Endothelial progenitor cells as a therapeutic option in intracerebral hemorrhage

Intracerebral hemorrhage （ICH） is the most severe cerebrovascular disease, which represents a leading cause of death and disability in developed countries. However, therapeutic options are limited, so is mandatory to investigate repairing processes after stroke in order to develop new therapeutic strategies able to promote brain repair processes. Therapeutic angiogenesis and vasculogenesis hold promise to improve outcome of ICH patients. In this regard, circulating endothelial progenitor cells （EPCs） have recently been suggested to be a marker of vascular risk and endothelial function. Moreover, EPC levels have been associated with good neurological and functional outcome as well as reduced residual hematoma volume in ICH patients. Finally, experimental and clinical studies indicate that EPC might mediate endothelial cell regeneration and neovascularization. Therefore, EPC-based therapy could be an excellent therapeutic option in ICH. In this mini-review, we discuss the present status of knowledge about the possible therapeutic role of EPCs in ICH, molecular mechanisms, and the future perspectives and strategies for their use in clinical practice.

New strategies for ischemic stroke: internal photobiomodulation therapy

Epidemiology and physiopathology of ischemic stroke:Every year, around 15 million of people suffer a stroke event all around the world. Among those, around 6.7 million will die, and most of the survivors will suffer some grade of disability.

CD34^(+ )progenitor cells as diagnostic and therapeutic targets in Alzheimer's disease

Alzheimer’s disease(AD)is the main neurodegenerative disease leading to dementia and cognitive impairment in the elderly.Considering AD to be an epidemic,an increase from the current 50 million to more than 150 million patients is expected by the year 2050.

Dynamic interplay of T helpercell subsets in experimental autoimmune encephalomyelitis

AIM： To investigate the temporal onset and dynamic interplay of CD4^＋ T helper cell subsets in experimental autoimmune encephalomyelitis （EAE）.METHODS： EAE was induced in C57BL/6 mice by im-munization with myelin oligodendrocyte glycoprotein peptide p35-55. The clinical signs were scored and the tissue samples and immune cells isolated for analysis at different phases of EAE. The expression levels of inflammatory cytokines and related transcription fac-tors were detected by quantitative reverse transcription polymerase chain reaction （PCR） and enzyme linked immunosorbant assay （ELISA）. The percentages of Th1, Th17, Th2, Treg and memory T cell subsets in EAE were analyzed by immunostaining and fow cytometry. The data were analyzed by statistical techniques.RESULTS： Quantitative real-time PCR analysis showed that EAE mice express elevated levels of Th1 [interferon gamma （ IFNγ ）, interleukin （ IL ） -12p40 ], Th17 [ IL-17 , related orphan receptor gamma （RORγ ）, IL-12p40] and Treg [ Foxp3, Epstein-Barr virus induced gene 3 （EBI3）, IL-10] genes in the central nervous system at the peak of the disease. Whereas, the expression of Th1 （ IFNγ , T-bet, IL-12p35, IL-12p40 ）, Th17 （RORγ, IL-12p40 ）, Th2 （ IL-4） and Treg （ Foxp3, EBI3） response genes was reduced in the spleen during pre-disease but gradually recovered at the later phases of EAE. ELISA and fow cytometry analyses showed an increase in Th17 re-sponse in the periphery, while Th1 response remained unchanged at the peak of disease. The mRNA levels of IFNγ, IL-17 and IL-12p40 in the brain were increased by 23 （P 〈 0.001）, 9 （P 〈 0.05） and 14 （P 〈 0.01） fold, respectively, on day 21 of EAE. Conversely, the mRNA expression of IL-10 was increased by 2 fold （P 〈 0.05） in the spleen on day 21. CD4^＋CD25^＋Foxp3＋Treg response was reduced at pre-disease but recovered to na？ve levels by disease onset. The percentage of CD25 Foxp3 regulatory T cells decreased from 7.7% in the na？ve to 3.2% （P 〈 0.05） on day 7 of EAE, which then increased to 8.4% by day 28. Moreover, the CD4＋CD127＋CD44high memory T cell response was increased during the onset and recovery phases of EAE. The memory and effector cells showed an in-verse relationship in EAE, where the memory T cells increased from 12.3% in nave to 20% by day 21, and the effector cells decreased from 32% in na？ve to 21% （P 〈 0.01） by day 21. The wild type C57BL/6 mice with EAE showed elevated levels of effector-memory T cells （TEM） with concomitant reduction in central-memory T cells （TCM）, but the EAE-resistant IL-7R defcient mice showed elevated TCM with no effect on TEM cells in EAE.CONCLUSION： Our fndings highlight the temporal on-set and dynamic interplay of effector, memory and regu-latory CD4^＋ T cell subsets and its signifcance to clinical outcome in EAE and other autoimmune diseases.

sTWEAK is a marker of early haematoma growth and leukoaraiosis in intracerebral haemorrhage

Objective To study the association between early growth of haematoma with biomarkers of endothelial dysfunction such as leukoaraiosis(LA)and the soluble tumour necrosis factor-like weak inducer of apoptosis(sTWEAK)in patients with intracerebral haemorrhage(ICH).Methods This is a retrospective observational study of patients with nontraumatic ICH.Clinical and biochemical parameters were analysed.sTWEAK levels were measured by ELISA.LA was analysed in the hemisphere without haemorrhage to avoid interference with the acute injury.The main endpoint was the haematoma growth evaluated by the difference in volume between the second and the initial neuroimage.Poor functional outcome,defined as a modified Rankin Scale>2 at 3 months,was considered as secondary endpoint.Receiver operating characteristic curve analysis was performed to stablish the best cut-off for sTWEAK levels associated with haematoma growth.Results We included 653 patients with ICH in our analysis(71.1±11.9 years,44%women).Haematoma growth was observed in 188 patients(28.8%).sTWEAK levels≥5600 pg/mL predicted ICH growth with a sensitivity of 84%and a specificity of 87%.sTWEAK levels≥5600 pg/mL and the presence of LA were associated with haematoma growth(OR:42.46;(CI 95%22.67 to 79.52)and OR:2.73(CI 95%1.39 to 5.34),respectively).Also,the presence of LA(OR:4.31(CI 95%2.89 to 6.42))and the interaction between ICH growth and sTWEAK(OR:2.23(CI 95%1.40 to 3.55))were associated with poor functional outcome at 3 months.Conclusion sTWEAKs,together with the presence and grade of LA,are biomarkers able to predict ICH growth and poor functional outcome in patients with ICH.

Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer’s disease protects against mitochondrial dysfunction and mitigates brain pathology

Background Alzheimer’s disease(AD)exhibits mitochondrial dysfunctions associated with dysregulated metabolism,brain inflammation,synaptic loss,and neuronal cell death.As a key protein serving as the mitochondrial gatekeeper,the voltage-dependent anion channel-1(VDAC1)that controls metabolism and Ca2+homeostasis is positioned at a convergence point for various cell survival and death signals.Here,we targeted VDAC1 with VBIT-4,a newly developed inhibitor of VDAC1 that prevents its pro-apoptotic activity,and mitochondria dysfunction.Methods To address the multiple pathways involved in AD,neuronal cultures and a 5×FAD mouse model of AD were treated with VBIT-4.We addressed multiple topics related to the disease and its molecular mechanisms using immunoblotting,immunofluorescence,q-RT-PCR,3-D structural analysis and several behavioral tests.Results In neuronal cultures,amyloid-beta(Aβ)-induced VDAC1 and p53 overexpression and apoptotic cell death were prevented by VBIT-4.Using an AD-like 5×FAD mouse model,we showed that VDAC1 was overexpressed in neurons surrounding Aβplaques,but not in astrocytes and microglia,and this was associated with neuronal cell death.VBIT-4 prevented the associated pathophysiological changes including neuronal cell death,neuroinflammation,and neuro-metabolic dysfunctions.VBIT-4 also switched astrocytes and microglia from being pro-inflammatory/neurotoxic to neuroprotective phenotype.Moreover,VBIT-4 prevented cognitive decline in the 5×FAD mice as evaluated using several behavioral assessments of cognitive function.Interestingly,VBIT-4 protected against AD pathology,with no significant change in phosphorylated Tau and only a slight decrease in Aβ-plaque load.Conclusions The study suggests that mitochondrial dysfunction with its gatekeeper VDAC1 is a promising target for AD therapeutic intervention,and VBIT-4 is a promising drug candidate for AD treatment.

Correction:Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer’s disease protects against mitochondrial dysfunction and mitigates brain pathology

Correction:Translational Neurodegeneration(2022)11:58 https://doi.org/10.1186/s40035-022-00329-7 Following publication of this article[1],the authors iden-tified an error in the family name of Alon Monsonego.The incorrect author name is:Alon Monsengo.The correct author name is:Alon Monsonego.The author group has been updated above and the orig-inal article[1]has been corrected.