Ferroptosis is an atypical form of regulated cell death, which is different from apoptosis, necrosis, pyroptosis, and autophagy. Ferroptosis is characterized by iron-dependent oxidative destruction ...of cellular membranes following the antioxidant system’s failure. The sensitivity of ferroptosis is tightly regulated by a series of biological processes, the metabolism of iron, amino acids, and polyunsaturated fatty acids, and the interaction of glutathione (GSH), NADPH, coenzyme Q10 (CoQ10), and phospholipids. Elevated oxidative stress (ROS) level is a hallmark of cancer, and ferroptosis serves as a link between nutrition metabolism and redox biology. Targeting ferroptosis may be an effective and selective way for cancer therapy. The underlying molecular mechanism of ferroptosis occurrence is still not enough. This review will briefly summarize the process of ferroptosis and introduce critical molecules in the ferroptotic cascade. Furthermore, we reviewed the occurrence and regulation of reduction-oxidation (redox) for ferroptosis in cancer metabolism. The role of the tumor suppressor and the epigenetic regulator in tumor cell ferroptosis will also be described. Finally, old drugs that can be repurposed to induce ferroptosis will be characterized, aiming for drug repurposing and novel drug combinations for cancer therapy more efficiently and economically.
Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of heart failure cases. The molecular mechanisms by which HFpEF leads to impaired diastolic function of the heart ...have not been clarified, nor have the drugs that target the clinical symptoms of HFpEF patients.
HFpEF chip data (GSE180065) was downloaded from the National Center for Biotechnology Information (NCBI) database. Differentially expressed genes (DEGs) were filtered by the limma package in R and processed for GO and KEGG pathway analyses. Then, ferroptosis-related genes in HFpEF were identified by taking the intersection between DEGs and ferroptosis-related genes. CytoHubba and MCODE were used to screen ferroptosis-related hub DEGs in the protein-protein interaction (PPI) network. Establishment of a mouse HFpEF model to validate the transcript levels of ferroptosis-related hub DEGs and ferroptosis-related phenotypes. Transcript levels of ferroptosis-related hub DEGs and HFpEF phenotypic changes in the hearts of HFpEF mice were further examined after the use of ferroptosis inhibitors.
GO and KEGG enrichment analyses suggested that the DEGs in HFpEF were significantly enriched in ferroptosis-related pathways. A total of 24 ferroptosis-related DEGs were identified between the ferroptosis gene dataset and the DEGs. The established PPI network was further analyzed by CytoHubba and MCODE modules, and 11 ferroptosis-related hub DEGs in HFpEF were obtained. In animal experiments, HFpEF mice showed significant abnormal activation of ferroptosis. The expression trends of the 11 hub DEGs associated with ferroptosis, except for Cdh1, were consistent with the results of the bioinformatics analysis. Inhibition of ferroptosis alters the transcript levels of 11 ferroptosis-related hub DEGs and ameliorates HFpEF phenotypes.
The present study contributes to a deeper understanding of the specific mechanisms by which ferroptosis is involved in the development of HFpEF and suggests that inhibition of ferroptosis may mitigate the progression of HFpEF. In addition, eleven hub genes were recognized as potential drug binding targets.
Discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase family, and its ligand is collagen. Previous studies demonstrated that DDR1 is highly expressed in many tumors. However, ...its role in hepatocellular carcinoma (HCC) remains obscure. In this study, we found that DDR1 was upregulated in HCC tissues, and the expression of DDR1 in TNM stage II-IV was higher than that in TNM stage I in HCC tissues, and high DDR1 expression was associated with poor prognosis. Gene expression analysis showed that DDR1 target genes were functionally involved in HCC metastasis. DDR1 positively regulated the migration and invasion of HCC cells and promoted lung metastasis. Human Phospho-Kinase Array showed that DDR1 activated ERK/MAPK signaling pathway. Mechanically, DDR1 interacted with ARF6 and activated ARF6 through recruiting PSD4. The kinase activity of DDR1 was required for ARF6 activation and its role in metastasis. High expression of PSD4 was associated with poor prognosis in HCC. In summary, our findings indicate that DDR1 promotes HCC metastasis through collagen induced DDR1 signaling mediated PSD4/ARF6 signaling, suggesting that DDR1 and ARF6 may serve as novel prognostic biomarkers and therapeutic targets for metastatic HCC.
Globally, cardiovascular diseases are the leading cause of death. Research has focused on the metabolism of carbohydrates, fatty acids, and amino acids to improve the prognosis of cardiovascular ...diseases. There are three types of branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) required for protein homeostasis, energy balance, and signaling pathways. Increasing evidence has implicated BCAAs in the pathogenesis of multiple cardiovascular diseases. This review summarizes the biological origin, signal transduction pathways and function of BCAAs as well as their significance in cardiovascular diseases, including myocardial hypertrophy, heart failure, coronary artery disease, diabetic cardiomyopathy, dilated cardiomyopathy, arrhythmia and hypertension.
The vast majority of volatile organic compounds (VOCs) are of biological origin and do not affect human health, while some VOCs or their oxidation products can damage the respiratory system, nervous ...system, digestive system and blood system after long-term inhalation by humans. There is limited evidence regarding the association of VOCs exposure with childhood asthma. In this study, we examined the associations between metabolites of VOCs (mVOCs) in urine and childhood asthma. We included a total of 1542 children aged 3–12 years who had information on urinary mVOCs, asthma and essential covariates in the current analyses. After controlling for covariates, we used logistic regression to assess the association between urinary mVOCs and childhood asthma. Then, we examined effect measure modification by child age, gender, race/ethnicity and serum cotinine. 2-Methylhippuric acid (xylene metabolites) (OR: 1.14; 95 % CI: 0.87, 1.59), N-acetyl-S-(benzyl)-l-cysteine (toluene metabolites) (OR: 1.15 95 % CI: 0.76, 1.71), N-acetyl-S-(2-carboxyethyl)-l-cysteine (acrolein metabolites) (OR: 1.09; 95 % CI: 0.61, 1.75), N-acetyl-S-(3-hydroxypropyl)-l-cysteine (acrolein metabolites) (OR: 1.10; 95 % CI: 0.66, 1.80), and N-acetyl-S-(3-hydroxypropyl-1-methyl)-l-cysteine (crotonaldehyde metabolites) (OR: 1.18; 95 % CI: 0.68, 2.01) were weakly associated with the prevalence of asthma in children. Among female children, 2MHA (2-methylhippuric acid) in urine was significantly associated with the prevalence of asthma (OR: 1.81 95 % CI: 1.07, 3.05). At the same time, BMA (N-acetyl-S-(benzyl)-l-cysteine) was significantly associated with the prevalence of asthma in non-Hispanic White (OR:2.09 95 % CI: 0.91, 4.66) and Black (OR:1.90 95 % CI: 0.96, 3.71) children. We found that gender modified the associations between urinary 2MHA and the odds of asthma (interaction term p value = 0.03). Therefore, exposure to VOCs and the development of childhood asthma remains controversial, and the interpretation of these results needs to be treated with caution and should be confirmed in future studies.Therefore, exposure to VOCs and the development of childhood asthma remains controversial, and the interpretation of these results needs to be treated with caution and should be confirmed in future studies.
Understanding the phenotypic heterogeneity of antibiotic‐resistant bacteria following treatment and the transitions between different phenotypes is crucial for developing effective infection control ...strategies. The study expands upon previous work by explicating chloramphenicol‐induced phenotypic heterogeneities in growth rate, gene expression, and morphology of resistant Escherichia coli using time‐lapse microscopy. Correlating the bacterial growth rate and cspC expression, four interchangeable phenotypic subpopulations across varying antibiotic concentrations are identified, surpassing the previously described growth rate bistability. Notably, bacterial cells exhibiting either fast or slow growth rates can concurrently harbor subpopulations characterized by high and low gene expression levels, respectively. To elucidate the mechanisms behind this enhanced heterogeneity, a concise gene expression network model is proposed and the biological significance of the four phenotypes is further explored. Additionally, by employing Hidden Markov Model fitting and integrating the non‐equilibrium landscape and flux theory, the real‐time data encompassing diverse bacterial traits are analyzed. This approach reveals dynamic changes and switching kinetics in different cell fates, facilitating the quantification of observable behaviors and the non‐equilibrium dynamics and thermodynamics at play. The results highlight the multi‐dimensional heterogeneous behaviors of antibiotic‐resistant bacteria under antibiotic stress, providing new insights into the compromised antibiotic efficacy, microbial response, and associated evolution processes.
This study explores dynamic phenotypic heterogeneity in antibiotic‐resistant bacteria under chloramphenicol treatment. By dissecting and integrating the heterogeneity in growth rates, gene expressions, and morphologies, novel cell fates are uncovered, and the underlying mechanisms are elucidated using a gene expression network model. Moreover, the quantitative analysis provides valuable insights into the dynamics and thermodynamics of the antibiotic‐resistant bacteria under chloramphenicol treatment.
Hypoxia is an important feature of the tumor microenvironment(TME) and is closely associated with cancer metastasis, immune evasion, and drug resistance. However, the precise role of hypoxia in ...hepatocellular carcinoma(HCC), as well as its influence on the TME, and drug sensitivity remains unclear. We found the excellent survival prediction value of Hypoxia_DEGs_Score model. In hypoxic HCC, somatic mutation, copy number variation, and DNA methylation were closely related to hypoxic changes and affected tumorigenesis, progression, metastasis, and drug resistance. In HCC, aggravated hypoxic stress was found to be accompanied by an immune exclusion phenotype and increased infiltration of immunosuppressive cells. In the validation cohort, patients with high Hypoxia_DEGs_Score were found to have worse immunotherapeutic outcomes and prognoses, and may benefit from drugs against cell cycle signaling pathways rather than those inhibiting the PI3K/mTOR pathway. Hypoxia_DEGs_Score has an excellent predictive capability of changes in the TME, the efficacy of immunotherapy, and the response of drugs. Therefore, Hypoxia_DEGs_Score can help develop personalized immunotherapy regimens and improve the prognosis of HCC patients.
Purpose
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world with a high mortality rate. Receptor tyrosine kinases play important roles in the occurrence and development of ...various cancers. Discoid protein domain receptor 1 (DDR1) is a special type of transmembrane receptor tyrosine kinase. Here, we show that the expression of DDR1 is significantly increased in HCC and is related to a poor clinical prognosis.
Methods
The expression of DDR1 in HCC cell lines and primary HCC specimens was evaluated using Western blotting and immunohistochemistry. A correlation between DDR1 and SLC1A5 expression was also investigated in primary HCC specimens. Cell proliferation was evaluated using in vitro CCK8 and colony formation assays. Gene knock-down and overexpression assays, CHX, NH
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CL and Mg132 interference tests and immunoprecipitation, as well as nude mouse xenograft models were used to assess the mechanism by which DDR1 promotes tumorigenesis in vitro and in vivo.
Results
We found that DDR1 promotes the proliferation of HCC cells and accelerates the growth of HCC tumor xenografts, while DDR1 downregulation had the opposite effect. We also found that loss or gain of DDR1 expression affected HCC cell cycle progression. Mechanistically, we found that DDR1 interacts with SLC1A5, which belongs to the solute carrier (SLC) family of transporters, and regulates its stability, thereby affecting the mTORC1 signaling pathway. In addition, we found that SLC1A5 regulation by DDR1 can be restored by lysosome inhibitors. We also found that DDR1 is highly expressed in HCC tissues and that increased DDR1 expression predicts a shorter overall survival (OS) time. We additionally found that the expression of SLC1A5 was positively correlated with that of DDR1. Together, our data indicate that DDR1 acts as a tumor-promoting factor that can control HCC cell proliferation and cell cycle progression by stabilizing SLC1A5 in a lysosome-dependent way.
Conclusions
Our study reveals a new mechanism by which DDR1 plays a liver cancer-promoting role. We also found that DDR1 expression serves as an independent prognostic marker, and that DDR1 and SLC1A5 expression levels are positively correlated in clinical samples. Our findings provide a new perspective for understanding HCC development and offers new targets for the treatment and management of HCC.
Lenvatinib is a standard therapy option for advanced hepatocellular carcinoma (HCC), but resistance limits clinical benefits. In this study, we identified inhibition of ROS levels and reduced redox ...status in Lenvatinib-resistant HCC. Integrating RNA-seq with unbiased whole-genome CRISPR-Cas9 screen analysis indicated LINC01607 regulated the P62 to enhance drug resistance by affecting mitophagy and antioxidant pathways. Underlying mechanisms were investigated both in vitro and in vivo. We initially confirmed that LINC01607, as a competing endogenous RNA (ceRNA) competing with mirRNA-892b, triggered protective mitophagy by upregulating P62, which reduced ROS levels and promoted drug resistance. Furthermore, LINC01607 was proved to resist oxidative stress by regulating the P62-Nrf2 axis, which transcriptionally regulated the expression of LINC01607 to form a positive feedback loop. Finally, silencing LINC01607 combined with Lenvatinib reversed resistance in animal and patient-derived organoid models. In conclusion, we proposed a novel mechanism of Lenvatinib resistance involving ROS homeostasis. This work contributed to understanding redox homeostasis-related drug resistance and provided new therapeutic targets and strategies for HCC patients.
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•Lenvatinib resistance limits clinical efficacy.•The ROS levels in resistant HCC decrease and the antioxidant capacity increases.•LINC01607 promotes drug resistance by enhancing mitophagy.•Nrf2 transcriptionally regulated LINC01607 to form a positive feedback loop.
Although Brain-derived neurotrophic factor (BDNF) has been identified as an orexigenic peptide in zebrafish, its role in regulating feeding behavior in other fish species is still unclear. This study ...aimed to investigate the regulatory role of BDNF in feeding behavior of Siberian sturgeon (Acipenser baerii). The bdnf and its receptor TrkB genes (Abbdnf and AbTrkB) of Siberian sturgeon were cloned and found to be most highly expressed in the hypothalamus. Short- and long-term fasting experiments showed that Abbdnf and AbTrkB mRNA levels decreased in the hypothalamus after fasting, but increased after refeeding, consistent with the pattern observed for anorexigenic peptides. The NGF(nerve growth factor) structural domain has an important role in mediating the binding of BDNF to the TrkB receptor. To explore the feeding regulatory role of BDNF, recombinant AbBDNFNGF protein was expressed using prokaryotic expression system. Intraperitoneal injection of AbBDNFNGF suppressed cumulative food intake at 1 h, 3 h, and 6 h after administration, and resulted in upregulation of anorexigenic peptides (pomc and leptin) mRNA and downregulation of orexigenic peptides (npy and agrp) mRNA in both central and peripheral tissues. Additionally, AbBDNFNGF injection led to activation of TrkB receptors and pi3k-akt-mtor signaling pathway in the hypothalamus. Overall, this study confirms the anorexigenic effect of BDNF in Siberian sturgeon.
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•Gene sequences of Abbdnf and its receptor AbTrkB were obtained from Siberian sturgeon, revealing their high expression in the hypothalamus.•Expression patterns of Abbdnf and AbTrkB mRNA during fasting and re-feeding were consistent with those of an anorexigenic peptide.•A prokaryotic expression system successfully produced a recombinant protein comprising the NGF region of AbBDNF.•AbBDNFNGF administered via intraperitoneal injection effectively suppressed cumulative food intake at 1, 3, and 6 h post-administration.•Intraperitoneal injection of AbBDNFNGF induced changes in mRNA levels for appetite-regulating peptides in both central and peripheral tissues, activating AbTrkB receptors and the PI3K-Akt-mTOR signaling pathway in the hypothalamus.
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