PurposeSpinal cord injury (SCI) is a relatively common, devastating traumatic condition resulting in permanent disability. In this study, the use of exosomes derived from bone mesenchymal stem cells (BMSCs-Exo) as a cell-free therapy for the treatment of SCI in rats was investigated to gain insights into their mechanisms of action.MethodsRats were randomly divided into three groups, Sham (treated with PBS), SCI (SCI injury + PBS) and SCI + Exo (SCI injury + BMSCs-Exo). Changes in the complement system between the three groups were assessed with the use of proteomics. The proteomic data were verified using reverse transcription-polymerase chain reaction (RT-PCR). In addition, the distributions of BMSCs-Exo in rats with SCI were detected by immunofluorescence. Moreover, SCI-activated NF-κB levels were determined using Western blot.ResultsSCI insult increased complement levels, including C4, C5, C6, C4 binding protein alpha and complement factor H. In contrast, the SCI + BMSCs-Exo group exhibited attenuated SCI-induced complement levels. Immunofluorescence assay results revealed that BMSCs-Exo mainly accumulated at the spinal cord injury site and were bound to microglia cells. Western blot analysis of tissue lysates showed that BMSCs-Exo treatment also inhibited SCI-activated nuclear factor kappa-B (NF-κB).ConclusionBMSCs-Exo play a protective role in spinal cord injury by inhibiting complement mRNA synthesis and release and by inhibiting SCI-activated NF-κB by binding to microglia.

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Subarachnoid hemorrhage (SAH) is a devastating form of stroke that leads to incurable outcomes. Increasing evidence has proved that early brain injury (EBI) contributes mostly to unfavorable outcomes after SAH. A previously unknown mechanism of regulated cell death known as necroptosis has recently been reported. Necrostatin-1 (nec-1), a specific and potent inhibitor of necroptosis, can attenuate brain impairments after SAH. However, the effect of nec-1 on the hippocampus and its neuroprotective impact on synapses after SAH is not well understood. Our present study was designed to investigate the potential effects of nec-1 administration on synapses and its relevant signal pathway in EBI after SAH. Nec-1 was administrated in a rat model via intracerebroventricular injection after SAH. Neurobehavior scores and brain edema were detected at 24 h after SAH occurred. The expression of the receptor-interacting proteins 1 and 3 (RIP1and3) was examined as a marker of necroptosis. We used hematoxylin and eosin staining, Nissl staining, silver staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) to observe the morphological changes in hippocampus. The protective effect of nec-1 on synapses was evaluated using western blotting and electron microscopy and Western blotting was used to detect the cAMP responsive element binding (CREB) protein and brain-derived neurotrophic factor (BDNF), and we used transmission electron microscopy and TUNEL to detect the protective effects of nec-1 when a specific inhibitor of CREB, known as 666-15, was used. Our results showed that in the SAH group, RIP1, and RIP3 significantly increased in the hippocampus. Additionally, injection of nec-1 alleviated brain edema and improved neurobehavior scores, compared with those in the SAH group. The damage to neurons was attenuated, and synaptic structure also improved in the Sham+nec-1 group. Furthermore, nec-1 treatment significantly enhanced the levels of phospho-CREB and BDNF compared with those in the SAH group. The protective effect of nec-1 could hindered by 666-15. Thus, nec-1 mitigated SAH-induced synaptic impairments in the hippocampus through the inhibition of necroptosis in connection with the CREB-BDNF pathway. This study may provide a new strategy for SAH patients in clinical practice.

In this case-matched two-centered study, comparable improvements were noted in patients with tLV-CRT and eLV-CRT. Operators should target nonanterior and nonapical locations during eLV-CRT implantation. Use of eLV-CRT should be considered a viable alternative for CRT candidates.

The present study was designed to determine the association between atrial fibrillation (AF) and inflammation in a goat sterile pericarditis model and to assess the effect of atorvastatin, a cholesterol-reducing drug, on AF. A total of 15 adult male goats were randomly divided into control, untreated pericarditis and atorvastatin-treated pericarditis groups. Pericarditis was induced via thoracotomy and atorvastatin was administered orally (60 mg/day) to the goats in the latter group for the duration of the study, commencing 1 week prior to surgery. The levels of high-sensitivity C-reactive protein (hs-CRP), interleukin(IL)-6 and tumor necrosis factor-α (TNF-α) were significantly elevated following surgery in the untreated pericarditis and atorvastatin groups compared with the control group (P<0.05). However, lower levels of hs-CRP, IL-6 and TNF-α were observed in the atorvastatin group compared with the untreated pericarditis group (P<0.05). Additionally, the animals in the atorvastatin-treated pericarditis group had a longer effective refractory period (ERP) and a higher rate adaptation of the ERP compared with those in the untreated pericarditis group (P<0.05). There was a significant negative correlation between the levels of ERP and hs-CRP in the untreated pericarditis group. The inducibility of AF in the left atrium and the duration of AF in the untreated pericarditis and atorvastatin-treated groups increased significantly following surgery (P<0.05). The pericarditis group, however, had a longer duration of AF compared with the atorvastatin group (P<0.05). Thus, inflammation may promote AF by shortening atrial ERP and by reducing the rate adaptation of ERP. These results suggested that atorvastatin can attenuate AF by inhibiting inflammation and may assist in preventing the occurrence and recurrence of AF following cardiac surgery.

Purmorphamine (PUR), an agonist of the Smoothened (Smo) receptor, has been shown to function as a neuroprotectant in acute experimental ischemic stroke. Its role in hypoxic-ischemic (HI) brain injury in neonatal mice remains unknown. Here we show that PUR attenuated acute brain injury, with a decrease in Bax/Bcl-2 ratio as well as inhibition of caspase-3 activation. These beneficial effects of PUR were associated with suppressing neuro-inflammation and oxidative stress. PUR exerted long-term protective effects upon tissue loss and improved neurobehavioral outcomes as determined at 14 and 28 days post-HI insult. Moreover, PUR increased synaptophysin (Syn) and postsynaptic density (PSD) protein 95 expression in HI-treated mice and attenuated synaptic loss. PUR upregulated the expression of Shh pathway mediators, while suppression of the Shh signaling pathway with cyclopamine (Cyc) reversed these beneficial effects of PUR on HI insult. Our study suggests a therapeutic potential for short-term PUR administration in HI-induced injury as a result of its capacity to exert multiple protective actions upon acute brain injury, long-term memory deficits, and impaired synapses. Moreover, we provide evidence indicating that one of the mechanisms underlying these beneficial effects of PUR involves activation of the Shh signaling pathway.

We have reported previously that L-cysteine-derived hydrogen sulfide (H2S) demonstrates a remarkable neuroprotective effect against hypoxia-ischemic (HI) insult in neonatal animals. Here, we assessed some of the mechanisms of this protection as exerted by L-cysteine. Specifically, we examined the capacity for L-cysteine to stimulate microglial polarization of the M2 phenotype and its modulation of complement expression in response to HI in neonatal mice. L-cysteine treatment suppressed the production of inflammatory cytokines, while dramatically up-regulating levels of anti-inflammatory cytokines in the damaged cortex. This L-cysteine administration promoted the conversion of microglia from an inflammatory M1 to an anti-inflammatory M2 phenotype, an effect which was associated with inhibiting the p38 and/or JNK pro-inflammatory pathways, nuclear factor-κB activation and a decrease in HI-derived levels of the C1q, C3a and C3a complement receptor proteins. Notably, blockade of H2S-production clearly prevented L-cysteine-mediated M2 polarization and complement expression. L-cysteine also inhibited neuronal apoptosis as induced by conditioned media from activated M1 microglia in vitro. We also show that L-cysteine promoted AMP-activated protein kinase (AMPK) activation and the AMPK inhibitor abolished these anti-apoptotic and anti-inflammatory effects of L-cysteine. Taken together, our findings demonstrate that L-cysteine-derived H2S attenuated neuronal apoptosis after HI and suggest that these effects, in part, result from enhancing microglia M2 polarization and modulating complement expression via AMPK activation.