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Nearly all geriatric surgical complications are studied in the context of a single organ system, e.g., cardiac complications and the heart; delirium and the brain; infections and the immune system. Yet, we know that advanced age, physiological stress, and infection all increase sympathetic and decrease parasympathetic nervous system function. Parasympathetic function is mediated through the vagus nerve, which connects the heart, brain, and immune system to form, what we have termed, the brain-heart-immune axis. We hypothesize that this brain-heart-immune axis plays a critical role in surgical recovery among older adults. In particular, we hypothesize that the brain-heart-immune axis plays a critical role in the most common surgical complication among older adults: postoperative delirium. Further, we present heart rate variability as a measure that may eventually become a multi-system vital sign evaluating brain-heart-immune axis function. Finally, we suggest the brain-heart-immune axis as a potential interventional target for bio-electronic neuro-immune modulation to enhance resilient surgical recovery among older adults.
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Colorectal cancer is a leading cause of cancer-related morbidity and mortality worldwide, with a significant risk of recurrence following surgical treatment. Emerging evidence suggests that perioperative factors, particularly anesthetic techniques, may influence cancer recurrence rates. This comprehensive review aims to critically analyze the impact of various anesthetic techniques on colorectal cancer recurrence. We explore the distinct immunomodulatory and inflammatory effects of general, regional, and combined anesthetic approaches and their potential influence on tumor biology. The review synthesizes findings from clinical studies, experimental research, and theoretical models, highlighting the differential impact of anesthetic choices on long-term oncological outcomes. By examining recurrence rates, immune responses, and inflammatory markers associated with different anesthetic techniques, this review provides a holistic understanding of the role of anesthetic management in colorectal cancer surgery. Our findings suggest that anesthetic techniques can modulate the immune and inflammatory responses in ways that may affect tumor recurrence, underscoring the need for further research to optimize anesthetic protocols. The review offers clinical recommendations based on current evidence and identifies gaps in knowledge, proposing directions for future investigations. This comprehensive analysis aims to inform clinical practice and guide future research, ultimately improving long-term outcomes for colorectal cancer patients.
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The gut microbiota plays an essential role in maintaining immune homeostasis and influencing the immune landscape within the tumor microenvironment. This review aims to elucidate the interactions between gut microbiota and tumor immune dynamics, with a focus on colorectal cancer (CRC). The review spans foundational concepts of immuno-microbial interplay, factors influencing microbiome composition, and evidence linking gut microbiota to cancer immunotherapy outcomes. Gut microbiota modulates anti-cancer immunity through several mechanisms, including enhancement of immune surveillance and modulation of inflammatory responses. Specific microbial species and their metabolic byproducts can significantly influence the efficacy of cancer immunotherapies. Furthermore, microbial diversity within the gut microbiota correlates with clinical outcomes in CRC, suggesting potential as a valuable biomarker for predicting response to immunotherapy. Conclusions: Understanding the relationship between gut microbiota and tumor immune responses offers potential for novel therapeutic strategies and biomarker development. The gut microbiota not only influences the natural history and treatment response of CRC but also serves as a critical modulator of immune homeostasis and anti-cancer activity. Further exploration into the microbiome's role could enhance the effectiveness of existing treatments and guide the development of new therapeutic modalities.
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Neoplasias Colorrectales , Microbioma Gastrointestinal , Humanos , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/microbiología , Neoplasias Colorrectales/terapia , Microbioma Gastrointestinal/inmunología , Microambiente Tumoral/inmunología , Inmunoterapia/métodos , Animales , Inmunidad/inmunologíaRESUMEN
Abscisic acid (ABA), a phytohormone traditionally recognized for its role in plant stress responses, has recently emerged as a significant player in mammalian defense mechanisms. Like plants, various mammalian cell types synthesize ABA in response to specific health challenges, although the precise pathways remain not fully elucidated. ABA is associated with the regulation of inflammation and insulin signaling, prompting extensive research into its potential as a therapeutic agent for various diseases. ABA exerts its effects through its receptors, particularly PPAR-γ and LANCL-2, which serve as signaling hubs regulating numerous pathways. Through these interactions, ABA profoundly impacts mammalian health, and new ABA targets continue to be identified. Numerous studies in animal models demonstrate ABA's benefit in managing conditions such as neurological and psychiatric disorders, cancer, and malaria infections, all of which involve significant inflammatory dysregulation. In this manuscript we review the studies covering ABA synthesis and release in cell cultures, the signaling pathways regulated by ABA, and how these impact health in preclinical models. Furthermore, we highlight recent research suggesting that measuring ABA levels in human body fluids could serve as a useful biomarker for pathological conditions, providing insights into disease progression and treatment efficacy. This comprehensive review outlines the current understanding of ABA in mammalian pathophysiology, identifying gaps in knowledge, particularly concerning ABA biosynthesis and metabolism in mammals. In addition, this study emphasizes the need for clinical trials to validate the effectiveness of ABA-based therapies and its reliability as a biomarker for various diseases.
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INTRODUCTION/AIM: Vitamin D plays a crucial role in immune modulation, which may influence the development of graft-versus-host disease (GvHD) in patients undergoing hematopoietic stem cell transplantation (HSCT). This study aims to evaluate the impact of vitamin D levels and supplementation on the incidence of GvHD in HSCT patients. METHODS: A narrative review was conducted across PubMed/Medline, Cochrane Library, CINAHL, and Embase databases. RESULTS: The reviewed studies indicated widespread vitamin D deficiency among HSCT patients, with baseline levels ranging from 12.8 to 29.2 ng/mL. Supplementation protocols varied significantly, with dosages ranging from 1000 IU/day to 60,000 IU/week. Post-supplementation levels improved in some studies. Studies exploring the relationship between vitamin D and GvHD showed mixed results. Lower baseline vitamin D levels were associated with an increased risk of acute GvHD in some studies, while others found no significant correlation. However, a significant association between low levels of vitamin D and the incidence of chronic GvHD was observed. CONCLUSION: Vitamin D deficiency is prevalent in HSCT patients and may influence the risk of developing chronic GvHD. Future research should focus on larger and more rigorous studies to determine the optimal role of vitamin D as an adjuvant therapy in the context of HSCT.
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Suplementos Dietéticos , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Deficiencia de Vitamina D , Vitamina D , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/sangre , Vitamina D/sangre , Vitamina D/administración & dosificación , Deficiencia de Vitamina D/sangre , Femenino , Incidencia , MasculinoRESUMEN
Over time, researchers have accumulated significant evidence indicating that vitamin D deficiency not only impacts skeletal health but also contributes to the development and progression of various diseases, including cancer, diabetes, and cardiovascular conditions. The risk of low serum 1, 25(OH)2D3 level ultimately directs the way to morbidity, the beginning of new diseases, and numerous infections. Infections are the first entity that affects those with vitamin D deficiency. The common infection is urinary tract infection (UTI), and its relationship with vitamin D deficiency or insufficiency remains controversial. This infection affects both men and women, but comparatively, women are more prone to this infection because of the short length of the urethra, which makes an easy entry for the bacteria. The low level of serum vitamin D increases the risk of UTIs in children. Recurrent UTIs are one of the major weaknesses in women; if left untreated, they progress to appallingly serious conditions like kidney dysfunction, liver damage, etc. Hence improving the vitamin D status may help to improve the immune system, thus making it more resistant to infections. In this review, we have focused on examining whether vitamin D deficiency and insufficiency are the causes of UTIs and the association between them in women and children. We have also described the connection between vitamin D deficiency and insufficiency with UTIs and additional nanotechnology- based treatment strategies.
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Infecciones Urinarias , Deficiencia de Vitamina D , Vitamina D , Humanos , Infecciones Urinarias/sangre , Vitamina D/sangre , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/complicaciones , Niño , Femenino , Masculino , AdultoRESUMEN
A cutting-edge approach in cell-based immunotherapy for combating resistant cancer involves genetically engineered chimeric antigen receptor T (CAR-T) lymphocytes. In recent years, these therapies have demonstrated effectiveness, leading to their commercialization and clinical application against certain types of cancer. However, CAR-T therapy faces limitations, such as the immunosuppressive tumour microenvironment (TME) that can render CAR-T cells ineffective, and the adverse side effects of the therapy, including cytokine release syndrome (CRS). Extracellular vesicles (EVs) are a diverse group of membrane-bound particles released into the extracellular environment by virtually all cell types. They are essential for intercellular communication, transferring cargoes such as proteins, lipids, various types of RNAs, and DNA fragments to target cells, traversing biological barriers both locally and systemically. EVs play roles in numerous physiological processes, with those from both immune and non-immune cells capable of modulating the immune system through activation or suppression. Leveraging this capability of EVs to enhance CAR-T cell therapy could represent a significant advancement in overcoming its current limitations. This review examines the current landscape of CAR-T cell immunotherapy and explores the potential role of EVs in augmenting its therapeutic efficacy.
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The protozoan parasite Entamoeba histolytica is the causative agent of amebiasis, with clinical outcomes ranging from asymptomatic infections to severe invasive diseases. The innate immune system, particularly macrophages, is of paramount importance in resisting the invasion of host tissues and organs by the trophozoites of E. histolytica. Parasite-derived pathogenic factors, such as lectins, play a pivotal role in the promotion of macrophage polarization phenotypes that have undergone alteration. Nevertheless, the precise mechanisms by which E. histolytica modulates immune polarization remain largely unknown. The current study focused on the immunomodulatory effects of the Igl-C fragment of E. histolytica Gal/GalNAc lectin on macrophage polarization. These results demonstrated that Igl-C could induce the secretion of IL-1ß, IL-6, and other cytokines, activating a mixed M1/M2 polarization state. M1 polarization of macrophages occurs in the early stages and gradually transitions to M2 polarization in the later stages, which may contribute to the persistence of the infection. Igl-C induces the macrophage M1 phenotype and causes the release of immune effector molecules, including iNOS and cytokines, by activating the NF-κB p65 and JAK-STAT1 transcription factor signaling pathways. Furthermore, Igl-C supports the macrophage M2 phenotype via JAK-STAT3 and IL-4-STAT6 pathways, which activate arginase expression in later stages, contributing to the tissue regeneration and persistence of the parasite. The involvement of distinct signaling pathways in mediating this response highlights the complex interplay between the parasite and the host immune system. These findings enhance our understanding of the Igl-C-mediated pathogenic mechanisms during E. histolytica infection.
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Entamoeba histolytica , Entamebiasis , Lectinas , Macrófagos , Entamoeba histolytica/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/parasitología , Entamebiasis/inmunología , Entamebiasis/parasitología , Animales , Ratones , Lectinas/metabolismo , Lectinas/inmunología , Citocinas/metabolismo , Activación de Macrófagos , Humanos , Transducción de Señal , Proteínas Protozoarias/inmunología , Proteínas Protozoarias/metabolismoRESUMEN
Background and Aim: Aeromonas hydrophila infections in fish result in significant financial losses within aquaculture. Previous research indicates black soldier fly (BSF) prepupae provide immunomodulatory benefits through their fatty acids, chitin, and proteins. The study evaluated the impact of hexane extract from black soldier fly prepupae (HEBP) on interleukin (IL)-4 and IL-10 cytokine expression in zebrafish, both infected and uninfected with A. hydrophila. Materials and Methods: Adult zebrafish (aged 4-5 months) was assigned to a negative control group (fed commercial feed), a positive control group (commercial feed + A. hydrophila infection at 107 colony-forming unit/mL), and three treatment groups (T1, T2, T3) that received HEBP at doses of 1000; 2000 and 4000 mg/kg feed for 30 days, respectively. A. hydrophila infection was introduced on day 31 through immersion. Analysis of IL-4 and IL-10 expression in the head kidney trunk region (body without head and tail) through quantitative polymerase chain reaction was conducted on day 33. Results: The HEBP modulated the immune response to A. hydrophila infection at a concentration of 1000 mg/kg feed, as evidenced by an increase in IL-4 and IL-10 expression in the groups not infected with the bacteria. However, these cytokines were decreased in the infected groups. Conclusion: A feed concentration of 1000 mg/kg HEBP was identified as optimal for cytokine modulation. This discovery marks a significant advancement in the development and benefit of a natural extract-based immunomodulator in a zebrafish model, which is potentially immunotherapeutic against bacterial infections in fish for the aquaculture industry.
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Platelet-derived extracellular vesicles (pEVs) are emerging as pivotal players in numerous physiological and pathological processes, extending beyond their traditional roles in hemostasis and thrombosis. As one of the most abundant vesicle types in human blood, pEVs transport a diverse array of bioactive molecules, including growth factors, cytokines, and clotting factors, facilitating crucial intercellular communication, immune regulation, and tissue healing. The unique ability of pEVs to traverse tissue barriers and their biocompatibility position them as promising candidates for targeted drug delivery and regenerative medicine applications. Recent studies have underscored their involvement in cancer progression, viral infections, wound healing, osteoarthritis, sepsis, cardiovascular diseases, rheumatoid arthritis, and atherothrombosis. For instance, pEVs promote tumor progression and metastasis, enhance tissue repair, and contribute to thrombo-inflammation in diseases such as COVID-19. Despite their potential, challenges remain, including the need for standardized isolation techniques and a comprehensive understanding of their mechanisms of action. Current research efforts are focused on leveraging pEVs for innovative anti-cancer treatments, advanced drug delivery systems, regenerative therapies, and as biomarkers for disease diagnosis and monitoring. This review highlights the necessity of overcoming technical hurdles, refining isolation methods, and establishing standardized protocols to fully unlock the therapeutic potential of pEVs. By understanding the diverse functions and applications of pEVs, we can advance their use in clinical settings, ultimately revolutionizing treatment strategies across various medical fields and improving patient outcomes.
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This review explores the complex challenges and advancements in the treatment of traumatic brain injury (TBI) and spinal cord injury (SCI). Traumatic injuries to the central nervous system (CNS) trigger intricate pathophysiological responses, frequently leading to profound and enduring disabilities. This article delves into the dual phases of injury-primary impacts and the subsequent secondary biochemical cascades-that worsen initial damage. Conventional treatments have traditionally prioritized immediate stabilization, surgical interventions, and supportive medical care to manage both the primary and secondary damage associated with central nervous system injuries. We explore current surgical and medical management strategies, emphasizing the crucial role of rehabilitation and the promising potential of stem cell therapies and immune modulation. Advances in stem cell therapy, gene editing, and neuroprosthetics are revolutionizing treatment approaches, providing opportunities not just for recovery but also for the regeneration of impaired neural tissues. This review aims to emphasize emerging therapeutic strategies that hold promise for enhancing outcomes and improving the quality of life for affected individuals worldwide.
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Background: Neoadjuvant chemotherapy (NACT) is increasingly being used in the management of locally advanced biliary tract cancer (BTC). The evidence suggests a contributing role of tumor infiltrating immune cells in the prognosis and response. We set out to characterize immune modulation of tumor immune microenvironment in BTC following NACT. Case Description: Patients with BTC who underwent diagnostic biopsy, then NACT then resection between 2014-2018 were identified. Multiplexed immunohistochemical consecutive staining on single slide (MICSSS) analysis was performed with a series of immune markers to characterize T-cells, immune checkpoints etc. on pre- & post-NACT tumor tissue. Density was calculated for each marker. The final analysis included five patients. Median age was 48 (range, 41-56) years, with 4 female, 4 intrahepatic cholangiocarcinoma and 1 gallbladder. All patients received gemcitabine/cisplatin as NACT (median of 5 cycles). Median time from diagnosis to surgery was 4.3 (range, 1.4-7.8) months. All patients were mismatch repair proficient (pMMR). NACT on average produced a depletion of all immune markers. Given small sample size, each patient was considered their own control and changes in mean cell densities post-NACT were calculated. Patient #2 with a 40-fold increase in PD-L1 expression & 5-fold decrease in CD8:FOXP3 ratio after NACT notably had the shortest disease-free interval (DFI). Patient #3 with the longest DFI had the largest increase in CD8:FOXP3 by about 8-fold with a decrease in PD-L1. Conclusions: Preliminary results suggest NACT may differentially modulate various compartments of the immune tumor contexture despite overall cell depletion. Future studies should focus on strategies to expand immune modulation of tumor microenvironment, including immune-oncology agents to augment the effects of chemotherapy.
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Extracellular vesicles (EVs) from mesenchymal stem cells (MSCs), specifically those preconditioned with deferoxamine (DFO) in canine adipose tissue-derived MSCs (cAT-MSCs), were explored for treating autoimmune diseases. This study assessed the effects of DFO-preconditioned EVs (EVDFO) in an experimental autoimmune encephalomyelitis (EAE) mouse model. cAT-MSCs were treated with DFO for 48 h, after which EVs were isolated. EAE mice received intranasal EV or EVDFO treatments and were euthanized following histopathologic analysis; RNA and protein expression levels were measured. Histologically, EV and EVDFO groups showed a significant reduction in inflammatory cell infiltration and demyelination. Immunofluorescence revealed increased CD206 and Foxp3 expression, indicating elevated M2 macrophages and regulatory T (Treg) cells, particularly in the EVDFO group. Treg cells also notably increased in the spleen of EVDFO -treated mice. STAT3 and pSTAT3 proteins were upregulated in the EAE groups compared to the naïve group. However, following EV treatment, STAT3 expression decreased compared to the EAE group, whereas pSTAT3 expression was similar in both the EV and EAE groups. In conclusion, EVDFO treatment resulted in reduced STAT3 expression, suggesting its role in T cell regulation and the potential of EVDFO in modulating the STAT3 pathway for reducing inflammation more effectively than non-preconditioned EVs.
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Deferoxamina , Encefalomielitis Autoinmune Experimental , Vesículas Extracelulares , Inflamación , Células Madre Mesenquimatosas , Factor de Transcripción STAT3 , Linfocitos T Reguladores , Animales , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/trasplante , Factor de Transcripción STAT3/metabolismo , Ratones , Perros , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismo , Deferoxamina/farmacología , Deferoxamina/uso terapéutico , Células Madre Mesenquimatosas/metabolismo , Inflamación/patología , Femenino , Modelos Animales de EnfermedadRESUMEN
Introduction: Bacterial urinary tract infections (UTI) are among the most common infectious diseases worldwide. The rise of multidrug-resistant (MDR) uropathogenic Escherichia coli (UPEC) UTI cases is a significant threat to healthcare systems. Several probiotic bacteria have been proposed as an alternative to combat MDR UTI. Lactic acid bacteria in the genus Limosilactobacillus are some of the most studied and used probiotics. However, strain-specific effects play a critical role in probiotic properties. L. reuteri KUB-AC5 (AC5), isolated from the chicken gut, confers antimicrobial and immunobiotic effects against some human pathogens. However, the antibacterial and immune modulatory effects of AC5 on UPEC have never been explored. Methods: Here, we investigated both the direct and indirect effects of AC5 against UPEC isolates (UTI89, CFT073, and clinical MDR UPEC AT31) in vitro. Using a spot-on lawn, agar-well diffusion, and competitive growth assays, we found that viable AC5 cells and cell-free components of this probiotic significantly reduced the UPEC growth of all strains tested. The human bladder epithelial cell line UM-UC-3 was used to assess the adhesion and pathogen-attachment inhibition properties of AC5 on UPEC. Results and discussion: Our data showed that AC5 can attach to UM-UC-3 and decrease UPEC attachment in a dose-dependent manner. Pretreatment of UPEC-infected murine macrophage RAW264.7 cells with viable AC5 (multiplicity of infection, MOI = 1) for 24 hours enhanced macrophage-killing activity and increased proinflammatory (Nos2, Il6, and Tnfa) and anti-inflammatory (Il10) gene expression. These findings indicate the gut-derived AC5 probiotic could be a potential urogenital probiotic against MDR UTI.
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Limosilactobacillus reuteri , Macrófagos , Probióticos , Escherichia coli Uropatógena , Probióticos/farmacología , Escherichia coli Uropatógena/efectos de los fármacos , Escherichia coli Uropatógena/inmunología , Limosilactobacillus reuteri/fisiología , Animales , Ratones , Macrófagos/inmunología , Macrófagos/microbiología , Humanos , Urotelio/microbiología , Infecciones Urinarias/microbiología , Infecciones Urinarias/prevención & control , Línea Celular , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/prevención & control , Células RAW 264.7 , Células Epiteliales/microbiología , Pollos , Adhesión Bacteriana/efectos de los fármacosRESUMEN
The alarming prevalence of inflammatory bowel disease (IBD) in early childhood is associated with imbalances in the microbiome, the immune response, and environmental factors. Some pathogenic Escherichia coli (E. coli) strains have been found in IBD patients, where they may influence disease progression. Therefore, the discovery of new harmful bacterial strains that have the potential to drive the inflammatory response is of great importance. In this study, we compared the immunomodulatory properties of two E. coli strains of serotype O6: the probiotic E. coli Nissle 1917 and the uropathogenic E. coli O6:K13:H1. Using the epithelial Caco-2 cell line, we investigated the different abilities of the strains to adhere to and invade epithelial cells. We confirmed the potential of E. coli Nissle 1917 to modulate the Th1 immune response in a specific manner in an in vitro setting by stimulating mouse bone marrow-derived dendritic cells (BM-DCs). In gnotobiotic in vivo experiments, we demonstrated that neonatal colonization with E. coli Nissle 1917 achieves a stable high concentration in the intestine and protects mice from the progressive effect of E. coli O6:K13:H1 in developing ulcerative colitis in an experimental model. In contrast, a single-dose treatment with E. coli Nissle 1917 is ineffective in achieving such high concentrations and does not protect against DSS-induced ulcerative colitis in mice neonatally colonized with pathobiont E. coli O6:K13:H1. Despite the stable coexistence of both E. coli strains in the intestinal environment of the mice, we demonstrated a beneficial competitive interaction between the early colonizing E. coli Nissle 1917 and the late-arriving strain O6:K13:H1, suggesting its anti-inflammatory potential for the host. This study highlights the importance of the sequence of bacterial colonization, which influences the development of the immune response in the host gut and potentially impacts future quality of life.
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Chronic wounds impact 2.5% of the United States population and will continue to be a major clinical challenge due to increases in population age, chronic disease diagnoses, and antibiotic-resistant infection. Nitric oxide (NO) is an endogenous signaling molecule that represents an attractive, simple therapeutic for chronic wound treatment due to its innate antibacterial and immunomodulatory function. Unfortunately, modulating inflammation for extended periods by low levels of NO is not possible with NO gas. Herein, we report the utility of a NO-releasing glycosaminoglycan biopolymer (GAG) for promoting wound healing. GAGs are naturally occurring biopolymers that are immunomodulatory and known to be involved in the native wound healing process. Thus, the combination of NO and GAG biopolymers represents an attractive wound therapeutic due to these known independent roles. The influence and contribution of chondroitin sulfate C (CSC) modified to facilitate controlled and targeted delivery of NO (CSC-HEDA/NO) was evaluated using in vitro cell proliferation and migration assays and an in vivo wound model.
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Proliferación Celular , Sulfatos de Condroitina , Óxido Nítrico , Cicatrización de Heridas , Óxido Nítrico/metabolismo , Cicatrización de Heridas/efectos de los fármacos , Sulfatos de Condroitina/química , Sulfatos de Condroitina/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Ratones , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Humanos , Tamaño de la Partícula , Ensayo de Materiales , Movimiento Celular/efectos de los fármacos , Estructura MolecularRESUMEN
Despite the high mortality associated with sepsis, effective and targeted treatments remain scarce. The use of conventional antibiotics such as TIENAM (imipenem and cilastatin sodium for injection, TIE) is challenging because of the increasing bacterial resistance, which diminishes their efficacy and leads to adverse effects. Our previous studies demonstrated that ulinastatin (UTI) exerts a therapeutic impact on sepsis by reducing systemic inflammation and modulating immune responses. In this study, we examined the possibility of administering UTI and TIE after inducing sepsis in a mouse model using cecal ligation and puncture (CLP). We assessed the rates of survival, levels of inflammatory cytokines, the extent of tissue damage, populations of immune cells, microbiota in ascites, and important signaling pathways. The combination of UTI and TIE significantly improved survival rates and reduced inflammation and bacterial load in septic mice, indicating potent antimicrobial properties. Notably, the survival rates of UTI+TIE-treated mice increased from 10 % to 75 % within 168 h compared to those of mice that were subjected to CLP. The dual treatment successfully regulated the levels of inflammatory indicators (interleukin [IL]-6, IL-1ß, and tumor necrosis factor [TNF]-α) and immune cell numbers by reducing B cells, natural killer cells, and TNFR2+ Treg cells and increasing CD8+ T cells. Additionally, the combination of UTI and TIE alleviated tissue damage, reduced bacterial load in the peritoneal cavity, and suppressed the NF-κB signaling pathway. Our findings indicate that UTI and TIE combination therapy can significantly enhance sepsis outcomes by reducing inflammation and boosting the immune system. The results offer a promising therapeutic approach for future sepsis treatment.
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Ciego , Citocinas , Glicoproteínas , Sepsis , Animales , Sepsis/tratamiento farmacológico , Sepsis/inmunología , Sepsis/mortalidad , Glicoproteínas/uso terapéutico , Glicoproteínas/farmacología , Ligadura , Ciego/cirugía , Citocinas/metabolismo , Ratones , Masculino , Combinación Cilastatina e Imipenem/uso terapéutico , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Globulinas , Punciones , Quimioterapia Combinada , Inflamación/tratamiento farmacológico , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Cilastatina/uso terapéutico , Cilastatina/farmacología , Humanos , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacologíaRESUMEN
Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by intense pruritus and eczematous lesions, significantly impacting physical health and quality of life. The pathogenesis of AD involves genetic predisposition, immune dysregulation, and environmental factors, with a defective skin barrier playing a crucial role. Treatment options for AD include both topical and systemic therapies, with advanced treatments like Janus kinase inhibitors and biologics offering significant improvements but facing limitations in safety and dosing frequency. Extended half-life antibodies represent a promising advancement for the management of immune-mediated inflammatory diseases, including AD. These antibodies, engineered for prolonged circulation and reduced dosing frequency, target key cytokines and immune pathways known to be involved in the pathogenesis of AD, offering potential for less frequent administration while maintaining efficacy. Currently, two such agents are in phase 2 trials. APG777, targeting interleukin-13 (IL-13), and IMG-007, targeting OX40 receptor, have shown promising preclinical and early clinical results. They demonstrated prolonged half-lives and the potential for less frequent dosage regimen, along with significant improvements in AD symptoms. These therapies could enhance patient adherence and reduce healthcare burdens by decreasing injection frequencies and clinic visits. As research continues, extended half-life antibodies could significantly improve AD management and patient quality of life. Further studies will determine the long-term safety and efficacy of extended half-life antibodies, with ongoing innovations in antibody engineering likely to broaden their applications and benefits.
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Metal implants holds significant promise for diverse fixed prostheses. However, their long-term reliability and broader application are hindered by challenges related to the disequilibrium at the soft-hard tissue interface. By using anti-inflammatory (PDA/IL4) and pro-inflammatory (PDA/LPS/IFNγ) coatings to modulate distinct immune characteristics, we discovered a dynamic bioactive structure at the soft-hard tissue interface around metal implant, which we have named the 'Remodeling Triangle Area' (RTA). We further demonstrate that the RTA can be influenced by the PDA/IL4 coating to favor a phenotype that enhances both innate and adaptive immunity. This leads to stronger epithelial adhesion, the formation of dense connective tissue via IGF1 secretion, and a more balanced soft-hard tissue interface through the OPG/RANKL axis. Conversely, the PDA/LPS/IFNγ coating shifts the RTA towards a phenotype that activates the innate immune response. This results in a less cohesive tissue structure and bone resorption, characterized by reduced IGF1 secretion and an imbalanced OPG/RANKL axis. Over all, our study introduces the novel concept termed the 'Remodeling Triangle Area' (RTA), an immune-rich anatomical region located at the nexus of the implant interface, epithelial, connective, and bone tissue, which becomes highly interactive post-implantation to modulate the soft-hard tissue interface equilibrium. We believe that an RTA-centric, immunomodulatory approach has the potential to revolutionize the design of next-generation metal implants, providing unparalleled soft-hard tissue interface equilibrium properties.
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The Stimulator of Interferon Genes (STING) is involved in cytosolic DNA sensing and type I Interferons (IFN-I) induction. Aiming to identify new STING agonists with antiviral activity and given the known biological activity of benzothiazole and benzimidazole derivatives, a series of benzofuran derivatives were tested for their ability to act as STING agonists, induce IFN-I and inhibit viral replication. Compounds were firstly evaluated in a gene reporter assay measuring luciferase activity driven by the human IFN-ß promoter in cells expressing exogenous STING (HEK293T). Seven of them were able to induce IFN-ß transcription while no induction of the IFN promoter was observed in the presence of a mutated and inactive STING, showing specific protein-ligand interaction. Docking studies were performed to predict their putative binding mode. The best hit compounds were then tested on human coronavirus 229E replication in BEAS-2B and MRC-5 cells and three derivatives showed EC50 values in the µM range. Such compounds were also tested on SARS-CoV-2 replication in BEAS-2B cells and in Calu-3 showing they can inhibit SARS-CoV-2 replication at nanomolar concentrations. To further confirm their IFN-dependent antiviral activity, compounds were tested to verify their effect on phospho-IRF3 nuclear localization, that was found to be induced by benzofuran derivatives, and SARS-CoV-2 replication in Vero E6 cells, lacking IFN production, founding them to be inactive. In conclusion, we identified benzofurans as STING-dependent immunostimulatory compounds and host-targeting inhibitors of coronaviruses representing a novel chemical scaffold for the development of broad-spectrum antivirals.