TfR1 Expression Research Articles

Resveratrol alleviates Mono-2-ethylhexyl phthalate-induced mitophagy, ferroptosis, and immunological dysfunction in grass carp hepatocytes by regulating the Nrf2 pathway

Mono-2-ethylhexyl phthalate (MEHP) is the major biologically active metabolite of Di(2-ethylhexyl) phthalate (DEHP). This MEHP mono-ester metabolite can be transported through the bloodstream into tissues such as the liver, kidneys, fat, and testes and cause corresponding damage. Resveratrol (RSV) has anti-inflammatory, antioxidant, and detoxification characteristics. Our research examined whether RSV alleviates MEHP-induced grass carp hepatocyte (L8824 cell) injury and its relationship with the Nrf2 pathway, mitophagy, ferroptosis, and immune function. Therefore, we treated L8824 cells with 85 μM MEHP and/or 2 μM RSV. The findings indicated that exposing MEHP resulted in increased reactive oxygen species (ROS) content and decreased mitochondrial membrane potential in L8824 cells, which induced an up-regulation of the expression of mitophagy-related indicators (PINK1, Parkin, Beclin1, LC3B, and ATG5) and a down-regulation of P62. An up-regulation of the expression of the ferroptosis-related indicators TFR1 and COX-2, and GPX4 and FTH expression was down-regulated. In addition, there was a decrease in the expression of IL-2 and IFN-γ and an increase in the expression of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 after exposure to MEHP. RSV activates the Nrf2 pathway and effectively alleviates MEHP-induced mitophagy, ferroptosis, and immunologic dysfunction of L8824 cells.

Discovery of potential ferroptosis and osteoporosis biomarkers through TMT proteomics and bioinformatics analysis

BackgroundPrimary osteoporosis has increasingly emerged as a major issue affecting human health, with a complex specific pathogenic mechanism. As a research hotspot, ferroptosis plays a vital role in the pathogenesis of primary osteoporosis, aiming to explore the link and specific target genes between ferroptosis and primary osteoporosis.MethodsBy utilizing TMT proteomics and bioinformatics analyses, we elucidated the linkages and key targets of the ferroptosis pathway in an ovariectomized osteoporotic rat model. Forty 12-week-old SD female rats were employed in the study, of which 20 female SD rats were ovariectomized as the OVX group and 20 female SD rats were employed as the SHAM group. At the end of the experiments, the femurs of the rats were excised for computed tomography tests and used for hematoxylin and eosin staining. Finally, we extracted bone tissue proteins for TMT proteomics analysis and protein blotting verification.ResultsThe proteomics results of the VX and SHAM groups showed that 133 proteins were significantly changed, of which 91 proteins were upregulated and 42 proteins were downregulated, including TXN, TMSB4X, TFRC, TF, RELA, PARP14, CP, CAPG, and ADIPOQ. The expression of key proteins in the bone tissues was detected by protein blotting. The expression of TFR1, TFRC and TF was upregulated, whereas the expression of Cp, TXN and BMP-2 was downregulated.ConclusionsTMT proteomics and functional enrichment analyses in our study substantiated that in osteoporosis, disturbances in lipid metabolism lead to the emergence of oxidative stress with iron homeostasis imbalance.

Edaravone mitigates calcium oxalate-induced renal tubular epithelial cell injury by inhibiting autophagy-mediated ferroptosis.

Edaravone (EDA) has been found to exert protective effects on kidney injury. Nevertheless, the functions of EDA in kidney stones as well as the potential mechanism are vague. Calcium oxalate (CaOx) was used to induce kidney stones cell model with human renal tubular epithelial cell line HK-2. CCK-8 assay was employed to detect cell viability injury. Oxidative stress was measured by DCFH-DA staining and detection of MDA, SOD, and GSH. Staining of FerroOrange and western blot were applied for ferroptosis. In addition, autophagy was elucidated by western blot and immunofluorescence staining. The data showed that CaOx treatment aggravated HK-2 cell viability injury, increased the levels of ROS, MDA, and Fe2+ in HK-2 cells, and reduced the contents of SOD and GSH. Additionally, CaOx enhanced the expression of KIM1, TFR1, LC3II/LC31, and BECLIN1 in HK-2 cells, while resulting in a decrease in the expression of GPX4, SLC7A11, and P62. Pretreatment of EDA mitigated CaOx-induced oxidative stress and ferroptosis, as well as autophagy in renal tubular epithelial cells. However, autophagy inducer rapamycin (Rap) reversed the protective role of EDA on renal tubular epithelial cell injury, oxidative stress, and ferroptosis. In conclusion, EDA contributes to suppressing oxidative stress and ferroptosis in CaOx-induced HT22 cells by restraining autophagy, which may be a potential candidate for the treatment of kidney stones caused by renal tubular epithelial cell damage.

Ceftiofur induced intestinal flora disorder exacerbates liver toxicity via microbiota-gut-liver axis

As a common antibiotic, ceftiofur was widely used in animal husbandry. It is estimated that the consumption of ceftiofur (CEF) in animal production will continue to increase due to the role of promoting growth. Accumulating evidences showed that excessive supplementation of ceftiofur in feed disrupted the intestinal flora. However, the mechanism of liver injury caused by excessive supplementation of ceftiofur induced intestinal flora disturbance remains unclear. In this study, our finding indicated that excessive ceftiofur uptake significantly disrupted intestinal flora, which lead to serious liver injury through the gut-liver axis. Our results showed that CEF exposure causes significantly decreased the expression of jejunum tight junction proteins (ZO-1, Claudin, and Occludin); and reduced the number of intestinal goblet cells. In addition, excessive CEF uptake significantly promoted the expression of inflammatory-related proteins in jejunum. Meanwhile, 16s rDNA analysis found that CEF exposure disrupted the abundance of Lactobacillus, HT002, Escherichia-Shigella, Klebaiella, Enterococcus, and Citrobacter, thereby affecting metal iron binding, molecular function, and mitochondrial function in the liver. Furthermore, CEF exposure caused ferroptosis in hepatocytes, as shown by increased the expression of TFR1, FACL4, FLC, COX2, HMGB1, and TXNIP protein, and reduced the expression of GPX4, XCT, and Ferritin protein. These results suggest that the significant adverse impacts of excessive CEF supplementation on gut-liver axis in mice may increase the long-term risks related to liver diseases.

Cartilage Endplate‐Targeted Engineered Exosome Releasing and Acid Neutralizing Hydrogel Reverses Intervertebral Disc Degeneration

AbstractCartilage endplate cell (CEPC) and nucleus pulposus cell (NPC) inflammation are critical factors that contribute to intervertebral disc degeneration (IVDD). Recent evidence indicated that iron ion influx, reactive oxygen species (ROS), and the cGAS‐STING pathway are involved in CEPC inflammatory degeneration. Moreover, cytokines produced by degenerating CEPCs and lactic acid accumulation within the microenvironment significantly contribute to NPC inflammation. Consequently, simultaneous alleviation of CEPC inflammation and correction of the acidic microenvironment are anticipated to reverse IVDD. Herein, CEPC‐targeted engineered exosomes loaded with salvianolic acid A are incorporated into a CaCO3/chitosan hydrogel, forming a composite gel, CAP‐sEXOs@Gel. Notably, CAP‐sEXOs@Gel shows long local retention, realizes the slow release of CAP‐sEXOs and specific uptake by CEPCs. After uptake by CEPCs, CAP‐sEXOs reduce intracellular iron ion and ROS by inhibiting hypoxia‐inducible factor‐2α (HIF‐2α)/TfR1 expression. Iron ion influx and ROS inhibition contribute to the maintenance of normal mitochondrial function and reduced mtDNA leakage, suppresing the cGAS‐STING pathway. Additionally, the CaCO3 component of CAP‐sEXOs@Gel neutralizes H+, thereby alleviating NPC inflammation. Collectively, this novel composite hydrogel demonstrates the ability to concurrently inhibit CEPC and NPC inflammation, thereby presenting a promising therapeutic approach for IVDD.

MiRNA-144/451 Regulates Cell Surface TfR1 Expression in Normal and β-Thalassemic Erythroblasts

miRNA-144/451 Regulates Cell Surface TfR1 Expression in Normal and β-Thalassemic Erythroblasts

Dexmedetomidine preconditioning attenuates ferroptosis in myocardial ischemia-reperfusion injury via α2 adrenergic receptor activation

ObjectiveDexmedetomidine (Dex) is a potent agonist of the α2 adrenergic receptor that has been shown to possess sedative and hypnotic properties. Dex can protect against myocardial ischemia-reperfusion injury (MIRI) by inhibiting ferroptosis. However, these studies were based on Dex post-conditioning, and the role of α2 adrenergic receptors in this process is unclear. In this study, we investigated whether Dex preconditioning can prevent MIRI by attenuating ferroptosis and whether this effect depends on α2 adrenergic receptors in rats. MethodsMale Sprague–Dawley rats were randomly assigned to five groups: sham (saline-treated), I/R (ischemia-exposed), Dex + I/R (Dex pre-treatment), Dex + Yoh + I/R (Dex and yohimbine pre-treatment), and Yoh + I/R (yohimbine pre-treatment). Cardiac function, myocardial infarction, and morphological changes were assessed. Transmission electron microscopy was used to analyze mitochondrial morphology. Ferroptosis-related indicators and lipid peroxidation were measured using western blotting and qRT-PCR. ResultsOur findings indicated that Dex preconditioning improved cardiac function, reduced infarct size and apoptosis, and inhibited ferroptosis in the rat myocardium after MIRI. These effects were associated with the upregulation of Nrf2, SLC7A11, and GPX4 expression, as well as the downregulation of Ferritin, TFR1, ACSL4, COX2, IL-1β, IL-6, and TNF-α expression. Importantly, yohimbine, an α2 adrenergic receptor antagonist, abolished these protective effects. ConclusionThese results suggest that Dex preconditioning can prevent MIRI by attenuating ferroptosis via α2 adrenergic receptor activation and by modulating the Nrf2/SLC7A11/GPX4 pathway.

Lactoferrin alleviates gentamicin-induced acute kidney injury in rats by suppressing ferroptosis: Highlight on ACSL4, SLC7A11, NCOA4, FSP1 pathways and miR-378a-3p, LINC00618 expression

The use of gentamicin (GNT) is associated with acute kidney injury (AKI). Ferroptosis is a newly recognized iron-dependent, non-apoptotic cell death that can lead to AKI. Lactoferrin (LF), an iron-binding glycoprotein, was previously reported to be renoprotective. Nonetheless, LF's impact on GNT-induced AKI and ferroptosis has not yet been investigated. Accordingly, we assessed the dose-dependent effect of LF on GNT-induced AKI and its influence on ferroptosis. Thirty-six male rats were allocated as control, LF, GNT (100 mg/kg/day, i.p.), and groups given LF (100, 200, and 300 mg/kg, p.o.) for 14 days prior concurrently with GNT (Day 8–14). The high dose of LF (300 mg/kg) showed better histopathological picture, higher creatinine clearance, reduced serum and urine levels of kidney injury markers when compared to the GNT group and the lower two doses. These nephroprotective effects of LF can be attributed to the observed reduction in renal ferrous iron, 4-HNE, and MDA, miR-378a-3p and ALOX15 expression, TFR1, NCOA4, and ACSL4 protein expression and the increased LINC00618 expression, GSH levels, GPX4, SLC7A11, and FSP1 protein expression. In conclusion, LF high dose was the most renoprotective against GNT-induced AKI, in which suppression of ferroptosis pathways was a likely contributor to its protective mechanism.

New insights into zinc alleviating renal toxicity of arsenic-exposed carp (Cyprinus carpio) through YAP-TFR/ROS signaling pathway

Environmental pollution caused by arsenic or its compounds is called arsenic pollution. Arsenic pollution mainly comes from people mining and smelting arsenic compounds. In addition, arsenic compounds' widespread use and production of arsenic-containing pesticides, arsenic-rich water used to irrigate farms, or high arsenic levels in foods caused by coal burning are all sources of arsenic contamination. Arsenic contamination poses a significant threat to global public health. It is reported that exposure to arsenic can induce severe renal injury. However, the underlying mechanism needs to be clarified. In this study, the arsenic exposure model in vivo and in vitro was used to explore the mechanism of arsenic-induced renal injury, especially the role of ferroptosis and its regulatory mechanism, and then to evaluate its anti-pollution effect by supplementing zinc. The results showed that arsenic significantly induced ferroptosis, characterized by up-regulating the expression of YAP and TFR in kidney and CIK cells and then increasing the levels of Fe2+ and ROS, lipid peroxidation, and iron metabolism. Microscopic observation revealed the shrinkage of mitochondria and the increase in membrane density. In addition, molecular docking and inhibitor experiments further confirmed that arsenic is involved in the process of ferroptosis by activating YAP and TFR. These results clarify the harmful effects of arsenic on carp kidneys and its mechanism and highlight the critical interactions between the YAP-TFR pathway, ROS, and ferroptosis. Importantly, this study found that zinc can reduce ferroptosis caused by the arsenic-activated YAP-TFR pathway by inhibiting YAP activation and lipid peroxidation.

Platycodin D ameliorates polycystic ovary syndrome-induced ovarian damage by upregulating CD44 to attenuate ferroptosis

Recently, the potential association between polycystic ovary syndrome (PCOS) development and progression and ferroptosis has garnered attention. Increasing evidence suggests that targeting ferroptosis may be an effective strategy for treating PCOS. First, we observed that the expression of the ferroptosis regulatory molecules SLC7A11, GPX4, and FTH1 was decreased in the granulosa cells (GCs) of patients with PCOS and ovarian tissues of rats with PCOS; in contrast, TFR1 expression was increased. This suggests that GC ferroptosis is involved in PCOS pathogenesis. Furthermore, bioinformatics analysis of GC datasets from patients with PCOS and PCOS clinical samples and animal model analysis revealed CD44 as a key molecule regulating ferroptosis in PCOS, which was down-regulated in GCs of PCOS patients and rats. Subsequently, molecular docking was performed to screen existing natural compounds for inhibiting ferroptosis. Dynamic simulation and cellular thermal shift assay identified platycodin D as a natural plant extract for inhibiting ferroptosis by targeting CD44 in GCs. Subsequently, a series of functional experiments revealed that platycodin D ameliorated ovarian damage in rats with PCOS. This was primarily owing to the protective effects achieved by promoting glutathione production, attenuating lipid accumulation and lipid peroxidation in GCs, inhibiting iron overload, and scavenging reactive oxygen species. In addition, western blotting and immunofluorescence staining revealed that platycodin D upregulated the expression of CD44 and SLC7A11 in GCs. Furthermore, by knocking down CD44 and SLC7A11 in vivo and in vitro, respectively, the ameliorative effect of platycodin D on ferroptosis in the GCs of rats with PCOS was reversed. Collectively, these findings suggest that platycodin D attenuates ferroptosis in GCs by activating CD44/SLC7A11 axis, thereby upregulating system Xc−. In conclusion, platycodin D can attenuate ferroptosis in GCs by activating CD44, potentially ameliorating ovarian damage in PCOS.

Angelica sinensis polysaccharides ameliorate 5-FU-induced stress anemia via promoting extramedullary erythroblastic island central macrophage-mediated erythroid differentiation

BackgroundChronic anemia, especially chemotherapy-induced anemia, is a common and intractable symptom. Puzzlingly, the conventional anemic treatment may lead to various side effects, and the mechanism of stress anemia remains unclear. MethodsHere, peripheral blood, histopathological and transmission electron microscopical examination, colony forming test, flow cytometry, and qRT-PCR assay were used to investigate the effects of Angelia sinensis polysaccharide (ASP), one main active ingredient of Chinese herb medicine Angelica sinensis, on ameliorating 5-fluorouracil (5-FU)-induced stress anemia. ResultsWe found that intraperitoneal injection to a C57BL/6J mouse ASP 100 mg/kg per day for consecutive 10 days or 14 days, remarkably accelerated the recovery of RBC, hemoglobin, and hematocrit in blood. ASP alleviated 5-FU-caused impairment of bone marrow cell and BFU-E enumeration. Meanwhile, ASP antagonized 5-FU promoting extramedullary erythropoiesis in the spleen, inducing splenomegaly due to stress erythroblastic islands, and occurrence of megakaryocytes and hematopoietic precursors in splenic colonies. ASP increased splenic stress BFU-E enumeration, driving BFU-E differentiation towards Pro-E and end-stage erythroblasts. Furthermore, ASP increased the number of F4/80+VCAM-1+ splenic erythroblastic island central macrophages, upregulating genetic expression of EPOR, Emp, VCAM-1, Hmox-1, Trf, TfR1, Fpn1, Spi-C, DNase2a, Tim4, MertK, and Klf1 in splenocytes. ConclusionsOur findings indicate that the possible mechanism of chemotherapy-induced anemia is related to stress erythroid maturation arrest. Whereas, ASP may promote stress erythroid differentiation via elevated EPO sensitivity in extramedullary hematopoietic organs and enhanced macrophage-mediated adhesion, iron homeostasis and transfer, and nuclear engulfment, which may represent a promising therapeutic strategy.

Phlorotannin Alleviates Liver Injury by Regulating Redox Balance, Apoptosis, and Ferroptosis of Broilers under Heat Stress.

Heat stress (HS) poses a great challenge to the poultry industry by inducing oxidative damage to the liver, endangering the health and production of broilers. As an important type of seaweed polyphenols, phlorotannin has been shown to have antioxidant properties. The present study evaluated the protective effects of dietary phlorotannin on HS-induced liver injury in broilers based on oxidative damage parameters. A total of 108 twenty-one days old male Arbor Acres plus (AA+) broilers were randomly divided into three groups: TN group (thermoneutral, 24 ± 1 °C, fed with basal diet), HS group (HS, 33 ± 1 °C for 8 h/day, fed with basal diet), and HS + phlorotannin group (HS + 600 mg/kg phlorotannin). Each group has six replicate cages with six birds per cage. The feeding experiment lasted 21 days. At the termination of the feeding experiment (42 days old), samples were collected for analysis of morphological and biochemical features. The results showed that HS decreased the liver index, serum albumin (ALB) content, hepatic antioxidant enzymes activities of catalase (CAT), total superoxide dismutase (T-SOD), glutathione S-transferase (GST), and glutathione peroxidase (GSH-Px) (p < 0.05), while increasing the hepatic histopathology score, apoptosis rate, and malondialdehyde (MDA) content (p < 0.05) in 42-day-old broilers. Compared with the HS group, dietary phlorotannin improved the activities of antioxidant enzymes (GST and GSH-Px) but decreased the histopathology score and apoptosis rate in the liver (p < 0.05). Moreover, HS down-regulated hepatic mRNA expression of CAT1, NQO1, HO-1, and SLC7A11 (p < 0.05), while up-regulated hepatic mRNA expression of Keap1, MafG, IκBα, NF-κB P65, IFN-γ, TFR1, ACSL4, Bax, and Caspase-9 (p < 0.05). Compared with HS group, dietary phlorotannin up-regulated hepatic mRNA expression of Nrf2, CAT1, MafF, GSTT1, NQO1, HO-1, GCLC, GPX1, TNF-α, Fpn1, and SLC7A11 (p < 0.05), while down-regulated hepatic mRNA expression of IκBα, Bax, Caspase-9, and TFR1 (p < 0.05). In conclusion, dietary supplementation of 600 mg/kg phlorotannin could alleviate HS-induced liver injury via regulating oxidative status, apoptosis, and ferroptosis in broilers; these roles of phlorotannin might be associated with the regulation of the Nrf2 signaling pathway.

Selenium nanoparticles alleviates cadmium induced hepatotoxicity by inhibiting ferroptosis and oxidative stress in vivo and in vitro

Cadmium (Cd) is an important environmental toxicant that could cause serious damage to various organs including severe hepatotoxicity in intoxicated animals. Selenium has been reported to possess the protective effects against Cd toxicity, but the specific mechanism is still unclear. The purpose of this study was to explore the effects and mechanism of chitosan coated selenium nanoparticles (CS-SeNPs) against Cd-induced hepatotoxicity in animal and cellular models. ICR mice and rat hepatocyte BRL-3A cells were exposed to cadmium chloride (CdCl2) to evaluate the therapeutic efficiency of CS-SeNPs. Analysis of histopathological images, mitochondrial membrane potential (MMP) and ultramicrostructure, serum liver enzyme activities, ferroptosis-related indicators contents, and further molecular biology experiments were performed to investigate the underlying mechanisms. In vivo experiment results showed that CdCl2 caused significant pathological damage involving significant increase of liver index, contents of tissue MDA and serum ALT and AST, and significant decrease of serum GSH-Px activity. Moreover, CdCl2 exposure upregulated ACSL4 and HO-1 protein levels, downregulated GPX4, TfR1, ferritin protein levels in the liver. Notably, CS-SeNPs increased the expression level of GPX4 and ameliorated CdCl2-induced changes in above-mentioned indicators. In vitro experimental results showed that treatment with CS-SeNPs significantly elevated GSH-Px activity and GPX4 protein level, reversed CdCl2-induced expression of several ferroptosis-related proteins TfR1, FTH1 and HO-1, and repressed ROS production and increased MMP of the cells exposed to CdCl2. Our research indicated that CdCl2 induced hepatocyte injury by inducing ferroptosis, while CS-SeNPs can inhibit ferroptosis and reduce the degree of hepatocyte injury. This study is of great significance for further revealing the mechanism of Cd hepatotoxicity and expanding the clinical application of SeNPs.

Curcumol promotes ferroptosis of colon cancer by targeting the ubiquitination and degradation of GPX4

Background and aimColon cancer (CC) is one of the common malignant tumors in the digestive tract, the prognosis of CC patients has never been satisfying. A Ferrous-dependent form that regulates cell death, plays a key role in cancer development. As a core regulator of ferroptosis, GPX4 has become a potential molecular target for the development of antitumor drugs. Curcumol (Cur), a sesquiterpene natural product, it has significant anti-tumor effect. However, whether Cur mediates ferroptosis in colon cancer and its mechanism are still unclear. This study aimed to investigate the underlying mechanisms of Cur anti-tumor. Experimental procedureBy investigating the Cancer Genome Atlas (TCGA) database and tissue immunofluorescence staining was also used to detect the levels of GPX4 protein in CC and matching paracancerous tissues. The anti-CC and pro-ferroptosis effects of Cur were detected in the vivo and vitro experiment. The interaction between Cur and GPX4 was predicted. In addition, the potential mechanism of Cur anti-CC was further discussed. Co-immunoprecipitation was used to confirm Cur-mediated GPX4 ubiquitination. Results and conclusionGPX4 was upregulated in CC tissue and was correlated with poor survival of patients. Cur inhibited the proliferation of CC cells, accompanied by regulating Fe2+ overload, reactive oxygen species (ROS) formation, malondialdehyde (MDA) production and superoxide dismutase (SOD) consumption. Furthermore, GPX4 was predicted and verified as the direct target of Cur by molecular docking and structure-based virtual prediction. Meanwhile, Cur could promote the ubiquitination-mediated degradation of GPX4, induce ferroptosis in CC cells and regulate the expression of ferroptosis-related protein FTH1 and TfR1. In addition, when GPX4 was overexpressed (GPX4-OE), the inhibitory effect of Cur on the expression of GPX4 and ferroptosis-related protein FTH1 and the promotion of TfR1 expression were abolished. Cur could inhibit CC by increasing the ubiquitination degradation level of GPX4 to induce ferroptosis in CC cells.

Upregulation of Transferrin Receptor 1 (TfR1) but Not Glucose Transporter 1 (GLUT1) or CD98hc at the Blood-Brain Barrier in Response to Valproic Acid.

Transferrin receptor 1 (TfR1), glucose transporter 1 (GLUT1), and CD98hc are candidates for targeted therapy at the blood-brain barrier (BBB). Our objective was to challenge the expression of TfR1, GLUT1, and CD98hc in brain capillaries using the histone deacetylase inhibitor (HDACi) valproic acid (VPA). Primary mouse brain capillary endothelial cells (BCECs) and brain capillaries isolated from mice injected intraperitoneally with VPA were examined using RT-qPCR and ELISA. Targeting to the BBB was performed by injecting monoclonal anti-TfR1 (Ri7217)-conjugated gold nanoparticles measured using ICP-MS. In BCECs co-cultured with glial cells, Tfrc mRNA expression was significantly higher after 6 h VPA, returning to baseline after 24 h. In vivo Glut1 mRNA expression was significantly higher in males, but not females, receiving VPA, whereas Cd98hc mRNA expression was unaffected by VPA. TfR1 increased significantly in vivo after VPA, whereas GLUT1 and CD98hc were unchanged. The uptake of anti-TfR1-conjugated nanoparticles was unaltered by VPA despite upregulated TfR expression. VPA upregulates TfR1 in brain endothelium in vivo and in vitro. VPA does not increase GLUT1 and CD98hc proteins. The increase in TfR1 does not result in higher anti-TfR1 antibody targetability, suggesting targeting sufficiently occurs with available transferrin receptors without further contribution from accessory VPA-induced TfR1.

Acupuncture improve proteinuria in diabetic kidney disease rats by inhibiting ferroptosis and epithelial-mesenchymal transition

ObjectiveTo explore the mechanism of acupuncture to relieve diabetic proteinuria in Diabetic Kidney Disease (DKD). MethodsA total of 10 male Sprague-Dawley rats were randomly selected as the negative control group (NC), and a further 30 rats were fed a high-fat diet (HFD) and intraperitoneal streptozotocin (STZ). The DKD model rats in the model group (DKD) and the acupuncture group (DKD + Acu) were randomly assigned. After 4 weeks of intervention, collected urine, peripheral blood, and renal tissues from all rats, and assessed blood urea nitrogen, serum creatinine, triglyceride, 24-h urine protein quantification, and blood glucose, left kidney weight, kidney body ratio index, then observe changes in renal histology in the rats. The renal cortex tissues of three rats from each group were sent for transcriptomic analysis. According to the results of transcriptomic analysis, various kits were used to detect SOD, MDA, GSH, GSH-px, and iron concentration. The expression levels of GPX4 and System Xc-, members of the antioxidative stress pathway, and TfR 1, SLC39A14, FTH 1, and SLC40A1, involved in iron metabolism, in the kidney tissues were measured by western blotting and reverse transcription-quantitative PCR. The expression of mesenchymal phenotype markers and podocyte-specific markers were evaluated by immunofluorescence. ResultsAcupuncture promoted the levels of GSH, GSH-px, and SOD, decreased the level of MDA (P < 0.05), promoted the expression of GPX4 and System Xc- (P < 0.05), decreased the expression of TfR1 and SLC39A14 (P < 0.01), and increased the expression of FTH 1 and SLC40A1 (P < 0.05), inhibited the expression of TGF-β1, desmin, FSP-1, and α-SMA (P < 0.05), promoted the expression of Nephrin, Podocin, and CD2AP (P < 0.05). ConclusionImproving the ability of podocytes to prevent oxidative stress and restoring iron ion homeostasis, can improve Ferroptosis and block epithelial-mesenchymal transition, improve podocyte injury, restore filtration function, and reduce proteinuria in DKD rats.

Clinical efficacy of ganciclovir combined with transfer factor oral solution for pediatric infectious mononucleosis

This study investigates the clinical efficacy of ganciclovir combined with transfer factor oral solution in the treatment of patients with infectious mononucleosis (IM) to provide a reference for clinical application. A total of 150 children with IM who received treatment in our hospital from 2020 to 2022 were randomly selected as the research subjects. They were randomly divided into a control group receiving intravenous administration of ganciclovir (n = 75) and an observation group receiving transfer factor oral liquid in combination with intravenous administration of ganciclovir (n=75). The results showed that after treatment, the serum levels of CK-MB, CK, CRP, IL-6, and TNF-α were significantly reduced in both groups. The observation group showed lower levels than the control group. Additionally, peripheral blood CD4+ T cells, CD4+/CD8+ ratio, and Tfr expression were higher in the observation group compared to the control group, while the level of CD8+ T cells was lower than that of the control group. Furthermore, there were no significant changes in the levels of IgA, IgM, and IgG antibodies in the two groups before and after treatment. In conclusion, the combination therapy of transfer factor oral solution and ganciclovir demonstrates favorable clinical efficacy and safety in the treatment of children with IM, as it effectively reduces inflammatory reactions, regulates cellular immune function, promotes Tfr differentiation, and shortens recovery time.

Gene expression of iron transporters, markers of vascularization and structural integrity in placenta of mothers with and without anemia.

To compare the mRNA expression of placental iron transporters (TfR-1 and FPN), markers of placental vascularization (VEGF and sFLT1) and marker of structural integrity (LMN-A) in term women with and without iron deficiency anemia. A total of 30 pregnant women were enrolled; 15 cases of iron deficiency anemia (Hb 7-10.9 gm/dL) and 15 gestational age matched healthy controls (Hb ≥ 11 gm/dL). Peripheral venous blood was collected for assessment of hemoglobin levels and serum iron profile. Placental tissue was used for assessing the mRNA expression of TfR-1, FPN, VEGF, sFLT-1 and LMN-A via real time PCR. Placental expression of TfR-1, VEGF and LMN-A was increased in pregnant women with anemia compared to healthy pregnant controls. Placental expression of sFLT-1 was decreased in pregnant women with anemia compared to healthy pregnant controls. There was no change in the placental expression of FPN. The increased expression of TfR-1, VEGF and LMN-A in cases of iron deficiency anemia are most likely to be compensatory in nature to help maintain adequate fetal iron delivery. Compensatory changes in the placenta aimed at buffering transport of iron to the fetus are seen in pregnant women with anemia compared to healthy pregnant controls.

Phenylhydrazine-induced haemolysis disturbed iron pool homeostasis and activated expression pattern of FPN1 in the intestine of grass carp (Ctenopharyngodon idella)

As the only molecule that can transport iron to the cell exterior, the ferroportin 1 (FPN1) plays a key role in regulating the homeostasis of the iron ion. However, the function of FPN1 in teleost is remains unclear. In this study, the fpn1 gene was cloned from grass carp and its characteristics were studied. The results showed that grass carp Fpn1 protein contains eight transmembrane domains, which are similar to the amino acid sequences of different species. The tissue distribution of fpn1 was investigated by quantitative real-time PCR (qRT-PCR), which showed that the expression of fpn1 was the highest in the liver, followed by the spleen and muscle. Secondly, the haemolysis model of grass carp was established by the injection of phenylhydrazine (PHZ), and the effect of Fpn1 on the intestine in during haemolysis was explored. The determination data revealed that the PHZ-induced haemolysis increased the number of goblet cells in intestinal, as well as malondialdehyde (Mda), decreased glutathione peroxidase 4 (Gpx4) content in foregut. The result of tissue immunofluorescence assay showed that the PHZ-induced haemolysis modulated the expression of iron metabolism related genes, including Fpn1 and Tfr1 (transferrin receptor 1) in the intestine. Further determination data suggested that the iron deposition and apoptosis were higher in PHZ treatment group than that of the group. Taken together, the PHZ-induced haemolysis destroyed the iron homeostasis in intestinal and caused oxidative damage, the data of this study lays a foundation for the study of the mechanisms of intestinal iron homeostasis and provides a theoretical basis for understanding intestinal healthy.

Rocaglamide regulates iron homeostasis by suppressing hepcidin expression

The anemia of inflammation (AI) is characterized by the presence of inflammation and abnormal elevation of hepcidin. Accumulating evidence has proved that Rocaglamide (RocA) was involved in inflammation regulation. Nevertheless, the role of RocA in AI, especially in iron metabolism, has not been investigated, and its underlying mechanism remains elusive. Here, we demonstrated that RocA dramatically suppressed the elevation of hepcidin and ferritin in LPS-treated mice cell line RAW264.7 and peritoneal macrophages. In vivo study showed that RocA can restrain the depletion of serum iron (SI) and transferrin (Tf) saturation caused by LPS. Further investigation showed that RocA suppressed the upregulation of hepcidin mRNA and downregulation of Fpn1 protein expression in the spleen and liver of LPS-treated mice. Mechanistically, this effect was attributed to RocA's ability to inhibit the IL-6/STAT3 pathway, resulting in the suppression of hepcidin mRNA and subsequent increase in Fpn1 and TfR1 expression in LPS-treated macrophages. Moreover, RocA inhibited the elevation of the cellular labile iron pool (LIP) and reactive oxygen species (ROS) induced by LPS in RAW264.7 cells. These findings reveal a pivotal mechanism underlying the roles of RocA in modulating iron homeostasis and also provide a candidate natural product on alleviating AI.