Vitamin C enhances the sensitivity of osteosarcoma to arsenic trioxide via inhibiting aerobic glycolysis.

Osteosarcoma (OS) is a common malignant tumor disease in the department of orthopedics, which is prone to the age of adolescents and children under 20 years old. Arsenic trioxide (ATO), an ancient poison, has been reported to play a critical role in a variety of tumor treatments, including OS. However, due to certain poisonous side effects such as cardiotoxicity and hepatotoxicity, clinical application of ATO has been greatly limited. Here we report that low doses of ATO (1 µM) observably reduced the half-effective inhibitory concentration (IC50) of vitamin C on OS cells. Compared with the treatment alone, the synthetic application of vitamin C (VitC, 800 µM) and ATO (1 µM) significantly further inhibited the proliferation, migration, and invasion of OS cells and promoted cell apoptosis in vitro. Meanwhile, we observed that the combined application of VitC and ATO directly suppresses the aerobic glycolysis of OS cells with the decreased production of pyruvate, lactate, and ATP via inhibiting the expression of the critical glycolytic genes (PGK1, PGM1, and LDHA). Moreover, the combination of VitC (200 mg/kg) and ATO (1 mg/kg) with tail vein injection significantly delayed OS growth and migration of nude mice by inhibiting aerobic glycolysis of OS. Thus, our results demonstrate that VitC effectively increases the sensitivity of OS to low concentrations of ATO via inhibiting aerobic glycolysis to alleviate the toxic side effects of high doses of arsenic trioxide, suggesting that synthetic application of VitC and ATO is a promising approach for the clinical treatment of human OS.

NAT10 mediated ac4C acetylation driven m6A modification via involvement of YTHDC1-LDHA/PFKM regulates glycolysis and promotes osteosarcoma.

The dynamic changes of RNA N6-methyladenosine (m6A) during cancer progression participate in various cellular processes. However, less is known about a possible direct connection between upstream regulator and m6A modification, and therefore affects oncogenic progression. Here, we have identified that a key enzyme in N4-acetylcytidine (ac4C) acetylation NAT10 is highly expressed in human osteosarcoma tissues, and its knockdown enhanced m6A contents and significantly suppressed osteosarcoma cell growth, migration and invasion. Further results revealed that NAT10 silence inhibits mRNA stability and translation of m6A reader protein YTHDC1, and displayed an increase in glucose uptake, a decrease in lactate production and pyruvate content. YTHDC1 recognizes differential m6A sites on key enzymes of glycolysis phosphofructokinase (PFKM) and lactate dehydrogenase A (LDHA) mRNAs, which suppress glycolysis pathway by increasing mRNA stability of them in an m6A methylation-dependent manner. YTHDC1 partially abrogated the inhibitory effect caused by NAT10 knockdown in tumor models in vivo, lentiviral overexpression of YTHDC1 partially restored the reduced stability of YTHDC1 caused by lentiviral depleting NAT10 at the cellular level. Altogether, we found ac4C driven RNA m6A modification can positively regulate the glycolysis of cancer cells and reveals a previously unrecognized signaling axis of NAT10/ac4C-YTHDC1/m6A-LDHA/PFKM in osteosarcoma. Video Abstract.

Diagnostic performance of serum galactomannan and ß-D-glucan for invasive aspergillosis in suspected patients: A meta-analysis.

BACKGROUND: Serum galactomannan (GM) and ß-D-glucan (BG) are known markers of invasive aspergillosis (IA). The aim of this meta-analysis was to evaluate the efficiency of serum GM and BG as diagnostic markers of symptomatic IA infection and compare the performance of the combined tests with that of either test individually. METHODS: A literature search was carried out using PubMed, Web of Science, and EMBASE databases to include relevant studies published in English up to May 2023. The quality assessment was performed using Review Manager 5.3 software. A bivariate model was applied to pool diagnostic parameters using Stata 14.0 software. We used Cochrane I2 index to assess heterogeneity and identify the potential source of heterogeneity by meta-regression. Paired t tests were used to compare the value of GM and BG for IA diagnosis when used in combination or alone. RESULTS: Sixteen studies were eligible for inclusion in the meta-analysis. For proven or probable IA, serum GM and BG yielded a pooled sensitivity of 0.53 (95% CI 0.40-0.66) vs 0.72 (95% CI 0.61-0.81) and a pooled specificity of 0.94 (95% CI 0.91-0.97) vs 0.82 (95% CI 0.73-0.88). The area under the curve (AUC) of ROC was 0.90 (95% CI 0.87-0.92) vs 0.83 (95% CI 0.80-0.86) for all studies. The pooled sensitivity and specificity for IA diagnosis by combined GM and BG assays (GM/BG) were 0.84 (95% CI 0.69-0.86) and 0.76 (95% CI 0.69-0.81), respectively. The sensitivity of the combined GM/BG test to diagnose IA was higher than of the GM or BG test alone. CONCLUSION: Serum GM and BG tests had a relatively high accuracy for IA diagnosis in suspected patients. The diagnostic accuracy of both assays is comparable, and the diagnostic sensitivity is further improved by the combined detection of the 2 markers.