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Oxidative stress is a major component of harmful cascades activated in neurodegenerative disorders. We sought to elucidate possible effects of phillyrin, an active constituent isolated from the Chinese medicinal herb Forsythia suspense, on hydrogen peroxide (H2O2)-induced cell death and determine the underlying molecular mechanisms in neuron-like PC12 cells. By MTT assay and lactate dehydrogenase (LDH) leakage assay, we found that phillyrin treatment effectively protected PC12 cells against H2O2-induced cell damage. H2O2 exposure induced oxidative stress in PC12 cells, as revealed by enhanced oxidative stress and decreased activities of antioxidative enzymes, which were inhibited by phillyrin pretreatment. ROS activated mitochondria-dependent apoptosis. The anti-apoptotic effects of phillyrin were also confirmed by acridine orange/ethidium bromide (AO/EB) staining. Mitochondrial membrane potential decrease, cytochrome c release, caspases activation, activation of AIF and Endo G were observed in H2O2-treated cells by rhodamine 123 or western blot. Interestingly, phillyrin effectively suppressed these changes. Moreover, phillyrin could inhibit H2O2-induced up-regulation of Bax/Bcl-2 ratio. In conclusion, phillyrin effectively inhibited H2O2-induced oxidative stress and apoptosis in PC12 cells.

Schwann cells (SCs) are the major cells constituting the peripheral nerve structure and function, and also secret a variety of neurotrophic factors. Schwann cell (SC) transplantation has recently emerged as a promising therapeutic strategy for spinal cord injury (SCI). In the present study, the ability of genetically modified SCs producing high levels of glial cell line‑derived neurotrophic factor (GDNF) to promote spinal cord repair was assessed. The GDNF gene was transduced into SCs. The engineered SCs were characterized by their ability to express and secrete biologically active GDNF, which was shown to inhibit apoptosis of primary rat neurons induced by radiation, and upregulate the expression of B‑cell lymphoma 2 (Bcl‑2) and downregulate the expression of Bcl‑2 associated X protein (Bax) in vitro. Following SC implantation into the spinal cord of adult rats with SCI induced by weight‑drop impact, the survival of rats with transplanted SCs, histology of the spinal cord and expression levels of Bcl‑2 and Bax were examined. Transplantation of unmodified and genetically modified SCs producing GDNF attenuated SCI by inhibiting apoptosis via the Bcl‑2/Bax pathways. The genetically modified SCs demonstrated markedly improved recovery of SCI as compared with unmodified SCs. The present study combined the outgrowth‑promoting property of SCs with the neuroprotective effects of overexpressed GDNF and identified this as a potential novel therapeutic strategy for SCI.

Melatonin is a bioamine produced primarily in the pineal gland, although peripheral sites, including the gut, may also be its minor source. Melatonin regulates various functions, including circadian rhythm, reproduction, temperature regulation, immune system, cardiovascular system, energy metabolism, and bone metabolism. Studies on cultured bone cells, preclinical disease models of bone loss, and clinical trials suggest favorable modulation of bone metabolism by melatonin. This narrative review gives a comprehensive account of the current understanding of melatonin at the cell/molecular to the systems levels. Melatonin predominantly acts through its cognate receptors, of which melatonin receptor 2 (MT2R) is expressed in mesenchymal stem cells (MSCs), osteoblasts (bone-forming), and osteoclasts (bone-resorbing). Melatonin favors the osteoblastic fate of MSCs, stimulates osteoblast survival and differentiation, and inhibits osteoclastogenic differentiation of hematopoietic stem cells. Produced from osteoblastic cells, osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) critically regulate osteoclastogenesis and melatonin by suppressing the osteoclastogenic RANKL, and upregulating the anti-osteoclastogenic OPG exerts a strong anti-resorptive effect. Although the anti-inflammatory role of melatonin favors osteogenic function and antagonizes the osteoclastogenic function with the participation of SIRT signaling, various miRNAs also mediate the effects of the hormone on bone cells. In rodent models of osteoporosis, melatonin has been unequivocally shown to have an anti-osteoporotic effect. Several clinical trials indicate the bone mass conserving effect of melatonin in aging/postmenopausal osteoporosis. This review aims to determine the possibility of melatonin as a novel class of anti-osteoporosis therapy through the critical assessment of the available literature.

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