Maternal prednisone exposure during pregnancy elevates susceptibility to osteoporosis in female offspring: The role of mitophagy/FNDC5 alteration in skeletal muscle.

Maternal exposure to glucocorticoids has been associated with adverse outcomes in offspring. However, the consequences and mechanisms of gestational exposure to prednisone on susceptibility to osteoporosis in the offspring remain unclear. Here, we found that gestational prednisone exposure enhanced susceptibility to osteoporosis in adult mouse offspring. In a further exploration of myogenic mechanisms, results showed that gestational prednisone exposure down-regulated FNDC5/irisin protein expression and activation of OPTN-dependent mitophagy in skeletal muscle of adult offspring. Additional experiments elucidated that activated mitophagy significantly inhibited the expression of FNDC5/irisin in skeletal muscle cells. Likewise, we observed delayed fetal bone development, downregulated FNDC5/irisin expression, and activated mitophagy in fetal skeletal muscle upon gestational prednisone exposure. In addition, an elevated total m6A level was observed in fetal skeletal muscle after gestational prednisone exposure. Finally, gestational supplementation with S-adenosylhomocysteine (SAH), an inhibitor of m6A activity, attenuated mitophagy and restored FNDC5/irisin expression in fetal skeletal muscle, which in turn reversed fetal bone development. Overall, these data indicate that gestational prednisone exposure increases m6A modification, activates mitophagy, and decreases FNDC5/irisin expression in skeletal muscle, thus elevating osteoporosis susceptibility in adult offspring. Our results provide a new perspective on the earlier prevention and treatment of fetal-derived osteoporosis.

Application of a Brain-Computer Interface System with Visual and Motor Feedback in Limb and Brain Functional Rehabilitation after Stroke: Case Report.

(1) Objective: To investigate the feasibility, safety, and effectiveness of a brain-computer interface (BCI) system with visual and motor feedback in limb and brain function rehabilitation after stroke. (2) Methods: First, we recruited three hemiplegic stroke patients to perform rehabilitation training using a BCI system with visual and motor feedback for two consecutive days (four sessions) to verify the feasibility and safety of the system. Then, we recruited five other hemiplegic stroke patients for rehabilitation training (6 days a week, lasting for 12-14 days) using the same BCI system to verify the effectiveness. The mean and Cohen's w were used to compare the changes in limb motor and brain functions before and after training. (3) Results: In the feasibility verification, the continuous motor state switching time (CMSST) of the three patients was 17.8 ± 21.0s, and the motor state percentages (MSPs) in the upper and lower limb training were 52.6 ± 25.7% and 72.4 ± 24.0%, respectively. The effective training revolutions (ETRs) per minute were 25.8 ± 13.0 for upper limb and 24.8 ± 6.4 for lower limb. There were no adverse events during the training process. Compared with the baseline, the motor function indices of the five patients were improved, including sitting balance ability, upper limb Fugel-Meyer assessment (FMA), lower limb FMA, 6 min walking distance, modified Barthel index, and root mean square (RMS) value of triceps surae, which increased by 0.4, 8.0, 5.4, 11.4, 7.0, and 0.9, respectively, and all had large effect sizes (Cohen's w ≥ 0.5). The brain function indices of the five patients, including the amplitudes of the motor evoked potentials (MEP) on the non-lesion side and lesion side, increased by 3.6 and 3.7, respectively; the latency of MEP on the non-lesion side was shortened by 2.6 ms, and all had large effect sizes (Cohen's w ≥ 0.5). (4) Conclusions: The BCI system with visual and motor feedback is applicable in active rehabilitation training of stroke patients with hemiplegia, and the pilot results show potential multidimensional benefits after a short course of treatment.

Changes and roles of IL-17A, VEGF-A and TNF-α in patients with cerebral infarction during the acute phase and early stage of recovery.

BACKGROUND AND PURPOSE: Interleukin 17A (IL-17A), vascular endothelial growth factor A (VEGF-A) and tumour necrosis factor alpha (TNF-α) are important cytokines detected mostly within two weeks after stroke in previous clinical studies. Longer clinical studies investigating these cytokines are lacking. We aimed to explore the roles of these cytokines in patients within 35 days after cerebral infarction. METHODS: Thirty patients with cerebral infarction and 30 healthy individuals were enrolled. Venous blood was collected from each patient at specific times and from each healthy individual only once. Coma and neurological functional deficits of the patients were evaluated by the Glasgow Coma Scale (GCS) and the National Institutes of Health Stroke Scale (NIHSS), respectively. Three cytokines were measured. The correlations among the three cytokines and between each cytokine and the GCS/NIHSS scores were analysed. RESULTS: IL-17A and TNF-α began to increase on day 1 after cerebral infarction, peaked on day 4, then decreased, and increased again on day 18. IL-17A returned to normal on day 35, but TNF-α remained higher than normal on day 35. VEGF-A began to increase on day 1, peaked on day 7, and returned to normal on day 35. From days 18 to 35, IL-17A was positively correlated with the GCS scores, and both IL-17A and VEGF-A were negatively correlated with the NIHSS scores. CONCLUSION: After cerebral infarction, VEGF-A from the acute phase and IL-17A from the early stage of recovery may be important for nerve protection and repair; TNF-α plays a complex role within 35 days.

Dendrobium officinale polysaccharide-induced neuron-like cells from bone marrow mesenchymal stem cells improve neuronal function a rat stroke model.

Various methods have been used to induce the neuronal differentiation of marrow mesenchymal stem cells (MSCs). However, the limited induction efficiency of cells in vitro has restricted their use. Therefore, identifying a simple and efficient treatment method is necessary. Dendrobium officinale is an important traditional Chinese medicine, and its main component, polysaccharides, has many pharmacological activities. However, the effects of D. officinale polysaccharide (DOP) on the neuronal differentiation of bone marrow mesenchymal stem cells (BMSCs) and treatment of ischaemic stroke remain unknown. We found that DOP promoted the neuronal differentiation of BMSCs by increasing the expression levels of neural markers, and the optimal concentration of DOP was 25 µg/mL. Additionally, the Notch signalling pathway was inhibited during the neuronal differentiation of BMSCs induced by DOP, and this effect was strengthened using an inhibitor of this pathway. The Wnt signalling pathway was activated during the differentiation of BMSCs, and inhibition of the Wnt signalling pathway downregulated the expression of neuronal genes. Furthermore, the transplantation of neuron-like cells induced by DOP improved neuronal recovery, as the brain infarct volume, neurologic severity scores and levels of inflammatory factors were all significantly reduced in vivo. In conclusion, DOP is an effective inducer of the neuronal differentiation of BMSCs and treatment option for ischaemic stroke.

miR-29b and miR-29c are involved in Toll-like receptor control of glucocorticoid-induced apoptosis in human plasmacytoid dendritic cells.

Glucocorticoids (GCs) are frequently used to treat many of the acute disease manifestations associated with inflammatory and autoimmune disorders. However, Toll-like receptor (TLR) pathway-activated plasmacytoid dendritic cells (pDCs) are resistant to GC-induced apoptosis, which leads to the inefficiency of GCs in the treatment of type I interferon-related autoimmune diseases, such as systemic lupus erythematosus (SLE). Therefore, compounds promoting pDC apoptosis may be helpful for improving the efficacy of GCs. In this study, we performed screening to identify microRNAs (miRNAs) involved in TLR-inhibited GC-induced pDC apoptosis and found an array of miRNAs that may regulate pDC apoptosis. Among those demonstrating altered expression, 6 miRNAs were inhibited in TLR-activated pDCs. Bioinformatics analysis and functional studies indicated that miR-29b and miR-29c were 2 key miRNAs involved in TLR-inhibited GC-induced pDC apoptosis. Furthermore, both of these miRNAs promoted pDC apoptosis by directly targeting Mcl-1 and Bcl-2 in human primary pDCs. Our findings provide new targets that could improve the efficacy of GCs for the treatment of SLE.