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Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with high mortality rates partially due to limited therapeutic options and drug resistance. Arsenic trioxide (ATO), a compound clinically proven for acute promyelocytic leukemia (APL), has garnered attention for its emerging efficacy in solid tumors, including HCC. However, the molecular mechanisms driving ATO's antitumor activity in HCC remain incompletely understood. In this study, we aimed to elucidate the ferroptosis-dependent effects of ATO on HCC and and propose a potential therapeutic strategy. The response of HCC cells to ATO was evaluated using cell viability, wound healing, colony formation, Transwell migration assays, and cell cycle analysis. ATO-induced ferroptosis was assessed by measuring lipid peroxidation (via C11-BODIPY staining), intracellular iron levels, and malondialdehyde (MDA) production. Western blotting was performed to quantify protein levels of NRF2, HO-1, SLC7A11, and GPX4; immunofluorescence staining was employed to determine NRF2 subcellular localization. ATO exhibited significant cytotoxicity and inhibited the progression of HCC cells. Treatment with ATO resulted in a notable increase in lipid ROS and MDA levels, which were subsequently reversed by the ferroptosis inhibitors Fer-1 and DFO. Mechanistically, ATO induced ferroptosis by inhibiting GPX4. Furthermore, NRF2 and its downstream targets, HO-1 and SLC7A11, were upregulated during ferroptosis. NRF2 knockdown enhanced lipid peroxidation and ATO-induced cell death. ATO significantly promoted ferroptosis in HCC cells, and NRF2 knockdown enhanced the cytotoxic effects of ATO.

Uraria crinite (UC), a medicinal food commonly used in China, has been demonstrated to possess neuroprotective properties against oxidative stress. However, its potential to achieve neuroprotection by inhibiting endoplasmic reticulum (ER) stress remains unverified. This study employed a manganese chloride (Mncl 2 )-induced SH-SY5Y cells model to simulate ER stress-mediated neurodegeneration and investigated whether UC can exert neuroprotective effects by alleviating ER stress. The results showed that within the concentration range of 50-200 μg/ml, water extract of UC inhibited Mncl 2 -induced ER stress, oxidative stress, and autophagy levels, restored mitochondrial membrane potential, and prevented neuronal apoptosis. The mechanism may involve upregulating the expression of proteins such as Bcl-2, SirT-1, OPA1, MFN1, MFN2, and P62, while downregulating the expression of proteins including Bax, cleaved-caspase 3, GRP78, CHOP, p-PERK, p47 phox , DRP1, and Beclin-1. This study demonstrates that UC exhibits protective effects against Mncl 2 -induced neuronal apoptosis, suggesting its potential for development as a neuroprotective functional food.

Background The metastasis-associated gene 1 (MTA1) has been extensively reported as a crucial oncogene, and its abnormal expression has been associated with the progression of numerous cancers. However, the role of MTA1 in renal cell carcinoma (RCC) progression and metastasis remains unclear. Herein, we investigated the expression of MTA1 and its role in RCC. Methods 109 matched clear cell RCCs (ccRCCs) and corresponding normal tissue samples were analyzed via immunohistochemistry to test the expression of MTA1. Human A498 cell lines were transfected with pcDNA3.1-Flag (control) or Flag-MTA1 to overexpress MTA1 or with specific interfering RNA (si-MTA1) or specific interfering negative control to knockdown MTA1 expression. Transfected cells were used in wound healing and transwell invasion assay. Quantitative real time polymerase chain reaction was used to assess the effect of MTA1 on MMP2/MMP9 and E-cadherin gene expression. Western blot was used to qualify the phosphorylation of p65. Results Herein, we found a significantly increased expression of MTA1 in 109 ccRCCs, compared to the corresponding normal tissue. In addition, the overexpression of MTA1 in A498 cells facilitated cell migration and invasion, while the down-regulation of MTA1 expression using specific interfering RNA sequences could decrease cell migration and invasion. Furthermore, we showed that MTA1 is up-regulated in ccRCCs, which contributes to the migration and invasion of human kidney cancer cells by mediating the expression of MMP2 and MMP9 through the NF-κB signaling pathway. Similarly, we found that MTA1 could regulate E-cadherin expression in RCCs. Conclusions MTA1 is overexpressed in RCC and is involved in the progression of RCC through NF-κB.

Background miR-198 is involved in the formation, migration, invasion, and metastasis of various malignant cancers. However, the function and mechanism of action of miR-198 in the tumorigenesis of renal cell carcinoma (RCC) remain elusive. Here, we aimed to explore the role of miR198 in RCC. Methods Immunohistochemistry was performed to estimate the level of survivin in RCC sections. Quantitative real-time polymerase chain reaction was performed to determine the expression level of miR-198 in fresh RCC tissues. Furthermore, the target relationship between miR-198 and BIRC5 was predicted using the TargetScanHuman 7.2 database and verified via dual-luciferase reporter assay and western blotting. The effects of miR-198 on the viability, apoptosis, invasion, and migration of A498 and ACHN cells were studied using Cell Counting Kit-8, flow cytometry, transwell migration assay, and wound healing assay, respectively. Additionally, a xenograft nude mouse model was established to evaluate the effect of miR-198 on RCC tumorigenesis. Results The expression levels of BIRC5 and miR-198 were respectively higher and lower in RCC tissues than those in normal adjacent tissues. Furthermore, miR-198 could inhibit luciferase activity and reduce the protein level of survivin without affecting the BIRC5 mRNA levels. miR-198 inhibited cell viability, migration, and invasion and promoted cell apoptosis; co-transfection with BIRC5 could rescue these effects. Moreover, miR-198 could repress tumor growth in the xenograft nude mouse model of RCC. Conclusions Our study demonstrates that miR-198 suppresses RCC progression by targeting BIRC5 .

Atrial fibrillation (AF) is the most common cardiac arrhythmia at the clinic. Recent GWAS identified several variants associated with AF, but they account for <10% of heritability. Gene-gene interaction is assumed to account for a significant portion of missing heritability. Among GWAS loci for AF, only three were replicated in the Chinese Han population, including SNP rs2106261 (G/A substitution) in ZFHX3, rs2200733 (C/T substitution) near PITX2c, and rs3807989 (A/G substitution) in CAV1. Thus, we analyzed the interaction among these three AF loci. We demonstrated significant interaction between rs2106261 and rs2200733 in three independent populations and combined population with 2,020 cases/5,315 controls. Compared to non-risk genotype GGCC, two-locus risk genotype AATT showed the highest odds ratio in three independent populations and the combined population (OR=5.36 (95% CI 3.87-7.43), P=8.00×10-24). The OR of 5.36 for AATT was significantly higher than the combined OR of 3.31 for both GGTT and AACC, suggesting a synergistic interaction between rs2106261 and rs2200733. Relative excess risk due to interaction (RERI) analysis also revealed significant interaction between rs2106261 and rs2200733 when exposed two copies of risk alleles (RERI=2.87, P<1.00×10-4) or exposed to one additional copy of risk allele (RERI=1.29, P<1.00×10-4). The INTERSNP program identified significant genotypic interaction between rs2106261 and rs2200733 under an additive by additive model (OR=0.85, 95% CI: 0.74-0.97, P=0.02). Mechanistically, PITX2c negatively regulates expression of miR-1, which negatively regulates expression of ZFHX3, resulting in a positive regulation of ZFHX3 by PITX2c; ZFHX3 positively regulates expression of PITX2C, resulting in a cyclic loop of cross-regulation between ZFHX3 and PITX2c. Both ZFHX3 and PITX2c regulate expression of NPPA, TBX5 and NKX2.5. These results suggest that cyclic cross-regulation of gene expression is a molecular basis for gene-gene interactions involved in genetics of complex disease traits.

Atrial fibrillation (AF) is the most common cardiac arrhythmia at the clinic. Recent GWAS identified several variants associated with AF, but they account for <10% of heritability. Gene-gene interaction is assumed to account for a significant portion of missing heritability. Among GWAS loci for AF, only three were replicated in the Chinese Han population, including SNP rs2106261 (G/A substitution) in ZFHX3, rs2200733 (C/T substitution) near PITX2c, and rs3807989 (A/G substitution) in CAV1. Thus, we analyzed the interaction among these three AF loci. We demonstrated significant interaction between rs2106261 and rs2200733 in three independent populations and combined population with 2,020 cases/5,315 controls. Compared to non-risk genotype GGCC, two-locus risk genotype AATT showed the highest odds ratio in three independent populations and the combined population (OR=5.36 (95% CI 3.87-7.43), P=8.00×10-24). The OR of 5.36 for AATT was significantly higher than the combined OR of 3.31 for both GGTT and AACC, suggesting a synergistic interaction between rs2106261 and rs2200733. Relative excess risk due to interaction (RERI) analysis also revealed significant interaction between rs2106261 and rs2200733 when exposed two copies of risk alleles (RERI=2.87, P<1.00×10-4) or exposed to one additional copy of risk allele (RERI=1.29, P<1.00×10-4). The INTERSNP program identified significant genotypic interaction between rs2106261 and rs2200733 under an additive by additive model (OR=0.85, 95% CI: 0.74-0.97, P=0.02). Mechanistically, PITX2c negatively regulates expression of miR-1, which negatively regulates expression of ZFHX3, resulting in a positive regulation of ZFHX3 by PITX2c; ZFHX3 positively regulates expression of PITX2C, resulting in a cyclic loop of cross-regulation between ZFHX3 and PITX2c. Both ZFHX3 and PITX2c regulate expression of NPPA, TBX5 and NKX2.5. These results suggest that cyclic cross-regulation of gene expression is a molecular basis for gene-gene interactions involved in genetics of complex disease traits.

Precise genome engineering of a handful of genes enables rapid domestication of wild tomato plants. Crop improvement by inbreeding often results in fitness penalties and loss of genetic diversity. We introduced desirable traits into four stress-tolerant wild-tomato accessions by using multiplex CRISPR–Cas9 editing of coding sequences, cis -regulatory regions or upstream open reading frames of genes associated with morphology, flower and fruit production, and ascorbic acid synthesis. Cas9-free progeny of edited plants had domesticated phenotypes yet retained parental disease resistance and salt tolerance.

To maintain and increase household wealth, this study studies the optimal allocation ratio of household investment and consumption. When considering venture capital, it is assumed that the theoretical price of risky asset obeys the CEV model. Our goal was to maximize the expectation of household cumulative consumption and the discounted utility of terminal wealth and to solve the optimal consumption and investment ratio using the dynamic programming principle and HJB equation. Using logarithmic utility and isoelastic power utility function with residual utility, we get the analytical solution of the household investment-consumption ratio by means of guessing and variable transformation. Finally, the influence of general parameters on the optimal ratio in the market is analyzed by numerical simulation and diagram, which is consistent with the description of actual situation. This study not only enriches portfolio theory but also provides investors with investment strategies.

Aim: To investigate the application and the related influencing factors of ultrafast pulse wave velocity (ufPWV) in the evaluation of carotid artery elasticity in patients with Immunoglobulin A nephropathy (IgAN).Material and methods: A total of 156 IgAN patients and 50 healthy individuals were selected as the control group. The ufPWV technique was employed to measure carotid arterial elasticity parameters, including carotid intima-media thickness (cIMT), pulse wave velocity at the beginning of systole (BS-PWV) and pulse wave velocity at the end of systole (ES-PWV).Results: Across the three groups (control group, IgAN patients with normal renal function, and IgAN patients with renal dysfunction) there was an increasing trend observed in cIMT, BS-PWV, and ES-PWV. Additionally, ES-PWV exhibited higher sensitivity than BS-PWV. Correlation analysis revealed that BS-PWV and ES-PWV were positively correlated with age, body mass index (BMI), systolic blood pressure (SBP), high-sensitivity C-reactive protein (hs-CRP), creatinine (Cr), blood urea nitrogen (BUN), and uric acid (UA) and negatively correlated with estimated glomerular filtration rate (eGFR).Conclusion: The ufPWV technique allows for the rapid and direct measurement of arterial elasticity parameters in the neck and represents a novel approach for the early diagnosis and quantitative assessment of arterial stiffness risk in IgAN patients.