Axonal growth inhibitors and their receptors in spinal cord injury:from biology to clinical translation

Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.

Autoimmune hepatitis and eosinophilia:A rare case report

BACKGROUND Autoimmune hepatitis consists of a chronic liver disease whose etiology is unknown.It is comprised of relevant immunological aspects and of immunemediated liver injury.Eosinophilia may be a considerable feature,particularly happening in male patients.CASE SUMMARY We report here a Crohn´s disease patient presenting with de novo hypergammaglobulinemia,circulating autoantibodies and elevated transaminase levels.He also had significant peripheral eosinophilia and elevated immunoglobulin E levels at diagnosis.The pathology findings from liver biopsy were compatible with autoimmune hepatitis with eosinophilic infiltration.CONCLUSION This is the first report of autoimmune hepatitis with exuberant eosinophilic infiltration in the liver and bone marrow,described in a patient with Crohn’s disease.

Nanoparticle-encapsulated retinoic acid for the modulation of bone marrow hematopoietic stem cell niche

More effective approaches are needed in the treatment of blood cancers,in particular acute myeloid leukemia(AML),that are able to eliminate resistant leukemia stem cells(LSCs)at the bone marrow(BM),after a chemotherapy session,and then enhance hematopoietic stem cell(HSC)engraftment for the re-establishment of the HSC compartment.Here,we investigate whether light-activatable nanoparticles(NPs)encapsulating all-trans-retinoic acid(RA^(+)NPs)could solve both problems.Our in vitro results show that mouse AML cells transfected with RA^(+)NPs differentiate towards antitumoral M1 macrophages through RIG.1 and OASL gene expression.Our in vivo results further show that mouse AML cells transfected with RA^(+)NPs home at the BM after transplantation in an AML mouse model.The photo-disassembly of the NPs within the grafted cells by a blue laser enables their differentiation towards a macrophage lineage.This macrophage activation seems to have systemic anti-leukemic effect within the BM,with a significant reduction of leukemic cells in all BM compartments,of animals treated with RA^(+)NPs,when compared with animals treated with empty NPs.In a separate group of experiments,we show for the first time that normal HSCs transfected with RA^(+)NPs show superior engraftment at the BM niche than cells without treatment or treated with empty NPs.This is the first time that the activity of RA is tested in terms of long-term hematopoietic reconstitution after transplant using an in situ activation approach without any exogenous priming or genetic conditioning of the transplanted cells.Overall,the approach documented here has the potential to improve consolidation therapy in AML since it allows a dual intervention in the BM niche:to tackle resistant leukemia and improve HSC engraftment at the same time.

Emerging trends in materials and devices-based electric stimulation therapy for tumors

Electrical stimulation(ES),as one of the physical therapy modalities for tumors,has attracted extensive attention of researchers due to its promising efficacy.With the continuous development of material science,nanotechnology,and micro/nano processing techniques,novel electroactive nanomaterials and delicately designed devices have emerged to realize innovative ES therapies,which provide more possibilities and approaches for tumor treatment.Meanwhile,exploring the molecular biological mechanisms underlying different ES modalities affecting tumor cells and their immune microenvironment is also an unresolved hotspot emerging from the current biomedical engineering research.Focusing on the above research interests,in this review,we systematically summarized the effects of different ES parameters on the subcellular structure of tumor cells and the tumor immune microenvironment(TIME)in conjunction with the involved signaling pathways.In addition,we also reviewed the latest progress in novel self-powered devices and electroactive nanomaterials for tumor therapy.Finally,the prospects for the development of electrostimulation tumor therapy are also discussed,bringing inspiration for the development of new physical therapy strategies in the future.

Expression and activity of heterologous hydroxyisocaproate dehydrogenases in Synechocystis sp.PCC 6803ΔhoxYH

Exploiting light to drive redox reactions is currently a hot topic since light is considered as an environmentally friendly source of energy.Consequently,cyanobacteria,which can use light e.g.,for generating NADPH,are in the focus of research.Previously,it has been shown that various heterologous redox enzymes could be expressed in these microorganisms.Here we demonstrated the successful inducer-free expression of𝛼-keto-acid dehydroge-nases(L-HicDH and D-HicDH)from Lactobacillus confusus DSM 20196 and Lactobacillus paracasei DSM 20008 in Synechocystis sp.PCC 6803ΔhoxYH mutant using replicative plasmids.While the L-HicDH showed poor activity limited by the amount of expressed enzyme,the D-HicDH was applied both in vivo and in vitro,transforming the selected𝛼-keto acids to the corresponding optically pure(R)-𝛼-hydroxy acids(ee>99%)in up to 53%and 90%conversion,respectively.