RESUMO
SIGNIFICANCE STATEMENT: Emerging evidence suggests that melanocortin neuropeptides-specifically adrenocorticotropic hormone-offer a novel, steroidogenic-independent therapeutic modality for membranous nephropathy (MN). The molecular mechanism underlying this beneficial effect, however, remains largely elusive. To investigate whether melanocortins modulate humoral immunity, the authors induced passive Heymann nephritis, a model of human MN, in wild-type and melanocortin 1 receptor (MC1R) knockout rats and treated them with melanocortin agents. Additional rats received adoptive transfer of bone marrow-derived cells beforehand from wild-type or MC1R knockout rats. The findings indicate that MC1R signaling plays a key role in negative modulation of B-cell activation and thereby suppresses humoral immune responses in passive Heymann nephritis, and suggest that MC1R signaling might offer a novel B cell-targeted therapeutic strategy for MN. BACKGROUND: Emerging evidence suggests that the pituitary neuropeptide melanocortins-specifically, adrenocorticotropic hormone-offer a novel nonsteroidogenic therapeutic modality for membranous nephropathy (MN). However, the mechanism(s) of action remains elusive. METHODS: To investigate whether melanocortins modulate humoral immunity, we induced passive Heymann nephritis (PHN), a model of MN, in wild-type (WT) and melanocortin 1 receptor (MC1R) knockout (KO) rats. We treated the animals with melanocortin agents-repository corticotropin injection, the nonsteroidogenic pan-melanocortin receptor agonist [Nle 4 , DPhe 7 ]-α-melanocyte stimulating hormone, the selective MC1R agonist MS05, vehicle gel, or phosphate-buffered saline-and evaluated kidney function, histology, and molecular changes. Additional rats received adoptive transfer of syngeneic bone marrow-derived cells beforehand from WT or MC1R KO rats. RESULTS: KO of MC1R worsened PHN and this was associated with increased deposition of autologous immunoglobulin G (IgG) and complement C5b-9 in glomeruli and higher circulating levels of autologous IgG-evidence of a sensitized humoral immune response. Melanocortin therapy ameliorated PHN in WT rats, coinciding with reduced glomerular deposition of autologous IgG and C5b -9. The beneficial efficacy of melanocortins was blunted in KO rats but restored by adoptive transfer of syngeneic bone marrow-derived cells derived from WT rats. Mechanistically, MC1R was expressed in B lymphocytes and was negatively associated with B cell activation. MC1R agonism triggered the expression of microphthalmia-associated transcription factor in activated B cells in a cAMP-dependent mode and also repressed the expression of interferon regulatory factor 4 (a lymphoid transcription factor essential for B-cell development and maturation), resulting in suppressed plasma cell differentiation and IgG production. CONCLUSIONS: MC1R signaling negatively modulates B cell activation and suppresses humoral immune responses in PHN, suggesting that MC1R signaling might offer a novel therapeutic target for MN.
Assuntos
Glomerulonefrite Membranosa , Animais , Ratos , Hormônio Adrenocorticotrópico , alfa-MSH/farmacologia , Complexo de Ataque à Membrana do Sistema Complemento , Imunoglobulina G , Melanocortinas , Receptor Tipo 1 de Melanocortina/agonistas , Receptor Tipo 1 de Melanocortina/metabolismoRESUMO
The melanocortin hormone system has emerged as a novel therapeutic target for treating refractory glomerular diseases. However, the role of hematopoietic melanocortin 1 receptor (MC1R) signaling remains unknown. Upon insult by rabbit nephrotoxic serum, MC1R null-mutant mice developed more severe crescentic glomerulonephritis than wild-type mice, marked by aggravated proteinuria, kidney dysfunction and histologic lesions. Melanocortin therapy, using Repository Corticotropin Injection (Acthar Gel), the pan-melanocortin receptor agonist NDP-MSH, or the MC1R agonist MS05, ameliorated experimental nephritis in wild-type mice but this effect was blunted in null mice. Exacerbated experimental nephritis in null mice was associated with increased glomerular deposition of autologous IgG and C5b-9, in parallel with higher circulating levels of autologous IgG2c and IgG3. Additionally, the Th1 immune response was potentiated in null mice with experimental nephritis, accompanied by diminished kidney FoxP3+ regulatory T cells. Kidney infiltration of macrophages was also augmented by MC1R deficiency with an enhanced M1 polarization. Moreover, adoptive transfer of syngeneic bone marrow-derived cells from wild-type mice mitigated experimental nephritis in null mice and restored the beneficial efficacy of melanocortins. Mechanistically, MC1R was expressed by diverse subsets of kidney leukocytes, including macrophages, T and B lymphocytes, and was inversely associated with the NFκB pathway, a key player in immune responses. MS05 attenuated the production of rabbit IgG-specific IgG2c and IgG3 in cultured wild-type splenocytes, and promoted M2 polarization in M1-primed wild-type macrophages, associated with NFκB inhibition. In contrast, in null splenocytes or macrophages, this effect of MS05 was barely detectable, but was mimicked by an NFκB inhibitor. Thus, hematopoietic MC1R signaling attenuates experimental nephritis and mediates the beneficial effect of melanocortin therapy via, in part, regulating the immune response.
Assuntos
Nefrite , Insuficiência Renal , Animais , Camundongos , Coelhos , Receptor Tipo 1 de Melanocortina/genética , Rim , Transdução de Sinais , NF-kappa BRESUMO
OBJECTIVE: The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial, a multicenter randomized controlled trial with 947 patients, concluded that there was no benefit of renal artery stenting (RAS) over medical therapy. However, patients with chronic kidney disease (CKD) were not analyzed separately in the CORAL trial. CKD is a risk factor for cardiovascular and renal morbidity. We hypothesized that improved renal function after RAS would be associated with increased long-term survival and a lower risk of cardiovascular and renal events in patients with CKD. METHODS: This post hoc analysis of the CORAL trial included 842 patients with CKD stages 2 to 4 at baseline who were randomized to optimal medical therapy alone (OMT; n = 432) or RAS plus OMT (RAS + OMT; n = 410). Patients were categorized as responders or nonresponders based on the change in the estimated glomerular filtration rate (eGFR) from baseline to last follow-up (median, 3.6 years; interquartile range, 2.6-4.6 years). Responders were defined by a 20% or greater increase in eGFR from baseline; all others were designated as nonresponders. Event-free survival was defined as freedom from death and multiple cardiovascular and renal complications. Event-free survival was analyzed using the Kaplan-Meier method and log-rank test. Multivariable Cox proportional hazards regression analysis was used to identify independent predictors of event-free survival. RESULTS: The RAS + OMT group had a higher proportion of patients with improved renal function (≥20% increase in eGFR over baseline), compared with the OMT group (25.6% vs 17.1%; P = .003). However, event-free survival was no different for the two cohorts (P = .18 by the log-rank test). Multivariable Cox proportional hazards regression analysis identified four variables that independently correlated with event-free survival for the stented cohort. Higher preoperative eGFR (hazard ratio, 0.98; 95% confidence interval [CI], 0.96-0.99; P = .002) and being a responder to stenting (hazard ratio, 0.49; 95% CI, 0.26-0.95; P = .033) increased event-free survival, whereas a history of congestive heart failure (hazard ratio, 2.52; 95% CI, 1.46-4.35; P < .001) and a higher preoperative systolic BP (hazard ratio, 1.02; 95% CI, 1.01-1.03; P = .002) decreased event-free survival. Within the stented group, 105 of 410 patients (25.6%) were responders. Event-free survival was superior for responders, compared with nonresponders (P = .009 by log-rank test). The only independent preoperative negative predictor of improved renal function after stenting was diabetes (odds ratio, 0.37; 95% CI, 0.16-0.84; P = .017), which decreased the probability of improved renal function after RAS + OMT. A subset of patients (23.4%) after RAS had worsened renal function, but OMT alone produced an equivalent incidence of worsened renal function. An increased urine albumin/creatinine ratio was an independent predictor of worsened renal function after RAS. CONCLUSIONS: CORAL participants who demonstrated improved kidney function after RAS + OMT demonstrated improved event-free survival. This finding reinforces the need for predictors of outcome to guide patient selection for RAS.
Assuntos
Aterosclerose , Insuficiência Renal Crônica , Humanos , Artéria Renal , Intervalo Livre de Progressão , Rim/irrigação sanguínea , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/terapia , Aterosclerose/complicações , Aterosclerose/terapia , Aterosclerose/patologia , Fatores de Risco , Taxa de Filtração Glomerular , Resultado do TratamentoRESUMO
Diet-induced models of chronic kidney disease (CKD) offer several advantages, including clinical relevance and animal welfare, compared with surgical models. Oxalate is a plant-based, terminal toxic metabolite that is eliminated by the kidneys through glomerular filtration and tubular secretion. An increased load of dietary oxalate leads to supersaturation, calcium oxalate crystal formation, renal tubular obstruction, and eventually CKD. Dahl-Salt-Sensitive (SS) rats are a common strain used to study hypertensive renal disease; however, the characterization of other diet-induced models on this background would allow for comparative studies of CKD within the same strain. In the present study, we hypothesized that SS rats on a low-salt, oxalate rich diet would have increased renal injury and serve as novel, clinically relevant and reproducible CKD rat models. Ten-week-old male SS rats were fed either 0.2% salt normal chow (SS-NC) or a 0.2% salt diet containing 0.67% sodium oxalate (SS-OX) for five weeks.Real-time PCR demonstrated an increased expression of inflammatory marker interleukin-6 (IL-6) (p < 0.0001) and fibrotic marker Timp-1 metalloproteinase (p < 0.0001) in the renal cortex of SS-OX rat kidneys compared with SS-NC. The immunohistochemistry of kidney tissue demonstrated an increase in CD-68 levels, a marker of macrophage infiltration in SS-OX rats (p < 0.001). In addition, SS-OX rats displayed increased 24 h urinary protein excretion (UPE) (p < 0.01) as well as significant elevations in plasma Cystatin C (p < 0.01). Furthermore, the oxalate diet induced hypertension (p < 0.05). A renin-angiotensin-aldosterone system (RAAS) profiling (via liquid chromatography-mass spectrometry; LC-MS) in the SS-OX plasma showed significant (p < 0.05) increases in multiple RAAS metabolites including angiotensin (1-5), angiotensin (1-7), and aldosterone. The oxalate diet induces significant renal inflammation, fibrosis, and renal dysfunction as well as RAAS activation and hypertension in SS rats compared with a normal chow diet. This study introduces a novel diet-induced model to study hypertension and CKD that is more clinically translatable and reproducible than the currently available models.
Assuntos
Hipertensão , Insuficiência Renal Crônica , Ratos , Animais , Ratos Endogâmicos Dahl , Oxalatos/metabolismo , Rim/metabolismo , Hipertensão/metabolismo , Cloreto de Sódio na Dieta/metabolismo , Cloreto de Sódio/metabolismo , Insuficiência Renal Crônica/metabolismo , Dieta/efeitos adversos , Pressão SanguíneaRESUMO
Evasion of innate immunity represents a frequently employed method by which tumor cells survive and thrive. Previously, the development of immunotherapeutic agents capable of overcoming this evasion has realized pronounced clinical utility across a variety of cancer types. More recently, immunological strategies have been investigated as potentially viable therapeutic and diagnostic modalities in the management of carcinoid tumors. Classic treatment options for carcinoid tumors rely upon surgical resection or non-immune pharmacology. Though surgical intervention can be curative, tumor characteristics, such as size, location, and spread, heavily limit success. Non-immune pharmacologic treatments can be similarly limited, and many demonstrate problematic side effects. Immunotherapy may be able to overcome these limitations and further improve clinical outcomes. Similarly, emerging immunologic carcinoid biomarkers may improve diagnostic capabilities. Recent developments in immunotherapeutic and diagnostic modalities of carcinoid management are summarized here.
Assuntos
Tumor Carcinoide , Humanos , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/patologia , Tumor Carcinoide/terapia , Biomarcadores , Fatores ImunológicosRESUMO
Hemopexin, a heme scavenging protein, accumulates in the kidneys during acute kidney injury (AKI). However, the function of this accumulated hemopexin in the kidney is unclear. In both the cisplatin-induced and the unilateral kidney ischemia-reperfusion injury models of AKI, we found accumulation of hemoglobin and hemopexin in the kidneys localized to the proximal tubules. Next, hemopexin wild-type and knockout mice were compared in both AKI models and hemopexin wild type mice had significantly worse kidney injury. Furthermore, there was increased kidney expression of kidney injury molecule-1 (a biomarker of AKI) and heme oxygenase-1 (an indicator of oxidative stress) in hemopexin wild type compared with knockout mice in both models of AKI. Next, the interaction of hemopexin and hemoglobin in vitro was investigated using cultured proximal tubular cells. Co-incubation of hemopexin with hemoglobin resulted in hemoglobin deposition and exaggerated hemoglobin-induced injury. Deferoxamine, an iron chelator, and ferrostatin-1, a ferroptosis inhibitor, inhibited this deleterious effect of hemoglobin and hemopexin in proximal tubular cells, implicating iron toxicity in the mechanism of hemopexin mediated injury. Furthermore, the protective effect of deferoxamine in cisplatin-induced AKI was apparent in hemopexin wild type, but not in hemopexin knockout mice, further implicating hemopexin as a mediator of iron toxicity in AKI. Thus, our findings demonstrate that hemopexin accumulates in the kidneys and worsens kidney injury in AKI by increasing hemoglobin deposition on proximal tubular cells to exaggerate hemoglobin-induced cell injury.
Assuntos
Injúria Renal Aguda , Hemopexina , Camundongos , Animais , Hemopexina/metabolismo , Cisplatino/toxicidade , Desferroxamina , Injúria Renal Aguda/etiologia , Túbulos Renais Proximais/metabolismo , Rim/metabolismo , Camundongos Knockout , Hemoglobinas/metabolismo , Ferro/efeitos adversos , Camundongos Endogâmicos C57BL , Túbulos Renais/metabolismoRESUMO
Diabetic kidney disease (DKD) is one of the most common complications of diabetes and is clinically featured by progressive albuminuria, consequent to glomerular destruction that involves podocyte senescence. Burgeoning evidence suggests that ketosis, in particular ß-hydroxybutyrate, exerts a beneficial effect on aging and on myriad metabolic or chronic diseases, including obesity, diabetes and chronic kidney diseases. Its effect on DKD is largely unknown. In vitro in podocytes exposed to a diabetic milieu, ß-hydroxybutyrate treatment substantially mitigated cellular senescence and injury, as evidenced by reduced formation of γH2AX foci, reduced staining for senescence-associated-ß-galactosidase activity, diminished expression of key mediators of senescence signaling like p16INK4A and p21, and preserved expression of synaptopodin. This beneficial action of ß-hydroxybutyrate coincided with a reinforced transcription factor Nrf2 antioxidant response. Mechanistically, ß-hydroxybutyrate inhibition of glycogen synthase kinase 3ß (GSK3ß), a convergent point for myriad signaling pathways regulating Nrf2 activity, seems to contribute. Indeed, trigonelline, a selective inhibitor of Nrf2, or ectopic expression of constitutively active mutant GSK3ß abolished, whereas selective activation of Nrf2 was sufficient for the anti-senescent and podocyte protective effects of ß-hydroxybutyrate. Moreover, molecular modeling and docking analysis revealed that ß-hydroxybutyrate is able to directly target the ATP-binding pocket of GSK3ß and thereby block its kinase activity. In murine models of streptozotocin-elicited DKD, ß-hydroxybutyrate therapy inhibited GSK3ß and reinforced Nrf2 activation in glomerular podocytes, resulting in lessened podocyte senescence and injury and improved diabetic glomerulopathy and albuminuria. Thus, our findings may pave the way for developing a ß-hydroxybutyrate-based novel approach of therapeutic ketosis for treating DKD.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Podócitos , Ácido 3-Hidroxibutírico , Albuminúria , Animais , Nefropatias Diabéticas/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta , Glomérulos Renais , CamundongosRESUMO
Homologous recombination and DNA repair are important for genome maintenance. Genetic variations in essential homologous recombination genes, including BRCA1 and BRCA2 results in homologous recombination deficiency (HRD) and can be a target for therapeutic strategies including poly (ADP-ribose) polymerase inhibitors (PARPi). However, response is limited in patients who are not HRD, highlighting the need for reliable and robust HRD testing. This manuscript will review BRCA1/2 function and homologous recombination proficiency in respect to breast and ovarian cancer. The current standard testing methods for HRD will be discussed as well as trials leading to approval of PARPi's. Finally, standard of care treatment and synthetic lethality will be reviewed.
Assuntos
Neoplasias da Mama/genética , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Recombinação Homóloga/fisiologia , Neoplasias Ovarianas/genética , Reparo de DNA por Recombinação/fisiologia , Neoplasias da Mama/tratamento farmacológico , Feminino , Variação Genética , Humanos , Mutação , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/fisiologiaRESUMO
Radiation therapy (RT) in some cases results in a systemic anticancer response known as the abscopal effect. Multiple hypotheses support the role of immune activation initiated by RT-induced DNA damage. Optimal radiation dose is necessary to promote the cGAS-STING pathway in response to radiation and initiate an IFN-1 signaling cascade that promotes the maturation and migration of dendritic cells to facilitate antigen presentation and stimulation of cytotoxic T cells. T cells then exert a targeted response throughout the body at areas not subjected to RT. These effects are further augmented through the use of immunotherapeutic drugs resulting in increased T-cell activity. Tumor-infiltrating lymphocyte presence and TREX1, KPNA2 and p53 signal expression are being explored as prognostic biomarkers.
Assuntos
Quimiorradioterapia/métodos , Células Dendríticas/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/radioterapia , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Movimento Celular/efeitos da radiação , Ensaios Clínicos como Assunto , Dano ao DNA/imunologia , Dano ao DNA/efeitos da radiação , Células Dendríticas/efeitos da radiação , Exodesoxirribonucleases/análise , Exodesoxirribonucleases/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/efeitos da radiação , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/mortalidade , Fosfoproteínas/análise , Fosfoproteínas/metabolismo , Prognóstico , Intervalo Livre de Progressão , Dosagem Radioterapêutica , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/efeitos da radiação , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiação , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/metabolismo , alfa Carioferinas/análise , alfa Carioferinas/metabolismoRESUMO
Burgeoning evidence points to glycogen synthase kinase (GSK)3ß as a key player in diverse kidney diseases. However, as a pivotal transducer of the insulin signaling pathway, the role of GSK3ß in diabetic kidney disease remains uncertain. In db/db mice, renal expression of total and activated GSK3ß was increasingly elevated. This preceded the development of diabetic kidney disease, and correlated with the progression of signs of diabetic kidney injury, including albuminuria and extracellular matrix accumulation in glomeruli and tubulointerstitia. In vitro, exposure of glomerular podocytes, mesangial cells, and renal tubular cells to a diabetic milieu induced GSK3ß overexpression and hyperactivity, which seem essential and sufficient for eliciting diabetic cellular damages in kidney cells, because the cytopathic effect of the diabetic milieu was mitigated by GSK3ß knockdown, but was mimicked by ectopic expression of constitutively active GSK3ß even in the normal milieu. In consistency, kidney biopsy specimens procured from patients with varying stages of diabetic nephropathy revealed an amplified expression of total and activated GSK3ß in glomeruli and renal tubules, associated with the severity of diabetic nephropathy. Moreover, in retrospective cohorts of type 2 diabetic patients that were followed for over five years, the relative activity of GSK3ß in banked urinary exfoliated cells represented an independent risk factor for development or progression of renal impairment. Furthermore, receiver operating characteristic curve analysis demonstrated that GSK3ß activity in urinary exfoliated cells provided much better power than albuminuria in discriminating diabetic patients with progressive renal impairment from those with stable kidney function. Thus, renal expression and activity of GSK3ß are amplified in experimental and clinical diabetic nephropathy. Hence, GSK3ß in urinary exfoliated cells may serve as a novel biomarker for predicting diabetic kidney disease progression.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/diagnóstico , Glicogênio Sintase Quinase 3 beta/metabolismo , Urina/citologia , Adulto , Idoso , Animais , Biomarcadores/metabolismo , Biomarcadores/urina , Biópsia , Linhagem Celular , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/urina , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/urina , Diagnóstico Diferencial , Modelos Animais de Doenças , Progressão da Doença , Células Epiteliais/metabolismo , Feminino , Seguimentos , Glicogênio Sintase Quinase 3 beta/urina , Humanos , Túbulos Renais/citologia , Túbulos Renais/patologia , Masculino , Células Mesangiais/metabolismo , Camundongos , Pessoa de Meia-Idade , Podócitos/metabolismo , Curva ROC , Estudos Retrospectivos , Medição de Risco/métodos , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Prolonged use of corticosteroids continues to be the mainstay in the management of most proteinuric glomerulopathies, but is limited by extensive side effects. Alternative medications such as adrenocorticotropic hormone (ACTH) have been recently used to treat refractory glomerulopathies and have shown superior outcomes when compared with steroids. However, the clinical responsiveness to ACTH therapy varies considerably with a number of patients exhibiting de novo or acquired resistance. The underlying mechanism remains unknown. METHODS: A patient with steroid-dependent focal segmental glomerulosclerosis (FSGS) developed severe steroid side effects impacting quality of life and was converted to repository porcine ACTH therapy. Immediate response in the form of remission of nephrotic syndrome was noted followed by relapse in 10 weeks. Suspecting the role of some ACTH-antagonizing factors, the patient's serum was examined. RESULTS: Immunoblot-based antibody assay revealed high titers of de novo IgG antibodies in the patient's serum that were reactive to the porcine corticotropin with negligible cross-reactivity to human corticotropin. In vitro, in cultured B16 melanoma cells that express abundant melanocortin receptors, addition of the patient's serum substantially abrogated the porcine corticotropin triggered signaling activity of the melanocortinergic pathway, marked by phosphorylation of glycogen synthase kinase 3ß, thus suggesting a mitigating effect on the biological functionality of porcine corticotropin. CONCLUSION: ACTH is a useful alternative therapeutic modality for refractory proteinuric glomerulopathies like FSGS. However, as quintessential therapeutic biologics, natural ACTH, regardless of purity and origin, is inevitably antigenic and may cause the formation of neutralizing antibodies in some sensitive patients, followed by resistance to ACTH therapy. It is imperative to develop ACTH analogues with less immunogenicity for improving its responsiveness in patients with glomerular diseases.
Assuntos
Hormônio Adrenocorticotrópico/imunologia , Anticorpos Heterófilos/sangue , Anticorpos Neutralizantes/sangue , Glucocorticoides/farmacologia , Síndrome Nefrótica/tratamento farmacológico , Hormônio Adrenocorticotrópico/análogos & derivados , Hormônio Adrenocorticotrópico/uso terapêutico , Adulto , Animais , Anticorpos Heterófilos/imunologia , Anticorpos Neutralizantes/imunologia , Biópsia , Doença Crônica , Resistência a Medicamentos , Substituição de Medicamentos , Feminino , Glucocorticoides/uso terapêutico , Humanos , Rim/imunologia , Rim/patologia , Síndrome Nefrótica/sangue , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/imunologia , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Recidiva , Indução de Remissão/métodos , SuínosRESUMO
The clinical effectiveness of adrenocorticotropin in inducing remission of steroid-resistant nephrotic syndrome points to a steroidogenic-independent anti-proteinuric activity of melanocortins. However, which melanocortin receptors (MCR) convey this beneficial effect and if systemic or podocyte-specific mechanisms are involved remain uncertain. In vivo, wild-type (WT) mice developed heavy proteinuria and kidney dysfunction following Adriamycin insult, concomitant with focal segmental glomerulosclerosis (FSGS) and podocytopathy, marked by loss of podocin and synaptopodin, podocytopenia and extensive foot process effacement on electron microscopy. All these pathologic findings were prominently attenuated by NDP-MSH, a potent non-steroidogenic pan-MCR agonist. Surprisingly, MC1R deficiency in MC1R-null mice barely affected the severity of Adriamycin-elicited injury. Moreover, the beneficial effect of NDP-MSH was completely preserved in MC1R-null mice, suggesting that MC1R is likely non-essential for the protective action. A direct podocyte effect seems to contribute to the beneficial effect of NDP-MSH, because Adriamycin-inflicted cytopathic signs in primary podocytes prepared from WT mice were all mitigated by NDP-MSH, including apoptosis, loss of podocyte markers, de novo expression of the podocyte injury marker desmin, actin cytoskeleton derangement and podocyte hypermotility. Consistent with in vivo findings, the podoprotective activity of NDP-MSH was fully preserved in MC1R-null podocytes. Mechanistically, MC1R expression was predominantly distributed to glomerular endothelial cells in glomeruli but negligibly noted in podocytes in vivo and in vitro, suggesting that MC1R signaling is unlikely involved in direct podocyte protection. Ergo, melanocortin therapy protects against podocyte injury and ameliorates proteinuria and glomerulopathy in experimental FSGS, at least in part, via a podocyte-specific non-MC1R-mediated melanocortinergic signaling.
Assuntos
Albuminúria/prevenção & controle , Apoptose/efeitos dos fármacos , Glomerulosclerose Segmentar e Focal/prevenção & controle , Podócitos/efeitos dos fármacos , Receptor Tipo 1 de Melanocortina/agonistas , alfa-MSH/análogos & derivados , Albuminúria/induzido quimicamente , Albuminúria/metabolismo , Albuminúria/patologia , Animais , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Doxorrubicina , Glomerulosclerose Segmentar e Focal/induzido quimicamente , Glomerulosclerose Segmentar e Focal/metabolismo , Glomerulosclerose Segmentar e Focal/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Permeabilidade , Podócitos/metabolismo , Podócitos/ultraestrutura , Receptor Tipo 1 de Melanocortina/genética , Receptor Tipo 1 de Melanocortina/metabolismo , Transdução de Sinais , alfa-MSH/farmacologiaRESUMO
Given recent advances in cancer immune therapy, specifically use of checkpoint inhibitors, understanding the link between autoimmunity and cancer is essential. Rheumatoid arthritis (RA) affects about 1% of the population, and early diagnosis is key to prevent joint damage. Management consists of disease-modifying antirheumatic drugs that alter normal immunologic pathways, which could affect malignancy growth and survival. Prolonged immune dysregulation and the resulting inflammatory response associated with development of RA may also lead to increased cancer development risk. RA has long been associated with increased risk of non-Hodgkin's lymphoma [1] and further evidence supports relationship to lung cancer [2]. This review will address the mechanisms behind cancer development and progression in RA patients, biomarkers and assess cancer risk and early detection.
Assuntos
Artrite Reumatoide/etiologia , Neoplasias/patologia , Neoplasias/terapia , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Progressão da Doença , Humanos , Imunoterapia/efeitos adversos , Inflamação , Neoplasias/imunologia , RiscoRESUMO
Chimeric antigen receptor (CAR) modified T-cell therapy, a unique platform technology highlighting precision medicine through utilization of molecular biology and cell-based therapeutics has shown unprecedented rates in patients with hematological malignancies such as acute lymphocyte leukemia, non-Hodgkin's lymphoma and multiple myeloma (MM). With the approval of CD19-targeted CAR T-cells by the Food and Drug Administration in acute lymphoblastic leukemia (ALL) and NHL, this technology is positioned for aggressive expansion to combination therapeutic opportunities and proof of principle towards utility in other malignant disorders. However, despite the impressive results seen with hematological malignancies, CAR T-cells have shown limited efficacy in solid tumors with several unsuccessful preclinical studies. Regardless, these attempts have provided us with a better understanding of the imminent challenges specific to solid tumors even if they have not so far led to expanded clinical treatment opportunities outside ALL/NHL/MM. This review summarizes our current understanding of CAR T-cell mechanism of action, while presenting the major limitations of CAR T-cell derived treatments in solid tumors. We further discuss recent findings and present new potential strategies to overcome the challenges facing solid tumor targeting by CAR T-cell platforms.
Assuntos
Imunoterapia Adotiva , Linfoma não Hodgkin/terapia , Mieloma Múltiplo/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/imunologia , Antígenos CD19/imunologia , Humanos , Estudo de Prova de ConceitoRESUMO
BACKGROUND: The aim of this study was to examine the relationship of albuminuria to cardiovascular disease outcomes in diabetic patients undergoing treatment for stable coronary artery disease. METHODS AND RESULTS: We analyzed data from 2176 participants of the Bypass Angioplasty Revascularization Investigation in type-2 diabetes (BARI-2D) trial, a randomized clinical trial comparing Percutaneous coronary intervention/Coronary artery bypass grafting (PCI/CABG) to medical therapy for people with diabetes. The population was stratified by baseline spot urine albumin-creatinine ratio (uACR) into normal (uACR <10 mg/g), mildly (uACR ≥10 mg/g < 30 mg/g), moderately (uACR ≥30 mg/g < 300 mg/g) and severely increased (uACR ≥300 mg/g) groups, and outcomes compared between groups. Death, myocardial infarction (MI) and/or stroke were experienced by 489 patients at a mean follow-up of 4.3 ± 1.5 years. Compared with normal uACR, mildly increased uACR was associated with a 1.4 times (P = 0.042) increase in all-cause mortality. Additionally, nonwhites with type-II diabetes and stable coronary artery disease who had mildly increased albuminuria had a Hazard ratio (HR) of 3.3 times (P = 0.028) for cardiovascular death, 3.1 times for (P = 0.002) all-cause mortality, and two times for (P = 0.015) MI during follow-up. CONCLUSIONS: Mildly increased albuminuria is a significant predictor of all-cause mortality in those with type-II diabetes mellitus and stable coronary artery disease, as well as for cardiovascular events those who are nonwhites.
Assuntos
Albuminúria/etnologia , Fármacos Cardiovasculares/uso terapêutico , Ponte de Artéria Coronária , Doença da Artéria Coronariana/terapia , Diabetes Mellitus Tipo 2/etnologia , Nefropatias Diabéticas/etnologia , Intervenção Coronária Percutânea , Idoso , Albuminúria/diagnóstico , Albuminúria/mortalidade , Brasil/epidemiologia , Fármacos Cardiovasculares/efeitos adversos , Ponte de Artéria Coronária/efeitos adversos , Ponte de Artéria Coronária/mortalidade , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/etnologia , Doença da Artéria Coronariana/mortalidade , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/mortalidade , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etnologia , Infarto do Miocárdio/mortalidade , América do Norte/epidemiologia , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/etnologia , Acidente Vascular Cerebral/mortalidade , Fatores de Tempo , Resultado do TratamentoRESUMO
Selective delivery of therapeutic agents into solid tumors has been a major challenge impeding the achievement of long-term disease remission and cure. The need to develop alternative drug delivery routes to achieve higher drug concentration in tumor tissue, reduce unwanted off-target side effects and thus achieve greater therapeutic efficacy, has resulted in an explosive body of research. Bifidobacterium spp. are anaerobic, nonpathogenic, Gram-positive bacteria, commensal to the human gut that are a possible anticancer drug-delivery vehicle. In this review, we describe Bifidobacterium's microbiology, current clinical applications, overview of the preclinical work investigating Bifidobacterium's potential to deliver anticancer therapy, and review the different strategies used up to date. Finally, we discuss both current challenges and future prospects.
Assuntos
Bifidobacterium/fisiologia , Sistemas de Liberação de Medicamentos/métodos , Imunoterapia/métodos , Oncologia/métodos , Neoplasias/terapia , Medicina de Precisão/métodos , Animais , Antineoplásicos/administração & dosagem , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Genes Reporter/genética , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Oncologia/tendências , Neoplasias/genética , Neoplasias/imunologia , Plasmídeos/genética , Medicina de Precisão/tendências , Probióticos/administração & dosagem , Resultado do TratamentoRESUMO
Natural killer (NK) cells lead immune surveillance against cancer and early elimination of small tumors. Owing to their ability to engage tumor targets without the need of specific antigen, the therapeutic potential of NK cells has been extensively explored in hematological malignancies. In solid tumors, however, their role in the clinical arena remains poorly exploited despite a broad accumulation of preclinical data. In this article, we review our current knowledge of NK cells' biology, and highlight the challenges facing NK cell antitumor strategies in solid tumors. We further summarize the abundant preclinical attempts at overcoming these challenges, present past and ongoing clinical trial data and finally discuss the potential impact of novel insights on the development of NK cell-based therapies.
Assuntos
Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Animais , Humanos , Vigilância Imunológica , Imunoterapia Adotiva , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/terapia , Células-Tronco Neoplásicas/metabolismo , Receptores KIR/metabolismo , Transdução de Sinais , Evasão Tumoral/genética , Evasão Tumoral/imunologiaRESUMO
BACKGROUND/AIMS: Ecdysteroids are steroidal insect molting hormones that also exist in herbs. Ecdysteroid-containing adaptogens have been popularly used to improve well-being and by bodybuilders for muscle growth. However, the use of ecdysone in mammals is also associated with kidney growth and enlargement, indications of disturbed kidney homeostasis. The underlying pathogenic mechanism remains to be clarified. METHODS: Virtual screening tools were employed to identify compounds that are homologous to ecdysone and to predict putative ecdysone-interacting proteins. The kidney effect of ecdysone was examined in vitro and in vivo and compared with that of aldosterone. Cellular apoptosis was estimated by terminal deoxynucleotidyl transferase dUTP nick end labeling. Cell motility was assessed by scratch-wound cell migration assay. Blood urea nitrogen was measured to evaluate renal function. Western immunblot analysis was employed to determine the expression profile of interested proteins. RESULTS: Computational molecular structure analysis revealed that ecdysone is highly homologous to aldosterone. Moreover, virtual screening based on compound-protein interaction profiles identified the Mineralocorticoid Receptor (MR) to potentially interact with ecdysone. Accordingly, to assess potential biological functions of ecdysone in mammals, ecdysone was applied to mineralocorticoid-sensitive inner medullar collecting duct cells. Ecdysone induced mesenchymal accumulation of extracellular matrix and epithelial dedifferentiation characterized by de novo expression of α-smooth muscle actin. In addition, ecdysone elicited cellular apoptosis and retarded cell motility, akin to the effect of aldosterone. In vivo, daily treatment of mice with ecdysone increased cell apoptosis in the kidney, impaired renal function and elicited early signs of renal fibrogenesis, marked by deposition of collagen and fibronectin in tubulointerstitium, reminiscent of the action of aldosterone. The MR signaling pathway is likely responsible for the cellular and pathobiological effects of ecdysone, as evidenced by strong ecdysone-induced MR nuclear translocation in renal tubular cells both in vitro and in vivo, while blockade of MR by concomitant spironolactone treatment largely abolished the detrimental effects of ecdysone. CONCLUSION: Our findings suggest that ecdysone induces mineralocorticoid-dependent activities that impair renal function and elicit renal injury.
Assuntos
Apoptose/efeitos dos fármacos , Ecdisona/farmacologia , Mineralocorticoides/farmacologia , Insuficiência Renal Crônica/patologia , Aldosterona/farmacologia , Animais , Nitrogênio da Ureia Sanguínea , Desdiferenciação Celular , Linhagem Celular , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Fibronectinas/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Mineralocorticoides/metabolismo , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
PURPOSE: Obstructive sleep apnea is common in patients with end-stage renal disease, and there is increasing evidence that clinical factors specific to end-stage renal disease contribute pathophysiologically to obstructive sleep apnea. It is not known whether circumstances specific to dialysis modality, in this case peritoneal dialysis, affect obstructive sleep apnea. Our study aimed to investigate the prevalence of obstructive sleep apnea in the peritoneal dialysis population and the relevance of dialysis-specific measures and kidney function in assessing this bidirectional relationship. METHODS: Participants with end-stage renal disease who were treated with nocturnal automated peritoneal dialysis for at least 3 months were recruited from a hospital-based dialysis center. Laboratory measures of dialysis adequacy, peritoneal membrane transporter status, and residual renal function were gathered by chart review. Patients participated in a home sleep apnea test using a level III sleep apnea monitor. RESULTS: Of fifteen participants recruited, 33% had obstructive sleep apnea diagnosed by apnea-hypopnea index ≥ 5 events per hour of sleep. Renal creatinine clearance based upon 24-h urine collection was negatively correlated with apnea-hypopnea index (ρ = - 0.63, p = 0.012). There were no significant associations between anthropometric measures, intra-abdominal dwell volume, or peritoneal membrane transporter status and obstructive sleep apnea measures. CONCLUSIONS: The prevalence of obstructive sleep apnea and sleep disturbances is high in participants receiving peritoneal dialysis. Elevated apnea-hypopnea index is associated with lower residual renal function, whereas dialysis-specific measures such as intra-abdominal dwell volume and peritoneal membrane transporter status do not correlate with severity of obstructive sleep apnea.
Assuntos
Falência Renal Crônica/terapia , Rim/fisiopatologia , Diálise Peritoneal/efeitos adversos , Apneia Obstrutiva do Sono/epidemiologia , Adulto , Idoso , Feminino , Humanos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prevalência , Rhode Island/epidemiologia , Fatores de Risco , Índice de Gravidade de Doença , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/fisiopatologia , Fatores de Tempo , Resultado do TratamentoRESUMO
The original version of this article unfortunately contained a mistake in the article title. The correct article title is "Residual Renal Function and Obstructive Sleep Apnea in Peritoneal Dialysis: A Pilot Study".