Incidence of cancer and related deaths in hemoglobinopathies: A follow-up of 4631 patients between 1970 and 2021.

BACKGROUND: The correlation between thalassemia and malignancies other than hepatocellular carcinoma (HCC) and the possible relationship between other hemoglobinopathies and tumor risk have been poorly evaluated. METHODS: Eight Italian specialized centers evaluated the incidence of malignant neoplasms in hemoglobinopathies as well as their sites and features. The study cohort included 4631 patients followed between 1970 and 2021 (transfusion-dependent ß-thalassemia, 55.6%; non-transfusion-dependent thalassemia, 17.7%; sickle cell disease, 17.6%; hemoglobin H disease, 8.3%). RESULTS: A total of 197 diagnoses of cancer were reported (incidence rate, 442 cases per 100,000 person-years). The liver was the most frequent site of tumors in both sexes, with a higher incidence (190 cases per 100,000 person-years) in comparison with the general population found in all types of hemoglobinopathies (except hemoglobin H disease). In recent years, tumors have become the second cause of death in patients with transfusion-dependent thalassemia. A lower risk of breast and prostate cancer was observed in the whole group of patients with hemoglobinopathies. The first cancer diagnoses dated back to the 1980s, and the incidence rate sharply increased after the 2000s. However, although the incidence rate of cancers of all sites but the liver continued to show an increasing trend, the incidence of HCC showed stability. CONCLUSIONS: These findings provide novel insights into the relationship between cancer and hemoglobinopathies and suggest that the overall risk is not increased in these patients. HCC has been confirmed as the most frequent tumor, but advances in chelation and the drugs that have led to the eradication of hepatitis C may explain the recent steadiness in the number of diagnoses that is reported here.

How Can Malnutrition Affect Autophagy in Chronic Heart Failure? Focus and Perspectives.

Chronic heart failure (CHF) is a disease with important clinical and socio-economic ramifications. Malnutrition and severe alteration of the protein components of the body (protein disarrangements), common conditions in CHF patients, are independent correlates of heart dysfunction, disease progression, and mortality. Autophagy, a prominent occurrence in the heart of patients with advanced CHF, is a self-digestive process that prolongs myocardial cell lifespan by the removal of cytosolic components, such as aging organelles and proteins, and recycles the constituent elements for new protein synthesis. However, in specific conditions, excessive activation of autophagy can lead to the destruction of molecules and organelles essential to cell survival, ultimately leading to organ failure and patient death. In this review, we aim to describe the experimental and clinical evidence supporting a pathophysiological role of nutrition and autophagy in the progression of CHF. The understanding of the mechanisms underlying the interplay between nutrition and autophagy may have important clinical implications by providing molecular targets for innovative therapeutic strategies in CHF patients.

Is the Response of Tumours Dependent on the Dietary Input of Some Amino Acids or Ratios among Essential and Non-Essential Amino Acids? All That Glitters Is Not Gold.

Energy production is the main task of the cancer cell metabolism because the costs of duplicating are enormous. Although energy is derived in cells by dismantling the carbon-to-carbon bonds of any macronutrient, cancer nutritional needs for energetic purposes have been studied primarily as being dependent on glycolysis. Since the end of the last century, the awareness of the dependence of cancer metabolism on amino acids not only for protein synthesis but also to match energy needs has grown. The roles of specific amino acids such as glutamine, glycine and serine have been explored in different experimental conditions and reviewed. Moreover, epidemiological evidence has revealed that some amino acids used as a supplement for therapeutic reasons, particularly the branched-chain ones, may reduce the incidence of liver cancer and a specific molecular mechanism has been proposed as functional to their protective action. By contrast and puzzling clinicians, the metabolomic signature of some pathologies connected to an increased risk of cancer, such as prolonged hyperinsulinemia in insulin-resistant patients, is identified by elevated plasma levels of the same branched-chain amino acids. Most recently, certain formulations of amino acids, deeply different from the amino acid compositions normally present in foods, have shown the power to master cancer cells epigenetically, slowing growth or driving cancer cells to apoptotic death, while being both beneficial for normal cell function and the animal's health and lifespan. In this review, we will analyze and try to disentangle some of the many knots dealing with the complexities of amino acid biology and links to cancer metabolism.

Dietary supplementation with essential amino acids boosts the beneficial effects of rosuvastatin on mouse kidney.

The effects of high-potency statins on renal function are controversial. To address the impact of statins on renal morpho-functional aspects, normotensive young mice were treated with rosuvastatin (Rvs). Moreover, because statins may impair mitochondrial function, mice received either dietary supplementation with an amino acid mixture enriched in essential amino acids (EAAm), which we previously demonstrated to increase mitochondrial biogenesis in muscle or an unsupplemented control diet for 1 month. Mitochondrial biogenesis and function, apoptosis, and insulin signaling pathway events were studied, primarily in cortical proximal tubules. By electron microscopy analysis, mitochondria were more abundant and more heterogeneous in size, with dense granules in the inner matrix, in Rvs- and Rvs plus EAAm-treated animals. Rvs administration increased protein kinase B and endothelial nitric oxide synthase phosphorylation, but the mammalian target of rapamycin signaling pathway was not affected. Rvs increased the expression of sirtuin 1, peroxisome proliferator-activated receptor γ coactivator-1α, cytochrome oxidase type IV, cytochrome c, and mitochondrial biogenesis markers. Levels of glucose-regulated protein 75 (Grp75), B-cell lymphoma 2, and cyclin-dependent kinase inhibitor 1 were increased in cortical proximal tubules, and expression of the endoplasmic reticulum-mitochondrial chaperone Grp78 was decreased. EAAm supplementation maintained or enhanced these changes. Rvs promotes mitochondrial biogenesis, with a probable anti-apoptotic effect. EAAm boosts these processes and may contribute to the efficient control of cellular energetics and survival in the mouse kidney. This suggests that appropriate nutritional interventions may enhance the beneficial actions of Rvs, and could potentially prevent chronic renal side effects.

Essential Amino Acids-Rich Diet Increases Cardiomyocytes Protection in Doxorubicin-Treated Mice.

BACKGROUND: Doxorubicin (Doxo) is a widely prescribed drug against many malignant cancers. Unfortunately, its utility is limited by its toxicity, in particular a progressive induction of congestive heart failure. Doxo acts primarily as a mitochondrial toxin, with consequent increased production of reactive oxygen species (ROS) and attendant oxidative stress, which drives cardiac dysfunction and cell death. A diet containing a special mixture of all essential amino acids (EAAs) has been shown to increase mitochondriogenesis, and reduce oxidative stress both in skeletal muscle and heart. So, we hypothesized that such a diet could play a favorable role in preventing Doxo-induced cardiomyocyte damage. METHODS: Using transmission electron microscopy, we evaluated cells' morphology and mitochondria parameters in adult mice. In addition, by immunohistochemistry, we evaluated the expression of pro-survival marker Klotho, as well as markers of necroptosis (RIP1/3), inflammation (TNFα, IL1, NFkB), and defense against oxidative stress (SOD1, glutathione peroxidase, citrate synthase). RESULTS: Diets with excess essential amino acids (EAAs) increased the expression of Klotho and enhanced anti-oxidative and anti-inflammatory responses, thereby promoting cell survival. CONCLUSION: Our results further extend the current knowledge about the cardioprotective role of EAAs and provide a novel theoretical basis for their preemptive administration to cancer patients undergoing chemotherapy to alleviate the development and severity of Doxo-induced cardiomyopathy.

Cubic Fe-bearing majorite synthesized at 18-25 GPa and 1000 °C: implications for element transport, subducted slab rheology and diamond formation.

The chemistry and mineralogy of slabs subducted into lower mantle control slab rheology and impact the deep volatile cycle. It is known that the metamorphism of little-altered oceanic crust results in eclogite rocks with subequal proportions of garnet and clinopyroxene. With increasing pressure, these minerals react to stabilize pyrope-rich tetragonal majoritic garnet. However, some eclogites contain higher proportions of omphacitic clinopyroxene, caused by Na- and Si-rich metasomatism on the ocean floor or during subduction. The mineralogy of such eclogites is expected to evolve differently. Here, we discuss the results of the crystallization products of omphacitic glass at ~ 18 and ~ 25 GPa and 1000 °C to simulate P-T regimes of cold subduction. The full characterization of the recovered samples indicates evidence of crystallization of Na-, Si-rich cubic instead of tetragonal majorite. This cubic majorite can incorporate large amounts of ferric iron, promoting redox reactions with surrounding volatile-bearing fluids and, ultimately, diamond formation. In addition, the occurrence of cubic majorite in the slab would affect the local density, favoring the continued buoyancy of the slab as previously proposed by seismic observations. Attention must be paid to omphacitic inclusions in sublithospheric diamonds as these might have experienced back-transformation from the HP isochemical cubic phase.

A comprehensive database of crystal-bearing magmas for the calibration of a rheological model.

In this work, we present a comprehensive rheological database including most of the existing data relevant for crystal-bearing magmas collected from the scientific literature, covering the entire range of natural volcanic conditions, in terms of crystal content (1-80%), crystal shape (aspect ratio R from 1 to 13), and strain rate (between 10-7 and 102 s-1). Datasets were collected and discerned as a function of the information which we considered necessary for building a general systematic model describing relative viscosity of crystal-bearing magmas, such as the apparent and melt viscosity, the crystal concentration, crystal shape, and the strain rate. The selected dataset was then used for modelling the relative viscosity of a liquid-solid mixture having different concentrations of particles with different R, subjected to different strain rates. The proposed model allows us to quantitatively describe the rheological behaviour of crystal-bearing magmatic systems.

Essential Amino Acids-Rich Diet Decreased Adipose Tissue Storage in Adult Mice: A Preliminary Histopathological Study.

BACKGROUND: Excess body adipose tissue accumulation is a common and growing health problem caused by an unbalanced diet and/or junk food. Although the effects of dietary fat and glucose on lipid metabolism regulation are well known, those of essential amino acids (EAAs) have been poorly investigated. Our aim was to study the influence of a special diet containing all EAAs on retroperitoneal white adipose tissue (rpWAT) and interscapular brown adipose tissue (BAT) of mice. METHODS: Two groups of male Balb/C mice were used. The first was fed with a standard diet. The second was fed with an EAAs-rich diet (EAARD). After 3 weeks, rpWAT and BAT were removed and prepared for subsequent immunohistochemical analysis. RESULTS: EAARD, although consumed significantly less, moderately reduced body weight and BAT, but caused a massive reduction in rpWAT. Conversely, the triceps muscle increased in mass. In rpWAT, the size of adipocytes was very small, with increases in leptin, adiponectin and IL-6 immunostaining. In BAT, there was a reduction in lipid droplet size and a simultaneous increase in UCP-1 and SIRT-3. CONCLUSIONS: A diet containing a balanced mixture of free EAA may modulate body adiposity in mice, promoting increased thermogenesis.

Qualitative Nitrogen Malnutrition Damages Gut and Alters Microbiome in Adult Mice. A Preliminary Histopathological Study.

Amino-acids (AAs) are the exclusive source of nitrogen for cells. AAs result from the breakdown of food proteins and are absorbed by mucosa of the small intestine that act as a barrier to harmful materials. The quality of food proteins may differ, since it reflects content in Essential-AAs (EAAs) and digestibility but, until now, attention was paid mainly to the interaction between indigested proteins as a whole and microbiota. The link between microbiome and quality of proteins has been poorly studied, although these metabolic interactions are becoming more significant in different illnesses. We studied the effects of a special diet containing unbalanced EAAs/Non-EAAs ratio, providing excess of Non-EAAs, on the histopathology of gut epithelium and on the microbiome in adult mice, as model of qualitative malnutrition. Excess in Non-EAAs have unfavorable quick effect on body weight, gut cells, and microbiome, promoting weakening of the intestinal barrier. Re-feeding these animals with standard diet partially reversed the body alterations. The results prove that an unbalanced EAAs/Non-EAAs ratio is primarily responsible for microbiome modifications, not vice-versa. Therefore, treating microbiota independently by treating co-existing qualitative malnutrition does not make sense. This study also provides a reproducible model of sarcopenia-wasting cachexia like the human protein malnutrition.

Management of Anaemia of Chronic Disease: Beyond Iron-Only Supplementation.

Chronic diseases are characterised by altered autophagy and protein metabolism disarrangement, resulting in sarcopenia, hypoalbuminemia and hypo-haemoglobinaemia. Hypo-haemoglobinaemia is linked to a worse prognosis independent of the target organ affected by the disease. Currently, the cornerstone of the therapy of anaemia is iron supplementation, with or without erythropoietin for the stimulation of haematopoiesis. However, treatment strategies should incorporate the promotion of the synthesis of heme, the principal constituent of haemoglobin (Hb) and of many other fundamental enzymes for human metabolism. Heme synthesis is controlled by a complex biochemical pathway. The limiting step of heme synthesis is D-amino-levulinic acid (D-ALA), whose availability and synthesis require glycine and succinil-coenzyme A (CoA) as precursor substrates. Consequently, the treatment of anaemia should not be based only on the sufficiency of iron but, also, on the availability of all precursor molecules fundamental for heme synthesis. Therefore, an adequate clinical therapeutic strategy should integrate a standard iron infusion and a supply of essential amino acids and vitamins involved in heme synthesis. We reported preliminary data in a select population of aged anaemic patients affected by congestive heart failure (CHF) and catabolic disarrangement, who, in addition to the standard iron therapy, were treated by reinforced therapeutic schedules also providing essential animo acids (AAs) and vitamins involved in the maintenance of heme. Notably, such individualised therapy resulted in a significantly faster increase in the blood concentration of haemoglobin after 30 days of treatment when compared to the nonsupplemented standard iron therapy.

Serum Metabolic Profile in Patients With Long-Covid (PASC) Syndrome: Clinical Implications.

Background: Many patients who have been suffering by Covid-19 suffer of long-Covid syndrome, with symptoms of fatigue and muscular weakness that characterize post-acute sequelae SARS-CoV-2 infection (PASC). However, there is limited knowledge about the molecular pathophysiology, and about the serum profile of these patients. Methods: We studied the blood serum profile of 75 selected patients, with previous confirmed Covid-19, 2 months after hospital discharge, who reported new-onset fatigue, muscle weakness and/or dyspnea not present prior to the virus infection and independently from concomitant diseases and/or clinical conditions. Results: All patients had very high serum concentrations of ferritin and D-Dimer. 87 and 72% of patients had clinically significant low levels of hemoglobin and albumin, respectively. Seventy three percentage had elevations in erythrocyte sedimentation rate and CRP. Twenty seven percentage had elevations in LDH. Conclusions: The co-existence of patient symptoms along with blood markers of coagulation, protein disarrangement and inflammation suggests ongoing alterations in the metabolism, promoting an inflammatory/hypercatabolic state which maintains a vicious circles implicated in the persistence of PASC. The persistence of altered D-Dimer levels raises the possibility of long-term risks of thromboembolic disease. All these markers levels should be accurately evaluated in the long-term follow-up, with individualized consideration for prophylactic nutritional, anti-inflammatory and/or anticoagulant therapy if indicated.

Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.

BACKGROUND: Intestinal dysbiosis has been proposed as a possible contributor of the development of type 2 diabetes (T2D). Indeed, commensal fungi and opportunistic bacteria stimulate the local immune system, altering intestinal permeability with consequent leaky gut, which in turn activates systemic inflammation responsible for insulin resistance. It is also well known that chronic exercise improves glucose control and diabetes-induced damage. The aim of this study was to evaluate the role of chronic exercise on gut flora composition and leaky gut in T2D stable patients. METHODS: Thirty clinically stable patients with T2D were studied before and after a six months program of endurance, resistance and flexibility training. Metabolic and anthropometric evaluations were carried out. Gut flora and intestinal permeability were measured in stools by selective agar culture medium and molecular biology measurements of zonulin, which is the protein that modulates enterocyte tight junctions. RESULTS: Diabetes causes significant intestinal mycetes overgrowth, increased intestinal permeability and systemic low-grade inflammation. However, exercise improved glycemia, functional and anthropometric variables. Moreover, chronic exercise reduced intestinal mycetes overgrowth, leaky gut, and systemic inflammation. Interestingly, these variables are closely correlated. CONCLUSIONS: Exercise controls diabetes by also modifying intestinal microbiota composition and gut barrier function. This data shows an additional mechanism of chronic exercise and suggests that improving gut flora could be an important step in tailored therapies of T2D.

Influence of Diets with Varying Essential/Nonessential Amino Acid Ratios on Mouse Lifespan.

An adequate intake of essential (EAA) and non-essential amino acids (NEAA) is crucial to preserve cell integrity and whole-body metabolism. EAA introduced with diet may be insufficient to meet the organismal needs, especially under increased physiological requirements or in pathological conditions, and may condition lifespan. We therefore examined the effects of iso-caloric and providing the same nitrogenous content diets, any diet containing different stoichiometric blends of EAA/NEAA, on mouse lifespan. Three groups of just-weaned male Balb/C mice were fed exclusively with special diets with varying EAA/NEAA ratios, ranging from 100%/0% to 0%/100%. Three additional groups of mice were fed with different diets, two based on casein as alimentary proteins, one providing the said protein, one reproducing the amino acidic composition of casein, and the third one, the control group, was fed by a standard laboratory diet. Mouse lifespan was inversely correlated with the percentage of NEAA introduced with each diet. Either limiting EAA, or exceeding NEAA, induced rapid and permanent structural modifications on muscle and adipose tissue, independently of caloric intake. These changes significantly affected food and water intake, body weight, and lifespan. Dietary intake of varying EAA/NEAA ratios induced changes in several organs and profoundly influenced murine lifespan. The balanced content of EAA provided by dietary proteins should be considered as the preferable means for "optimal" nutrition and the elevated or unbalanced intake of NEAA provided by food proteins may negatively affect the health and lifespan of mice.

Urocortin Induces Phosphorylation of Distinct Residues of Signal Transducer and Activator of Transcription 3 (STAT3) via Different Signaling Pathways.

BACKGROUND Urocortin (Ucn) is a member of the hypothalamic corticotrophin-releasing factor family and has been shown to reduce cell death in the heart caused by ischemia/reperfusion (I/R) injury. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor known to function as a pro-survival and anti-apoptotic factor, whose activation depends on a variety of cytokines, including IL-6. A recent study demonstrated that urocortin induced IL-6 release from cardiomyocytes in a CRF-R2-dependent manner, suggesting a possible link between CRF-R2 stimulation and STAT3 activation. MATERIAL AND METHODS Experimental work was carried out in HL-1 cardiac myocytes exposed to serum starvation for 16-24 h. RESULTS Ucn stimulation led to IL-6 expression and release from mouse atrial HL-1 cardiomyocytes. Ucn treatment led to rapid phosphorylation of JAK2, which was blocked by the protein synthesis inhibitor cycloheximide or the JAK inhibitor AG490. Urocortin treatment induced STAT3 phosphorylation at Y705 and S727 through transactivation of JAK2 in an IL-6-dependent manner, but had no effect on STAT1 activity. Kinase inhibition experiments revealed that urocortin induces STAT3 S727 phosphorylation through ERK1/2 and Y705 phosphorylation through Src tyrosine kinase. In line with this finding, urocortin failed to induce phosphorylation of Y705 residue in SYF cells bearing null mutation of Src, while phosphorylation of S727 residue was unchanged. CONCLUSIONS Here, we have shown that Ucn induces activation of STAT3 through diverging signaling pathways. Full understanding of these signaling pathways will help fully exploit the cardioprotective properties of endogenous and exogenous Ucn.

Autophagy and Oncosis/Necroptosis Are Enhanced in Cardiomyocytes from Heart Failure Patients.

BACKGROUND Although originally described as a survival mechanism, it is unknown whether and to what extent autophagy is implicated in the terminal stages of heart failure. Here, we studied magnitude and evolution of autophagy in patients with intractable heart failure. MATERIAL AND METHODS Myocardial samples were obtained from 22 patients with ischemic cardiomyopathy and idiopathic dilated cardiomyopathy who were undergoing cardiac transplantation. Hearts from 11 patients who died from non-cardiac causes were used as control samples. Autophagy was evaluated by immunostaining with a monoclonal microtubule associated protein light chain 3 (LC3)-II antibody, while the relationship of autophagy with apoptosis and oncosis was assessed by double staining with TUNEL (terminal deoxynucleotidyl transferase - mediated deoxyuridine triphosphate nick end labeling) assay and complement 9 (C9) immunological staining, respectively. In addition, several necroptotic markers, including RIP1 and RIP3 (receptor interacting protein kinase 1 and 3), anti-C3 (cleaved-caspase-3), and anti-NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) were assessed by immunohistochemistry. RESULTS Anti-LC3-II staining was detected in 8.7±1.6% of the heart failure patient heart samples and in 1.2±0.3% of control patient heart samples. Vacuole formation started at one nuclear pole, before becoming bipolar and involving the cytosol. Subsequently, the autophagic process extended also to the nuclei, which underwent a progressive vacuolization and disintegration, assuming a peculiar "strawberry like appearance". Myocytes with extensive vacuole formation exhibited nuclear degeneration, which was associated with TUNEL, C3, C9, RIP1, and RIP3 positive staining. Conversely, myocytes with less extensive vacuole formation showed RIP1 and NF-κB positive staining, though not positivity for other cell death markers. CONCLUSIONS Autophagy was extensively detected in end-stage heart failure and its progression, resulted in secondary cell death, with occurrence of oncosis and necroptosis exceeding that of apoptosis. Conversely, activation of the RIP1/NF-κB pathway was associated with cell survival.

Protein-Amino Acid Metabolism Disarrangements: The Hidden Enemy of Chronic Age-Related Conditions.

Proteins are macro-molecules crucial for cell life, which are made up of amino acids (AAs). In healthy people, protein synthesis and degradation are well balanced. However, in the presence of hypercatabolic stimulation (i.e., inflammation), protein breakdown increases as the resulting AAs are consumed for metabolic proposes. Indeed, AAs are biochemical totipotent molecules which, when deaminated, can be transformed into energy, lipids, carbohydrates, and/or biochemical intermediates of fundamental cycles, such as the Krebs' cycle. The biochemical consequence of hyper-catabolism is protein disarrangement, clinically evident with signs such as sarcopenia, hypalbuminemia, anaemia, infection, and altered fluid compartmentation, etc. Hypercatabolic protein disarrangement (HPD) is often underestimated by clinicians, despite correlating with increased mortality, hospitalization, and morbidity quite independent of the primary disease. Simple, cheap, repeatable measurements can be used to identify HPD. Therefore, identification and treatment of proteins' metabolic impairment with appropriate measurements and therapy is a clinical strategy that could improve the prognosis of patients with acute/chronic hypercatabolic inflammatory disease. Here, we describe the metabolism of protein and AAs in hypercatabolic syndrome, illustrating the clinical impact of protein disarrangement. We also illustrate simple, cheap, repeatable, and worldwide available measurements to identify these conditions. Finally, we provide scientific evidence for HPD nutritional treatment.

Body Weight Loss and Tissue Wasting in Late Middle-Aged Mice on Slightly Imbalanced Essential/Non-essential Amino Acids Diet.

Objective: Inadequate protein intake can impair protein balance thus leading to skeletal muscle atrophy, impaired body growth, and functional decline. Foods provide both non-essential (NEAAs) and essential amino acids (EAAs) that may convey different metabolic stimuli to specific organs and tissues. In this study, we sought to evaluate the impact of six diets, with various EAA/NEAA blends, on body composition and the risk of developing tissue wasting in late middle-aged male mice. Methods: Six groups of late middle-aged male mice were fed for 35 days with iso-nutrients, iso-caloric, and iso-nitrogenous special diets containing different EAA/NEAA ratios ranging from 100/0% to 0/100%. One group fed with standard laboratory rodent diet (StD) served as control. Preliminarily, we verified the palatability of the diets by recording the mice preference, and by making accessible all diets simultaneously, in comparison to StD. Body weight, food and water consumption were measured every 3 days. Blood and urine samples, as well as heart, kidneys, liver, spleen, triceps surae, retroperitoneal WAT, and BAT were harvested and weighed. Results: Mice consuming NEAA-based diets, although showing increased food and calorie intake, suffered the most severe weight loss. Interestingly, the diet containing a EAA/NEAA-imbalance, with moderate NEAAs prevalence, was able to induce catabolic stimuli, generalized body wasting, and systemic metabolic alterations comparable to those observed with diet containing NEAA alone. In addition, complete depletion of retroperitoneal white adipose tissue and a severe loss (>75%) of brown adipose tissue were observed together with muscle wasting. Conversely, EAA-containing diets induced significant decreases in body weight by reducing primarily fat reserves, but at the same time they improved the clinical parameters. On these basis we can deduce that tissue wasting was caused by altered AA quality, independent of reduced nitrogen or caloric intake. Conclusion: Our results indicate that diets containing an optimized balance of AA composition is necessary for preserving overall body energy status. These findings are particularly relevant in the context of aging and may be exploited for contrasting its negative correlates, including body wasting.

Maintenance of renal function in a patient with a history of acute paroxysmal nocturnal hemoglobinuria-associated kidney injury.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening blood disorder characterized by intravascular hemolysis, thrombosis and bone marrow failure. Acute kidney injury, including acute renal failure, have been reported in patients with PNH. We report the case of a 36-year-old male patient with PNH who developed acute kidney injury following an infection of undetermined diagnosis. Although hemolysis was initially controlled and renal function stabilized following packed red blood cell transfusion and empirical levofloxacin and prednisone, he later experienced recurrent episodes of hemolysis and hematuria requiring monthly red blood cell support. Given the high risk of thromboembolic events, treatment with standard-dose eculizumab was started. The patient's hematologic values improved, renal function was maintained, and no thromboembolic events occurred.

Endoplasmic Reticulum Stress and Apoptosis Triggered by Sub-Chronic Lead Exposure in Mice Spleen: a Histopathological Study.

Lead (Pb) is an environmental oncogenic metal that induces immunotoxicity and anaemia. Emerging evidence has linked Pb toxicity with endoplasmic reticulum-driven apoptosis and autophagy. Glucose-regulated protein of 78 kDa (Grp78 or binding immunoglobulin protein (BiP)), a master endoplasmic reticulum chaperone, drives macrophage activation and regulates protein folding and calcium flux in response to heavy metals. The spleen may be involved in Pb poisoning due to its crucial role in erythrocatheresis and immune response, although there are no data to support this theory. Here, we found haematic and histopathological changes in the spleen of mice exposed to medium doses of Pb acetate (200 ppm-1 mM) in drinking water for 45 days. Pb deposition was also detected in organs such as the liver, kidney, brain, bone, blood and faeces, indicating an accumulation of this metal despite relatively short exposure time. Blood Pb content (BBL) reached 21.6 µg/dL; echinocytes and poikilocytes were found in Pb smears of treated group. Inside the spleen, higher Fe(II) and Fe(III) deposits inside macrophages were observed. Grp78 immunostaining, weakly expressed in spleen cells of control mice, after Pb exposure was specifically restricted to macrophages and megakaryocytes of the marginal zone of red pulp. Furthermore, Pb exposure induced superoxide dismutase 1 (SOD1) expression, cleaved caspase-3 and p62/SQSTM1, consistent with oxidative stress, apoptosis and dysregulated autophagy in spleen compartments. We suggest that even at a middle dose, oral Pb intake induces oxidant iron deposition in the spleen and that this may trigger sustained Grp78 redistribution to cells, thus leading to oxidative and autophagy dysfunction as early local reactions to this dangerous metal.