•An integrated view on different protein kinases and sirtuins in MSCs is provided.•The regulation of mitochondrial biogenesis and metabolism in MSCs are summarized.•Recent advances in mitochondrial ...dynamics and transfer are discussed.
Mesenchymal stem cells (MSCs) are characterized to have the capacity of self-renewal and the potential to differentiate into mesoderm, ectoderm-like and endoderm-like cells. MSCs hold great promise for cell therapies due to their multipotency in vitro and therapeutic advantage of hypo-immunogenicity and lower tumorigenicity. Moreover, it has been shown that MSCs can serve as a vehicle to transfer mitochondria into cells after cell transplantation. Mitochondria produce most of the energy through oxidative phosphorylation in differentiated cells. It has been increasingly clear that the switch of energy supply from glycolysis to aerobic metabolism is essential for successful differentiation of MSCs. Post-translational modifications of proteins have been established to regulate mitochondrial function and metabolic shift during MSCs differentiation. In this article, we review and provide an integrated view on the roles of different protein kinases and sirtuins in the maintenance and differentiation of MSCs. Importantly, we provide evidence to suggest that alteration in the expression of Sirt3 and Sirt5 and relative changes in the acylation levels of mitochondrial proteins might be involved in the activation of mitochondrial function and adipogenic differentiation of adipose-derived MSCs. We summarize their roles in the regulation of mitochondrial biogenesis and metabolism, oxidative responses and differentiation of MSCs. On the other hand, we discuss recent advances in the study of mitochondrial dynamics and mitochondrial transfer as well as their roles in the differentiation and therapeutic application of MSCs to improve cell function in vitro and in animal models. Accumulating evidence has substantiated that the therapeutic potential of MSCs is conferred not only by cell replacement and paracrine effects but also by transferring mitochondria into injured tissues or cells to modulate the cellular metabolism in situ. Therefore, elucidation of the underlying mechanisms in the regulation of mitochondrial metabolism of MSCs may ultimately improve therapeutic outcomes of stem cell therapy in the future.
Adult mammalian brains have largely lost neuroregeneration capability except for a few niches. Previous studies have converted glial cells into neurons, but the total number of neurons generated is ...limited and the therapeutic potential is unclear. Here, we demonstrate that NeuroD1-mediated in situ astrocyte-to-neuron conversion can regenerate a large number of functional new neurons after ischemic injury. Specifically, using NeuroD1 adeno-associated virus (AAV)-based gene therapy, we were able to regenerate one third of the total lost neurons caused by ischemic injury and simultaneously protect another one third of injured neurons, leading to a significant neuronal recovery. RNA sequencing and immunostaining confirmed neuronal recovery after cell conversion at both the mRNA level and protein level. Brain slice recordings found that the astrocyte-converted neurons showed robust action potentials and synaptic responses at 2 months after NeuroD1 expression. Anterograde and retrograde tracing revealed long-range axonal projections from astrocyte-converted neurons to their target regions in a time-dependent manner. Behavioral analyses showed a significant improvement of both motor and cognitive functions after cell conversion. Together, these results demonstrate that in vivo cell conversion technology through NeuroD1-based gene therapy can regenerate a large number of functional new neurons to restore lost neuronal functions after injury.
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After ischemic brain injury, many neurons die but surviving astrocytes become activated and proliferative. Using NeuroD1 AAV-based gene therapy, Chen and colleagues demonstrate robust neuroregeneration through direct astrocyte-to-neuron conversion and significantly improved functional recovery. This study provides a new paradigm for brain repair using in vivo cell conversion technology.
MicroRNAs (miRNAs) are small non-coding RNA molecules capable of negatively regulating gene expression to control many cellular mechanisms. The miRTarBase database ...(http://mirtarbase.mbc.nctu.edu.tw/) provides the most current and comprehensive information of experimentally validated miRNA-target interactions. The database was launched in 2010 with data sources for >100 published studies in the identification of miRNA targets, molecular networks of miRNA targets and systems biology, and the current release (2013, version 4) includes significant expansions and enhancements over the initial release (2010, version 1). This article reports the current status of and recent improvements to the database, including (i) a 14-fold increase to miRNA-target interaction entries, (ii) a miRNA-target network, (iii) expression profile of miRNA and its target gene, (iv) miRNA target-associated diseases and (v) additional utilities including an upgrade reminder and an error reporting/user feedback system.
Complex hydrogels formed with chitosan (CS) and ring-opened polyvinyl pyrrolidone (roPVP) as a swellable mucoadhesive gastroretentive drug dosage form (smGRDDF) were prepared and characterized. ...CS/roPVP hydrogels were produced by blending CS with roPVP obtained by basic treatment of PVP. Effects of the heating time and NaOH concentration employed for preparing roPVP, and CS molecular weights (Mws), and roPVP/CS ratios on the swelling ability of the resultant hydrogels were characterized. Rheological characteristics were further examined. Results demonstrated that roPVP obtained in a 0.5 M NaOH solution heated to 50 °C for 4 h was suitable for producing complex hydrogels with CS. At a roPVP/CS ratio of 20:1, hydrogels composed of three different Mws of CS possessed optimal swelling and mucoadhesive abilities and rheological properties. In vitro dissolution revealed sustained drug release. A pharmacokinetic study exhibited that the plasma profile of alendronate followed a sustained manner with 3-fold enhancement of the oral bioavailability. In conclusion, the smGRDDF composed of CS/roPVP complex hydrogels was successfully developed and is potentially applicable to improve the clinical efficacy of bisphosphonates.
Microglia-mediated neuroinflammation is recognized to mainly contribute to the progression of neurodegenerative diseases. Epigallocatechin-3-gallate (EGCG), known as a natural antioxidant in green ...tea, can inhibit microglia-mediated inflammation and protect neurons but has disadvantages such as high instability and low bioavailability. We developed an EGCG liposomal formulation to improve its bioavailability and evaluated the neuroprotective activity in in vitro and in vivo neuroinflammation models. EGCG-loaded liposomes have been prepared from phosphatidylcholine (PC) or phosphatidylserine (PS) coated with or without vitamin E (VE) by hydration and membrane extrusion method. The anti-inflammatory effect has been evaluated against lipopolysaccharide (LPS)-induced BV-2 microglial cells activation and the inflammation in the substantia nigra of Sprague Dawley rats. In the cellular inflammation model, murine BV-2 microglial cells changed their morphology from normal spheroid to activated spindle shape after 24 h of induction of LPS. In the in vitro free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, EGCG scavenged 80% of DPPH within 3 min. EGCG-loaded liposomes could be phagocytized by BV-2 cells after 1 h of cell culture from cell uptake experiments. EGCG-loaded liposomes improved the production of BV-2 microglia-derived nitric oxide and TNF-α following LPS. In the in vivo Parkinsonian syndrome rat model, simultaneous intra-nigral injection of EGCG-loaded liposomes attenuated LPS-induced pro-inflammatory cytokines and restored motor impairment. We demonstrated that EGCG-loaded liposomes exert a neuroprotective effect by modulating microglia activation. EGCG extracted from green tea and loaded liposomes could be a valuable candidate for disease-modifying therapy for Parkinson's disease (PD).
Hot flashes, the most bothering symptom of menopause, are linked to a metabolic inflammation. Due to estrogen deficiency in menopause, dysbiosis is observed. The intestinal barrier affects the ...interaction of microbiota in healthy or unhealthy individuals. This study investigates the relationship between hot flashes and gut permeability in postmenopausal women. In this cross-sectional study, we divided 289 women, aged 40-65 years, into four groups based on their hot-flash severity: HF.sub.0 : never experienced hot flashes; HF.sub.m : mild hot flashes; HF.sub.M : moderate hot flashes; HF.sub.S : severe hot flashes. The measured variables included the clinical parameters; hot flashes experience; fasting plasma levels of zonulin, fatty acid binding protein 2 (FABP2), endotoxin, and cytokines/chemokines. We used multiple linear regression analysis to evaluate the relationship between hot flashes and the previously mentioned gut barrier proteins. The study was performed in a hospital medical center. The hot flashes had a positive tendency toward increased levels of circulating FABP2 (P-trend = 0.001), endotoxin (P-trend = 0.031), high-sensitivity C-reactive protein (hs-CRP) (P-trend = 0.033), tumor necrosis factor alpha (TNF-alpha) (P-trend = 0.017), and interferon-inducible protein-10 (IP10) (P-trend = 0.021). Spearman's correlation analysis revealed significant correlations of FABP2 with endotoxin, TNF-alpha, monocyte chemoattractant protein-1, IP10, and hs-CRP in the 289 postmenopausal women included in this study. Linear regression analysis revealed that hot-flash severity had significant assoiciations with FABP2 (P-trend = 0.002), but not with zonulin. After adjusting for body mass index, age, and menopause duration, multivariate linear regression analysis revealed the differences between HFs (% difference (95% confidence interval), 22.36 (8.04, 38.59), P = 0.01) and HF.sub.0 groups in terms of FABP2 levels. This study shows that hot flashes are significantly associated with FABP2 levels in postmenopausal women. It suggests that severe hot flashes are linked to an increase in intestinal barrier permeability and low-grade systemic inflammation.
Two‐dimensional (2D) tin (Sn)‐based perovskites have recently received increasing research attention for perovskite transistor application. Although some progress is made, Sn‐based perovskites have ...long suffered from easy oxidation from Sn2+ to Sn4+, leading to undesirable p‐doping and instability. In this study, it is demonstrated that surface passivation by phenethylammonium iodide (PEAI) and 4‐fluorophenethylammonium iodide (FPEAI) effectively passivates surface defects in 2D phenethylammonium tin iodide (PEA2SnI4) films, increases the grain size by surface recrystallization, and p‐dopes the PEA2SnI4 film to form a better energy‐level alignment with the electrodes and promote charge transport properties. As a result, the passivated devices exhibit better ambient and gate bias stability, improved photo‐response, and higher mobility, for example, 2.96 cm2 V−1 s−1 for the FPEAI‐passivated films—four times higher than the control film (0.76 cm2 V−1 s−1). In addition, these perovskite transistors display non‐volatile photomemory characteristics and are used as perovskite‐transistor‐based memories. Although the reduction of surface defects in perovskite films results in reduced charge retention time due to lower trap density, these passivated devices with better photoresponse and air stability show promise for future photomemory applications.
Surface passivation of two‐dimensional PEA2SnI4 films with organic ligands proves to be effective in protecting the films from oxygen and moisture, and in improving the performance of the transistors. On the one hand, the degradation rate after passivation is retarded. On the other hand, passivation leads to fewer defect states and better energy‐level alignment, yielding higher mobility and light‐induced photocurrents.
Oxidative stress is an important pathomechanism found in numerous ocular degenerative diseases. To provide a better understanding of the mechanism and treatment of oxidant/antioxidant ...imbalance-induced ocular diseases, this article summarizes and provides updates on the relevant research. We review the oxidative damage (e.g., lipid peroxidation, DNA lesions, autophagy, and apoptosis) that occurs in different areas of the eye (e.g., cornea, anterior chamber, lens, retina, and optic nerve). We then introduce the antioxidant mechanisms present in the eye, as well as the ocular diseases that occur as a result of antioxidant imbalances (e.g., keratoconus, cataracts, age-related macular degeneration, and glaucoma), the relevant antioxidant biomarkers, and the potential of predictive diagnostics. Finally, we discuss natural antioxidant therapies for oxidative stress-related ocular diseases.
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