Exosome-mediated delivery and regulation in neurological disease progression.

Exosomes (EXOs), membranous structures originating from diverse biological sources, have recently seized the attention of researchers due to their theranostic potential for neurological diseases. Released actively by various cells, including stem cells, adipose tissue, and immune cells, EXOs wield substantial regulatory influence over the intricate landscape of neurological complications, exhibiting both positive and negative modulatory effects. In AD, EXOs play a pivotal role in disseminating and breaking down amyloid-ß protein. Moreover, EXOs derived from mesenchymal stem cells showcase a remarkable capacity to mitigate pro-inflammatory phenotypes by regulating miRNAs in neurodegenerative diseases. These vesicles possess the unique ability to traverse the blood-brain barrier, governing the aggregation of mutant huntingtin protein. Understanding the exosomal functions within the CNS holds significant promise for enhancing treatment efficacy in neurological diseases. This review intricately examines the regulatory mechanisms involving EXOs in neurological disease development, highlighting therapeutic prospects and exploring their utility in exosome-based nanomedicine for various neurological complications. Additionally, the review highlights the challenges associated with drug delivery to the brain, emphasizing the complexities inherent in this critical aspect of neurotherapeutics.

Glioblastoma preclinical models: Strengths and weaknesses.

Glioblastoma multiforme is a highly malignant brain tumor with significant intra- and intertumoral heterogeneity known for its aggressive nature and poor prognosis. The complex signaling cascade that regulates this heterogeneity makes targeted drug therapy ineffective. The development of an optimal preclinical model is crucial for the comprehension of molecular heterogeneity and enhancing therapeutic efficacy. The ideal model should establish a relationship between various oncogenes and their corresponding responses. This review presents an analysis of preclinical in vivo and in vitro models that have contributed to the advancement of knowledge in model development. The experimental designs utilized in vivo models consisting of both immunodeficient and immunocompetent mice induced with intracranial glioma. The transgenic model was generated using various techniques, like the viral vector delivery system, transposon system, Cre-LoxP model, and CRISPR-Cas9 approaches. The utilization of the patient-derived xenograft model in glioma research is valuable because it closely replicates the human glioma microenvironment, providing evidence of tumor heterogeneity. The utilization of in vitro techniques in the initial stages of research facilitated the comprehension of molecular interactions. However, these techniques are inadequate in reproducing the interactions between cells and extracellular matrix (ECM). As a result, bioengineered 3D-in vitro models, including spheroids, scaffolds, and brain organoids, were developed to cultivate glioma cells in a three-dimensional environment. These models have enabled researchers to understand the influence of ECM on the invasive nature of tumors. Collectively, these preclinical models effectively depict the molecular pathways and facilitate the evaluation of multiple molecules while tailoring drug therapy.

Mitochondrial NIR imaging probe mitigating oxidative damage by targeting HDAC6.

Despite the apparent copious fluorescent probes targeting mitochondria, the development of low cytotoxic probes is still needed for improving validation of mitochondrial function assessment. Herein, we report a novel cyanine-based NIR fluorescent probe, T2, which selectively targets mitochondria with significantly low toxicity by modulating the intracellular redox status. Additionally, T2 inhibits oxidative stress-induced cell death in cortical neurons. This study provides new insight into developing low-toxic mitochondrial imaging agents by regulating redox homeostasis.

CRISPR/Cas9 assisted stem cell therapy in Parkinson's disease.

Since its discovery in 2012, CRISPR Cas9 has been tried as a direct treatment approach to correct the causative gene mutation and establish animal models in neurodegenerative disorders. Since no strategy developed until now could completely cure Parkinson's disease (PD), neuroscientists aspire to use gene editing technology, especially CRISPR/Cas9, to induce a permanent correction in genetic PD patients expressing mutated genes. Over the years, our understanding of stem cell biology has improved. Scientists have developed personalized cell therapy using CRISPR/Cas9 to edit embryonic and patient-derived stem cells ex-vivo. This review details the importance of CRISPR/Cas9-based stem cell therapy in Parkinson's disease in developing PD disease models and developing therapeutic strategies after elucidating the possible pathophysiological mechanisms.

IPA and WPA-SOAP position statement on deprivation of liberty of older persons with mental health conditions.

In recognition of the challenges faced by older persons deprived of their liberty, a call was made for input into the 2022 report to the United Nations Human Rights Council (HRC) on older persons. This Position Statement outlines the views of two global organizations, the International Psychogeriatric Association (IPA) and the World Psychiatric Association Section of Old Age Psychiatry (WPA-SOAP), working together to provide rights and dignity-based mental health services to older persons and it was sent to the Independent Expert on the enjoyment of all human rights by older persons at HRC.

Past, present, and future perspectives of transcription factor EB (TFEB): mechanisms of regulation and association with disease.

Transcription factor EB (TFEB), a member of the MiT/TFE family of basic helix-loop-helix leucine zipper transcription factors, is an established central regulator of the autophagy/lysosomal-to-nucleus signaling pathway. Originally described as an oncogene, TFEB is now widely known as a regulator of various processes, such as energy homeostasis, stress response, metabolism, and autophagy-lysosomal biogenesis because of its extensive involvement in various signaling pathways, such as mTORC1, Wnt, calcium, and AKT signaling pathways. TFEB is also implicated in various human diseases, such as lysosomal storage disorders, neurodegenerative diseases, cancers, and metabolic disorders. In this review, we present an overview of the major advances in TFEB research over the past 30 years, since its description in 1990. This review also discusses the recently discovered regulatory mechanisms of TFEB and their implications for human diseases. We also summarize the moonlighting functions of TFEB and discuss future research directions and unanswered questions in the field. Overall, this review provides insight into our understanding of TFEB as a major molecular player in human health, which will take us one step closer to promoting TFEB from basic research into clinical and regenerative applications.

Cell-line dependency in cerebral organoid induction: cautionary observations in Alzheimer's disease patient-derived induced pluripotent stem cells.

The cerebral organoid (CO) model has been used in the study of various neurodegenerative diseases owing to its physiological implications. However, the CO model may only be representative of certain clinical findings in affected patients, while some features are not recapitulated. In this study, we found that neurons in the CO model from patients with Alzheimer's disease were less responsive to depolarization, in contrast to previous reports. This difference may be partly attributed to the variations in brain spatial identity depending on the genetic background of the induced pluripotent stem cells. Our current observation raises concerns that the phenotypes observed in the CO model need to be carefully evaluated for their clinical implications.

Neural Epidermal Growth Factor-Like Like Protein 2 Is Expressed in Human Oligodendroglial Cell Types.

Neural epidermal growth factor-like like 2 (NELL2) is a cytoplasmic and secreted glycosylated protein with six epidermal growth factor-like domains. In animal models, NELL2 is predominantly expressed in neural tissues where it regulates neuronal differentiation, polarization, and axon guidance, but little is known about the role of NELL2 in human brain development. In this study, we show that rostral neural stem cells (rNSC) derived from human-induced pluripotent stem cell (hiPSC) exhibit particularly strong NELL2 expression and that NELL2 protein is enriched at the apical side of neural rosettes in hiPSC-derived brain organoids. Following differentiation of human rostral NSC into neurons, NELL2 remains robustly expressed but changes its subcellular localization from >20 small cytoplasmic foci in NSC to one-five large peri-nuclear puncta per neuron. Unexpectedly, we discovered that in human brain organoids, NELL2 is readily detectable in the oligodendroglia and that the number of NELL2 puncta increases as oligodendrocytes mature. Artificial intelligence-based machine learning further predicts a strong association of NELL2 with multiple human white matter diseases, suggesting that NELL2 may possess yet unexplored roles in regulating oligodendrogenesis and/or myelination during human cortical development and maturation.

Hypermethylation of Mest promoter causes aberrant Wnt signaling in patients with Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to dementia and behavioral changes. Extracellular deposition of amyloid plaques (Aß) and intracellular deposition of neurofibrillary tangles in neurons are the major pathogenicities of AD. However, drugs targeting these therapeutic targets are not effective. Therefore, novel targets for the treatment of AD urgently need to be identified. Expression of the mesoderm-specific transcript (Mest) is regulated by genomic imprinting, where only the paternal allele is active for transcription. We identified hypermethylation on the Mest promoter, which led to a reduction in Mest mRNA levels and activation of Wnt signaling in brain tissues of AD patients. Mest knockout (KO) using the CRIPSR/Cas9 system in mouse embryonic stem cells and P19 embryonic carcinoma cells leads to neuronal differentiation arrest. Depletion of Mest in primary hippocampal neurons via lentivirus expressing shMest or inducible KO system causes neurodegeneration. Notably, depletion of Mest in primary cortical neurons of rats leads to tau phosphorylation at the S199 and T231 sites. Overall, our data suggest that hypermethylation of the Mest promoter may cause or facilitate the progression of AD.

TFEB regulates pluripotency transcriptional network in mouse embryonic stem cells independent of autophagy-lysosomal biogenesis.

Transcription factor EB (TFEB), a well-known master regulator of autophagy and lysosomal biogenesis, is a member of the microphthalmia family of transcription factors (MiT family). Over the years, TFEB has been shown to have diverse roles in various physiological processes such as clearance for intracellular pathogenic factors and having developmental functions such as dendritic maturation, as well as osteoclast, and endoderm differentiation. However, in the present study, we propose a novel mechanism for TFEB governing pluripotency of mouse ESCs (mESCs) by regulating the pluripotency transcriptional network (PTN) in these cells. We observed high levels of TFEB mRNA and protein levels in undifferentiated mESCs. Interestingly, we found a reduction of Nanog and Sox2 levels in TFEB knockout (KO) mESCs while pluripotency was maintained as there was an upregulation of TFE3, a potent stem cell maintenance factor. In consistent, double knockout of TFEB/TFE3 (TFEB/3 DKO) reduced mESC pluripotency, as indicated by the loss of ESC morphology, reduction of ESC markers, and the emergence of differentiation markers. We further discovered that Nanog was a TFEB target gene in undifferentiated mESCs. TFEB also promoted sex-determining region Y-box2 (Sox2) transcription by forming a heterodimer with Sox2 in mESCs. Notably, Sox2, Oct4, and Nanog were also binding to the TFEB promoter and thus generating a feed-forward loop in relation to TFEB. Although high levels of nuclear TFEB are expected to enhance autophagy-lysosomal activity, undifferentiated mESC remarkably displayed low basal autophagy-lysosomal activity. Overexpression or knockout of TFEB did not affect the expression of TFEB lysosomal-autophagy target genes and TFEB also had a lesser binding affinity to its own lysosomal promoter-target genes in mESCs compared to differentiated cells. Collectively, these findings define a newly incorporative, moonlighting function for TFEB in regulating PTN, independent of its autophagy-lysosomal biogenesis roles.

A concise review of human brain methylome during aging and neurodegenerative diseases.

DNA methylation at CpG sites is an essential epigenetic mark that regulates gene expression during mammalian development and diseases. Methylome refers to the entire set of methylation modifications present in the whole genome. Over the last several years, an increasing number of reports on brain DNA methylome reported the association between aberrant methylation and the abnormalities in the expression of critical genes known to have critical roles during aging and neurodegenerative diseases. Consequently, the role of methylation in understanding neurodegenerative diseases has been under focus. This review outlines the current knowledge of the human brain DNA methylomes during aging and neurodegenerative diseases. We describe the differentially methylated genes from fetal stage to old age and their biological functions. Additionally, we summarize the key aspects and methylated genes identified from brain methylome studies on neurodegenerative diseases. The brain methylome studies could provide a basis for studying the functional aspects of neurodegenerative diseases. [BMB Reports 2019; 52(10): 577-588].

Ketamine-based anesthesia improves electroconvulsive therapy outcomes: a randomized-controlled study.

BACKGROUND: Major depressive disorder (MDD) is a common and debilitating condition that can be challenging to treat. Electroconvulsive therapy (ECT) is currently the therapeutic gold standard for treatment-resistant MDD. We tested our hypothesis that ketamine-based anesthesia for ECT results in superior improvement in treatment-resistant MDD outcomes compared with propofol-based anesthesia. METHODS: Patients with treatment-resistant MDD were enrolled in a randomized clinical trial with assignment to ketamine- or propofol-based anesthesia arms. Using a modified intention-to-treat analysis, we compared the median number of ECT treatments required to achieve a 50% reduction (primary outcome) and a score ≤ 10 (secondary outcome) on the Montgomery-Asberg depression rating scale (MADRS) between anesthesia groups. RESULTS: The study was terminated as significant results were found after the first planned interim analysis with 12 patients in each of the ketamine (intervention) and propofol (control) groups. All ketamine patients achieved at least a 50% MADRS reduction after a median of two ECT treatments whereas ten propofol patients (83%) achieved the same outcome after a median of four ECT treatments. All ketamine patients and seven propofol patients (58%) achieved MDD remission (MADRS ≤ 10). Log rank tests showed that both time-to-50% reduction and remission differed significantly between groups. Adverse events and recovery time were similar between groups. CONCLUSIONS: In this early-terminated small-sized study, ketamine-based anesthesia compared with propofol-based anesthesia provided response and remission after fewer ECT sessions. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01935115). Registered 4 September 2013.

A Clinical Study to Examine the Effect of Complete Denture on Head Posture/Craniovertical Angle.

INTRODUCTION: Edentulous patients show some significant changes in ridge relationship caused by resorption of alveolar ridge. The changes are characterized by an upward rotation of mandible, increase in mandibular prognathism that ultimately results in change of natural head posture. AIM: This clinical study was planned to know the effect of complete denture on head posture in different age groups of Indian completely edentulous population, after placement of complete denture at various time intervals. MATERIALS AND METHODS: The sample consisted of completely edentulous patients without previous experience of the dentures. They were divided into 2 age groups: Group A (45-60) and Group B (61-75). During placement of complete denture craniovertical angle was measured with the help of custom made ruler protector device. Readings were taken before denture placement, immediately after denture placement, 30 minutes, 24 hours and 30 days after dentures placement. RESULTS: The results of this study indicated that in most of the patients (90%) despite their age, change in head posture (extension) occurred immediately after the denture placement. Thereafter reading remains same for measurement at 30 minutes and 24 hours of denture placement. However after 30 days, observation revealed that all the patients showed reduced craniovertical angle (flexion). Even though the values of craniovertical angle remain higher than its baseline in both groups, significant changes were noticed only in Group A. CONCLUSION: Findings revealed that head posture was significantly altered by the placement of dentures in completely edentulous patients. Within the time interval of 30 minutes and 24 hours extension of head posture remained constant with slight variation. Although after 30 days, changes remained significant for group 'A', but no significant changes were observed in the subjects of group 'B'.