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1.
Oxid Med Cell Longev ; 2023: 6144967, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36644578

RESUMO

Introduction: Obesity and metabolic syndrome (MetS) constitute a rapidly increasing health problem and contribute to the development of multiple comorbidities like acute and chronic kidney disease. Insulin resistance, inappropriate lipolysis, and excess of free fatty acids (FFAs) are associated with glomerulus hyperfiltration and atherosclerosis. The important component of MetS, oxidative stress, is also involved in the destabilization of kidney function and the progression of kidney injury. Natural polyphenols have the ability to reduce the harmful effect of reactive oxygen and nitrogen species (ROS/RNS). Extract derived from Punica granatum L. is rich in punicalagin that demonstrates positive effects in MetS and its associated diseases. The aim of the study was to investigate the effect of bioactive substances of pomegranate peel to kidney damage associated with the MetS. Methods: In this study, we compared biomarkers of oxidative stress in kidney tissue of adult male Zucker Diabetic Fatty (ZDF) rats with MetS and healthy controls that were treated with Punica granatum L. extract at a dose of 100 or 200 mg/kg. Additionally, we evaluated the effect of polyphenolic extract on kidney injury markers and remodeling. The concentration of ROS/RNS, oxLDL, glutathione (GSH), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), metalloproteinase 2 and 9 (MMP-2, MMP-9), and the activity of superoxide dismutase (SOD) and catalase (CAT) were measured. Results: The data showed significant differences in oxidative stress markers between treated and untreated MetS rats. ROS/RNS levels, oxLDL concentration, and SOD activity were lower, whereas CAT activity was higher in rats with MetS receiving polyphenolic extract. After administration of the extract, markers for kidney injury (NGAL, KIM-1) decreased. Conclusion: Our study confirmed the usefulness of pomegranate polyphenols in the treatment of MetS and the prevention of kidney damage. However, further, more detailed research is required to establish the mechanism of polyphenol protection.


Assuntos
Nefropatias , Síndrome Metabólica , Extratos Vegetais , Romã (Fruta) , Animais , Masculino , Ratos , Antioxidantes/farmacologia , Glutationa/metabolismo , Rim , Nefropatias/tratamento farmacológico , Lipocalina-2/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Estresse Oxidativo , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Polifenóis/metabolismo , Romã (Fruta)/química , Ratos Zucker , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
2.
FASEB J ; 37(1): e22701, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36520031

RESUMO

Calcification of the medial layer, inducing arterial stiffness, contributes significantly to cardiovascular mortality in patients with chronic kidney disease (CKD). Extracellular nucleotides block the mineralization of arteries by binding to purinergic receptors including the P2Y2 receptor. This study investigates whether deletion of the P2Y2 receptor influences the development of arterial media calcification in CKD mice. Animals were divided into: (i) wild type mice with normal renal function (control diet) (n = 8), (ii) P2Y2 R-/- mice with normal renal function (n = 8), (iii) wild type mice with CKD (n = 27), and (iv) P2Y2 R-/- mice with CKD (n = 22). To induce CKD, animals received an alternating (0.2-0.3%) adenine diet for 7 weeks. All CKD groups developed a similar degree of chronic renal failure as reflected by high serum creatinine and phosphorus levels. Also, the presence of CKD induced calcification in the heart and medial layer of the aortic wall. However, deletion of the P2Y2 receptor makes CKD mice more susceptible to the development of calcification in the heart and aorta (aortic calcium scores (median ± IQR), CKD-wild type: 0.34 ± 4.3 mg calcium/g wet tissue and CKD-P2Y2 R-/- : 4.0 ± 13.2 mg calcium/g wet tissue). As indicated by serum and aortic mRNA markers, this P2Y2 R-/- mediated increase in CKD-related arterial media calcification was associated with an elevation of calcification stimulators, including alkaline phosphatase and inflammatory molecules interleukin-6 and lipocalin 2. The P2Y2 receptor should be considered as an interesting therapeutic target for tackling CKD-related arterial media calcification.


Assuntos
Fosfatase Alcalina , Lipocalina-2 , Insuficiência Renal Crônica , Túnica Íntima , Calcificação Vascular , Animais , Camundongos , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Cálcio/metabolismo , Lipocalina-2/genética , Lipocalina-2/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Túnica Íntima/metabolismo , Túnica Íntima/patologia , Regulação para Cima , Calcificação Vascular/etiologia , Calcificação Vascular/genética , Calcificação Vascular/metabolismo
3.
Sci Rep ; 12(1): 22360, 2022 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-36572735

RESUMO

Diabetic nephropathy (DN) is a serious complicating factor in human type 2 diabetes mellitus (T2DM), and it commonly results in end-stage renal disease (ESRD) that requires kidney dialysis. Here, we report that the α7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 exerts a novel anti-inflammatory action to ameliorate DN, as studied using an inbred strain of Leprdb/db mice in which hyperglycemia and obesity co-exist owing to defective leptin receptor (Lepr) signaling. For this analysis, GTS-21 was administered to 10-12 week-old male and female mice as a 4 mg/kg intraperitoneal injection, twice-a-day, for 8 weeks. Kidney function and injury owing to DN were monitored by determination of plasma levels of BUN, creatinine, KIM-1 and NGAL. Histologic analysis of glomerular hypertrophy and mesangial matrix expansion were also used to assess DN in these mice. Concurrently, renal inflammation was assessed by measuring IL-6 and HMGB1, while also quantifying renal cell apoptosis, and apoptotic signaling pathways. We found that Leprdb/db mice exhibited increased markers of BUN, creatinine, NGAL, KIM-1, IL-6, cytochrome C, and HMGB-1. These abnormalities were also accompanied by histologic kidney injury (mesangial matrix expansion and apoptosis). Remarkably, all such pathologies were significantly reduced by GTS-21. Collectively, our results provide new evidence that the α7nAChR agonist GTS-21 has the ability to attenuate diabetes-induced kidney injury. Additional studies are warranted to further investigate the involvement of the vagal cholinergic anti-inflammatory reflex pathway (CAP) in ameliorating diabetic nephropathy.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Animais , Feminino , Masculino , Camundongos , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Creatinina/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/patologia , Interleucina-6/metabolismo , Rim/metabolismo , Lipocalina-2/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Receptores para Leptina/genética , Receptores para Leptina/metabolismo
4.
Int J Mol Sci ; 23(24)2022 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-36555403

RESUMO

JAK/STAT plays a key role in regulating uropathogenic Escherichia coli (UPEC) infection in urothelial cells, probably via antimicrobial peptide (AMP) production, in diabetic patients with urinary tract infections. Whether multiple pathways regulate AMPs, especially lipid-carrying protein-2 (LCN2), to achieve a vital effect is unknown. We investigated the effects of an LCN2 pretreatment on the regulation of the JAK/STAT pathway in a high-glucose environment using a bladder cell model with GFP-UPEC and phycoerythrin-labeled TLR-4, STAT1, and STAT3. Pretreatment with 5 or 25 µg/mL LCN2 for 24 h dose-dependently suppressed UPEC infections in bladder cells. TLR-4, STAT1, and STAT3 expression were dose-dependently downregulated after LCN2 pretreatment. The LCN2-mediated alleviation of UPEC infection in a high-glucose environment downregulated TLR-4 and the JAK/STAT transduction pathway and decreased the UPEC-induced secretion of exogenous inflammatory interleukin (IL)-6 and IL-8. Our study provides evidence that LCN2 can alleviate UPEC infection in bladder epithelial cells by decreasing JAK/STAT pathway activation in a high-glucose environment. LCN2 dose-dependently inhibits UPEC infection via TLR-4 expression and JAK/STAT pathway modulation. These findings may provide a rationale for targeting LCN2/TLR-4/JAK/STAT regulation in bacterial cystitis treatment. Further studies should explore specific mechanisms by which the LCN2, TLR-4, and JAK/STAT pathways participate in UPEC-induced inflammation to facilitate the development of effective therapies for cystitis.


Assuntos
Cistite , Infecções por Escherichia coli , Infecções Urinárias , Escherichia coli Uropatogênica , Humanos , Bexiga Urinária/metabolismo , Peptídeos Antimicrobianos , Janus Quinases/metabolismo , Receptor 4 Toll-Like/metabolismo , Transdução de Sinais , Fatores de Transcrição STAT/metabolismo , Infecções Urinárias/microbiologia , Cistite/tratamento farmacológico , Cistite/metabolismo , Infecções por Escherichia coli/microbiologia , Células Epiteliais/metabolismo , Glucose/metabolismo , Lipocalina-2/metabolismo
5.
Front Endocrinol (Lausanne) ; 13: 975724, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36440213

RESUMO

This study explored the possible connection between the insulin resistance-targeting protein adipokine lipocalin-2 (LCN-2) and NF-κB signaling pathway in the inflammatory microenvironment in PCOS-IR model rats to determine the pharmacological mechanism of modified Cangfu Daotan decoction (MCDD) intervention for PCOS-IR. We used a high-fat diet (42 days) combined with letrozole (1 mg/kg/day, 42 days) to establish a PCOS-IR rat model. From the third week after modeling, the rats were given continuous administration of MCDD (high dose with 31.68 g/kg, medium dose with 15.84 g/kg, and low dose with 7.92 g/kg) for 28 days. Serum, ovarian tissue, liver, and adipose tissue were collected after the last gavage. Enzyme-linked immunosorbent assay, hematoxylin-eosin (HE) staining, Masson staining, qRT-PCR, and Western blot experiments were performed to detect various indicators. Our results showed that MCDD could reduce body weight and abdominal fat weight; restore normal estrous cycle and ovarian function; alleviate fatty liver; regulate HOMA-IR and OGTT index; reduce serum inflammatory factor levels, LCN-2 level, and gene expression; and regulate the insulin signal transduction and NF-κB pathways in PCOS-IR rats. Thus, MCDD may play a role in improving ovarian function in PCOS-IR rats by downregulating NF-κB/LCN-2 proteins and upregulating the gene expression of Insr/Irs-1/Glut4 in the insulin signaling pathway in the inflammatory environment.


Assuntos
Resistência à Insulina , Síndrome do Ovário Policístico , Humanos , Feminino , Ratos , Animais , Resistência à Insulina/genética , NF-kappa B/metabolismo , Lipocalina-2/metabolismo , Transdução de Sinais , Insulina/metabolismo , Microambiente Tumoral
6.
Front Endocrinol (Lausanne) ; 13: 1006790, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36387895

RESUMO

In recent studies, primary aldosteronism (PA) has been reported as the most common etiology for secondary hypertension of endocrine origin, accounting for approximately 10% of cases. In PA, excess aldosterone production can lead to deleterious effects at the cardiovascular (CV) and renal levels by activating mineralocorticoid receptors, which involves an increase in pro-inflammatory and pro-fibrotic mediators. Among these mediators, neutrophil gelatinase-associated lipocalin (NGAL), a secretion glycoprotein belonging to the lipocalin superfamily, has been closely linked to CV and renal damage in several pathological conditions. Because NGAL can be detected in biofluids such as plasma and urine, it has been proposed as a damage biomarker for target tissues and has also been studied for its role in hypertension and associated with PA. NGAL is produced by many different cell types, can be carried on extracellular vesicles, and is modulated by microRNAs, which would support its use as a biomarker for endocrine hypertension due to PA. Over the last decade, studies have shown that NGAL is necessary for the development of aldosterone-induced hypertension and that is associated with end-organ damage. In addition, it has been proposed that some mechanisms are dependent on the activation of immune cells, such as dendritic cells and macrophages, where the release of specific cytokines (i.e., interleukin [IL]-23) or chemokines (i.e., CCL-5) induced by aldosterone would depend on NGAL. Subsequently, this activates the T helper (Th) lymphocytes, such as Th17 and Th2, resulting in CV and renal fibrosis due to the high aldosterone levels. Although the immune system has been closely associated with essential hypertension, its participation in endocrine hypertension has not been fully elucidated. This review discusses the link between NGAL and endocrine hypertension, particularly in the context of PA, and their possible regulators and mechanisms, with a focus on its role as an immunomodulator.


Assuntos
Doenças das Glândulas Suprarrenais , Hipertensão , Humanos , Lipocalina-2/metabolismo , Aldosterona , Hipertensão/etiologia , Fatores Imunológicos , Fibrose , Biomarcadores
7.
Mol Med Rep ; 26(6)2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36263611

RESUMO

Lipocalin 2 (LCN2) is highly expressed in several infectious and inflammatory disorders. However, the expression level and underlying mechanism of LCN2 in inflammatory bowel disease (IBD) are poorly understood. The current study used murine IBD models and LPS­activated macrophages to elucidate the role of LCN2 in IBD pathogenesis. The levels of LCN2 protein and concentration were confirmed to be much higher in the colons of colitis­induced mice compared with healthy mice using immunohistochemistry, western blotting and ELISA assay. In vitro, the level of LCN2 in RAW264.7 macrophages increased significantly following LPS stimulation and diminished markedly upon using NF­κB­specific inhibitors. Assembly of the NOD­, LRR­, and pyrin domain­containing protein 3 (NLRP3) inflammasome was inhibited when LCN2 expression was knocked down, as evidenced by decreased NLRP3, ASC­1 and caspase­1 activation. Furthermore, secretion and maturation of IL­1ß was attenuated when LCN2 was silenced in LPS­stimulated macrophages. Together, these results suggested that LCN2 directly upregulated the NLRP3 inflammasome complex via NF­κB activation in response to stimulating macrophages with LPS, and that it acted as a pro­inflammatory regulator in macrophage activation modulated by NF­κB activation. Overall, LCN2 may serve as a promising target for the prevention and treatment of IBD.


Assuntos
Inflamassomos , Doenças Inflamatórias Intestinais , Camundongos , Animais , Inflamassomos/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Lipopolissacarídeos/farmacologia , Lipocalina-2/genética , Lipocalina-2/metabolismo , Camundongos Endogâmicos NOD , Macrófagos/metabolismo , Caspases/metabolismo , Doenças Inflamatórias Intestinais/metabolismo
8.
Anal Chim Acta ; 1233: 340515, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36283789

RESUMO

Sensitive and selective detection of neutrophil gelatinase-associated lipocalin (NGAL) is critical for the prediction and early diagnosis of acute renal injury. In this work, the establishment of an aptamer-based, highly sensitive and label-free method for detecting NGAL in diluted human serums via metal ion-dependent DNAzyme- and exonuclease III (Exo III)-triggered recycling signal amplification cascades is described. NGAL binds with the aptamer strands in the DNAzyme/aptamer duplexes and results in the liberation of the metal ion-dependent DNAzyme sequences to cleave the hairpin signal probes on the electrode to liberate the G-quadruplex and intermediate strands. The released intermediate strands further complement with the DNAzyme/aptamer duplexes to form favorable substrate for Exo III, which digests the duplexes to release the DNAzyme strands to initiate the cascaded recycling cycles for the yield of plenty of G-quadruplex strands. Hemin can associate with G-quadruplex strands to produce many G-quadruplex/hemin complexes and electrochemical reduction of hemin thus generates highly amplified current for detecting NGAL with the detection limit of 4.45 ng mL-1. Such biosensor also shows high selectivity and can be utilized for monitoring NGAL spiked in diluted serum, indicating its extension potential for detecting various protein biomarkers with different aptamers for disease diagnosis.


Assuntos
Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , DNA Catalítico , Quadruplex G , Humanos , DNA Catalítico/química , Hemina/química , Lipocalina-2/metabolismo , Técnicas Biossensoriais/métodos , Limite de Detecção , Técnicas Eletroquímicas/métodos , Aptâmeros de Nucleotídeos/química
9.
Sci Adv ; 8(41): eabo5224, 2022 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-36223471

RESUMO

Despite abundant research demonstrating that platelets can promote tumor cell metastasis, whether primary tumors affect platelet-producing megakaryocytes remains understudied. In this study, we used a spontaneous murine model of breast cancer to show that tumor burden reduced megakaryocyte number and size and disrupted polyploidization. Single-cell RNA sequencing demonstrated that megakaryocytes from tumor-bearing mice exhibit a pro-inflammatory phenotype, epitomized by increased Ctsg, Lcn2, S100a8, and S100a9 transcripts. Protein S100A8/A9 and lipocalin-2 levels were also increased in platelets, suggesting that tumor-induced alterations to megakaryocytes are passed on to their platelet progeny, which promoted in vitro tumor cell invasion and tumor cell lung colonization to a greater extent than platelets from wild-type animals. Our study is the first to demonstrate breast cancer-induced alterations in megakaryocytes, leading to qualitative changes in platelet content that may feedback to promote tumor metastasis.


Assuntos
Megacariócitos , Neoplasias , Animais , Plaquetas/metabolismo , Catepsina G/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Lipocalina-2/metabolismo , Camundongos , Neoplasias/metabolismo
10.
Front Endocrinol (Lausanne) ; 13: 973962, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36187125

RESUMO

Purpose: This study compared the changes in tear inflammatory cytokine levels after intense pulsed light (IPL) combined with meibomian gland expression (MGX) (IPL group) and instant warm compresses combined with MGX (physiotherapy group) as treatments for meibomian gland dysfunction (MGD)-related dry eye disease (DED) to explore their similarities and differences in therapeutic mechanisms. Methods: This study was a post-hoc analysis of a randomized controlled trial. Thirteen patients with MGD-related DED were enrolled in each group and received three treatments correspondingly with 3-week intervals. The levels of 20 tear cytokines, namely, TNF-α, IL-6, MMP-9, CXCL8/IL-8, CXCL10/IP-10, IL-10, EGF, IL-6R, IL-1ß, IFN-γ, lactoferrin, Fas ligand, IL-17A, LT-α, S100A9, LCN2/NGAL, IL-13, IL-12/IL-23p40, Fas, and CCL11/Eotaxin, were measured at baseline, before the second and third treatments, and 3 weeks after the third treatment. The primary outcome was the difference in cytokine levels between baseline and the last measurement, and the trends were analyzed at each measurement point. Results: At the last measurement, a significant decrease was observed in all tear cytokines for both IPL and physiotherapy groups compared with baseline. The IPL group showed greater reductions in IL-6, IL-6R, IL-1ß, IL-13, and CCL11/Eotaxin than the physiotherapy group. TNF-α, CXCL8/IL-8, CXCL10/IP-10, IL-10, EGF, IL-1ß, IFN-γ, and Lipocalin-2/NGAL levels continued to decrease with treatment time. Important interactions were found in the changes of IL-6 and IL-13 levels, where the levels first decreased and then slightly increased in the physiotherapy group after treatment, while they continued to decrease in the IPL group. Conclusions: The mechanisms of IPL and physiotherapy in treating MGD-related DED were both associated with reducing inflammation, and the superiority of IPL could be attributed to its better inhibitory effect on inflammatory cytokines like IL-6. In addition, several cytokines were on a downward trend during treatment, suggesting that the vicious cycle of DED was suppressed.


Assuntos
Síndromes do Olho Seco , Disfunção da Glândula Tarsal , Quimiocina CXCL10/metabolismo , Citocinas/metabolismo , Síndromes do Olho Seco/metabolismo , Síndromes do Olho Seco/terapia , Fator de Crescimento Epidérmico/metabolismo , Proteína Ligante Fas/metabolismo , Humanos , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Interleucina-13/metabolismo , Interleucina-17 , Interleucina-6 , Interleucina-8/metabolismo , Lactoferrina/metabolismo , Lipocalina-2/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Disfunção da Glândula Tarsal/terapia , Glândulas Tarsais/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
Int Immunopharmacol ; 112: 109264, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36183679

RESUMO

Krüppel-like factor 2 (KLF2) and NLR family pyrin domain containing 3 (NALP3) are important regulators of macrophage activation in the context of various pathological conditions. NALP3 also plays an important role in the maturation of IL-1 ß which is central to the pathogenesis of acute oxalate nephropathy. The functional role of KLF2 and regulation of both KLF2 and NALP3 in the pathogenesis of acute oxalate nephropathy is comparably less studied. Here, we explored the regulation of KLF2 and NALP3 by Histone deacetylase 5 (HDAC5) in oxalate crystals stimulated macrophages, and in the pathogenesis of acute oxalate nephropathy in mice. We observed upregulated expression of HDAC5 along with IL-1ß, Caspase1, and NALP3, while the expression of KLF2 was downregulated in stimulated macrophages and in the renal tissue of mice with acute oxalate nephropathy. We formulated chitosan HDAC5 siRNA nanoparticles to deliver the siRNA in in-vitro and in-vivo settings. siHDAC5 treated cells exhibited decreased expression of IL-1ß, and TNF-α in the supernatant, and reduced expression of NALP3, Pro-caspase1, active caspase1, Pro-IL-1ß, and IL-1ß in cell lysate. Concurrently, the expression of KLF2 was upregulated in HDAC5 depleted cells upon stimulation with crystals. Mice treated with siHDAC5 nanoparticles showed protection against renal impairment with improved renal function (plasma BUN and creatinine levels), reduced inflammation (IL-1ß expression), reduced accumulation of neutrophils, reduced tubular injury, reduced acute renal injury markers (KIM-1, NGAL-1), reduced expression of NALP3, Pro-caspase1, active caspase1, Pro-IL-1ß, and IL-1ß. Whereas, the expression of KLF2 was significantly upregulated by depletion of HDAC5 in mice.


Assuntos
Injúria Renal Aguda , Quitosana , Animais , Camundongos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/genética , Injúria Renal Aguda/terapia , Creatinina , Modelos Animais de Doenças , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Lipocalina-2/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Oxalatos , Interferência de RNA , RNA Interferente Pequeno , Fatores de Transcrição/genética , Fator de Necrose Tumoral alfa/metabolismo
12.
PLoS Pathog ; 18(9): e1010809, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36054235

RESUMO

Acinetobacter baumannii is an opportunistic pathogen and an emerging global health threat. Within healthcare settings, major presentations of A. baumannii include bloodstream infections and ventilator-associated pneumonia. The increased prevalence of ventilated patients during the COVID-19 pandemic has led to a rise in secondary bacterial pneumonia caused by multidrug resistant (MDR) A. baumannii. Additionally, due to its MDR status and the lack of antimicrobial drugs in the development pipeline, the World Health Organization has designated carbapenem-resistant A. baumannii to be its priority critical pathogen for the development of novel therapeutics. To better inform the design of new treatment options, a comprehensive understanding of how the host contains A. baumannii infection is required. Here, we investigate the innate immune response to A. baumannii by assessing the impact of infection on host gene expression using NanoString technology. The transcriptional profile observed in the A. baumannii infected host is characteristic of Gram-negative bacteremia and reveals expression patterns consistent with the induction of nutritional immunity, a process by which the host exploits the availability of essential nutrient metals to curtail bacterial proliferation. The gene encoding for lipocalin-2 (Lcn2), a siderophore sequestering protein, was the most highly upregulated during A. baumannii bacteremia, of the targets assessed, and corresponds to robust LCN2 expression in tissues. Lcn2-/- mice exhibited distinct organ-specific gene expression changes including increased transcription of genes involved in metal sequestration, such as S100A8 and S100A9, suggesting a potential compensatory mechanism to perturbed metal homeostasis. In vitro, LCN2 inhibits the iron-dependent growth of A. baumannii and induces iron-regulated gene expression. To elucidate the role of LCN2 in infection, WT and Lcn2-/- mice were infected with A. baumannii using both bacteremia and pneumonia models. LCN2 was not required to control bacterial growth during bacteremia but was protective against mortality. In contrast, during pneumonia Lcn2-/- mice had increased bacterial burdens in all organs evaluated, suggesting that LCN2 plays an important role in inhibiting the survival and dissemination of A. baumannii. The control of A. baumannii infection by LCN2 is likely multifactorial, and our results suggest that impairment of iron acquisition by the pathogen is a contributing factor. Modulation of LCN2 expression or modifying the structure of LCN2 to expand upon its ability to sequester siderophores may thus represent feasible avenues for therapeutic development against this pathogen.


Assuntos
Infecções por Acinetobacter , Acinetobacter baumannii , Bacteriemia , COVID-19 , Pneumonia Bacteriana , Acinetobacter baumannii/genética , Acinetobacter baumannii/metabolismo , Animais , Carbapenêmicos/farmacologia , Humanos , Imunidade Inata , Ferro/metabolismo , Lipocalina-2/genética , Lipocalina-2/metabolismo , Camundongos , Pandemias , Sideróforos/metabolismo
13.
Biomed Pharmacother ; 153: 113415, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076483

RESUMO

We propose the use of a peripheral blood mononuclear cell therapy based on cell NGAL release to be used in the clinical setting for acute kidney injury (AKI) and the derived fibrosis. First, we designed a procedure whereby PBMC overexpress NGAL and anti-inflammatory agents when subjected to repetitive anoxia/reoxygenation (PBMC (A/R)). Using an in vivo AKI model, we observed that PBMC(A/R) reduces BUN and creatinine levels in blood and inflammation, enhances anti-inflammation, induces proliferation of tubular epithelial cells and reduces AKI-induced fibrosis. Flow cytometry analysis evidenced that monocytes are the only cells accumulated in the injured kidney and phenotype analysis of freshly isolated kidney macrophages, revealed that the healing phenotype is maintained the time needed for recovery. NGAL release from PBMC(A/R) determines the beneficial effect of the therapy since administration of a NGAL antibody previous to the therapy or injection of PBMC(A/R) obtained from NGAL KO animals abolished the beneficial effects. CD11b-NGAL positive cells were enhanced in tissue after PBMC (A/R) therapy and were produced by the injected monocytes. In an in vitro model with tubular epithelial cells (NRK52e) we proved that NGAL release by PBMC(A/R) induced epithelial proliferation and activation of PI3K/Akt pathway.


Assuntos
Injúria Renal Aguda , Leucócitos Mononucleares , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Animais , Biomarcadores , Fibrose , Leucócitos Mononucleares/metabolismo , Lipocalina-2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo
14.
Ecotoxicol Environ Saf ; 245: 114118, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36174321

RESUMO

Mori fructus aqueous extracts (MFAEs) have been used as a traditional Chinese medicine for thousands of years with the function of strengthening the liver and tonifying the kidney. However, its inner mechanism to alleviative renal injury is unclear. To investigate the attenuation of MFAEs on nephrotoxicity and uncover its potential molecular mechanism, we established a nephrotoxicity model induced by carbon tetrachloride (CCl4). The mice were randomly divided into control group, CCl4 model group (10% CCl4), CCl4 + low and high MFAEs groups (10% CCl4 + 100 mg/kg and 200 mg/kg MFAEs). We found that MFAEs decreased the kidney index of mice, restored the pathological changes of renal structure induced by CCl4, reduced cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (Kim-1) blood urea nitrogen and creatinine contents in serum, promoted the nuclear transportation of Nrf2 (nuclear factor erythroid derived 2 like 2), elevated the expression of HO-1 (heme oxygenase 1), GPX4 (glutathione peroxidase 4), SLC7A11 (solute carrier family 7 member 11), ZO-1 (zonula occludens-1) and Occludin, suppressed the expression of Keap1 (kelch-like ECH-associated protein 1), HMGB1 (High Mobility Group Protein 1), ACSL4 (acyl-CoA synthetase long chain family member 4) and TXNIP (thioredoxin interacting protein), upregulated the flora of Akkermansia, Anaerotruncus, Clostridium_sensu_stricto, Ihubacter, Alcaligenes, Dysosmobacter, and downregulated the flora of Clostridium_XlVa, Helicobacter, Paramuribaculum. Overlapped with Disbiome database, Clostridium_XlVa, Akkermansia and Anaerotruncus may be the potential genera treated with renal injury. It indicated that MFAEs could ameliorate kidney injury caused by CCl4 via Nrf2 signaling.


Assuntos
Microbioma Gastrointestinal , Proteína HMGB1 , Animais , Tetracloreto de Carbono/metabolismo , Tetracloreto de Carbono/toxicidade , Coenzima A/metabolismo , Creatinina , Cistatina C/metabolismo , Proteína HMGB1/metabolismo , Heme Oxigenase-1/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Rim/metabolismo , Ligases/metabolismo , Lipocalina-2/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ocludina/metabolismo , Estresse Oxidativo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Tiorredoxinas/metabolismo
15.
Basic Clin Pharmacol Toxicol ; 131(5): 355-363, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35971882

RESUMO

Copper and copper alloys have antimicrobial activity through the rapid contact killing of viruses, bacteria and yeasts on their surface. Dysregulation of host microbiota can contribute to the pathogenesis of inflammatory diseases such as obesity, diabetes and cardiovascular disease. Anecdotal evidence noted improved overall well-being in individuals sleeping on copper-containing fabric bedding. We hypothesized that the beneficial effect of copper-infused fabric bedding on cardiometabolic health is linked to changes in gut microbiota composition. This study utilized a mouse model of diet-induced obesity to assess the beneficial effects of copper-infused fabric bedding on metabolic health. Body composition, inflammatory markers, metabolic and cardiovascular status and changes in the faecal microbiota composition were evaluated for up to 2 months in mice fed with a normal chow diet or high fat high cholesterol diet in the presence of bedding made with and without copper-infused fabric. Results showed that mice subjected to diet-induced obesity and housed in cages with copper-infused fabric liner displayed less body weight gain than mice in cages with control fabric. Mice housed with copper-infused fabric also displayed improved glucose tolerance and reduced inflammation biomarker lipocalin-2. We also observed a beneficial shift in gut bacterial composition of obese mice housed with copper fabric bedding. Taken in conjunction, our study provides direct animal-based evidence supporting the beneficial effects of copper fabric on metabolic health.


Assuntos
Anti-Infecciosos , Microbioma Gastrointestinal , Resistência à Insulina , Ligas/metabolismo , Ligas/farmacologia , Animais , Biomarcadores/metabolismo , Colesterol , Cobre/metabolismo , Cobre/farmacologia , Dieta Hiperlipídica , Glucose/metabolismo , Lipocalina-2/metabolismo , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo
16.
Metabolism ; 136: 155293, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35995279

RESUMO

Diabetic retinopathy (DR) is one of the leading causes of severe visual impairment worldwide. However, the role of adaptive immune inflammation driven by microglia/macrophages in DR is not yet well elucidated. Kdm6a is a histone demethylase that removes the trimethyl groups of histones H3K27 and plays important biological roles in activating target genes. To elucidate the role of Kdm6a in microglia/macrophages in diabetic retinas, we established diabetic animal models with conditional knockout mice to investigate the impacts of Kdm6a deficiency. The RNA-seq analysis, mass spectrum examination, immunohistochemistry and detection of enzyme activities were used to elucidate the effect of Kdm6a deletion on gene transcription in microglia/macrophages. The expression of Kdm6a was increased in the retinas of diabetic mice compared to the control group. Loss of Kdm6a in microglia/macrophages ameliorated the diabetes-induced retinal thickness decrease, inflammation, and visual impairment. Kdm6a in microglia/macrophages regulated Lcn2 expression in a demethylase activity-dependent manner and inhibited glycolysis progression in photoreceptor cells through Lcn2. These results suggest that Kdm6a in microglia/macrophages aggravated diabetic retinopathy by promoting the expression of Lcn2 and impairing glycolysis progression in photoreceptor cells.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Histona Desmetilases , Lipocalina-2 , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Retinopatia Diabética/genética , Histona Desmetilases/genética , Histonas/metabolismo , Inflamação/genética , Inflamação/metabolismo , Lipocalina-2/genética , Lipocalina-2/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Microglia/metabolismo , Células Fotorreceptoras/metabolismo
17.
Nat Rev Endocrinol ; 18(11): 683-698, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35986176

RESUMO

Iron is critical for the appearance and maintenance of life on Earth. Almost all organisms compete or cooperate for iron acquisition, demonstrating the importance of this essential element for the biological and physiological processes that are key for the preservation of metabolic homeostasis. In humans and other mammals, the bidirectional interactions between the bacterial component of the gut microbiota and the host for iron acquisition shape both host and microbiota metabolism. Bacterial functions influence host iron absorption, whereas the intake of iron, iron deficiency and iron excess in the host affect bacterial biodiversity, taxonomy and function, resulting in changes in bacterial virulence. These consequences of the host-microbial crosstalk affect systemic levels of iron, its storage in different tissues and host glucose metabolism. At the interface between the host and the microbiota, alterations in the host innate immune system and in circulating soluble factors that regulate iron (that is, hepcidin, lipocalin 2 and lactoferrin) are associated with metabolic disease. In fact, patients with obesity-associated metabolic dysfunction and insulin resistance exhibit dysregulation in iron homeostasis and alterations in their gut microbiota profile. From an evolutionary point of view, the pursuit of two important nutrients - glucose and iron - has probably driven human evolution towards the most efficient pathways and genes for human survival and health.


Assuntos
Ferro , Microbiota , Animais , Bactérias/metabolismo , Glucose/metabolismo , Hepcidinas/metabolismo , Humanos , Ferro/metabolismo , Lactoferrina/metabolismo , Lipocalina-2/metabolismo
18.
Sci Rep ; 12(1): 13905, 2022 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-35974137

RESUMO

In the current world, a major challenge to diagnose environmental enteric dysfunction (EED) is the lack of validated non-invasive biomarkers. Intestine derived molecules, including intestinal fatty acid binding protein (I-FABP), trefoil factor-3 (TFF3), lactoferrin, lipocalin-2 (LCN2), and mucin-2, have been reported as indicators of intestinal inflammation and gut health. Therefore, we aimed to investigate the levels of these bio-molecules as biomarkers of EED among under-2 children in Bangladesh. A total of 140 children were recruited in a case-control design. All the biomarkers were measured by ELISA. Spearman's rank correlation was performed to see the correlation between the biomarkers and the EED score. Moreover, multivariable linear regression was performed to investigate the association of biomarkers with length-for-age z-score (LAZ). TFF3 correlates positively with myeloperoxidase (r = 0.26, p < 0.05) and EED score (r = 0.17, p < 0.05). Likewise, LCN2 correlates positively with myeloperoxidase (r = 0.37, p < 0.05), neopterin (r = 0.33, p < 0.05) and EED score (r = 0.31, p < 0.05). Moreover, multivariable linear regression revealed a negative association of I-FABP with LAZ of the study participants. Our results imply that TFF3 and LCN2 might be promising biomarkers to diagnose intestinal inflammation and EED, while I-FABP is negatively associated with linear growth of Bangladeshi children.


Assuntos
Proteínas de Ligação a Ácido Graxo , Enteropatias , Lipocalina-2 , Peroxidase , Fator Trefoil-3 , Bangladesh , Biomarcadores/metabolismo , Desenvolvimento Infantil , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Lactente , Inflamação , Enteropatias/metabolismo , Lipocalina-2/metabolismo , Peroxidase/metabolismo , Fator Trefoil-3/metabolismo
19.
Blood Press ; 31(1): 200-206, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35941820

RESUMO

PURPOSE: To investigate the relationship between morning blood pressure surge (MBPS) and neutrophilgelatinase associated lipocalin (NGAL) in patients with H-type hypertension. MATERIALS AND METHODS: A total of 224 patients with diagnosed H-type hypertension [homocysteine (Hcy)≧10umol/L] were selected and underwent 24-hour ambulatory blood pressure monitoring (ABPM). In the morning peak group (115 cases), NGAL and serum cystatin C levels, ß2-microglobulin levels were detected in each group, and general biochemical indicators were also detected. RESULTS: There was no significant difference in the course of hypertension, age, blood glucose, blood lipids, Hcy, BUN, Cr, and UA between the two groups (p > 0.05). CysC, ß2-MG were higher than those in the nonmorning peak group, and the difference was statistically significant (p < 0.05).; Pearson correlation analysis showed that NGAL was moderately and highly correlated with CysC, systolic blood pressure morning peak, ß2-MG, and high (p < 0.05), low-density lipoprotein (LDL-C), and Hcy were lowly correlated (p < 0.05).) and morning peak diastolic blood pressure (p > 0.05); multiple linear stepwise regression analysis indicated that morning peak systolic blood pressure, CysC,ß2-MG, and FBG were the risk factors for NGAL. CONCLUSION: The morning peak of systolic blood pressure in H-type hypertension is an important factor causing kidney injury. Paying attention to the ambulatory blood pressure monitoring and the control of morning peak blood pressure in patients with H-type hypertension, and early screening of NGAL has important clinical significance for the early prevention and treatment of renal injury in patients with H-type hypertension. PLAIN LANGUAGE SUMMARYThe morning peak of blood pressure is closely related to target organ damage.There are few studies on the relationship between morning peak phenomenon and renal damage in patients with H-type hypertension at home and abroad.We investigated the relationship between MBPS and NGAL in H-type hypertensive patients with BUN, Cr and UA in the normal range to provide a clinical basis for early renal protection in hypertensive patients.


Assuntos
Hipertensão , Lipocalina-2/metabolismo , Lipocalinas , Pressão Sanguínea/fisiologia , Monitorização Ambulatorial da Pressão Arterial , Humanos , Rim
20.
Int J Mol Sci ; 23(16)2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-36012166

RESUMO

Although recent studies have demonstrated that polychlorinated biphenyls (PCB) exposure leads to toxicant-associated steatohepatitis, the underlying mechanism of this condition remains unsolved. Male C57Bl/6 mice fed a standard diet (SD) or 60% high fat diet (HFD) were exposed to the nondioxin-like PCB mixture Aroclor1260 or dioxin-like PCB congener PCB126 by intraperitoneal injection for a total of four times for six weeks. We observed hepatic injury, steatosis, inflammation, and fibrosis in not only the Aroclor1260-treated mice fed a HFD but the PCB126-treated mice fed either a SD or a HFD. We also observed that both types of PCB exposure induced hepatic iron overload (HIO). Noticeably, the expression of hepatic lipocalin-2 (LCN2) was significantly increased in the PCB-induced nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) models. The knockdown of LCN2 resulted in improvement of PCB-induced lipid and iron accumulation in vitro, suggesting that LCN2 plays a pivotal role in PCB-induced NAFLD/NASH. We observed that recombinant FGF21 improved hepatic steatosis and HIO in the PCB-induced NAFLD/NASH models. Importantly, recombinant FGF21 reduced the PCB-induced overexpression of hepatic LCN2 in vivo and in vitro. Our findings indicate that recombinant FGF21 attenuates PCB-induced NAFLD/NASH by modulating hepatic lipocalin-2 expression. Our data suggest that hepatic LCN2 might represent a suitable therapeutic target for improving PCB-induced NAFLD/NASH accompanying HIO.


Assuntos
Sobrecarga de Ferro , Hepatopatia Gordurosa não Alcoólica , Bifenilos Policlorados , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos , Sobrecarga de Ferro/metabolismo , Lipocalina-2/genética , Lipocalina-2/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Bifenilos Policlorados/toxicidade
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