Regulation Of Iron Metabolism Research Articles

Hypoxia reduces mouse urine output via HIF1α–mediated up–regulation of renal AQP1

Introduction: Patients with acute mountain sickness (AMS) due to hypoxia at high altitudes often exhibit abnormal water metabolism. Hypoxia-inducible factors (HIFs) are major regulators of adaptive responses to hypoxia. As transcription factors, HIFs are involved in the regulation of erythropoiesis, iron metabolism, angiogenesis, energy metabolism, and cell survival by promoting the transcriptional expression of hundreds of target genes. Roxadustat, a novel drug for the treatment of anemia associated with chronic kidney disease, acts by inhibiting the degradation of HIFs to increase their protein levels. However, the clinical use of roxadustat is frequently associated with peripheral edema, suggesting the involvement of HIFs in regulating the body's water balance possibly by modulating water reabsorption in the kidney. Methods: we first evaluated the effect of hypoxia (8% O2) on mouse urine output. We then performed in vitro experiments using hypoxia (1% O2) and roxadustat on mouse primary proximal tubular cells (mPTCs). The qPCR, western blot, and immunofluorescence were used to assess AQP1 mRNA and protein expression levels. Luciferase, CHIP, and EMSA were used to investigate the transcriptional regulation of AQP1 by HIF1α. Results: We found that mice exposed to hypoxia (8% O2) had significantly reduced urine volume compared to mice exposed to normoxia (21% O2). Hypoxia significantly elevated AQP1 expression at both mRNA and protein levels. In vitro experiments using mouse primary cultured proximal tubular cells (mPTCs) revealed that both hypoxia and roxadustat increased AQP1 expression. Mechanistically, overexpression of HIF1α, but not HIF2α, markedly increased AQP1 protein expression. Furthermore, the up-regulation of AQP1 by hypoxia and roxadustat can be blocked by the HIF1α inhibitor PX-478 in mPTCs. Finally, we found that the AQP1 gene promoter contains a putative hypoxia response element (HRE) and confirmed that AQP1 is a target gene of HIF1α using Luciferase reporter, CHIP, and EMSA assays. Conclusion: This study demonstrates that hypoxia can reduce the urine volume of mice via upregulating AQP1 expression by HIF1α in the proximal tubular epithelial cells. Our findings also suggest a potential mechanism involved in water metabolism disorders in patients with AMS and in patients with chronic kidney disease (CKD) receiving roxadustat treatment.

Iron deficiency and its impact on post-vaccination immunity: a review

Modern vaccination programs are vital to overcoming the burden of infectious diseases and saving countless lives. The effective functioning of the adaptive immune system involves the interaction of many factors. Recent clinical studies have shown a significant role of iron in developing an immune response to infection and vaccination. Lymphocytes, the immune system's leading cells, cannot fully perform their functions without access to the circulating iron. The amount of iron bound to blood transferrin depends on its intake from food, and it is reduced during active inflammation due to the increase in the production of hepcidin, the main hormone regulating iron metabolism. Since iron deficiency conditions and chronic inflammatory processes are common, the potential impact of iron deficiency on the immune response warrants extensive study. The review presents data confirming the importance of iron for the correct functioning of the immune system and information on the effect of iron deficiency on the development of post-vaccination immunity.

Leveraging explainable deep learning methodologies to elucidate the biological underpinnings of Huntington’s disease using single-cell RNA sequencing data

BackgroundHuntington’s disease (HD) is a hereditary neurological disorder caused by mutations in HTT, leading to neuronal degeneration. Traditionally, HD is associated with the misfolding and aggregation of mutant huntingtin due to an extended polyglutamine domain encoded by an expanded CAG tract. However, recent research has also highlighted the role of global transcriptional dysregulation in HD pathology. However, understanding the intricate relationship between mRNA expression and HD at the cellular level remains challenging. Our study aimed to elucidate the underlying mechanisms of HD pathology using single-cell sequencing data.ResultsWe used single-cell RNA sequencing analysis to determine differential gene expression patterns between healthy and HD cells. HD cells were effectively modeled using a residual neural network (ResNet), which outperformed traditional and convolutional neural networks. Despite the efficacy of our approach, the F1 score for the test set was 96.53%. Using the SHapley Additive exPlanations (SHAP) algorithm, we identified genes influencing HD prediction and revealed their roles in HD pathobiology, such as in the regulation of cellular iron metabolism and mitochondrial function. SHAP analysis also revealed low-abundance genes that were overlooked by traditional differential expression analysis, emphasizing its effectiveness in identifying biologically relevant genes for distinguishing between healthy and HD cells. Overall, the integration of single-cell RNA sequencing data and deep learning models provides valuable insights into HD pathology.ConclusionWe developed the model capable of analyzing HD at single-cell transcriptomic level.

Targeting the Labile Iron Pool with Engineered DFO Nanosheets to Inhibit Ferroptosis for Parkinson's Disease Therapy.

Ferroptosis in neurons is considered one of the key factors that induces Parkinson's disease (PD), which is caused by excessive iron accumulation in the intracellular labile iron pool (LIP). The iron ions released from the LIP lead to the aberrant generation of reactive oxygen species (ROS) to trigger ferroptosis and exacerbate PD progression. Herein, a pioneering design of multifunctional nanoregulator deferoxamine (DFO)-integrated nanosheets (BDPR NSs) is presented that target the LIP to restrict ferroptosis and protect against PD. The BDPR NSs are constructed by incorporating a brain-targeting peptide and DFO into polydopamine-modified black phosphorus nanosheets. These BDPR NSs can sequester free iron ions, thereby ameliorating LIP overload and regulating iron metabolism. Furthermore, the BDPR NSs can decrease lipid peroxidation generation by mitigating ROS accumulation. More importantly, BDPR NSs can specifically accumulate in the mitochondria to suppress ROS generation and decrease mitochondrial iron accumulation. In vivo experiments demonstrated that the BDPR NSs highly efficiently mitigated dopaminergic neuronloss and its associated behavioral disorders by modulating the LIP and inhibiting ferroptosis. Thus, the BDPR-based nanovectors holds promise as a potential avenue for advancing PD therapy.

Hypoxia-inducible factor-1α promotes ferroptosis by inducing ferritinophagy and promoting lactate production in yak longissimus thoracis et lumborum postmortem

Ferroptosis has emerged as a novel, crucial regulator of meat quality in the postmortem hypoxia environment, with its role in mediating protein oxidation and cell death. However, the interaction between ferroptosis and the hypoxia response, especially the involvement of hypoxia-inducible factor-1α (HIF-1α), remains poorly studied. This study aimed to characterize whether HIF-1α influences ferroptosis, and, if so, explore the underlying mechanisms involved. The results showed that ferroptosis mediated by HIF-1α negatively impacts meat color and water holding capacity (WHC) but improving tenderness. Inhibition of HIF-1α by 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole (YC-1) reduced ferroptosis, as evidenced by lower lipid ROS levels, malondialdehyde (MDA), along with higher glutathione (GSH) levels compared to the control (P < 0.05). Additionally, inhibition of HIF-1α shifted iron homeostasis towards decreased uptake via downregulation of transferrin receptor 1 (TfR1) and induced export/storage via upregulation of ferroportin (FPN) and ferritin heavy chain (FTH) (P < 0.05). The relative expression of the ferritinophagy mediator nuclear receptor coactivator 4 (NCOA4), LC3-II/LC3-I ratio, and ATG were inhibited by YC-1 (P < 0.05), these findings suggest a general decrease in ferritinophagy associated with HIF-1α inhibition. YC-1-treated samples exhibited significantly diminished lactate accumulation and lactate dehydrogenase (LDH) activity compared to the control (P < 0.05). Unexpectedly, the inhibition of ferroptosis caused by YC-1 was further amplified by lactate enhancement, suggesting that lactate can exert its suppressive effects on ferroptosis independently of HIF-1α. Collectively, these findings demonstrate that HIF-1α drives ferroptosis by regulating iron metabolism, while lactate inhibits ferroptosis in a HIF-1α-independent manner. Overall, the HIF-1α mediated ferroptosis of postmortem yak muscle had a negative impact on WHC and color, while as a contributing factor of tenderness.

Leech Granules Inhibit Ferroptosis and Alleviate Renal Injury in Mice with Diabetic Kidney Disease

Ethnopharmacological relevanceThe underlying mechanisms of diabetic kidney disease (DKD) and effective treatment strategies remain unclear. DKD progression is closely associated with abnormal iron metabolism and ferroptosis in vivo. Leeches, used in traditional Chinese medicine for promoting blood circulation and resolving blood stasis, are utilized to treat diabetes and its associated complications. Leeches effectively antagonize oxidative stress injury and exert protective effects on renal function. However, whether leeches can inhibit ferroptosis by modulating oxidative stress and iron metabolism remains unclear. Aim of the studyTo investigate the therapeutic potential of leech granules in DKD and, specifically, their effects on ferroptosis. Materials and methodsWe used a mouse model of DKD. The mice were treated with leech granules via gavage. Component identification and analysis of leech granules were performed using UPLC-MS, and efficacy was assessed by histopathology and analysis of blood glucose, lipids, and renal function. Additionally, the pharmacological mechanisms of leech granules were explored via proteomics, immunohistochemical staining, western blotting, and cell culture. ResultsProteomic analysis showed that iron metabolism was dysregulated and ferroptosis increased in DKD mice. Leech granules significantly reduced iron accumulation and renal pathological damage, decreased ROS levels, upregulated GSH levels, and inhibited ferroptosis in the kidneys of DKD mice. Furthermore, in vitro cellular experiments demonstrated that leech granules could inhibit erastin-induced ferroptosis and protect renal cells. ConclusionsThe regulation of renal iron metabolism and inhibition of ferroptosis mediates the therapeutic effect of leech granules on DKD. Leech granules represent a promising approach for DKD treatment.

NDRG1 regulates iron metabolism and inhibits pathological cardiac hypertrophy

BackgroundCardiac pathological hypertrophy, a pathological physiological alteration in many cardiovascular diseases, can progress to heart failure. The cellular biology underlying myocardial hypertrophy remains to be fully elucidated. While NDRG1 has been reported to participate in cellular proliferation, differentiation, and cellular stress responses, its role in cardiac diseases remains unexplored. Here, we investigated the role of NDRG1 in pathological hypertrophy. MethodCardiomyocyte-specific-NDRG1 knockout (KO) transgenic mice and NDRG1-AAV9 were used in mice. Angiotensin II (AngII) stimulation were applied to induce hypertrophy. Histological, molecular, and RNA-sequencing analyses were performed, and ferroptosis markers and iron levels were studied. We used co-IP and application of iron chelator to further studied the mechanisms of NDRG1 in cardiac hypertrophy. ResultsWe found that NDRG1 expression is decreased in pathological hypertrophy induced by AngII stimulation. Conditional knockout of NDRG1 in mouse cardiomyocytes led to progressive cardiac hypertrophy and heart failure. Cardiomyocyte-specific overexpression of NDRG1 via AAV9 significantly reversed AngII-induced ventricular hypertrophy and fibrosis. Mechanistically, NDRG1-deficient cardiomyocytes exhibited iron overload and increased ferroptosis, accompanied by elevated levels of reactive oxygen species (ROS) and lipid peroxidation. Subsequently, we confirmed the involvement of NDRG1 in regulating ferroptosis and iron metabolism in myocardial cells. Finally, we identified an interaction between NDRG1 and transferrin in cells. The iron chelator Dp44mT effectively reduced myocardial iron overload and ventricular remodeling induced by NDRG1 deficiency. ConclusionThese findings highlight NDRG1's critical role in iron metabolism and ferroptosis in cardiomyocytes, suggesting that NDRG1 or iron metabolism may serve as therapeutic targets for cardiac hypertrophy.

The effect of tau K677 lactylation on ferritinophagy and ferroptosis in Alzheimer's disease

Alzheimer's disease (AD) is characterized by cognitive decline and the accumulation of amyloid-beta plaques and hyperphosphorylated tau protein. The role of tau lactylation at the K677 site in AD progression is not well understood. This study explores how tau K677 lactylation affects ferritinophagy, ferroptosis, and their functions in an AD mouse model. Results show that mutating the K677 site to R reduces tau lactylation and inhibits ferroptosis by regulating iron metabolism factors like NCOA4 and FTH1.Tau-mutant mice showed improved memory and learning skills compared to wild-type mice. The mutation also reduced neuronal damage and was associated with decreased tau lactylation at the K677 site, regardless of phosphorylated tau levels. Gene set enrichment analysis showed that lactylation at this site was linked to the MAPK pathway, which was important for ferritinophagy in AD mice. In summary, our research indicates that the K677 mutation in tau protein may protect against AD by influencing ferritinophagy and ferroptosis through MAPK signaling pathways. Understanding these modifications in tau could lead to new treatments for AD.

RGM Family Involved in the Regulation of Hepcidin Expression in Anemia of Chronic Disease

The persistent production of inflammatory cytokines causes anemia of chronic disease (ACD). Playing a central role in the pathophysiology of ACD is hepcidin, a key regulator of iron metabolism. The regulation of hepcidin expression is a complex process intricately controlled by multiple pathways. These include the BMP/SMAD, the HFE–TFR2, and the IL-6/STAT3 pathway, each playing a significant role in this regulation. We detail the critical role of the repulsive guidance molecule (RGM) family, especially hemojuvelin (HJV/RGMc), in regulating hepcidin expression in ACD. HJV functions as a co-receptor for BMPs and positively regulates hepcidin expression. RGMa and RGMb may also regulate hepcidin expression and inflammatory responses. RGM family proteins play essential roles in the interplay between inflammation, iron metabolism, and the immune system, and elucidating them could lead to a better understanding of the pathophysiology of ACD and the development of new therapeutic strategies.

COPZ1 regulates ferroptosis through NCOA4-mediated ferritinophagy in lung adenocarcinoma

BackgroundFerroptosis, a type of autophagy-dependent cell death, has been implicated in the pathogenesis of lung adenocarcinoma (LUAD). This study aimed to investigate the involvement of coatomer protein complex I subunit zeta 1 (COPZ1) in ferroptosis and ferritinophagy in LUAD. MethodsPublicly available human LUAD sample data were obtained from the TCGA database to analyze the association of COPZ1 expression with LUAD grade and patient survival. Clinical samples of LUAD and para-carcinoma tissues were collected. COPZ1-deficient LUAD cell model and xenograft model were established. These models were analyzed to evaluate tumor growth, lipid peroxidation levels, mitochondrial structure, autophagy activation, and iron metabolism. ResultsHigh expression of COPZ1 was indicative of malignancy and poor overall survival. Clinical LUAD tissues showed increased COPZ1 expression and decreased nuclear receptor coactivator 4 (NCOA4) expression. COPZ1 knockdown inhibited xenograft tumor growth and induced apoptosis. COPZ1 knockdown elevated the levels of ROS, Fe2+ and lipid peroxidation. COPZ1 knockdown also caused mitochondrial shrinkage. Liproxstatin-1, deferoxamine, and z-VAD-FMK reversed the effects of COPZ1 knockdown on LUAD cell proliferation and ferroptosis. Furthermore, COPZ1 was directly bound to NCOA4. COPZ1 knockdown restricted FTH1 expression and promoted NCOA4 and LC3 expression. NCOA4 knockdown reversed the regulation of iron metabolism, lipid peroxidation, and mitochondrial structure induced by COPZ1 knockdown. COPZ1 knockdown induced the translocation of ferritin to lysosomes for degradation, whereas NCOA4 knockdown disrupted this process. ConclusionThis study provides novel evidence that COPZ1 regulates NCOA4-mediated ferritinophagy and ferroptosis. These findings provide new insights into the pathogenesis and potential treatment of LUAD.

Inhibition of IRP2-dependent reprogramming of iron metabolism suppresses tumor growth in colorectal cancer

BackgroundDysregulation of iron metabolism is implicated in malignant transformation, cancer progression, and therapeutic resistance. Here, we demonstrate that iron regulatory protein 2 (IRP2) preferentially regulates iron metabolism and promotes tumor growth in colorectal cancer (CRC).MethodsIRP2 knockdown and knockout cells were generated using RNA interference and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 methodologies, respectively. Cell viability was evaluated using both CCK-8 assay and cell counting techniques. Furthermore, IRP2 inhibition was determined by surface plasmon resonance (SPR) and RNA immunoprecipitation (IP). The suppressive effects of IRP2 were also corroborated in both organoid and mouse xenograft models, providing a comprehensive validation of IRP2’s role.ResultsWe have elucidated the role of IRP2 as a preferential regulator of iron metabolism, actively promoting tumorigenesis within CRC. Elevated levels of IRP2 expression in patient samples are correlated with diminished overall survival, thereby reinforcing its potential role as a prognostic biomarker. The functional suppression of IRP2 resulted in a pronounced delay in tumor growth. Building on this proof of concept, we have developed IRP2 inhibitors that significantly reduce IRP2 expression and hinder its interaction with iron-responsive elements in key iron-regulating proteins, such as ferritin heavy chain 1 (FTH1) and transferrin receptor (TFRC), culminating in iron depletion and a marked reduction in CRC cell proliferation. Furthermore, these inhibitors are shown to activate the AMPK-ULK1-Beclin1 signaling cascade, leading to cell death in CRC models.ConclusionsCollectively, these findings highlight the therapeutic potential of targeting IRP2 to exploit the disruption of iron metabolism in CRC, presenting a strategic advancement in addressing a critical area of unmet clinical need.

Anemia of chronic diseases

Anemia of chronic diseases (ACD) is a pathological process that develops in patients with systemic inflammation in a wide range of diseases of both infectious and non-infectious origin. ACD is the second most common disease in the world after iron deficiency anemia (IDA) and is a factor that aggravates the course of the underlying disease and increases mortality. Pathophysiologically, ACD is a complex multifactorial process and includes 3 main development mechanisms: an increase in the production of hepcidin, a decrease in the formation of erythropoietin and inhibition of normal erythropoiesis in the bone marrow. These processes are triggered by pro-inflammatory cytokines. Special attention in the article is paid to the universal humoral regulator of iron metabolism – hepcidin. For a doctor of any specialty it is important to identify ACD, conduct a differential diagnosis that allows one to distinguish ACD from other types of anemia (including iron deficiency), establish a possible combination of IDA and ACD, since different types of anemia require their own therapeutic approaches. The patient’s prognosis will depend on the correct treatment. In order to verify ACD a thorough search for the underlying disease is carried out, СBC indicators and iron metabolism indicators are assessed. The basis of the therapeutic approach to the treatment of ACD is the treatment of the underlying disease. Therapy for this type of anemia includes the use of iron preparations, erythropoietin and replacement therapy with blood components.

SNHG1: Redefining the Landscape of Hepatocellular Carcinoma through Long Noncoding RNAs.

Hepatocellular carcinoma (HCC) represents a global health concern, ranking as the sixth most common malignancy worldwide and the third leading cause of cancer-related mortality. Despite advances in research, the diagnosis and prognosis of such malignancy remain challenging. Alpha-fetoprotein, the current serum biomarker used in the management of HCC, has limited sensitivity and specificity, making early detection and effective management more difficult. Thus, new management approaches in diagnosis and prognosis are needed to improve the outcome and survival of HCC patients. SNHG1 is a long noncoding RNA mainly expressed in the cell and cytoplasm of cells and is consistently upregulated in tissues and cell lines of HCC, where it acts as an important regulator of various processes: modulation of p53 activity, sponging of microRNAs with consequent upregulation of their target mRNAs, regulation of fatty acid, iron and glucose metabolism, and interaction with immune cells. The deregulation of these processes results in abnormal cell division, angiogenesis, and apoptosis, thus promoting various aspects of tumorigenesis, including proliferation, invasion, and migration of cells. Clinically, a higher expression of SNHG1 predicts poorer clinical outcomes by significantly correlating with bigger, less differentiated, and more aggressive tumors, more advanced disease stages, and lower overall survival in HCC patients. This article comprehensively summarizes the current understanding of the multifaceted roles of SNHG1 in the pathogenesis of HCC, while also highlighting its clinicopathological correlations, therefore concluding that it has potential as a biomarker in HCC diagnosis and prognosis.

Protopanaxadiol prevents cisplatin-induced acute kidney injury by regulating ferroptosis.

Acute kidney injury (AKI) caused by cisplatin (CDDP) is a complex, critical illness with no effective or specific treatment. The purpose of the study was to assess the protective effect of protopanaxadiol (PPD) on the kidneys in CDDP-induced AKI models and its possible mechanisms. In vitro, the protection of PPD was assessed in HK-2. KM mice were injected with CDDP to induce AKI models in vivo. The determination of blood urea nitrogen and serum creatinine (SCr) was performed, and pathological changes were examined by histopathological examination. Immunostaining and western blot analyses were used to analyze the expression levels of proteins. PPD can increase the viability of HK-2 cells damaged by CDDP, improve cell morphology, and alleviate the symptoms of AKI in mice. In addition, PPD can down-regulate the protein expression of TRF and up-regulate the protein expression of Ferritin heavy chain, Glutathione peroxidase 4, and ferroptosis suppressor protein 1 reduce the iron content in cells and kidney tissues, and restore the antioxidant defense system. PPD has an inhibitory effect on cisplatin-induced nephrotoxicity, which may be related to the inhibition of ferroptosis by regulating iron metabolism and lipid peroxidation.

Microbe-induced coordination of plant iron–sulfur metabolism enhances high-light-stress tolerance of Arabidopsis

High-light stress strongly limits agricultural production in subtropical and tropical regions owing to photo-oxidative damage, decreased growth, and decreased yield. Here, we investigated whether beneficial microbes can protect plants under high-light stress. We found that Enterobacter sp. SA187 (SA187) supports the growth of Arabidopsis thaliana under high-light stress by reducing the accumulation of reactive oxygen species and maintaining photosynthesis. Under high-light stress, SA187 triggers dynamic changes in the expression of Arabidopsis genes related to fortified iron metabolism and redox regulation, thereby enhancing the antioxidative glutathione/glutaredoxin redox system of the plant. Genetic analysis showed that the enhancement of iron and sulfur metabolism by SA187 is coordinated by ethylene signaling. In summary, beneficial microbes could be an effective and inexpensive means of enhancing high-light-stress tolerance in plants.

Fibrinogen-like 1: A hepatokine linking liver physiology to hematology.

A recent study identified the critical contribution of the hepatokine FGL1 to the regulation of iron metabolism during the recovery from anemia. FGL1 is secreted by hepatocytes in response to hypoxia to sequester BMP ligands and repress the transcription of the iron-regulatory hormone hepcidin. This process ensures the proper supply of iron to the bone marrow for new red blood cell synthesis and the restoration of physiological oxygen levels. FGL1 may therefore contribute to the recovery from common anemias and cause iron overload in chronic anemias with ineffective erythropoiesis, such as ß-thalassemia, dyserythropoietic anemia, and myelodysplastic syndromes. However, FGL1 has also been described as a regulator of hepatocyte proliferation, glucose homeostasis, and insulin signaling, as well as a mediator of liver steatosis and immune evasion. Chronic exposure to elevated levels of FGL1 during anemia may therefore have systemic metabolic effects besides iron regulation and erythropoiesis. Here, we are providing an overview of the proposed functions of FGL1 in physiology and pathophysiology.

Modulation of the HIF-1α-NCOA4-FTH1 Signaling Axis Regulating Ferroptosis-induced Hepatic Stellate Cell Senescence to Explore the Anti-hepatic Fibrosis Mechanism of Curcumol.

Senescence of activated hepatic stellate cells (HSC) reduces extracellular matrix expression to reverse liver fibrosis. Ferroptosis is closely related to cellular senescence, but its regulatory mechanisms need to be further investigated. The iron ions weakly bound to ferritin in the cell are called labile iron pool (LIP), and together with ferritin, they maintain cellular iron homeostasis and regulate the cell's sensitivity to ferroptosis. We used lipopolysaccharide (LPS) to construct a pathological model group and divided the hepatic stellate cells into a blank group, a model group, and a curcumol 12.5 mg/L group, a curcumol 25 mg/L group, and a curcumol 50 mg/L group. HIF-1α-NCOA4- FTH1 signalling axis, ferroptosis and cellular senescence were detected by various cellular molecular biology experiments. We found that curcumol could induce hepatic stellate cell senescence by promoting iron death in hepatic stellate cells. Curcumol induced massive deposition of iron ions in hepatic stellate cells by activating the HIF-1α-NCOA4-FTH1 signalling axis, which further led to iron overload and lipid peroxidation-induced ferroptosis. Interestingly, our knockdown of HIF-1α rescued curcumol-induced LIP and iron deposition in hepatic stellate cells, suggesting that HIF-1α is a key target of curcumol in regulating iron metabolism and ferroptosis. We were able to rescue curcumol-induced hepatic stellate cell senescence when we reduced LIP and iron ion deposition using iron chelators. Overall, curcumol induces ferroptosis and cellular senescence by increasing HIF-1α expression and increasing NCOA4 interaction with FTH1, leading to massive deposition of LIP and iron ions, which may be the molecular biological mechanism of its anti-liver fibrosis.

Potential Neuroprotective Effect of Melatonin in the Hippocampus of Male BTBR Mice.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder identified by impairments in common social interactions and repetitive behaviors. In ASD patients, substantial morphological alterations have been observed in the hippocampus, which represents an important region for the development of social skills. Melatonin, commonly found in many foods and plants, is also produced by the pineal gland. This indolamine, known to regulate the circadian rhythm, shows antioxidant and anti-inflammatory properties. We therefore hypothesized that melatonin may reduce oxidative stress and inflammation in the hippocampus of ASD patients. We explored our hypothesis using the BTBR mouse, a well-regarded murine transgenic model for ASD. Immediately after weaning, male BTBR and C57BL/6 mice underwent an 8-week treatment with melatonin or vehicle. Later, through immunohistochemistry and the immunoblotting analysis of the hippocampus, we evaluated the overall expression and cellular localization of Nrf2 and SOD1, two enzymes involved in the oxidative stress response. Similarly, we evaluated NLRP3 and NFkB, two mediators of inflammation, and GAD67, an enzyme responsible for the synthesis of GABA. Ultimately, we addressed melatonin's potential to regulate iron metabolism through a DAB-enhanced Perls reaction assay. Results showed melatonin's potential for modulating the analyzed markers in BTBR mice, suggesting a potential neuroprotective effect in ASD patients.

Targeting Intrinsic and Extrinsic Pathways of Ferroptosis: A Novel Anticancer Strategy of Curcumin

Background The turmeric rhizome yields a medicinal compound called curcumin. Curcumin’s anticancer methods mostly involve blocking cell invasion and proliferation, controlling gene expression, preventing angiogenesis, triggering apoptosis, and inducing ferroptosis. A brand-new nonapoptotic kind of planned cell death is called ferroptosis. Ferroptosis can be initiated through two major pathways: the extrinsic or transporter-dependent pathway, and the intrinsic or enzyme-regulated pathway. It is unknown, therefore, how curcumin and its derivatives prevent cancer by controlling ferroptosis. Purpose Through this review, we concentrate on the possible anticancer mechanisms of curcumin by means of its effect on ferroptosis; the regulation of iron metabolism, the synthesis of reactive oxygen species, and the targeting of antioxidant pathways represent a few of these processes. Methods Retrieve English literature of curcumin and its derivatives in the treatment of tumor by ferroptosis from databases such as Web of Science, etc. Conclusion This review provides a rationale for the clinical use of curcumin and its derivatives as anticancer agents.

CYB561 supports the neuroendocrine phenotype in castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) is associated with resistance to androgen deprivation therapy, and an increase in the population of neuroendocrine (NE) differentiated cells. It is hypothesized that NE differentiated cells secrete neuropeptides that support androgen-independent tumor growth and induce aggressiveness of adjacent proliferating tumor cells through a paracrine mechanism. The cytochrome b561 (CYB561) gene, which codes for a secretory vesicle transmembrane protein, is constitutively expressed in NE cells and highly expressed in CRPC. CYB561 is involved in the α-amidation-dependent activation of neuropeptides, and contributes to regulating iron metabolism which is often dysregulated in cancer. These findings led us to hypothesize that CYB561 may be a key player in the NE differentiation process that drives the progression and maintenance of the highly aggressive NE phenotype in CRPC. In our study, we found that CYB561 expression is upregulated in metastatic and NE prostate cancer (NEPC) tumors and cell lines compared to normal prostate epithelia, and that its expression is independent of androgen regulation. Knockdown of CYB561 in androgen-deprived LNCaP cells dampened NE differentiation potential and transdifferentiation-induced increase in iron levels. In NEPC PC-3 cells, depletion of CYB561 reduced the secretion of growth-promoting factors, lowered intracellular ferrous iron concentration, and mitigated the highly aggressive nature of these cells in complementary assays for cancer hallmarks. These findings demonstrate the role of CYB561 in facilitating transdifferentiation and maintenance of NE phenotype in CRPC through its involvement in neuropeptide biosynthesis and iron metabolism pathways.