Targeting YTHDF1 effectively re-sensitizes cisplatin-resistant colon cancer cells by modulating GLS-mediated glutamine metabolism.

Colorectal cancer (CRC) has a high mortality rate and poor prognosis. Despite chemotherapeutic agents such as cisplatin, which has achieved a better prognosis and survival rate against cancer, drug resistance leads to significant challenges. Accumulating evidence suggests that YTHDF1, the N 6-methyladenosine (m6A) "reader," is an important regulator in tumor progresses. Herein, we report that YTHDF1 was significantly upregulated in human colon tumors and cell lines. Overexpression of YTHDF1 decreased the cisplatin sensitivity of colon cancer cells. From the established cisplatin-resistant CRC cell line (LoVo CDDP R), we detected that YTHDF1 was significantly upregulated in cisplatin-resistant CRC cells. Intriguingly, RNA sequencing (RNA-seq) results revealed that glutamine metabolism enzymes were clearly upregulated in LoVo CDDP R cells. Glutamine uptake, that is, glutaminase (GLS) activity, was upregulated in LoVo CDDP R cells. Furthermore, bioinformatics analysis indicated that the 3' UTR of GLS1 contained a putative binding motif of YTHDF1, and an interaction was further validated by a protein-RNA interaction assay (RNA immunoprecipitation [RIP]). Furthermore, we demonstrated that YTHDF1 promoted protein synthesis of GLS1. Inhibiting GLS1 effectively synergizes with cisplatin to induce colon cancer cell death. Finally, that YTHDF1 mediated cisplatin through the GLS1-glutamine metabolism axis was validated by an in vivo xenograft mouse model. In summary, our study reveals a new mechanism for YTHDF1-promoted cisplatin resistance, contributing to overcoming chemoresistant colon cancers.

Underwater vs conventional endoscopic mucosal resection in treatment of colorectal polyps: A meta-analysis.

BACKGROUND: Underwater endoscopic mucosal resection (UEMR) of colorectal lesions is emerging as an alternative method to conventional endoscopic mucosal resection (EMR); however, it is still controversial whether there is a difference in the effectiveness between UEMR and EMR. AIM: To evaluate the effectiveness and safety of UEMR in the treatment of colorectal polyps. METHODS: Clinical studies comparing the effectiveness or safety of UEMR in the treatment of colorectal polyps were searched in medical databases, including PubMed, Embase, Cochrane Library, CNKI, and Wanfang Data, monographs, theses, and papers presented at conferences. Statistical analyses were performed using Revman 5.3 software. RESULTS: Seven non-randomized controlled trials and one randomized controlled trial met the inclusion criteria. In total, 1382 patients (1511 polyps) were included in the study, including 722 who received UEMR and 789 who received EMR. In the UEMR and EMR groups, the en bloc resection rates were 85.87% and 73.89%, respectively, with a relative risk (RR) value of 1.14 (95% confidence interval [CI]: 1.01-1.30; P < 0.05). In the sub-group analysis, the en bloc resection rate showed no statistically significant difference between the EMR and UEMR groups for polyps less than 20 mm in diameter. However, a statistically significant difference was found between the EMR and UEMR groups for polyps equal to or greater than 20 mm in diameter. The post-endoscopic resection recurrence rates at 3-6 mo of the UEMR and EMR groups were 3.26% and 15.17%, respectively, with an RR value of 0.27 (95%CI: 0.09-0.83; P < 0.05). The post-endoscopic resection recurrence rates of UEMR and EMR at 12 mo were 6.25% and 14.40%, respectively, with an RR value of 0.43 (95%CI: 0.20-0.92; P < 0.05). Additionally, the incidence of adverse events was 8.17% and 6.21%, respectively, with an RR value of 1.07 (95%CI: 0.50-2.30; P > 0.05). CONCLUSION: UEMR is an effective technique for colorectal polyps and appears to have some advantages over EMR, particularly with regard to some treatment outcomes.

New anti-HBV caryophyllane-type sesquiterpenoids from Euphorbia humifusa Willd.

Activity-guided fractionation of Euphorbia humifusa for anti-HBV activity led to the isolation of two novel sesquiterpenoids, named humifusane A (1) and humifusane B (2). Their structures were elucidated by spectral data to show that they have a caryophyllane-type precursor structure. The two new sesquiterpenoids showed anti-HBV activities through specifically inhibiting the secretion of HBsAg in HepG2.2.15.

Anti-HBV active flavone glucosides from Euphorbia humifusa Willd.

Thirteen flavone glucosides from the herb of Euphorbia humifusa were isolated and elucidated. Among them, five compounds including apigenin-7-O-ß-D-glucopyranoside (2), apigenin-7-O-(6''-O-galloyl)-ß-D-glucopyranoside (3), luteolin-7-O-ß-D-glucopyranoside (7), luteolin-7-O-(6''-O-trans-feruloyl)-ß-D-glucopyranoside (8) and luteolin-7-O-(6''-O-coumaroyl)-ß-D-glucopyranoside (9) showed anti-HBV activity in vitro. The structure-activity relationship showed that the parent structure was closely relevant to the anti-HBV activity of these compounds (agigenin>luteolin>quercetin). It was found that the number of glucoside in the structure may significantly influence their activities (flavone monoglucoside>flavone diglucoside) and cytotoxicity (flavone>flavone monoglucoside>flavone diglucoside). In addition, the substitution of acyl group on glucoside may be important to keep the anti-HBV activities of these compounds (galloyl>feruloyl>coumaroyl).

[Apigenin glycosides from Euphorbia humifusa wild].

The investigation on the herbal of Euphorbia humifusa Wild. was carried out in order to find its anti-HBV constituents. The isolation and purification were performed by chromatography such as Sephadex LH-20, MCI GEL CHP 20P, etc. Based on the spectral analysis, five apigenin glycosides were identified as apigenin-7-O-(6"-O-galloyl)-beta-D-glucopyranoside (1), apigenin-7-O-beta-D-apiofuranosyl (1-->2)-beta-D-glucopyranoside (2), apigenin-7-O-beta-D-lutinoside (3), apigenin-7-O-beta-D-glucopyranside (4) and apigenin (5). Among them, compound 1 is a new compound, compound 2 and 3 were isolated from this plant for the first time.