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Atopic dermatitis (AD) is a widespread, recurrent, and chronic inflammatory skin condition that imposes a major burden on patients. Conventional treatments, such as corticosteroids, are associated with various side effects, underscoring the need for innovative therapeutic approaches. In this study, the possibility of using indole-3-acetic acid-loaded layered double hydroxides (IAA-LDHs) is evaluated as a novel treatment for AD. IAA is an auxin-class plant hormone with antioxidant and anti-inflammatory effects. Following the synthesis of IAA-LDH nanohybrids, their ability to induce M2-like macrophage polarization in macrophages obtained from mouse bone marrow is assessed. The antioxidant activity of IAA-LDH is quantified by assessing the decrease in intracellular reactive oxygen species levels. The anti-inflammatory and anti-atopic characteristics of IAA-LDH are evaluated in a mouse model of AD by examining the cutaneous tissues, immunological organs, and cells. The findings suggest that IAA-LDH has great therapeutic potential as a candidate for AD treatment based on its in vitro and in vivo modulation of AD immunology, enhancement of macrophage polarization, and antioxidant activity. This inorganic drug delivery technology represents a promising new avenue for the development of safe and effective AD treatments.
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BACKGROUND: Cardiac fibroblasts are the main non-myocyte population responsible for extracellular matrix (ECM) production. During perinatal development, fibroblast expansion coincides with the transition from hyperplastic to hypertrophic myocardial growth. Therefore, we investigated the consequences of fibroblast loss at the time of cardiomyocyte maturation by depleting fibroblasts in the perinatal mouse. METHODS AND RESULTS: We evaluated the microenvironment of the perinatal heart in the absence of fibroblasts and the potential functional impact of fibroblast loss in regulation of cardiomyocyte cell cycle arrest and binucleation. Cre-mediated expression of diphtheria toxin A in PDGFRα expressing cells immediately after birth eliminated 70-80% of the cardiac fibroblasts. At postnatal day 5, hearts lacking fibroblasts appeared similar to controls with normal morphology and comparable numbers of endothelial and smooth muscle cells, despite a pronounced reduction in fibrillar collagen. Immunoblotting and proteomic analysis of control and fibroblast-deficient hearts identified differential abundance of several ECM proteins. In addition, fibroblast loss decreased tissue stiffness and resulted in increased cardiomyocyte mitotic index, DNA synthesis, and cytokinesis. Moreover, decellularized matrix from fibroblast-deficient hearts promoted cardiomyocyte DNA replication. While cardiac architecture was not overtly affected by fibroblast reduction, few pups survived past postnatal day 11, suggesting an overall requirement for PDGFRα expressing fibroblasts. CONCLUSIONS: These studies demonstrate the key role of fibroblasts in matrix production and cardiomyocyte cross-talk during mouse perinatal heart maturation and revealed that fibroblast-derived ECM may modulate cardiomyocyte maturation in vivo. Neonatal depletion of fibroblasts demonstrated that although hearts can tolerate reduced ECM composition, fibroblast loss eventually leads to perinatal death as the approach simultaneously reduced fibroblast populations in other organs.
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Proteômica , Receptor alfa de Fator de Crescimento Derivado de Plaquetas , Animais , Matriz Extracelular/metabolismo , Feminino , Fibroblastos/metabolismo , Camundongos , Miócitos Cardíacos/metabolismo , Gravidez , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismoRESUMO
Transcription factor 21 (Tcf21) is a basic helix-loop-helix transcription factor required for mesenchymal development in several organs. Others have demonstrated that Tcf21 is expressed in embryonic lung mesenchyme and that loss of Tcf21 results in a pulmonary hypoplasia phenotype. Although recent single-cell transcriptome analysis has described multiple mesenchymal cell types in the lung, few have characterized the Tcf21 expressing population. To explore the Tcf21 mesenchymal lineage, we traced Tcf21-expressing cells during embryogenesis and in the adult. Our results showed that Tcf21 progenitor cells at embryonic day (E)11.5 generated a subpopulation of fibroblasts and lipofibroblasts and a limited number of smooth muscle cells. After E15.5, Tcf21 progenitor cells exclusively become lipofibroblasts and interstitial fibroblasts. Lipid metabolism genes were highly expressed in perinatal and adult Tcf21 lineage cells. Overexpression of Tcf21 in primary neonatal lung fibroblasts led to increases in intracellular neutral lipids, suggesting a regulatory role for Tcf21 in lipofibroblast function. Collectively, our results reveal that Tcf21 expression after E15.5 delineates the lipofibroblast and a population of interstitial fibroblasts. The Tcf21 inducible Cre mouse line provides a novel method for identifying and manipulating the lipofibroblast.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Pulmão/citologia , Pulmão/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular , Linhagem da Célula/genética , Células Cultivadas , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Idade Gestacional , Metabolismo dos Lipídeos/genética , Pulmão/embriologia , Masculino , Mesoderma/citologia , Mesoderma/embriologia , Mesoderma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , GravidezRESUMO
The involvement of neutrophils in the lungs during the recovery phase of coronavirus disease 2019 (COVID-19) is not well defined mainly due to the limited accessibility of lung tissues from COVID-19 survivors. The lack of an appropriate small animal model has affected the development of effective therapeutic strategies. We here developed a long COVID mouse model to study changes in neutrophil phenotype and association with lung injury. Our data shows persistent neutrophil recruitment and neutrophil extracellular trap formation in the lungs for up to 30 days post-infection which correlates with lung fibrosis and inflammation.
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COVID-19 , Modelos Animais de Doenças , Armadilhas Extracelulares , Pulmão , Neutrófilos , SARS-CoV-2 , Animais , Armadilhas Extracelulares/imunologia , COVID-19/imunologia , COVID-19/complicações , Camundongos , Neutrófilos/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Pulmão/patologia , Pulmão/imunologia , Pulmão/virologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/virologia , Lesão Pulmonar/patologia , Lesão Pulmonar/etiologia , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Infiltração de Neutrófilos/imunologia , Humanos , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Fibrose Pulmonar/etiologiaRESUMO
BACKGROUND: We analyzed trends in cancer incidence and regional disparities of eight major types of cancer in Korea. METHODS: This retrospective cohort study used the data of 17 cities/provinces from the Korea Central Cancer Registry (1999-2020) in South Korea. Age-standardized incidence rates (per 100,000 person-years), between-group variance (per 100,000 person-years)2, and annual percentage changes ( %) were calculated for the eight most common malignancies. Joinpoint regression was utilized to identify the points at which significant changes occur in cancer incidence or regional disparity trends over time to characterize these trends. RESULTS: The incidence of stomach cancer decreased as regional disparity decreased and that of colorectal cancer initially increased but recently declined, showing fluctuations in regional disparity. The incidence and regional disparity in liver cancer decreased. The incidence of lung cancer remained stable, with reduced regional disparities. The incidence of breast cancer rose with increasing regional disparity, whereas the incidence of cervical cancer decreased, accompanied by decreased regional disparity. A significant increase in prostate cancer was found, with initially reduced regional disparities but later showed a resurgence. The incidence of thyroid cancer fluctuated alongside variations in regional disparities. CONCLUSION: This study revealed cancer incidence and regional variations in each cancer type in Korea. More studies are needed to understand the underlying factors and potential interventions for reducing cancer incidence and addressing regional disparity.
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Neoplasias , Sistema de Registros , Humanos , República da Coreia/epidemiologia , Estudos Retrospectivos , Incidência , Masculino , Feminino , Neoplasias/epidemiologia , Sistema de Registros/estatística & dados numéricos , Pessoa de Meia-Idade , Disparidades nos Níveis de Saúde , Idoso , AdultoRESUMO
Background: In South Korea, the cancer incidence rate has increased by 56.5% from 2001 to 2021. Nevertheless, the 5-year cancer survival rate from 2017 to 2021 increased by 17.9% compared with that from 2001 to 2005. Cancer survival rates tend to decline with lower socioeconomic status, and variations exist in the survival rates among different cancer types. Analyzing socioeconomic patterns in the survival of patients with cancer can help identify high-risk groups and ensure that they benefit from interventions. Objective: The aim of this study was to analyze differences in survival rates among patients diagnosed with six types of cancer-stomach, colorectal, liver, breast, cervical, and lung cancers-based on socioeconomic status using Korean nationwide data. Methods: This study used the Korea Central Cancer Registry database linked to the National Health Information Database to follow up with patients diagnosed with cancer between 2014 and 2018 until December 31, 2021. Kaplan-Meier curves stratified by income status were generated, and log-rank tests were conducted for each cancer type to assess statistical significance. Hazard ratios with 95% CIs for any cause of overall survival were calculated using Cox proportional hazards regression models with the time since diagnosis. Results: The survival rates for the six different types of cancer were as follows: stomach cancer, 69.6% (96,404/138,462); colorectal cancer, 66.6% (83,406/125,156); liver cancer, 33.7% (23,860/70,712); lung cancer, 30.4% (33,203/109,116); breast cancer, 91.5% (90,730/99,159); and cervical cancer, 78% (12,930/16,580). When comparing the medical aid group to the highest income group, the hazard ratios were 1.72 (95% CI 1.66-1.79) for stomach cancer, 1.60 (95% CI 1.54-1.56) for colorectal cancer, 1.51 (95% CI 1.45-1.56) for liver cancer, 1.56 (95% CI 1.51-1.59) for lung cancer, 2.19 (95% CI 2.01-2.38) for breast cancer, and 1.65 (95% CI 1.46-1.87) for cervical cancer. A higher deprivation index and advanced diagnostic stage were associated with an increased risk of mortality. Conclusions: Socioeconomic status significantly mediates disparities in cancer survival in several cancer types. This effect is particularly pronounced in less fatal cancers such as breast cancer. Therefore, considering the type of cancer and socioeconomic factors, social and medical interventions such as early cancer detection and appropriate treatment are necessary for vulnerable populations.
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Neoplasias , Humanos , República da Coreia/epidemiologia , Feminino , Neoplasias/mortalidade , Neoplasias/epidemiologia , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Adulto , Idoso , Taxa de Sobrevida/tendências , Disparidades nos Níveis de Saúde , Fatores Socioeconômicos , Estudos de Coortes , Sistema de Registros , Classe Social , Disparidades Socioeconômicas em SaúdeRESUMO
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a family of chronic disorders along the gastrointestinal tract. Because of its idiopathic nature, IBD does not have a fundamental cure; current available therapies for IBD are limited to prolonged doses of immunomodulatory agents. While these treatments may reduce inflammation, limited therapeutic efficacy, inconsistency across patients, and adverse side effects from aggressive medications remain as major drawbacks. Recently, excessive production and accumulation of neutrophil extracellular traps (NETs) also known as NETosis have been identified to exacerbate inflammatory responses and induce further tissue damage in IBD. Such discovery invited many researchers to investigate NETs as a potential therapeutic target. DNase-I is a natural agent that can effectively destroy NETs and, therefore, potentially reduce NETs-induced inflammations even without the use of aggressive drugs. However, low stability and rapid clearance of DNase-I remain as major limitations for further therapeutic applications. In this research, polymeric nanozymes were fabricated to increase the delivery and therapeutic efficacy of DNase-I. DNase-I was immobilized on the surface of polymeric nanoparticles to maintain its enzymatic properties while extending its activity in the colon. Delivery of DNase-I using this platform allowed enhanced stability and prolonged activity of DNase-I with minimal toxicity. When administered to animal models of IBD, DNase-I nanozymes successfully alleviated various pathophysiological symptoms of IBD. More importantly, DNase-I nanozyme administration successfully attenuated neutrophil infiltration and NETosis in the colon compared to free DNase-I or mesalamine.
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Background: Cancer recurrence and metastasis are major contributors to treatment failure following tumor resection surgery. We developed a novel implantable drug delivery system utilizing glycol chitosan to address these issues. Glycol chitosan is a natural adjuvant, inducing dendritic cell activation to promote T helper 1 cell immune responses, macrophage activation, and cytokine production. Effective antigen production by dendritic cells initiates T-cell-mediated immune responses, aiding tumor growth control. Methods: In this study, we fabricated multifunctional methacrylated glycol chitosan (MGC) hydrogels with extended release of DNA/doxorubicin (DOX) complex for cancer immunotherapy. We constructed the resection model of breast cancer to verify the anticancer effects of MGC hydrogel with DNA/DOX complex. Results: This study demonstrated the potential of MGC hydrogel with extended release of DNA/DOX complex for local and efficient cancer therapy. The MGC hydrogel was implanted directly into the surgical site after tumor resection, activating tumor-related immune cells both locally and over a prolonged period of time through immune-reactive molecules. Conclusions: The MGC hydrogel effectively suppressed tumor recurrence and metastasis while enhancing immunotherapeutic efficacy and minimizing side effects. This biomaterial-based drug delivery system, combined with cancer immunotherapy, can substantial improve treatment outcomes and patient prognosis.
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The objective of this study is to investigate the correlation between the neighborhood deprivation index and survival rates of cancer patients in Korea. In this study, 5-year age-standardized survival rates of patients with cancer were determined using the National Cancer Cohort from 2014 to 2018 in Korea. The primary cancer sites were the stomach, colorectum, liver, lung, breast, cervix, prostate, and thyroid. Disparities were measured, and their impact on the overall survival rates was assessed using the Korean version of the Neighborhood Deprivation Index. Pearson's correlation coefficient was calculated to determine the strength of the correlation. The study cohort comprised 726,665 patients with cancer, of whom 50.7% were male. The predominant primary cancer sites were the stomach (n = 138,462), colorectum (n = 125,156), and thyroid gland (n = 120,886). Urban residents showed better survival outcomes than those situated in rural areas. The most deprived quartile had the lowest survival rate, while the least deprived quartile had the highest (p < 0.001). Most cancer types revealed significant correlations between neighborhood deprivation and 5-year age-standardized overall survival, with lung cancer showing the most substantial negative correlation (r = -0.510), followed by prostate cancer (r = -0.438). However, thyroid cancer showed only a marginal correlation (p = 0.069). The results of this study suggested that neighborhood deprivation is closely linked to disparities in overall survival across various types of cancer. A substantial negative correlation between the neighborhood deprivation index and all-cause mortality for lung and prostate cancer, as compared to breast and cervical cancers covered by the National Cancer Screening Program, may reinforce the need to address healthcare access and improve the early detection of cancer in socioeconomically deprived neighborhoods.
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BACKGROUND: Recent nationwide studies of disparities in cancer incidence by income are scarce in Korea. This study investigated such disparities in cancer incidence and the stage at cancer diagnosis across income groups in Korea. METHODS: This study utilized data from a national cancer database, specifically focusing on cases recorded in the year 2018. Income levels were categorized into quintiles according to the insurance premium paid in addition to the Medicaid benefit. The slope index of inequality (SII) and relative index of inequality (RII) were used to measure absolute and relative differences in cancer incidence by income. A multivariable logistic regression was performed to estimate the risk of a distant stage at cancer diagnosis. RESULTS: The total number of cases of incident cancer was 223,371 (men: 116,320, women: 107,051) with shares of the total of 29.5% (5Q), 20.4% (4Q), 16.0% (3Q), 13.5% (2Q), 15.6% (1Q), and 5% (Medicaid). The most common cancer type was thyroid cancer, followed by gastric and colorectal cancers. The age-standardized incidence rate for all cancers was lowest in the highest income group, but the SII was not statistically significant (SII: -35.7), and the RII was -0.07. Colorectal and cervical cancers had lower incidence rates for higher income groups, while thyroid and prostate cancers had higher incidence rates for higher income groups. The odds ratio for a distant stage at diagnosis for all cancers increased for lower income groups relative to 5Q. CONCLUSIONS: Disparities in cancer incidence in a Korean population differed by cancer type, and lower income was a significant predictor of a distant stage at diagnosis for cancers overall. These results emphasize the need for further study of the underlying causes of disparities in cancer incidence and the stage at diagnosis, as well as the need for interventions to mitigate these disparities.
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BACKGROUND: People living with HIV (PLWH) have higher rates of chronic kidney disease (CKD) compared with HIV-uninfected individuals. The pathogenesis of CKD in HIV remains poorly understood but is likely from a combination of various factors, such as traditional comorbidities, prolonged antiretroviral therapy, immune dysregulation, and direct HIV effect on the kidneys. We evaluated plasma galectin-3 (Gal-3), a circulating marker of fibrosis, and its association with renal function. METHODS: Estimated glomerular filtration rate (eGFR) was assessed by CKD-EPI. Plasma galectin-3 was obtained from banked specimens by ELISA. Factors associated with eGFR were analyzed using step-wise multiple linear regression. RESULTS: A total of 45 PLWH and 58 HIV-uninfected participants were included with similar demographic parameters. Among PLWH, majority had undetectable plasma HIV RNA (82.2%). Gal-3 was significantly higher in PLWH than in HIV-uninfected participants (6.4 [IQR 4.0, 8.5] ng/mL and 4.5 [IQR 2.3, 6.5] ng/mL, respectively; p = 0.020) while a trend towards lower eGFR was found in PLWH compared to the HIV-uninfected cohort (86.8 [IQR 71.3, 91.8] and 89.0 [IQR 78.6, 97.4] mL/min/1.73 m2, respectively; p = 0.071). In univariable analysis, HIV status was marginally associated with decreased eGFR (ß coefficient= -0.035, p = 0.051). In the final multivariable regression model adjusted for traditional risk factors of CKD, Gal-3 independently predicted a decrease in eGFR (unstandardized B= -0.008, p < 0.001) while HIV status did not demonstrate any significant association. CONCLUSION: Gal-3 was higher in PLWH compared with HIV-uninfected participants. In multivariable adjusted analyses, Gal-3, but not HIV status, was associated with decreased eGFR. The role of Gal-3 as a biomarker of kidney function needs to be further elucidated.
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Infecções por HIV , Insuficiência Renal Crônica , Humanos , Galectina 3 , Taxa de Filtração Glomerular/fisiologia , Infecções por HIV/complicações , Fatores de Risco , Insuficiência Renal Crônica/complicaçõesRESUMO
This study investigated the lay perception of inequalities in society, healthcare utilization, and health in Korea. We also examined the association between socioeconomic status (SES) and perception of inequalities. Data from an online survey on the perception of health and healthcare inequalities related to cancer conducted between October 19, 2021, and November 12, 2021, were used. Data of 3,769 participants aged 20 to 74 years from 17 provinces were analyzed. We examined the perceived level of inequalities according to SES or residential area using frequency analysis, a t-test or analysis of variance (ANOVA), multiple linear regression analysis, and multiple logistic regression analysis. The mean score for perception of social inequality was 5.99 [Standard Deviation (SD) = 1.95] and that for perception of healthcare utilization inequality was 4.75 (SD = 1.96). The perception rate of health inequality according to SES and residential area was approximately 59 % and 61 %, respectively. Higher the income level, lower the level of perception of social inequalities ß = -0.22, p < 0.01). Higher the education level, higher the level of perception of healthcare utilization inequalities (ß = 0.21, p < 0.01). Higher the education level, higher the level of perception of health inequalities according to SES or residential area [adjusted odds ratio (aOR): 2.33 (95 % CI: 1.48, 3.66); aOR: 2.73 (95 % CI: 1.73, 4.31)]. Socioeconomic inequalities were observed in the perception of inequalities in healthcare utilization and health. Policymakers should establish policies to bridge the gap between perceived healthcare utilization inequalities and health inequalities. Future research should investigate the perception of healthcare utilization and health inequalities.
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Platelets are anucleate cytoplasmic cell fragments that circulate in the blood, where they are involved in regulating hemostasis. Beyond their normal physiologic role, platelets have emerged as versatile effectors of immune response. During an infection, cell surface receptors enable platelets to recognize viruses, resulting in their activation. Activated platelets release biologically active molecules that further trigger host immune responses to protect the body against infection. Their impact on the immune response is also associated with the recruitment of circulating leukocytes to the site of infection. They can also aggregate with leukocytes, including lymphocytes, monocytes, and neutrophils, to immobilize pathogens and prevent viral dissemination. Despite their host protective role, platelets have also been shown to be associated with various pathophysiological processes. In this review, we will summarize platelet and HIV interactions during infection. We will also highlight and discuss platelet and platelet-derived mediators, how they interact with immune cells, and the multifaceted responsibilities of platelets in HIV infection. Furthermore, we will give an overview of non-AIDS comorbidities linked to platelet dysfunction and the impact of antiretroviral therapy on platelet function.
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Infecções por HIV , Humanos , Inflamação/metabolismo , Plaquetas/metabolismo , Hemostasia , LeucócitosRESUMO
Socioeconomic barriers to cancer screening exist at a regional level. The deprivation index is used to estimate socioeconomic gradients and health disparities across different geographical regions. We aimed to examine the impact of deprivation on breast cancer screening participation rates among South Korean women. Municipal breast cancer screening participation rates in women were extracted from the National Cancer Screening Information System and linked to the Korean version of the deprivation index constructed by the Korea Institute for Health and Social Affairs. A generalised linear mixed model was employed to investigate the association between the deprivation index and age-standardised breast cancer screening participation rates in 2005, 2012, and 2018. Participation rates increased gradually across all age groups from 2005 to 2018. Participants in their 60 s consistently had one of the highest participation rates (2005: 30.37%, 2012: 61.57%, 2018: 65.88%). In 2005, the most deprived quintile had a higher estimate of breast cancer screening participation than the least deprived quintile (2nd quintile; estimate: 1.044, p = 0.242, 3rd quintile; estimate: 1.153, p = 0.192, 4th quintile; estimate: 3.517, p = 0.001, 5th quintile; estimate: 6.913, p = < 0.0001). In 2012, the participation rate also increased as the level of deprivation increased. There were no statistically meaningful results in 2018. Regions with high deprivation have a higher participation rate in breast cancer screening. The role of health disparities in determining cancer outcomes among women in Korea requires further examination.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/prevenção & controle , Detecção Precoce de Câncer , República da Coreia/epidemiologia , Coreia (Geográfico) , Fatores SocioeconômicosRESUMO
Background: Monocytes and macrophages play a pivotal role in inflammation during acute SARS-CoV-2 infection. However, their contribution to the development of post-acute sequelae of SARS-CoV-2 infection (PASC) are not fully elucidated. Methods: A cross-sectional study was conducted comparing plasma cytokine and monocyte levels among three groups: participants with pulmonary PASC (PPASC) with a reduced predicted diffusing capacity for carbon monoxide [DLCOc, <80%; (PG)]; fully recovered from SARS-CoV-2 with no residual symptoms (recovered group, RG); and negative for SARS-CoV-2 (negative group, NG). The expressions of cytokines were measured in plasma of study cohort by Luminex assay. The percentages and numbers of monocyte subsets (classical, intermediate, and non-classical monocytes) and monocyte activation (defined by CD169 expression) were analyzed using flow cytometry analysis of peripheral blood mononuclear cells. Results: Plasma IL-1Ra levels were elevated but FGF levels were reduced in PG compared to NG. Circulating monocytes and three subsets were significantly higher in PG and RG compared to NG. PG and RG exhibited higher levels of CD169+ monocyte counts and higher CD169 expression was detected in intermediate and non-classical monocytes from RG and PG than that found in NG. Further correlation analysis with CD169+ monocyte subsets revealed that CD169+ intermediate monocytes negatively correlated with DLCOc%, and CD169+ non-classical monocytes positively correlated with IL-1α, IL-1ß, MIP-1α, Eotaxin, and IFN-γ. Conclusion: This study present evidence that COVID convalescents exhibit monocyte alteration beyond the acute COVID-19 infection period even in convalescents with no residual symptoms. Further, the results suggest that monocyte alteration and increased activated monocyte subsets may impact pulmonary function in COVID-19 convalescents. This observation will aid in understanding the immunopathologic feature of pulmonary PASC development, resolution, and subsequent therapeutic interventions.
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COVID-19 , Monócitos , Humanos , Monócitos/metabolismo , Leucócitos Mononucleares , Estudos Transversais , Síndrome de COVID-19 Pós-Aguda , COVID-19/patologia , SARS-CoV-2 , Citocinas/metabolismoRESUMO
Particulate matter (PM) exposure disrupts the skin barrier, causing cutaneous inflammation that may eventually contribute to the development of various skin diseases. Herein, we introduce anti-inflammatory artificial extracellular vesicles (AEVs) fabricated through cell extrusion using the biosurfactant PEGylated mannosylerythritol lipid (P-MEL), hereafter named AEVP-MEL. The P-MEL has anti-inflammatory abilities with demonstrated efficacy in inhibiting the secretion of pro-inflammatory mediators. Mechanistically, AEVP-MEL enhanced anti-inflammatory response by inhibiting the mitogen-activated protein kinase (MAPK) pathway and decreasing the release of inflammatory mediators such as reactive oxygen species (ROS), cyclooxygenase-2 (COX-2), and pro-inflammatory cytokines in human keratinocytes. Moreover, AEVP-MEL promoted increased expression levels of skin barrier proteins (e.g., involucrin, IVL) and water-proteins (e.g., aquaporin 3, AQP3). In vivo studies revealed that repeated PM exposure to intact skin resulted in cutaneous inflammatory responses, including increased skin thickness (hyperkeratosis) and mast cell infiltration. Importantly, our data showed that the AEVP-MEL treatment significantly restored immune homeostasis in the skin affected by PM-induced inflammation and enhanced the intrinsic skin barrier function. This study highlights the potential of the AEVP-MEL in promoting skin health against PM exposure and its promising implications for the prevention and treatment of PM-related skin disorders.
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Material Particulado , Pele , Humanos , Pele/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/uso terapêuticoRESUMO
Background: Although our understanding of the immunopathology and subsequent risk and severity of COVID-19 disease is evolving, a detailed account of immune responses that contribute to the long-term consequences of pulmonary complication in COVID-19 infection remain unclear. Few studies have detailed the immune and cytokine profiles associated with post-acute sequalae of SARS-CoV-2 infection with persistent pulmonary symptoms (PPASC). However, the dysregulation of the immune system that drives pulmonary sequelae in COVID-19 survivors and PASC sufferers remains largely unknown. Results: To characterize the immunological features of pulmonary PASC (PPASC), we performed droplet-based single-cell RNA sequencing to study the transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) from participants naïve to SARS-CoV-2 (Control) and infected with SARS-CoV-2 with chronic pulmonary symptoms (PPASC). We analyzed more than 34,139 PBMCs by integrating our dataset with previously reported control datasets (GSM4509024) cell distribution. In total, 11 distinct cell populations were identified based on the expression of canonical markers. The proportion of myeloid-lineage cells ([MLCs]; CD14 + /CD16 + monocytes and dendritic cells) was increased in PPASC compared to controls. MLCs from PPASC displayed up-regulation of genes associated with pulmonary symptoms/fibrosis, while glycolysis metabolism-related genes were downregulated. Similarly, pathway analysis showed that fibrosis- related ( VEGF , WNT , and SMAD ) and cell death pathways were up-regulated, but immune pathways were down-regulated in PPASC. In PPASC, we observed interactive VEGF ligand- receptor pairs among MLCs, and network modules in CD14 + (cluster 4) and CD16 + (Cluster 5) monocytes displayed a significant enrichment for biological pathways linked to adverse COVID- 19 outcomes, fibrosis, and angiogenesis. Further analysis revealed a distinct metabolic alteration in MLCs with a down-regulation of glycolysis/gluconeogenesis in PPASC compared to SARS- CoV-2 naïve samples. Conclusion: This study offers valuable insights into the immune response and cellular landscape in PPASC. The presence of elevated MLC levels and their corresponding gene signatures associated with fibrosis, immune response suppression, and altered metabolic states suggests their potential role as a driver of PPASC.
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While the protective role of neutrophil extracellular traps (NETs) in limiting human immunodeficiency virus (HIV) spread to susceptible cells has been documented, there is comparatively little insight into whether NET formation is harmful in people living with HIV (PLWH). To gain insight into neutrophil dysregulation and the pathological role of NETs in HIV, we examined expressions of NET-associated markers [cell-free DNA (cfDNA) and citrullinated histone H3 (CitH3)] in the plasmas from a cohort of the Hawaii Aging with HIV-cardiovascular and HIV-seronegative (HIV-) individuals. In a subset of participants, circulating low-density granulocyte (LDG) levels and their maturation and activation status were analyzed via flow cytometry. We demonstrated higher plasma levels of CitH3 in PLWH compared to HIV- individuals. LDGs from PLWH had heightened CD66b, but reduced CD16 expression. The percentages and counts of CD10+ LDGs were significantly decreased in PLWH. In addition, the CD16Lo LDG subsets were enriched in PLWH, compared to HIV- group, indicating that immature LDGs are increased in PLWH. Moreover, LDGs from PLWH exhibited significantly higher NET forming capacity. In summary, our study presents evidence that LDGs from PLWH on ART display an immature and altered phenotype with increased NET formation. Among PLWH, plasma NET levels as well as LDG parameters correlated with blood markers for inflammation and coagulation, suggesting that neutrophil activation and NETs may exert proinflammatory and coagulation effects. Our data provide insights into the pathologic role of LDGs at least in part mediated through NET formation in PLWH.
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Granulócitos , Infecções por HIV , Humanos , Histonas , Neutrófilos , EnvelhecimentoRESUMO
[This corrects the article DOI: 10.3389/fimmu.2022.1076724.].
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Background: Although our understanding of the immunopathology and subsequent risk and severity of COVID-19 disease is evolving, a detailed account of immune responses that contribute to the long-term consequences of pulmonary complications in COVID-19 infection remains unclear. Few studies have detailed the immune and cytokine profiles associated with post-acute sequelae of SARS-CoV-2 infection (PASC) with persistent pulmonary symptoms. The dysregulation of the immune system that drives pulmonary sequelae in COVID-19 survivors and PASC sufferers remains largely unknown. Results: To characterize the immunological features of pulmonary PASC (PPASC), we performed droplet-based single-cell RNA sequencing (scRNA-seq) to study the transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) from a participant naïve to SARS-CoV-2 (Control) (n=1) and infected with SARS-CoV-2 with chronic pulmonary symptoms (PPASC) (n=2). After integrating scRNA-seq data with a naïve participant from a published dataset, 11 distinct cell populations were identified based on the expression of canonical markers. The proportion of myeloid-lineage cells ([MLCs]; CD14+/CD16+monocytes, and dendritic cells) was increased in PPASC (n=2) compared to controls (n=2). MLCs from PPASC displayed up-regulation of genes associated with pulmonary symptoms/fibrosis, while glycolysis metabolism-related genes were downregulated. Similarly, pathway analysis showed that fibrosis-related (VEGF, WNT, and SMAD) and cell death pathways were up-regulated, but immune pathways were down-regulated in PPASC. Further comparison of PPASC with scRNA-seq data with Severe COVID-19 (n=4) data demonstrated enrichment of fibrotic transcriptional signatures. In PPASC, we observed interactive VEGF ligand-receptor pairs among MLCs, and network modules in CD14+ (cluster 4) and CD16+ (Cluster 5) monocytes displayed a significant enrichment for biological pathways linked to adverse COVID-19 outcomes, fibrosis, and angiogenesis. Further analysis revealed a distinct metabolic alteration in MLCs with a down-regulation of glycolysis/gluconeogenesis in PPASC compared to SARS-CoV-2 naïve samples. Conclusion: Analysis of a small scRNA-seq dataset demonstrated alterations in the immune response and cellular landscape in PPASC. The presence of elevated MLC levels and their corresponding gene signatures associated with fibrosis, immune response suppression, and altered metabolic states suggests a potential role in PPASC development.