Metabolic reprogramming in septic acute kidney injury: pathogenesis and therapeutic implications.

Acute kidney injury (AKI) is a frequent and severe complication of sepsis and is characterized by significant mortality and morbidity. However, the pathogenesis of septic acute kidney injury (S-AKI) remains elusive. Metabolic reprogramming, which was originally referred to as the Warburg effect in cancer, is strongly related to S-AKI. At the onset of sepsis, both inflammatory cells and renal parenchymal cells, such as macrophages, neutrophils and renal tubular epithelial cells, undergo metabolic shifts toward aerobic glycolysis to amplify proinflammatory responses and fortify cellular resilience to septic stimuli. As the disease progresses, these cells revert to oxidative phosphorylation, thus promoting anti-inflammatory reactions and enhancing functional restoration. Alterations in mitochondrial dynamics and metabolic reprogramming are central to the energetic changes that occur during S-AKI. In this review, we summarize the current understanding of the pathogenesis of metabolic reprogramming in S-AKI, with a focus on each cell type involved. By identifying relevant key regulatory factors, we also explored potential metabolic reprogramming-related therapeutic targets for the management of S-AKI.

SKLB023 protects against inflammation and apoptosis in sepsis-associated acute kidney injury via the inhibition of toll-like receptor 4 signaling.

Sepsis-associated acute kidney injury (SA-AKI) is one of common critical illnesses with high morbidity and mortality. At present, effective therapeutic drugs for SA-AKI are remain lacking. SKLB023 is a synthetic small-molecule compound which exerts potent anti-inflammatory effects in our previous studies. Here, this study aimed to characterize the protective effect of SKLB023 on SA-AKI and explore its underlying mechanism. The SA-AKI experimental models have been established by cecum ligation/puncture (CLP) and lipopolysaccharide (LPS) injection in male C57BL/6J mice. SKLB023 was administered by gavage (50 or 25 mg/kg in CLP model and 50 mg/kg in LPS model) daily 3 days in advance and 30 min earlier on the day of modeling. Our results confirmed SKLB023 treatment could improve the survival of SA-AKI mice and ameliorate renal pathological injury, inflammation, and apoptosis in the two types of septic AKI mice. Mechanically, SKLB023 deceased the expression of TLR4 in LPS-triggered renal tubular epithelial cells, and inhibited the activation of downstream pathways including NF-κB and MAPK pathways. Our study suggested that SKLB023 is expected to be a potential drug for the prevention and treatment of septic AKI.

Two C-terminal isoforms of Aplysia tachykinin-related peptide receptors exhibit phosphorylation-dependent and independent desensitization mechanisms.

Diversity, a hallmark of G protein-coupled receptor (GPCR) signaling, partly stems from alternative splicing of a single gene generating more than one isoform for a receptor. Additionally, receptor responses to ligands can be attenuated by desensitization upon prolonged or repeated ligand exposure. Both phenomena have been demonstrated and exemplified by the deuterostome tachykinin (TK) signaling system, although the role of phosphorylation in desensitization remains a subject of debate. Here, we describe the signaling system for tachykinin-related peptides (TKRPs) in a protostome, mollusk Aplysia. We cloned the Aplysia TKRP precursor, which encodes three TKRPs (apTKRP-1, apTKRP-2a, and apTKRP-2b) containing the FXGXR-amide motif. In situ hybridization and immunohistochemistry showed predominant expression of TKRP mRNA and peptide in the cerebral ganglia. TKRPs and their post-translational modifications were observed in extracts of CNS ganglia using mass spectrometry. We identified two Aplysia TKRP receptors (TKRPRs), named apTKRPR-A and apTKRPR-B. These receptors are two isoforms generated through alternative splicing of the same gene and differ only in their intracellular C-termini. Structure-activity relationship analysis of apTKRP-2b revealed that both C-terminal amidation and conserved residues of the ligand are critical for receptor activation. C-terminal truncates and mutants of apTKRPRs suggested that there is a C-terminal phosphorylation-independent desensitization for both receptors. Moreover, apTKRPR-B also exhibits phosphorylation-dependent desensitization through the phosphorylation of C-terminal Ser/Thr residues. This comprehensive characterization of the Aplysia TKRP signaling system underscores the evolutionary conservation of the TKRP and TK signaling systems, while highlighting the intricacies of receptor regulation through alternative splicing and differential desensitization mechanisms.

The Time-Varying Impact of COVID-19 on the Acute Kidney Disorders: A Historical Matched Cohort Study and Mendelian Randomization Analysis.

Background: This study aimed to explore the time-varying impact of COVID-19 on acute kidney disorders, including acute kidney injury and other acute kidney diseases. Methods: From the UK Biobank, 10,121 participants with COVID-19 were matched with up to 3 historically unexposed controls by age, sex, Townsend deprivation index, and the status of hospitalization or receiving critical care. We investigated the association between COVID-19 and incidence of acute kidney disorders, within the first 4 weeks after infection, using conditional and time-varying Cox proportional hazard regression. In addition, one-sample Mendelian randomization, utilizing the polygenic risk score for COVID-19 as an instrumental variable, was conducted to explore the potential causality of the association. Results: In the matched cohort study, we observed a significant association between COVID-19 and acute kidney disorders predominantly within the first 3 weeks. The impact of COVID-19 was time dependent, peaking in the second week (hazard ratio, 12.77; 95% confidence interval, 5.93 to 27.70) and decreasing by the fourth week (hazard ratio, 2.28; 95% confidence interval, 0.75 to 6.93). In subgroup analyses, only moderate to severe COVID-19 cases were associated with acute worsening of renal function in a time-dependent pattern. One-sample Mendelian randomization analyses further showed that COVID-19 might exert a "short-term" causal effect on the risk of acute kidney disorders, primarily confined to the first week after infection. Conclusions: The risk of acute kidney disorders following COVID-19 demonstrates a time-varying pattern. Hazard effects were observed only in patients with moderate or severe but not mild COVID-19.

Research on coronavirus disease 2019 and the kidney: A bibliometric analysis.

Background: In addition to damage to the lungs, coronavirus disease 2019 (COVID-19) can damage multiple organs, including the kidney. Our purpose was to analyze the research hotspots and trends in COVID-19 and kidney diseases using bibliometrics to help clarify the development direction of this field. Methods: We selected and extracted all relevant publications related to COVID-19 and the kidney from the Web of Science from December 1, 2019, to July 24, 2022. VOSviewer, RStudio, CiteSpace, and other software were used to visualize keywords, publishing trends, authors and their countries, and institutions in this field and perform the statistical analysis. Results: A total of 645 articles published in 220 journals were included in this study. The United States and China contributed the most publications and were most active in international cooperation. In addition to COVID-19 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), acute kidney injury (AKI), kidney transplant and mortality were the three keywords with the highest frequencies. In the initial stage of the COVID-19 outbreak, research focused on the clinical symptoms of COVID-19 and other macrocharacteristics, while in a later stage, the associations between SARS-CoV-2 infection and CKD and AKI, as well as the prognosis of patients with kidney disease or those who underwent kidney transplantation, gained more attention. The immune response and vaccines were also recent research hotspots. Conclusions: This bibliometric analysis provides a comprehensive overview of research on COVID-19 and kidney disease, which has received continuous, global attention. AKI, CKD, kidney transplantation, immune response and vaccines are among the hotspots in this field.

Pitavastatin sensitizes the EGFR-TKI associated resistance in lung cancer by inhibiting YAP/AKT/BAD-BCL-2 pathway.

BACKGROUND: Despite effective strategies, resistance in EGFR mutated lung cancer remains a challenge. Metabolic reprogramming is one of the main mechanisms of tumor drug resistance. A class of drugs known as "statins" inhibit lipid cholesterol metabolism and are widely used in patients with cardiovascular diseases. Previous studies have also documented its ability to improve the therapeutic impact in lung cancer patients who receive EGFR-TKI therapy. Therefore, the effect of statins on targeted drug resistance to lung cancer remains to be investigated. METHODS: Prolonged exposure to gefitinib resulted in the emergence of a resistant lung cancer cell line (PC9GR) from the parental sensitive cell line (PC9), which exhibited a traditional EGFR mutation. The CCK-8 assay was employed to assess the impact of various concentrations of pitavastatin on cellular proliferation. RNA sequencing was conducted to detect differentially expressed genes and their correlated pathways. For the detection of protein expression, Western blot was performed. The antitumor activity of pitavastatin was evaluated in vivo via a xenograft mouse model. RESULTS: PC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC9 cells, and the YAP expression was inhibited by pitavastatin administration. With YAP RNA interference, pAKT, pBAD and BCL-2 expression was decreased, while BAX expression as increased. Accordingly, YAP down-regulated significantly increased apoptosis and decreased the survival rate of gefitinib-resistant lung cancer cells. After pAKT was increased by SC79, apoptosis of YAP down-regulated cells induced by gefitinib was decreased, and the cell survival rate was increased. Mechanistically, these effects of pitavastatin are associated with the YAP pathway, thereby inhibiting the downstream AKT/BAD-BCL-2 signaling pathway. CONCLUSION: Our study provides a molecular basis for the clinical application of the lipid-lowering drug pitavastatin enhances the susceptibility of lung cancer to EGFR-TKI drugs and alleviates drug resistance.

Identification of the central role of RNA polymerase mitochondrial for angiogenesis.

Mitochondria are central to endothelial cell activation and angiogenesis, with the RNA polymerase mitochondrial (POLRMT) serving as a key protein in regulating mitochondrial transcription and oxidative phosphorylation. In our study, we examined the impact of POLRMT on angiogenesis and found that its silencing or knockout (KO) in human umbilical vein endothelial cells (HUVECs) and other endothelial cells resulted in robust anti-angiogenic effects, impeding cell proliferation, migration, and capillary tube formation. Depletion of POLRMT led to impaired mitochondrial function, characterized by mitochondrial depolarization, oxidative stress, lipid oxidation, DNA damage, and reduced ATP production, along with significant apoptosis activation. Conversely, overexpressing POLRMT promoted angiogenic activity in the endothelial cells. In vivo experiments demonstrated that endothelial knockdown of POLRMT, by intravitreous injection of endothelial specific POLRMT shRNA adeno-associated virus, inhibited retinal angiogenesis. In addition, inhibiting POLRMT with a first-in-class inhibitor IMT1 exerted significant anti-angiogenic impact in vitro and in vivo. Significantly elevated expression of POLRMT was observed in the retinal tissues of streptozotocin-induced diabetic retinopathy (DR) mice. POLRMT endothelial knockdown inhibited pathological retinal angiogenesis and mitigated retinal ganglion cell (RGC) degeneration in DR mice. At last, POLRMT expression exhibited a substantial increase in the retinal proliferative membrane tissues of human DR patients. These findings collectively establish the indispensable role of POLRMT in angiogenesis, both in vitro and in vivo.

Integrin αM promotes macrophage alternative M2 polarization in hyperuricemia-related chronic kidney disease.

Hyperuricemia is an essential risk factor in chronic kidney disease (CKD), while urate-lowering therapy to prevent or delay CKD is controversial. Alternatively activated macrophages in response to local microenvironment play diverse roles in kidney diseases. Here, we aim to investigate whether and how macrophage integrin αM (ITGAM) contributes to hyperuricemia-related CKD. In vivo, we explored dynamic characteristics of renal tissue in hyperuricemia-related CKD mice. By incorporating transcriptomics and phosphoproteomics data, we analyzed gene expression profile, hub genes and potential pathways. In vitro, we validated bioinformatic findings under different conditions with interventions corresponding to core nodes. We found that hyperuricemia-related CKD was characterized by elevated serum uric acid levels, impaired renal function, activation of macrophage alternative (M2) polarization, and kidney fibrosis. Integrated bioinformatic analyses revealed Itgam as the potential core gene, which was associated with focal adhesion signaling. Notably, we confirmed the upregulated expression of macrophage ITGAM, activated pathway, and macrophage M2 polarization in injured kidneys. In vitro, through silencing Itgam, inhibiting p-FAK or p-AKT1 phosphorylation, and concurrent inhibiting of p-FAK while activating p-AKT1 all contributed to the modulation of macrophage M2 polarization. Our results indicated targeting macrophage ITGAM might be a promising therapeutic approach for preventing CKD.

Lactate metabolism and acute kidney injury.

ABSTRACT: Acute kidney injury (AKI) is a common clinically critical syndrome in hospitalized patients with high morbidity and mortality. At present, the mechanism of AKI has not been fully elucidated, and no therapeutic drugs exist. As known, glycolytic product lactate is a key metabolite in physiological and pathological processes. The kidney is an important gluconeogenic organ, where lactate is the primary substrate of renal gluconeogenesis in physiological conditions. During AKI, altered glycolysis and gluconeogenesis in kidneys significantly disturb the lactate metabolic balance, which exert impacts on the severity and prognosis of AKI. Additionally, lactate-derived posttranslational modification, namely lactylation, is novel to AKI as it could regulate gene transcription of metabolic enzymes involved in glycolysis or Warburg effect. Protein lactylation widely exists in human tissues and may severely affect non-histone functions. Moreover, the strategies of intervening lactate metabolic pathways are expected to bring a new dawn for the treatment of AKI. This review focused on renal lactate metabolism, especially in proximal renal tubules after AKI, and updated recent advances of lactylation modification, which may help to explore potential therapeutic targets against AKI.

Global burden of non-communicable diseases attributable to kidney dysfunction with projection into 2040.

BACKGROUND: Spatiotemporal disparities exist in the disease burden of non-communicable diseases (NCDs) attributable to kidney dysfunction, which has been poorly assessed. The present study aimed to evaluate the spatiotemporal trends of the global burden of NCDs attributable to kidney dysfunction and to predict future trends. METHODS: Data on NCDs attributable to kidney dysfunction, quantified using deaths and disability-adjusted life-years (DALYs), were extracted from the Global Burden of Diseases Injuries, and Risk Factors (GBD) Study in 2019. Estimated annual percentage change (EAPC) of age-standardized rate (ASR) was calculated with linear regression to assess the changing trend. Pearson's correlation analysis was used to determine the association between ASR and Sociodemographic Index (SDI) for 21 GBD regions. A Bayesian age-period-cohort (BAPC) model was used to predict future trends up to 2040. RESULTS: Between 1990 and 2019, the absolute number of deaths and DALYs from NCDs attributable to kidney dysfunction increased globally. The death cases increased from 1,571,720 (95% uncertainty interval [UI]: 1,344,420-1,805,598) in 1990 to 3,161,552 (95% UI: 2,723,363-3,623,814) in 2019 for both sexes combined. Both the ASR of death and DALYs increased in Andean Latin America, the Caribbean, Central Latin America, Southeast Asia, Oceania, and Southern Sub-Saharan Africa. In contrast, the age-standardized metrics decreased in the high-income Asia Pacific region. The relationship between SDI and ASR of death and DALYs was negatively correlated. The BAPC model indicated that there would be approximately 5,806,780 death cases and 119,013,659 DALY cases in 2040 that could be attributed to kidney dysfunction. Age-standardized death of cardiovascular diseases (CVDs) and CKD attributable to kidney dysfunction were predicted to decrease and increase from 2020 to 2040, respectively. CONCLUSION: NCDs attributable to kidney dysfunction remain a major public health concern worldwide. Efforts are required to attenuate the death and disability burden, particularly in low and low-to-middle SDI regions.

HSD17B1 Compensates for HSD17B3 Deficiency in Fetal Mouse Testis but Not in Adults.

Hydroxysteroid (17ß) dehydrogenase (HSD17B) enzymes convert 17-ketosteroids to 17beta-hydroxysteroids, an essential step in testosterone biosynthesis. Human XY individuals with inactivating HSD17B3 mutations are born with female-appearing external genitalia due to testosterone deficiency. However, at puberty their testosterone production reactivates, indicating HSD17B3-independent testosterone synthesis. We have recently shown that Hsd17b3 knockout (3-KO) male mice display a similar endocrine imbalance, with high serum androstenedione and testosterone in adulthood, but milder undermasculinization than humans. Here, we studied whether HSD17B1 is responsible for the remaining HSD17B activity in the 3-KO male mice by generating a Ser134Ala point mutation that disrupted the enzymatic activity of HSD17B1 (1-KO) followed by breeding Hsd17b1/Hsd17b3 double-KO (DKO) mice. In contrast to 3-KO, inactivation of both HSD17B3 and HSD17B1 in mice results in a dramatic drop in testosterone synthesis during the fetal period. This resulted in a female-like anogenital distance at birth, and adult DKO males displayed more severe undermasculinization than 3-KO, including more strongly reduced weight of seminal vesicles, levator ani, epididymis, and testis. However, qualitatively normal spermatogenesis was detected in adult DKO males. Furthermore, similar to 3-KO mice, high serum testosterone was still detected in adult DKO mice, accompanied by upregulation of various steroidogenic enzymes. The data show that HSD17B1 compensates for HSD17B3 deficiency in fetal mouse testis but is not the enzyme responsible for testosterone synthesis in adult mice with inactivated HSD17B3. Therefore, other enzymes are able to convert androstenedione to testosterone in the adult mouse testis and presumably also in the human testis.

Mesenchymal-epithelial transition factor amplification correlates with adverse pathological features and poor clinical outcome in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related mortality worldwide. Mesenchymal-epithelial transition factor (MET) gene participates in multiple tumor biology and shows clinical potential for pharmacological manipulation in tumor treatment. MET amplification has been reported in CRC, but data are very limited. Investigating pathological values of MET in CRC may provide new therapeutic and genetic screening options in future clinical practice. AIM: To determine the pathological significance of MET amplification in CRC and to propose a feasible screening strategy. METHODS: A number of 205 newly diagnosed CRC patients undergoing surgical resection without any preoperative therapy at Shenzhen Cancer Hospital of Chinese Academy of Medical Sciences were recruited. All patients were without RAS/RAF mutation or microsatellite instability-high. MET amplification and c-MET protein expression were analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), respectively. Correlations between MET aberration and pathological features were detected using the chi-squared test. Progression free survival (PFS) during the two-year follow-up was detected using the Kaplan-Meier method and log rank test. The results of MET FISH and IHC were compared using one-way ANOVA. RESULTS: Polysomy-induced MET amplification was observed in 14.4% of cases, and focal MET amplification was not detected. Polysomy-induced MET amplification was associated with a higher frequency of lymph node metastasis (LNM) (P < 0.001) and higher tumor budding grade (P = 0.02). In the survival analysis, significant difference was detected between patients with amplified- and non-amplified MET in a two-year follow-up after the first diagnosis (P = 0.001). C-MET scores of 0, 1+, 2+, and 3+ were observed in 1.4%, 24.9%, 54.7%, and 19.0% of tumors, respectively. C-MET overexpression correlated with higher frequency of LNM (P = 0.002), but no significant difference of PFS was detected between patients with different protein levels. In terms of concordance between MET FISH and IHC results, MET copy number showed no difference in c-MET IHC 0/1+ (3.35 ± 0.18), 2+ (3.29 ± 0.11) and 3+ (3.58 ± 0.22) cohorts, and the MET-to-CEP7 ratio showed no difference in three groups (1.09 ± 0.02, 1.10 ± 0.01, and 1.09 ± 0.03). CONCLUSION: In CRC, focal MET amplification was a rare event. Polysomy-induced MET amplification correlated with adverse pathological characteristics and poor prognosis. IHC was a poor screening tool for MET amplification.

Accurately Modulating Binuclear Metal Nodes of Metal-Organic Frameworks for Oxygen Evolution.

The accurate manipulation of the species and locations of catalytic centers is crucial for regulating the catalytic activity of catalysts, which is essential for their efficient design and development. Metal-organic frameworks (MOFs) with coordinated metal sites are ideal materials for investigating the origin of catalytic activity. In this study, we present a Ni2-MOF featuring novel Ni-based binuclear nodes with open metal sites (OMSs) and saturated metal sites (SMSs). The nickel was replaced by iron to obtain Ni1Fe1-MOF. In the electrocatalytic oxygen evolution reaction, Ni1Fe1-MOF exhibited an overpotential and Tafel slope of 370 mV@10 mA cm-2 and 87.06 mV dec-1, respectively, which were higher than those of Ni2-MOF (283 mV@10 mA cm-2 and 39.59 mV dec-1, respectively), demonstrating the superior performance of Ni1Fe1-MOF. Furthermore, theoretical calculations revealed that iron as an SMS may effectively regulate the electronic structure of the nickel catalytic center to reduce the free energy barrier ΔG*OH of the rate-determining step.

Prognostic value of neutrophil-to-lymphocyte ratio dynamics in patients with septic acute kidney injury: a cohort study.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been suggested to be a prognostic marker for various diseases, but whether NLR dynamics (ΔNLR) is related to mortality and disease severity in patients with septic acute kidney injury (AKI) has not been determined. METHODS: Between August 2013 and August 2021, septic AKI patients at our center were retrospectively enrolled. ΔNLR was defined as the difference between the NLR at septic AKI diagnosis and at hospital admission. The relationship between the ΔNLR and mortality was evaluated by Kaplan-Meier curves, Cox proportional hazards, and cubic spline analyses. The prediction values were compared by area under the receiver-operating characteristic curve (AUROC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) analyses. RESULTS: Of the 413 participants, the mean age was 63 ± 17 years, and 134 were female (32.4%). According to the median value, patients in the high-ΔNLR group had significantly greater 90-d mortality (74.4% vs. 46.6%, p < 0.001). After adjustment for potential confounders, high ΔNLR remained an independent predictor of 90-d mortality (HR = 2.80; 95% CI = 1.74-4.49, p < 0.001). Furthermore, ΔNLR had the highest AUROC for 90-d mortality (0.685) among the various biomarkers and exhibited an improved NRI (0.314) and IDI (0.027) when incorporated with PCT and CRP. For secondary outcomes, patients with high ΔNLR had increased risk of 30-d mortality (p = 0.004), need for renal replacement therapy (p = 0.011), and developing stage-3 AKI (p = 0.040) according to the adjusted models. CONCLUSIONS: High ΔNLR is independently associated with increased risk of patient mortality and adverse outcomes. ΔNLR might be utilized to facilitate risk stratification and optimize septic AKI management.

Inhibition of ACSS2-mediated histone crotonylation alleviates kidney fibrosis via IL-1ß-dependent macrophage activation and tubular cell senescence.

Histone lysine crotonylation (Kcr), as a posttranslational modification, is widespread as acetylation (Kac); however, its roles are largely unknown in kidney fibrosis. In this study, we report that histone Kcr of tubular epithelial cells is abnormally elevated in fibrotic kidneys. By screening these crotonylated/acetylated factors, a crotonyl-CoA-producing enzyme ACSS2 (acyl-CoA synthetase short chain family member 2) is found to remarkably increase histone 3 lysine 9 crotonylation (H3K9cr) level without influencing H3K9ac in kidneys and tubular epithelial cells. The integrated analysis of ChIP-seq and RNA-seq of fibrotic kidneys reveal that the hub proinflammatory cytokine IL-1ß, which is regulated by H3K9cr, play crucial roles in fibrogenesis. Furthermore, genetic and pharmacologic inhibition of ACSS2 both suppress H3K9cr-mediated IL-1ß expression, which thereby alleviate IL-1ß-dependent macrophage activation and tubular cell senescence to delay renal fibrosis. Collectively, our findings uncover that H3K9cr exerts a critical, previously unrecognized role in kidney fibrosis, where ACSS2 represents an attractive drug target to slow fibrotic kidney disease progression.

DMT1 ubiquitination by Nedd4 protects against ferroptosis after intracerebral hemorrhage.

OBJECTIVE: Neuronal precursor cells expressed developmentally down-regulated 4 (Nedd4) are believed to play a critical role in promoting the degradation of substrate proteins and are involved in numerous biological processes. However, the role of Nedd4 in intracerebral hemorrhage (ICH) remains unknown. This study aims to investigate the regulatory role of Nedd4 in the ICH model. METHODS: Male C57BL/6J mice were induced with ICH. Subsequently, the levels of glutathione peroxidase 4 (GPX4), malondialdehyde (MDA) concentration, iron content, mitochondrial morphology, as well as the expression of divalent metal transporter 1 (DMT1) and Nedd4 were assessed after ICH. Furthermore, the impact of Nedd4 overexpression was evaluated through analyses of hematoma area, ferroptosis, and neurobehavioral function. The mechanism underlying Nedd4-mediated degradation of DMT1 was elecidated using immunoprecipitation (IP) after ICH. RESULTS: Upon ICH, the level of DMT1 in the brain increased, but decreased when Nedd4 was overexpressed using Lentivirus, suggesting a negative correlation between Nedd4 and DMT1. Additionally, the degradation of DMT1 was inhibited after ICH. Furthermore, it was found that Nedd4 can interact with and ubiquitinate DMT1 at lysine residues 6, 69, and 277, facilitating the degradation of DMT1. Functional analysis indicated that overexpression of Nedd4 can alleviate ferroptosis and promote recovery following ICH. CONCLUSION: The results demonstrated that ferroptosis occurs via the Nedd4/DMT1 pathway during ICH, suggesting it potential as a valuable target to inhibit ferroptosis for the treatment of ICH.

[Baicalin induces ferroptosis in HepG2 cells by inhibiting ROS-mediated PI3K/Akt/FoxO3a signaling pathway].

This study aims to investigate whether baicalin induces ferroptosis in HepG2 cells and decipher the underlying mechanisms based on network pharmacology and cell experiments. HepG2 cells were cultured in vitro and the cell viability was detected by the cell counting kit-8(CCK-8). The transcriptome data of hepatocellular carcinoma were obtained from the Cancer Genome Atlas(TCGA), and the ferroptosis gene data from FerrDb V2. The DEG2 package was used to screen the differentially expressed genes(DEGs), and the common genes between DEGs and ferroptosis genes were selected as the target genes that mediate ferroptosis to regulate hepatocellular carcinoma progression. The functions and structures of the target genes were analyzed by Gene Ontology(GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment with the thresholds of P<0.05 and |log_2(fold change)|>0.5. DCFH-DA probe was used to detect the changes in the levels of cellular reactive oxygen species(ROS) in each group. The reduced glutathione(GSH) assay kit was used to measure the cellular GSH level, and Fe~(2+) assay kit to determine the Fe~(2+) level. Real-time quantitative PCR(RT-PCR) was employed to measure the mRNA levels of glutathione peroxidase 4(GPX4) and solute carrier family 7 member 11(SLC7A11) in each group. Western blot was employed to determine the protein levels of GPX4, SLC7A11, phosphatidylinositol 3-kinase(PI3K), p-PI3K, protein kinase B(Akt), p-Akt, forkhead box protein O3a(FoxO3a), and p-FoxO3a in each group. The results showed that treatment with 200 µmol·L~(-1) baicalin for 48 h significantly inhibited the viability of HepG2 cells. Ferroptosis in hepatocellular carcinoma could be regulated via the PI3K/Akt signaling pathway. The cell experiments showed that baicalin down-regulated the expression of SLC7A11 and GPX4, lowered the GSH level, and increased ROS accumulation and Fe~(2+) production in HepG2 cells. However, ferrostatin-1, an ferroptosis inhibitor, reduced baicalin-induced ROS accumulation, up-regulated the expression of SLC7A11 and GPX4, elevated the GSH level, and decreased PI3K, Akt, and FoxO3a phosphorylation. In summary, baicalin can induce ferroptosis in HepG2 cells by inhibiting the ROS-mediated PI3K/Akt/FoxO3a pathway.

Ferroptosis in organ fibrosis: From mechanisms to therapeutic medicines.

Fibrosis occurs in many organs, and its sustained progress can lead to organ destruction and malfunction. Although numerous studies on organ fibrosis have been carried out, its underlying mechanism is largely unknown, and no ideal treatment is currently available. Ferroptosis is an iron-dependent process of programmed cell death that is characterized by lipid peroxidation. In the past decade, a growing body of evidence demonstrated the association between ferroptosis and fibrotic diseases, while targeting ferroptosis may serve as a potential therapeutic strategy. This review highlights recent advances in the crosstalk between ferroptosis and organ fibrosis, and discusses ferroptosis-targeted therapeutic approaches against fibrosis that are currently being explored.

Intravenous immunoglobulin protects the integrity of the intestinal epithelial barrier and inhibits ferroptosis induced by radiation exposure by activating the mTOR pathway.

Radiation exposure often leads to serious health problems in humans. The intestinal epithelium is sensitive to radiation damage, and radiation causes destruction of the intestinal epithelial barrier, which leads to radiation enteritis (RE), the loss of fluids, and the translocation of intestinal bacteria and toxins; radiation can even threaten survival. In this study, we aimed to explore the influence of IVIg on the integrity of the intestinal epithelial barrier after RE. Using a RE mouse model, we investigated the protective effects of intravenous immunoglobulin (IVIg) on the epithelial junctions of RE mice and validated these findings with intestinal organoids cultured in vitro. In addition, transmission electron microscopy (TEM), western blotting (WB) and immunostaining were used to further investigate changes in intestinal epithelial ferroptosis and related signaling pathways. When RE occurs, the intestinal epithelial barrier is severely damaged. IVIg treatment significantly ameliorated this damage to epithelial tight junctions both in vivo and in vitro. Notably, IVIg alleviated RE by inhibiting intestinal epithelial ferroptosis in RE mice. Mechanistically, IVIg promoted activation of the mTOR pathway and inhibited ferroptosis in the intestinal epithelium of mice. Rapamycin, which is a potent inhibitor of the mTOR protein, significantly abolished the protective effect of IVIg against radiation-induced damage to intestinal epithelial tight junctions. Overall, IVIg can prevent RE-induced damage to the intestinal epithelial barrier and inhibit ferroptosis by activating the mTOR pathway; this study provides a new treatment strategy for patients with RE caused by radiotherapy or accidental nuclear exposure.