Autophagy and Polyphenols in Osteoarthritis: A Focus on Epigenetic Regulation

Autophagy is an intracellular mechanism that maintains cellular homeostasis in different tissues. This process declines in cartilage due to aging, which is correlated with osteoarthritis (OA), a multifactorial and degenerative joint disease. Several studies show that microRNAs regulate different steps of autophagy but only a few of them participate in OA. Therefore, epigenetic modifications could represent a therapeutic opportunity during the development of OA. Besides, polyphenols are bioactive components with great potential to counteract diseases, which could reverse altered epigenetic regulation and modify autophagy in cartilage. This review aims to analyze epigenetic mechanisms that are currently associated with autophagy in OA, and to evaluate whether polyphenols are used to reverse the epigenetic alterations generated by aging in the autophagy pathway.

The mitochondrial deubiquitinase USP30 regulates AKT/mTOR signaling

Mitophagy is an intracellular mechanism to maintain mitochondrial health by removing dysfunctional mitochondria. The E3 ligase Parkin ubiquitinates the membrane proteins on targeted mitochondria to initiate mitophagy, and USP30 antagonizes this Parkin-dependent mitophagy. AKT/mTOR signaling is a master regulator of cell proliferation, differentiation, survival, and growth. Although mounting evidence showed mitophagy and AKT/mTOR signaling interact with each other during mitophagy, the specific mechanisms between Parkin/USP30 and AKT/mTOR signaling have not been elucidated. This research artificially expressed Parkin and USP30 in Hela cells and compared AKT/mTOR and apoptosis signals between Hela cells, HeLa Parkin cells, and Hela Parkin USP30 cells during mitophagy. The study results suggest that Parkin promotes AKT degradation via ubiquitination, which induces cell apoptosis during mitochondrial stress. On the contrary, USP30 protects AKT via deubiquitination. These findings provide new insights into the roles of Parkin and USP30 in cell apoptosis and physiological and pathological functions of USP30 beyond mitophagy.

Coronaviruses construct an interconnection way with ERAD and autophagy

Coronaviruses quickly became a pandemic or epidemic, affecting large numbers of humans, due to their structural features and also because of their impacts on intracellular communications. The knowledge of the intracellular mechanism of virus distribution could help understand the coronavirus’s proper effects on different pathways that lead to the infections. They protect themselves from recognition and damage the infected cell by using an enclosed membrane through hijacking the autophagy and endoplasmic reticulum-associated protein degradation pathways. The present study is a comprehensive review of the coronavirus strategy in upregulating the communication network of autophagy and endoplasmic reticulum-associated protein degradation.

Effects of a New Combination of Natural Extracts on Glaucoma-Related Retinal Degeneration

Background: Glaucoma is currently the leading cause of irreversible blindness; it is a neuropathy characterized by structural alterations of the optic nerve, leading to visual impairments. The aim of this work is to develop a new oral formulation able to counteract the early changes connected to glaucomatous degeneration. The composition is based on gastrodin and vitamin D3 combined with vitamin C, blackcurrant, and lycopene. Methods: Cells and tissues of the retina were used to study biological mechanisms involved in glaucoma, to slow down the progression of the disease. Experiments mimicking the conditions of glaucoma were carried out to examine the etiology of retinal degeneration. Results: Our results show a significant ability to restore glaucoma-induced damage, by counteracting ROS production and promoting cell survival by inhibiting apoptosis. These effects were confirmed by the intracellular mechanism that was activated following administration of the compound, either before or after the glaucoma induction. In particular, the main results were obtained as a preventive action of glaucoma, showing a beneficial action on all selected markers, both on cells and on eyecup preparations. It is therefore possible to hypothesize both the preventive and therapeutic use of this formulation, in the presence of risk factors, and due to its ability to inhibit the apoptotic cycle and to stimulate cell survival mechanisms, respectively. Conclusion: This formulation has exhibited an active role in the prevention or restoration of glaucoma damage for the first time.

Leaf Plasmodesmata Respond Differently to TMV, ToBRFV and TYLCV Infection

Macromolecule and cytosolic signal distribution throughout the plant employs a unique cellular and intracellular mechanism called plasmodesmata (PD). Plant viruses spread throughout plants via PD using their movement proteins (MPs). Viral MPs induce changes in plasmodesmata’s structure and alter their ability to move macromolecule and cytosolic signals. The developmental distribution of a family member of proteins termed plasmodesmata located proteins number 5 (PDLP5) conjugated to GFP (PDLP5-GFP) is described here. The GFP enables the visual localization of PDLP5 in the cell via confocal microscopy. We observed that PDLP5-GFP protein is present in seed protein bodies and immediately after seed imbibition in the plasma membrane. The effect of three different plant viruses, the tobacco mosaic virus (TMV), tomato brown rugose fruit virus (ToBRFV, tobamoviruses), and tomato yellow leaf curl virus (TYLCV, begomoviruses), on PDLP5-GFP accumulation at the plasmodesmata was tested. In tobacco leaf, TMV and ToBRFV increased PDLP5-GFP amount at the plasmodesmata of cell types compared to control. However, there was no statistically significant difference in tomato leaf. On the other hand, TYLCV decreased PDLP5-GFP quantity in plasmodesmata in all tomato leaf cells compared to control, without any significant effect on plasmodesmata in tobacco leaf cells.

Intracellular role of IL-6 in mesenchymal stromal cell immunosuppression and proliferation

Interleukin (IL)-6 is a pleiotropic cytokine involved in the regulation of hematological and immune responses. IL-6 is secreted chiefly by stromal cells, but little is known about its precise role in the homeostasis of human mesenchymal stromal cells (hMSCs) and the role it may play in hMSC-mediated immunoregulation. We studied the role of IL-6 in the biology of bone marrow derived hMSC in vitro by silencing its expression using short hairpin RNA targeting. Our results show that IL-6 is involved in immunosuppression triggered by hMSCs. Cells silenced for IL-6 showed a reduced capacity to suppress activated T-cell proliferation. Moreover, silencing of IL-6 significantly blocked the capacity of hMSCs to proliferate. Notably, increasing the intracellular level of IL-6 but not recovering the extracellular level could restore the proliferative impairment observed in IL-6-silenced hMSC. Our data indicate that IL-6 signals in hMSCs by a previously undescribed intracellular mechanism.

High phosphate levels promote muscle atrophy via myostatin expression in differentiated L6 myotubes

Background: Sarcopenia is the age-induced, progressive loss of skeletal muscle mass and function. This phenomenon is observed in patients with chronic kidney disease (CKD). However, the intracellular mechanism underlying the progressive sarcopenia in CKD has not been completely elucidated. Although hyperphosphatemia contributes to cellular senescence, it is unclear whether this condition induces skeletal muscle atrophy. The aim of this study was to determine the effect of hyperphosphatemia on skeletal muscle. Methods: Differentiated rat myoblast cells (L6) were exposed to normal (0.9 mM; CON), medium (2.5 mM), and high (3.8mM; HPi) phosphate conditions for 10 days. We measured the protein levels of myosin heavy chain (MHC) and myostatin and determined the ratio of phosphorylated p70S6K and cleaved caspase-3 by western blot. The expression levels of the myogenic transcriptional regulators MyoD and myogenin were measured by qPCR. Results: The levels of MHC were gradually downregulated depending on the phosphate concentration. Myostatin in HPi was about 20 times higher than in CON (P<0.001). In myotubes cultured in HPi, protein synthesis was significantly lower, and degradation was significantly higher than in CON (P<0.01). The mRNA expression of MyoD in HPi was significantly lower than in CON. Conclusions: This study showed that hyperphosphatemia strongly induced muscle atrophy with the accumulation of myostatin. This mechanism might include the downregulation of protein synthesis, upregulation of proteolysis, and attenuated muscle regeneration.

Enhanced mitochondrial membrane potential and ATP synthesis by photobiomodulation increases viability of the auditory cell line after gentamicin-induced intrinsic apoptosis

Photobiomodulation (PBM) has been suggested to have a therapeutic effect on irreversible hearing loss induced by aminoglycosides, including gentamicin (GM). However, its intracellular mechanism(s) in GM-induced ototoxicity remain poorly understood. In the present study, we investigated the effect of PBM in GM-induced ototoxicity in auditory cells. We tried to characterize the downstream process by PBM, and the process that triggered the increased cell viability of auditory cells. As a result, the effects of PBM against GM-induced ototoxicity by increasing ATP levels and mitochondrial membrane potential was confirmed. These results suggest a theory to explain the therapeutic effects and support the use of PBM for aminoglycoside-induced hearing loss.

Peroxisome proliferator-activated receptors and thiazolidinediones in diabetic nephropathy

Diabetic nephropathy is global problem with several drugs into trial without much success the current article highlights the role of thiazolidinedione’s in diabetic nephropathy by scrutinizing and reconnoitring the cellular and intracellular mechanism and shielding action and the role of peroxisome proliferator-activated gamma receptors (PPARγ) receptors. Not only anti-diabetic action but renal protective effect with evidence based study has been highlighted. PPAR γ-is versatile target having numerous benefits and mainly preventing fibrosis in diabetic experimental model and some clinical case report yet, the benefits are not up to mark, since renal failure itself causes volume expansion and the thiazolidinedione’s (TZDs) also preserve salt and water and lead to congestive heart failure which constraints its clinical application. Dual activators and balaglitazone selective PPAR modulator are having upcoming potential for treatment of diabetic nephropathy. Further detail investigation on such drug is needed to explore. However adverse effect like heart failure, osteoporosis and volume expansion effect over-rides the beneficial effect thus limiting its clinical use of currently available TZDs.