βPIX and GIT control cellular senescence through integrin signaling.

Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are disorders characterized by progressive degeneration of the nervous system. Currently, there is no disease-modifying treatments for most NDs. Meanwhile, numerous studies conducted on human and animal models over the past decades have showed that exercises had beneficial effects on NDs. Inter-tissue communication by myokine, a peptide produced and secreted by skeletal muscles during exercise, is thought to be an important underlying mechanism for the advantages. Here, we reviewed studies about the effects of myokines regulated by exercise on NDs and their mechanisms. Myokines could exert beneficial effects on NDs through a variety of regulatory mechanisms, including cell survival, neurogenesis, neuroinflammation, proteostasis, oxidative stress, and protein modification. Studies on exercise-induced myokines are expected to provide a novel strategy for treating NDs, for which there are no adequate treatments nowadays. To date, only a few myokines have been investigated for their effects on NDs and studies on mechanisms involved in them are in their infancy. Therefore, future studies are needed to discover more myokines and test their effects on NDs.

Terpenes are vital metabolites found in various plants and animals and known to be beneficial in the treatment of various diseases. Previously, our group identified terpenes that increased the survival of Alzheimer’s disease (AD) model flies expressing human amyloid β (Aβ) and identified linalool as a neuroprotective terpene against Aβ toxicity. Linalool is a monoterpene that is commonly present as a constituent in essential oils from aromatic plants and is known to have anti‐inflammatory, anticancer, antihyperlipidemia, antibacterial, and neuroprotective properties. Although several studies have shown the beneficial effect of linalool in AD animal models, the mechanisms underlying the beneficial effect of linalool on AD are yet to be elucidated. In the present study, we showed that linalool intake increased the survival of the AD model flies during development in a dose‐dependent manner, while the survival of wild‐type flies was not affected even at high linalool concentrations. Linalool also decreases Aβ‐induced apoptosis in eye discs as well as the larval brain. Moreover, linalool intake was found to reduce neurodegeneration in the brain of adult AD model flies. However, linalool did not affect the total amount of Aβ42 protein or Aβ42 aggregation. Rather, linalool decreased Aβ‐induced ROS levels, oxidative stress, and inflammatory response in the brains of AD model flies. Furthermore, linalool attenuated the induction of oxidative stress and gliosis by Aβ_1-42 treatment in the rat hippocampus. Taken together, our data suggest that linalool exerts its beneficial effects on AD by reducing Aβ42‐induced oxidative stress and inflammatory reactions.

Age-related macular degeneration (AMD) is a prevalent retinal disorder that leads to central vision loss, mainly due to chronic inflammation. Tumor necrosis factor-alpha (TNF-α) is a critical mediator of inflammatory responses within the retinal environment. This study has investigated TNF-α’s influence on inflammatory cytokine production and endothelial barrier integrity in human microglial (HMC3) and endothelial (HUVEC) cells. We found that TNF-α significantly elevated the expression and secretion of interleukin-6 (IL-6) and interleukin-1β (IL-1β) in HMC3 cells and disrupted endothelial tight junctions in HUVECs, as evidenced by weakened ZO-1 staining and compromised barrier function. To mitigate these effects and further investigate the in vitro mechanism of actions in CRG-01’s in vivo therapeutic efficacy of anti-inflammation, we employed AAV2-shmTOR, CRG-01, as the candidate for therapeutic vector targeting the mammalian target of the rapamycin (mTOR) pathway. TNF-α-induced IL-6, IL-1β, and NF-κB signaling in HMC3 cells were significantly reduced by AAV2-shmTOR treatment, which may present a promising avenue for the fight against AMD. It also effectively preserved endothelial tight junction integrity in TNF-α-treated HUVECs, providing reassurance about its effectiveness. Furthermore, the supernatant medium collected from AAV2-shmTOR-treated HMC3 cells decreased oxidative stress, protein oxidation, and cytotoxicity in ARPE retinal pigment epithelial cells. These results strongly suggested that CRG-01, the candidate therapeutic vector of AAV2-shmTOR, may have a therapeutic potential to treat AMD-related retinal inflammation.

So-Yoon Won, Soon-Tae You, Seung-Won Choi, Catriona McLean, Eun-Young Shin, and Eung-Gook Kim. Mol. Cells 2021;44:493-9. https://doi.org/10.14348/molcells.2021.2250

Elevated intraocular pressure (IOP) in glaucoma causes retinal ganglion cell (RGC) loss and damage to the optic nerve. Although IOP is controlled pharmacologically, no treatment is available to restore retinal and optic nerve function. In this paper, we aimed to develop a novel gene therapy for glaucoma using an AAV2-based thioredoxin 2 (Trx2)-exoenzyme C3 transferase (C3) fusion protein expression vector (scAAV2-Trx2-C3). We evaluated the therapeutic effects of this vector in vitro and in vivo using dexamethasone (DEX)-induced glaucoma models. We found that scAAV2-Trx2-C3-treated HeLa cells had significantly reduced GTP-bound active RhoA and increased phosphor-cofilin Ser3 protein expression levels. scAAV2-Trx2-C3 was also shown to inhibit oxidative stress, fibronectin expression, and alpha-SMA expression in DEX-treated HeLa cells. NeuN immunostaining and TUNEL assay in mouse retinal tissues was performed to evaluate its neuroprotective effect upon RGCs, whereas changes in mouse IOP were monitored via rebound tonometer. The present study showed that scAAV2-Trx2-C3 can protect RGCs from degeneration and reduce IOP in a DEX-induced mouse model of glaucoma, while immunohistochemistry revealed that the expression of fibronectin and alpha-SMA was decreased after the transduction of scAAV2-Trx2-C3 in murine eye tissues. Our results suggest that AAV2-Trx2-C3 modulates the outflow resistance of the trabecular meshwork, protects retinal and other ocular tissues from oxidative damage, and may lead to the development of a gene therapeutic for glaucoma.