• 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • 2021-03
  • At this point it is at least clearly known that


    At this point, it is at least clearly known that O-GlcNAcylation plays a significant role in AD pathophysiology which makes this post-translational modification an attractive target to tackle this devastating neurodegenerative disease. Using a pharmacological approach to modulate O-GlcNAcylation in differentiated SH-SY5Y cells, this study reveals that Thiamet-G is able to induce a robust augment in global O-GlcNAcylation levels (Fig. 8C and D) without affecting neither cell viability (Fig. 8A) nor ΔΨm (Fig. 8B). Accordingly, Yuzwa and collaborators demonstrated that Thiamet-G increases O-GlcNAcylation levels in PC12 cells and no signs of toxicity were detected [55]. Concerning the protective potential of Thiamet-G, we found that only the pre-treatment with Thiamet- G was able to prevent loss of O-GlcNAcylation levels (Fig. 9) and cell viability (Fig. 10) demonstrating that under our in vitro experimental settings Thiamet-G demonstrated a preventive role. It has been previously demonstrated that Thiamet-G increases O-GlcNAcylation levels in JNPL3 transgenic mice, which express a mutant hyperphosphorylated and aggregate-prone tau isoform, and decreases the extent of NFTs in the brain, slowing down tau-driven neurodegeneration [56]. The same authors also found that increased O-GlcNAcylation decreases the formation of tau Omadacycline in vitro, without changing its structural monomeric form, causing neuronal cell loss [56,57]. In the same line, Hastings and colleagues [58] reported that chronic inhibition of OGA, through genetic and pharmacological approaches, reduces pathological tau in the brain and total tau in cerebrospinal fluid of rTg4510 mice probably by directly increasing O- GlcNAcylation of tau and thereby maintaining tau in the soluble, non-toxic form by reducing tau aggregation. Yuzwa and colleagues also demonstrated that Thiamet-G increases O-GlcNAcylation, attenuates Aβ burden, the formation of neuritic plaques and memory deficits in a mice bearing both mutated human tau and APP (TAPP mice) [59]. Another OGA inhibitor, 1,2-dideoxy-2′-propyl-α-d-glucopyranoso-[2,1-D]-Δ2′-thiazoline (NButGT), caused a reduction of Aβ production by lowering γ-secretase activity both in vitro and in vivo [60]. Moreover, NButGT attenuated the accumulation of Aβ, neuroinflammation, and memory impairment in the 5XFAD mice [60].
    Conclusion Our results support the idea that reduced O-GlcNAcylation underlies AD pathology representing a “sweet” route to tackle this devastating neurodegenerative disease. However, further studies are required to clarify the key mechanisms associated to the loss O-GlcNAcylation that contribute to the onset and/or aggravation of AD pathology.
    Transparency document
    Acknowledgements Sónia C. Correia has a post-doctoral fellowship (SFRH/BPD/109822/2015) from the Fundação para a Ciência e a Tecnologia (FCT). Tiffany S. Pinho is recipient of a research fellowship from the Healthy Aging 2020 (CENTRO-01-0145-FEDER-000012). The authors' work is supported by FEDER funds through the Operational Programme Competitiveness Factors — COMPETE, national funds by FCT under the project PEst-C/SAU/LA0001/2013-2014 and strategic project UID/NEU/04539/2013 and Santa Casa da Misericórdia de Lisboa - Mantero Belard Award 2015 (MB-1049-2015).
    Introduction One of the main objectives in regenerative medicine is to generate a native-similar tissue replacement for joint diseases. Since articular cartilage (AC) has a significantly poor self-renewal ability, is avascular, aneural and has a complex associated surgery, it constitutes a sought-after target for researchers and clinicians. Currently, there are many different treatments: from nonsteroidal anti-inflammatory drugs (NSAIDs) to invasive interventions including implants, cellular treatments or osteochondral rupture among others. Some of them have achieved meaningful results for patients, though without achieving the levels of quality of life prior to the injury. In addition, the biomechanics of the joint is always deteriorated after the disease, independently of the treatment applied. Because of this, many scientists tried to discover the physical principles that govern AC and how they change in different joint disorders. Until now, this has not been an easy task and there is no consensus about which biomechanical principles are governing the regeneration of cartilage tissue. This review compiles the principles behind the biomechanics of the cartilage (Fig. 1), describing the characteristics of healthy AC and how it changes in osteoarthritis (OA), the most common cartilage disease. In addition, we describe previous studies about the application of biomechanics fundamentals into regenerative therapies of AC. Biomechanics is a ground part of cell biology and requires interaction with biochemical pathways and cell metabolism. Consequently, optimizing biomechanics and the biochemical niche as an interconnected system can potentially contribute to the consecution of a real long-term viable replacement for can overcoming OA.