Sodium-glucose co-transporter-2 inhibitors increase Klotho in patients with diabetic kidney disease: a clinical and experimental study

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) provide cardiorenal protection. However, the molecular mechanisms remain poorly understood. We explored the impact of SGLT2i on Klotho, a kidney-derived protein with antiaging, renal-protective and heart-protective properties. A real world prospective observational study addressed the impact of initiating SGLT2i (canagliflozin, dapagliflozin, empagliflozin) or dipeptidyl peptidase-4 inhibitors (DPP4i) in patients with early diabetic kidney disease (DKD). Serum and urinary soluble Klotho, albuminuria and serum and urinary tumor necrosis factor-alpha (TNFa) were measured. The effect of SGLT2i on Klotho mRNA and protein was explored in vitro in kidney proximal tubular cells stressed with high glucose concentrations to simulate the diabetic milieu, albumin to simulate albuminuria, and the inflammatory cytokine TWEAK to simulate the inflammatory environment in DKD. Baseline urinary Klotho was negatively associated with albuminuria (r − 0.45, P < 0.001) and urinary TNFa (r − 0.40, P < 0.01). Both DPP4i and SGLT2i reduced HbA1c similarly, but only SGLT2i decreased eGFR, albuminuria and urinary TNFa and increased (P < 0.001) serum (5.2 %) and urinary Klotho (38.9 %). Changes in urinary TNFa (β − 0.53, P = 0.001) and albuminuria (β − 0.31, P < 0.05) were independently associated with changes in urinary Klotho (adjusted R2 = 0.54, P < 0.001). Studies in renal tubular cells demonstrated that high glucose, albumin and TWEAK decreased Klotho mRNA expression and protein levels, an effect similarly prevented by SGLT2i. SGLT2i increase Klotho availability in type 2 diabetic patients with poorly controlled diabetes and early DKD, as well as in stressed tubular cells. This effect on Klotho may contribute to the kidney and heart protection afforded by SGLT2iThe authors thank all the study participants, without whom this study would not have been possible. The authors acknowledge the support from Instituto de Salud Carlos III (ISCIII) FIS/Fondos FEDER (PI18/01366, PI19/00815, PI19/00035, PI20/00744, PI21/00251, DTS18/00032), ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064, ISCIII-RETIC REDinREN RD16/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM, Fundacion ´ Canaria Instituto de Investigación Sanitaria de Canarias (FIISC), PIFUN05/18. Instituto de Salud Carlos III (ISCIII) RICORS program to RICORS2040 (RD21/0005/0001 and RD21/0005/0013) and SPACKDc PMP21/00109, FEDER funds, Cátedra Mundipharma-UAM of Diabetic Kidney Disease and Cátedra Astrazeneca-UAM of Chronic Kidney Disease and Electrolytes. J.D.C is recipient of a contract from Miguel Servet Programme (CP20/00122), ISCII

Repurposing drugs for highly prevalent diseases: pentoxifylline, an old drug and a new opportunity for diabetic kidney disease

Diabetic kidney disease is one of the most frequent complications in patients with diabetes and constitutes a major cause of end-stage kidney disease. The prevalence of diabetic kidney disease continues to increase as a result of the growing epidemic of diabetes and obesity. Therefore, there is mounting urgency to design and optimize novel strategies and drugs that delay the progression of this pathology and contain this trend. The new approaches should go beyond the current therapy focussed on the control of traditional risk factors such as hyperglycaemia and hypertension. In this scenario, drug repurposing constitutes an economic and feasible approach based on the discovery of useful activities for old drugs. Pentoxifylline is a nonselective phosphodiesterase inhibitor currently indicated for peripheral artery disease. Clinical trials and meta-analyses have shown renoprotection secondary to anti-inflammatory and antifibrotic effects in diabetic patients treated with this old known drug, which makes pentoxifylline a candidate for repurposing in diabetic kidney diseaseThis work was supported by Instituto de Salud Carlos III (ISCIII): PI07/0870, PI15/00298, PI16/02057, PI16/00024, PI19/00035, PI20/00744, PI21/00251, PI21/01037, PI19/00815, DTS18/00032 ISCIII-RETIC REDinREN RD16/0009, and RICORS2040. We acknowledge cofunding by Fondo Europeo de Desarrollo Regional [FEDER], Unión Europea [‘Una forma de hacer Europa’]. J.D.-C. is the recipient of a contract from Miguel Servet Program (CP20/00122) of the ISCIII. A.G.-L. and C.F. are recipients of contracts from Agencia Canaria de Investigación Innovación y Sociedad de la Información del Gobierno de Canarias (ACIISI) (TESIS2021010045 and TESIS2018010110). E.M.-N. is funded by a research contract from REDinREN-ISCIII (RD16/0009/0022). V.G.- T. is supported by Cabildo de Tenerife, TF Innova, Fondo de Desarrollo de Canarias (FDCAN) and Marco Estratégico de Desarrollo Insular (MEDI), in the Agustín de Betancourt programm

Asymptotically Lifshitz wormholes and black holes for Lovelock gravity in vacuum

Static asymptotically Lifshitz wormholes and black holes in vacuum are shown to exist for a class of Lovelock theories in d=2n+1>7 dimensions, selected by requiring that all but one of their n maximally symmetric vacua are AdS of radius l and degenerate. The wormhole geometry is regular everywhere and connects two Lifshitz spacetimes with a nontrivial geometry at the boundary. The dynamical exponent z is determined by the quotient of the curvature radii of the maximally symmetric vacua according to n(z^2-1)+1=(l/L)^2, where L corresponds to the curvature radius of the nondegenerate vacuum. Light signals are able to connect both asymptotic regions in finite time, and the gravitational field pulls towards a fixed surface located at some arbitrary proper distance to the neck. The asymptotically Lifshitz black hole possesses the same dynamical exponent and a fixed Hawking temperature given by T=z/(2^z pi l). Further analytic solutions, including pure Lifshitz spacetimes with a nontrivial geometry at the spacelike boundary, and wormholes that interpolate between asymptotically Lifshitz spacetimes with different dynamical exponents are also found.Comment: 19 pages, 1 figur

Role of Klotho and AGE/RAGE-Wnt/β-catenin signalling pathway on the development of cardiac and renal fibrosis in diabetes

Fibrosis plays an important role in the pathogenesis of long-term diabetic complications and contributes to the development of cardiac and renal dysfunction. The aim of this experimental study, performed in a long-term rat model, which resembles type 1 diabetes mellitus, was to investigate the role of soluble Klotho (sKlotho), advanced glycation end products (AGEs)/receptor for AGEs (RAGE), fibrotic Wnt/β-catenin pathway, and pro-fibrotic pathways in kidney and heart. Diabetes was induced by streptozotocin. Glycaemia was maintained by insulin administration for 24 weeks. Serum and urine sKlotho, AGEs, soluble RAGE (sRAGE) and biochemical markers were studied. The levels of Klotho, RAGEs, ADAM10, markers of fibrosis (collagen deposition, fibronectin, TGF-β1, and Wnt/β-catenin pathway), hypertrophy of the kidney and/or heart were analysed. At the end of study, diabetic rats showed higher levels of urinary sKlotho, AGEs and sRAGE and lower serum sKlotho compared with controls without differences in the renal Klotho expression. A significant positive correlation was found between urinary sKlotho and AGEs and urinary albumin/creatinine ratio (uACR). Fibrosis and RAGE levels were significantly higher in the heart without differences in the kidney of diabetic rats compared to controls. The results also suggest the increase in sKlotho and sRAGE excretion may be due to polyuria in the diabetic rats

Hacia una metodología estandarizada para el muestreo de escarabajos peloteros (Coleoptera: Scarabaeinae) en el Neotrópico: Una revisión crítica

Introducción: La estandarización de los protocolos de muestreo es imprescindible para el estudio robusto de cualquier grupo taxonómico. Los métodos replicables permiten la comparación de datos entre diferentes estudios espaciales y temporales. En el caso de los escarabajos coprófagos, uno de los grupos indicadores mejor estudiados en los análisis de perturbaciones ambientales, se utiliza una amplia gama de metodologías de recolección, desde trampas de caída básicas hasta métodos más complejos o complementarios, como el extractor mini-Winkler. Además, en los estudios de escarabajos coprófagos se utilizan diferentes tipos de cebos atractivos, esfuerzos de muestreo, duraciones y diseños. Las variaciones en los enfoques metodológicos se notan particularmente en el Neotrópico, lo que puede estar relacionado con la gran cantidad de estrategias biológicas y el comportamiento de los escarabajos coprófagos que habitan esta región. La falta de unificación metodológica para la región Neotropical imposibilita un análisis transversal de la información. Métodos: Realizamos una recopilación y revisión analítica de la literatura existente para el muestreo de escarabajos coprófagos en el Neotrópico, discutiendo las metodologías más utilizadas, sus ventajas y desventajas, y casos específicos en los que modelos particulares son más eficientes. Resultados: Las trampas Pitfall cebadas con excremento humano son el método de muestreo más común, pero existe una amplia gama de modelos y variaciones en la estructura de esta trampa. El efecto complementario generado por las trampas de interceptación de vuelos, las trampas de luz y las colecciones directas, particularmente dentro de los microhábitats, es emocionante por el potencial de encontrar nuevas especies. Algunas metodologías, como mini-Winkler extractor, fogging, o cebos muy específicos, se utilizan con poca frecuencia. Discusión: Hubo una falta de inclusión de la variación espacial y temporal entre los estudios. Por lo tanto, es necesario considerar ventanas de muestreo más amplias, que incluyan diferentes escalas espaciales, estaciones y años. Finalmente, proponemos un protocolo estándar para el muestreo de escarabajos coprófagos en el Neotrópico, dependiendo de cada objetivo, e incluyendo una metodología básica para la obtención de inventarios locales completos. Copyright © 2023 Mora-Aguilar, Arriaga-Jiménez, Correa, da Silva, Korasaki, López-Bedoya, Hernández, Pablo-Cea, Salomão, Valencia, Vulinec, Edwards, Edwards, Halffter y Noriega. Proponemos un protocolo estándar para el muestreo de escarabajos coprófagos en el Neotrópico, dependiendo de cada objetivo, e incluyendo una metodología básica para la obtención de inventarios locales completos. Copyright © 2023 Mora-Aguilar, Arriaga-Jiménez, Correa, da Silva, Korasaki, López-Bedoya, Hernández, Pablo-Cea, Salomão, Valencia, Vulinec, Edwards, Edwards, Halffter y Noriega. Proponemos un protocolo estándar para el muestreo de escarabajos coprófagos en el Neotrópico, dependiendo de cada objetivo, e incluyendo una metodología básica para la obtención de inventarios locales completos.Introduction: The standardization of sampling protocols is imperative for robustly studying any taxonomic group. Replicable methods allow the comparison of data between different spatial and temporal studies. In the case of dung beetles, one of the best-studied indicator groups in analyses of environmental disturbance, a wide range of collection methodologies are used, from basic pitfall traps to more complex or complementary methods such as mini-Winkler extractor. Also, different types of attractive baits, sampling effort, durations, and designs are used in dung beetle studies. Variations in methodological approaches are particularly noted in the Neotropics, which may be related to the vast number of biological strategies and behavior of dung beetles that inhabit this region. A lack of methodological unification for the Neotropical region makes a cross-sectional analysis of the information impossible. Methods: We performed a compilation and analytical review of the existing literature for dung beetle sampling in the Neotropics, discussing the most used methodologies, their advantages and disadvantages, and specific cases in which particular models are more efficient. Results: Pitfall traps baited with human excrement are the most common sampling method, but there is a wide range of models and variations in the structure of this trap. The complementary effect generated by flight interception traps, light traps, and direct collections, particularly within microhabitats, is exciting for the potential of finding new species. Some methodologies, such as mini-Winkler extractor, fogging, or very specific baits, are infrequently used. Discussion: There was a lack of inclusion of spatial and temporal variation among studies. Therefore, it is necessary to consider broader sampling windows, which include different spatial scales, seasons, and years. Finally, we propose a standard protocol for sampling dung beetles in the Neotropics, depending on each objective, and including a basic methodology for obtaining complete local inventories

Fractal diagnosis of severe cardiac dysfunction Fractal dynamic of the left coronary branching

INTRODUCCIÓN Y OBJETIVOS: la geometría fractal evalúa la irregularidad de los objetos naturales, permitiendo caracterizar de forma imparcial la totalidad de la ramifi cación coronaria izquierda a diferencia de la metodología actual que evalúa únicamente partes de ésta. Con base en esta medida se generalizó una nueva metodología diagnóstica para detectar cualquier tipo de disfunción cardiaca severa. MÉTODOS: estudio de concordancia diagnóstica en el que se utilizó el método de box counting para medir dimensiones fractales de imágenes consecutivas entre sístole y diástole de la ramifi cación coronaria izquierda en proyección oblicua derecha anterior de angiografías de ocho pacientes con enfermedad arterial oclusiva leve. Así mismo, se evaluaron sus cambios por medio de los conceptos de variabilidad y diferencia neta y se compararon estos resultados con pacientes sin enfermedad arterial oclusiva, con enfermedad arterial oclusiva moderada y severa evaluados previamente de igual forma, para obtener una metodología matemática que evalúa el impacto de cualquier patología en la dinámica cardiaca. RESULTADOS: los casos que presentan diferencias netas de cero corresponden a pacientes con disfunciones cardiacas severas, independientemente del grado o ausencia de enfermedad arterial oclusiva diagnosticada. CONCLUSIONES: se generalizó una nueva metodología diagnóstica de aplicación clínica que detecta disfunciones cardiacas severas sub-diagnosticadas con las metodologías actuales, mediante la caracterización de la dinámica total de la ramifi cación coronaria izquierda.INTRODUCTION AND OBJECTIVES: fractal geometry evaluates the irregularity of natural objects, allowing impartially characterize the entire left coronary branching unlike the current methodology which evaluates only parts of it. Based on this measure, a new diagnostic method was generalized to detect any type of severe cardiac dysfunction. METHODS: Concordance study using the box counting method to measure fractal dimensions of consecutive images between systole and diastole of the left coronary branch in right anterior oblique projection in angiograms of eight patients with mild arterial occlusive disease. Likewise, we evaluated its changes through the concepts of variability and net difference and compared these results with patients without occlusive arterial disease, with moderate to severe arterial occlusive disease previously and similarly evaluated, to obtain a mathematical methodology to assess the impact of any pathology in cardiac dynamics.RESULTS: The cases with zero net differences occur in patients with severe cardiac dysfunction, regardless of the degree or absence of diagnosed occlusive arterial disease. CONCLUSIONS: a new diagnostic methodology of clinical application to detect sub-diagnosed severe heart dysfunction was generalized with current methodologies, through the characterization of the total dynamics of the left coronary branch

Predicting Survival after Allogeneic Hematopoietic Cell Transplantation in Myelofibrosis : Performance of the Myelofibrosis Transplant Scoring System (MTSS) and Development of a New Prognostic Model

Accurate prognostic tools are crucial to assess the risk/benefit ratio of allogeneic hematopoietic cell transplantation (allo-HCT) in patients with myelofibrosis (MF). We aimed to evaluate the performance of the Myelofibrosis Transplant Scoring System (MTSS) and identify risk factors for survival in a multicenter series of 197 patients with MF undergoing allo-HCT. After a median follow-up of 3.1 years, 47% of patients had died, and the estimated 5-year survival rate was 51%. Projected 5-year risk of nonrelapse mortality and relapse incidence was 30% and 20%, respectively. Factors independently associated with increased mortality were a hematopoietic cell transplantation-specific comorbidity index (HCT-CI) ≥3 and receiving a graft from an HLA-mismatched unrelated donor or cord blood, whereas post-transplant cyclophosphamide (PT-Cy) was associated with improved survival. Donor type was the only parameter included in the MTSS model with independent prognostic value for survival. According to the MTSS, 3-year survival was 62%, 66%, 37%, and 17% for low-, intermediate-, high-, and very high-risk groups, respectively. By pooling together the low- and intermediate-risk groups, as well as the high- and very high-risk groups, we pinpointed 2 categories: standard risk and high risk (25% of the series). Three-year survival was 62% in standard-risk and 25% in high-risk categories (P <.001). We derived a risk score based on the 3 independent risk factors for survival in our series (donor type, HCT-CI, and PT-Cy). The corresponding 5-year survival for the low-, intermediate-, and high-risk categories was 79%, 55%, and 32%, respectively (P <.001). In conclusion, the MTSS model failed to clearly delineate 4 prognostic groups in our series but may still be useful to identify a subset of patients with poor outcome. We provide a simple prognostic scoring system for risk/benefit considerations before transplantation in patients with MF

Fulde-Ferrell-Larkin-Ovchinnikov State in Heavy Fermion Superconductors

The Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) state is a novel superconducting state in a strong magnetic field characterized by the formation of Cooper pairs with nonzero total momentum (k \uparrow, -k+q \downarrow), instead of the ordinary BCS pairs (k \uparrow, -k \downarrow). A fascinating aspect of the FFLO state is that it exhibits inhomogeneous superconducting phases with a spatially oscillating order parameter and spin polarization. The FFLO state has been of interest in various research fields, not only in superconductors in solid state physics, but also in neutral Fermion superfluid of ultracold atomic gases and in color superconductivity in high energy physics. In spite of extensive studies of various superconductors, there has been no undisputed experimental verification of the FFLO state, mainly because of the very stringent conditions required of the superconducting materials. Among several classes of materials, certain heavy fermion and organic superconductors are believed to provide conditions that are favorable to the formation of the FFLO state. This review presents recent experimental and theoretical developments of the FFLO state mainly in heavy fermion superconductors. In particular we address the recently discovered quasi-two-dimensional superconductor CeCoIn_5, which is a strong candidate for the formation of the FFLO state.Comment: 17 pages, 12 figures with jpsf2.cls, to be published in J. Phys. Soc. Jpn. (Special Topics - Frontiers of Novel Superconductivity in Heavy Fermion Compounds