Copper overload exacerbates testicular aging mediated by lncRNA:CR43306 deficiency through ferroptosis in Drosophila.

Testicular aging manifests as impaired spermatogenesis and morphological alterations in Drosophila. Nonetheless, the comprehensive molecular regulatory framework remains largely undisclosed. This investigation illustrates the impact of copper overload on testicular aging and underscores the interplay between copper overload and lncRNA. Copper overload triggers Cuproptosis through the mitochondrial TCA cycle, facilitating intracellular interactions with Ferroptosis, thereby governing testicular aging. Dysfunction of lncRNA:CR43306 also contributes to testicular aging in Drosophila, emphasizing the significance of lncRNA:CR43306 as a novel aging-associated lncRNA. Moreover, copper overload exacerbates spermatid differentiation defects mediated by lncRNA:CR43306 deficiency through oxidative stress, copper, and iron transport. Therapeutically, Ferrostatin-1 and Resveratrol emerge as potential remedies for addressing testicular aging. This study offers perspectives on the regulatory mechanisms involving copper overload and lncRNA:CR43306 deficiency in the context of testicular aging.

Neurodegeneration in a domestic rabbit with severe malnourishment and low hepatic copper.

Copper is a trace element that plays an essential role in neurodevelopment and neurologic function. Acquired copper deficiency has a range of neurologic manifestations, with myelopathy being the most common association. We describe here the clinical, radiologic, histopathologic, and toxicologic findings of a rabbit with malnutrition, neurodegeneration, and suspected copper deficiency. A stray, adult female dwarf rabbit cross (Oryctolagus cuniculus) in poor body condition developed ataxia and pelvic limb weakness progressing to lateral recumbency and urine retention. The clinical findings suggested multifocal brainstem disease with right-sided central vestibular involvement; however, microscopic examination identified thoracic and lumbosacral spinal cord myelopathy. Differentials for the spinal cord changes included neurodegenerative disease, nutritional deficiency, neurotoxin, trauma to the lumbosacral region, and ischemia. Hepatic copper levels were suboptimal at 18 ppm dry weight (RI: 24-150 ppm dry weight). While speculative, copper-deficiency myelopathy is a treatable cause of non-compressive myelopathy that may occur in this species.

Micronutrient deficiencies in inflammatory bowel disease: an incidence analysis.

BACKGROUND: Micronutrient deficiencies associated with malnutrition in patients with inflammatory bowel disease (IBD) can lead to complications including anemia, coagulopathy, poor wound healing, and colorectal cancer. This study aimed to investigate micronutrient deficiencies (copper, vitamins A, B 9 , E, and K) in IBD patients and highlight associated symptoms to aid in the recognition of micronutrient deficiencies. METHODS: A retrospective electronic chart review was performed on adults diagnosed with Crohn's disease or ulcerative colitis hospitalized at a tertiary care center for IBD flare between January 2013 and June 2017. Patients with serum or whole blood micronutrient levels were included. Pregnant and incarcerated patients were excluded. RESULTS: A total of 611 IBD patients (440 Crohn's disease, 171 ulcerative colitis) met the inclusion criteria. Micronutrients were assessed in a subset of IBD patients (copper: 12.3%, A: 10.1%, B 9  : 95.9%, E: 10.3%, and K: 4.6%). Overall, 10.1% of patients had micronutrient deficiencies. The proportion of patients with copper, A, B 9 , E, and K deficiencies were 25.4, 53.3, 1.9, 23.7, and 29.4% for Crohn's disease and 50, 52.9, 1.2, 43.8, and 18.2% for ulcerative colitis, respectively. The most common symptoms or historical features associated with micronutrient deficiency were anemia (copper, B 9 ), muscle weakness (copper, E) thrombocytopenia, fatigue (copper, B 9 ), diarrhea (B 9 ), dry skin, hyperkeratosis, pruritus, significant weight loss, elevated C-reactive protein (A), bleeding, and osteoporosis (K). CONCLUSION: Micronutrient deficiencies are common in IBD patients, yet they are not routinely assessed. Copper, vitamins A, E, and K deficiencies are particularly underrecognized. Associated historical features should raise suspicion and prompt assessment and treatment.

Intermittent hypoxia exacerbates metabolic dysfunction-associated fatty liver disease by aggravating hepatic copper deficiency-induced ferroptosis.

Intermittent hypoxia (IH) is an independent risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD). Copper deficiency can disrupt redox homeostasis, iron, and lipid metabolism. Here, we investigated whether hepatic copper deficiency plays a role in IH-associated MAFLD and explored the underlying mechanism(s). Male C57BL/6 mice were fed a western-type diet with adequate copper (CuA) or marginally deficient copper (CuD) and were exposed separately to room air (RA) or IH. Hepatic histology, plasma biomarkers, copper-iron status, and oxidative stress were assessed. An in vitro HepG2 cell lipotoxicity model and proteomic analysis were used to elucidate the specific targets involved. We observed that there were no differences in hepatic phenotypes between CuA-fed and CuD-fed mice under RA. However, in IH exposure, CuD-fed mice showed more pronounced hepatic steatosis, liver injury, and oxidative stress than CuA-fed mice. IH induced copper accumulation in the brain and heart and exacerbated hepatic copper deficiency and secondary iron deposition. In vitro, CuD-treated cells with IH exposure showed elevated levels of lipid accumulation, oxidative stress, and ferroptosis susceptibility. Proteomic analysis identified 360 upregulated and 359 downregulated differentially expressed proteins between CuA and CuD groups under IH; these proteins were mainly enriched in citrate cycle, oxidative phosphorylation, fatty acid metabolism, the peroxisome proliferator-activated receptor (PPAR)α pathway, and ferroptosis. In IH exposure, CuD significantly upregulated the ferroptosis-promoting factor arachidonyl-CoA synthetase long chain family member (ACSL)4. ACSL4 knockdown markedly eliminated CuD-induced ferroptosis and lipid accumulation in IH exposure. In conculsion, IH can lead to reduced hepatic copper reserves and secondary iron deposition, thereby inducing ferroptosis and subsequent MAFLD progression. Insufficient dietary copper may worsen IH-associated MAFLD.

Trace Element Deficiency in Systemic Sclerosis-Too Much Effort for Some Traces?

Trace elements are essential for several physiological processes. To date, various data have suggested that inadequate levels of trace elements may be involved in the pathogenesis of different chronic diseases, including immune-mediated ones, or may develop during their course. Systemic sclerosis (SSc) is a complex autoimmune multisystemic disease, primarily characterized by microvascular dysregulation, the widespread activation of the immune system and tissue fibrosis. According to the latest reports regarding the pathogenesis of SSc, the main pathophysiological processes-inflammation, vasculopathy and fibrosis-may include various trace element derangements. The present literature review aims to update the available data regarding iron, zinc, copper and selenium status in SSc as well as to underline the possible implications of these trace elements in the complexity of the pathogenic process of the disease. We observe that the status of trace elements in SSc plays a crucial role in numerous pathogenic processes, emphasizing the necessity for proper monitoring and supplementation. The reported data are heterogenous and scarce, and future studies are needed in order to draw clearer conclusions about their complete spectrum.

Molecular Mechanisms of Plant Responses to Copper: From Deficiency to Excess.

Copper (Cu) is an essential nutrient for plant growth and development. This metal serves as a constituent element or enzyme cofactor that participates in many biochemical pathways and plays a key role in photosynthesis, respiration, ethylene sensing, and antioxidant systems. The physiological significance of Cu uptake and compartmentalization in plants has been underestimated, despite the importance of Cu in cellular metabolic processes. As a micronutrient, Cu has low cellular requirements in plants. However, its bioavailability may be significantly reduced in alkaline or organic matter-rich soils. Cu deficiency is a severe and widespread nutritional disorder that affects plants. In contrast, excessive levels of available Cu in soil can inhibit plant photosynthesis and induce cellular oxidative stress. This can affect plant productivity and potentially pose serious health risks to humans via bioaccumulation in the food chain. Plants have evolved mechanisms to strictly regulate Cu uptake, transport, and cellular homeostasis during long-term environmental adaptation. This review provides a comprehensive overview of the diverse functions of Cu chelators, chaperones, and transporters involved in Cu homeostasis and their regulatory mechanisms in plant responses to varying Cu availability conditions. Finally, we identified that future research needs to enhance our understanding of the mechanisms regulating Cu deficiency or stress in plants. This will pave the way for improving the Cu utilization efficiency and/or Cu tolerance of crops grown in alkaline or Cu-contaminated soils.

The possible association of mitochondrial fusion and fission in copper deficiency-induced oxidative damage and mitochondrial dysfunction of the heart.

INTRODUCTION: As an essential trace element, Copper (Cu) participates in numerous physiological and biological reactions in the body. Cu is closely related to heart health, and an imbalance of Cu will cause cardiac dysfunction. The research aims to examine how Cu deficiency affects the heart, assess mitochondrial function in the hearts, and disclose possible mechanisms of its influence. METHODS: Weaned mice were fed Cu-deficient diets and intraperitoneally given copper sulfate (CuSO4) to correct the Cu deficiency. The pathological change of the heart was assessed using histological inspection. Cardiac function and oxidative stress levels were evaluated by biochemical assay kits. ELISA and ATP detection kits were used to detect the levels of complexes I-IV in the mitochondrial respiratory chain (MRC) and ATP, respectively. Real time PCR was utilized to determine mRNA expressions, and Western blotting was adopted to determine protein expressions, of molecules related to mitochondrial fission and fusion. RESULTS: Cu deficiency gave rise to elevated heart index, cardiac histological alterations and oxidation injury, increased serum levels of creatine kinase (CK), lactic dehydrogenase (LDH), and creatine kinase isoenzyme MB (CK-MB) together with increased malondialdehyde (MDA) production, decreased the glutathione (GSH), Superoxide Dismutase (SOD), and Catalase (CAT) activities or contents. Besides, Cu deficiency caused mitochondrial damage characterized by decreased contents of complexes I-IV in the MRC and ATP in the heart. In the meantime, Cu deficiency also reduced protein and mRNA expressions of factors associated with mitochondrial fusion, including Mfn1 and Mfn2, while significantly increased factors Drip1 and Fis1 related to mitochondrial fission. However, adding CuSO4 improved the above changes significantly. CONCLUSION: According to research results, Cu deficiency can cause heart damage in mice, along with oxidative damage and mitochondrial dysfunction, which are closely related to mitochondrial fusion and fission disorders.

LLL 44-1 Micronutrients in clinical nutrition: Trace elements.

BACKGROUND: Trace elements are an essential component of metabolism and medical nutrition therapy, with key roles in metabolic pathways, antioxidation, and immunity, which the present course aims at summarizing. RESULTS: Medical nutrition therapy includes the provision of all essential trace elements. The clinical essential issues are summarized for Copper, Iron, Selenium, Zinc, Iodine, Chromium, Molybdenum, and Manganese: the optimal analytical techniques are presented. The delivery of all these elements occurs nearly automatically when the patient is fed with enteral nutrition, but always requires separate prescription in case of parenteral nutrition. Isolated deficiencies may occur, and some patients have increased requirements, therefore a regular monitoring is required. The clinicians should always consider the impact of inflammation on blood levels, mostly lowering them even in absence of deficiency. CONCLUSION: This text summarises the most relevant clinical manifestations of trace element depletion and deficiency, the difficulties in assessing status, and makes practical recommendations for provision for enteral and parenteral nutrition.

Cuproptosis and copper deficiency in ischemic vascular injury and repair.

Ischemic vascular diseases are on the rise globally, including ischemic heart diseases, ischemic cerebrovascular diseases, and ischemic peripheral arterial diseases, posing a significant threat to life. Copper is an essential element in various biological processes, copper deficiency can reduce blood vessel elasticity and increase platelet aggregation, thereby increasing the risk of ischemic vascular disease; however, excess copper ions can lead to cytotoxicity, trigger cell death, and ultimately result in vascular injury through several signaling pathways. Herein, we review the role of cuproptosis and copper deficiency implicated in ischemic injury and repair including myocardial, cerebral, and limb ischemia. We conclude with a perspective on the therapeutic opportunities and future challenges of copper biology in understanding the pathogenesis of ischemic vascular disease states.

Are the elements zinc, copper, magnesium, and rubidium related to nutrition and iodine deficiency in pregnant Bulgarian women from iodine deficient region?

OBJECTIVE: Trace elements are essential for the biochemistry of the cell. Their reference values have been found to differ considerably in pregnant women stratified by age, place of residence, anthropometric status, and length of pregnancy. In optimal amounts, these elements reduce the risk of pregnancy complications. Subclinical hypothyroidism in pregnancy is associated with adverse maternal and neonatal outcomes. The aim of the study was to determine the effects of zinc (Zn), copper (Cu), magnesium (Mg), and rubidium (Rb) on pregnant women in an iodine deficiency region and find the relationship with the thyroid status and nutrition. METHODS: We evaluated the iodine status of 61 healthy pregnant women from an iodine deficient region in Bulgaria. Thyroid stimulating hormone (TSH) and thyroxin free (FT4) levels were measured using ELISA. RESULTS: We found elevated levels of copper that differed the most between the first and second trimesters; Cu and TSH were found to be positively correlated (р < 0.05). Lower Cu levels were found in pregnant women consuming pulses more than 2-3 times a week (р = 0.033). The women consuming fish more than 2-3 times a week had higher levels of Rb. We found a pronounced iodine deficiency in more than half of the examined women in the first to third trimesters, without any effect of pregnancy on the ioduria (р=0.834). All second and third trimester cases were associated with severe ioduria (< 150 µg/L). CONCLUSION: The high Cu levels were associated with subclinical hypothyroidism (SCH) and less pulse consumption during pregnancy in an iodine deficiency endemic area. SCH was found in 24% of the pregnant women in such an area while in 13% of them SCH had progressed to overt hypothyroidism.

Maternal dietary copper deficiency induces cardiomyopathy and liver injury in mice by activating autophagy.

Maternal nutritional deficiencies during pregnancy result in birth defects and elevate the risk of cardiovascular diseases and metabolic diseases. Accumulating evidence suggests that deficiency of copper, a fundamental trace element involved in several pivotal physiological processes, promotes the onset of multiple diseases, notably heart and liver diseases. Yet, exploration into the effects of maternal copper deficiency (CuD) on offspring is still limited. In this study, we hypothesized that maternal CuD induced cardiomyopathy and liver injury in offspring through the activation of autophagy. We established a maternal CuD mouse model by feeding pregnant C57BL/6 mice with a CuD diet until the end of the experiment. Echocardiography, histological analysis, western blotting, and quantitative polymerase chain reaction were performed on offspring at postnatal day 14. We found that maternal CuD caused growth retardation and early postnatal death in the offspring. Furthermore, our results revealed that CuD induced cardiac systolic dysfunction, cardiac hypertrophy, hepatic steatosis, and liver injury. Moreover, higher expression of LC3 and lower expression of p62 were observed in the heart tissues and liver tissues of CuD mice compared with the control group, indicating that CuD induced autophagy activation. In conclusion, maternal CuD caused severely deleterious effects on the heart and liver of the offspring via activating autophagy.

Fructose aggravates copper-deficiency-induced cardiac remodeling by inhibiting SERCA2a.

OBJECTIVES: Accumulating evidence demonstrates that copper deficiency (CuD) is a risk factor for cardiovascular diseases, besides, fructose has been strongly linked to the development of cardiovascular diseases. However, how CuD or fructose causes cardiovascular diseases is not clearly delineated. The present study aims to investigate the mechanism of CuD or fructose on cardiac remodeling. METHODS: We established a model of CuD- or fructose-induced cardiac hypertrophy in 3-week-old male Sprague-Dawley (SD) rats by CuD diet supplemented with or without 30% fructose for 4 weeks. In vitro study was performed by treating cardiomyocytes with tetrathiomolydbate (TM) and fructose. Echocardiography, histology analysis, immunofluorescence, western blotting, and qPCR were performed. KEY FINDINGS: Our findings revealed that CuD caused noticeable cardiac hypertrophy either in the presence or absence of fructose supplement. Fructose exacerbated CuD-induced cardiac remodeling and intramyocardial lipid accumulation. Furthermore, we presented that the inhibition of autophagic flux caused by Ca2+ disturbance is the key mechanism by which CuD- or fructose-induced cardiac remodeling. The reduced expression of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) in cardiomyocytes accounts for the elevated cytoplasmic Ca2+ concentration. CONCLUSIONS: Collectively, our study suggested that fructose aggravated CuD-induced cardiac remodeling through the blockade of autophagic flux via SERCA2a decreasing-induced Ca2+ imbalance.

Expression of cardiac copper chaperone encoding genes and their correlation with cardiac function parameters in goats.

Copper deficiency (CuD) is a common cause of oxidative cardiac tissue damage in ruminants. The expression of copper chaperone (Cu-Ch) encoding genes enables an in-depth understanding of copper-associated disorders, but no previous studies have been undertaken to highlight Cu-Ch disturbances in heart tissue in ruminants due to CuD. The current study aimed to investigate the Cu-Ch mRNA expression in the heart of goats after experimental CuD and highlight their relationship with the cardiac measurements. Eleven male goats were enrolled in this study and divided into the control group (n = 4) and CuD group (n = 7), which received copper-reducing dietary regimes for 7 months. Heart function was evaluated by electrocardiography and echocardiography, and at the end of the experiment, all animals were sacrificed and the cardiac tissues were collected for histopathology and quantitative mRNA expression by real-time PCR. In the treatment group, cardiac measurements revealed increased preload and the existence of cardiac dilatation, and significant cardiac tissue damage by histopathology. Also, the relative mRNA expression of Cu-Ch encoding genes; ATP7A, CTr1, LOX, COX17, as well as ceruloplasmin (CP), troponin I3 (TNNI3), glutathione peroxidase (GPX1), and matrix metalloprotease inhibitor (MMPI1) genes were significantly down-regulated in CuD group. There was a significant correlation between investigated genes and some cardiac function measurements; meanwhile, a significant inverse correlation was observed between histopathological score and ATP7B, CTr1, LOX, and COX17. In conclusion, this study revealed that CuD induces cardiac dilatation and alters the mRNA expression of Cu-Ch genes, in addition to TNNI3, GPX1, and MMPI1 that are considered key factors in clinically undetectable CuD-induced cardiac damage in goats which necessitate further studies for feasibility as biomarkers.

Comparison of the one-year outcomes of bariatric surgery in adolescents and young adults: a matched case-control study, Tehran Obesity Treatment Study (TOTS).

PURPOSES: The increasing use of bariatric surgery in adolescents has raised some concerns regarding the postoperative outcomes and the optimal time of surgery at young ages. However, no study has yet compared the weight loss and comorbidity resolution following bariatric surgery between adolescents and young adults. METHODS: This study was conducted on a case group of adolescents (aged 11-18) and a control group of young adults (aged 19-29) undergoing bariatric surgery (sleeve gastrectomy or gastric bypass). The two groups were matched in terms of gender, body mass index (BMI), and surgery type and were assessed regarding the surgical outcomes at 1 year after surgery. RESULTS: The baseline characteristics of the adolescents (n = 118, mean age: 17.0 ± 1.6 years) and young adults (n = 236, mean age: 25.2 ± 3.2 years) were similar, as well as surgery-associated complications. The mean loss of BMI (- 15.4 ± 3.6 vs. -15.8 ± 4.6 kg/m2) and 12-month percentage of excess weight loss (80.4 ± 20.1 vs. 80.2 ± 20.1%) were similar in the two groups. Both groups showed parallel reductions in the cardiovascular risk factors. The remission of hypertension, diabetes mellitus, and dyslipidemia was similar between the groups. The increase in the hemoglobin level and copper deficiency was greater in young adults, whereas the increase in ferritin deficiency was greater in adolescents. CONCLUSION: Similar to young adults, bariatric surgery is an effective and safe method to achieve weight loss, resolve obesity-related comorbidities, and improve cardiovascular risk factors in the adolescents.

Do Only Calcium and Vitamin D Matter? Micronutrients in the Diet of Inflammatory Bowel Diseases Patients and the Risk of Osteoporosis.

Osteoporosis is one of the most common extraintestinal complications among patients suffering from inflammatory bowel diseases. The role of vitamin D and calcium in the prevention of a decreased bone mineral density is well known, although other nutrients, including micronutrients, are also of extreme importance. Despite the fact that zinc, copper, selenium, iron, cadmium, silicon and fluorine have not been frequently discussed with regard to the prevention of osteoporosis, it is possible that a deficiency or excess of the abovementioned elements may affect bone mineralization. Additionally, the risk of malnutrition, which is common in patients with ulcerative colitis or Crohn's disease, as well as the composition of gut microbiota, may be associated with micronutrients status.

Inactivation of cytosolic FUMARASE2 enhances growth and photosynthesis under simultaneous copper and iron deprivation in Arabidopsis.

Copper (Cu) and iron (Fe) are essential for plant growth and are often in short supply under natural conditions. Molecular responses to simultaneous lack of both metals (-Cu-Fe) differ from those seen in the absence of either alone. Metabolome profiling of plant leaves previously revealed that fumarate levels fall under -Cu-Fe conditions. We employed lines lacking cytosolic FUMARASE2 (FUM2) activity to study the impact of constitutive suppression of cytosolic fumarate synthesis on plant growth under Cu and/or Fe deficiency. In fum2 mutants, photosynthesis and growth were less impaired under -Cu-Fe conditions than in wild-type (WT) seedlings. In particular, levels of photosynthetic proteins, chloroplast ultrastructure, amino acid profiles and redox state were less perturbed by simultaneous Cu-Fe deficiency in lines that cannot produce fumarate in the cytosol. Although cytosolic fumarate has been reported to promote acclimation of photosynthesis to low temperatures when metal supplies are adequate, the photosynthetic efficiency of fum2 lines grown under Cu-Fe deficiency in the cold was higher than in WT. Uptake and contents of Cu and Fe are similar in WT and fum2 plants under control and -Cu-Fe conditions, and lack of FUM2 does not alter the ability to sense metal deficiency, as indicated by marker gene expression. Collectively, we propose that reduced levels of cytosolic fumarate synthesis ultimately increase the availability of Fe for incorporation into metalloproteins.

ASCORBATE PEROXIDASE6 delays the onset of age-dependent leaf senescence.

Age-dependent changes in reactive oxygen species (ROS) levels are critical in leaf senescence. While H2O2-reducing enzymes such as catalases and cytosolic ASCORBATE PEROXIDASE1 (APX1) tightly control the oxidative load during senescence, their regulation and function are not specific to senescence. Previously, we identified the role of ASCORBATE PEROXIDASE6 (APX6) during seed maturation in Arabidopsis (Arabidopsis thaliana). Here, we show that APX6 is a bona fide senescence-associated gene. APX6 expression is specifically induced in aging leaves and in response to senescence-promoting stimuli such as abscisic acid (ABA), extended darkness, and osmotic stress. apx6 mutants showed early developmental senescence and increased sensitivity to dark stress. Reduced APX activity, increased H2O2 level, and altered redox state of the ascorbate pool in mature pre-senescing green leaves of the apx6 mutants correlated with the early onset of senescence. Using transient expression assays in Nicotiana benthamiana leaves, we unraveled the age-dependent post-transcriptional regulation of APX6. We then identified the coding sequence of APX6 as a potential target of miR398, which is a key regulator of copper redistribution. Furthermore, we showed that mutants of SQUAMOSA PROMOTER BINDING PROTEIN-LIKE7 (SPL7), the master regulator of copper homeostasis and miR398 expression, have a higher APX6 level compared with the wild type, which further increased under copper deficiency. Our study suggests that APX6 is a modulator of ROS/redox homeostasis and signaling in aging leaves that plays an important role in developmental- and stress-induced senescence programs.