Preclinical findings: The pharmacological targets and molecular mechanisms of ferulic acid treatment for COVID-19 and osteosarcoma via targeting autophagy.

The variant virus-based 2019 coronavirus disease (COVID-19) pandemic has reportedly impacted almost all populations globally, characterized by a huge number of infected individuals. Clinical evidence proves that patients with cancer are more easily infected with severe acute respiratory disease coronavirus 2 (SARS-CoV-2) because of immunologic deficiency. Thus, there is an urgent need to develop candidate medications to treat patients with cancer plus COVID-19, including those with osteosarcoma (OS). Ferulic acid, a latent theriacal compound that has anti-tumor and antivirus activities, is discovered to have potential pharmacological use. Thus, in this study, we aimed to screen and determine the potential therapeutic targets of ferulic acid in treating patients with OS plus COVID-19 as well as the pharmacological mechanisms. We applied a well-established integrated methodology, including network pharmacology and molecular docking technique, to detail target prediction, network construction, gene ontology, and pathway enrichment in core targets. The network pharmacology results show that all candidate genes, by targeting autophagy, were the core targets of ferulic acid in treating OS and COVID-19. Through molecular docking analysis, the signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase 1 (MAPK1), and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) were identified as the pharmacological targets of ferulic acid in treating OS. These preclinical findings from bioinformatics analysis altogether effectively determined the pharmacological molecules and mechanisms via targeting autophagy, demonstrating the therapeutic effectiveness of ferulic acid against COVID-19 and OS.

Oenothein B inhibits human non-small cell lung cancer A549 cell proliferation by ROS-mediated PI3K/Akt/NF-κB signaling pathway.

Oenothein B has a wide range of biological activities. The present study probed into the underlying mechanism on how Oenothein B inhibits the proliferation of a lung cancer line A549. Our results showed that Oenothein B effectively inhibited the proliferation of A549 cells by inducing apoptosis and arresting cells at G1 stage. Furthermore, Oenothein B not only increased the level of intracellular reactive oxygen species (ROS), but also induced the upregulation of intracellular apoptotic triggers (cleavage caspase-3, PARP, cytochrome c level in the cytosol, Bax). Moreover, ROS inhibitor (N-acetyl-L-cystein, NAC) and PI3K agonist (Insulin-like growth factor 1, IGF-1) could resist cell proliferation inhibition induced by Oenothein B, respectively. ROS inhibitor significantly abrogated the activation of caspase 3/7 and 9 in the presence of Oenothein B. Additionally, suppression of p-PI3K and p-Akt, p-NF-κB by Oenothein B could be compensated by treatment with ROS inhibitor. To summarize, these results demonstrated that Oenothein B was able to prevent cell proliferation probably via ROS-mediated PI3K/Akt/NF-κB signaling pathway.

Anti-osteoporotic activity of puerarin 6"-O-xyloside on ovariectomized mice and its potential mechanism.

CONTEXT: Osteoporosis is one of the most common bone diseases, and radix of Pueraria lobata (Willd.) Ohwi possesses an obvious therapeutical effect on postmenopausal osteoporosis. OBJECTIVE: This study investigates the anti-osteoporotic activity of the puerarin 6"-O-xyloside (PXY) on ovariectomized mice and its related mechanism. MATERIALS AND METHODS: Osteoporotic mice model was established by ovariectomy (OVX). A total of 50 mice were divided into five groups (n = 10): sham, OVX group, PXY treatment groups (20, 40, and 60 mg/kg/d, i.p.). After 12 weeks' treatment, body weights were recorded. Then, mice were sacrificed, and serum samples were collected to determine the blood calcium, blood phosphorus, alkaline phosphatase (ALP), and osteoprotegerin (OPG) concentrations and uterine index was assayed. The thigh-bones of mice were collected to evaluate histopathological changes. In the in vitro experiment, the effect of PXY on osteoblasts' proliferation was evaluated and western blotting was performed to determine expressions of OPG and the receptor activators of NF-κB ligand (RANKL), as well as the ratio of OPG/RANKL. RESULTS: PXY (40 and 60 mg/kg/d, i.p.) obviously decreased body weights and increased uterine index of OVX (p < 0.05), and improved osteoporotic syndromes of OVX mice; PXY also significantly increased the concentrations of blood calcium, blood phosphorus, ALP, and OPG of OVX mice (p < 0.05); moreover, PXY obviously up-regulated the ratio of OPG/RANKL (p < 0.05). CONCLUSION: Our results demonstrated that the puerarin 6"-O-xyloside possesses significant anti-osteoporotic activity on ovariectomy mice.

Genetic variation in interleukin-10 gene and risk of oral cancer.

BACKGROUND: Common genetic variants in immune and inflammatory response genes can affect the risk of developing oral cancer. Interleukin-10 (IL-10) is an immunosuppressive cytokine which may facilitate development of cancer by supporting tumor escape from the immune response. Inter-individual variations in IL-10 production were genetically contributed to polymorphisms within IL-10 promoter region. We determined whether single nucleotide polymorphisms (SNPs) at positions -1082 A/G (rs1800870), -819 T/C (rs1800871) and -592 A/C (rs1800872) in the IL-10 gene promoter were involved in predisposing an individual to oral cancer. METHODS: We analyzed 3 SNPS of IL-10 gene promoter in 280 patients with oral cancer and 300 age and sex matched controls in a Chinese population, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) strategy. RESULTS: There were significant differences in the genotype and allele distribution of -1082 A/G (rs1800870) polymorphism of the IL-10 gene among cases and controls. The -1082 G alleles carriers were associated with a significantly increased risk of oral cancer compared with the non-carriers (OR=1.821, 95% CI, 1.329-2.496, P<0.001). Haplotype analysis revealed that the GCC haplotype (defined by SNPs at positions -1082, -819 and -592) of IL-10 gene conveys the highest risk for oral cancer compared with the ATA haplotype (OR=1.716; 95% CI, 1.230-2.395; P=0.001). CONCLUSION: IL-10 gene promoter -1082 A/G (rs1800870) polymorphism, and its haplotype are significantly associated with the risk of oral cancer. Our data suggests that IL-10 gene plays an important role in the development of oral cancer.

Genetic polymorphisms of the interleukin-18 gene and risk of prostate cancer.

Genetic factors are known to be important in the development of prostate cancer. Interleukin-18 (IL-18) is a multifunctional cytokine that induces interferon-gamma secretion and plays an important role in antitumor immunity. Variations in the DNA sequence in the IL-18 gene promoter may lead to altered IL-18 production and/or activity, and so this can modulate an individual's susceptibility to prostate cancer. To test this hypothesis, we investigated the relationship of IL-18 gene promoter -137 G/C and -607 C/A polymorphisms and their haplotypes with the risk of prostate cancer. We analyzed two single nucleotide polymorphisms of IL-18 gene promoter -137 G/C and -607 C/A in 265 patients with prostate cancer and 280 age- and sex-matched controls, using sequence-specific primers-polymerase chain reaction strategy. There were significant differences in the genotype and allele distribution of -137 G/C polymorphism of the IL-18 gene among cases and controls. The -137 GC and CC genotypes were associated with a significantly increased risk of prostate cancer as compared with the -137 GG genotypes [odds ratio (OR) = 1.721; 95% confidence interval (CI): 1.187-2.496; p = 0.004, and OR = 2.181; 95% CI: 1.034-4.603; p = 0.037, for GC and CC, respectively]. Consistent with the results of the genotyping analyses, the -137C/-607A haplotype was associated with a significantly increased risk of prostate cancer as compared with the -137G/-607C haplotype (OR = 1.544; 95% CI, 1.137-2.096; p = 0.005). This study shows for the first time an association between IL-18 gene promoter -137 G/C polymorphism and prostate cancer in a Chinese population.