RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1.

RUNX1 transcription factor regulates normal and malignant hematopoiesis. Somatic or germline mutant RUNX1 (mtRUNX1) is associated with poorer outcome in acute myeloid leukemia (AML). Knockdown or inhibition of RUNX1 induced more apoptosis of AML expressing mtRUNX1 versus wild-type RUNX1 and improved survival of mice engrafted with mtRUNX1-expressing AML. CRISPR/Cas9-mediated editing-out of RUNX1 enhancer (eR1) within its intragenic super-enhancer, or BET protein BRD4 depletion by short hairpin RNA, repressed RUNX1, inhibited cell growth, and induced cell lethality in AML cells expressing mtRUNX1. Moreover, treatment with BET protein inhibitor or degrader (BET-proteolysis targeting chimera) repressed RUNX1 and its targets, inducing apoptosis and improving survival of mice engrafted with AML expressing mtRUNX1. Library of Integrated Network-based Cellular Signatures 1000-connectivity mapping data sets queried with messenger RNA signature of RUNX1 knockdown identified novel expression-mimickers (EMs), which repressed RUNX1 and exerted in vitro and in vivo efficacy against AML cells expressing mtRUNX1. In addition, the EMs cinobufagin, anisomycin, and narciclasine induced more lethality in hematopoietic progenitor cells (HPCs) expressing germline mtRUNX1 from patients with AML compared with HPCs from patients with familial platelet disorder (FPD), or normal untransformed HPCs. These findings highlight novel therapeutic agents for AML expressing somatic or germline mtRUNX1.

Derived loss of signal complexity and plasticity in a genus of weakly electric fish.

Signal plasticity can maximize the usefulness of costly animal signals such as the electric organ discharges (EODs) of weakly electric fishes. Some species of the order Gymnotiformes rapidly alter their EOD amplitude and duration in response to circadian cues and social stimuli. How this plasticity is maintained across related species with different degrees of signal complexity is poorly understood. In one genus of weakly electric gymnotiform fish (Brachyhypopomus), only one species, B. bennetti, produces a monophasic signal while all other species emit complex biphasic or multiphasic EOD waveforms produced by two overlapping but asynchronous action potentials in each electric organ cell (electrocyte). One consequence of this signal complexity is the suppression of low-frequency signal content that is detectable by electroreceptive predators. In complex EODs, reduction of the EOD amplitude and duration during daytime inactivity can decrease both predation risk and the metabolic cost of EOD generation. We compared EOD plasticity and its underlying physiology in Brachyhypopomus focusing on B. bennetti. We found that B. bennetti exhibits minimal EOD plasticity, but that its electrocytes retained vestigial mechanisms of biphasic signaling and vestigial mechanisms for modulating the EOD amplitude. These results suggest that this species represents a transitional phenotypic state within a clade where signal complexity and plasticity were initially gained and then lost. Signal mimicry, mate recognition and sexual selection are potential factors maintaining the monophasic EOD phenotype in the face of detection by electroreceptive predators.

Versatile technique for assessing thickness of 2D layered materials by XPS.

X-ray photoelectron spectroscopy (XPS) has been utilized as a versatile method for thickness characterization of various two-dimensional (2D) films. Accurate thickness can be measured simultaneously while acquiring XPS data for chemical characterization of 2D films having thickness up to approximately 10 nm. For validating the developed technique, thicknesses of few-layer graphene (FLG), MoS2 and amorphous boron nitride (a-BN) layer, produced by microwave plasma chemical vapor deposition (MPCVD), plasma enhanced chemical vapor deposition (PECVD), and pulsed laser deposition (PLD) respectively, were accurately measured. The intensity ratio between photoemission peaks recorded for the films (C 1s, Mo 3d, B 1s) and the substrates (Cu 2p, Al 2p, Si 2p) is the primary input parameter for thickness calculation, in addition to the atomic densities of the substrate and the film, and the corresponding electron attenuation length (EAL). The XPS data was used with a proposed model for thickness calculations, which was verified by cross-sectional transmission electron microscope (TEM) measurement of thickness for all the films. The XPS method determines thickness values averaged over an analysis area which is orders of magnitude larger than the typical area in cross-sectional TEM imaging, hence provides an advanced approach for thickness measurement over large areas of 2D materials. The study confirms that the versatile XPS method allows rapid and reliable assessment of the 2D material thickness and this method can facilitate in tailoring growth conditions for producing very thin 2D materials effectively over a large area. Furthermore, the XPS measurement for a typical 2D material is non-destructive and does not require special sample preparation. Therefore, after XPS analysis, exactly the same sample can undergo further processing or utilization.

Proper development of the outer longitudinal smooth muscle of the mouse pylorus requires Nkx2-5 and Gata3.

BACKGROUND & AIMS: Infantile hypertrophic pyloric stenosis is a common birth anomaly characterized by obstruction of the pyloric lumen. A genome-wide association study implicated NKX2-5, which encodes a transcription factor that is expressed in embryonic heart and pylorus, in the pathogenesis of infantile hypertrophic pyloric stenosis. However, the function of the NKX2-5 in pyloric smooth muscle development has not been examined directly. We investigated the pattern of Nkx2-5 during the course of murine pyloric sphincter development and examined coexpression of Nkx2-5 with Gata3 and Sox9-other transcription factors with pyloric-specific mesenchymal expression. We also assessed pyloric sphincter development in mice with disruption of Nkx2-5 or Gata3. METHODS: We used immunofluorescence analysis to compare levels of NKX2-5, GATA3, and SOX9 in different regions of smooth muscle cells. Pyloric development was assessed in mice with conditional or germline deletion of Nkx2-5 or Gata3, respectively. RESULTS: Gata3, Nkx2-5, and Sox9 are coexpressed in differentiating smooth muscle cells of a distinct fascicle of the pyloric outer longitudinal muscle. Expansion of this fascicle coincides with development of the pyloric sphincter. Disruption of Nkx2-5 or Gata3 causes severe hypoplasia of this fascicle and alters pyloric muscle shape. Although expression of Sox9 requires Nkx2-5 and Gata3, there is no apparent hierarchical relationship between Nkx2-5 and Gata3 during pyloric outer longitudinal muscle development. CONCLUSIONS: Nkx2-5 and Gata3 are independently required for the development of a pyloric outer longitudinal muscle fascicle, which is required for pyloric sphincter morphogenesis in mice. These data indicate that regulatory changes that alter Nkx2-5 or Gata3 expression could contribute to pathogenesis of infantile hypertrophic pyloric stenosis.

Roles for Nkx2-5 and Gata3 in the ontogeny of the murine smooth muscle gastric ligaments.

The gastric ligaments are superficial cord-like structures, located on the lesser curvature of the stomach, that extend from the pylorus to the esophagus. These ligaments have been documented in a wide variety of mammalian species, including humans, but their composition and ontogeny is unexplored. Here, we demonstrate that, during ontogeny, the gastric ligaments are first visible as extensions from a C-shaped domain of Gata3-expressing cells that surround the future pylorus; this domain will later give rise to the pyloric outer longitudinal muscle (OLM). The open ends of the C are located ventrally, and, beginning at embryonic day (E) 13.5, the ligaments grow anteriorly from these points. Whereas most other ligaments of the stomach are neurovascular in nature, the gastric ligaments are composed of smooth muscle cells that mature between E14.5 and E16.5. The gastric ligaments coexpress the transcription factors Gata3, Nkx2-5, and Sox9, and germline loss of Gata3 or conditional deletion of Nkx2-5 abrogates Sox9 expression and impairs gastric ligament smooth muscle development; similar phenotypes were previously seen in the OLM. In accord with this molecular contiguity between the OLM and gastric ligaments, three-dimensional image reconstruction highlights physical contiguity between these smooth muscle structures, suggesting that they may work together as a unit to control flexure of the pyloric region, a function similar to the ligament of Treitz at the duodenojejunal junction. These findings may have implications for our understanding of normal pyloric sphincter function, as well as the common human congenital pathology idiopathic hypertrophic pyloric stenosis.

Stem Cell Therapy in the Treatment of Patients With Autism Spectrum Disorder: a Systematic Review and Meta-analysis.

OBJECTIVE: Assess the safety and efficacy of upcoming stem cell treatments and analyze their effects on the cognitive and behavioral impairments in patients diagnosed with autism. METHODS: We included controlled and noncontrolled, randomized and non-randomized trials evaluating stem cell therapy as a treatment in patients with autism spectrum disorder compared to placebo or without comparator. DATA SOURCES: Scopus, Web of Science, MEDLINE and EMBASE. Risk of bias was assessed using Cochrane's Risk of Bias tool and the NIH's Quality Assessment Tool for Studies With No Control Group. RESULTS: Eleven trials including 461 patients proved eligible. ABC scale meta-analysis showed a mean raw of -11.97 in the intervention groups (95 % CI -91.45 to 67.52, p < 0.01). CARS scale reported a mean raw of -9.08 (95 % CI -15.43 to -2.73, p < 0.01). VABS scale was reported by their domains: communication domain reported a mean raw of 2.69 (95 % CI 1.30 to 4.08, p = 0.92); daily living domain, 1.99 (95 % CI 0.83 to 3.15, p = 0.51); motor domain, 1.06 (95 % CI -0.37 to 2.48, p = 0.20); socialization domain, 3.09 (95 % CI 1.71 to 4.48, p = 0.61); adaptive behavior domain, 2.10 (95 % CI 1.04 to 3.16, p = 0.36). Furthermore, the most common side effects reported included fever, hyperactivity, vomit, headache, and aggressiveness; no serious adverse events were reported. CONCLUSIONS: The body of evidence suggests that stem cell therapy significantly improves scales in patients with autism spectrum disorder, hence, future studies should help us have more confidence in the results. We found no serious adverse events related to the stem cell therapy.

Spinal epidural hematoma in a child with hemophilia A with high titer inhibitors and follow-up with prophylactic emicizumab: case report and literature review.

Hemorrhage in the central nervous system is the most severe and debilitating manifestation affecting patients with hemophilia A. The spinal epidural space is the most unusual and clinically challenging site of central nervous system hemorrhage in hemophilia A. These patients often show insidious neurological signs and symptoms that delay diagnosis and treatment. We share our experience treating a 4-year-old male patient with severe hemophilia A and high titer inhibitors with a spontaneous spinal epidural hematoma. The patient presented initially with intense headache and neck pain. After blood tests and imaging studies, bypassing agent therapy with recombinant-activated factor VII was used until discharge; this was later replaced with emicizumab. After 18 months, the patient is without neurological sequelae and has not experienced subsequent bleeding episodes. We review the available literature and discuss the relevance of emicizumab compared with standard therapies in the context of spontaneous spinal epidural hematoma.

Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells.

First-generation bromodomain extra-terminal protein (BETP) inhibitors (BETi) (e.g., OTX015) that disrupt binding of BETP BRD4 to chromatin transcriptionally attenuate AML-relevant progrowth and prosurvival oncoproteins. BETi treatment induces apoptosis of AML BPCs, reduces in vivo AML burden and induces clinical remissions in a minority of AML patients. Clinical efficacy of more potent BETis, e.g., ABBV-075 (AbbVie, Inc.), is being evaluated. Venetoclax and A-1210477 bind and inhibit the antiapoptotic activity of BCL2 and MCL1, respectively, lowering the threshold for apoptosis. BETi treatment is shown here to perturb accessible chromatin and activity of enhancers/promoters, attenuating MYC, CDK6, MCL1 and BCL2, while inducing BIM, HEXIM1, CDKN1A expressions and apoptosis of AML cells. Treatment with venetoclax increased MCL1 protein levels, but cotreatment with ABBV-075 reduced MCL1 and Bcl-xL levels. ABBV-075 cotreatment synergistically induced apoptosis with venetoclax or A-1210477 in patient-derived, CD34+ AML cells. Compared to treatment with either agent alone, cotreatment with ABBV-075 and venetoclax was significantly more effective in reducing AML cell-burden and improving survival, without inducing toxicity, in AML-engrafted immune-depleted mice. These findings highlight the basis of superior activity and support interrogation of clinical efficacy and safety of cotreatment with BETi and BCL2 or MCL1 inhibitor in AML.

MAP3K kinases and kidney injury.

Mitogen-activated protein kinases (MAP kinases) are functionally connected kinases that regulate key cellular process involved in kidney disease such as all survival, death, differentiation and proliferation. The typical MAP kinase module is composed by a cascade of three kinases: a MAP kinase kinase kinase (MAP3K) that phosphorylates and activates a MAP kinase kinase (MAP2K) which phosphorylates a MAP kinase (MAPK). While the role of MAPKs such as ERK, p38 and JNK has been well characterized in experimental kidney injury, much less is known about the apical kinases in the cascade, the MAP3Ks. There are 24 characterized MAP3K (MAP3K1 to MAP3K21 plus RAF1, BRAF and ARAF). We now review current knowledge on the involvement of MAP3K in non-malignant kidney disease and the therapeutic tools available. There is in vivo interventional evidence clearly supporting a role for MAP3K5 (ASK1) and MAP3K14 (NIK) in the pathogenesis of experimental kidney disease. Indeed, the ASK1 inhibitor Selonsertib has undergone clinical trials for diabetic kidney disease. Additionally, although MAP3K7 (MEKK7, TAK1) is required for kidney development, acutely targeting MAP3K7 protected from acute and chronic kidney injury; and targeting MAP3K8 (TPL2/Cot) protected from acute kidney injury. By contrast MAP3K15 (ASK3) may protect from hypertension and BRAF inhibitors in clinical use may induced acute kidney injury and nephrotic syndrome. Given their role as upstream regulators of intracellular signaling, MAP3K are potential therapeutic targets in kidney injury, as demonstrated for some of them. However, the role of most MAP3K in kidney disease remains unexplored.

Targeting nuclear ß-catenin as therapy for post-myeloproliferative neoplasm secondary AML.

Transformation of post-myeloproliferative neoplasms into secondary (s) AML exhibit poor clinical outcome. In addition to increased JAK-STAT and PI3K-AKT signaling, post-MPN sAML blast progenitor cells (BPCs) demonstrate increased nuclear ß-catenin levels and TCF7L2 (TCF4) transcriptional activity. Knockdown of ß-catenin or treatment with BC2059 that disrupts binding of ß-catenin to TBL1X (TBL1) depleted nuclear ß-catenin levels. This induced apoptosis of not only JAKi-sensitive but also JAKi-persister/resistant post-MPN sAML BPCs, associated with attenuation of TCF4 transcriptional targets MYC, BCL-2, and Survivin. Co-targeting of ß-catenin and JAK1/2 inhibitor ruxolitinib (rux) synergistically induced lethality in post-MPN sAML BPCs and improved survival of mice engrafted with human sAML BPCs. Notably, co-treatment with BET protein degrader ARV-771 and BC2059 also synergistically induced apoptosis and improved survival of mice engrafted with JAKi-sensitive or JAKi-persister/resistant post-MPN sAML cells. These preclinical findings highlight potentially promising anti-post-MPN sAML activity of the combination of ß-catenin and BETP antagonists against post-MPN sAML BPCs.

8-Oxoguanine DNA glycosylase1-driven DNA repair-A paradoxical role in lung aging.

Age-associated changes in lung structure and function are some of the most important predictors of overall health, cognitive activities and longevity. Common to all aging cells is an increase in oxidatively modified DNA bases, primarily 8-oxo-7,8-dihydroguanine (8-oxoG). It is repaired via DNA base excision repair pathway driven by 8-oxoguanine DNA glycosylase-1 (OGG1-BER), whose role in aging has been the focus of many studies. This study hypothesizes that signaling and consequent gene expression during cellular response to OGG1-BER "wires" senescence/aging processes. To test OGG1-BER was mimicked by repeatedly exposing diploid lung fibroblasts cells and airways of mice to 8-oxoG base. Results showed that repeated exposures led to G1 cell cycle arrest and pre-matured senescence of cultured cells in which over 1000 genes were differentially expressed -86% of them been identical to those in naturally senesced cells. Gene ontology analysis of gene expression displayed biological processes driven by small GTPases, phosphoinositide 3-kinase and mitogen activated kinase cascades both in cultured cells and lungs. These results together, points to a new paradigm about the role of DNA damage and repair by OGG1 in aging and age-associated disease processes.

Effect of probiotics (Saccharomyces boulardii) on microbial translocation and inflammation in HIV-treated patients: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Microbial translocation has been associated with an increase in immune activation and inflammation in HIV infection despite effective highly active antiretroviral therapy. It has been shown that some probiotics have a beneficial effect by reducing intestinal permeability and, consequently, microbial translocation. OBJECTIVES: To assess changes in microbial translocation and inflammation after treatment with probiotics (Saccharomyces boulardii) in HIV-1-infected patients with virologic suppression. METHODS: A double-blind, randomized, placebo-controlled trial was conducted in 44 nonconsecutive HIV-1-infected patients with viral load of <20 copies per milliliter for at least 2 years. Patients were randomized to oral supplementation with probiotics or placebo during 12 weeks. Markers of microbial translocation (lipopolysaccharide-binding protein [LBP] and soluble CD14), inflammation (interleukin 6 [IL-6], tumor necrosis factor alpha, interferon gamma, high-sensitivity C-reactive protein), and immunological and clinical data were determined before and after the intervention and 3 months after treatment discontinuation. Quantitative variables were compared using the Mann-Whitney U test, and categorical variables were compared using the Fisher exact test. RESULTS: After 12 weeks of treatment, differences between the probiotic arm and the placebo arm were observed in LBP values (-0.30 vs +0.70 pg/mL) and IL-6 (-0.60 vs +0.78 pg/mL). These differences were also noted at 3 months after treatment withdrawal. Qualitative analysis was performed, defining a variable as "decreased" or "increased" from baseline LBP. A significant decrease of LBP at 12 weeks of treatment was observed (57.9% patients in the probiotic group vs 6.2% in the placebo group, P = 0.002). CONCLUSIONS: Treatment with S. boulardii decreases microbial translocation (LBP) and inflammation parameters (IL-6) in HIV-1-infected patients with long-term virologic suppression.

Seasonal variation in fish trophic networks in two clear-water streams in the Central Llanos region, Venezuela

Food webs are not static entities; consumer resource interactions vary in both time and space, which complicates depiction and comparisons of food web structures. We estimated fish assemblage structure and diets in two clear-water streams in the Venezuelan Llanos region (Charcote and Charcotico) and constructed trophic networks (sub-webs defined by fishes as the principal consumers) during four periods of the annual flood pulse. As stream conditions changed from high-water to low-water, we hypothesized that: 1) the piscivore-non-piscivore ratio would increase; 2) dietary diversity would decrease; 3) interspecific dietary overlap would decline; 4) fewer allochthonous food items would be consumed; and 5) food-web connectance would increase. The piscivore-non-piscivore abundance ratio was higher in both streams during the low-water period. Dietary diversity declined as water levels dropped and availability of aquatic habitats and resources declined, but interspecific dietary overlap was not lower. Contrary to our hypothesis, average interspecific dietary overlap increased at Charcote as the dry season progressed, even though dietary overlap among species was significantly lower than expected by chance. We did not find strong support for our hypotheses regarding seasonal patterns of consumption of allochthonous resources and food web connectance, both of which revealed little seasonal variation.(AU)

Redes alimentares não são entidades estáticas; interações entre consumidores e recursos variam no tempo e no espaço, o que complica as representações das estruturas de redes alimentares. Nós estimamos a estrutura da assembléia de peixes e dieta em dois riachos de água clara na região venezuelana dos Llanos (Charcote e Charcotico) e construímos redes tróficas (sub-redes definidas por peixes como os principais consumidores) para quatro períodos do pulso anual de inundação. À medida que as condições dos riachos mudam de águas altas para águas baixas, nós hipotetizamos que: 1) a razão piscívoros e não piscívoros irá aumentar; 2) a diversidade da dieta irá diminuir; 3) a sobreposição alimentar interespecífica irá diminuir; 4) menos itens alimentares alóctones serão consumidos; e 5) a conectância da teia alimentar irá aumentar. A razão da abundância de piscívoros e não piscívoros foi maior em ambos riachos durante a estação de águas baixas. A diversidade da dieta declinou à medida que as águas baixavam e a disponibilidade de habitats aquáticos e recursos declinavam, mas a sobreposição alimentar interespecífica não foi menor. Contrária à nossa hipótese, a média de sobreposição alimentar interespecífica aumentou no Charcote à medida que a estação cheia progrediu, mesmo com a sobreposição alimentar significativamente menor do que o esperado ao acaso. Não encontramos forte suporte para nossas hipóteses relacionadas aos padrões sazonais de consumo de recursos alóctones e conectância da cadeia trófica, os quais revelaram pouca variação sazonal.(AU)

Effects of Colostrinin on gene expression-transcriptomal network analysis.

Colostrinin (CLN) is a uniform mixture of low-molecular weight proline-rich polypeptides isolated from the mother's first milk, colostrum. Exposure of cells to CLN decreases intracellular levels of reactive oxygen species by regulating glutathione metabolism and modulating activities of antioxidant enzymes and mitochondrial function. It also inhibits beta amyloid-induced apoptosis and induces neurite outgrowth of pheochromocytoma cells. Administration of CLN to Alzheimer's disease patients has resulted in a stabilizing effect on cognitive function. We analyzed CLN-induced gene expression changes using high-density oligonucleotide arrays and transcriptomal network analysis. We found that CLN elicited highly complex and multiphasic changes in the gene expression profile of treated cells. CLN treatment affected a total of 58 molecular networks, 27 of which contained at least 10 differentially expressed genes. Here we present CLN-modulated gene networks as potential underlying molecular mechanisms leading to the reported effects of CLN on cellular oxidative state, chemokine and cytokine production, and cell differentiation, as well as on pathological processes like allergy, asthma, Alzheimer's, and other neurological diseases. Based on our results, we also predict possible modulatory effects of CLN on adipocytokine gene networks that play a crucial role in the pathobiology of diabetes, cardiovascular disorders, obesity, and inflammation. Taken together, CLN-altered gene expression networks presented here provide the molecular basis for previously described biological phenomena and predict potential fields of application for CLN in the prevention and treatment of diseases.

MAP3K kinases and kidney injury / MAP3K quinasas y daño renal

Mitogen-activated protein kinases (MAP kinases) are functionally connected kinases that regulate key cellular process involved in kidney disease such as all survival, death, differentiation and proliferation. The typical MAP kinase module is composed by a cascade of three kinases: a MAP kinase kinase kinase (MAP3K) that phosphorylates and activates a MAP kinase kinase (MAP2K) which phosphorylates a MAP kinase (MAPK). While the role of MAPKs such as ERK, p38 and JNK has been well characterized in experimental kidney injury, much less is known about the apical kinases in the cascade, the MAP3Ks. There are 24 characterized MAP3K (MAP3K1 to MAP3K21 plus RAF1, BRAF and ARAF). We now review current knowledge on the involvement of MAP3K in non-malignant kidney disease and the therapeutic tools available. There is in vivo interventional evidence clearly supporting a role for MAP3K5 (ASK1) and MAP3K14 (NIK) in the pathogenesis of experimental kidney disease. Indeed, the ASK1 inhibitor Selonsertib has undergone clinical trials for diabetic kidney disease. Additionally, although MAP3K7 (MEKK7, TAK1) is required for kidney development, acutely targeting MAP3K7 protected from acute and chronic kidney injury; and targeting MAP3K8 (TPL2/Cot) protected from acute kidney injury. By contrast MAP3K15 (ASK3) may protect from hypertension and BRAF inhibitors in clinical use may induced acute kidney injury and nephrotic syndrome. Given their role as upstream regulators of intracellular signaling, MAP3K are potential therapeutic targets in kidney injury, as demonstrated for some of them. However, the role of most MAP3K in kidney disease remains unexplored

Las proteínas quinasas activadas por mitógenos (MAP quinasas) son quinasas conectadas funcionalmente que regulan procesos celulares clave involucrados en la enfermedad renal como la supervivencia, la muerte, la diferenciación y la proliferación. El típico módulo MAP quinasa está compuesto por una cascada de 3 quinasas: una MAP quinasa quinasa quinasa (MAP3K) que fosforila y activa una MAP quinasa quinasa (MAP2K) que, a su vez, fosforila una MAP quinasa (MAPK). Si bien el papel de las MAPK como ERK, p38 y JNK se ha caracterizado bien en las lesiones renales experimentales, se sabe mucho menos acerca de las quinasas apicales en la cascada, las MAP3K. Hay 24 MAP3K (MAP3K1 a MAP3K21, más RAF1, BRAF y ARAF). En este trabajo revisamos el conocimiento actual sobre la participación de MAP3K en la enfermedad renal no maligna y las herramientas terapéuticas disponibles. Existe evidencia intervencionista experimental in vivo que respalda claramente el papel de MAP3K5 (ASK1) y MAP3K14 (NIK) en la patogenia de la enfermedad renal experimental. De hecho, el inhibidor de ASK1, selonsertib, ha sido estudiado en ensayos clínicos en la enfermedad renal diabética. Además, aunque la MAP3K7 (MEKK7, TAK1) es necesaria para el desarrollo renal, la inhibición de MAP3K7 en el adulto protegió de la lesión renal aguda y crónica experimental; e inhibir MAP3K8 (TPL2/Cot) protegió de la lesión renal aguda. Por el contrario, MAP3K15 (ASK3) puede proteger de la hipertensión y los inhibidores de BRAF, en uso clínico, pueden inducir lesión renal aguda y síndrome nefrótico. Dado su papel como reguladores de los primeros pasos de la señalización intracelular, las MAP3K son posibles dianas terapéuticas en la lesión renal, como se ha demostrado para algunas de ellos. Sin embargo, el papel de la mayoría de las MAP3K en la enfermedad renal no ha sido explorado