Ubiquitin ligase RNF125 targets PD-L1 for ubiquitination and degradation

As a critical immune checkpoint molecule, PD-L1 is expressed at significantly higher levels in multiple neoplastic tissues compared to normal ones. PD-L1/PD-1 axis is a critical target for tumor immunotherapy, blocking the PD-L1/PD-1 axis is recognized and has achieved unprecedented success in clinical applications. However, the clinical efficacy of therapies targeting the PD-1/PD-L1 pathway remains limited, emphasizing the need for the mechanistic elucidation of PD-1/PD-L1 expression. In this study, we found that RNF125 interacted with PD-L1 and regulated PD-L1 protein expression. Mechanistically, RNF125 promoted K48-linked polyubiquitination of PD-L1 and mediated its degradation. Notably, MC-38 and H22 cell lines with RNF125 knockout, transplanted in C57BL/6 mice, exhibited a higher PD-L1 level and faster tumor growth than their parental cell lines. In contrast, overexpression of RNF125 in MC-38 and H22 cells had the opposite effect, resulting in lower PD-L1 levels and delayed tumor growth compared with parental cell lines. In addition, immunohistochemical analysis of MC-38 tumors with RNF125 overexpression showed significantly increased infiltration of CD4+, CD8+ T cells and macrophages. Consistent with these findings, analyses using The Cancer Genome Atlas (TCGA) public database revealed a positive correlation of RNF125 expression with CD4+, CD8+ T cell and macrophage tumor infiltration. Moreover, RNF125 expression was significantly downregulated in several human cancer tissues, and was negatively correlated with the clinical stage of these tumors, and patients with higher RNF125 expression had better clinical outcomes. Our findings identify a novel mechanism for regulating PD-L1 expression and may provide a new strategy to increase the efficacy of immunotherapy

Purification and Identification of Novel Myeloperoxidase Inhibitory Antioxidant Peptides from Tuna (Thunnas albacares) Protein Hydrolysates

Antioxidative peptides that inhibit myeloperoxidase (MPO) enzyme activity can effectively defend against oxidative stress damage. The antioxidant peptides from tuna protein were produced using alcalase hydrolysis and purified by ultrafiltration and Sephadex G-15, and the fractions with the highest free radicals scavenging ability and oxygen radical absorbance capacity (ORAC) values were sequenced using HPLC–MS/MS. Fifty-five peptide sequences were identified, 53 of which were successfully docked into MPO. The representative peptide ACGSDGK had better antioxidant activity and inhibition of MPO chlorination and peroxidation than the reference peptide hLF1-11. The docking model further showed intense molecular interactions between ACGSDGK and MPO, including hydrogen bonds, charge, and salt bridge interactions, which occluded the active site and blocked the catalytic activity of MPO. These results suggested that the antioxidant peptide ACGSDGK has the potential to inhibit oxidative stress and alleviate inflammation in vivo because of its inhibitory effect on the MPO enzyme

Risk factors associated with the prevalence of thyroid nodules in adults in Northeast China: a cross-sectional population-based study

Objectives This study examined the association between anthropometric measurements, lifestyle factors and the prevalence of thyroid nodules among adults in Northeast China.Design We employed a cross-sectional approach involving a questionnaire survey, which focused on participants’ living habits, and a physical examination that included anthropometry and ultrasound imaging.Setting The data were procured during multiple trips by medical teams from the first hospital of China Medical University to towns in Northeast China.Participants Of the 1092 participants, 489 did not have thyroid nodules (mean age: 54.02±11.49 years; 297 females (60.7%)), 99 had single thyroid nodules (mean age: 58.19±10.77 years; 59 females (59.6%)) and 504 had multiple thyroid nodules (mean age: 60.05±10.68 years; 394 females (78.2%)). Inclusion criteria mandated participants be over 20 years old without other medical conditions. We excluded individuals who had undergone surgical resection for thyroid nodules.Results The prevalence of thyroid nodules was significantly associated with being female (OR 2.569, 95% CI 1.937 to 3.405, p<0.001) and increased age (OR 1.054, 95% CI 1.041 to 1.066, p<0.001). This association was more pronounced in those with multiple thyroid nodules. For males under 60, non-smoking was inversely correlated with the prevalence of multiple thyroid nodules (OR 0.321, 95%CI 0.149 to 0.69, p<0.05). For females under 60, diastolic blood pressure (DBP) was significantly linked with the prevalence of thyroid nodules (OR 0.978, 95% CI 2.614 to 2.705, p<0.05).Conclusions Besides gender and age, the prevalence of thyroid nodules in Northeast China correlates with smoking habits and DBP

A composition of bractatin and neobractatin from the fruits of Garcinia bracteata induces apoptosis in throat cancer through the endoplasmic reticulum stress, mitochondrial apoptotic and Akt pathways

Throat cancer is a common head and neck malignant tumor with a relatively high mortality rate. Prenylxanthone, is the major bioactive substance isolated from the genus Garcinia with anti-cancer effects. However, the anti-tumor activity of Prenylxanthone and its molecular mechanism in throat cancer have not been reported yet. In this study, a composition of two prenylxanthones (CPX) from the fruits of Garcinia bracteata was obtained to evaluate its chemical composition, anti-throat cancer ability and underlying mechanism in vitro and in vivo. The data revealed that CPX, composed of bractatin and neobractatin, dose-dependently suppressed throat cancer cells Hep-2 and FaDu proliferation and apoptosis, and inhibited xenografts growth in nude mice without significant toxicity. Furthermore, CPX exerted anti-throat cancer effect by inducing apoptosis through endoplasmic reticulum (ER) stress, mitochondrial apoptotic and Akt pathways. All results suggested that CPX could be considered as a potential chemotherapeutic drug for throat cancer