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BACKGROUND: Patients with endometriosis suffer with chronic pelvic pain and infertility, and from the lack of pharmacologic therapies that consistently halt disease progression. Differences in the endometrium of patients with endometriosis vs. unaffected controls are well-documented. Specifically, shed endometrial tissues (delivered to the pelvic cavity via retrograde menstruation) reveal that a subset of stromal cells exhibiting pro-inflammatory, pro-fibrotic, and pro-senescence-like phenotypes is enhanced in endometriosis patients compared to controls. Additionally, cultured biopsy-derived endometrial stromal cells from endometriosis patients exhibit impaired decidualization, a defined differentiation process required for human embryo implantation and pregnancy. Quercetin, a senolytic agent, shows therapeutic potential for pulmonary fibrosis, a disorder attributed to senescent pulmonary fibroblasts. In rodent models of endometriosis, quercetin shows promise, and quercetin improves decidualization in vitro. However, the exact mechanisms are not completely understood. Therefore, we investigated the effects of quercetin on menstrual effluent-derived endometrial stromal cells from endometriosis patients and unaffected controls to define the signaling pathways underlying quercetin's effects on endometrial stromal cells. METHODS: Menstrual effluent-derived endometrial stromal cells were collected and cultured from unaffected controls and endometriosis patients and then, low passage cells were treated with quercetin (25 µM) under basal or standard decidualization conditions. Decidualization responses were analyzed by measuring the production of IGFBP1 and PRL. Also, the effects of quercetin on intracellular cAMP levels and cellular oxidative stress responses were measured. Phosphokinase arrays, western blotting, and flow cytometry methods were performed to define the effects of quercetin on various signaling pathways and the potential mechanistic roles of quercetin. RESULTS: Quercetin significantly promotes decidualization of control- and endometriosis-endometrial stromal cells. Quercetin substantially reduces the phosphorylation of multiple signaling molecules in the AKT and ERK1/2 pathways, while enhancing the phosphorylation of p53 and total p53 levels. Furthermore, p53 inhibition blocks decidualization while p53 activation promotes decidualization. Finally, we provide evidence that quercetin increases apoptosis of endometrial stromal cells with a senescent-like phenotype. CONCLUSIONS: These data provide insight into the mechanisms of action of quercetin on endometrial stromal cells and warrant future clinical trials to test quercetin and other senolytics for treating endometriosis.
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Senescência Celular , Endometriose , Proteínas Proto-Oncogênicas c-akt , Quercetina , Células Estromais , Proteína Supressora de Tumor p53 , Quercetina/farmacologia , Feminino , Humanos , Endometriose/metabolismo , Endometriose/patologia , Endometriose/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adulto , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Senescência Celular/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Endométrio/patologia , Decídua/efeitos dos fármacos , Decídua/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células CultivadasRESUMO
BACKGROUND: In this investigation, we explored the effects of pharmacological cholinergic stimulation on cardiac function and renal inflammation following acute myocardial infarction (AMI) in spontaneously hypertensive rats (SHRs). METHODS: Adult male SHRs were randomized into three experimental groups: sham-operated; AMI + Veh (infarcted, treated with vehicle); and AMI + PY (infarcted, treated with the cholinesterase inhibitor, pyridostigmine bromide (PY)-40 mg/kg, once daily for seven days). Rats were euthanized 7 or 30 days post-surgery. The clinical parameters were assessed on the day before euthanasia. Subsequent to euthanasia, blood samples were collected and renal tissues were harvested for histological and gene expression analyses aimed to evaluate inflammation and injury. RESULTS: Seven days post-surgery, the AMI + PY group demonstrated improvements in left ventricular diastolic function and autonomic regulation, and a reduction in renal macrophage infiltration compared to the AMI + Veh group. Furthermore, there was a notable downregulation in pro-inflammatory gene expression and an upregulation in anti-inflammatory gene expression. Analysis 30 days post-surgery showed that PY treatment had a sustained positive effect on renal gene expression, correlated with a decrease in biomarkers, indicative of subclinical kidney injury. CONCLUSIONS: Short-term cholinergic stimulation with PY provides both cardiac and renal protection by mitigating the inflammatory response after AMI.
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This case study describes a 45-year-old Caucasian male with a past medical history of obesity, hypertension, and non-insulin-dependent diabetes mellitus, who in the setting of coronavirus disease 2019 (COVID-19) pneumonia, developed portal vein thrombosis (PVT) presenting as an acute abdomen after hospital discharge from a cholecystitis episode. PVT is a very infrequent thromboembolic condition, classically occurring in patients with systemic conditions such as cirrhosis, malignancy, pancreatitis, diverticulitis, autoimmunity, and thrombophilia. PVT can cause serious complications, such as intestinal infarction, or even death, if not promptly treated. Due to the limited number of reports in the literature describing PVT in the COVID-19 setting, its prevalence, natural history, mechanism, and precise clinical features remain unknown. Therefore, clinical suspicion should be high for PVT, in any COVID-19 patient who presents with abdominal pain or associated signs and symptoms. To the best of our knowledge, this is the first report of COVID-19-associated PVT causing extensive thrombosis in the portal vein and its right branch, occurring in the setting of early-stage cirrhosis after a preceding episode of cholecystitis.
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Chronic low-grade inflammation has been recognized as an underlying event linking obesity to cardiovascular disease (CVD). However, inflammatory alterations in individuals who are overweight remain understudied. To provide insight, we determined the levels of key circulating biomarkers of endotoxemia and inflammation, including lipopolysaccharide-binding protein (LBP), CRP, IL-6, leptin, and adiponectin in adult female subjects (n = 20) who were lean or overweight and had high cholesterol and/or high blood pressure - two important conventional risk factors for CVD. Plasma levels of LBP (a recognized marker of metabolic endotoxemia in obesity) were significantly higher in the overweight group compared with the lean group (P = 0.005). The levels of CRP, a general marker of inflammation, were also significantly higher in overweight subjects (P = 0.01), as were IL-6 (P = 0.02) and leptin (P = 0.002), pro-inflammatory mediators associated with cardiovascular risk. Levels of adiponectin, an adipokine with anti-inflammatory and anti-atherogenic functions, were significantly lower in the overweight group (P = 0.002). The leptin/adiponectin ratio, a preferential atherogenic marker was significantly increased in women who are overweight (P = 0.02). LBP, CRP, leptin, and adiponectin levels significantly correlated with BMI, but not with age. These results reveal the presence of subclinical endotoxemia and a pro-inflammatory state in overweight women and are of interest for further studies with the goal for improved understanding of women's cardiovascular health.
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Chronic low-grade inflammation has been recognized as an underlying event linking obesity to cardiovascular disease (CVD). However, inflammatory alterations in individuals who are overweight remain understudied. To provide insight, we determined the levels of key circulating biomarkers of endotoxemia and inflammation, including lipopolysaccharide-binding protein (LBP), CRP, IL-6, leptin, and adiponectin in adult female subjects (n=40) who were lean or overweight and had high cholesterol and/or high blood pressure - two important conventional risk factors for CVD. Plasma levels of LBP were significantly higher in the overweight group compared with the lean group (P=0.005). The levels of CRP were also significantly higher in overweight subjects (P=0.01), as were IL-6 (P=0.02) and leptin (P=0.002), pro-inflammatory mediators associated with cardiovascular risk. Levels of adiponectin, an adipokine with anti-inflammatory and anti-atherogenic functions, were significantly lower in the overweight group (P=0.002). The leptin/adiponectin ratio, a preferential atherogenic marker was significantly increased in women who are overweight (P=0.02). LBP, CRP, leptin, and adiponectin levels significantly correlated with BMI, but not with age and there was a significant correlation between LBP and IL-6 levels. These results reveal the presence of subclinical endotoxemia and a pro-inflammatory state in overweight women and are of interest for further studies with the goal for improved understanding of cardiovascular health risks in women.
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INTRODUCTION: Chronic Pelvic Pain (CPP) is a complex, multifaceted condition that affects both women and men. There is limited literature on the cost utilization the healthcare system and CPP patients incur. The purpose of this analysis is to characterize the overall healthcare utilization, cost burden, and quality-of-life restrictions experienced by CPP patients using data from an outpatient pelvic rehabilitation practice. METHODS: Healthcare utilization data was gathered by systematically reviewing and analyzing data from new patient visit progress notes stored in the clinic's electronic health records (EHR). We obtained in-network costs by using the FAIR Health Consumer online database. Overall costs were then calculated as the utilization times the per-unit costs from the FAIR database. Additionally, data on patients' visual analogue scale (VAS), absenteeism, presenteeism emergency room visits, usage of common pain medications, use of diagnostics, and participation in common treatment modalities was gathered. RESULTS: Data from 607 patients was used. The overall cost burden per patient for all surgeries combined was $15,750 for in-network services. The cost burden for diagnostics was $5,264.22 and treatments was $8,937 per patient for in-network treatments. CONCLUSION: Chronic Pelvic Pain was found to have a large cost burden of $29,951 for in-network services which includes treatments, diagnostics, and surgeries. This analysis sets the stage for future investigations involving data on costs of medications that patients have tried prior to presenting to us and costs associated with work hours lost.
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Dor Crônica , Qualidade de Vida , Masculino , Humanos , Feminino , Pacientes Ambulatoriais , Aceitação pelo Paciente de Cuidados de Saúde , Medição da Dor , Dor Pélvica/terapia , Dor Crônica/terapiaRESUMO
Classical cadherins, including vascular endothelial (VE)-cadherin, are targeted by matrix metalloproteinases (MMPs) and γ-secretase during adherens junction (AJ) disassembly, a mechanism that might have relevance for endothelial cell (EC) integrity and vascular homeostasis. Here, we show that oxidative stress triggered by H2O2 exposure induced efficient VE-cadherin proteolysis by MMPs and γ-secretase in human umbilical endothelial cells (HUVECs). The cytoplasmic domain of VE-cadherin produced by γ-secretase, VE-Cad/CTF2-a fragment that has eluded identification so far-could readily be detected after H2O2 treatment. VE-Cad/CTF2, released into the cytosol, was tightly regulated by proteasomal degradation and was sequentially produced from an ADAM10/17-generated C-terminal fragment, VE-Cad/CTF1. Interestingly, BMP9 and BMP10, two circulating ligands critically involved in vascular maintenance, significantly reduced VE-Cad/CTF2 levels during H2O2 challenge, as well as mitigated H2O2-mediated actin cytoskeleton disassembly during VE-cadherin processing. Notably, BMP9/10 pretreatments efficiently reduced apoptosis induced by H2O2, favoring endothelial cell recovery. Thus, oxidative stress is a trigger of MMP- and γ-secretase-mediated endoproteolysis of VE-cadherin and AJ disassembly from the cytoskeleton in ECs, a mechanism that is negatively controlled by the EC quiescence factors, BMP9 and BMP10.
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Secretases da Proteína Precursora do Amiloide , Complexo de Endopeptidases do Proteassoma , Humanos , Secretases da Proteína Precursora do Amiloide/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Células Endoteliais/metabolismo , Peróxido de Hidrogênio/farmacologia , Peróxido de Hidrogênio/metabolismo , Caderinas/metabolismo , Estresse Oxidativo , Metaloproteinases da Matriz/metabolismo , Células Cultivadas , Junções Aderentes/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismoRESUMO
BACKGROUND: Brain metabolic alterations and neuroinflammation have been reported in several peripheral inflammatory conditions and present significant potential for targeting with new diagnostic approaches and treatments. However, non-invasive evaluation of these alterations remains a challenge. METHODS: Here, we studied the utility of a micro positron emission tomography (microPET) dual tracer ([11C]PBR28 - for microglial activation and [18F]FDG for energy metabolism) approach to assess brain dysfunction, including neuroinflammation in murine endotoxemia. MicroPET imaging data were subjected to advanced conjunction and individual analyses, followed by post-hoc analysis. RESULTS: There were significant increases in [11C]PBR28 and [18F]FDG uptake in the hippocampus of C57BL/6 J mice 6 h following LPS (2 mg/kg) intraperitoneal (i.p.) administration compared with saline administration. These results confirmed previous postmortem observations. In addition, patterns of significant simultaneous activation were demonstrated in the hippocampus, the thalamus, and the hypothalamus in parallel with other tracer-specific and region-specific alterations. These changes were observed in the presence of robust systemic inflammatory responses manifested by significantly increased serum cytokine levels. CONCLUSIONS: Together, these findings demonstrate the applicability of [11C]PBR28 - [18F]FDG dual tracer microPET imaging for assessing neuroinflammation and brain metabolic alterations in conditions "classically" characterized by peripheral inflammatory and metabolic pathogenesis.
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Peptides, polymers of amino acids, comprise a vital and expanding therapeutic approach. Their rapid degradation by proteases, however, represents a major limitation to their therapeutic utility and chemical modifications to native peptides have been employed to mitigate this weakness. Herein, we describe functionalized thiocarbazate scaffolds as precursors of aza-amino acids, that, upon activation, can be integrated in a peptide sequence to generate azapeptides using conventional peptide synthetic methods. This methodology facilitates peptide editing-replacing targeted amino acid(s) with aza-amino acid(s) within a peptide-to form azapeptides with preferred therapeutic characteristics (extending half-life/bioavailability, while at the same time typically preserving structural features and biological activities). We demonstrate the convenience of this azapeptide synthesis platform in two well-studied peptides with short half-lives: FSSE/P5779, a tetrapeptide inhibitor of HMGB1/MD-2/TLR4 complex formation, and bradykinin, a nine-residue vasoactive peptide. This bench-stable thiocarbazate platform offers a robust and universal approach to optimize peptide-based therapeutics.
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Aminoácidos , Bradicinina , Meia-Vida , Peptídeo Hidrolases , EndopeptidasesRESUMO
BACKGROUND: Endometriosis is a common, complex disorder which is underrecognized and subject to prolonged delays in diagnosis. It is accompanied by significant changes in the eutopic endometrial lining. METHODS: We have undertaken the first single-cell RNA-sequencing (scRNA-Seq) comparison of endometrial tissues in freshly collected menstrual effluent (ME) from 33 subjects, including confirmed endometriosis patients (cases) and controls as well as symptomatic subjects (who have chronic symptoms suggestive of endometriosis but have not been diagnosed). RESULTS: We identify a unique subcluster of proliferating uterine natural killer (uNK) cells in ME-tissues from controls that is almost absent from endometriosis cases, along with a striking reduction of total uNK cells in the ME of cases (p < 10-16). In addition, an IGFBP1+ decidualized subset of endometrial stromal cells are abundant in the shed endometrium of controls when compared to cases (p < 10-16) confirming findings of compromised decidualization of cultured stromal cells from cases. By contrast, endometrial stromal cells from cases are enriched in cells expressing pro-inflammatory and senescent phenotypes. An enrichment of B cells in the cases (p = 5.8 × 10-6) raises the possibility that some may have chronic endometritis, a disorder which predisposes to endometriosis. CONCLUSIONS: We propose that characterization of endometrial tissues in ME will provide an effective screening tool for identifying endometriosis in patients with chronic symptoms suggestive of this disorder. This constitutes a major advance, since delayed diagnosis for many years is a major clinical problem in the evaluation of these patients. Comprehensive analysis of ME is expected to lead to new diagnostic and therapeutic approaches to endometriosis and other associated reproductive disorders such as female infertility.
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Endometriose , Endometriose/diagnóstico , Endométrio , Feminino , Humanos , Células Matadoras Naturais , Fenótipo , Análise de Célula ÚnicaRESUMO
OBJECTIVE: To evaluate if patient-derived organoids (PDOs) may predict response to neoadjuvant (NAT) chemotherapy in patients with pancreatic adenocarcinoma. BACKGROUND: PDOs have been explored as a biomarker of therapy response and for personalized therapeutics in patients with pancreatic cancer. METHODS: During 2017-2021, patients were enrolled into an IRB-approved protocol and PDO cultures were established. PDOs of interest were analyzed through a translational pipeline incorporating molecular profiling and drug sensitivity testing. RESULTS: One hundred thirty-six samples, including both surgical resections and fine needle aspiration/biopsy from 117 patients with pancreatic cancer were collected. This biobank included diversity in stage, sex, age, and race, with minority populations representing 1/3 of collected cases (16% Black, 9% Asian, 7% Hispanic/Latino). Among surgical specimens, PDO generation was successful in 71% (15 of 21) of patients who had received NAT prior to sample collection and in 76% (39 of 51) of patients who were untreated with chemotherapy or radiation at the time of collection. Pathological response to NAT correlated with PDO chemotherapy response, particularly oxaliplatin. We demonstrated the feasibility of a rapid PDO drug screen and generated data within 7 days of tissue resection. CONCLUSION: Herein we report a large single-institution organoid biobank, including ethnic minority samples. The ability to establish PDOs from chemotherapy-naive and post-NAT tissue enables longitudinal PDO generation to assess dynamic chemotherapy sensitivity profiling. PDOs can be rapidly screened and further development of rapid screening may aid in the initial stratification of patients to the most active NAT regimen.
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Adenocarcinoma , Antineoplásicos , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Antineoplásicos/uso terapêutico , Etnicidade , Humanos , Grupos Minoritários , Terapia Neoadjuvante , Organoides , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias PancreáticasRESUMO
OBJECTIVE: To identify immune cells, cytokines, and immune cell transcriptome in the menstrual effluent (ME) of women with endometriosis compared with that of healthy donors. DESIGN: Live immune cells were isolated from human ME samples and were analyzed by flow cytometry to identify various immune cell populations. Selected cytokines from the same patients were evaluated using multiplex cytokine analyses. The transcriptome of the immune cell population was subsequently profiled using NanoString nCounter's PanCancer Immune panel. SETTING: Academic institution. PATIENT(S): Surgically confirmed endometriosis patients (n = 14) and healthy fertile donors (n = 19). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): In-depth immune cell profiling of ME obtained from women with endometriosis compared with that of healthy donors. RESULT(S): ME analysis revealed that the number of T helper 17 (TH17) cells was significantly lower in patients with endometriosis compared with that of healthy donors; the number of macrophages was also lower (P=.06) in the former. Multiplex cytokine analysis revealed significantly lower transforming growth factor α in the ME "serum" of patients with endometriosis. Transcriptomic analysis of CD45+ cells revealed 47 differentially expressed genes, mainly associated with the TH17 axis (IL10, IL23A, and IL6), as well as genes associated with macrophage signaling/activation (CD74, CD83, CXCL16, and CCL3). CONCLUSION(S): We demonstrate for the first time that the levels of TH17 axis, macrophages, and transforming growth factor α were altered in the ME of women with endometriosis compared with that of healthy donors. These findings shed light on the potential immune pathways that could partly explain the pathogenesis and progression of endometriosis. Future large-scale studies on ME samples are warranted to exploit the use of these markers to study the pathogenesis of endometriosis.
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Endometriose , Macrófagos , Células Th17 , Citocinas/imunologia , Endometriose/patologia , Endométrio , Feminino , Humanos , Macrófagos/imunologia , Células Th17/imunologia , Fator de Crescimento Transformador alfa/imunologiaRESUMO
BACKGROUND: Recent epidemiologic research shows many environmental chemicals exhibit endocrine disrupting effects on the female reproductive system. Few studies have examined exposure at reproductive organs. Our aim was to perform a preliminary untargeted metabolomic characterization of menstrual blood, a novel biofluid, to identify environmental toxins present in the endometrium and evaluate the suitability of this sample type for exposome research. METHODS: Whole blood menstrual samples were collected from four women using a menstrual cup. Samples were analyzed for small molecules that include both environmental chemicals and endogenous metabolites using untargeted liquid chromatography with high-resolution mass spectrometry (LC-HRMS). Principal component analysis (PCA) and ANOVA was used to identify differences within and between individuals' menstrual blood metabolomic profiles, and the influence of the sample processing method. To assess the presence of environmental exposures, LC-HRMS chemical profiles were matched to the ToxCast chemical database, which includes 4557 commonly used commercial chemicals. Select compounds were confirmed by comparison to reference standards. RESULTS: PCA of metabolome profiles showed analysis of menstrual blood samples were highly reproducible, with high variability in detected metabolites between participants and low variability between analytical replicates of an individual's sample. Endogenous metabolites detected in menstrual blood samples achieved good coverage of the human blood metabolome. We found 1748 annotations for environmental chemicals, including suspected reproductive toxicants such as phenols, parabens, phthalates, and organochlorines. Storage temperature for the first 24 h did not significantly influence global metabolomic profiles. CONCLUSION: Our results show chemical exposures linked to reproductive toxicity and endocrine disruption are present in menstrual blood, a sampling medium for the endometrium.
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Metaboloma , Metabolômica , Cromatografia Líquida/métodos , Endométrio , Feminino , Substâncias Perigosas , Humanos , Espectrometria de Massas/métodos , Metabolômica/métodosRESUMO
Sepsis is a potentially life-threatening systemic inflammatory syndrome characterized by dysregulated host immunological responses to infection. Uncontrolled immune cell activation and exponential elevation in circulating cytokines can lead to sepsis, septic shock, multiple organ dysfunction syndrome, and death. Sepsis is associated with high re-hospitalization and recovery may be incomplete, with long term sequelae including post-sepsis syndrome. Consequently, sepsis continues to be a leading cause of morbidity and mortality across the world. In our recent review of human chorionic gonadotropin (hCG), we noted that its major properties including promotion of fertility, parturition, and lactation were described over a century ago. By contrast, the anti-inflammatory properties of this hormone have been recognized only more recently. Vasopressin, a hormone best known for its anti-diuretic effect, also has anti-inflammatory actions. Surprisingly, vasopressin's close cousin, oxytocin, has broader and more potent anti-inflammatory effects than vasopressin and a larger number of pre-clinical studies supporting its potential role in limiting sepsis-associated organ damage. This review explores possible links between oxytocin and related octapeptide hormones and sepsis-related modulation of pro-inflammatory and anti-inflammatory activities.
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Hormônios Peptídicos , Sepse , Anti-Inflamatórios/uso terapêutico , Feminino , Humanos , Ocitocina/uso terapêutico , Sepse/complicações , Sepse/tratamento farmacológico , VasopressinasRESUMO
OBJECTIVES: Oxytocin (OXT) is widely used to facilitate labor. However, little is known about the effects of perinatal OXT exposure on the developing brain. We investigated the effects of maternal OXT administration on gene expression in perinatal mouse brains. METHODS: Pregnant C57BL/6 mice were treated with saline or OXT at term (n=6-7/group). Dams and pups were euthanized on gestational day (GD) 18.5 after delivery by C-section. Another set of dams was treated with saline or OXT (n=6-7/group) and allowed to deliver naturally; pups were euthanized on postnatal day 9 (PND9). Perinatal/neonatal brain gene expression was determined using Illumina BeadChip Arrays and real time quantitative PCR. Differential gene expression analyses were performed. In addition, the effect of OXT on neurite outgrowth was assessed using PC12 cells. RESULTS: Distinct and sex-specific gene expression patterns were identified in offspring brains following maternal OXT administration at term. The microarray data showed that female GD18.5 brains exhibited more differential changes in gene expression compared to male GD18.5 brains. Specifically, Cnot4 and Frmd4a were significantly reduced by OXT exposure in male and female GD18.5 brains, whereas Mtap1b, Srsf11, and Syn2 were significantly reduced only in female GD18.5 brains. No significant microarray differences were observed in PND9 brains. By quantitative PCR, OXT exposure reduced Oxtr expression in female and male brains on GD18.5 and PND9, respectively. PC12 cell differentiation assays revealed that OXT induced neurite outgrowth. CONCLUSIONS: Prenatal OXT exposure induces sex-specific differential regulation of several nervous system-related genes and pathways with important neural functions in perinatal brains.
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Ocitocina , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ocitocina/farmacologia , GravidezRESUMO
Pre-clinical research advances our understanding of the vagus nerve-mediated regulation of immunity and clinical trials successfully utilize electrical vagus nerve stimulation in the treatment of patients with inflammatory disorders. This symbiotic relationship between pre-clinical and clinical research exploring the vagus nerve-based 'inflammatory reflex' has substantially contributed to establishing the field of bioelectronic medicine. Recent studies identify a crosstalk between the vagus nerve and other neural circuitries in controlling inflammation and delineate new neural immunoregulatory pathways. Here we outline current mechanistic insights into the role of vagal and non-vagal neural pathways in neuro-immune communication and inflammatory regulation. We also provide a timely overview of expanding opportunities for bioelectronic neuromodulation in the treatment of various inflammatory disorders.
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Neuroimunomodulação , Nervo Vago , Humanos , Imunidade , Inflamação , Nervo Vago/fisiologiaRESUMO
Sepsis continues to be a major cause of morbidity, mortality, and post-recovery disability in patients with a wide range of non-infectious and infectious inflammatory disorders, including COVID-19. The clinical onset of sepsis is often marked by the explosive release into the extracellular fluids of a multiplicity of host-derived cytokines and other pro-inflammatory hormone-like messengers from endogenous sources ("cytokine storm"). In patients with sepsis, therapies to counter the pro-inflammatory torrent, even when administered early, typically fall short. The major focus of our proposed essay is to promote pre-clinical studies with hCG (human chorionic gonadotropin) as a potential anti-inflammatory therapy for sepsis.
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Anti-Inflamatórios/uso terapêutico , Gonadotropina Coriônica/uso terapêutico , Peptídeos/uso terapêutico , Sepse/tratamento farmacológico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Bactérias/metabolismo , Gonadotropina Coriônica/química , Gonadotropina Coriônica/metabolismo , Síndrome da Liberação de Citocina/tratamento farmacológico , Glicoproteínas/química , Glicoproteínas/metabolismo , Humanos , Inflamação , Peptídeos/química , Peptídeos/metabolismoRESUMO
This case series reviews four critically ill patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [coronavirus disease 2019 (COVID-19)] suffering from pneumatosis intestinalis (PI) during their hospital admission. All patients received the biological agent tocilizumab (TCZ), an interleukin (IL)-6 antagonist, as an experimental treatment for COVID-19 before developing PI. COVID-19 and TCZ have been independently linked to PI risk, yet the cause of this relationship is unknown and under speculation. PI is a rare condition, defined as the presence of gas in the intestinal wall, and although its pathogenesis is poorly understood, intestinal ischemia is one of its causative agents. Based on COVID-19's association with vasculopathic and ischemic insults, and IL-6's protective role in intestinal epithelial ischemia-reperfusion injury, an adverse synergistic association of COVID-19 and TCZ can be proposed in the setting of PI. To our knowledge, this is the first published, single center, case series of pneumatosis intestinalis in COVID-19 patients who received tocilizumab therapy.
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After more than four decades of post-approval, cisplatin is still an important treatment for numerous cancers. However, acute kidney injury (AKI), defined as significant impairment of renal filtration as discussed below, is the major limiting side effect of cisplatin, occurring in approximately 30% of patients (25-33% after the first course). Cisplatin also damages the kidneys' ability to reabsorb magnesium in 40-100% of patients, with collateral health risks due to subsequent hypomagnesemia. Multiple methods and drugs have been proposed for preventing cisplatin-induced AKI, including saline infusion with or without mannitol, which has not always prevented AKI and has been found to activate a cellular stress response in renal tubular cells. While numerous reports and trials, as well as the National Comprehensive Cancer Network (NCCN), support premedication with magnesium and hydration, this practice has not been universally accepted. Many clinics administer intravenous magnesium (IV) only after identification of hypomagnesemia post-cisplatin treatment, thus placing patients at risk for AKI and chronic renal loss of magnesium. We present the following case report and additional supporting evidence identifying the immediate effect of IV magnesium prior to intraperitoneal cisplatin for cycle 4 because of documented hypomagnesemia resulting in normalization of oliguria, which had been experienced for the first three cycles. The patient subsequently requested and received IV magnesium before cisplatin for the next two cycles with continuation of normal urinary output. The effect of pretreatment with IV magnesium on urine output following cisplatin has not been previously reported and further supports pre-cisplatin administration. In addition, two recent meta-analyses of clinical trials and pre-clinical research are reviewed that demonstrate effectiveness of magnesium pretreatment to preventing AKI without reducing its chemotherapeutic efficacy. This case report with additional evidence supports the adoption of administration of 1-3 g IV magnesium before cisplatin as best practice to prevent cisplatin induced AKI and hypomagnesemia regardless of patient baseline serum magnesium levels.