Advanced nanoparticle strategies for optimizing RNA therapeutic delivery in neurodegenerative disorders.

Neurodegenerative diseases affect many people worldwide, and as the population ages, the incidence of these conditions increases. Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent neurodegenerative disorders worldwide. Different medicines are being used to control symptoms related to these conditions, but no treatment has yet been approved. Both genetic and environmental factors are involved in disease pathogenesis, and research on the pathophysiological pathways is still ongoing. The role of subcellular pathways and dysregulation in RNA pathways has been highlighted in pathophysiological studies, and treatment strategies focused on these pathways can be a promising approach. Many experiments have been conducted on delivering RNA cargo to the CNS to modulate various pathways involved. Yet another challenge to be faced is the effective transport of desired molecules to targets, which can be greatly hindered by distinct barriers limiting transport to the CNS, most noticeably the blood-brain barrier (BBB). Nanotechnology and the use of different nano-carriers for the delivery of nucleotides, peptides, proteins, and drug molecules are currently of great interest as these carriers help with better delivery and protection and, as a result, improve the effectiveness of the cargo. Nanocarriers can protect susceptible RNA molecules from possible degradation or destruction and improve their ability to reach the brain by enhancing BBB penetration. Different mechanisms for this process have been hypothesized. This review will go through the therapeutic application of RNA molecules in the treatment of AD and PD and the role of nanocarriers in overcoming delivery challenges and enhancing efficacy.

Circulating levels of inflammatory biomarkers in Huntington's disease: A systematic review and meta-analysis.

BACKGROUND: Huntington's disease (HD) is an autosomal dominant disease caused by an abnormally high number of CAG repeats at the huntingtin-encoding gene, HTT. This genetic alteration results in the expression of a mutant form of the protein (mHTT) and the formation of intracellular aggregates, inducing an inflammatory state within the affected areas. This dysfunction of inflammatory response leads to elevated levels of related inflammatory markers in both CNS tissue samples and body fluids. This study aims to investigate peripheral/blood concentrations of inflammatory molecules in HD. METHODS: A search was conducted in MEDLINE, Scopus, Web of Science, and Embase databases until March 30th, 2023. Random-effect meta-analysis was used for exploring concentrations of inflammatory molecules in HD. Subgroup and sensitivity analyses were used to assess heterogeneity among the included studies. The study protocol has been registered in PROSPERO with the ID number CRD42022296078. RESULTS: Ten studies were included in the meta-analysis. Plasma levels of Interleukin 6 (IL-6) and IL-10 were higher in HD compared to controls. Other biomarkers, namely, complement component C-reactive protein (CRP), C3, interferon-γ (IFN-γ), IL-1, IL-2, IL-8, and tumor necrosis factor-α (TNF-α), did not show any significant differences between the two groups. In addition, the subgroup analysis results established no significant differences in levels of these biomarkers in body fluids among premanifest and manifest HD patients. CONCLUSION: The results of this study provide evidence for the presence of higher plasma levels of IL-6 and IL-10 in HD patients in comparison with healthy controls.

Glia Signaling and Brain Microenvironment in Migraine.

Migraine is a complicated neurological disorder affecting 6% of men and 18% of women worldwide. Various mechanisms, including neuroinflammation, oxidative stress, altered mitochondrial function, neurotransmitter disturbances, cortical hyperexcitability, genetic factors, and endocrine system problems, are responsible for migraine. However, these mechanisms have not completely delineated the pathophysiology behind migraine, and they should be further studied. The brain microenvironment comprises neurons, glial cells, and vascular structures with complex interactions. Disruption of the brain microenvironment is the main culprit behind various neurological disorders. Neuron-glia crosstalk contributes to hyperalgesia in migraine. In the brain, microenvironment and related peripheral regulatory circuits, microglia, astrocytes, and satellite cells are necessary for proper function. These are the most important cells that could induce migraine headaches by disturbing the balance of the neurotransmitters in the nervous system. Neuroinflammation and oxidative stress are the prominent reactions glial cells drive during migraine. Understanding the role of cellular and molecular components of the brain microenvironment on the major neurotransmitters engaged in migraine pathophysiology facilitates the development of new therapeutic approaches with higher effectiveness for migraine headaches. Investigating the role of the brain microenvironment and neuroinflammation in migraine may help decipher its pathophysiology and provide an opportunity to develop novel therapeutic approaches for its management. This review aims to discuss the neuron-glia interactions in the brain microenvironment during migraine and their potential role as a therapeutic target for the treatment of migraine.

Whole-Heart Tissue Engineering and Cardiac Patches: Challenges and Promises.

Despite all the advances in preventing, diagnosing, and treating cardiovascular disorders, they still account for a significant part of mortality and morbidity worldwide. The advent of tissue engineering and regenerative medicine has provided novel therapeutic approaches for the treatment of various diseases. Tissue engineering relies on three pillars: scaffolds, stem cells, and growth factors. Gene and cell therapy methods have been introduced as primary approaches to cardiac tissue engineering. Although the application of gene and cell therapy has resulted in improved regeneration of damaged cardiac tissue, further studies are needed to resolve their limitations, enhance their effectiveness, and translate them into the clinical setting. Scaffolds from synthetic, natural, or decellularized sources have provided desirable characteristics for the repair of cardiac tissue. Decellularized scaffolds are widely studied in heart regeneration, either as cell-free constructs or cell-seeded platforms. The application of human- or animal-derived decellularized heart patches has promoted the regeneration of heart tissue through in vivo and in vitro studies. Due to the complexity of cardiac tissue engineering, there is still a long way to go before cardiac patches or decellularized whole-heart scaffolds can be routinely used in clinical practice. This paper aims to review the decellularized whole-heart scaffolds and cardiac patches utilized in the regeneration of damaged cardiac tissue. Moreover, various decellularization methods related to these scaffolds will be discussed.

Cytokines and chemokines profile in encephalitis patients: A meta-analysis.

BACKGROUND: Encephalitis is caused by autoimmune or infectious agents marked by brain inflammation. Investigations have reported altered concentrations of the cytokines in encephalitis. This study was conducted to determine the relationship between encephalitis and alterations of cytokine levels in cerebrospinal fluid (CSF) and serum. METHODS: We found possibly suitable studies by searching PubMed, Embase, Scopus, and Web of Science, systematically from inception to August 2021. 23 articles were included in the meta-analysis. To investigate sources of heterogeneity, subgroup analysis and sensitivity analysis were conducted. The protocol of the study has been registered in PROSPERO with a registration ID of CRD42021289298. RESULTS: A total of 23 met our eligibility criteria to be included in the meta-analysis. A total of 12 cytokines were included in the meta-analysis of CSF concentration. Moreover, 5 cytokines were also included in the serum/plasma concentration meta-analysis. According to the analyses, patients with encephalitis had higher CSF amounts of IL-6, IL-8, IL-10, CXCL10, and TNF-α than healthy controls. The alteration in the concentration of IL-2, IL-4, IL-17, CCL2, CXCL9, CXCL13, and IFN-γ was not significant. In addition, the serum/plasma levels of the TNF-α were increased in encephalitis patients, but serum/plasma concentration of the IL-6, IL-10, CXCL10, and CXCL13 remained unchanged. CONCLUSIONS: This meta-analysis provides evidence for higher CSF concentrations of IL-6, IL-8, IL-10, CXCL10, and TNF-α in encephalitis patients compared to controls. The diagnostic and prognostic value of these cytokines and chemokines should be investigated in future studies.

The role of spinal cord tractography in detecting lesions following selective bladder afferent and efferent fibers injury: A novel method for induction of neurogenic lower urinary tract dysfunction in rabbit.

OBJECTIVE: Neurogenic lower urinary tract dysfunction (NLUTD), a challenging disorder, is defined by lack of bladder control due to the abnormalities in neural pathways and can be classified based on the location of lesions within the nervous system, thus investigating the neural pathways can help us to know the site of the lesion and specify the class of the NLUTD. Diffusion Tensor Imaging (DTI) tractography, a noninvasive advanced imaging method, is capable of detecting central nervous system pathologies, even if routine magnetic resonance imaging shows no abnormality. Accordingly, tractography is an ideal technique to evaluate patients with NLUTD and visualize the pathology site within the spine. This study aimed to introduce a novel method of spinal cord injury (SCI) to establish NLUTD in the rabbit and to investigate the potential of tractography in tracing neural tracts of the spinal cord in an induced NLUTD animal model. MATERIALS AND METHODS: An animal model of NLUTD was induced through cauterization of the spinal cord at the level T12-L1 in 12 rabbits. Then rabbits were assessed via DTI, urodynamic studies (UDS), voiding cystourethrogram (VCUG), and pathology assessments using antineurofilament 200 (NF200) antibody, anti-S100, anti-Smooth Muscle Actin, anti-Myogenin, and anti-MyoD1. RESULTS: The tractography visualized lesions within spinal cord fibers. DTI parameters including fractional anisotropy (FA) value and tract density were significantly decreased (FA: p-value = 0.01, Tract density: p-value = 0.05) after injury. The mean diffusivity (MD) was insignificantly increased compared to before the injury. Also, the results of UDS and pathology assessments corroborated that applying SCI and the establishment of the NLUTD model was completely successful. CONCLUSION: In the present study, we investigated the auxiliary role of tractography in detecting the spinal cord lesions in the novel established rabbit model of NLUTD. The introduced method of NLUTD induction was without the leg's neurological deficit, easily applicable, low-cost, and was accompanied by minimal surgical preparation and a satisfactory survival rate in comparison with other SCI animal models.

Decellularization in Tissue Engineering and Regenerative Medicine: Evaluation, Modification, and Application Methods.

Reproduction of different tissues using scaffolds and materials is a major element in regenerative medicine. The regeneration of whole organs with decellularized extracellular matrix (dECM) has remained a goal despite the use of these materials for different purposes. Recently, decellularization techniques have been widely used in producing scaffolds that are appropriate for regenerating damaged organs and may be able to overcome the shortage of donor organs. Decellularized ECM offers several advantages over synthetic compounds, including the preserved natural microenvironment features. Different decellularization methods have been developed, each of which is appropriate for removing cells from specific tissues under certain conditions. A variety of methods have been advanced for evaluating the decellularization process in terms of cell removal efficiency, tissue ultrastructure preservation, toxicity, biocompatibility, biodegradability, and mechanical resistance in order to enhance the efficacy of decellularization methods. Modification techniques improve the characteristics of decellularized scaffolds, making them available for the regeneration of damaged tissues. Moreover, modification of scaffolds makes them appropriate options for drug delivery, disease modeling, and improving stem cells growth and proliferation. However, considering different challenges in the way of decellularization methods and application of decellularized scaffolds, this field is constantly developing and progressively moving forward. This review has outlined recent decellularization and sterilization strategies, evaluation tests for efficient decellularization, materials processing, application, and challenges and future outlooks of decellularization in regenerative medicine and tissue engineering.

Neuroinflammation and Proinflammatory Cytokines in Epileptogenesis.

Increasing evidence corroborates the fundamental role of neuroinflammation in the development of epilepsy. Proinflammatory cytokines (PICs) are crucial contributors to the inflammatory reactions in the brain. It is evidenced that epileptic seizures are associated with elevated levels of PICs, particularly interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α), which underscores the impact of neuroinflammation and PICs on hyperexcitability of the brain and epileptogenesis. Since the pathophysiology of epilepsy is unknown, determining the possible roles of PICs in epileptogenesis could facilitate unraveling the pathophysiology of epilepsy. About one-third of epileptic patients are drug-resistant, and existing treatments only resolve symptoms and do not inhibit epileptogenesis; thus, treatment of epilepsy is still challenging. Accordingly, understanding the function of PICs in epilepsy could provide us with promising targets for the treatment of epilepsy, especially drug-resistant type. In this review, we outline the role of neuroinflammation and its primary mediators, including IL-1ß, IL-1α, IL-6, IL-17, IL-18, TNF-α, and interferon-γ (IFN-γ) in the pathophysiology of epilepsy. Furthermore, we discuss the potential therapeutic targeting of PICs and cytokine receptors in the treatment of epilepsy.

Prenatal Neural Tube Anomalies: A Decade of Intrauterine Stem Cell Transplantation Using Advanced Tissue Engineering Methods.

Neural tube defects (NTDs) are among the most common congenital defects during neurulation. Spina bifida is a type of NTD that can occur in different forms. Since myelomeningocele (MMC) is the most severe form of spina bifida, finding a satisfactory treatment for MMC is a gold standard for the treatment of spina bifida. The Management of Myelomeningocele Study (MOMS) demonstrated that intrauterine treatment of spina bifida could ameliorate the complications associated with spina bifida and would also reduce the placement of ventriculoperitoneal (VP) shunt by 50%. Recently developed tissue engineering (TE) approaches using scaffolds, stem cells, and growth factors allow treatment of the fetus with minimally invasive methods and promising outcomes. The application of novel patches with appropriate stem cells and growth factors leads to better coverage of the defect with fewer complications. These approaches with less invasive surgical procedures, even in animal models with similar characteristics as the human MMC defect, paves the way for the modern application of less invasive surgical methods. Significantly, the early detection of these problems and applying these approaches can increase the potential efficacy of MMC treatment with fewer complications. However, further studies should be conducted to find the most suitable scaffolds and stem cells, and their application should be evaluated in animal models. This review intends to discuss advanced TE methods for treating MMC and recent successes in increasing the efficacy of the treatment.