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INTRODUCTION: Intestinal inflammation and gut microbiota dysbiosis can stimulate degeneration of dopaminergic neurons and development of Parkinson's disease (PD) via the gut-brain axis in certain patients. METHODS: In a case-control study, fecal markers of intestinal inflammation and permeability were measured using the ELISA method in PD patients and healthy controls. Motor and nonmotor symptoms were assessed using the Movement Disorder Society (MDS) Unified PD Rating Scale, Hoehn & Yahr scale, MDS Non-Motor Symptom Scale, Scales for Outcomes in PD - Autonomic Dysfunction, PD Sleep Scale - 2, Montreal Cognitive Assessment, Beck Anxiety Inventory, and Beck Depression Inventory-II. A correlation was established between the intestinal inflammation and permeability markers and PD symptoms. RESULTS: Higher levels of beta-defensin 2, zonulin and lactoferrin were recorded in PD patients compared to controls. Calprotectin and secretory immunoglobulin A showed no significant differences. Regression analysis indicated the roles of beta-defensin 2 and lactoferrin in predicting PD likelihood. Calprotectin yielded positive correlations with disease duration, depression, motor fluctuations, and gastrointestinal symptoms; beta defensin 2 with thermoregulation; and secretory immunoglobulin A with depression. Secretory immunoglobulin A showed negative correlation with age and age at disease onset, while zonulin showed negative correlation with the MDS Unified PD Rating Scale total score. CONCLUSIONS: Fecal markers differed in PD patients compared to controls and correlated with age, disease duration, and some nonmotor symptoms. Future studies should identify the subgroups of PD patients that are likely to develop intestinal inflammation.
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Haptoglobinas , Lactoferrina , Enfermedad de Parkinson , Precursores de Proteínas , beta-Defensinas , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/metabolismo , Femenino , Masculino , Persona de Mediana Edad , Anciano , Estudios de Casos y Controles , Toxina del Cólera/metabolismo , Biomarcadores , Complejo de Antígeno L1 de Leucocito/análisis , Permeabilidad , Heces/química , Gastroenteritis/complicacionesRESUMEN
Functional dyspepsia is a common functional disorder of the gastrointestinal tract that is responsible for many primary care visits. No organic changes have been found to explain its symptoms. We hypothesize that modern lifestyles and environmental factors, especially psychological stress, play a crucial role in the high prevalence of functional dyspepsia and metabolic syndrome. While gastrointestinal tract diseases are rarely linked to metabolic disorders, chronic stress, obesity-related metabolic syndrome, chronic inflammation, intestinal dysbiosis, and functional dyspepsia have significant pathophysiological associations. Functional dyspepsia, often associated with anxiety and chronic psychological stress, can activate the neuroendocrine stress axis and immune system, leading to unhealthy habits that contribute to obesity. Additionally, intestinal dysbiosis, which is commonly present in functional dyspepsia, can exacerbate systemic inflammation and obesity, further promoting metabolic syndrome-related disorders. It is worth noting that the reverse is also true: obesity-related metabolic syndrome can worsen functional dyspepsia and its associated symptoms by triggering systemic inflammation and intestinal dysbiosis, as well as negative emotions (depression) through the brain-gut axis. To understand the pathophysiology and deliver an effective treatment strategy for these two difficult-to-cure disorders, which are challenging for both caregivers and patients, a psychosocial paradigm is essential.
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Dispepsia , Síndrome Metabólico , Humanos , Dispepsia/epidemiología , Dispepsia/etiología , Síndrome Metabólico/epidemiología , Síndrome Metabólico/complicaciones , Disbiosis , Inflamación/epidemiología , Inflamación/complicaciones , Obesidad/complicaciones , Obesidad/epidemiologíaRESUMEN
In metastatic urothelial cancer (mUC), cisplatin versus carboplatin leads to durable disease control in a subset of patients. The IMvigor130 trial reveals more favorable effects with atezolizumab combined with gemcitabine and cisplatin (GemCis) versus gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin as a potential explanation for these observations. Our findings indicate that improved outcomes with GemCis versus GemCarbo are primarily observed in patients with pretreatment tumors exhibiting features of restrained adaptive immunity. In addition, GemCis versus GemCarbo ± atezolizumab induces transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T cell activation programs. In vitro experiments demonstrate that cisplatin, compared with carboplatin, exerts direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in mUC and highlight the importance of specific chemotherapy backbones in immunotherapy combination regimens.
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Anticuerpos Monoclonales Humanizados , Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Neoplasias Urológicas , Humanos , Carboplatino/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/inducido químicamente , Carcinoma de Células Transicionales/patología , Cisplatino/uso terapéutico , Desoxicitidina/uso terapéutico , Gemcitabina , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/inducido químicamente , Neoplasias Urológicas/patologíaRESUMEN
Ubiquitination is a posttranslational modification that is crucial for the dynamic regulation of diverse signaling pathways. To enhance our understanding of ubiquitination-mediated signaling, we generated a new class of bispecific antibodies that combine recognition of ubiquitination substrates and specific polyubiquitin linkages. RIP1-K63 and RIP1-linear (Lin) linkage polyubiquitin bispecific antibodies detected linkage-specific ubiquitination of the proinflammatory kinase RIP1 in cells and in tissues and revealed RIP1 ubiquitination by immunofluorescence. Similarly, ubiquitination of the RIP1-related kinase RIP2 with K63 or linear linkages was specifically detected with the RIP2-K63 and RIP2-Lin bispecific antibodies, respectively. Furthermore, using the RIP2-K63 and RIP2-Lin bispecific antibodies, we found prominent K63-linked and linear RIP2 ubiquitination in samples from patients with ulcerative colitis and Crohn's disease. We also developed a bispecific antibody (K63-Lin) that simultaneously recognizes K63-linked and linear ubiquitination of components of various signaling pathways. Together, these bispecific antibodies represent a new class of reagents with the potential to be developed for the detection of inflammatory biomarkers.
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Anticuerpos Biespecíficos , Ubiquitina , Humanos , Anticuerpos Biespecíficos/metabolismo , Poliubiquitina/metabolismo , Transducción de Señal/fisiología , Ubiquitina/metabolismo , UbiquitinaciónRESUMEN
Graft-versus-host disease (GVHD) remains the major cause of morbidity and nonrelapse mortality (NRM) after hematopoietic cell transplantation (HCT). Inflammatory cytokines mediate damage to key GVHD targets such as intestinal stem cells (ISCs) and also activate receptor interacting protein kinase 1 (RIP1; RIPK1), a critical regulator of apoptosis and necroptosis. We therefore investigated the role of RIP1 in acute GVHD using samples from HCT patients, modeling GVHD damage in vitro with both human and mouse gastrointestinal (GI) organoids, and blocking RIP1 activation in vivo using several well-characterized mouse HCT models. Increased phospho-RIP1 expression in GI biopsies from patients with acute GVHD correlated with tissue damage and predicted NRM. Both the genetic inactivation of RIP1 and the RIP1 inhibitor GNE684 prevented GVHD-induced apoptosis of ISCs in vivo and in vitro. Daily administration of GNE684 for 14 days reduced inflammatory infiltrates in three GVHD target organs (intestine, liver, and spleen) in mice. Unexpectedly, GNE684 administration also reversed the marked loss of regulatory T cells in the intestines and liver during GVHD and reduced splenic T cell exhaustion, thus improving immune reconstitution. Pharmacological and genetic inhibition of RIP1 improved long-term survival without compromising the graft-versus-leukemia (GVL) effect in lymphocytic and myeloid leukemia mouse models. Thus, RIP1inhibition may represent a nonimmunosuppressive treatment for GVHD.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Reconstitución Inmune , Leucemia , Humanos , Ratones , Animales , Citocinas , Leucemia/terapiaRESUMEN
Cellular inhibitor of apoptosis proteins (cIAPs) are RING-containing E3 ubiquitin ligases that ubiquitylate receptor-interacting protein kinase 1 (RIPK1) to regulate TNF signalling. Here, we established mice simultaneously expressing enzymatically inactive cIAP1/2 variants, bearing mutations in the RING domains of cIAP1/2 (cIAP1/2 mutant RING, cIAP1/2MutR ). cIap1/2MutR/MutR mice died during embryonic development due to RIPK1-mediated apoptosis. While expression of kinase-inactive RIPK1D138N rescued embryonic development, Ripk1D138N/D138N /cIap1/2MutR/MutR mice developed systemic inflammation and died postweaning. Cells expressing cIAP1/2MutR and RIPK1D138N were still susceptible to TNF-induced apoptosis and necroptosis, implying additional kinase-independent RIPK1 activities in regulating TNF signalling. Although further ablation of Ripk3 did not lead to any phenotypic improvement, Tnfr1 gene knock-out prevented early onset of systemic inflammation and premature mortality, indicating that cIAPs control TNFR1-mediated toxicity independent of RIPK1 and RIPK3. Beyond providing novel molecular insights into TNF-signalling, the mouse model established in this study can serve as a useful tool to further evaluate ongoing therapeutic protocols using inhibitors of TNF, cIAPs and RIPK1.
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Proteínas Inhibidoras de la Apoptosis , Receptores Tipo I de Factores de Necrosis Tumoral , Animales , Ratones , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Muerte Celular , Apoptosis , Inflamación/genética , Inflamación/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Receptor-interacting protein 1 (RIP1) is a key regulator of multiple signaling pathways that mediate inflammatory responses and cell death. RIP1 kinase activity mediates apoptosis and necroptosis induced by tumor necrosis factor (TNF)-α, Toll-like receptors, and ischemic tissue damage. RIP1 has been implicated in several human pathologies and consequently, RIP1 inhibition may represent a therapeutic approach for diseases dependent on RIP1-mediated inflammation and cell death. GDC-8264 is a potent, selective, and reversible small molecule inhibitor of RIP1 kinase activity. This phase I, randomized, placebo-controlled, double-blinded trial examined safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single- (5-225 mg) and multiple- (50 and 100 mg once daily, up to 14 days) ascending oral doses of GDC-8264 in healthy volunteers, and also tested the effect of food on the PKs of GDC-8264. All adverse events in GDC-8264-treated subjects in both stages were mild. GDC-8264 exhibited dose-proportional increases in systemic exposure; the mean terminal half-life ranged from 10-13 h, with limited accumulation on multiple dosing (accumulation ratio [AR] ~ 1.4); GDC-8264 had minimal renal excretion at all doses. A high-fat meal had no significant effect on the PKs of GDC-8264. In an ex vivo stimulation assay of whole blood, GDC-8264 rapidly and completely inhibited release of CCL4, a downstream marker of RIP1 pathway activation, indicating a potent pharmacological effect. Based on PK-PD modeling, the GDC-8264 half-maximal inhibitory concentration for the inhibition of CCL4 release was estimated to be 0.58 ng/mL. The favorable safety, PKs, and PDs of GDC-8264 support its further development for treatment of RIP1-driven diseases.
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Proteína Serina-Treonina Quinasas de Interacción con Receptores , Transducción de Señal , Humanos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Voluntarios Sanos , Proteína Serina-Treonina Quinasas de Interacción con Receptores/antagonistas & inhibidoresRESUMEN
XIAP is a caspase-inhibitory protein that blocks several cell death pathways, and mediates proper activation of inflammatory NOD2-RIP2 signaling. XIAP deficiency in patients with inflammatory diseases such as Crohn's disease, or those needing allogeneic hematopoietic cell transplantation, is associated with a worse prognosis. In this study, we show that XIAP absence sensitizes cells and mice to LPS- and TNF-mediated cell death without affecting LPS- or TNF-induced NF-κB and MAPK signaling. In XIAP deficient mice, RIP1 inhibition effectively blocks TNF-stimulated cell death, hypothermia, lethality, cytokine/chemokine release, intestinal tissue damage and granulocyte migration. By contrast, inhibition of the related kinase RIP2 does not affect TNF-stimulated events, suggesting a lack of involvement for the RIP2-NOD2 signaling pathway. Overall, our data indicate that in XIAP's absence RIP1 is a critical component of TNF-mediated inflammation, suggesting that RIP1 inhibition could be an attractive option for patients with XIAP deficiency.
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Lipopolisacáridos , Trastornos Linfoproliferativos , Animales , Ratones , Lipopolisacáridos/farmacología , FN-kappa B/metabolismo , Transducción de Señal , Factores de Necrosis Tumoral/metabolismoRESUMEN
Receptor interacting protein 1 (RIP1) kinase is a critical regulator of inflammation and cell death signaling, and plays a crucial role in maintaining immune responses and proper tissue homeostasis. Mounting evidence argues for the importance of RIP1 post-translational modifications in control of its function. Ubiquitination by E3 ligases, such as inhibitors of apoptosis (IAP) proteins and LUBAC, as well as the reversal of these modifications by deubiquitinating enzymes, such as A20 and CYLD, can greatly influence RIP1 mediated signaling. In addition, cleavage by caspase-8, RIP1 autophosphorylation, and phosphorylation by a number of signaling kinases can greatly impact cellular fate. Disruption of the tightly regulated RIP1 modifications can lead to signaling disbalance in TNF and/or TLR controlled and other inflammatory pathways, and result in severe human pathologies. This review will focus on RIP1 and its many modifications with an emphasis on ubiquitination, phosphorylation, and cleavage, and their functional impact on the RIP1's role in signaling pathways.
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Procesamiento Proteico-Postraduccional , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Apoptosis/fisiología , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Fosforilación , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Transducción de Señal , UbiquitinaciónRESUMEN
Elevated expression of the X-linked inhibitor of apoptosis protein (XIAP) has been frequently reported in malignant melanoma suggesting that XIAP renders apoptosis resistance and thereby supports melanoma progression. Independent of its anti-apoptotic function, XIAP mediates cellular inflammatory signalling and promotes immunity against bacterial infection. The pro-inflammatory function of XIAP has not yet been considered in cancer. By providing detailed in vitro analyses, utilising two independent mouse melanoma models and including human melanoma samples, we show here that XIAP is an important mediator of melanoma neutrophil infiltration. Neutrophils represent a major driver of melanoma progression and are increasingly considered as a valuable therapeutic target in solid cancer. Our data reveal that XIAP ubiquitylates RIPK2, involve TAB1/RIPK2 complex and induce the transcriptional up-regulation and secretion of chemokines such as IL8, that are responsible for intra-tumour neutrophil accumulation. Alteration of the XIAP-RIPK2-TAB1 inflammatory axis or the depletion of neutrophils in mice reduced melanoma growth. Our data shed new light on how XIAP contributes to tumour growth and provides important insights for novel XIAP targeting strategies in cancer.
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Proteínas Inhibidoras de la Apoptosis , Melanoma , Infiltración Neutrófila , Neoplasias Cutáneas , Proteína Inhibidora de la Apoptosis Ligada a X , Proteínas Adaptadoras Transductoras de Señales/inmunología , Animales , Apoptosis/genética , Apoptosis/inmunología , Modelos Animales de Enfermedad , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/inmunología , Interleucina-8/biosíntesis , Melanoma/genética , Melanoma/inmunología , Ratones , Infiltración Neutrófila/genética , Infiltración Neutrófila/inmunología , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor/inmunología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Proteína Inhibidora de la Apoptosis Ligada a X/inmunología , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismoRESUMEN
Visceral adipose tissue is an independent risk factor for the development of atherosclerotic coronary disease, arterial hypertension, diabetes and metabolic syndrome. Right heart morphology often involves the presence of adipose tissue, which can be quantified by non-invasive imaging methods. The last decade brought a wealth of new insights into the function and morphology of adipose tissue, with great emphasis on its role in the pathogenesis of heart disease. Cardiac adipose tissue is involved in thermogenesis, mechanical protection of the heart and energy storage. However, it can also be an endocrine organ that synthesises numerous pro-inflammatory and anti-inflammatory cytokines, the effect of which is accomplished by paracrine and vasocrine mechanisms. Visceral adipose tissue has several compartments that differ in their embryological origin and vascularisation. Deficiency of cardiac adipose tissue, often due to chronic pathological conditions such as oncological diseases or chronic infectious diseases, predicts increased mortality and morbidity. To date, knowledge about the influence of visceral adipose tissue on cardiac morphology is limited, especially the effect on the morphology of the right heart in a state of excess or deficient visceral adipose tissue.
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Proper recognition of invading pathogens and prompt initiation of host defense mechanisms are instrumental for the maintenance of organismal homeostasis. Nucleotide-binding oligomerization domain-containing (NOD)-like receptors (NLRs) serve as pathogen-recognition receptors that specifically recognize bacterial peptidoglycans. NOD2 detects muramyl dipeptide (MDP) through its carboxy-terminal leucine rich repeats (LRRs), which enables the activation of downstream inflammatory signaling. Synthesis of MDP conjugates based on solution phase chemistry have been previously reported. Our solid phase approach synthetically provides a facile approach for the conjugation of biological probes to MDP, with the advantage of minimal functional/protecting group manipulation, and reduction in the laborious process of intermediate purification and isolation. MDP conjugates that we generated using solid phase synthesis allow detection of NOD2 is cell lysates and NOD2 subcellular localization by immunofluorescence microscopy. MDP-PEG6-Cyanine5.5 conjugate selectively colocalized with WT NOD2 but not NOD2 variant found in Crohn's disease, which lacks carboxy-terminal end and cannot bind MDP. Overall, these data indicate that distinct solid phase-produced MDP conjugates can be used to examine biological properties of NOD2 and could potentially facilitate further development of NOD2 targeting agents.
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Acetilmuramil-Alanil-Isoglutamina/síntesis química , Proteína Adaptadora de Señalización NOD2/análisis , Técnicas de Síntesis en Fase Sólida , Células A549 , Acetilmuramil-Alanil-Isoglutamina/química , Células HEK293 , Humanos , Microscopía Fluorescente , Estructura MolecularRESUMEN
The term resilience, which has been present in science for almost half a century, stands for the capacity of some system needed to overcome an amount of disturbance from the environment in order to avoid a change to another stable state. In medicine, the concept of resilience means the ability to deal with daily stress and disturbance to our homeostasis with the intention of protecting it from disturbance. With aging, the organism becomes more sensitive to environmental impacts and more susceptible to changes. Mental disturbances and a decline in psychological resilience in older people are potentiated with many social and environmental factors along with a subjective perception of decreasing health. Distinct from findings in younger age groups, mental and physical medical conditions in older people are closely associated with each other, sharing common mechanisms and potentiating each other's development. Increased inflammation and oxidative stress have been recognized as the main driving mechanisms in the development of aging diseases. This paper aims to reveal, through a translational approach, physiological and molecular mechanisms of emotional distress and low psychological resilience in older individuals as driving mechanisms for the accelerated development of chronic aging diseases, and to systematize the available information sources on strategies for mitigation of low resilience in order to prevent chronic diseases.
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Envejecimiento/fisiología , Resiliencia Psicológica , Estrés Psicológico/psicología , Anciano , Anciano de 80 o más Años , Enfermedad Crónica/psicología , Femenino , Humanos , Inflamación/fisiopatología , Masculino , Persona de Mediana Edad , Estrés Oxidativo/fisiologíaRESUMEN
Proper maintenance of organismal homeostasis, development, and immune defense requires precise regulation of survival and signaling pathways. Inhibitor of apoptosis (IAP) proteins are evolutionarily conserved regulators of cell death and immune signaling that impact numerous cellular processes. Although initially characterized as inhibitors of apoptosis, the ubiquitin ligase activity of IAP proteins is critical for modulating various signaling pathways (e.g., NF-κB, MAPK) and cell survival. Cellular IAP1 and 2 regulate the pro-survival canonical NF-κB pathway by ubiquitinating RIP1 and themselves thus enabling recruitment of kinase (IKK) and E3 ligase (LUBAC) complexes. On the other hand, c-IAP1 and c-IAP2 are negative regulators of noncanonical NF-κB signaling by promoting ubiquitination and consequent proteasomal degradation of the NF-κB-inducing kinase NIK. Here we describe the involvement of c-IAP1 and c-IAP2 in NF-κB signaling and provide detailed methodology for examining functional roles of c-IAPs in these pathways.
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Transducción de Señal , Apoptosis , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , FN-kappa B/metabolismo , Receptores del Factor de Necrosis Tumoral , Factor de Necrosis Tumoral alfa/metabolismo , UbiquitinaciónRESUMEN
We hypothesized that the proximity-driven ubiquitylation of E3-interacting small molecules could affect the degradation of E3 ubiquitin ligases. A series of XIAP BIR2 domain-binding small molecules was modified to append a nucleophilic primary amine. This modification transforms XIAP binders into inducers of XIAP degradation. The degradation of XIAP is E1- and proteasome-dependent, dependent on the ligase function of XIAP, and is rescued by subtle modifications of the small molecule that would obviate ubiquitylation. We demonstrate in vitro ubiquitylation of the small molecule that is dependent on its interaction with XIAP. Taken together, these results demonstrate the designed ubiquitylation of an engineered small molecule and a novel approach for the degradation of E3 ubiquitin ligases.
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Aminas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Proteína Inhibidora de la Apoptosis Ligada a X/antagonistas & inhibidores , Aminas/química , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/química , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismoRESUMEN
Management of hair loss in women presents several challenges for general practitioners, who are the first in identifying its cause and consequences in everyday clinical practice. It is usually associated with multiple secondary factors, including endocrine disorders, drug side effects, and physical or emotional stress. We report a possible pathophysiological link between hyperprolactinemia and alopecia in a patient with preexisting autoimmune thyroid disease, which has not been documented in a significant number in the literature. A 27-year-old female patient with a previous history of an autoimmune thyroid disease on hormone substitution therapy presented to a family doctor with signs of frontal alopecia that had started several months previously. On examination, frontal alopecia was confirmed. Laboratory results and thyroid ultrasound confirmed autoimmune thyroid disease, with reduced parathyroid hormone and elevated prolactin. Her female sex hormones were in the normal range. Due to elevated prolactin levels, computed tomography of the pituitary gland was performed, which excluded any brain pathology. Based on available data, there is no published systematic analysis on hyperprolactinemia-induced alopecia in previous autoimmune diseases (large cohort studies). This report indicates that, due to moderately elevated prolactin values, consideration of alternative causes and further diagnostics are necessary to exclude a prolactin-producing tumor of the pituitary gland.
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Enfermedad de Hashimoto , Hiperprolactinemia , Adulto , Alopecia/inducido químicamente , Medicina Familiar y Comunitaria , Femenino , Humanos , Hiperprolactinemia/inducido químicamente , Hiperprolactinemia/complicaciones , ProlactinaRESUMEN
INTRODUCTION: Rifampicin is currently used to treat various bacterial infections, with the most significant application in the treatment of tuberculosis. Dose-independent side effects of the drug can lead to the development of various coagulation disorders, among which disseminated intravascular coagulation is the most dangerous. The mechanism of coagulopathy itself is multifactorial, but it is thought to be mediated by an immune response (formation of antigen-antibody complexes) and consequent damage to platelets and the vascular endothelium. PATIENT CONCERNS: A 66-year-old woman, with numerous comorbidities including chronic renal failure, condition after implantation of a permanent pacemaker, and a positive blood culture for Staphylococcus aureus, presented with spontaneous bleeding in the muscle wall, and in the clinical picture of hemorrhagic shock. DIAGNOSIS: Knowing the multifactorial mechanism of rifampicin-induced coagulopathy, possible factors were considered, such as infections, comorbidities, drug use and drug-drug interactions, pathological laboratory parameters, and coagulograms. Clinical presentation of abdominal pain and intra-abdominal mass, with laboratory verification of prolonged activated partial thromboplastin time and computed tomography-proven hematoma suspected of acute bleeding, redirects clinical suspicion of drug-induced coagulopathy. INTERVENTIONS: By discontinuing rifapicin and administering vitamin K and fresh frozen plasma, normalization of laboratory coagulation parameters was achieved. Bleeding from the muscle wall required correction of acute anemia with red cell concentrates, surgical intervention, and additional antibiotic therapy for secondary infection of the operative wound. OUTCOMES: At the end of 6âweeks of antibiotic (antistaphylococcal) therapy (due to the basic suspicion of possible infectious endocarditis), the normalization of inflammatory parameters occurred with a sterile control blood culture and a normal coagulogram. CONCLUSION: Clinicians should be aware of the possible side effects of the administered drugs, especially taking into account the overall clinical picture of a patient, including comorbidities and possible drug interactions.
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Pared Abdominal/irrigación sanguínea , Antibacterianos/efectos adversos , Coagulación Intravascular Diseminada/inducido químicamente , Rifampin/efectos adversos , Infecciones Estafilocócicas/tratamiento farmacológico , Anciano , Coagulación Intravascular Diseminada/terapia , Femenino , Humanos , Plasma , Vitamina K/uso terapéuticoRESUMEN
RIP1 kinase-mediated inflammatory and cell death pathways have been implicated in the pathology of acute and chronic disorders of the nervous system. Here, we describe a novel animal model of RIP1 kinase deficiency, generated by knock-in of the kinase-inactivating RIP1(D138N) mutation in rats. Homozygous RIP1 kinase-dead (KD) rats had normal development, reproduction and did not show any gross phenotypes at baseline. However, cells derived from RIP1 KD rats displayed resistance to necroptotic cell death. In addition, RIP1 KD rats were resistant to TNF-induced systemic shock. We studied the utility of RIP1 KD rats for neurological disorders by testing the efficacy of the genetic inactivation in the transient middle cerebral artery occlusion/reperfusion model of brain injury. RIP1 KD rats were protected in this model in a battery of behavioral, imaging, and histopathological endpoints. In addition, RIP1 KD rats had reduced inflammation and accumulation of neuronal injury biomarkers. Unbiased proteomics in the plasma identified additional changes that were ameliorated by RIP1 genetic inactivation. Together these data highlight the utility of the RIP1 KD rats for target validation and biomarker studies for neurological disorders.