Multi-omics and single cell characterization of cancer immunosenescence landscape.

Cellular senescence (CS) is closely related to tumor progression. However, the studies about CS genes across human cancers have not explored the relationship between cancer senescence signature and telomere length. Additionally, single-cell analyses have not revealed the evolutionary trends of malignant cells and immune cells at the CS level. We defined a CS-associated signature, called "senescence signature", and found that patients with higher senescence signature had worse prognosis. Higher senescence signature was related to older age, higher genomic instability, longer telomeres, increased lymphocytic infiltration, higher pro-tumor immune infiltrates (Treg cells and MDSCs), and could predict responses to immune checkpoint inhibitor therapy. Single-cell analysis further reveals malignant cells and immune cells share a consistent evolutionary trend at the CS level. MAPK signaling pathway and apoptotic processes may play a key role in CS, and senescence signature may effectively predict sensitivity of MEK1/2 inhibitors, ERK1/2 inhibitors and BCL-2 family inhibitors. We also developed a new CS prediction model of cancer survival and established a portal website to apply this model ( https://bio-pub.shinyapps.io/cs_nomo/ ).

Preparation and functional properties of rice bran globulin-chitooligosaccharide-quercetin-resveratrol covalent complex.

BACKGROUND: As the major protein (approximately 36%) in rice bran, globulin exhibits excellent foaming and emulsifying properties, endowing its useful application as a foaming and emulsifying agent in the food industry. However, the low water solubility restricts its commercial potential in industrial applications. The present study aimed to improve this protein's processing and functional properties. RESULTS: A novel covalent complex was fabricated by a combination of the Maillard reaction and alkaline oxidation using rice bran globulin (RBG), chitooligosaccharide (C), quercetin (Que) and resveratrol (Res). The Maillard reaction improved the solubility, emulsifying and foaming properties of RBG. The resultant glycosylated protein was covalently bonded with quercetin and resveratrol to form a (RBG-C)-Que-Res complex. (RBG-C)-Que-Res exhibited higher thermal stability and antioxidant ability than the native protein, binary globulin-chitooligosaccharide or ternary globulin-chitooligosaccharide-polyphenol (only containing quercetin or resveratrol) conjugates. (RBG-C)-Que-Res exerted better cytoprotection against the generation of malondialdehyde and reactive oxygen species in HepG2 cells, which was associated with increased activities of antioxidative enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) through upregulated genes SOD1, CAT, GPX1 (i.e. gene for glutathione peroxidase-1), GCLM (i.e. gene for glutamate cysteine ligase modifier subunit), SLC1A11 (i.e. gene for solute carrier family 7, member 11) and SRXN1 (i.e. gene for sulfiredoxin-1). The anti-apoptotic effect of (RBG-C)-Que-Res was confirmed by the downregulation of caspase-3 and p53 and the upregulation of B-cell lymphoma-2 gene expression. CONCLUSION: The present study highlights the potential of (RBG-C)-Que-Res conjugates as functional ingredients in healthy foods. © 2024 Society of Chemical Industry.

Association with the plasma atherogenic index with hepatic steatosis and fibrosis in the US population.

Plasma atherogenic index (AIP) reflects a novel intricate biochemical indicator of lipids' metabolism. The involvement of lipid metabolism for pathogenesis concerning nonalcoholic fatty liver disease (NAFLD) has been established. However, the precise association across AIP and hepatic steatosis and fibrosis remains unclear. This present investigation explored the potential correlation across AIP, hepatic steatosis and fibrosis. Data were acquired through National Health and Nutrition Examination Survey (NHANES) from 2017 to 2020. Hepatic steatosis was detected through the controlled attenuation parameter (CAP), while hepatic fibrosis was examined via liver stiffness measurement (LSM). The study employed multiple linear, Fitted smoothed curves and subgroup analyses were used for investigating relationships between the AIP, CAP, and LSM. The study recruited 6239 participants. In multivariate linear regression analysis, findings indicated a remarkable correlation between AIP and exacerbated NAFLD risk [odds ratio (95% confidence interval), 1.17 (1.12, 1.21)]. Analysis further revealed a positive link across AIP and hepatic steatosis, as indicated through the CAP [ß (95% CI), 4.07 (3.32, 4.82)]. Tests for non-linearity, revealed a non-linear correlation between AIP and CAP (inflection point = 0.22). Subgroup analyses assessed the consistency of the link across AIP and CAP, indicating that the association remained comparable across all subgroups. Following the adjustment for all relevant variables, the linear regression analysis revealed a lack of statistical significance across the AIP and hepatic fibrosis. [LSM, ß (95% CI), -0.39 (-1.06, 0.28), P = .2501]. Smooth-fitting curves examined the link across AIP and LSM and showed a U-shaped pattern, indicating their positive correlation with AIP less than 0.48. However, no significant correlation was observed with AIP more than 0.48. This study highlighted a substantial positive relationship across AIP and hepatic steatosis, as measured through CAP, and suggests that it may be used as an efficient and rapid measure for clinical prediction of hepatic steatosis.

Novel insights into the ecDNA formation mechanism involving MSH3 in methotrexate­resistant human colorectal cancer cells.

Extrachromosomal DNAs (ecDNAs), also known as double minutes (DMs), can induce a fast increase in gene copy numbers and promote the development of cancer, including drug resistance. MutS homolog 3 (MSH3), a key protein in mismatch repair, has been indicated to participate in the regulation of DNA double­strand break (DSB) repair, which has been reported to be associated with the formation of ecDNAs. However, it remains unclear whether MSH3 can influence drug resistance via ecDNAs in cancer. In the present study, high MSH3 expression was observed in methotrexate (MTX)­resistant HT29 cells [DM­ and homogeneously staining region (HSR)­containing cells] compared with parental HT29 cells. Additionally, decreased amounts of ecDNAs, HSRs and amplified genes locating on ecDNAs and HSRs were detected following depletion of MSH3 and this could be reversed by overexpressing MSH3 in DM­containing cells. No corresponding changes were found in HSR­containing cells. The present study further verified the involvement of MSH3­regulated DNA DSB repair pathways in the formation of ecDNAs by detecting the expression of core proteins and pathway activity. Furthermore, expulsion of ecDNAs/HSRs was detected and increased frequencies of micronuclei/nuclear buds with dihydrofolate reductase (DHFR) signals were observed in MSH3­depleted DM­containing cells. Finally, changes in MSH3 expression could affect DHFR amplification­derived DHFR expression and cell sensitivity to MTX, suggesting that MSH3 may influence cancer drug resistance by altering the amount of ecDNAs. In conclusion, the present study revealed a novel mechanism involving MSH3 in the regulation of ecDNAs by DSB repair, which will have clinical value in the treatment of ecDNA­based drug resistance in cancer.

Mitochondrial transplantation ameliorates doxorubicin-induced cardiac dysfunction via activating glutamine metabolism.

Doxorubicin is a wildly used effective anticancer agent. However, doxorubicin use is also related to cardiotoxic side effect in some patients. Mitochondrial damage has been shown to be one of the pathogeneses of doxorubicin-induced myocardial injury. In this study, we demonstrated that mitochondrial transplantation could inhibit doxorubicin-induced cardiotoxicity by directly supplying functional mitochondria. Mitochondrial transplantation improved contractile function and respiratory capacity, reduced cellular apoptosis and oxidative stress in cardiomyocytes. Mitochondria isolated from various sources, including mouse hearts, mouse and human arterial blood, and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), all exerted similar cardioprotective effects. Mechanically, mitochondrial transplantation activates glutamine metabolism in doxorubicin-treated mice heart and blocking glutamine metabolism attenuated the cardioprotective effects of mitochondrial transplantation. Overall, our study demonstrates that mitochondria isolated from arterial blood could be used for mitochondrial transplantation, which might serve as a feasible promising therapeutic option for patients with doxorubicin-induced cardiotoxicity.

Galangin alleviated myocardial ischemia-reperfusion injury by enhancing autophagic flux and inhibiting inflammation.

Autophagy is critically involved in myocardial ischemia-reperfusion (I/R). Autophagy inhibition exacerbates myocardial I/R injury. Few effective agents target autophagy to prevent myocardial I/R injury. Effective drugs that promote autophagy in myocardial I/R warrant further investigation. Galangin (Gal) enhances autophagy and alleviates I/R injury. Here we conducted both in vivo and in vitro experiments to observe the changes in autophagy after galangin treatment and investigated the cardioprotective effects of galangin on myocardial I/R. METHODS: After 45-min occlusion of the left anterior descending coronary artery, myocardial I/R was induced by slipknot release. One day before surgery and immediately after surgery, the mice were injected intraperitoneally with the same volume of saline or Gal. The effects of Gal were evaluated using echocardiography, 2,3,5-triphenyltetrazolium chloride staining (TTC staining), western blotting, and transmission electron microscopy. Primary cardiomyocytes and bone marrow-derived macrophages were extracted in vitro to measure the cardioprotective effects of Gal. RESULTS: Compared with the saline-treated group, Gal significantly improved cardiac function and limited infarct enlargement after myocardial I/R. In vivo and in vitro studies demonstrated that Gal treatment promoted autophagy during myocardial I/R. The anti-inflammatory effects of Gal were validated in bone marrow-derived macrophages. These results strongly suggest that Gal treatment can attenuate myocardial I/R injury. CONCLUSION: Our data demonstrated that Gal could improve left ventricular ejection fraction and reduce infarct size after myocardial I/R by promoting autophagy and inhibiting inflammation.

Intravenous Transplantation of an Ischemic-specific Peptide-TPP-mitochondrial Compound Alleviates Myocardial Ischemic Reperfusion Injury.

It is known that mitochondrial dysfunction is a critical factor involved in myocardial ischemia-reperfusion injury. Mitochondrial transplantation has been suggested as an effective therapeutic strategy to protect against myocardial ischemia-reperfusion injury. However, its clinical translation remains limited because it requires the local injection of mitochondria into the myocardium. Here, a polypeptide, CSTSMLKAC (PEP), bound to triphenylphosphonium cations (TPP+) effectively binds mitochondria to form a PEP-TPP-mitochondrial compound. Further investigation of this compound has revealed that the ischemia-sensing properties of PEP promote its translocation into the ischemic myocardium. Additionally, the targeting peptide, PEP, readily dissociates from the PEP-TPP-mitochondrial compound, allowing for the transplanted mitochondria to be efficiently internalized by cardiomyocytes or transferred to cardiomyocytes by endothelial cells. Mitochondrial transplantation promotes cardiomyocyte energetics and mechanical contraction, subsequently reducing cellular apoptosis, macrophage infiltration, and the pro-inflammatory response, all of which lead to attenuation of ischemia-reperfusion injury. Thus, this study provides promising evidence that the PEP-TPP-mitochondrial compound effectively promotes intravenous mitochondrial transplantation into the ischemic myocardium and subsequently ameliorates myocardial ischemia-reperfusion injury.

Investigation of the Effects of Large Bone Flap Craniotomy on Cerebral Hemodynamics, Intracranial Infection Rate, and Nerve Function in Patients with Severe Craniocerebral Trauma.

In order to explore the clinical value of large bone flap craniotomy, the effects of standard large bone flap craniotomy on cerebral hemodynamic indexes, incidence of postoperative intracranial infection, and neurological function in patients with severe craniocerebral trauma are investigated. 89 patients with severe craniocerebral trauma admitted from January 2020 to June 2021 are analyzed retrospectively. All patients are divided into a large craniotomy group (n = 45) and control group (n = 44) according to different surgical methods. The large craniotomy group is treated with large craniotomy decompression, and the control group is treated with traditional craniotomy decompression. The incidence of intracranial infection in each group is recorded, and NIHSS is applied to observe the neurological function recovery of 2 groups before and 1 month after operation. Besides, the patients are followed up after surgery and the Kaplan-Meier survival curve is obtained to compare the survival rate of patients in the two groups. It is clearly evident that the two surgical methods have certain clinical efficacy in the treatment of patients with severe craniocerebral trauma. Comparatively, the large craniotomy can further improve brain blood supply and improve neurological function recovery. Also, it can obtain low incidence of postoperative adverse reactions and intracranial infection.

CRL4DCAF8 dependent opposing stability control over the chromatin remodeler LSH orchestrates epigenetic dynamics in ferroptosis.

Despite the emerging evidence on ferroptosis implicated in diverse pathologies, molecular linkage between oxidative inducers and chromatin as epigenetic memory carrier for its propagation remains elusive. Here, we report the identification of two WD40 proteins DCAF8 and WDR76 as substrate adapter and molecular inhibitor respectively of the Cullin-4 RING ubiquitin ligase (CRL4) system for stability control of chromatin remodeler LSH. Degradation analysis and CRL4-DCAF8 complex reconstitution demonstrate that CRL4DCAF8 is a bona fide E3 ligase for LSH. In contrast, WDR76 antagonizes DCAF8-targeted LSH proteolysis through competitive inhibition of the holo-CRL4DCAF8-LSH complex assembly. Importantly, this opposing regulatory strategy is utilized in lipid hydroperoxide induced ferroptosis, where we identify key redox homeostasis genes significantly regulated by the DCAF8/WDR76/LSH axis through transcriptomic epistasis analysis. This regulation is mechanistically attributed to DNA hydroxymethylation fostered WDR76 interaction with LSH and increased ratio of DCAF8 to WDR76 for antagonistic LSH association accompanying decreased DNA oxidation along with ROS overproduction. Evaluation of epigenetic dynamics at ferroptosis gene promoters reveals linker histone H1- and LSH-associated transcriptional repression is coordinately removed upon lipid peroxidation stress. Together with the phenotypes driven by WDR76 and DCAF8 manipulations, these data identify DCAF8- and WDR76-adapted oxidative damage sensing through DNA hydroxymethylation for LSH degradation control as a crucial nexus in epigenetic regulation of ferroptosis.

EZH2 reduction is an essential mechanoresponse for the maintenance of super-enhancer polarization against compressive stress in human periodontal ligament stem cells.

Despite the ubiquitous mechanical cues at both spatial and temporal dimensions, cell identities and functions are largely immune to the everchanging mechanical stimuli. To understand the molecular basis of this epigenetic stability, we interrogated compressive force-elicited transcriptomic changes in mesenchymal stem cells purified from human periodontal ligament (PDLSCs), and identified H3K27me3 and E2F signatures populated within upregulated and weakly downregulated genes, respectively. Consistently, expressions of several E2F family transcription factors and EZH2, as core methyltransferase for H3K27me3, decreased in response to mechanical stress, which were attributed to force-induced redistribution of RB from nucleoplasm to lamina. Importantly, although epigenomic analysis on H3K27me3 landscape only demonstrated correlating changes at one group of mechanoresponsive genes, we observed a genome-wide destabilization of super-enhancers along with aberrant EZH2 retention. These super-enhancers were tightly bounded by H3K27me3 domain on one side and exhibited attenuating H3K27ac deposition and flattening H3K27ac peaks along with compensated EZH2 expression after force exposure, analogous to increased H3K27ac entropy or decreased H3K27ac polarization. Interference of force-induced EZH2 reduction could drive actin filaments dependent spatial overlap between EZH2 and super-enhancers and functionally compromise the multipotency of PDLSC following mechanical stress. These findings together unveil a specific contribution of EZH2 reduction for the maintenance of super-enhancer stability and cell identity in mechanoresponse.

CRL4DCAF8 and USP11 oppositely regulate the stability of myeloid leukemia factors (MLFs).

Myeloid leukemia factors (MLF1 and MLF2) are proteins associated with leukemia and several other cancers. However, little is known about the regulatory mechanisms underlying the stability of these proteins. Here, we show that DDB1 and CUL4 associated factor 8 (DCAF8), which can form a functional E3 ligase complex (CRL4DCAF8), has a strong interaction with the MLF2 protein. DCAF8 could promote MLF2 degradation through the ubiquitin-proteasome pathway. In contrast, ubiquitin specific peptidase 11 (USP11) associates with MLF2, thereby increasing its stability. Since MLF1 is highly related to MLF2, we demonstrated that MLF1 also interacts with DCAF8 and USP11, suggesting that CRL4DCAF8 and USP11 may also regulate the expression of MLF1. TCGA analysis revealed that both the myeloid leukemia factors (MLF1 and MLF2) show significant differential expression in various tumors. The results of our study indicate that CRL4DCAF8 and USP11 play opposite roles in the regulation of MLF1 and MLF2, which may, in turn, affect their biological functions in various cancers.

Relationship between body mass index and outcomes of coronary artery disease in Asian population: Insight from the FOCUS registry.

BACKGROUND: Obesity is often considered as a risk factor of cardiovascular events, but recent researches showed conflicting results regarding to the effect of body weight on prognosis of coronary artery disease (CAD). This study aimed to evaluate the relationship between body mass index (BMI) and clinical outcomes of CAD in Asian population. METHODS: A total of 4315 patients from the FOCUS registry were enrolled into this analysis. Patients were divided into 4 groups according to BMI: lean group (BMI<18.5 kg/m2), normal group (BMI 18.5-24.9 kg/m2), overweight group (BMI 25-30 kg/m2) and obesity group (BMI>30 kg/m2). Follow-up was continued to 3 years to evaluate clinical outcomes, and the primary endpoint was a composite of all-cause death and myocardial infarction (MI). RESULTS: Patients with higher BMI were more likely to be associated with cardiovascular risk factors like hypertension, hypercholesterolemia and diabetes, but not smoking. At the end of the follow-up period, however, the incidence of a composite endpoint of all-cause death and MI was significantly lower in the higher BMI (overweight and obese) subsets, as compared with the lower BMI group (5.2% vs. 8.0%, p < 0.001). So did the cumulative rates of all-cause death (p < 0.001), cardiovascular death (p < 0.001), and a combined endpoint of cardiovascular death and MI (p = 0.001). CONCLUSIONS: In Asian patients with CAD, an inverse association between BMI and long-term prognosis was observed. Although overweight or obese patients were associated with more metabolism-associated comorbidities, they had significantly lower adverse events at 3-year follow up after percutaneous coronary intervention.

Gender-Related Differences in Clinical Characteristics and Outcomes of Premature Coronary Artery Disease: Insight from the FOCUS Registry.

INTRODUCTION: Although coronary artery disease (CAD) presentations and clinical outcomes differ by sex, little is known about premature CAD (PCAD). The present analysis aimed to evaluate the gender-related differences of PCAD in an Asian population from the FOCUS registry. METHODS: A total of 1397 Asian young patients with angiographically confirmed CAD undergoing drug-eluting stent implantation were included in this analysis and divided into two groups according to the genders. Patients were followed up for three years and clinical outcomes were compared between groups. RESULTS: Young women were older and more likely to have hypertension and diabetes than men (all p<0.001). In contrast, males with PCAD had higher BMI and higher prevalence of current smoking as well as previous vessel revascularizations (all p<0.05). Men were more likely to be manifested as total occlusive lesions (p<0.001). Regardless of the clinical characteristics, the cumulative incidences of adverse events such as major adverse cardiovascular event (MACE), cardiovascular death, and all-cause death were not significantly different at one- or three-year follow-up (all p>0.05). CONCLUSION: Despite remarkable differences in clinical characteristics between Asian males and females with PCAD, the two groups did not differ significantly in clinical outcomes.

Activation of NMDA receptors mediated iron accumulation via modulating iron transporters in Parkinson's disease.

Increasing evidence has confirmed that nigral iron accumulation and activation of NMDA receptors (NRs) contribute to the neurodegeneration of dopamine (DA) neurons in Parkinson's disease (PD). Earlier work indicated that activation of NRs participated in iron metabolism in the hippocampus. However, the relationship between activation of NRs and iron accumulation in DA neurons of the substantia nigra in PD was unknown. In this study, our results showed that NRs inhibitors MK-801 and AP5 protected nigrostriatal projection system and reduced nigral iron levels of 6-hydroxydopamine (6-OHDA)-induced PD rats. In vitro studies demonstrated that NMDA treatment increased the expression of iron importer divalent metal transporter 1 (DMT1) and decreased the expression of iron exporter ferropotin 1 (Fpn1), which were dependent on iron regulatory protein 1 (IRP1). This led to increased intracellular iron levels and intensified the decrease in mitochondrial transmembrane potential in MES23.5 dopaminergic neurons. In addition, we reported that MK801 and neuronal nitric oxide synthase inhibitor could antagonize 6-OHDA-induced up-regulation of IRP1 and DMT1 and down-regulation of Fpn1, thus attenuating 6-OHDA-induced iron accumulation in MES23.5 cells. This suggested that 6-OHDA-induced activation of NRs might modulate the expression of DMT1 and Fpn1 via the neuronal nitric oxide synthase-IRP1 pathway.-Xu, H., Liu, X., Xia, J., Yu, T., Qu, Y., Jiang, H., Xie, J., Activation of NMDA receptors mediated iron accumulation via modulating iron transporters in Parkinson's disease.