In Vitro Cytotoxicity of Antiresorptive and Antiangiogenic Compounds on Oral Tissues Contributing to MRONJ: Systematic Review.

BACKGROUND: Invasive dental treatment in patients exposed to antiresorptive and antiangiogenic drugs can cause medication-related osteonecrosis of the jaw (MRONJ). Currently, the exact pathogenesis of this disease is unclear. METHODS: In March 2022, Medline (Ovid), Embase (Ovid), Scopus, and Web of Science were screened to identify eligible in vitro studies investigating the effects of antiresorptive and antiangiogenic compounds on orally derived cells. RESULTS: Fifty-nine articles met the inclusion criteria. Bisphosphonates were used in 57 studies, denosumab in two, and sunitinib and bevacizumab in one. Zoledronate was the most commonly used nitrogen-containing bisphosphonate. The only non-nitrogen-containing bisphosphonate studied was clodronate. The most frequently tested tissues were gingival fibroblasts, oral keratinocytes, and alveolar osteoblasts. These drugs caused a decrease in cell proliferation, viability, and migration. CONCLUSIONS: Antiresorptive and antiangiogenic drugs displayed cytotoxic effects in a dose and time-dependent manner. Additional research is required to further elucidate the pathways of MRONJ.

Transcriptional regulation of glucose transporters in human oral squamous cell carcinoma cells.

The increased glucose uptake observed in cancer cells is mediated by glucose transporters (GLUTs), a class of transmembrane proteins that facilitate the transport of glucose and other substrates across the plasma membrane. Despite the important role of glucose in the pathophysiology of oral squamous cell carcinoma (OSCC), there is very limited data regarding the expression of GLUTs in normal or malignant cells from the oral mucosa. We analysed the messenger RNA (mRNA) expression of all 14 GLUTs in two OSCC (H357/H400) and one non-malignant oral keratinocyte (OKF6) cell line using a quantitative polymerase chain reaction. GLUT expression was evaluated at baseline and after treatment with two specific GLUT inhibitors, namely, BAY876 (GLUT1) and WZB117 (GLUT1, GLUT3 and GLUT4). Here, we show that GLUT1, GLUT3, GLUT4, GLUT5, GLUT6, GLUT8, GLUT12 and GLUT13 transcripts were measurably expressed in all cell lines while GLUT2, GLUT7, GLUT9, GLUT11 and GLUT14 were not expressed. GLUT10 was only found in H357. In the presence of BAY876 and WZB117, OSCC cells exhibited significant alterations in the transcriptional profile of GLUTs. In particular, we observed distinct proliferation-dependent changes of mRNAs to GLUT1, GLUT3, GLUT4, GLUT5 and GLUT6 in response to selective GLUT inhibitors. In summary, we documented for the first time the expression of GLUT5, GLUT6 and GLUT12 in normal and malignant oral keratinocytes. Whilst regulation of GLUT transcripts was cell line and inhibitor specific, GLUT3 was consistently upregulated in actively proliferating OSCC cell lines, but not in OKF6, regardless of the inhibitor used, suggesting that modulation of this transporter may act as one of the primary compensation mechanisms for OSCC cells upon inhibition of glucose uptake.

Systematic comparison of activity and mechanism of antimicrobial peptides against nosocomial pathogens.

The World Health Organisation has deemed several multi-drug resistant (MDR) nosocomial bacterial pathogens to be of significant threat to human health. A stark increase in morbidity, mortality and the burden to healthcare systems around the world can be attributed to the development of resistance in these bacteria. Accordingly, alternative antimicrobial agents have been sought as an attractive means to combat MDR pathogens, with one such example being antimicrobial peptides (AMPs). Given the reported activity of AMPs, including Pardaxin, MSI-78, dermaseptin-PC (DMPC) and Cecropin B, it is important to understand their activities and modes of action against bacteria for further AMP design. In this study, we compared these AMPs against a panel of nosocomial bacterial pathogens, followed by detailed mechanistic studies. It was found that Pardaxin (1-22) and MSI-78 (4-20) displayed the most pronounced antimicrobial activity against the tested bacteria. The mechanistic studies by membrane permeability and molecular dynamics simulation further confirmed the strong membrane interaction and structure of Pardaxin (1-22) and MSI-78 (4-20), which contributed to their potent activity. This study demonstrated a structure and activity guidance for further design of Pardaxin (1-22) and MSI-78 (4-20) as therapeutics against MDR pathogens. The different effects of DMPC (1-19) and Cecropin B (1-21) on membrane integrity and phospholipid membrane interactions provided critical information for the rational design of next-generation analogues with specificity against either Gram-negative or Gram-positive bacteria.

The Potential of Modified and Multimeric Antimicrobial Peptide Materials as Superbug Killers.

Antimicrobial peptides (AMPs) are found in nearly all living organisms, show broad spectrum antibacterial activity, and can modulate the immune system. Furthermore, they have a very low level of resistance induction in bacteria, which makes them an ideal target for drug development and for targeting multi-drug resistant bacteria 'Superbugs'. Despite this promise, AMP therapeutic use is hampered as typically they are toxic to mammalian cells, less active under physiological conditions and are susceptible to proteolytic degradation. Research has focused on addressing these limitations by modifying natural AMP sequences by including e.g., d-amino acids and N-terminal and amino acid side chain modifications to alter structure, hydrophobicity, amphipathicity, and charge of the AMP to improve antimicrobial activity and specificity and at the same time reduce mammalian cell toxicity. Recently, multimerisation (dimers, oligomer conjugates, dendrimers, polymers and self-assembly) of natural and modified AMPs has further been used to address these limitations and has created compounds that have improved activity and biocompatibility compared to their linear counterparts. This review investigates how modifying and multimerising AMPs impacts their activity against bacteria in planktonic and biofilm states of growth.