The recent coronavirus disease 2019 (COVID-19) pandemic is a global threat for healthcare management and the economic system, and effective treatments against the pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus responsible for this disease have not yet progressed beyond the developmental phases. As drug refinement and vaccine progression require enormously broad investments of time, alternative strategies are urgently needed. In this study, we examined phytochemicals extracted from Avicennia officinalis and evaluated their potential effects against the main protease of SARS-CoV-2. The antioxidant activities of A. officinalis leaf and fruit extracts at 150 µg/mL were 95.97% and 92.48%, respectively. Furthermore, both extracts displayed low cytotoxicity levels against Artemia salina. The gas chromatography–mass spectroscopy analysis confirmed the identifies of 75 phytochemicals from both extracts, and four potent compounds, triacontane, hexacosane, methyl linoleate, and methyl palminoleate, had binding free energy values of −6.75, −6.7, −6.3, and −6.3 Kcal/mol, respectively, in complexes with the SARS-CoV-2 main protease. The active residues Cys145, Met165, Glu166, Gln189, and Arg188 in the main protease formed non-bonded interactions with the screened compounds. The root-mean-square difference (RMSD), root-mean-square fluctuations (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), and hydrogen bond data from a molecular dynamics simulation study confirmed the docked complexes′ binding rigidity in the atomistic simulated environment. However, this study′s findings require in vitro and in vivo validation to ensure the possible inhibitory effects and pharmacological efficacy of the identified compounds.

δ-Valerobetaine (δVB) is a constitutive milk metabolite with antioxidant and anti-inflammatory activities. Here, we tested the antineoplastic properties of milk δVB on human colorectal cancer cells. CCD 841 CoN (non-tumorigenic), HT-29 (p53 mutant adenocarcinoma) and LoVo (APC/RAS mutant adenocarcinoma) cells were exposed to 3 kDa milk extract, δVB (2 mM) or milk+δVB up to 72 h. Results showed a time-and dose-dependent capability of δVB to inhibit cancer cell viability, with higher potency in LoVo cells. treatment with milk+δVB arrested cell cycle in G2/M and SubG1 phases by upregulating p21, cyclin A, cyclin B1 and p53 protein expressions. Noteworthy, δVB also increased necrosis (P < 0.01) and when used in combination with milk it improved its activity on live cell reduction (P < 0.05) and necrosis (P < 0.05). δVB-enriched milk activated caspase 3, caspase 9, Bax/ Bcl-2 apoptotic pathway and reactive oxygen species (ROS) production, whereas no effects on ROS generation were observed in CCD 841 CoN cells. The altered redox homeostasis induced by milk+δVB was accompanied by upregulation of sirtuin 6 (SIRT6). SIRT6 silencing by small interfering RnA blocked autophagy and apoptosis activated by milk+δVB, unveiling the role of this sirtuin in the RoS-mediated apoptotic LoVo cell death.

Papillary thyroid carcinoma (PTC) is the most frequent thyroid malignant neoplasia. Oncogene activation occurs in more than 70% of the cases. Indeed, about 40% of PTCs harbor mutations in BRAF gene, whereas RET rearrangements (RET/PTC oncogenes) are present in about 20% of cases. Finally, RAS mutations and TRK rearrangements account for about 5% each of these malignancies. We used RNA-Sequencing to identify fusion transcripts and mutations in cancer driver genes in a cohort of 18 PTC patients. Furthermore, we used targeted DNA sequencing to validate identified mutations. We extended the screening to 50 PTC patients and 30 healthy individuals. Using this approach we identified new missense mutations in CBL, NOTCH1, PIK3R4 and SMARCA4 genes. We found somatic mutations in DICER1, MET and VHL genes, previously found mutated in other tumors, but not described in PTC. We identified a new chimeric transcript generated by the fusion of WNK1 and B4GALNT3 genes, correlated with B4GALNT3 overexpression. Our data confirmed PTC genetic heterogeneity, revealing that gene expression correlates more with the mutation pattern than with tumor staging. Overall, this study provides new data about mutational landscape of this neoplasia, suggesting potential pharmacological adjuvant therapies against Notch signaling and chromatin remodeling enzymes.

In this study, chestnut shells (CS) were used in order to obtain bioactive compounds through different extraction procedures. The aqueous extracts were chemically characterized. The highest extraction yield and total phenolic content was obtained by conventional liquid extraction (CLE). Gallic and protocatechuic acids were the main simple phenols in the extract, with 86.97 and 11.20 mg/g chestnut shells dry extract (CSDE), respectively. Six tumor cell lines (DU 145, PC-3, LNCaP, MDA-MB-231, MCF-7, and HepG2) and one normal prostate epithelial cell line (PNT2) were exposed to increasing concentration of CSDE (1–100 µg/mL) for 24 h, and cell viability was evaluated using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide MTT assay. A reduced rate in cell viability was observed in DU 145, PC-3, LNCaP, and MCF-7 cells, while viability of the other assessed cells was not affected, except for PNT2 cells at a concentration of 100 μg/mL. Furthermore, CSDE—at concentrations of 55.5 and 100 µg/mL—lead to a significant increase of apoptotic cells in DU 145 cells of 28.2% and 61%, respectively. In conclusion, these outcomes suggested that CS might be used for the extraction of several polyphenols that may represent good candidates for alternative therapies or in combination with current chemotherapeutics.

Lung cancer is one of the most common causes of cancer-related death worldwide in men and women, and, despite the recent remarkable scientific advances, drug treatment is still unsatisfactory. Polycomb protein chromobox homolog 7 (CBX7) is involved in several biological processes, including development and cancer progression, indeed the lack of CBX7 protein correlates with a highly malignant phenotype and a poor prognosis. However, its role in lung cancer still remains unknown. Since CBX7 is drastically downregulated in human lung carcinomas, we investigated whether restoration of CBX7 expression could affect growth property of lung cancer cells and modulate their sensitivity to treatment with irinotecan and etoposide, two chemoterapy drugs most commonly used in lung cancer therapy. Here, we demonstrate that restoration of CBX7 in two human lung carcinoma cell lines (A549 and H1299), in which this protein is not detectable, leads to a decreased proliferation (at least in part through a downregulation of phosphorylated ERK and phosphorylated p38) and an increased apoptotic cell death after drug exposure (at least in part through the downregulation of Bcl-2, phosphorylated Akt, and phosphorylated JNK). Taken together, these results suggest that the retention of CBX7 expression may play a role in the modulation of chemosensitivity of lung cancer patients to the treatment with irinotecan and etoposide.

Colorectal cancer (CRC) is one of the most frequent and deadly malignancies worldwide. Despite the progresses made in diagnosis and treatment, the identification of tumor markers is still a strong clinical need, because current treatments are efficacious only in a subgroup of patients. UbcH10 represents a potential candidate biomarker, whose expression levels could be employed to predict response or resistance to chemotherapy or targeted agents. UbcH10 mRNA and protein expression levels have been evaluated in a large group of CRC patients and correlated with clinico-pathological characteristics, including KRAS mutations. Moreover, the endogenous levels of UbcH10 and its role on cell growth have been evaluated in CRC cells. Finally, to investigate the impact of UbcH10 protein expression on the response to irinotecan, its active metabolite SN-38 and cetuximab treatment, UbcH10 silencing experiments were carried-out on two colon carcinoma cell lines, Caco-2, and DLD1. Overexpression of UbcH10 mRNA and protein was observed in the vast majority of patients analyzed. UbcH10 suppression decreased CRC cell growth rate (at least in part through deregulation of Cyclin B and ERK1) and sensitized them to pharmacological treatments with irinotecan, SN-38 and cetuximab (at least in part through a down-regulation of AKT). Taken together, these findings indicate that UbcH10 expression regulates CRC growth and could play an important role in the personalization of the therapy of CRC patients.

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Several recent studies have reported the Polycomb Repressive Complex 1 member CBX7 as a tumor-suppressor gene whose expression progressively decreases in different human carcinomas in relation with tumor grade, malignant stage and poor prognosis. We have previously demonstrated that CBX7 is able to inhibit the expression of the SPP1 gene, encoding the chemokine osteopontin that is over-expressed in cancer and has a critical role in cancer progression.Here, we have analyzed the mechanism by which CBX7 regulates the SPP1 gene expression. We show that the SPP1 transcriptional regulation mechanism involves the CBX7-interacting protein HMGA1b, that acts as a positive regulator of the SPP1 gene. In fact, we demonstrate that, in contrast with the transcriptional activity of CBX7, HMGA1b is able to increase the SPP1 expression by inducing the activity of its promoter. Moreover, we show that CBX7 interferes with HMGA1b on the SPP1 promoter and counteracts the positive transcriptional activity of HMGA1b on the SPP1 expression.Furthermore, since we found that also the NF-κB complex resulted involved in the modulation of the SPP1 expression in thyroid cells, we suppose that CBX7/HMGA1b/NF-κB could take part in the same transcriptional mechanism that finally leads to the regulation of the SPP1 gene expression.Taken together, our data show the important role played by CBX7 in the negative regulation of the SPP1 gene expression, thus contributing to prevent the acquisition of a malignant phenotype.