Brain delivering RNA-based therapeutic strategies by targeting mTOR pathway for axon regeneration after central nervous system injury

Injuries to the central nervous system(CNS)such as stroke,brain,and spinal cord trauma often result in permanent disabilities because adult CNS neurons only exhibit limited axon regeneration.The brain has a surprising intrinsic capability of recovering itself after injury.However,the hostile extrinsic microenvironment significantly hinders axon regeneration.Recent advances have indicated that the inactivation of intrinsic regenerative pathways plays a pivotal role in the failure of most adult CNS neuronal regeneration.Particularly,substantial evidence has convincingly demonstrated that the mechanistic target of rapamycin(mTOR)signaling is one of the most crucial intrinsic regenerative pathways that drive axonal regeneration and sprouting in various CNS injuries.In this review,we will discuss the recent findings and highlight the critical roles of mTOR pathway in axon regeneration in different types of CNS injury.Importantly,we will demonstrate that the reactivation of this regenerative pathway can be achieved by blocking the key mTOR signaling components such as phosphatase and tensin homolog(PTEN).Given that multiple mTOR signaling components are endogenous inhibitory factors of this pathway,we will discuss the promising potential of RNA-based therapeutics which are particularly suitable for this purpose,and the fact that they have attracted substantial attention recently after the success of coronavirus disease 2019 vaccination.To specifically tackle the blood-brain barrier issue,we will review the current technology to deliver these RNA therapeutics into the brain with a focus on nanoparticle technology.We will propose the clinical application of these RNA-mediated therapies in combination with the brain-targeted drug delivery approach against mTOR signaling components as an effective and feasible therapeutic strategy aiming to enhance axonal regeneration for functional recovery after CNS injury.

Underlying IgM heavy chain amyloidosis in treatment-refractory IgA nephropathy: A case report

BACKGROUND Monoclonal immunoglobulin can cause renal damage,with a wide spectrum of pathological changes and clinical manifestations without hematological evidence of malignancy.These disorders can be missed,especially when combined with other kidney diseases.CASE SUMMARY A 61-year-old woman presented with moderate proteinuria with normal renal function.She was diagnosed with IgA nephropathy combined with monoclonal gammopathy of undetermined significance after the first renal biopsy.Although having received immunosuppressive treatment for 3 years,the patient developed nephrotic syndrome.Repeated renal biopsy and laser microdissection/mass spectrometry analysis confirmed heavy chain amyloidosis.After nine cycles of bortezomib,cyclophosphamide and dexamethasone,she achieved very good partial hematological and kidney responses.CONCLUSION Renal injury should be monitored closely in monoclonal gammopathy patients without obvious hematological malignancy,especially in patients with other preexisting renal diseases.

Comparative study for cardiovascular risk factors of rheumatoid arthritis and osteoarthritis

Objective： To compare the difference of cardiovascular risk factors in patients with rheumatoid arthritis （RA） and osteoarthritis （OA）. Methods： A retrospective analysis was performed to compare the difference of cardiovascular factors between 44 patients with RA and 36 patients with OA in terms of their gender, age, body mass index, course of disease, carotid ultrasound related indicators, homocysteine, blood lipid levels, inflammation index, echocardiographic index, etc. Results： （1） General situation： there was no significant difference between two groups in terms of gender and age （P 〉 0.05）. However, body mass index of OA group was significantly higher than that of RA group and the course of disease of RA group was significantly longer than that of OA group （P = 0.024）. （2） Laboratory index： the level of homocysteine of RA group was significantly higher than that of OA group （P = 0.002）. Though there was no significant difference between these two groups in terms of total cholesterol, triglyceride, low density lipoprotein, apolipoprotein B and high density lipoprotein （P 〉 0.05）, the level of apolipoprotein A1 of RA group was significantly lower than that of OA group （P 〈 0.001） and the level of lipoprotein A of RA group was significantly higher than that of OA group （P 〈 0.001）. The levels of erythrocyte sedimentation rate and C reactive protein of group RA were significantly higher than those of OA group （P 〈 0.001）. （3） Stroke volume and ejection fraction of echocardiography of RA patients were significantly lower than those of OA patients （P = 0.022, P = 0.009）. However, there was no significant difference between two groups in terms of aortic diameter, left atrial diameter, left ventricular end diastolic diameter, left ventricular end systolic diameter, left ventricular posterior wall thickness, left ventricular fractional shortening, right ventricular diameter, right atrial diameter, and interventricular septum thickness （P 〉 0.05）. Though significant difference in carotid artery plaque incidence between the two groups was not observed （P 〉 0.05）, the incidence of carotid artery thickening and carotid artery middle thickness were significantly different between the two groups （P 〈 0.001）. Conclusion： The rate for the occurrence of cardiovascular events in patients with RA was higher than those with OA. Additionally, effective control of RA patients’ conditions has the potential to reduce the risk of cardiovascular events.