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Purpose: According to some cohort studies, an association exists between acute intermittent porphyria (AIP) and liver cancer. However, establishing a definitive causal relationship between porphyria and hepatocellular carcinoma (HCC) remains challenging. Prexisting studies regarding porphyria biomarkers and alcohol-related hepatocellular carcinoma (AR-HCC) make possible an entry point. In this study, we aimed to investigate the causal relationships between biomarkers of two types of porphyria, AIP and congenital erythropoietic porphyria (CEP), and AR-HCC. Methods: Single-nucleotide polymorphisms (SNPs) associated with porphobilinogen deaminase (PBGD) and uroporphyrinogen-III synthase (UROS), along with outcome data on AR-HCC, were extracted from public genome-wide association studies (GWAS). The GWAS data were then used to explore the potential causal relationships via a two-sample Mendelian randomization (MR) analysis. The effect estimates were calculated using the random-effect inverse-variance-weighted (IVW) method. Additionally, the Cochrane's Q test, MR-Egger test, and leave-one-out analysis were conducted to detect heterogeneity and pleiotropy in the MR results. Results: Using the IVW method as the primary causal effects model in the MR analyses, we found that both PBGD (effect estimate = 1.51; 95% CI, from 1.08 to 2.11, p = 0.016) and UROS (effect estimate = 1.53; 95% CI, from 1.08 to 2.18, p = 0.018) have a significant causal effect on AR-HCC. Conclusion: Our findings revealed a causal effect of both PBGD and UROS on AR-HCC, suggesting that both AIP and CEP have a causal association with AR-HCC. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor 1 (IGF-1) is reported to inhibit autophagy of human colorectal carcinoma cells (HCT); however, little is known regarding the mechanisms underlying the inhibitory effect of IGF-1 on autophagy in HCT resistant strains. The present study aimed to analyze the inhibitory effect of IGF-1 on the autophagy of HCT resistant strains and its potential underlying mechanisms. The viability and apoptosis of HCT-8 colon cancer cells were analyzed, and expression levels of relevant genes and proteins were investigated using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Treatment of cells with IGF-1 induced apoptosis. IGF-1 treatment activated protein kinase B (AKT), which may inhibit autophagy via the AKT/mammalian target of rapamycin signaling pathway. Following inhibition of autophagy, drug resistant cells became sensitive to apoptosis induced by 5-fluorouracil. [ABSTRACT FROM AUTHOR]

Introduction: Physical frailty is reversible, but little is known about the sustainability of frailty remission and its impact on dementia., Methods: Data were derived from the National Health and Aging Trends Study (NHATS) (2011 to 2021). Physical frailty was assessed using the Fried frailty phenotype, and frailty transition patterns across three waves were defined. The relationship of sustained frailty remission with incident dementia was examined using Cox proportional regression, stratified by age and gender., Results: Among 1931 participants, 348 (18.0%) were capable of sustained frailty remission. During the 8-year follow-up, 279 participants developed dementia. In a fully adjusted model, sustained remission was associated with a lower risk of dementia (hazard ratio = 0.66, 95% confidence interval = 0.47 to 0.93). The association was more pronounced among younger-old and male participants but not observed among their counterparts., Discussion: Sustained frailty remission was associated with a reduced risk of developing dementia. Physical frailty could be an essential forewarning of dementia and a target for interventions., Highlights: We provided new insights into the natural progression of frailty and its impact on dementia risk using a nationally representative sample Sustained frailty remission reduced risk of incident dementia. Age and gender played a role in the frailty-dementia link, and thus individualized dementia risk screening is necessary. Physical frailty could be an essential forewarning of cognitive decline and an ideal target for interventions to prevent dementia., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Hepatocellular carcinoma (HCC) represents a lethal cancer, and most HCC cases occur in the fibrotic or cirrhotic livers. Hepatic stellate cells (HSCs), the main effector cells of liver fibrosis, could secret biological contents to maintain liver inflammation. Herein, we aimed to identify the key transcription factor secreted by extracellular vesicles (EVs) derived from HSCs and explored its oncogenic mechanism. The activated HSC cell line LX-2 was co-cultured with HCC cells with or without the EVs release inhibitor GW4869. The effects of co-culture with HSC on HCC cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition were analyzed. Co-culture with activated LX-2 enhanced HCC cell growth and motility, while GW4869 inhibited the pro-carcinogenic effect of HSC, suggesting that HSC promoted HCC progression through the secretion of EVs. HSC-derived EVs carried the key oncogenic transcription factor PRDM16, and uptake of EVs-derived PRDM16 by HCC cells activated the NOTCH1-mediated Notch signaling pathway. Knocking down PRDM16 in EVs or blocking Notch signaling in HCC cells significantly inhibited the tumor-promoting effects of HSC-derived EVs. Our study demonstrates that HSC-derived EVs activate the NOTCH1-mediated Notch signaling pathway in HCC cells by carrying PRDM16, leading to HCC progression., Competing Interests: None., (AJCR Copyright © 2023.)