Human papilloma virus (HPV) expressing E6 and E7 oncoproteins, is known to inactivate the tumor suppressor p53 through proteasomal degradation in cervical cancers. Therefore, use of small molecules for inhibition of proteasome function and induction of p53 reactivation is a promising strategy for induction of apoptosis in cervical cancer cells. The polyphenolic alkanone, 6-Gingerol (6G), present in the pungent extracts of ginger (Zingiber officinale Roscoe) has shown potent anti-tumorigenic and pro-apoptotic activities against a variety of cancers. In this study we explored the molecular mechanism of action of 6G in human cervical cancer cells in vitro and in vivo. 6G potently inhibited proliferation of the HPV positive cervical cancer cells. 6G was found to: (i) inhibit the chymotrypsin activity of proteasomes, (ii) induce reactivation of p53, (iii) increase levels of p21, (iv) induce DNA damage and G2/M cell cycle arrest, (v) alter expression levels of p53-associated apoptotic markers like, cleaved caspase-3 and PARP, and (vi) potentiate the cytotoxicity of cisplatin. 6G treatment induced significant reduction of tumor volume, tumor weight, proteasome inhibition and p53 accumulation in HeLa xenograft tumor cells in vivo. The 6G treatment was devoid of toxic effects as it did not affect body weights, hematological and osteogenic parameters. Taken together, our data underscores the therapeutic and chemosensitizing effects of 6G in the management and treatment of cervical cancer.

Repair of critical size bone defects is a clinical challenge that usually necessitates the use of bone substitutes. For successful bone repair, the substitute should possess osteoconductive, osteoinductive, and vascularization potential, with the ability to control post-implantation infection serving as an additional advantage. With an aim to develop one such substitute, we optimized a zinc-doped hydroxyapatite (HapZ) nanocomposite decorated on reduced graphene oxide (rGO), termed as G3HapZ, and demonstrated its potential to augment the bone repair. The biocompatible composite displayed its osteoconductive potential in biomineralization studies, and its osteoinductive property was confirmed by its ability to induce mesenchymal stem cell (MSC) differentiation to osteogenic lineage assessed by in vitro mineralization (Alizarin red staining) and expression of osteogenic markers including runt-related transcription factor 2 (RUNX-2), alkaline phosphatase (ALP), type 1 collagen (COL1), bone morphogenic protein-2 (BMP-2), osteocalcin (OCN), and osteopontin (OPN). While the potential of G3HapZ to support vascularization was displayed by its ability to induce endothelial cell migration, attachment, and proliferation, its antimicrobial activity was confirmed using S. aureus. Biocompatibility of G3HapZ was demonstrated by its ability to induce bone regeneration and neovascularization in vivo. These results suggest that G3HapZ nanocomposites can be exploited for a range of strategies in developing orthopedic bone grafts to accelerate bone regeneration.

Discoveries in the last few years have emphasized the existence of an enormous breadth of communication between osteo-immune systems. These discoveries fuel novel approaches for the treatment of several bone pathologies including osteoporosis. Bifidobacterium longum (BL) is a preferred probiotic of choice due to its varied immunomodulatory potential in alleviating various inflammatory diseases. Here, we evaluate the effect of BL in an ovariectomy (ovx)-induced post-menopausal osteoporotic mouse model. Our in vitro findings reveal that BL suppresses the differentiation and functional activity of RANKL-induced osteoclastogenesis in both mouse bone marrow cells and human PBMCs. Strikingly, BL-induced Bregs were found to be significantly more efficient in suppressing osteoclastogenesis and modulating Treg–Th17 cell balance with respect to control Bregs in vitro. Our in vivo µCT and bone mechanical strength data further confirm that BL supplementation significantly enhanced bone mass and bone strength, along with improving the bone microarchitecture in ovx mice. Remarkably, alterations in frequencies of CD19+CD1dhiCD5+IL-10+ Bregs, CD4+Foxp3+IL-10+ Tregs, and CD4+Rorγt+IL-17+ Th17 cells in distinct lymphoid organs along with serum-cytokine data (enhanced anti-osteoclastogenic cytokines IFN-γ and IL-10 and reduced osteoclastogenic-cytokines IL-6, IL-17, and TNF-α) strongly support the immunomodulatory potential of BL. Altogether, our findings establish a novel osteo-protective and immunomodulatory potential of BL in augmenting bone health under osteoporotic conditions.

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