This study aimed to establish a novel quantification system of ferroptosis patterns and comprehensively analyze the relationship between ferroptosis score (FS) and the immune cell infiltration (ICI) ...characterization, tumor mutation burden (TMB), prognosis, and therapeutic sensitivity in left-sided and right-sided colon cancers (LCCs and RCCs, respectively).
We comprehensively evaluated the ferroptosis patterns in 444 LCCs and RCCs based on 59 ferroptosis-related genes (FRGs). The FS was constructed to quantify ferroptosis patterns by using principal component analysis algorithms. Next, the prognostic value and therapeutic sensitivities were evaluated using multiple methods. Finally, we performed weighted gene co-expression network analysis (WGCNA) to identify the key FRGs. The IMvigor210 cohort, TCGA-COAD proteomics cohort, and Immunophenoscores were used to verify the predictive abilities of FS and the key FRGs.
Two ferroptosis clusters were determined. Ferroptosis cluster B demonstrated a high degree of congenital ICI and stromal-related signal enrichment with a poor prognosis. The prognosis, response of targeted inhibitors, and immunotherapy were significantly different between high and low FS groups (HSG and LSG, respectively). HSG was characterized by high TMB and microsatellite instability-high subtype with poor prognosis. Meanwhile, LSG was more likely to benefit from immunotherapy. ALOX5 was identified as a key FRG based on FS. Patients with high protein levels of ALOX5 had poorer prognoses.
This work revealed that the evaluation of ferroptosis subtypes will contribute to gaining insight into the heterogeneity in LCCs and RCCs. The quantification for ferroptosis patterns played a non-negligible role in predicting ICI characterization, prognosis, and individualized immunotherapy strategies.
The associations between obesity and Alzheimer's disease (AD) at different ages have been debated. Recent evidence implied the protective effects of metabolically healthy obesity on AD. We ...hypothesized that obesity and lipids could mitigate the detrimental impacts of AD pathological changes among metabolically healthy individuals in late life. In this study, a total of 604 metabolically healthy participants with normal cognition were included from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database. Multiple linear regression models were used to test the associations of body mass index (BMI) or lipids with cerebrospinal fluid (CSF) biomarkers after adjustment for age, gender, education, and Apolipoprotein E‐ɛ4 (APOE‐ɛ4). The results showed the lower CSF levels of total tau protein (t‐tau: p = .0048) and phosphorylated tau protein (p‐tau: p = .0035) in obese participants than in non‐obese participants, even after correcting for covariates. Moreover in late life, higher BMI was associated with decreased CSF t‐tau (β: −0.15, p = .0145) and p‐tau (β: −0.17, p = .0052). As for lipids, higher levels of total cholesterol (TC) and low‐density lipoprotein cholesterol (LDL‐C) were associated with decreased CSF t‐tau (TC: β: −0.16, p = .0115; LDL‐C: β: −0.16, p = .0082) and p‐tau (TC: β: −0.15, p = .0177; LDL‐C: β: −0.14, p = .0225) in obese participants. Furthermore, these associations were only significant in participants with late‐life obesity and APOE‐ɛ4 non‐carriers. Overall, in a cognitively normal population, we found metabolically healthy obesity and lipids in late life might be protective factors for neurodegenerative changes.
In a metabolically healthy population with normal cognition, we found that obese individuals had lower levels of CSF tau‐related biomarkers than non‐obese individuals in late life, and there were protective associations of TC or LDL‐C with CSF tau‐related biomarkers in the late‐life obese population. These findings provided new evidence that healthy obesity and lipids in late life might be protective factors for neurodegeneration, which may help us to clarify the associations of obesity or lipids with some neurodegenerative diseases.
•Midlife underweight, midlife obesity and late-life underweight increase dementia risk.•Late-life overweight and obesity conferred 21% and 25% reduced dementia risk.•ACD risk in midlife was ...significantly elevated when BMI surpassed 29 kg/m2.•AD risk in midlife was significantly elevated when BMI surpassed 30 kg/m2.•VaD risk in midlife was significantly elevated when BMI surpassed 32 kg/m2.•AD risk in late-life was decreased in the case of BMI cutoff under 27 kg/m2.
Controversies persist about the associations of body mass index (BMI) with risk of cognitive impairment and dementia. This study aimed to evaluate these associations from various aspects, in which Embase, PubMed and Cochrane databases were searched to identify prospective studies up to May 2019. Random-effects meta-analyses and dose-response meta-analysis were conducted, involving twenty-nine of 20,083 identified literatures. Meta-analysis showed that midlife underweight, obesity and late-life underweight conferred 1.39-, 1.31- and 1.64-fold excess risk for cognitive impairment and dementia, while late-life overweight and obesity conferred 21% and 25% reduced risk. In dose-response meta-analysis, all cause dementia (ACD), Alzheimer’s disease (AD) and vascular dementia (VaD) risk in midlife was significantly elevated when BMI surpassed 29, 30 and 32 kg/m2. AD risk in late-life was decreased when BMI was under 27 kg/m2, while this protection for VaD was absent when BMI surpassed 39 kg/m2. Higher BMI produced opposite exerted opposite effects on dementia in mid- and late-age population. Firstly reported, a dose-response relationship further supports the guideline from the standpoint of dementia prevention.
Controllable chemoselectivity and regioselectivity synthesis of 3‐sulfinylated, 3‐sulfenylated and 2‐sulfonylated indoles via direct C−H functionalization are realized under metal‐free conditions. In ...particular, the synthesis of 3‐arylsulfinylindoles in high yields from a sulfone substrate in water without additives is reported. The process displays excellent functional groups compatibility. p‐Toluenesulfonyl cyanide (TsCN) possesses a hexavalent sulfonyl group, as an odorless and easy‐to‐handle solid, which has been used as a new sulfur reagent through the cleavage of S−C and S=O bonds in our work.
Introduction
This study delineated the interrelationships among blood pressure (BP), cerebrospinal fluid (CSF) core biomarkers of Alzheimer's disease (AD), and cognition.
Methods
The linear ...regression analyses were conducted in 1546 non‐demented participants (mean age of 61.58 years, range 40 to 89 years; 40% female; average days of BP measurement, 9.10 days). Mediation analyses with 10,000 bootstrapped iterations were used to explore the mediation effects.
Results
A clear age‐related pattern of BP was delineated. Mid‐life hypertension (especially systolic BP), late‐life lower diastolic BP, as well as mid‐ and late‐life higher pulse pressure were associated with cognitive impairment and tau‐related biomarkers. BP variability was associated only with cognition but not with CSF biomarkers. Overall, the associations between BP and cognition were partially mediated (proportion: 11% to 30%) by tau pathologies, independently of amyloid pathology.
Discussion
Tau pathologies might play important roles in the relationship between BP and cognition, with significant age‐ and BP‐type dependences.
A novel quaternary selenide (Na0.60Ba0.70)Ga2Se4 (1) obtained by a high-temperature method crystallizes in the non-centrosymmetric space group I4cm, and its structure features {GaSe2−}∞ chains. It ...exhibits phase-matchable second-harmonic generation responses with the largest intensity of 0.3 times that of AgGaS2, and its powder sample has a laser-induced damage threshold of ∼2.4 times that of AgGaS2. Discussion about its relationship with other highly related structures are addressed as well. Theoretical calculations are performed to analyze its electronic structure and optical properties.
Abstract Reduction-sensitive micelles were prepared from monomethoxy-poly(ethylene glycol)-S-S-hexadecyl (mPEG-S-S-C16 ), an amphiphilic poly(ethylene glycol) derivative containing a disulfide bond. ...The micelles were then used for the intracellular delivery of the anticancer drug doxorubicin (DOX) into tumor cells, and the cellular uptake mechanisms of the micelles were determined. To serve as a control, monomethoxy-poly(ethylene glycol)-C-C-hexadecyl (mPEG-C-C-C16 ) with an analogous structure but without a disulfide bond was also prepared. The polymer could self-assemble into micelles in an aqueous solution and be loaded with high-content DOX. In vitro release studies revealed that DOX-loaded mPEG-S-S-C16 micelles released DOX faster than DOX-loaded mPEG-C-C-C16 micelles in the presence of dithiothreitol (DTT), but showed similar release rates in the absence of DTT. MTT assay demonstrated significantly enhanced cytotoxicity of DOX-loaded mPEG-S-S-C16 micelles against the human cervical cancer cells (HeLa) compared with DOX-loaded mPEG-C-C-C16 micelles, but there was no significant difference in the cytotoxicity between the two DOX-loaded micelles against the african green monkey SV40-transformed kidney fibroblast cells (COS-7). Confocal laser scanning microscopy observation and flow cytometry analyses indicated that DOX-loaded mPEG-S-S-C16 micelles were efficiently internalized into HeLa cells, released DOX into the cytoplasm, and entered the nuclei. By contrast, in the case of DOX-loaded mPEG-C-C-C16 micelles, little DOX was found in the nuclei. Endocytosis inhibition results proved that both mPEG-S-S-C16 and mPEG-C-C-C16 micelles entered the HeLa cells mainly through the clathrin-mediated endocytosis pathway, and caveolae-mediated endocytosis was involved to a small extent. These results indicated that the different behaviors of cell uptake between reduction-sensitive and -insensitive micelles may occur after the micelles were internalized into the cells, but not during endocytosis, and the potential of this reduction-sensitive polymer for the effective intracellular delivery of anticancer drugs.
Epigallocatechin gallate (EGCG) is associated with various health benefits. In this review, we searched current work about the effects of EGCG and its wound dressings on skin for wound healing. ...Hydrogels, nanoparticles, micro/nanofiber networks and microneedles are the major types of EGCG-containing wound dressings. The beneficial effects of EGCG and its wound dressings at different stages of skin wound healing (hemostasis, inflammation, proliferation and tissue remodeling) were summarized based on the underlying mechanisms of antioxidant, anti-inflammatory, antimicrobial, angiogenesis and antifibrotic properties. This review expatiates on the rationale of using EGCG to promote skin wound healing and prevent scar formation, which provides a future clinical application direction of EGCG.
Many cell death regulators physically or functionally interact with metabolic enzymes. These interactions provide insights into mechanisms of anticancer treatments from the perspective of tumor cell ...metabolism and apoptosis. Recent studies have shown that zinc and p53 not only induce tumor cell apoptosis, but also regulate tumor cell metabolism. However, the underlying mechanism is complex and remains unclear, making further research imperative to provide clues for future cancer treatments. In this study, we found that hexokinase 2 (HK2), which has dual metabolic and apoptotic functions, is downstream of zinc and p53 in both prostate cancer patient tissue and prostate cancer cell lines. Notably, the mitochondrial location of HK2 is crucial for its function. We demonstrate that zinc and p53 disrupt mitochondrial binding of HK2 in prostate cancer cells by phosphorylating VDAC1, which is mediated by protein kinase B (Akt) inhibition and glycogen synthase kinase 3β (GSK3β) activation. In addition, we found that zinc combined with p53 significantly inhibited tumor growth in a prostate cancer cell xenograft model. Therefore, interference of the mitochondrial localization of HK2 by zinc and p53 may provide a new treatment approach for cancer.
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•HK2 expression is positively correlated with p53 in prostate cancer patients.•Zinc cooperates with p53 to increase HK2 expression in prostate cancer cells.•Zinc and p53 enhance GSK3β activation by inhibiting Akt.•GSK3β activation disrupts HK2 binding to VDAC1 by phosphorylating VDAC1.•Disrupting mitochondrial localization of HK2 may be a potential therapeutic target.
Food safety can be seriously threatened by the existence of both aflatoxin M1 (AFM1) and ochratoxin A (OTA) in milk and corresponding products. The importance of intestine integrity in preserving ...human health is widely understood in vitro, but the fundamental processes by which AFM1 and OTA cause disruption of the intestinal barrier are as yet unknown, especially in vivo. Based on the analysis of the whole transcriptome of BALB/c mice, the competing endogenous RNA (ceRNA) regulation network was obtained in the current study. Each of 12 mice were separated into five treatments: saline solution treatment, 1.0% DMSO vehicle control treatment, 3.0 mg/kg b.w. individual AFM1 treatment (AFM1), 3.0 mg/kg b.w. individual OTA treatment (OTA), and combined mycotoxins treatment (AFM1 +OTA). The study period lasted 28 days. The jejunum tissue was collected for the histological assessment and whole transcriptome analysis, and the whole blood was collected, and determination of serum biochemical indicators. The phenotypic results demonstrated that AFM1 and OTA caused intestinal barrier disruption via an increased apoptosis level and decreased expression of tight junction (TJ) proteins. The ceRNA network demonstrated that AFM1 and OTA induced cell apoptosis through activating the expression of DUSP9 and suppressing the expression of PLA2G2D, which were regulated by differentially expressed microRNAs (DEmiRNAs) (miR-124-y, miR-194-z, miR-224-x, and miR-452-x) and differentially expressed long non-coding RNAs (DElncRNAs) (FUT8 and GPR31C). And AFM1 and OTA decreased TJ proteins via inhibiting the expression of PAK6, which was regulated by several important DEmiRNAs and DElncRNAs. These DE RNAs in intestinal integrity were involved in MAPK and Ras signaling pathway. Overall, our findings expand the current knowledge regarding the potential mechanisms of intestinal integrity disruption brought on by AFM1 and OTA in vivo.
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•AFM1 and OTA induced a disrupted intestinal barrier in vivo.•An intestinal barrier-related ceRNA network were conducted.•The disrupted intestinal barrier was related with an increased apoptosis level and decreased tight junction proteins level.•The MAPK and Ras signaling pathway was involved in the intestinal toxicity.
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