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BACKGROUND: The availability of soil phosphorus (P) often limits the productivities of wet tropical lowland forests. Little is known, however, about the metabolomic profile of different chemical P compounds with potentially different uses and about the cycling of P and their variability across space under different tree species in highly diverse tropical rainforests. RESULTS: We hypothesised that the different strategies of the competing tree species to retranslocate, mineralise, mobilise, and take up P from the soil would promote distinct soil 31P profiles. We tested this hypothesis by performing a metabolomic analysis of the soils in two rainforests in French Guiana using 31P nuclear magnetic resonance (NMR). We analysed 31P NMR chemical shifts in soil solutions of model P compounds, including inorganic phosphates, orthophosphate mono- and diesters, phosphonates, and organic polyphosphates. The identity of the tree species (growing above the soil samples) explained > 53% of the total variance of the 31P NMR metabolomic profiles of the soils, suggesting species-specific ecological niches and/or species-specific interactions with the soil microbiome and soil trophic web structure and functionality determining the use and production of P compounds. Differences at regional and topographic levels also explained some part of the the total variance of the 31P NMR profiles, although less than the influence of the tree species. Multivariate analyses of soil 31P NMR metabolomics data indicated higher soil concentrations of P biomolecules involved in the active use of P (nucleic acids and molecules involved with energy and anabolism) in soils with lower concentrations of total soil P and higher concentrations of P-storing biomolecules in soils with higher concentrations of total P. CONCLUSIONS: The results strongly suggest "niches" of soil P profiles associated with physical gradients, mostly topographic position, and with the specific distribution of species along this gradient, which is associated with species-specific strategies of soil P mineralisation, mobilisation, use, and uptake.

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BACKGROUND: Chronic inflammation is considered a risk factor for the development of atherosclerosis and cardiovascular (CV) events. We seek to assess the risk of CV events in patients with Systemic autoimmune diseases (SAD), such as Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), Psoriasis (Ps) and Ankylosing Spondylitis (AS), compared with the general population. METHODS AND RESULTS: A systematic search of MEDLINE from inception up to May 2021 was performed. Observational studies including individuals with and without autoimmune diseases (SLE, RA, Ps, AS), which reported a measure of association and variability for the effect of SAD on CV events, were included. The random effects meta-analysis was performed using the Hartung-Knapp-Sidik-Jonkman approach to obtain the pooled estimates. Cardiovascular Events including CV mortality, non-fatal myocardial infarction (MI), non-fatal stroke and coronary revascularization were the main outcomes evaluated. Fifty-four studies were selected, with a total of 24,107,072 participants. The presence of SAD was associated with an increased risk of CV mortality (HR 1.49 [95% CI 1.10-2.03]), non-fatal MI (HR 1.42 [95% CI 1.23-1.62]), and non-fatal stroke (HR 1.47 [95% CI 1.28-1.70]). RA, SLE, and Ps (particularly with arthritis) were significantly associated with a higher risk of MI and stroke. SAD was also associated with an increased risk of Major Adverse Cardiovascular Events (MACE) (HR 1.45 [95% CI 1.16-1.83]). CONCLUSION: Patients with SAD present an increased risk of CV morbidity and mortality, which should be considered when establishing therapeutic strategies. These findings support the role of systemic inflammation in the development of atherosclerosis-driven disease.

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NEW FINDINGS: What is the central question of this study? The aim was to explore the role and hitherto unclear mechanisms of action of iron proteins in protecting the lung against the harmful effects of iron accumulation and the ability of pulmonary cells to mobilize iron in iron deficiency. What is the main finding and its importance? We show that pulmonary hepcidin appears not to modify cellular iron mobilization in the lung. We propose pathways for supplying iron to the lung in iron deficiency and for protecting the lung against iron excess in iron overload, mediated by the co-ordinated action of iron proteins, such as divalent metal transporter 1, ZRT-IRE-like-protein 14, transferrin receptor, ferritin, haemochromatosis-associated protein and ferroportin. Iron dyshomeostasis is associated with several forms of chronic lung disease, but its mechanisms of action remain to be elucidated. The aim of the present study was to determine the role of the lung in whole-animal models with iron deficiency and iron overload, studying the divalent metal transporter 1 (DMT1), ZRT-IRE-like protein 14 (ZIP14), transferrin receptor (TfR), haemochromatosis-associated protein (HFE), hepcidin, ferritin and ferroportin (FPN) expression. In each model, adult CF1 mice were divided into the following groups (six mice per group): (i) iron-overload model, iron saccharate i.p. and control group (iron adequate), 0.9% NaCl i.p.; and (ii) iron-deficiency model, induced by repeated bleeding, and control group (sham operated). Proteins were assessed by immunohistochemistry and Western blot. In control mice, DMT1 was localized in the cytoplasm of airway cells, and in iron deficiency and overload it was in the apical membrane. Divalent metal transporter 1 and TfR increased in iron deficiency, without changes in iron overload. ZRT-IRE-like protein 14 decreased in airway cells in iron deficiency and increased in iron overload. In iron deficiency, HFE and FPN were immunolocalized close to the apical membrane. Ferroportin increased in iron overload. Prohepcidin was present in control groups, with no changes in iron deficiency and iron overload. In iron overload, ferritin showed intracytoplasmic localization close to the apical membrane of airway cells and intense immunostaining in macrophage-like cells. The results show that pulmonary hepcidin does not appear to modify cellular iron mobilization in the lung. We propose the following two novel pathways in the lung: (i) for supplying iron in iron deficiency, mediated principally by DMT1 and TfR and regulated by the action of FPN and HFE; and (ii) for iron detoxification in order to protect the lung against iron overload, facilitated by the action of DMT1, ZIP14, FPN and ferritin.

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It is well known that the iron content of the body is tightly regulated. Iron excess induces adaptive changes that are differentially regulated in each tissue. The pancreas is particularly susceptible to iron-related disorders. We studied the expression and regulation of key iron proteins in the pancreas, duodenum and liver, using an animal model of iron overload (female CF1 mice injected i.p. with iron saccharate, colloidal iron form). Divalent metal transporter 1, prohepcidin and ferritin (pancreas, duodenum, liver) were assessed by immunohistochemistry; divalent metal transporter 1 (pancreas, duodenum) by Western blot. In the iron overloaded mice, prohepcidin expression increased in islets of Langerhans and hepatocytes, and divalent metal transporter 1 expression decreased in cells of islets and in enterocytes. In the iron overloaded mice, ferritin expression decreased in islets of Langerhans and increased in acinar cells; hemosiderin was localized in connective tissue cells. The inverse relationship between divalent metal transporter 1 and prohepcidin may indicate a negative regulation by hepcidin, and hence reduction of iron stores in islets of Langerhans. Our data showed that in iron overloaded mice model, induced by colloidal iron form, a coordinated expression of key iron proteins in the pancreas, duodenum and liver may occur. Further research will be necessary to determine the adaptive responses induced by iron in the pancreas.

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To analyze the interconnection between erythropoiesis and iron metabolism, one of the issues raised in this study was to know iron bioavailability under physiopathological conditions. Our aim was to understand the functional axis response composed of erythropoietin (Epo)-hepcidin-ferroportin (FPN), when 2 dysfunctional states coexist, using an animal model of iron overload followed by hypoxia. FPN and prohepcidin were assessed by immunohistochemistry using rabbit anti-mouse FPN polyclonal and prohepcidin monoclonal antibodies. Goat-labeled polymer - horseradish peroxidase anti-rabbit EnVision + System (DAB) was used as the secondary antibody. Epo levels were measured by ELISA. Tissue iron was studied by Prussian blue iron staining. Erythropoietic response was assessed using conventional hematological tests. Iron overload increased prohepcidin that remained high in hypoxia, coexisting with high levels of Epo in hypoxia, with or without iron overload. In hypoxia, FPN was clearly evident in reticuloendothelial macrophages, more than in hypoxia with iron overload. Interestingly, duodenal FPN was clearly identified on the basolateral membrane in hypoxia, with or without iron overload. Our data indicate that 2 signals could induce the cell-specific response as follows: (i) iron signal, induced prohepcidin, which reduced reticuloendothelial FPN and reduced iron availability; and (ii) hypoxia signal, stimulated Epo, which affected iron absorption by stabilizing duodenal FPN and allowed iron supply to erythropoiesis independently of store size.

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Duodenum, spleen and liver have a crucial role in iron balance on the whole organism and are the major sites of Ferroportin (FPN) expression. Specific regulations between FPN and hepcidin are responsible for changes seen in physiopathological conditions such as inflammation. We studied in vivo effects of turpentine oil-induced acute inflammation on FPN expression, and its relation with prohepcidin and iron mobilization. Immunohistochemical procedures were performed using rabbit anti-mouse FPN and prohepcidin antibodies with goat-labeled polymer-HRP anti-rabbit (DAB) as secondary antibody. Plasma and tissular iron were also studied. Our results showed a notable expression and redistribution of duodenal FPN to basolateral membrane in turpentine-treated mice, compared with supranuclear and the weak basolateral expression observed in healthy mice. Red pulp macrophages of healthy mice showed FPN-hemosiderin co-localization, compared with turpentine-treated mice which showed lack of FPN. In liver of healthy mice, FPN was seen in Kupffer cells, whereas in turpentine-treated mice decreased. In addition, we observed an increment of hepatic pro-hepcidin with a significant hypoferremia. Our findings demonstrated that acute inflammation induced a differential distribution of FPN, showing a cell type specific response. In macrophages, increased hepatic prohepcidin induced degradation of FPN, resulting in hypoferremia. In enterocytes, the redistribution observed of duodenal FPN reflects a different regulation in this tissue. The observed response of the proteins studied may be part of a cyclical pattern of systemic effects of acute inflammation on mouse tissue.

El duodeno, bazo e hígado desempeñan un rol clave en el balance de Fe del organismo y son los mayores sitios de expresión de ferroportina (FPN). Regulaciones específicas entre FPN y hepcidina son las responsables de los cambios observados en condiciones fisiopatológicas como la inflamación. Nuestro objetivo fue estudiar los efectos in vivo de la inflamación aguda inducida con turpentina sobre la expresión de FPN y su relación con prohepcidina y la movilización de hierro. Los procedimientos inmunohistoquímicos fueron desarrollados utilizando anticuerpos anti FPN y prohepcidina de ratón, desarrollados en conejo y un polímero conjugado con anticuerpos secundarios anti conejo desarrollado en cabra (HRP-DAB). Se evaluaron los niveles de Fe plasmático y tisular. Nuestros resultados mostraron una clara expresión y redistribución de FPN duodenal hacia la membrana basolateral en ratones tratados con turpentina, con respecto a la expresión perinuclear y leve expresión basolateral observada en ratón sano. Macrófagos de la pulpa roja esplénica mostraron co-localización de FPN y hemosiderina, comparado con la ausencia de expresión en ratón tratado con turpentina. En hígado de ratón sano, se observó expresión de FPN en células de Kupffer, mientras que en ratón tratado con turpentina la expresión fue menos evidente. Además, observamos un aumento en la expresión de prohepcidina hepática con una hipoferremia significativa. Nuestros resultados demostraron que la inflamación aguda indujo una distribución diferencial de FPN, mostrando una respuesta específica del tipo celular. En macrófagos, el aumento de prohepcidina hepática indujo degradación de FPN, resultando en hipoferremia. En enterocitos, la redistribución observada de FPN duodenal, refleja una regulación diferente en este tejido. La respuesta observada de las proteínas estudiadas podría ser parte de un patrón cíclico de efectos sistémicos de la inflamación aguda en tejidos murinos.

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Ferroportin (FPN), the only iron exporter identified to date, participates in iron release from enterocytes and macrophages, regulating its absorption and recycling. We used a murine model of experimental hemolytic anemia to study adaptive changes in the localization of FPN in duodenum, liver, and spleen. FPN was assessed by IHC in healthy and anemic mice using rabbit anti-mouse FPN polyclonal antibodies. Goat-labeled polymer-horseradish peroxidase anti-rabbit Envision+System (DAB) was used as secondary antibody. Tissue iron was studied by Prussian blue iron staining. Anemia evolution and erythropoietic recovery was assessed using conventional hematological tests. Healthy mice showed mainly supranuclear expression of FPN in enterocytes and a weak basolateral expression, whereas in anemic mice, the expression was detected mainly at the basolateral membrane (days 4 and 5). Red pulp macrophages of healthy mice showed FPN-hemosiderin colocalization. In the liver of healthy mice, FPN was mainly cytoplasmic, whereas in anemic mice, it was redistributed to the cell membrane. Our findings clearly show that anemia induces adaptive changes in FPN expression, contributing to anemia restoration by increasing available iron. FPN expression in the membrane is the main pathway of iron release. Our data indicate that iron homeostasis in vivo is maintained through the coordinated expression of this iron exporter in both intestinal and phagocytic cells.

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It is known that renal tissue plays a role in normal iron homeostasis. The current study examines kidney function in iron metabolism under hemolytic anemia studying renal expression of Prohepcidin, Ferroportin (MTP1), and divalent metal transporter 1 (DMT1). The relationship between these proteins and iron pigments was also investigated. Immunohistochemical procedures to study renal expression of Prohepcidin, MTP1, and DMT1 were performed in healthy and anemic mice. Renal tissue iron was determined by Prussian blue iron staining. To assess anemia evolution and erythropoietic recovery, we used conventional tests. In healthy mice, Prohepcidin expression was marked in proximal tubules and inner medulla and absent in outer medulla. Cortical tissue of healthy mice also showed MTP1 immunostaining, mainly in the S2 segment of proximal tubules. Medullar tissue showed MTP1 expression in the inner zone. In addition, S2 segments showed intense DMT1 immunoreactivity with homogeneous DMT1 distribution throughout renal medulla. The main cortical findings in hemolytic anemia were in S2 segments of proximal tubules where we found that decreased Prohepcidin expression coincided with an increment in Ferroportin and DMT1 expression. This expression pattern was concomitant with increased iron in the same tubular zone. However, in medullar tissue both Prohepcidin and MTP1 decreased and DMT1 was detected mainly in larger diameter tubules. Our findings clearly demonstrate that in hemolytic anemia, renal Prohepcidin acts in coordination with renal Ferroportin and DMT1, indicating the key involvement of kidney in iron homeostasis when iron demand is high. Further research is required to learn more about these regulatory mechanisms.

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Evaluar por estudios morfológicos el grado de eritropoyesis hepática y renal en ratones esplenectomizados en respuesta a la hemólisis inducida por fenilhidrazina...(AU)

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Introducción: El bazo del ratón adulto participa en la recuperación del eritrón porque su estroma aporta un microentorno adecuado para la proliferación y maduración de progenitores. Objetivo: Evaluar por estudios morfológicos el grado de eritropoyesis hepática y renal en ratones esplenectomizados en respuesta a la hemólisis inducida por fenilhidrazina (FHZ). Materiales y Métodos: Ratones hembra CF1(30±3g) fueron agrupados en:1)GRUPO CONTROL (GC)(n=18): solución fisiológica (SF) intraperitoneal (ip) (300µL;días:0,2) postcirugía simulada; 2)GRUPO ANÉMICO (GA) (n=18): FHZ ip (60mg/Kg/ 300mL;días:0,2) postcirugía simulada;3)GRUPO ESPLENECTOMIZADO NO ANÉMICO(GENA) (n=18): SF ip postesplenectomía (300mL;días:0,2); 4) GRUPO ESPLENECTOMIZADO ANÉMICO (GEA)(n=18): FHZ ip (60mg/Kg/ 300mL;días:0,2) postesplenectomía. Sangre venosa: cada 2 días hasta el día 10 (n=3). Parámetros evaluados: Hb, HCT, reticulocitos y cuerpos de Heinz. La esplenectomía se realizó bajo anestesia. Los tejidos fueron fijados con Bouin y Formol 10% y procesados para Hematoxilina- Eosina. Islotes eritropoyéticos (IE) semicuantificados por un escore preestablecido. Resultados: Los grupos anémicos, con y sin bazo, mostraron hemólisis franca el día 4. La recuperación de la anemia fue el día 6 en el GA y el día 10 en el GEA. Reticulocitosis máxima: día 8 en el GEA y día 6 en el GA. Cuerpos de Heinz: elevados hasta el día 6 en GA y hasta el día 8 en GEA. Se observaron abundantes IE en hígado y en menor grado en riñón. Conclusiones: La recuperación eritropoyética en ratones esplenectomizados fue asumida principalmente por el hígado. La restauración tardía evidenció que el bazo es el órgano que compensa con mayor eficiencia la crisis hemolítica en esta cepa de ratones.

Introduction: The spleen of the adult mouse takes part in the recovery of erythron because its stroma provides a micro-environment that is adequate for progenitor proliferation and maturing. Objective: To assess, by means of morphological studies, the degree of hepatic and renal erythropoiesis in splenectomized mice in response to phenylhydrazine (PHZ)-induced hemolysis. Materials and Methods: Female mice CF1(30±3g) were grouped into: 1) CONTROL GROUP (CG) (n=18): intraperitoneal (ip) physiological solution (PS) (300 µL; days: 0,2) post simulated surgery; 2) ANEMIC GROUP (AG) (n=18): ip PHZ (60 mg / Kg / 300mL; days: 0, 2) post simulated surgery; 3) SPLENECTOMIZED NON- ANEMIC GROUP (SNAG) (n=18): ip PS postsplenectomy (300mL; days: 0, 2); 4) SPLENECTOMIZED ANEMIC GROUP (SAG) (n=18): ip PHZ (60 mg / Kg / 300 mL; days: 0, 2) post-splenectomy. Venous blood: every 2 days until day 10 (n=3). Parameters assessed: Hb, HCT, reticulocytes, and Heinz bodies. The splenectomy was performed under anesthesia. Tissues were fixed using Bouin and 10% Formalin and processed for Hematoxilin- Eosin. Erythropoietic Islands (EI) were semi-quantified by a pre-established score. Results: Anemic groups, with and without the spleen, showed marked hemolysis on day 4. Anemia recovery took place on day 6 in the AG and on day 10 in the SAG. Maximum Reticulocytosis: day 8 in the SAG and day 6 in the AG. Heinz Bodies were high until day 6 in AG and until day 8 in SAG. Abundant EI were observed in the liver and in a smaller degree in the kidney. Conclusions: Erythropoietic recovery in splenectomized mice was mainly assumed by the liver. Late restoration showed that the spleen is the organ that most efficiently compensates the hemolytic crisis in this mice strain.

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Chronic venous insufficiency (CVI) causes much discomfort and sick leave. Many randomized clinical trials (RCTs) have shown a beneficial effect of calcium dobesilate, but consensus is lacking about efficacy and safety. The authors report a meta-analysis of the effectiveness and safety of calcium dobesilate in CVI. Ten RCTs (778 patients) in which calcium dobesilate for CVI was compared with placebo met the inclusion criteria. Only 3 trials (608 patients) were of good methodological quality. Calcium dobesilate significantly improved night cramps and discomfort nearly twice as well as placebo, with the number needed to treat (NNT) being 8 (95% CI 4-50) and 4 (95% CI 3-7), respectively. Frequency of adverse events was not significantly different from placebo. Subgroup analysis found a differential response with respect to disease severity, with greater improvements in pain, heaviness, and malleolar swelling being seen in the severe group than in the mild group. Calcium dobesilate improved paresthesias significantly more than placebo in the severe but not in the mild group and the effect on leg volume was also significantly better in the severe group (-7.2% vs -1.6%). No difference in effect was found for different doses of calcium dobesilate (1,000 or 1,500 mg/day). Sensitivity analyses did not affect the results. Current evidence suggests that calcium dobesilate is more effective than placebo in improving some CVI symptoms, that there is higher efficacy in more severe disease, and that a dose of 1,000 mg/day is as effective and safe as 1,500 mg/day. Further adequately powered trials are needed to further evaluate these hypotheses.

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Se evaluó al receptor de transferrina (RsT) como marcador de hierro funcional en dos grupos: 1) controles (50 adultos sanos de ambos sexos residentes a nivel del mar); 2) 50 anémicos ferroprivos por alteraciones nutricionales, gastrointestinales o ginecológicas (AFP). El valor medio en los controles fue 16.6 nmol/l (8.8 a 26.2 nmol/l), sin diferencias significativas por edad y sexo. En el grupo AFP, el valor medio fue 66.3 nmol/l (16.1 a 148.4 nmol/l). El análisis estadístico (características del operador receptor, ROC) estableció un intervalo de referencia óptimo de 8.8 a 25.8 nmol/l, Los valores predictivos, positivo (VPP) y negativo (VPN), del RsT como prueba diagnóstica fueron 97.5 y 97.7 por ciento, respectivamente, y la eficiencia diagnóstica (ED) fue 97.7 por ciento. Tanto en los controles como en los AFP se observó: 1) concentraciones inversas entre el RsT y la ferritina (F) (tendencia potencial entre las variables (p<0.001) con un coeficiente de determinación del 72 por ciento); 2) ampilas variaciones del RsT para concentraciones de hemoglobina (Hb) inferiores a 100 g/l (tendencia exponencial (p < 0.001) con un coeficiente de determinación del 71 por ciento); 3) valores de la relación RsT/log ferritina (índice RsT/F) sensiblemente mayores en AFP (75.8) que en los controles (9.6). La administración de hierro normalizó los niveles del RsT en pacientes ferroprivos, sin cambiar significativamente las concentraciones de ferritina sérica. Nuestros estudios demuestran que el RsT mide con alta especificidad y sensibilidad el hierro funcional.

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Se evaluó al receptor de transferrina (RsT) como marcador de hierro funcional en dos grupos: 1) controles (50 adultos sanos de ambos sexos residentes a nivel del mar); 2) 50 anémicos ferroprivos por alteraciones nutricionales, gastrointestinales o ginecológicas (AFP). El valor medio en los controles fue 16.6 nmol/l (8.8 a 26.2 nmol/l), sin diferencias significativas por edad y sexo. En el grupo AFP, el valor medio fue 66.3 nmol/l (16.1 a 148.4 nmol/l). El análisis estadístico (características del operador receptor, ROC) estableció un intervalo de referencia óptimo de 8.8 a 25.8 nmol/l, Los valores predictivos, positivo (VPP) y negativo (VPN), del RsT como prueba diagnóstica fueron 97.5 y 97.7 por ciento, respectivamente, y la eficiencia diagnóstica (ED) fue 97.7 por ciento. Tanto en los controles como en los AFP se observó: 1) concentraciones inversas entre el RsT y la ferritina (F) (tendencia potencial entre las variables (p<0.001) con un coeficiente de determinación del 72 por ciento); 2) ampilas variaciones del RsT para concentraciones de hemoglobina (Hb) inferiores a 100 g/l (tendencia exponencial (p < 0.001) con un coeficiente de determinación del 71 por ciento); 3) valores de la relación RsT/log ferritina (índice RsT/F) sensiblemente mayores en AFP (75.8) que en los controles (9.6). La administración de hierro normalizó los niveles del RsT en pacientes ferroprivos, sin cambiar significativamente las concentraciones de ferritina sérica. Nuestros estudios demuestran que el RsT mide con alta especificidad y sensibilidad el hierro funcional. (AU)

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