Lung adenocarcinoma (LUAD) is one of the primary culprits of cancer-related deaths. Current treatment modalities for LUAD have certain limitations, necessitating innovating effective LUAD treatment strategies. Prostaglandin E synthase (PTGES) and TF activating protein 2C (TFAP2C) in the process of drug resistance in LUAD are less studied and need further in-depth research. This study aimed to investigate the specific molecular mechanisms of ‍PTGES and TFAP2C in gefitinib resistance in LUAD. The results indicated that PTGES and TFAP2C were considerably over­expressed in LUAD tissues and cells. Chromatin immuno­pre­cipitation and dual luciferase assay validated that TFAP2C targeted the PTGES promoter region. In addition, gene set enrichment analysis results demonstrated the notable enrichment of PTGES in the NOTCH3 signaling pathway. Overexpression of PTGES remarkably enhanced the viability of PC-9/GR (gefitinib-resistant) cells and their response to gefitinib resistance, which was reversed by the addition of a NOTCH3 inhibitor. Furthermore, overexpressing PTGES upon the TFAP2C silence restored the great inhibition effect conferred by TFAP2C silence in PC-9/GR cells on cell viability and cell response to gefitinib resistance. This study confirmed that TFAP2C can transcriptionally activate PTGES through the NOTCH3 signaling pathway to enhance the response of LUAD cells to gefitinib resistance, proffering a new approach for the treatment of gefitinib resistance in LUAD cells.

Lung adenocarcinoma (LUAD) is responsible for a substantial portion of cancer-related deaths, carrying a bleak treatment outlook. The application of ferroptosis-focused treatments has shown great potential. This research is committed to uncovering the molecular mechanisms by which Nei Like DNA Glycosylase 3 (NEIL3) impacts ferroptosis in LUAD, in the quest for robust biomarkers. Using The Cancer Genome Atlas database, qRT-PCR, and Western blot (WB), we evaluated the expression of NEIL3 in LUAD tissues and cells, then performed gene set enrichment analysis to identify enriched gene sets. Predictive tools hTFtarget and MoLoTool assisted in identifying potential upstream transcription factors and their promoter binding sites for NEIL3, following which we conducted Pearson correlation analysis. The binding affinity of NEIL3 to Forkhead box protein M1 (FOXM1) was validated with dual-luciferase and chromatin immunoprecipitation assays. Cell viability was determined by measuring MDA and Fe²⁺ content in cells with the aid of cell counting kit-8. Lipid reactive oxygen species (ROS) levels were detected by flow cytometry, and WB was employed to evaluate the expression of GPX4 and SLC7A11 proteins. An upregulation of NEIL3 is observed in LUAD tissues and cell lines, particularly within pathways linked to ferroptosis. When NEIL3 was knocked down, there was a decline in the viability of LUAD cells, coupled with elevated MDA, Fe²⁺, and lipid ROS levels. Protein expression of GPX4 and SLC7A11 was inhibited, but these phenotypes were rescued by the application of a ferroptosis inhibitor. FOXM1 could interact with the NEIL3 gene promoter, initiating its transcription. In the context of LUAD, the activation of NEIL3 by FOXM1 constitutes the FOXM1/NEIL3 axis that counteracts ferroptosis in LUAD cells.

Chemotherapy resistance is a key obstacle in the treatment of triple-negative breast cancer (TNBC). Single-cell RNA sequencing (scRNA-seq) plays a pivotal part in revealing the mechanism of ‍drug resistance in tumors. This work aimed to explore the molecular events driving TNBC resistance based on scRNA-seq data. Breast cancer (BC) scRNA-seq data GSE176078 was sourced from the GEO database. Nine TNBC samples were analyzed. The ‍cellular composition and differentially expressed genes of TNBC were clarified through dimension reduction, clustering, and ‍cell annotation. Drug-resistant and sensitive epithelial cell clusters in malignant epithelial cells were identified, with their ‍heterogeneity analyzed. Key genes driving drug-resistant epithelium were screened and KEGG enrichment analysis was undertaken. The expression of Ubiquitin Carboxy-Terminal Hydrolase L1 (UCHL1) in TNBC was examined. The effect and molecular mechanism of UCHL1 on cisplatin (CDDP) resistance in TNBC was confirmed by constructing CDDP-resistant cell lines. We successfully identified resistant and sensitive cell clusters in malignant epithelial cells of TNBC and screened for the greatly upregulated gene UCHL1 in the resistant epithelium. KEGG analysis revealed its enrichment in the ferroptosis signaling pathway. Further analyses demonstrated the upregulation of UCHL1 in CDDP-resistant TNBC cells. Knocking down UCHL1 potentiated the sensitivity of TNBC cells to CDDP treatment and reinforced ferroptosis. The ferroptosis inhibitor Ferrostatin-1 reversed the inhibitory effect of UCHL1 knockdown on CDDP resistance. UCHL1 reinforces CDDP resistance in TNBC by suppressing ferroptosis. The study brings new insights into the drug-resistance mechanism of TNBC.

To investigate the possible effects of Kurarinone on the ferroptosis and EMT of high glucose (HG)-stimulated HK2 cells, and uncover the mechanism. HK2 cells were treated with glucose to construct a DN cell model. CCK-8 and FCM assays exhibited the effects on growth as well as apoptosis of HK2 cells. DCF staining as well as Immunoblot assays exhibited the effects on ferroptosis. JC-1 staining exhibited the effects on mitochondrial function. Immunoblot assays showed the effects on the EMT process of HK2 cells. Immunoblot assays confirmed the mechanism. Kurarinone inhibited the apoptosis of HG-stimulated HK2 cells. It also blocked the ferroptosis of HG-stimulated HK2 cells. Further data showed that Kurarinone suppressed the mitochondrial damage in HG-stimulated HK2 cells, and restrained EMT process. Mechanically, Kurarinone activated the Nrf-2 pathway in HG-stimulated HK2 cells. Kurarinone activates the Nrf-2 pathway and alleviates HG-stimulated ferroptosis and EMT in HK2 cells.

Myocardial ischemia/reperfusion injury (MI/RI) is a prevalent condition encountered by many patients with ischemic heart disease, which can badly influence the health of patients and even do harm their lives. Sanguinarine (SA), one active ingredient separated from the poppy family, and exhibits anti-oxidant, anti-tumor, and anti-inflammation properties. However, the precise regulatory impacts and associated mechanisms of SA in the progression of MI/RI remain largely elusive. In this study, firstly, H9c2 cells were treated by hypoxia/reoxygenation (HR) to mimic MI/RI cell model. It was uncovered that SA strengthened HR-mediated cell viability of H9c2 cells. Following HR treatment, there was an increase in the production of inflammatory markers (TNF-α, IL-1β, and IL-6), whereas this effect was mitigated after SA ‍treatment. The oxidative stress was heightened after HR treatment, but this phenomenon was offset after SA treatment. SA activated the Nrf2/NLRP3 pathway and relieved proptosis. At ‍last, through rescue assays, it was demonstrated that SA improved HR-triggered inflammation and oxidative stress through Nrf2 pathway. SA also modulated HR-triggered cell viability, inflammation, and oxidative stress in rat primary cardiomyocytes. In summary, our findings indicate that SA protects against HR-induced H9c2 cell injury through activation of the Nrf2/NLRP3 pathway. This discovery suggests that SA may be one helpful drug for ameliorating MI/RI.

Ulcerative colitis (UC) is a debilitating inflammatory bowel disease that poses significant challenges in clinical management. Despite existing therapies, many patients fail to achieve adequate symptom relief, underscoring the need to address the underlying mechanisms contributing to the pathogenesis of UC. Andrographis paniculata has been extensively studied in traditional Chinese medicine for its anti-inflammatory properties. This study aimed to evaluate the effects of CX-10, a derivative of andrographolide, on ‍autophagy, oxidative stress, and inflammation in UC. Using dextran sulfate sodium (DSS)-induced mouse model of UC, our ‍findings demonstrated that CX-10 treatment resulted in significant reductions in body weight loss, Disease Activity Index ‍(DAI), and histopathological injury scores, characterized by decreased inflammatory cell infiltration and mucosal damage compared to DSS-treated controls. Quantitative real-time PCR (qRT-PCR) revealed a marked restoration of autophagy-related genes Becn1 and Atg5 in CX-10-treated colonic tissues. Western blot analysis further confirmed enhanced autophagic flux, evidenced by significant increases in the LC3-II/I ratio. CX-10 treatment also led to reduced endoplasmic reticulum (ER) stress, indicated by decreases in the transcript and protein levels of GRP78 and CHOP. Consistent with the in vivo findings, in vitro studies demonstrated that CX-10 effectively enhanced autophagy and reduced oxidative stress in lipopolysaccharides (LPS)-treated HT-29 colonic epithelial cells and RAW 264.7 macrophages. This was accompanied by a marked decrease in reactive oxygen species (ROS) levels, as determined by DCFDA assays. In conclusion, CX-10 exerts protective effects against DSS-induced UC through modulation of autophagy and oxidative stress pathways, suggesting its potential as a novel therapeutic agent for managing UC.

Intestinal ischemia-reperfusion (II/R) injury is a significant clinical concern with high mortality rates. Mitochondria play a crucial role in this process, and maintaining mitochondrial homeostasis is a potential treatment target. SENP1 is a de-SUMOylated hydrolase that may regulate SIRT3, a major mitochondrial deacetylase. However, the role of SENP1 and SIRT3 in II/R remains unclear. Employing a combination of in vitro cell culture experiments utilizing Caco-2 cells and in vivo II/R models with SD rats, along with an array of molecular biology techniques such as gene silencing, protein detection methods, immunoprecipitation, histological analysis, and functional assays, this study delved into the role of SENP1 and SIRT3 in intestinal ischemia-reperfusion injury. Statistical analysis was meticulously conducted to evaluate the significance of the obtained results. SENP1 and SIRT3 are co-‍expressed and interact in Caco-2 cells. In models of II/R, the expression of SENP1 increased while that of SIRT3 decreased. Reducing SENP1 expression by siRNA or enteral nutrition inter­ven­tion with bupropion alleviated intestinal II/R injury, reduced mitochondrial damage and oxidative stress, and improved the number and function of mitochondria. Our study demonstrates the importance of SENP1 and SIRT3 in intestinal ischemia-reperfusion injury. Reducing SENP1 expression through siRNA or enteral nutrition intervention shows promise as a potential therapeutic approach. This research provides new insights into the mechanism of II/R injury and paves the way for further investigations.

8-Prenylnaringenin (8-‍PN) is a prenylflavonoid found in hops (Humulus lupulus L.). It has several beneficial functions, which include the inhibition of bone loss and muscle atrophy. 8-‍PN is a metabolite of xanthohumol, which can prevent obesity in mice; however, the effect of 8-‍PN on obesity is still unknown. In the present study, we found that 8-‍PN prevented obesity in high-fat diet-fed mice. When C57BL6/J male mice were fed 8-‍PN at 0.0005% or 0.005% with a high-fat diet for 8 weeks, body weight gain, fat accumulation in adipose tissue, and fatty liver induced by the high-fat diet were prevented. In mice fed a high-fat diet and 8-‍PN, adenosine monophosphate-activated protein kinase (AMPK) was activated in visceral adipose tissue, which was accompanied by decreased expression of a fatty acid synthesis-related factor and increased expression of a mitochondrial biosynthesis-related factor downstream of AMPK. AMPK appeared to be activated by adiponectin secretion, which was associated with increased expression of adipocyte differentiation markers in mice fed a high-fat diet and 8-‍PN. For the first time, this study shows that 8-‍PN can prevent obesity in mice and that it is effective at low concentrations that humans could consume in their daily diet.

Levosimendan, a calcium sensitizer, has cardioprotective effects against myocardial ischemia-reperfusion injury (MIRI). Mitophagy plays an important role in MIRI, and the cGAS-STING signaling pathway can participate in mitophagy in a variety of ways. The ‍purpose of this study was to explore the new molecular mechanism by which levosimendan exerts cardioprotective effects in order to provide a new experimental basis for the clinical application of levosimendan. In this study, an isolated MIRI rat ‍model was established, and 48 rats were randomly divided into four groups (n = 12): continuous perfusion group (Group C), ischemia-reperfusion group (IR group), ischemia-reperfusion + levosimendan group (IR + L group), and ischemia-reperfusion + levosimendan + sting activator group (IR + LA group). The hemo­dynamic indices, myocardial infarction volume, expression of cGAS-STING signaling pathway proteins, and mitophagy-related proteins in isolated rat hearts of the four groups were compared. This study showed that levosimendan can reduce the level of myocardial mitophagy in ischemia-reperfusion rats by inhibiting the cGAS-STING signaling pathway, reducing myocardial injury, and playing a myocardial protective role.

Deficiency of pyridoxal 5'-phosphate (PLP) causes neurological abnormalities. The decline in blood PLP concentration has been associated with the onset of dementia, but no studies have been ‍conducted on Japanese. This study aimed to determine the relationship between serum PLP concentration and Alzheimer’s disease (AD) in older Japanese individuals. A total of 266 participants, 84 healthy participants, 87 participants with mild cognitive impairment (MCI), and 95 patients with AD were randomly selected from those who visited the National Center for ‍Geriatrics and Gerontology for Longevity Sciences. Serum PLP concentration was significantly lower in the AD compared to the ‍NC. Participants were divided into quartiles (Q1–Q4). The relationship between quartiles of serum PLP concentration and cognitive function was analyzed using logistic regression analyses adjusted with covariate factors (sex, age, number of applicable frailty evaluations, APOE4, educational level, albumin, homo­cysteine, vitamin B₁, B₁₂, and folate). The odds ratios (ORs) for MCI or AD were significantly lower for Q3 and Q4 compared to Q1, and the ORs (95% CI) for Q3 and Q4 were 0.40 (0.16–0.98) and 0.37 (0.13–0.99), respectively. Lower serum PLP concentration is independently related to the incidence of MCI or AD. Further research is needed to clarify the causal relationship.

Piceatannol is a type of polyphenol that is abundantly obtained from passion fruit. The present study aimed to determine the effect of 7 days of piceatannol supplementation on fat metabo­lism at rest, during and after low-intensity aerobic exercise. This randomized, double-blind, and crossover study included eight physically active male participants. The participants completed two experimental trials: placebo and piceatannol. They ingested either a placebo or piceatannol tablets containing 0 or 10 ‍‍mg of piceatannol for seven consecutive days. The participants visited the laboratory at 8:00 am after seven days. In the following baseline measurements, the participants performed 60 ‍‍min of pedaling exercise at 30% of their maximum oxygen uptake. Respiratory gas and blood samples were collected before, during, and after the exercise. No significant differences were found between the trials in oxygen uptake, carbon dioxide output, ventilation, and respiratory exchange ratio either at rest and during and after exercise. Similarly, serum growth hormone, cortisol, insulin, free fatty acid, glycerol, acetoacetic acid, 3-hydroxybutyric acid, and ketone body responses exhibited no significant differences between trials. These results indicate that the 7-day piceatannol supplementation did not promote fat metabolism at rest and during and after low-intensity aerobic exercise.

Bioelectrical impedance analysis cannot be used to measure muscle mass in some individuals. We aimed to determine cutoff values for low skeletal muscle mass index in sarcopenia diagnosis, based on the fat-free muscle mass index estimated using body fat percentage prediction equations, without relying on bioelectrical impedance analysis. The study included 564 residents from Wakasa, Fukui Prefecture, with a mean age of 76.0 ‍± 7.1 years. Body composition assessments using bioelectrical impedance analysis were conducted. Three prediction equations for body fat percentage (Ito et ‍al., Deurenberg et ‍al., and Gallagher et ‍al.’s model for Asians) were applied. The cutoff value of the fat-free muscle mass index corresponding to low skeletal muscle mass index in sarcopenia diagnostic criteria was determined using receiver operating characteristic curves. Receiver operating characteristic curve analysis showed that the formula by Ito et ‍al. yielded the highest area under the curve for estimating low skeletal muscle mass index in men, at 0.83. In women, the formulas by Ito et ‍al. and Gallagher et ‍al. performed similarly, each achieving an area under the curve of 0.779. The fat-free muscle mass index estimated using the body fat prediction formulas appear to be useful for screening low skeletal muscle mass index.