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It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncovered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant necrosome and NF-κB activation in hepatocytes, which physiologically express low concentrations of receptor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged "sublethal" state with leaky membranes, functioning as secretory cells that released specific chemokines including CCL20 and MCP-1. This triggered hepatic cell proliferation as well as activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis. In contrast, necrosome activation in hepatocytes with inactive NF-κB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-κB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogenesis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma.
Assuntos
Neoplasias Hepáticas , NF-kappa B , Humanos , NF-kappa B/metabolismo , Proteínas Quinases/metabolismo , Necroptose , Inflamação/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , ApoptoseRESUMO
Lipid droplets are organelles with unique spherical structures. They consist of a hydrophobic neutral lipid core that varies depending on the cell type and tissue. These droplets are surrounded by phospholipid monolayers, along with heterogeneous proteins responsible for neutral lipid synthesis and metabolism. Additionally, there are specialized lipid droplet-associated surface proteins. Recent evidence suggests that proteins from the perilipin family (PLIN) are associated with the surface of lipid droplets and are involved in their formation. These proteins have specific roles in hepatic lipid droplet metabolism, such as protecting the lipid droplets from lipase action and maintaining a balance between lipid storage and utilization in specific cells. Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by the accumulation of lipid droplets in more than 5% of the hepatocytes. This accumulation can progress into metabolic dysfunction-associated steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The accumulation of hepatic lipid droplets in the liver is associated with the progression of MASLD and other diseases such as sarcopenic obesity. Therefore, it is crucial to understand the role of perilipins in this accumulation, as these proteins are key targets for developing novel therapeutic strategies. This comprehensive review aims to summarize the structure and characteristics of PLIN proteins, as well as their pathogenic role in the development of hepatic steatosis and fatty liver diseases.
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Homeostase , Gotículas Lipídicas , Metabolismo dos Lipídeos , Perilipinas , Humanos , Gotículas Lipídicas/metabolismo , Perilipinas/metabolismo , Animais , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado/metabolismoRESUMO
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly increasing worldwide at an alarming pace, due to an increase in obesity, sedentary and unhealthy lifestyles, and unbalanced dietary habits. MASLD is a unique, multi-factorial condition with several phases of progression including steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Sterol element binding protein 1c (SREBP1c) is the main transcription factor involved in regulating hepatic de novo lipogenesis. This transcription factor is synthesized as an inactive precursor, and its proteolytic maturation is initiated in the membrane of the endoplasmic reticulum upon stimulation by insulin. SREBP cleavage activating protein (SCAP) is required as a chaperon protein to escort SREBP from the endoplasmic reticulum and to facilitate the proteolytic release of the N-terminal domain of SREBP into the Golgi. SCAP inhibition prevents activation of SREBP and inhibits the expression of genes involved in triglyceride and fatty acid synthesis, resulting in the inhibition of de novo lipogenesis. In line, previous studies have shown that SCAP inhibition can resolve hepatic steatosis in animal models and intensive research is going on to understand the effects of SCAP in the pathogenesis of human disease. This review focuses on the versatile roles of SCAP/SREBP regulation in de novo lipogenesis and the structure and molecular features of SCAP/SREBP in the progression of hepatic steatosis. In addition, recent studies that attempt to target the SCAP/SREBP axis as a therapeutic option to interfere with MASLD are discussed.
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Fígado Gorduroso , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Hepáticas , Proteínas de Membrana , Proteína de Ligação a Elemento Regulador de Esterol 1 , Animais , Humanos , Metabolismo dos Lipídeos , Lipogênese , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genéticaRESUMO
Obesity or excessive weight gain is identified as the most important and significant risk factor in the development and progression of type 2 diabetes mellitus (DM) in all age groups. It has reached pandemic dimensions, making the treatment of obesity crucial in the prevention and management of type 2 DM worldwide. Multiple clinical studies have demonstrated that moderate and sustained weight loss can improve blood glucose levels, insulin action and reduce the need for diabetic medications. A combined approach of diet, exercise and lifestyle modifications can successfully reduce obesity and subsequently ameliorate the ill effects and deadly complications of DM. This approach also helps largely in the prevention, control and remission of DM. Obesity and DM are chronic diseases that are increasing globally, requiring new approaches to manage and prevent diabetes in obese individuals. Therefore, it is essential to understand the mechanistic link between the two and design a comprehensive approach to increase life expectancy and improve the quality of life in patients with type 2 DM and obesity. This literature review provides explicit information on the clinical definitions of obesity and type 2 DM, the incidence and prevalence of type 2 DM in obese individuals, the indispensable role of obesity in the pathophysiology of type 2 DM and their mechanistic link. It also discusses clinical studies and outlines the recent management approaches for the treatment of these associated conditions. Additionally, in vivo studies on obesity and type 2 DM are discussed here as they pave the way for more rigorous development of therapeutic approaches.
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Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Qualidade de Vida , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/terapia , Fatores de Risco , Redução de PesoRESUMO
The lipocalin proteins are a large family of small extracellular proteins that demonstrate significant heterogeneity in sequence similarity and have highly conserved crystal structures. They have a variety of functions, including acting as carrier proteins, transporting retinol, participating in olfaction, and synthesizing prostaglandins. Importantly, they also play a critical role in human diseases, including cancer. Additionally, they are involved in regulating cellular homeostasis and immune response and dispensing various compounds. This comprehensive review provides information on the lipocalin family, including their structure, functions, and implications in various diseases. It focuses on selective important human lipocalin proteins, such as lipocalin 2 (LCN2), retinol binding protein 4 (RBP4), prostaglandin D2 synthase (PTGDS), and α1-microglobulin (A1M).
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Oxirredutases Intramoleculares , Lipocalinas , Humanos , Lipocalinas/metabolismo , Lipocalinas/química , Lipocalinas/genética , Neoplasias/metabolismo , Relação Estrutura-Atividade , AnimaisRESUMO
The role of probiotics in regulating intestinal flora to enhance host immunity has recently received widespread attention. Altering the human gut microbiota may increase the predisposition to several disease phenotypes such as gut inflammation and metabolic disorders. The intestinal microbiota converts dietary nutrients into metabolites that serve as biologically active molecules in modulating regulatory functions in the host. Probiotics, which are active microorganisms, play a versatile role in restoring the composition of the gut microbiota, helping to improve host immunity and prevent intestinal disease phenotypes. This comprehensive review provides firsthand information on the gut microbiota and their influence on human health, the dietary effects of diet on the gut microbiota, and how probiotics alter the composition and function of the human gut microbiota, along with their corresponding effects on host immunity in building a healthy intestine. We also discuss the implications of probiotics in some of the most important human diseases. In summary, probiotics play a significant role in regulating the gut microbiota, boosting overall immunity, increasing the abundance of beneficial bacteria, and helping ameliorate the symptoms of multiple diseases.
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Microbioma Gastrointestinal , Probióticos , Probióticos/farmacologia , Humanos , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , DietaRESUMO
The kidney injury molecule (KIM)-1 is shed from proximal tubular cells in acute kidney injury (AKI), relaying tubular epithelial proliferation. Additionally, KIM-1 portends complex immunoregulation and is elevated after exposure to lipopolysaccharides. It thus may represent a biomarker in critical illness, sepsis, and sepsis-associated AKI (SA-AKI). To characterise and compare KIM-1 in these settings, we analysed KIM-1 serum concentrations in 192 critically ill patients admitted to the intensive care unit. Irrespective of kidney dysfunction, KIM-1 serum levels were significantly higher in patients with sepsis compared with other critical illnesses (191.6 vs. 132.2 pg/mL, p = 0.019) and were highest in patients with urogenital sepsis, followed by liver failure. Furthermore, KIM-1 levels were significantly elevated in critically ill patients who developed AKI within 48 h (273.3 vs. 125.8 pg/mL, p = 0.026) or later received renal replacement therapy (RRT) (299.7 vs. 146.3 pg/mL, p < 0.001). KIM-1 correlated with markers of renal function, inflammatory parameters, hematopoietic function, and cholangiocellular injury. Among subcomponents of the SOFA score, KIM-1 was elevated in patients with hyperbilirubinaemia (>2 mg/dL, p < 0.001) and thrombocytopenia (<150/nL, p = 0.018). In univariate and multivariate regression analyses, KIM-1 predicted sepsis, the need for RRT, and multi-organ dysfunction (MOD, SOFA > 12 and APACHE II ≥ 20) on the day of admission, adjusting for relevant comorbidities, bilirubin, and platelet count. Additionally, KIM-1 in multivariate regression was able to predict sepsis in patients without prior (CKD) or present (AKI) kidney injury. Our study suggests that next to its established role as a biomarker in kidney dysfunction, KIM-1 is associated with sepsis, biliary injury, and critical illness severity. It thus may offer aid for risk stratification in these patients.
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Injúria Renal Aguda , Biomarcadores , Estado Terminal , Receptor Celular 1 do Vírus da Hepatite A , Sepse , Humanos , Receptor Celular 1 do Vírus da Hepatite A/sangue , Sepse/sangue , Sepse/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Injúria Renal Aguda/sangue , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/diagnóstico , Biomarcadores/sangue , Índice de Gravidade de Doença , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/etiologia , Unidades de Terapia Intensiva , AdultoRESUMO
Critical illness and sepsis may cause organ failure and are recognized as mortality drivers in hospitalized patients. Neuropilin-1 (NRP-1) is a multifaceted transmembrane protein involved in the primary immune response and is expressed in immune cells such as T and dendritic cells. The soluble form of NRP-1 (sNRP-1) acts as an antagonist to NRP-1 by scavenging its ligands. The aim of this study was to determine the value of sNRP-1 as a biomarker in critical illness and sepsis. We enrolled 180 critically ill patients admitted to a medical intensive care unit and measured serum sNRP-1 concentrations at admission, comparing them to 48 healthy individuals. Critically ill and septic patients showed higher levels of sNRP-1 compared to healthy controls (median of 2.47 vs. 1.70 nmol/L, p < 0.001). Moreover, sNRP-1 was also elevated in patients with sepsis compared to other critical illness (2.60 vs. 2.13 nmol/L, p = 0.01), irrespective of disease severity or organ failure. In critically ill patients, sNRP-1 is positively correlated with markers of kidney and hepatic dysfunction. Most notably, critically ill patients not surviving in the long term (one year after admission) showed higher concentrations of sNRP-1 at the time of ICU admission (p = 0.036), with this association being dependent on the presence of organ failure. Critically ill and septic patients exhibit higher serum concentrations of circulating sNRP-1, which correlates to organ failure, particularly hepatic and kidney dysfunction.
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Biomarcadores , Estado Terminal , Neuropilina-1 , Sepse , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biomarcadores/sangue , Estudos de Casos e Controles , Unidades de Terapia Intensiva , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/mortalidade , Neuropilina-1/metabolismo , Neuropilina-1/sangue , Sepse/sangue , Sepse/mortalidadeRESUMO
Acute and chronic liver diseases cause significant morbidity and mortality worldwide, affecting millions of people. Liver transplantation is the primary intervention method, replacing a non-functional liver with a functional one. However, the field of liver transplantation faces challenges such as donor shortage, postoperative complications, immune rejection, and ethical problems. Consequently, there is an urgent need for alternative therapies that can complement traditional transplantation or serve as an alternative method. In this review, we explore the potential of liver tissue engineering as a supplementary approach to liver transplantation, offering benefits to patients with severe liver dysfunctions.
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Liver fibrosis interferes with normal liver function and facilitates hepatocellular carcinoma (HCC) development, representing a major threat to human health. Here, we present a comprehensive perspective of microRNA (miRNA) function on targeting the fibrotic microenvironment. Starting from a murine HCC model, we identify a miRNA network composed of 8 miRNA hubs and 54 target genes. We show that let-7, miR-30, miR-29c, miR-335, and miR-338 (collectively termed antifibrotic microRNAs [AF-miRNAs]) down-regulate key structural, signaling, and remodeling components of the extracellular matrix. During fibrogenic transition, these miRNAs are transcriptionally regulated by the transcription factor Pparγ and thus we identify a role of Pparγ as regulator of a functionally related class of AF-miRNAs. The miRNA network is active in human HCC, breast, and lung carcinomas, as well as in 2 independent mouse liver fibrosis models. Therefore, we identify a miRNA:mRNA network that contributes to formation of fibrosis in tumorous and nontumorous organs of mice and humans.
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Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Cirrose Hepática/patologia , Neoplasias Hepáticas/genética , MicroRNAs/genética , PPAR gama/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Hepatocelular/patologia , Ilhas de CpG/genética , Metilação de DNA , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Epigênese Genética , Matriz Extracelular/patologia , Feminino , Células Estreladas do Fígado/patologia , Humanos , Fígado/citologia , Fígado/patologia , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Cultura Primária de Células , Regiões Promotoras Genéticas/genética , RNA-Seq , Microambiente Tumoral/genéticaRESUMO
Estrogen receptor alpha (ERα) is widely expressed in reproductive organs, but also in non-reproductive tissues of females and males. There is evidence that lipocalin 2 (LCN2), which has diverse immunological and metabolic functions, is regulated by ERα in adipose tissue. However, in many other tissues, the impact of ERα on LCN2 expression has not been studied yet. Therefore, we used an Esr1-deficient mouse strain and analyzed LCN2 expression in reproductive (ovary, testes) and non-reproductive tissues (kidney, spleen, liver, lung) of both sexes. Tissues collected from adult wild-type (WT) and Esr1-deficient animals were analyzed by immunohistochemistry, Western blot analysis, and RT-qPCR for Lcn2 expression. In non-reproductive tissues, only minor genotype- or sex-specific differences in LCN2 expression were detected. In contrast, significant differences in LCN2 expression were observed in reproductive tissues. Particularly, there was a strong increase in LCN2 in Esr1-deficient ovaries when compared to WTs. In summary, we found an inverse correlation between the presence of ERα and the expression of LCN2 in testes and ovaries. Our results provide an important basis to better understand LCN2 regulation in the context of hormones and in health and disease.
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Tecido Adiposo , Receptor alfa de Estrogênio , Animais , Feminino , Masculino , Camundongos , Tecido Adiposo/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Lipocalina-2/genética , Lipocalina-2/metabolismo , Camundongos Knockout , Ovário/metabolismo , Testículo/metabolismoRESUMO
Epidemiological evidence supports an association between cow's milk consumption and the risk of diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma worldwide. This narrative review intends to elucidate the potential impact of milk-related agents, predominantly milk-derived exosomes (MDEs) and their microRNAs (miRs) in lymphomagenesis. Upregulation of PI3K-AKT-mTORC1 signaling is a common feature of DLBCL. Increased expression of B cell lymphoma 6 (BCL6) and suppression of B lymphocyte-induced maturation protein 1 (BLIMP1)/PR domain-containing protein 1 (PRDM1) are crucial pathological deviations in DLBCL. Translational evidence indicates that during the breastfeeding period, human MDE miRs support B cell proliferation via epigenetic upregulation of BCL6 (via miR-148a-3p-mediated suppression of DNA methyltransferase 1 (DNMT1) and miR-155-5p/miR-29b-5p-mediated suppression of activation-induced cytidine deaminase (AICDA) and suppression of BLIMP1 (via MDE let-7-5p/miR-125b-5p-targeting of PRDM1). After weaning with the physiological termination of MDE miR signaling, the infant's BCL6 expression and B cell proliferation declines, whereas BLIMP1-mediated B cell maturation for adequate own antibody production rises. Because human and bovine MDE miRs share identical nucleotide sequences, the consumption of pasteurized cow's milk in adults with the continued transfer of bioactive bovine MDE miRs may de-differentiate B cells back to the neonatal "proliferation-dominated" B cell phenotype maintaining an increased BLC6/BLIMP1 ratio. Persistent milk-induced epigenetic dysregulation of BCL6 and BLIMP1 expression may thus represent a novel driving mechanism in B cell lymphomagenesis. Bovine MDEs and their miR cargo have to be considered potential pathogens that should be removed from the human food chain.
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Linfoma Difuso de Grandes Células B , MicroRNAs , Animais , Feminino , Bovinos , Recém-Nascido , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Leite/metabolismo , Fosfatidilinositol 3-Quinases , Linfoma Difuso de Grandes Células B/patologia , Linfócitos B/metabolismoRESUMO
Perilipin 5 (PLIN5) is a lipid droplet coat protein that is highly expressed in oxidative tissues such as those of muscles, the heart and the liver. PLIN5 expression is regulated by a family of peroxisome proliferator-activated receptors (PPARs) and modulated by the cellular lipid status. So far, research has focused on the role of PLIN5 in the context of non-alcoholic fatty liver disease (NAFLD) and specifically in lipid droplet formation and lipolysis, where PLIN5 serves as a regulator of lipid metabolism. In addition, there are only limited studies connecting PLIN5 to hepatocellular carcinoma (HCC), where PLIN5 expression is proven to be upregulated in hepatic tissue. Considering that HCC development is highly driven by cytokines present throughout NAFLD development and in the tumor microenvironment, we here explore the possible regulation of PLIN5 by cytokines known to be involved in HCC and NAFLD progression. We demonstrate that PLIN5 expression is strongly induced by interleukin-6 (IL-6) in a dose- and time-dependent manner in Hep3B cells. Moreover, IL-6-dependent PLIN5 upregulation is mediated by the JAK/STAT3 signaling pathway, which can be blocked by transforming growth factor-ß (TGF-ß) and tumor necrosis factor-α (TNF-α). Furthermore, IL-6-mediated PLIN5 upregulation changes when IL-6 trans-signaling is stimulated through the addition of soluble IL-6R. In sum, this study sheds light on lipid-independent regulation of PLIN5 expression in the liver, making PLIN5 a crucial target for NAFLD-induced HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Perilipina-5/genética , Perilipina-5/metabolismo , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Metabolismo dos Lipídeos/fisiologia , Lipídeos , Microambiente Tumoral , Fator de Transcrição STAT3/metabolismoRESUMO
Spinal cord injury (SCI) results in the production of proinflammatory cytokines due to inflammasome activation. Lipocalin 2 (LCN2) is a small secretory glycoprotein upregulated by toll-like receptor (TLR) signaling in various cells and tissues. LCN2 secretion is induced by infection, injury, and metabolic disorders. In contrast, LCN2 has been implicated as an anti-inflammatory regulator. However, the role of LCN2 in inflammasome activation during SCI remains unknown. This study examined the role of Lcn2 deficiency in the NLRP3 inflammasome-dependent neuroinflammation in SCI. Lcn2-/- and wild-type (WT) mice were subjected to SCI, and locomotor function, formation of the inflammasome complex, and neuroinflammation were assessed. Our findings demonstrated that significant activation of the HMGB1/PYCARD/caspase-1 inflammatory axis was accompanied by the overexpression of LCN2 7 days after SCI in WT mice. This signal transduction results in the cleaving of the pyroptosis-inducing protein gasdermin D (GSDMD) and the maturation of the proinflammatory cytokine IL-1ß. Furthermore, Lcn2-/- mice showed considerable downregulation in the HMGB1/NLRP3/PYCARD/caspase-1 axis, IL-1ß production, pore formation, and improved locomotor function compared with WT. Our data suggest that LCN2 may play a role as a putative molecule for the induction of inflammasome-related neuroinflammation in SCI.
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Proteína HMGB1 , Traumatismos da Medula Espinal , Camundongos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Lipocalina-2/genética , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Doenças Neuroinflamatórias , Traumatismos da Medula Espinal/metabolismo , Citocinas/metabolismo , Caspases/metabolismo , Piroptose/fisiologiaRESUMO
Midkine (Mdk) is a multifunctional protein involved in inflammatory processes. Hence, circulating Mdk is increased in sepsis and has been previously suggested as a potential biomarker in these patients. The aim of this study was to elucidate the role of Mdk serum concentrations in critical illness and sepsis and to verify its value as a prognostic biomarker. Thus, we analyzed the Mdk serum concentrations of 192 critically ill patients on admission to the medical intensive care unit (ICU). While the serum levels of Mdk at admission were similar in septic and nonseptic critical illness (362 vs. 337 ng/L, p = 0.727), we found several interesting correlations of Mdk to laboratory and clinical markers associated with ischemia or hypoxia, e.g., to renal failure and hepatic injury. Mdk serum concentrations at admission did not differ between various causes of sepsis or other critical illness. Most noticeable, we observed upregulated Mdk serum concentrations at admission in patients surviving in the long-term, which was only seen in nonseptic critical illness but not in sepsis. Our study suggests a relevant role of Mdk in critically ill patients in general and highlights the possible protective features of Mdk in critical illness.
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Estado Terminal , Sepse , Humanos , Biomarcadores , Hospitalização , MidkinaRESUMO
Multiple sclerosis (MS) is a central nervous system disease characterized by both degenerative and inflammatory processes. Various mediators are involved in the interplay of degeneration and innate immunity on one hand and peripheral adaptive immunity on the other hand. The secreted protein lipocalin 2 (LCN2) is an inflammatory modulator in a variety of pathologies. Although elevated intrathecal levels of LCN2 have been reported in MS patients, it's functional role is widely unknown. Here, we identified a subpopulation of astrocytes as a source of LCN2 in MS lesions and respective animal models. We investigated the functional role of LCN2 for both autoimmune and degenerative aspects in three MS mouse models including both wild type (WT) and Lcn2-/- mouse strains. While the experimental autoimmune encephalomyelitis (EAE) model reflects primary autoimmunity, the cuprizone model reflects selective oligodendrocyte loss and demyelination. In addition, we included a combinatory Cup/EAE model in which primary cytodegeneration is followed by inflammatory lesions within the forebrain. While in the EAE model, the disease outcome was comparable in between the two mouse strains, cuprizone intoxicated Lcn2-/- animals showed an increased loss of oligodendrocytes. In the Cup/EAE model, Lcn2-/- animals showed increased inflammation when compared to WT mice. Together, our results highlight LCN2 as a potentially protective molecule in MS lesion formation, which might be able to limit loss of oligodendrocytes immune-cell invasion. Despite these findings, it is not yet clear which glial cell phenotype (and to which extent) contributes to the observed neuroprotective effects, that is, microglia and/or astroglia or even endothelial cells in the brain.
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Encefalomielite Autoimune Experimental , Lipocalina-2/metabolismo , Esclerose Múltipla , Animais , Cuprizona , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/metabolismo , Células Endoteliais/metabolismo , Lipocalina-2/genética , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/patologia , Oligodendroglia/metabolismo , Prosencéfalo/patologiaRESUMO
Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-Cas technology possesses revolutionary potential to positively affect various domains of drug discovery. It has initiated a rise in the area of genetic engineering and its advantages range from classical science to translational medicine. These genome editing systems have given a new dimension to our capabilities to alter, detect and annotate specified gene sequences. Moreover, the ease, robustness and adaptability of the CRISPR/Cas9 technology have led to its extensive utilization in research areas in such a short period of time. The applications include the development of model cell lines, understanding disease mechanisms, discovering disease targets, developing transgenic animals and plants, and transcriptional modulation. Further, the technology is rapidly growing; hence, an overlook of progressive success is crucial. This review presents the current status of the CRISPR-Cas technology in a tailor-made format from its discovery to several advancements for drug discovery alongwith future trends associated with possibilities and hurdles including ethical concerns.
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Sistemas CRISPR-Cas , Edição de Genes , Animais , Sistemas CRISPR-Cas/genética , Edição de Genes/métodos , Engenharia Genética/métodos , Descoberta de Drogas , TecnologiaRESUMO
Non-alcoholic steatohepatitis (NASH) is a progressive form of Non-alcoholic fatty liver disease (NAFLD), which slowly progresses toward cirrhosis and finally leads to the development of hepatocellular carcinoma. Obesity, insulin resistance, type 2 diabetes mellitus and the metabolic syndrome are major risk factors contributing to NAFLD. Targeting these risk factors is a rational option for inhibiting NASH progression. In addition, NASH could be treated with therapies that target the metabolic abnormalities causing disease pathogenesis (such as de novo lipogenesis and insulin resistance) as well with medications targeting downstream processes such as cellular damage, apoptosis, inflammation, and fibrosis. Glucagon-like peptide (GLP-1), is an incretin hormone dysregulated in both experimental and clinical NASH, which triggers many signaling pathways including fibroblast growth factor (FGF) that augments NASH pathogenesis. Growing evidence indicates that GLP-1 in concert with FGF-21 plays crucial roles in the conservation of glucose and lipid homeostasis in metabolic disorders. In line, GLP-1 stimulation improves hepatic ballooning, steatosis, and fibrosis in NASH. A recent clinical trial on NASH patients showed that the upregulation of FGF-21 decreases liver fibrosis and hepatic steatosis, thus improving the pathogenesis of NASH. Hence, therapeutic targeting of the GLP-1/FGF axis could be therapeutically beneficial for the remission of NASH. This review outlines the significance of the GLP-1/FGF-21 axis in experimental and clinical NASH and highlights the activity of modulators targeting this axis as potential salutary agents for the treatment of NASH.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/metabolismo , Humanos , Incretinas/metabolismo , Incretinas/uso terapêutico , Lipídeos/uso terapêutico , Fígado/metabolismo , Cirrose Hepática/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismoRESUMO
BACKGROUND: The pathophysiology of hepatic encephalopathy (HE) is incompletely understood. It remains elusive how the contributing factors of neuronal ammonia accumulation, cell swelling, and inflammation interact. OBJECTIVE: The objective of this study was to find the correlation between neuronal autoantibody levels and the degree of HE as first indication of immune-mediated pathogenesis. METHODS: We investigated serum autoantibody levels of representative brain proteins in patients with HE as well as in an experimental rat model with cirrhosis and HE after carbon tetrachloride exposure. They were examined in relation to presence of HE and the degree of neurological impairment evaluated by quantitative scores. RESULTS: In HE, an increase in all of the examined antibodies was observed in serum. The grade of antibody elevation correlated to the degree of encephalopathy registered by quantitative evaluation of brain dysfunction. CONCLUSION: The degree of HE parallels neuronal autoantibody elevation. In case a causal relationship could finally be established, it adds to the understanding of HE and may open a new perspective for treatment of this handicapping condition by immunosuppressive strategies.
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Encefalopatia Hepática , Amônia , Animais , Autoanticorpos , Encefalopatia Hepática/etiologia , Humanos , Cirrose Hepática/complicações , Ratos , Fatores de VirulênciaRESUMO
Single-cell sequencing methods provide the highest resolution insight into cellular heterogeneity. Owing to their rapid growth and decreasing cost, they are now widely accessible to scientists worldwide. Single-cell technologies enable analysis of a large number of cells, making them powerful tools to characterise rare cell types and refine our understanding of diverse cell states. Moreover, single-cell application in biomedical sciences helps to unravel mechanisms related to disease pathogenesis and outcome. In this Viewpoint, we briefly describe existing single-cell methods (genomics, transcriptomics, epigenomics, proteomics, and mulitomics), comment on available analysis tools, and give examples of method applications in the biomedical field.