (PEL). We and others have recently demonstrated that Forkhead box (FOX) transcription factors can be dysregulated by KSHV, and they can affect KSHV infection. Herein, we focus on dissecting the role of two FOXK subfamily members, FOXK1 and FOXK2, in the KSHV life cycle. FOXK proteins are key host regulators of cellular functions, yet their role in KSHV infection remains unknown. Here, we demonstrated that both FOXK proteins are essential for efficient KSHV lytic reactivation in PEL cells. FOXK1 and FOXK2 are unique as they are the only FOX proteins that contain a Forkhead-associated (FHA) domain. The FHA domain is a specialized protein binding domain that recognizes a short linear serine/threonine-rich (S/T) motif. Through an unbiased motif survey, we found that KSHV viral protein ORF45 and its gammaherpesvirus homologs contain a putative FHA-binding motif. ORF45 is an immediate early tegument protein, vital for lytic reactivation and virus production. We demonstrated that ORF45 uses its novel conserved motif to interact with the FHA domain containing FOXK factors in the nucleus of infected cells. A single-point mutation of the conserved threonine residue in the motif within ORF45 abolished the ORF45-FOXK1/2 interaction. Our data indicates that FOXK proteins interact with ORF45 homologs encoded by murine gammaherpesvirus 68 (MHV68) and Rhesus macaque rhadinovirus (RRV), and that the FHA domains of FOXK proteins are sufficient for their interactions, highlighting a conserved mechanism.IMPORTANCEThe dysregulation of Forkhead transcription factors contributes to many different human diseases, including cancers, but their impact on herpesvirus lifecycle and pathogenesis is less understood. Our study uncovers a critical pro-lytic function of the FOXK subfamily and its requirement for KSHV lytic reactivation in PEL. We found that FOXK proteins bind to a key immediate early KSHV protein ORF45 using its novel short linear S/T motif. Notably, even though ORF45 homologs in gammaherpesviruses are highly diverse, we identified a similar S/T short linear motif in ORF45 homologs and also showed an evolutionary conserved interaction between FOXK proteins and ORF45 homologs of MHV68 and RRV. Our study provides a basis for future studies in animal models to evaluate the role of FOXK proteins and the impact of their interactions with ORF45 in gammaherpesvirus infection and pathogenesis. Targeting these interactions could allow a novel way to limit gammaherpesvirus infections., Competing Interests: The authors declare no conflict of interest.

Aims: Angioimmunoblastic T cell lymphoma (AITL) is a T cell lymphoma with aberrant immune activity. It is characterised by inflammatory and immune reactions. However, the impact of regulatory T (Treg) cells on AITL remains unclear., Methods: We retrospectively collected 46 AITL cases and performed immunohistochemical analysis of forkhead box P3 (FOXP3) expression. The number of immunostained FOXP3 cells was determined using a digital pathology system with whole-slide imaging. The average number of FOXP3+ cells per high-power field (HPF) was determined by randomly counting 20 HPFs. AITL cases were categorised into high-expression and low-expression groups based on the median count of FOXP3+ cells in all analysed samples. The relationship between FOXP3 expression and clinicopathological features was assessed., Results: Among the studied patients, 14 (30.4%) were females and 32 (69.6%) were males, and the median age at diagnosis was 64.1 years. The median expression of FOXP3 was 84.9 positive cells/HPF. FOXP3 expression negatively correlated with Epstein-Barr virus-encoded small RNA positivity in tumour (p=0.041). The patients with low FOXP3 expression presented with aggressive clinical behaviour, including advance-staged diseases (p=0.043), splenomegaly (p=0.008), B symptoms (p=0.019) and extranodal involvement (p=0.019). The neutrophil-to-lymphocyte ratio was higher in the patients with low FOXP3 expression, compared with those with high FOXP3 expression. Low FOXP3 expression had an adverse effect on progression-free survival (PFS, p=0.033), and increased the risk of recurrence 2.320-fold (HR 2.320 (95% CI 1.109 to 4.856); p=0.025)., Conclusions: Patients with AITL with low FOXP3 expression tend to have aggressive clinical presentation and shortened PFS. These findings may help with risk stratification and determination of new treatment strategy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

A finely tuned balance between excitation and inhibition (E/I) is essential for proper brain function. Disruptions in the GABAergic system, which alter this equilibrium, are a common feature in various types of neurological disorders, including autism spectrum disorders (ASDs). Mutations in Phosphatase and Tensin Homolog (PTEN) , the main negative regulator of the phosphatidylinositol 3-phosphate kinase/Akt pathway, are strongly associated with ASD. However, it is unclear whether PTEN deficiencies can differentially affect inhibitory and excitatory signaling. Using the Caenorhabditis elegans neuromuscular system, where both excitatory (cholinergic) and inhibitory (GABAergic) inputs regulate muscle activity, we found that daf-18 / PTEN mutations impact GABAergic (but not cholinergic) neurodevelopment and function. This selective impact results in a deficiency in inhibitory signaling. The defects observed in the GABAergic system in daf-18/PTEN mutants are due to reduced activity of DAF-16/FOXO during development. Ketogenic diets (KGDs) have proven effective for disorders associated with E/I imbalances. However, the mechanisms underlying their action remain largely elusive. We found that a diet enriched with the ketone body β-hydroxybutyrate during early development induces DAF-16/FOXO activity, therefore improving GABAergic neurodevelopment and function in daf-18/PTEN mutants. Our study provides valuable insights into the link between PTEN mutations and neurodevelopmental defects and delves into the mechanisms underlying the potential therapeutic effects of KGDs., Competing Interests: SG, MB, MD, DR No competing interests declared, (© 2024, Giunti et al.)

Regulatory T cells (T regs ) make major contributions to immune homeostasis. Because T reg dysfunction can lead to both allo- and autoimmunity, there is interest in correcting these disorders through T reg adoptive transfer. Two of the central challenges in clinically deploying T reg cellular therapies are ensuring phenotypic stability and maximizing potency. Here, we describe an approach to address both issues through the creation of OX40 ligand (OX40L)-specific chimeric antigen receptor (CAR)-T regs under the control of a synthetic forkhead box P3 ( FOXP3 ) promoter. The creation of these CAR-T regs enabled selective T reg stimulation by engagement of OX40L, a key activation antigen in alloimmunity, including both graft-versus-host disease and solid organ transplant rejection, and autoimmunity, including rheumatoid arthritis, systemic sclerosis, and systemic lupus erythematosus. We demonstrated that OX40L-CAR-T regs were robustly activated in the presence of OX40L-expressing cells, leading to up-regulation of T reg suppressive proteins without induction of proinflammatory cytokine production. Compared with control T regs , OX40L-CAR-T regs more potently suppressed alloreactive T cell proliferation in vitro and were directly inhibitory toward activated monocyte-derived dendritic cells (DCs). We identified trogocytosis as one of the central mechanisms by which these CAR-T regs effectively decrease extracellular display of OX40L, resulting in decreased DC stimulatory capacity. OX40L-CAR-T regs demonstrated an enhanced ability to control xenogeneic graft-versus-host disease compared with control T regs without abolishing the graft-versus-leukemia effect. These results suggest that OX40L-CAR-T regs may have wide applicability as a potent cellular therapy to control both allo- and autoimmune diseases.

Bisphenol S (BPS) is widely presented and affects aging with unclear mechanisms. Here, we applied C. elegans to evaluate the effects of BPS on lifespan and healthspan and to investigate the underlying mechanisms. Both early-life and whole-life exposure to BPS at environmentally relevant doses (0.6, 6, 60 μg/L) significantly decreased lifespan, and healthspan (body bend, pharyngeal pumping, and lipofuscin accumulation). BPS exposure impaired mitochondrial structure and function, which promoted ROS production to induce oxidative stress. Furthermore, BPS increased expressions of the insulin/IGF-like signaling (IIS). Also, BPS inhibited expression of the IIS transcription factor daf-16 and its downstream anti-oxidative genes. Quercetin effectively improved BPS-induced oxidative stress byreversing BPS-regulated IIS/daf-16 pathway and anti-oxidative gene expressions. In daf-2 and daf-16 mutants, the effects of BPS and quercetin on lifespan, healthspan, oxidative stress, and anti-oxidative genes expressions were reversed, demonstrating the requirement of IIS/daf-16 for aging regulation. Molecular docking and molecular dynamics simulations confirmed the stable interaction between DAF-2 and BPS mainly via three residues (VAL1260, GLU1329, and MET1395), which was attenuated by quercetin. Our results highlighted that adverse effects of BPS on impairing lifespan and healthspan by affecting IIS/daf-16 function against mitochondrial stress, which could be inhibited by quercetin treatment. Thus, we first revealed the underlying mechanisms of BPS-induced aging and the potential treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Glycogen metabolism is an important biological process for organisms. In Caenorhabditis elegans, effect of 6-PPD quinone (6-PPDQ) on glycogen accumulation and underlying mechanism were examined. Exposure to 6-PPDQ (1 and 10 μg/L) increased glycogen accumulation. Meanwhile, exposure to 6-PPDQ (1 and 10 μg/L) increased expression of gsy-1 encoding glycogen synthase and decreased expression of pygl-1 encoding glycogen phosphorylase. In 6-PPDQ exposed animals, glycogen content and glycogen accumulation were inhibited by RNAi of gsy-1 and enhanced by RNAi of pygl-1. RNAi of gsy-1 increased pygl-1 expression, and RNAi of pygl-1 increased gsy-1 expression after 6-PPDQ exposure. In 6-PPDQ exposed nematodes, daf-16 and aak-2 expressions were decreased and glycogen accumulation was suppressed by RNAi of daf-16 and aak-2, suggesting alteration in daf-16 and aak-2 expressions did not mediate glycogen accumulation. Moreover, resistance to 6-PPDQ toxicity on locomotion and brood size was observed in gsy-1(RNAi) animals, and susceptibility to 6-PPDQ toxicity was found in pygl-1(RNAi) animals. Therefore, glycogen accumulation could be enhanced by exposure to 6-PPDQ in nematodes. In addition, alteration in expressions of gsy-1 and pygl-1 governing this enhancement in glycogen accumulation mediated induction of 6-PPDQ toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Metastasis is the main cause of mortality in colorectal cancer (CRC) patients. Exploring the mechanisms of metastasis is of great importance in both clinical and fundamental CRC research. CRC is a highly heterogeneous disease with variable therapeutic outcomes of treatment. In this study, we applied spatial transcriptomics (ST) to generate a tissue-wide transcriptome from two primary colorectal cancer tissues and their matched liver metastatic tissues. Spatial RNA information showed intratumoral heterogeneity (ITH) of both primary and metastatic tissues. The comparison of gene expressions across tissues revealed an apparent enrichment of cancer stem cells (CSCs) in metastatic tissues and identified FOXD1 as a novel metastatic CSC marker. Trajectory and pseudo-time analyses revealed distinct evolutionary trajectories and a dedifferentiation-differentiation process during metastasis. CellphoneDB analysis suggested a dominant interaction of CD74-MIF with tumor cells in metastatic tissues. Further analysis confirmed FOXD1 as a maker of CSCs and the predictor of patient survival, especially in metastatic diseases. Our study found ITH of primary and metastatic tissues and provides novel insights into the cellular mechanisms underlying liver metastasis of CRC and foundations for therapeutic strategies for CRC metastasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

FOXG1 syndrome is a rare neurodevelopmental disorder of the telencephalon, for which there is no cure. Underlying heterozygous pathogenic variants in the Forkhead Box G1 ( FOXG1 ) gene with resulting impaired or loss of FOXG1 function lead to severe neurological impairments. Here, we report a patient with a de novo pathogenic single nucleotide deletion c.946del (p.Leu316Cysfs*10) of the FOXG1 gene that causes a premature protein truncation. To study this variant in vivo, we generated and characterized Foxg1 c946del mice that recapitulate hallmarks of the human disorder. Accordingly, heterozygous Foxg1 c946del mice display neurological symptoms with aberrant neuronal networks and increased seizure susceptibility. Gene expression profiling identified increased oligodendrocyte- and myelination-related gene clusters. Specifically, we showed that expression of the c946del mutant and of other pathogenic FOXG1 variants correlated with overexpression of proteolipid protein 1 ( Plp1 ), a gene linked to white matter disorders. Postnatal administration of Plp1 -targeting antisense oligonucleotides (ASOs) in Foxg1 c946del mice improved neurological deficits. Our data suggest Plp1 as a new target for therapeutic strategies mitigating disease phenotypes in FOXG1 syndrome patients.

The non-canonical PD-L1 pathway revealed that programmed-death ligand 1 (PD-L1) expression in immune cells also plays a crucial role in immune response. Moreover, immune cell distribution in a tumour microenvironment (TME) is pivotal for tumour genesis. However, the results remain controversial and further research is needed. Distribution of PD-L1-positive (PD-L1 + ) tumour-infiltrating lymphocytes in the context of TME was assessed in 72 archival I-III stage surgically resected NSCLC tumour specimens. Predominant PD-L1 + lymphocyte distribution in the tumour stroma, compared to islets, was found ( p = 0.01). Higher PD-L1 + lymphocyte infiltration was detected in smokers due to their predominance in the stroma. High PD-L1 + lymphocyte infiltration in tumour stroma was more common in tumours with higher CD4 + T cell infiltration in islets and stroma, Foxp3 + CD4 + T cell infiltration in islets and lover M1 macrophage infiltration in the stroma ( p = 0.034, p = 0.034, p = 0.005 and p = 0.034 respectively). Meanwhile, high PD-L1 + lymphocyte infiltration in islets was predominantly found in tumours with high levels of IL-17A + CD4 + T cells in islets and Foxp3 + CD4 + T cells in islets and stroma ( p = 0.032, p = 0.009 and p = 0.034, respectively). Significant correlations between PD-L1 + lymphocytes and tumour-infiltrating CD4 + , Foxp3 + CD4 + , IL-17A + CD4 + T cells and M2 macrophages were found. An analysis of the tumour-immune phenotype revealed a significant association between PD-L1 expression and IL17 + CD4 + and Foxp3 + CD4 + immune phenotypes. PD-L1 + lymphocytes are associated with the distribution of CD4 + , Foxp3 + CD4 + , IL17A + CD4 + T cells, M1 and M2 macrophages in TME of resected NSCLC.

Objective: This study aimed to elucidate the effects of Hederagenin (HG) on hepatocellular carcinoma (HCC) and explore its potential molecular mechanisms., Materials and Methods: Virtual screening was employed to identify potential targets within core pathways of liver cancer and to analyze the possible mechanisms of HG. CCK-8 assays were used to assess the viability of HCC cells, while Hoechst 33342/PI staining was utilized to evaluate apoptosis. The migration and invasion abilities of HCC cells were examined using Transwell and scratch assays, and single-cell cloning ability was assessed via colony formation assays. Subsequent qRT-PCR was conducted to determine the mRNA expression levels of FOXO1 and FOXO6 following HG treatment. Western blot (WB) analysis was employed to measure the protein expression levels of IGF1R, FOXO1, FOXO6, MMP2, MMP9, and VEGFA, as well as the phosphorylation status of FOXO1 Ser249., Results: Virtual screening indicated that HG might exert antitumor effects through the FOXO signaling pathway. Experimental results demonstrated that HG induces apoptosis in a dose-dependent manner and inhibits the proliferation, migration, invasion, and single-cell cloning ability of HCC cells. After HG treatment, FOXO1 expression was upregulated, while the expression levels of IGF1R, phosphorylated FOXO1 Ser249, MMP2, MMP9, and VEGFA were downregulated., Conclusion: In summary, our study is the first to demonstrate that HG regulates the phosphorylation of FOXO1, affecting the proliferation, migration, and invasion of HCC cells. The findings suggest that HG can inhibit the migration of HCC cells in vitro. The data indicate that HG-mediated targeting of the FOXO1/FOXO6 pathway holds promise as a novel therapeutic approach., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright: © 2024 Bao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Understanding the nature of human autoantigen-specific CD4 + T cells is limited by the difficulty of characterizing these cells ex vivo. In this issue of Immunity, Saggau et al. use ARTE technology to profile CD4 + T cells specific to disease-relevant autoantigens and find that such cells develop an exhausted phenotype that includes FOXP3 expression and persist for extended periods of time., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We hypothesized that after synovial injury, collagen V (Col V) expose occult antigens, and Col V autoantibodies develop, indicating the loss of immune tolerance against this molecule, thus leading to damage to mesenchymal-derived cells as well as the extracellular matrix in experimental arthritis. Thus, the present study investigated the effects of oral administration of Col V on the synovium after the development of inflammation in mBSA/CFA-induced arthritis. After fourteen days of intraarticular administration of mBSA, 10 male Lewis rats were orally administered Col V (500 μg/300 μL) diluted in 0.01 N acetic acid (IA-Col V group). The arthritic group (IA group, n = 10) received only intraarticular mBSA. An intra-articular saline injection (20 μL) was given to the control group (CT-Col V, n = 5). IA group presented damaged synovia, the expansion of the extracellular matrix by cellular infiltrate, which was characterized by T and B lymphocytes, and fibroblastic infiltration. In contrast, after Col V oral immunotherapy IA-Col V group showed a significant reduction in synovial inflammation and intense expression of IL-10+ and FoxP3+ cells, in addition to a reduction in Col V and an increase in Col I in the synovia compared to those in the IA group. Furthermore, an increase in IL-10 production was detected after IA-Col V group spleen cell stimulation with Col V in vitro. PET imaging did not differ between the groups. The evaluation of oral treatment with Col V, after mBSA/CFA-induced arthritis in rats, protects against inflammation and reduces synovial tissue damage, through modulation of the synovial matrix, showing an immunotherapeutic potential in inhibiting synovitis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ramos da Silveira et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Shc (Src homologous and collagen) proteins function in many different signaling pathways where they mediate phosphorylation-dependent protein-protein interactions. These proteins are characterized by the presence of two phosphotyrosine-binding domains, an N-terminal PTB and a C-terminal SH2. We describe a previously unrecognized Caenorhabditis elegans Shc gene, shc-3 and characterize its role in stress response. Both shc-3 and shc-1 are required for long-term survival in L1 arrest and survival in heat stress, however, they do not act redundantly but rather play distinct roles in these processes. Loss of shc-3 did not further decrease survival of daf-16 mutants in L1 arrest, suggesting that like SHC-1, SHC-3 functions in the insulin-like signaling pathway. In the absence of SHC-3, DAF-16 nuclear entry and exit are slowed, suggesting that SHC-3 is required for rapid changes in DAF-16 signaling., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Rapid elimination of paternal mitochondria following fertilization is a conserved event in most animals, but its physiological significance remains unclear. We find that modest delay of paternal mitochondrial elimination (PME) in Caenorhabditis elegans embryos unexpectedly impairs mating and cognition of adult animals and alters their locomotion behaviors. Delayed PME causes decreased adenosine triphosphate (ATP) levels in early embryos, which lead to impaired physiological functions of adult animals through an energy-sensing pathway mediated by an adenosine monophosphate (AMP)-activated protein kinase, AAK-2, and a forkhead box class O (FOXO) transcription factor, DAF-16. Treatment of PME-delayed animals with MK-4, a subtype of vitamin K 2 that can improve mitochondrial ATP production, restores ATP levels in early embryos, and rescues physiological defects of adult animals. Our results suggest that moderate PME delay during embryo development adversely affects crucial physiological functions in adults, which could be evolutionarily disadvantageous. These observations provide mechanistic explanations for the need to swiftly remove paternal mitochondria early during embryo development.

The gene FOXP2 is well established for a role in human speech and language; far less is known about FOXP1. However, this related gene has also been implicated in human language development as well as disorders associated with features of autism spectrum disorder (ASD). FOXP1 protein expression has also recently been identified in the cerebellum-a neural structure previously shown to express FOXP2 protein. The current study sought to elucidate the behavioral implications of a conditional knock-out of Foxp1 using an En1-Cre driver, which is active in the entirety of the cerebellum and a subset of neurons in the midbrain and spinal cord, in mice using a test battery including motor tasks associated with cerebellar dysfunction, as well as communicative and autistic-relevant behaviors. Male and female mice with a conditional knock-out (cKO, n = 31) and wildtype littermate controls (WT, n = 34) were assessed for gross and orofacial motor control, motor-coordination learning, locomotion, social behavior, anxiety, auditory processing and expressive vocalizations. Overall results suggest Foxp1 plays a specific role in the development of communicative systems, and phenotypic expression of disruptions may interact with sex. Robust motor deficits associated with Foxp1 protein loss may particularly affect vocalizations based on significant orofacial motor deficits in cKO subjects could also contribute to vocalization anomalies. In summary, the current study provides key insights into the role of Foxp1 in cerebellar function and associated behaviors in mice, with implications for an improved understanding of communicative and motor-based neurodevelopmental disabilities in humans., (© 2024 The Author(s). Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

Background: FOXC1 and ERK1-2 are proteins implicated in aggressive biological behavior of various malignancies including lymphomas., Material and Methods: We investigate the additive prognostic value of stromal FOXC1 expression and tumor phosphorylated ERK1-2 (pERK1-2) expression to the established National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), in 92 diffuse large B-cell lymphoma (DLBCL) cases. Multidimensional analysis using statistics and machine learning (ML) models assessed prognostic value of established clinicopathologic variables with stromal FOXC1 and tumor pERK1-2 expressions., Results: Both high FOXC1 stroma group and high pERK1-2 tumor group were significantly associated with shorter progression-free survival (PFS) and overall survival (OS) compared with low group (p = 0.015, 0.034 and p = 0.025, 0.025 each respectively). In multivariable analysis, high FOXC1 stromal expression was an independent prognostic factor of OS (p = 0.037). The addition of stromal FOXC1 and tumor pERK1-2 to the NCCN-IPI score significantly improved prediction of time to death compared with NCCN-IPI score alone (Harrell's C-index = 0.801 vs. 0.764; p = 0.030). ML models reconfirmed the addition of stromal FOXC1 expression and tumor pERK1-2 to NCCN-IPI score had the highest C-index (0.952) among combinations. Stromal FOXC1 and tumor pERK1-2 were determinants of DLBCL prognosis, whose addition significantly improved prognostic performance of the NCCN-IPI., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Doxorubicin (DOX) is an anthracycline antibiotic widely employed to treat carcinoma. Nevertheless, severe cardiotoxic side effects restrict its clinical use. Esculetin, a natural flavonoid, is found abundantly in plants. This study evaluated the protective effects of esculetin against DOX-induced hepatotoxicity in rat livers. Forty-eight rats were randomly divided into six groups with eight rats in each group: control (I), DOX (II), esculetin (III, 50 mg/kg), esculetin (IV, 100 mg/kg), DOX+esculetin 50 (V, DOX+esculetin 50 mg/kg), and DOX+esculetin 100 (VI, DOX+esculetin 100 mg/kg). The administration of esculetin effectively mitigated alterations in the measured biochemical parameters induced by DOX. Gene expression analyses demonstrated that esculetin treatment significantly reduced the DOX-induced expression of Foxo1, Hspa1a, Hsp4a, Hsp5a, Casp3, and Casp9 while increasing the DOX-induced expression of Foxo3. These findings suggest that esculetin, with its antioxidant and anti-inflammatory effects, might be a therapeutic option for protecting against DOX-induced hepatotoxicity., (© 2024 Wiley Periodicals LLC.)

Background: The Notch signaling pathway is an evolutionarily conserved regulatory cascade critical in skin development and homeostasis. Mice deficient of Notch signaling molecules have impaired skin and hair follicle development associated with local tissue inflammation. However, mechanisms underlying skin inflammation and pathology resulting from defective Notch signals are not well understood., Objective: To dissect molecular and cellular mechanisms underlying development of skin immunopathology in mice defective of the Notch ligand Jagged-1 (Jag1)., Methods: We assessed involvement of microbiota and immune cell subsets in skin pathogenic symptoms in Foxn1 Cre Jag1 fl/fl mice that were deficient of Jag1 in keratinocytes. We also used RNA-seq and 16S rRNA gene-seq analyses to identify molecular factors and bacterial species contributing to skin pathologic symptoms in Foxn1 Cre Jag1 fl/fl mice., Results: Compared to Jag1-sufficient littermate control mice, Foxn1 Cre Jag1 fl/fl mice had specific expansion of IL-17a-producing T cells accompanying follicular and epidermal hyperkeratosis and cyst formation while antibody blockage of IL-17a reduced the skin pathology. RNA-sequencing and 16S rRNA gene-sequencing analyses revealed dysregulated immune responses and altered microbiota compositions in the skin of Foxn1 Cre Jag1 fl/fl mice. Antibiotic treatment completely prevented over-activation of IL-17a-producing T cells and alleviated skin pathology in Foxn1 Cre Jag1 fl/fl mice., Conclusion: Dysbiosis-induced over-activation of IL-17a-producing T cells is critically involved in development of skin pathology in Foxn1 Cre Jag1 fl/fl mice, establishing Foxn1 Cre Jag1 fl/fl mice as a useful model to study pathogenesis and therapeutic targets in microbiota-IL-17-mediated skin inflammatory diseases such as hidradenitis suppurativa (HS) and psoriasis., (Copyright © 2024 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Heart failure (HF) represents the terminal stage of cardiovascular diseases, with limited therapeutic options currently available. Calotropin (CAL), a cardenolide isolated from Calotropis gigantea, exhibits a similar chemical structure and inhibitory effect on Na+/K+-ATPase to digoxin, a positive inotropic drugs used in heart failure treatment. However, the specific effect of calotropin in ischemic HF (IHF) remains unknown. The objective of this study is to assess the anti-HF effect and clarify its underlying mechanisms. The left anterior descending (LAD) artery ligation on Male Sprague-Dawley (SD) rats was used to construct ischemic HF model. Daily administration of CAL at 0.05 mg/kg significantly enhanced ejection fraction (EF) and fractional shortening (FS), while inhibiting cardiac fibrosis in IHF rats. CAL reduced the OGD/R-induced H9c2 cell injury. Furthermore, CAL upregulated the expression of SERCA2a and SIRT1. The cardioprotective effect of CAL against IHF was abrogated in the presence of the SIRT1 inhibitor EX527. Notably, we identified FOXD3 as a pivotal transcription factor mediating CAL-induced SERCA2a regulation. CAL promoted the deacetylation and nuclear translocation of FOXD3 in a SIRT1-dependent manner. In conclusion, our study explores a novel mechanism of calotropin for improving cardiac dysfunction in ischemic heart failure by regulating SIRT1/FOXD3/SERCA2a pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

ALI/ARDS can be a pulmonary manifestation of a systemic inflammatory response or a result of overexpression of the body's normal inflammatory response involving various effector cells, cytokines, and inflammatory mediators, which regulate the body's immune response through different signalling pathways. Forkhead box transcription factors are evolutionarily conserved transcription factors that play a crucial role in various cellular processes, such as cell cycle progression, proliferation, differentiation, migration, metabolism, and DNA damage response. Transcription factors control protein synthesis by regulating gene transcription levels, resulting in diverse biological outcomes. The Fox family plays a role in activating or inhibiting the expression of various molecules related to ALI/ARDS through phosphorylation, acetylation/deacetylation, and control of multiple signalling pathways. An in-depth analysis of the integrated Fox family's role in ALI/ARDS can aid in the development of potential diagnostic and therapeutic targets for the condition., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The microenvironment within solid tumors often becomes acidic due to various factors associated with abnormal metabolism and cellular activities, including increased lactate production as a result of dysregulated tumor glycolysis. Recently, we have identified multiple tumor microenvironment (TME) factors that potentiate regulatory T (T reg ) cell function in evading anti-tumor immunosurveillance. Despite the strong correlation between lactate and acidity, the potential roles of acidity in intratumoral T reg cell adaptation and underlying molecular mechanisms have gone largely unstudied. In this study, we demonstrate that acidity significantly enhances immunosuppressive functions of nT reg cells, but not iT reg cells, without altering the expression of either FoxP3 or the cell surface receptors CD25, CTLA4, or GITR in these cells. Surprisingly, the addition of lactate, often considered a major contributor to increased acidity of the TME, completely abolished the acidity-induced enhancement of nT reg suppressive functions. Consistently, metabolic flux analyses showed elevated basal mitochondrial respiratory capacity and ATP-coupled respiration in acidity-treated nT reg cells without altering glycolytic capacity. Genome-wide transcriptome and metabolomics analyses revealed alterations in multiple metabolic pathways, particularly the one-carbon folate metabolism pathway, with reduced SAM, folate, and glutathione, in nT reg cells exposed to low pH conditions. Addition of a one-carbon metabolic contributor, formate, diminished the acidity-induced enhancement in nT reg cell suppressive functions, but neither SAM nor glutathione could reverse the phenotype. Remarkably, in vitro transient treatment of nT reg cells resulted in sustained enhancement of their functions, as evidenced by more vigorous tumor growth observed in mice adoptively receiving acidity-treated nT reg cells. Further analysis of intratumoral infiltrated T cells confirmed a significant reduction in CD8+ T cell frequency and their granzyme B production. In summary, our study elucidates how acidity-mediated metabolic reprogramming leads to sustained Treg-mediated tumor immune evasion., Competing Interests: Declaration of Competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Neurogenesis lasts ~10 times longer in developing humans compared to mice, resulting in a >1,000-fold increase in the number of neurons in the CNS. To identify molecular and cellular mechanisms contributing to this difference, we studied human and mouse motor neurogenesis using a stem cell differentiation system that recapitulates species-specific scales of development. Comparison of human and mouse single-cell gene expression data identified human-specific progenitors characterized by coexpression of NKX2-2 and OLIG2 that give rise to spinal motor neurons. Unlike classical OLIG2 + motor neuron progenitors that give rise to two motor neurons each, OLIG2 + /NKX2-2 + ventral motor neuron progenitors remain cycling longer, yielding ~5 times more motor neurons that are biased toward later-born, FOXP1-expressing subtypes. Knockout of NKX2-2 converts ventral motor neuron progenitors into classical motor neuron progenitors. Such new progenitors may contribute to the increased production of human motor neurons required for the generation of larger, more complex nervous systems., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Endoplasmic reticulum (ER) stress is a major cause of hepatic steatosis through increasing de novo lipogenesis. Forkhead box O6 (FoxO6) is a transcription factor mediating insulin signaling to glucose and lipid metabolism. Therefore, dysregulated FoxO6 is involved in hepatic lipogenesis. This study elucidated the role of FoxO6 in ER stress-induced hepatic steatosis in vivo and in vitro. Hepatic ER stress responses and β-oxidation were monitored in mice overexpressed with constitutively active FoxO6 allele and FoxO6-null mice. For the in vitro study, liver cells overexpressing constitutively active FoxO6 and FoxO6-siRNA were treated with high glucose, and lipid metabolism alterations were measured. ER stress-induced FoxO6 activation suppressed hepatic β-oxidation in vivo. The expression and transcriptional activity of peroxisome proliferator-activated receptor α (PPARα) were significantly decreased in the constitutively active FoxO6 allele. Otherwise, inhibiting β-oxidation genes were reduced in the FoxO6-siRNA and FoxO6-KO mice. Our data showed that the FoxO6-induced hepatic lipid accumulation was negatively regulated by insulin signaling. High glucose treatment as a hyperglycemia condition caused the expression of ER stress-inducible genes, which was deteriorated by FoxO6 activation in liver cells. However, high glucose-mediated ER stress suppressed β-oxidation gene expression through interactions between PPARα and FoxO6 corresponding to findings in the in vivo study-lipid catabolism is also regulated by FoxO6. Furthermore, insulin resistance suppressed b-oxidation through the interaction between FoxO6 and PPARα promotes hepatic steatosis, which, due to hyperglycemia-induced ER stress, impairs insulin signaling. KEY MESSAGES: Our original aims were to delineate the interrelation between the regulation of PPARα and the transcription factor FoxO6 pathway in relation to lipid metabolism at molecular levels. Evidence on high glucose promoted FoxO6 activation induced lipid accumulation in liver cells. The effect of PPARα activation of the insulin signaling. FoxO6 plays a pivotal role in hepatic lipid accumulation through inactivation of PPARα in FoxO6-overexpression mice., (© 2024. The Author(s).)

The existence of heterogeneity has plunged cancer treatment into a challenging dilemma. We profiled malignant epithelial cells from 5 gastric adenocarcinoma patients through single-cell sequencing (scRNA-seq) analysis, demonstrating the heterogeneity of gastric adenocarcinoma (GA), and identified the CCKBR+ stem cell-like cancer cells associated poorly differentiated and worse prognosis. We further conducted targeted analysis using single-cell transcriptome libraries, including 40 samples, to confirm these screening results. In addition, we revealed that FOXOs are involved in the progression and development of CCKBR+ gastric adenocarcinoma. Inhibited the expression of FOXOs and disrupting cancer cell stemness reduce the CCKBR+ GA organoid formation and impede tumor progression. Mechanically, CUT&Tag sequencing and Lectin pulldown revealed that FOXOs can activate ST3GAL3/4/5 as well as ST6GALNAC6, promoting elevated sialyation levels in CCKBR+ tumor cells. This FOXO-sialyltransferase axis contributes to the maintenance of homeostasis and the growth of CCKBR+ tumor cells. This insight provides novel perspectives for developing targeted therapeutic strategies aimed at the treating CCKBR associated gastric cancer., (© 2024. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Basal cells are adult stem cells in the airway epithelium and regenerate differentiated cell populations, including the mucosecretory and ciliated cells that enact mucociliary clearance. Human basal cells can proliferate and produce differentiated epithelium in vitro. However, studies of airway epithelial differentiation mostly rely on immunohistochemical or immunofluorescence-based staining approaches, meaning that a dynamic approach is lacking, and quantitative data are limited. Here, we use a lentiviral reporter gene approach to transduce primary human basal cells with bioluminescence reporter constructs to monitor airway epithelial differentiation longitudinally. We generated three constructs driven by promoter sequences from the TP63 , MUC5AC , and FOXJ1 genes to quantitatively assess basal cell, mucosecretory cell, and ciliated cell abundance, respectively. We validated these constructs by tracking differentiation of basal cells in air-liquid interface and organoid ("bronchosphere") cultures. Transduced cells also responded appropriately to stimulation with interleukin 13 (IL-13; to increase mucosecretory differentiation and mucus production) and IL-6 (to increase ciliated cell differentiation). These constructs represent a new tool for monitoring airway epithelial cell differentiation in primary epithelial and/or induced pluripotent stem cell (iPSC)-derived cell cultures. NEW & NOTEWORTHY Orr et al. generated and validated new lentiviral vectors to monitor the differentiation of airway basal cells, goblet cells, or multiciliated cells using bioluminescence.

Male ageing is always accompanied by decreased fertility. The forkhead O (FOXO) transcription factor FOXO4 is reported to be highly expressed in senescent cells. Upon activation, it binds p53 in the nucleus, preventing senescent cell apoptosis and maintaining senescent cells in situ. Leydig cells play key roles in assisting spermatogenesis. Leydig cell senescence leads to deterioration of the microenvironment of the testes and impairs spermatogenesis. In this study, we observed that FOXO4-DRI, a specific FOXO4- p53 binding blocker, induced apoptosis in senescent Leydig cells, reduced the secretion of certain Senescence-Associated Secretory Phenotype and improved the proliferation of cocultured GC-1 SPG cells. In naturally aged mice, FOXO4-DRI-treated aged mice exhibited increased sperm quality and improved spermatogenesis., Competing Interests: Declaration of competing interest All of the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

FOXP2 is a transcription factor associated with speech and language. Like other FOX transcription factors, it has a DNA binding region called the forkhead domain (FHD). This domain can exist as a monomer or a domain swapped dimer. In addition to the FHD, the leucine zipper region (LZ) of FOXP2 is also believed to be associated with both DNA binding and oligomerization. To better understand the relationship between DNA binding and oligomerization of FOXP2, we investigated its structure, stability and dynamics, focusing specifically on the FHD and the LZ. We did this by using two constructs: one containing the isolated FHD and one containing both the LZ and the FHD (LZ-END). We demonstrate in this work, that while the FHD maintains a monomeric form that is capable of binding DNA, the LZ-END undergoes a dynamic transition between oligomeric states in the presence of DNA. Our findings suggest that FOXP2's LZ domain influences DNA binding affinity through a change in oligomeric state. We show through hydrogen exchange mass spectroscopy that certain parts of the FHD and interlinking region become less dynamic when in the presence of DNA, confirming DNA binding and oligomerization in these regions. Moreover, the detection of a stable equilibrium intermediate state during LZ-END unfolding supports the idea of cooperation between these two domains. Overall, our study sheds light on the interplay between two FOXP2 domains, providing insight into the protein's ability to respond dynamically to DNA, and enriching our understanding of FOXP2's role in gene regulation., (© 2024 The Author(s). Proteins: Structure, Function, and Bioinformatics published by Wiley Periodicals LLC.)

Intravenous infusion has been used as the method of cell delivery in many preclinical studies as well as in some early clinical trials. Among its advantages are broad distribution, ability to handle a large-volume infusion, and ease of access. Progenitor cells used in cell-based therapy act through their secretomes, rather than their ability to differentiate into lineage-specific cell type. Since not all progenitor cells have similar secretome potency, the innate abilities of the secretome of cells used in clinical trials will obviously dictate their effectiveness. We previously found that cardiac neonatal mesenchymal stromal cells (nMSCs) are more effective in repairing the infarcted myocardium compared to adult mesenchymal stromal cells (aMSCs) due to their robust secretome (Sharma et al Circulation Research 120:816-834, 2017). In this study, we explored the efficacy of intravenous (IV) delivery of nMSCs for myocardial recovery. Six-week-old male Brown Norway rats underwent acute MI by ligation of the left anterior descending artery, followed by IV infusion of cell dose 5 × 10 6 nMSCs/rat body weight (kg) or saline on days 0 and 5. We found that cardiac parameters in the rodent ischemia model improved 1 month after nMSCs infusion, and the result is comparable with the intramyocardial injection of nMSCs. Tracking the infused cells in target organ revealed that their movement after IV delivery was mediated by the cell surface receptor CD44. Systemic injection of nMSCs stimulated immunomodulatory responses specifically by increasing FoxP3 + T-regulatory cell influenced anti-inflammatory macrophages (M2) in heart. These data demonstrate that nMSCs promote immunogenic tolerance via CD44-driven T-reg/M2 stimulation that helps nMSCs for longer viability in the injured myocardium for better functional recovery. Our data also demonstrate a rationale for a clinical trial of IV infusion of nMSCs to promote cardiac function improvement in the ischemic patients., (© 2024. The Author(s).)

The need for novel anti-thyroid cancer (TC) medications is urgent due to the rising incidence and metastatic rates of malignant TC. In this study, we investigated the effect of Polyphyllin VII (PPVII) to TC cells, and explored their potential mechanism. B-CPAP and TPC-1 cells, were used to analyze the antitumor activity of PPVII by quantifying cell growth and metastasis as well as to study the effect on epithelial mesenchymal transition (EMT). The results showed that PPVII dramatically reduced the capacity of B-CPAP and TPC-1 cells to proliferate and migrate in a dose-response manner. Following PPVII treatment of TC cells, the expression levels of E-cadherin progressively increased and were higher than the control group, while the expression levels of EMT-related genes Vimentin, N-cadherin, Slug, Zeb-1, and Foxe1 gradually declined and were lower than the control group. It was proposed that PPVII might prevent TC from undergoing EMT. The Foxe1 gene was shown to be significantly expressed in TC, and a statistically significant variation in Foxe1 expression was observed across clinical stages of the disease, according to a bioinformatics database study. There was a strong link between the expression of the Foxe1 gene and the EMT-related gene. In the meantime, TC cells' expression of Foxe1 can be inhibited by PPVII. In conclusion, our results showed that PPVII may as a potential medication for targeting EMT in thyroid cancer., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Basic Helix-Loop-Helix (bHLH) transcription factors TFEB/TFE3 and HLH-30 are key regulators of autophagy induction and lysosomal biogenesis in mammals and C. elegans, respectively. While much is known about the regulation of TFEB/TFE3, how HLH-30 subcellular dynamics and transactivation are modulated are yet poorly understood. Thus, elucidating the regulation of C. elegans HLH-30 will provide evolutionary insight into the mechanisms governing the function of bHLH transcription factor family. We report here that HLH-30 is retained in the cytoplasm mainly through its conserved Ser201 residue and that HLH-30 physically interacts with the 14-3-3 protein FTT-2 in this location. The FoxO transcription factor DAF-16 is not required for HLH-30 nuclear translocation upon stress, despite that both proteins partner to form a complex that coordinately regulates several organismal responses. Similar as described for DAF-16, the importin IMB-2 assists HLH-30 nuclear translocation, but constitutive HLH-30 nuclear localization is not sufficient to trigger its distinctive transcriptional response. Furthermore, we identify FTT-2 as the target of diethyl maleate (DEM), a GSH depletor that causes a transient nuclear translocation of HLH-30. Together, our work demonstrates that the regulation of TFEB/TFE3 and HLH-30 family members is evolutionarily conserved and that, in addition to a direct redox regulation through its conserved single cysteine residue, HLH-30 can also be indirectly regulated by a redox-dependent mechanism, probably through FTT-2 oxidation., Competing Interests: Declaration of competing interest Authors declare no competing interests, (Copyright © 2024. Published by Elsevier Inc.)

Objectives: A decline in mitochondrial function and increased susceptibility to oxidative stress is a hallmark of ageing. Exercise endogenously generates reactive oxygen species (ROS) in skeletal muscle and promotes mitochondrial remodelling resulting in improved mitochondrial function. It is unclear how exercise induced redox signalling results in alterations in mitochondrial dynamics and morphology., Methods: In this study, a Caenorhabditis elegans model of exercise and ageing was used to determine the mechanistic role of Peroxiredoxin 2 (PRDX-2) in regulating mitochondrial morphology. Mitochondrial morphology was analysed using transgenic reporter strains and transmission electron microscopy, complimented with the analysis of the effects of ageing and exercise on physiological activity., Results: The redox state of PRDX-2 was altered with exercise and ageing, hyperoxidised peroxiredoxins were detected in old worms along with basally elevated intracellular ROS. Exercise generated intracellular ROS and rapid mitochondrial remodelling, which was disrupted with age. The exercise intervention promoted mitochondrial ER contact sites (MERCS) assembly and increased DAF-16/FOXO nuclear localisation. The prdx-2 mutant strain had a disrupted mitochondrial network as evidenced by increased mitochondrial fragmentation. In the prdx-2 mutant strain, exercise did not activate DAF-16/FOXO, mitophagy or increase MERCS assembly. The results demonstrate that exercise generated ROS increased DAF-16/FOXO transcription factor nuclear localisation required for activation of mitochondrial fusion events that were blunted with age., Conclusions: The data demonstrate the critical role of PRDX-2 in orchestrating mitochondrial remodelling in response to a physiological stress by regulating redox dependent DAF-16/FOXO nuclear localisation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)