Diagnostic value and method of soluble transferrin receptor for suspected coronary artery disease: a case-control study.

Background: Many studies have pointed out that iron overload in the body is a risk factor for coronary atherosclerosis (AS), while there are also studies that show that iron deficiency is associated with coronary AS. There is still no consensus on how iron metabolism affects coronary artery disease (CAD). This study aimed to analyze the relationship between iron metabolism indexes and CAD, investigate the diagnostic value of soluble transferrin receptor (sTfR) in suspected CAD, and establish a diagnostic model. Methods: This was a retrospective study. A total of 268 people with CAD-like symptoms who underwent coronary angiography in the Department of Cardiovascular Medicine, The Second Affiliated Hospital of Anhui Medical University from September 2022 to May 2023 without other chronic diseases or related medication history were included in the study and formed a continuous series including 188 CAD patients and 80 control subjects. Each iron metabolism index was divided into a grade variable according to tertile. The comparison of CAD morbidity between the tertiles and nonlinear correlation test was conducted to investigate the relationship between iron metabolism indexes and CAD risk. We used restricted cubic spline (RCS) to plot the relationship curve between sTfR and CAD risk and to determine the sTfR value corresponding to the minimal odds, according to which we divided the total sample into the "sTfR low level" subgroup and the "sTfR high level" subgroup. Logistic regression analyses were used to establish diagnostic models in both subgroups. The diagnostic efficiency of the indexes and models was compared by receiver operating characteristic (ROC) analysis. Results: There is a "J" shape correlation between sTfR and CAD risk. Age/sTfR ratio [area under the curve (AUC) =0.690, 95% confidence interval (CI): 0.598-0.782, specificity 0.488 and sensitivity 0.842] has the best diagnostic efficiency in the "sTfR low level" subgroup. The diagnostic efficiency of sTfR (AUC =0.701, 95% CI: 0.598-0.803, specificity 0.541 and sensitivity 0.797) in the "sTfR high level" subgroup was higher than that of cardiac troponin I (cTnI) (AUC =0.674, 95% CI: 0.564-0.784, specificity 0.719 and sensitivity 0.653). The specific diagnostic methods were as follows: (I) When sTfR ≤1.087 mg/L, calculate the age/sTfR ratio, which indicates the diagnosis of CAD when the result is >58.595; (II) We can directly make a preliminary clinical diagnosis of CAD when sTfR >1.205 mg/L. Except for the above 2 cases, we can initially rule out a diagnosis of CAD. Conclusions: The iron metabolism index sTfR correlates with CAD morbidity in a "J" shape. With superior diagnostic efficacy than cTnI, sTfR can assist in diagnosing CAD in patients with CAD-like symptoms. In addition, sTfR can provide guidance for the management of body iron levels in CAD patients.

Rosmarinic acid liposomes suppress ferroptosis in ischemic brain via inhibition of TfR1 in BMECs.

BACKGROUND: Iron deposition and ferroptosis are involved in ischemic stroke injury, but the choice of drugs for treatment is limited. PURPOSE: To investigate the potential neuroprotective effects of Rosmarinic acid (RosA) encapsulated within nanoliposomes (RosA-LIP) on ischemic stroke. METHODS: Wild-type (WT) and TfR1EC cKO (specific knockout of the TfR1 gene in BMECs) mice used to establish a dMCAO model, with simultaneous administration of RosA-LIP (20 mg/kg/d, i.p.) or RosA (20 mg/kg/d, i.p.). RESULTS: The successful synthesis of RosA-LIP resulted in enhanced stability and precise delivery in both the serum and brain. The administration of RosA-LIP effectively mitigated ischemia-induced behavioral abnormalities and pathological damage. RosA-LIP inhibited ferroptosis by ameliorating mitochondrial abnormalities, increasing GPX4 levels, and decreasing ACSL4/LPCAT3/Lox-dependent lipid peroxidation. RosA-LIP effectively improved blood‒brain barrier (BBB) permeability, increased tight junctions (TJs) protein expression and reduced iron levels in ischemic tissue and brain microvascular endothelial cells (BMECs) by modulating FPN1 and TfR1 levels. Furthermore, RosA-LIP suppressed TfR1 to attenuate ACSL4/LPCAT3/Lox-mediated ferroptosis in TfR1EC cKO mice subjected to dMCAO. CONCLUSION: RosA-LIP effectively increased the brain level of RosA and protected against ferroptosis through the regulation of TfR1 in BMECs.

Expression of transferrin receptor/TFRC protein in bladder cancer cell T24 and its role in inducing iron death in bladder cancer.

Bladder cancer (BC) is a very common malignant tumor in the urinary system. However, the incidence rate, recurrence rate, progression rate and metastasis rate of bladder cancer are still very high, leading to poor long-term prognosis of patients. This study was to investigate the expression of transferrin receptor/TFRC protein in bladder cancer tissue and its role in inducing iron death of T24 human bladder cancer cells. Based on the intersection of 259 FerrDb genes in the iron death database with GSE13507 and GSE13167 data sets, 54 genes related to iron death in bladder cancer were obtained. Analyzing 54 genes, KEGG enrichment analysis showed that the pathways involved were mainly focused on iron death, autophagy, and tumor center carbon metabolism. GO analysis found that the molecular functions mainly gather in ubiquitin like protein ligase binding, ubiquitin protein ligase binding, and antioxidant activity. In the cellular components, it is mainly distributed in pigment granules, melanosomes, and the basal lateral plasma membrane. In biological processes, it is enriched in nutrient level responses, responses to extracellular stimuli, and cellular redox homeostasis. Screen out the top 10 core genes. The 10 core genes are SLC2A1, TFRC, EGFR, KRAS, CAV1, HSPA5, NFE2L2, VEGFA, PIK3CA, and HRAS. Finally, TFRC was selected as the research object. TCGA analysis showed that the expression level in bladder cancer tissue was higher than that in normal tissue, and the difference was statistically significant (P < 0.001). Conclusion (1) TFRC is highly expressed in many kinds of tumors, and it is more highly expressed in bladder cancer than in normal bladder tissue. (2) TFRC has certain diagnostic and prognostic value in bladder cancer. (3) Erastin, an iron death inducer, induced the iron death of T24 human bladder cancer cells, knocked down the expression of TFRC in T24 human bladder cancer cells, and preliminarily verified that silencing TFRC could inhibit the iron death of T24 human bladder cancer cells.

An affordable label-free ultrasensitive immunosensor based on gold nanoparticles deposited on glassy carbon electrode for the transferrin receptor detection.

In recent decades, there has been a concerning and consistent rise in the incidence of cancer, posing a significant threat to human health and overall quality of life. The transferrin receptor (TfR) is one of the most crucial protein biomarkers observed to be overexpressed in various cancers. This study reports on the development of a novel voltammetric immunosensor for TfR detection. The electrochemical platform was made up of a glassy carbon electrode (GCE) functionalized with gold nanoparticles (AuNPs), on which anti-TfR was immobilized. The surface characteristics and electrochemical behaviors of the modified electrodes were comprehensively investigated through scanning electron microscopy, XPS, Raman spectroscopy FT-IR, electrochemical cyclic voltammetry and impedance spectroscopy. The developed immunosensor exhibited robust analytical performance with TfR fortified buffer solution, showing a linear range (LR) response from 0.01 to 3000 µg/mL, with a limit of detection (LOD) of 0.01 µg/mL and reproducibility (RSD <4 %). The fabricated sensor demonstrated high reproducibility and selectivity when subjected to testing with various types of interfering proteins. The immunosensor designed for TfR detection demonstrated several advantageous features, such as being cost-effective and requiring a small volume of test sample making it highly suitable for point-of-care applications.

Novel mutation of transferrin receptor 2 causing hereditary hemochromatosis type 3 in a Japanese patient.

Hereditary hemochromatosis (HH) is recognized as a progressive iron-storage disorder, and leading to severe organ impairments, including liver cirrhosis. Hereditary hemochromatosis type 3 arises from mutations in the transferrin receptor 2 (TFR2) gene. However, HH type 3 is rare in Asia, and information regarding genetic mutations and associated phenotypes remains limited. Here, we reported the case of a Japanese patient with HH type 3, with a novel homozygous mutation of the TFR2 gene. A 69-year-old woman presented to our hospital with hand joint pain and was referred due to liver impairment. Viral hepatitis and autoimmune liver diseases were ruled out. However, the transferrin saturation was 92.2%, and the serum ferritin level was 1611.8 ng/mL. Additionally, abdominal computed tomography showed diffuse increased density of the liver parenchyma. Abdominal magnetic resonance imaging also suggested iron deposition. There is no history of prior treatments involving blood transfusions or iron agents. Her parents were involved in a consanguineous marriage, prompting genetic testing. She had a homozygous novel mutation, c.1337G>A (p.G446E), in the TFR2 gene. Serum hepcidin-25 level was decreased to 2.9 ng/mL. According to the American Society of Medical Genetics and Genomics guideline, the mutation was classified as likely pathogenic, leading to the diagnosis of HH type 3. Following phlebotomy, her arthritis resolved, and serum transaminase levels were normalized. This case marks the first demonstration of homozygous mutation, c.1337G>A (p.G446E), in the TFR2 gene in patients with HH type 3.

Schizandrin A enhances the sensitivity of gastric cancer cells to 5-FU by promoting ferroptosis.

Schizandrin A (Sch A) exert anticancer and multidrug resistance-reversing effects in a variety of tumors, but its effect on 5-fluorouracil (5-Fu) in gastric cancer (GC) cells remains unclear. The aim of the present study was to examine the resistance-reversing effect of Schizandrin A and assess its mechanisms in 5-Fu-resistant GC cells.5-Fu-sensitive GC cells were treated with 5-Fu and 5-Fu-resistant GC cells AGS/5-Fu and SGC7901/5-Fu were were established. These cells were stimulated with Schizandrin A alone or co-treated with 5-Fu and their effect on tumor cell growth, proliferation, migration, invasion and ferroptosis-related metabolism were investigated both in vitro and in vivo. A number of additional experiments were conducted in an attempt to elucidate the molecular mechanism of increased ferroptosis. The results of our study suggest that Schizandrin A in combination with 5-Fu might be useful in treating GC by reverse drug resistance. It was shown that Schizandrin A coadministration suppressed metastasis and chemotherapy resistance in 5-Fu-resistant GC cells through facilitating the onset of ferroptosis, which is an iron-dependent form of cell death, which was further demonstrated in a xenograft nude mouse model. Mechanistically, Schizandrin A co-administration synergistically increased the expression of transferin receptor, thus iron accumulates within cells, leading to lipid peroxidation, which ultimately results in 5-Fu-resistant GC cells death. The results of this study have provided a novel strategy for increasing GC chemosensitivity, indicating Schizandrin A as a novel ferroptosis regulator. Mechanistically, ferroptosis is induced by Schizandrin A coadministration via increasing transferrin receptor expression.

CD71: Role in permafrost immunity.

Iron, an essential constituent of cell metabolism, is transported intra-cellularly bound to the ubiquitous 76 kDa blood glycoprotein transferrin via the transferrin receptor, CD71. Because of its structure, CD71 facilitates the binding and penetration of a large variety of viruses into the host. Among which the hemorrhagic fever-causing New World mammarena viruses (family of single stranded ambisense segmented RNA Arenaviridae), the single stranded positive sense RNA hepatitis C virus, the single stranded negative sense segmented influenza A virus, the single stranded negative sense RNA rabies virus, the single stranded positive sense SARS-CoV2 and possibly many others. In this process, CD71 is associated with the target of the anti-proliferative antibody-1 (CD81) viral co-receptor. In light of the plethora of novel and ancient viruses and microbes emerging from melting eternal glacier ice and permafrost, it is timely and critical to define and characterize interventions, besides the soluble form of CD71 (sCD71), that can abrogate or minimize this novice non-canonical function of CD71.

Annexin 1 Reduces Dermatitis-Induced Itch and Cholestatic Itch through Inhibiting Neuroinflammation and Iron Overload in the Spinal Dorsal Horn of Mice.

The unclear pathogenesis of chronic itch originating from several systemic disorders poses challenges to clinical intervention. Recent studies recapitulate the spinal neurocircuits associated with neuroinflammation and synaptic plasticity responsible for pruriceptive sensations. The resolution of nociception and inflammation by Annexin 1 (ANXA1) has been identified. Given that pain and itch share many neural mechanisms, we employed two mice models of chronic itch to study the underlying targets and therapeutic potential of ANXA1, comprising allergic contact dermatitis-induced itch and cholestatic itch. Herein, we report that spinal expression of ANXA1 is down-regulated in mice with dermatitis-induced itch and cholestatic itch. Repetitive injections of ANXA1-derived peptide Ac2-26 (intrathecal, 10 µg) reduce itch-like scratching behaviors following dermatitis and cholestasis. Single exposure to Ac2-26 (intrathecal, 10 µg) alleviates the established itch phenotypes. Moreover, systemic delivery of Ac2-26 (intravenous, 100 µg) is effective against chronic dermatitis-induced itch and cholestatic itch. Strikingly, Ac2-26 therapy inhibits transferrin receptor 1 over-expression, iron accumulation, cytokine IL-17 release and the production of its receptor IL-17R, as well as astrocyte activation in the dorsal horn of spinal cord in mouse with dermatitis and cholestasis. Pharmacological intervention with iron chelator deferoxamine impairs chronic itch behaviors and spinal iron accumulation after dermatitis and cholestasis. Also, spinal IL-17/IL-17R neutralization attenuates chronic itch. Taken together, this current research indicates that ANXA1 protects against the beginning and maintenance of long-term dermatitis-induced itch and cholestatic itch, which may occur via the spinal suppression of IL-17-mediated neuroinflammation, astrocyte activation and iron overload.

Uncoupling Protein 2 Alleviates Myocardial Ischemia/Reperfusion Injury by Inhibiting Cardiomyocyte Ferroptosis.

INTRODUCTION: Following our recent finding that Ucp2 knockout promotes ferroptosis, we aimed to examine whether UCP2 alleviates myocardial ischemia/reperfusion injury (MI/RI) by inhibiting ferroptosis. METHODS: The left anterior descending coronary arteries of wild-type and Ucp2-/- C57BL/6 mice were ligated for 30 min and reperfused for 2 h to establish an MI/RI model. The effects of UCP2 on ferroptosis and MI/RI were determined by echocardiography, 2,3,5-triphenylttrazolium chloride staining, hematoxylin-eosin staining, Masson's trichrome staining, Sirius red staining, and analysis of myocardial injury markers and ferroptosis indicators. Ferrostatin-1 (Fer-1) and erastin (Era) were used to investigate whether UCP2 alleviated MI/RI by inhibiting ferroptosis and the molecular mechanism. RESULTS: UCP2 was upregulated in the MI/RI model in WT mice. Deletion of Ucp2 exacerbated ferroptosis, altered the expression levels of multiple ferroptosis-related genes, and significantly exacerbated MI/RI. Knockout of Ucp2 promoted ferroptosis induced by Era and inhibited the antiferroptotic effects of Fer-1. Knockout of Ucp2 activated the p53/TfR1 pathway to exacerbate ferroptosis. CONCLUSION: Our results showed that UCP2 inhibited ferroptosis in MI/RI, which might be related to regulation of the p53/TfR1 pathway.

New Transferrin Receptor-Targeted Peptide-Doxorubicin Conjugates: Synthesis and In Vitro Antitumor Activity.

Poor selectivity to tumor cells is a major drawback in the clinical application of the antitumor drug doxorubicin (DOX). Peptide-drug conjugates (PDCs) constructed by modifying antitumor drugs with peptide ligands that have high affinity to certain overexpressed receptors in tumor cells are increasingly assessed for their possibility of tumor-selective drug delivery. However, peptide ligands composed of natural L-configuration amino acids have the defects of easy enzymatic degradation and insufficient biological stability. In this study, two new PDCs (LT7-SS-DOX and DT7-SS-DOX) were designed and synthesized by conjugating a transferrin receptor (TfR) peptide ligand LT7 (HAIYPRH) and its retro-inverso analog DT7 (hrpyiah), respectively, with DOX via a disulfide bond linker. Both conjugates exhibited targeted antiproliferative effects on TfR overexpressed tumor cells and little toxicity to TfR low-expressed normal cells compared with free DOX. Moreover, the DT7-SS-DOX conjugate possessed higher serum stability, more sustained reduction-triggered drug release characteristics, and stronger in vitro antiproliferative activity as compared to LT7-SS-DOX. In conclusion, the coupling of antitumor drugs with the DT7 peptide ligand can be used as a promising strategy for the further development of stable and efficient PDCs with the potential to facilitate TfR-targeted drug delivery.

Targeted Nanoparticle-Based Diagnostic and Treatment Options for Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancers, presents significant challenges in diagnosis and treatment due to its aggressive, metastatic nature and lack of early detection methods. A key obstacle in PDAC treatment is the highly complex tumor environment characterized by dense stroma surrounding the tumor, which hinders effective drug delivery. Nanotechnology can offer innovative solutions to these challenges, particularly in creating novel drug delivery systems for existing anticancer drugs for PDAC, such as gemcitabine and paclitaxel. By using customization methods such as incorporating conjugated targeting ligands, tumor-penetrating peptides, and therapeutic nucleic acids, these nanoparticle-based systems enhance drug solubility, extend circulation time, improve tumor targeting, and control drug release, thereby minimizing side effects and toxicity in healthy tissues. Moreover, nanoparticles have also shown potential in precise diagnostic methods for PDAC. This literature review will delve into targeted mechanisms, pathways, and approaches in treating pancreatic cancer. Additional emphasis is placed on the study of nanoparticle-based delivery systems, with a brief mention of those in clinical trials. Overall, the overview illustrates the significant advances in nanomedicine, underscoring its role in transcending the constraints of conventional PDAC therapies and diagnostics.

Enhanced TfR1 Recognition of Myocardial Injury after Acute Myocardial Infarction with Cardiac Fibrosis via Pre-Degrading Excess Fibrotic Collagen.

The fibrosis process after myocardial infarction (MI) results in a decline in cardiac function due to fibrotic collagen deposition and contrast agents' metabolic disorders, posing a significant challenge to conventional imaging strategies in making heart damage clear in the fibrosis microenvironment. To address this issue, we developed an imaging strategy. Specifically, we pretreated myocardial fibrotic collagen with collagenase I combined with human serum albumin (HSA-C) and subsequently visualized the site of cardiac injury by near-infrared (NIR) fluorescence imaging using an optical contrast agent (CI, CRT-indocyanine green) targeting transferrin receptor 1 peptides (CRT). The key point of this strategy is that pretreatment with HSA-C can reduce background signal interference in the fibrotic tissue while enhancing CI uptake at the heart lesion site, making the boundary between the injured heart tissue and the normal myocardium clearer. Our results showed that compared to that in the untargeted group, the normalized fluorescence intensity of cardiac damage detected by NIR in the targeted group increased 1.28-fold. The normalized fluorescence intensity increased 1.21-fold in the pretreatment group of the targeted groups. These data demonstrate the feasibility of applying pretreated fibrotic collagen and NIR contrast agents targeting TfR1 to identify ferroptosis at sites of cardiac injury, and its clinical value in the management of patients with MI needs further study.

Modulation of hippocampal protein expression by a brain penetrant biologic TNF-α inhibitor in the 3xTg Alzheimer's disease mice.

BACKGROUND: Biologic TNF-α inhibitors (bTNFIs) can block cerebral TNF-α in Alzheimer's disease (AD) if these macromolecules can cross the blood-brain barrier (BBB). Thus, a model bTNFI, the extracellular domain of type II TNF-α receptor (TNFR), which can bind to and sequester TNF-α, was fused with a mouse transferrin receptor antibody (TfRMAb) to enable brain delivery via BBB TfR-mediated transcytosis. Previously, we found TfRMAb-TNFR to be protective in a mouse model of amyloidosis (APP/PS1) and tauopathy (PS19), and herein we investigated its effects in mice that combine both amyloidosis and tauopathy (3xTg-AD). METHODS: Eight-month-old female 3xTg-AD mice were injected intraperitoneally with saline (n = 11) or TfRMAb-TNFR (3 mg/kg; n = 11) three days per week for 12 weeks. Age-matched wild-type (WT) mice (n = 9) were treated similarly with saline. Brains were processed for immunostaining and high-resolution multiplex NanoString GeoMx spatial proteomics. RESULTS: We observed regional differences in proteins relevant to Aß, tau, and neuroinflammation in the hippocampus of 3xTg-AD mice compared with WT mice. From 64 target proteins studied using spatial proteomics, a comparison of the Aß-plaque bearing vs. plaque-free regions in the 3xTg-AD mice yielded 39 differentially expressed proteins (DEP) largely related to neuroinflammation (39% of DEP) and Aß and tau pathology combined (31% of DEP). Hippocampal spatial proteomics revealed that the majority of the proteins modulated by TfRMAb-TNFR in the 3xTg-AD mice were relevant to microglial function (⁓ 33%). TfRMAb-TNFR significantly reduced mature Aß plaques and increased Aß-associated microglia around larger Aß deposits in the 3xTg-AD mice. Further, TfRMAb-TNFR increased mature Aß plaque-associated microglial TREM2 in 3xTg-AD mice. CONCLUSION: Overall, despite the low visual Aß load in the 11-month-old female 3xTg-AD mice, our results highlight region-specific AD-relevant DEP in the hippocampus of these mice. Chronic TfRMAb-TNFR dosing modulated several DEP involved in AD pathology and showed a largely microglia-centric mechanism of action in the 3xTg-AD mice.

E3 ubiquitin ligase CHIP interacts with transferrin receptor 1 for degradation and promotes cell proliferation through inhibiting ferroptosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the major form of liver malignancy with high incidence and mortality. Identifying novel biomarkers and understanding regulatory mechanisms underlying the development and progression of HCC are critical for improving diagnosis, treatment and patient outcomes. Carboxyl terminus of Hsc-70-interacting protein (CHIP) is a well-described U-box-type E3 ubiquitin ligase which promotes the ubiquitination and degradation of numerous tumor-associated proteins. Recent studies have shown that CHIP can play as a tumor-suppressor gene or an oncogene in different kinds of malignancies. To date, the function and mechanism of CHIP in hepatocellular carcinoma remains largely unknown. Based on TCGA data, we found that compared with high CHIP expression, the overall survival of HCC patients with low expression of CHIP was better. In addition, CHIP overexpression markedly enhanced HCC cell proliferation and colony formation. Conversely, knockdown of CHIP restrained the proliferation and colony formation of HCC cells. Meanwhile, knockdown of CHIP decreased mitochondrial cristae or ruptured outer mitochondrial membrane, promoted the accumulation of Fe2+ and ferroptosis of HCC cells. Further research for the first time confirmed that CHIP interacts and degrades transferrin receptor 1 (TfR1) by ubiquitin-proteasome pathway, which leads to the inhibition of ferroptosis and promotes the proliferation of HCC cells. The analysis of proteomics data from CPTAC revealed a negative correlation between CHIP and TfR1 protein expression levels in HCC. These findings indicate that CHIP acts as a negative modulator of ferroptosis and functions as an oncogene in HCC.

Iron status determined changes in health measures induced by nordic walking with time-restricted eating in older adults- a randomised trial.

BACKGROUND AND AIMS: This study evaluated whether stored iron determines the adaptive response induced by Nordic walking (NW) training combined with 10 hours' time-restricted eating (TRE) in older adults. TRIAL DESIGN AND METHODS: Twenty-four participants underwent 12-week NW training supported by 10 h of TRE. The group was divided due to baseline ferritin concentration low < 75 ng/ml (LF) and high level ≥ 75 ng/ml (HF). Body composition, physical fitness and blood collection were assessed at baseline and post-intervention. RESULTS: NW + TRE induced a statistically significant decrease in ferritin levels in all participants (p = 0.01). Additionally, statistically significant intergroup differences in the LF vs. HF in the reduction of serum ferritin levels (p = 0.04) were observed. The procedure NW + TRE diminished HbA1c levels (p < 0.01) and glucose in all participants (p = 0.05). The range of HbA1c drop was more pronounced among those participants who experienced a greater decrease in the stored iron (p = 0.04, [Formula: see text]=0.17, F=4.59). Greater changes in body weight and percent of body fat were recorded in the HF group (for both p<0.01). CONCLUSION: Body iron stores determine the effects of a 12-week NW + TRE intervention on serum ferritin. The changes in HbA1c are more pronounced in subjects with a higher decrease in serum ferritin. TRIAL REGISTRATION: All experimental protocols were approved by the Bioethical Committee of the Regional Medical Society in Gdansk, Poland (NKBBN/330/2021) according to the Declaration of Helsinki. We confirm that all methods were carried out in accordance with relevant guidelines and regulations. The trial was registered as a clinical trial (NCT05229835, date of first registration: 14/01/2022, direct link: https://classic. CLINICALTRIALS: gov/ct2/show/NCT05229835 ). Informed consent was obtained from all subjects.

TfR1 mediated iron metabolism dysfunction as a potential therapeutic target for osteoarthritis.

OBJECTIVE: Transferrin receptor-1 (TfR1) plays important roles in controlling cellular iron levels, but its role in OA pathology is unknown. Herein we aim to investigate the role of TfR1 in OA progression and its underlying mechanisms. METHODS: TfR1 expression in cartilage during OA development were examined both in vivo and in vitro. Then IL-1ß was used to induce chondrocytes degeneration in vitro and TfR1 siRNA was used for observing the effect of TfR1 in modulating iron homeostasis, mitochondrial function and degrading enzymes expression. Also the inhibitor of TfR1 was exploited to analyze the protective effect of TfR1 inhibition in vivo. RESULTS: TfR1 is elevated in OA cartilage and contributes to OA inflammation condition. Excess iron not only results in oxidative stress damage and sensitizes chondrocytes to ferroptosis, but also triggers c-GAS/STING-mediated inflammation by promoting mitochondrial destruction and the release of mtDNA. Silencing TfR1 using TfR1 siRNA not only reduced iron content in chondrocytes and inhibited oxidative stress, but also facilitated the mitophagy process and suppressed mtDNA/cGAS/STING-mediated inflammation. Importantly, we also found that Ferstatin II, a novel and selective TfR1 inhibitor, could substantially suppress TfR1 activity both in vivo and in vitro and ameliorated cartilage degeneration. CONCLUSION: Our work demonstrates that TfR1 mediated iron influx plays important roles in chondrocytes degeneration and OA pathogenesis, suggesting that maintaining iron homeostasis through the targeting of TfR1 may represent a novel therapeutic strategy for the treatment of OA.

Pathophysiological aspects of transferrin-A potential nano-based drug delivery signaling molecule in therapeutic target for varied diseases.

Transferrin (Tf), widely known for its role as an iron-binding protein, exemplifies multitasking in biological processes. The role of Tf in iron metabolism involves both the uptake of iron from Tf by various cells, as well as the endocytosis mediated by the complex of Tf and the transferrin receptor (TfR). The direct conjugation of the therapeutic compound and immunotoxin studies using Tf peptide or anti-Tf receptor antibodies as targeting moieties aims to prolong drug circulation time and augment efficient cellular drug uptake, diminish systemic toxicity, traverse the blood-brain barrier, restrict systemic exposure, overcome multidrug resistance, and enhance therapeutic efficacy with disease specificity. This review primarily discusses the various biological actions of Tf, as well as the development of Tf-targeted nano-based drug delivery systems. The goal is to establish the use of Tf as a disease-targeting component, accentuating the potential therapeutic applications of this protein.

Association of soluble transferrin receptor/log ferritin index with all-cause and cause-specific mortality: National Health and Nutrition Examination Survey.

Background: Soluble transferrin receptor (sTfR)/log ferritin index (sTfR Index) can be used to assess the entire spectrum of iron status, and is valuable in evaluating iron status in population studies. There is still a lack of evidence on the association between sTfR index and all-cause mortality. Object: To explore the association between sTfR index and all-cause mortality, as well as mortality due to cardiovascular disease (CVD) and cancer. Method: Data were from the National Health and Nutrition Examination Survey (NHANES) between 2003 to 2020. Participants aged 16 years and older who had complete data of serum ferritin and sTfR were included. Pregnant individuals or those with ineligible data on death or follow-up were excluded from the analysis. Baseline sTfR index was calculated by baseline sTfR/log (ferritin) and classified as three tertile. We performed the Cox proportional hazard regression to assess the association of sTfR index (both continuous and categorical scale) with all-cause and cause-specific mortality and further assess the non-linear relationship between sTfR index and the outcomes with restricted cubic spline. Result: In this study, 11,525 participants, a total of 231 (2.0%) all-cause deaths occurred during a median follow-up of 51 months. The risk of all-cause mortality, CVD-related mortality, and cancer-related mortality was higher in participants with highest tertile of sTfR index. After confounding factors adjustment, participants with highest tertile of sTfR index were associated with an increased risk of all-cause mortality (HR: 1.71, 95% CI: 1.14-2.57) as compared with lowest tertile. Additionally, sTfR index per SD increment was associated with a 25% increasing risk of all-cause mortality (HR: 1.25, 95% CI: 1.08-1.45, p = 0.003) and a 38% cancer-related mortality (HR: 1.38, 95% CI: 1.07-1.77, p = 0.018). These associations remained robust after adjusting for the serum ferritin as well as in various subgroups stratified by age, sex, smoking statue, hypertension, diabetes, and CVD. Spline analysis showed that there is approximately linear relationship between sTfR index with all-cause mortality (p for non-linear = 0.481). Moreover, ferritin was not a predictor of all-cause death after adjustment for confounding factors. Significance: This cohort study demonstrated a significant association between sTfR index increment and an increased risk of all-cause and cancer-related mortality, independent of ferritin levels.

Genomic characterization of Moraxella bovis and Moraxella bovoculi Uruguayan strains isolated from calves with infectious bovine keratoconjunctivitis.

Infectious bovine keratoconjunctivitis (IBK) is an ocular disease that affects bovines and has significant economic and health effects worldwide. Gram negative bacteria Moraxella bovis and Moraxella bovoculi are its main etiological agents. Antimicrobial therapy against IBK is often difficult in beef and dairy herds and, although vaccines are commercially available, their efficacy is variable and dependent on local strains. The aim of this study was to analyze for the first time the genomes of Uruguayan clinical isolates of M. bovis and M. bovoculi. The genomes were de novo assembled and annotated; the genetic basis of fimbrial synthesis was analyzed and virulence factors were identified. A 94% coverage in the reference genomes of both species, and more than 80% similarity to the reference genomes were observed. The mechanism of fimbrial phase variation in M. bovis was detected, and the tfpQ orientation of these genes confirmed, in an inversion region of approximately 2.18kb. No phase variation was determined in the fimbrial gene of M. bovoculi. When virulence factors were compared between strains, it was observed that fimbrial genes have 36.2% sequence similarity. In contrast, the TonB-dependent lactoferrin/transferrin receptor exhibited the highest percentage of amino acid similarity (97.7%) between strains, followed by cytotoxins MbxA/MbvA and the ferric uptake regulator. The role of these virulence factors in the pathogenesis of IBK and their potential as vaccine components should be explored.

Tetramethylpyrazine attenuates renal tubular epithelial cell ferroptosis in contrast-induced nephropathy by inhibiting transferrin receptor and intracellular reactive oxygen species.

Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired acute kidney injury (AKI). Recently, ferroptosis was reported to be crucial for AKI pathogenesis. Our previous studies indicated antioxidant tetramethylpyrazine (TMP) prevent CIN in vivo. However, whether ferroptosis is involved in TMP nephroprotective mechanism against CIN is unclear. In the present study, we investigated the role of renal tubular epithelial cell ferroptosis in TMP reno-protective effect against CIN and the molecular mechanisms by which TMP regulates ferroptosis. Classical contrast-medium, Iohexol, was used to construct CIN models in rats and HK-2 cells. Results showed that tubular cell injury was accompanied by ferroptosis both in vivo and in vitro, including the typical features of ferroptosis, Fe2+ accumulation, lipid peroxidation and decreased glutathione peroxidase 4 (GPX4). Ferroptosis inhibition by classic inhibitors Fer-1 and DFO promoted cell viability and reduced intracellular ROS production. Additionally, TMP significantly inhibited renal dysfunction, reduced AKI biomarkers, prevented ROS production, inhibited renal Fe2+ accumulation and increased GPX4 expression. Expressions of various proteins associated with iron ion metabolism, including transferrin receptor (TFRC), divalent metal transporter 1, iron-responsive element binding protein 2, ferritin heavy chain 1, ferroportin 1, and heat shock factor binding protein 1, were examined using mechanistic analyses. Among these, TFRC changes were the most significant after TMP pretreatment. Results of siRNA knockdown and plasmid overexpression of TFRC indicated that TFRC is essential for TMP to alleviate ferroptosis and reduce LDH release, Fe2+ accumulation and intracellular ROS. Our findings provide crucial insights about the potential of TMP in treating AKI associated with ferroptosis.