Brain disorders (Amsterdam, Netherlands)最新文献

Background

Inflammation in the brain is a severe pathological state to facilitate neurodegenerative disorders. Various inflammatory mediators, such as tumor necrosis factor-α (TNF-α), nitric oxide (NO), interleukin-1 (IL-1), and prostaglandins, promote inflammation. The expression of these major inflammatory mediators is induced by the activation of microglia and astrocytes. Diseases likewise Parkinson's disease (PD), Alzheimer's disease (AD) and multiple sclerosis are caused by uncontrolled release of pro-inflammatory cytokines.

Methods

Acute (5, 50, and 300 mg kg⁻¹), subacute study (30, 100, and 300 mg kg⁻¹) toxicity in rats. In addition, consequence of tannic acid (TA) on haloperidol stimulated catalepsy model of PD in Wistar rats (6–8 weeks) was analysed. Toxicity study of TA has been done to identify the safer dose for experimental animals.

Results

In vivo antioxidant assays demonstrate the suppressed amount of oxidative stress caused due to lipid peroxidation (LPO) and elevated amount of reduced glutathione (GSH),superoxide dismutase (SOD) and catalase (CAT) after assessment with TA as compared to those in only haloperidol treated rats. TNF-α and NO amount were too found to be reduced in rat model of PD when pretreated with TA. haematological analyses also demonstrated the normal level of haemoglobin (Hb), Red blood cell (RBC) count, White blood cell(WBC) count, lymphocyte count, granulocyte count, mean corpuscular volume (MCV) and platelet count in rats pretreated with TA. Histopathological analysis of rat brain tissue showed neuroprotection in groups pretreated with TA. In addition, ADMET results based on structure to activity calculation related to pharmacokinetics and toxicity assessment revealed that TA had reasonably acceptable qualities. These attributes add to our understanding of structural aspects that may boost the bioavailability of TA before going on to the early stages of medication development.

Conclusion

Results obtained from the present study suggest that TA have potential to be extended as effective curative candidate for PD and various neurodegenerative diseases.

Diffuse intrinsic pontine glioma (DIPG) also referred as paediatric high-grade glioma (pHGG) is a fast-growing and aggressive type of childhood brain cancer. Recent studies investigating the molecular pathogenesis of DIPG have identified new therapeutic targets, paving the way for a new line of drugs mainly HDAC inhibitors. However, despite long years of trials, no significant results have been generated yet. Panobinostat is a HDAC inhibitor that has shown promising preclinical cytotoxicity in DIPG but failed so far in clinical trials. This study aims to re-evaluate the efficacy of Panobinostat in DIPG in vitro using patient-derived DIPG cell cultures obtained directly from patients. ONC201 is another potentially effective drug in DIPG. This apoptotic agent has been considered in a few clinical trials in diffuse glioma including DIPG. Our results reveal a dose-dependent response to Panobinostat and ONC201 in DIPG cells. However, Panobinostat caused a significant reduction in the mean percentage cell viability at a lower concentration compared to ONC201. Panobinostat caused significant decreases in DIPG cell viability at concentrations greater than or equal to 0.002 μM (p<0.05), the response reached a plateau after 0.1 μM, which reduced cell viability to 32.81 % ± 0.25 % (p = 6.74E⁻⁰⁶) when compared to control cells. ONC201 only significantly induced apoptosis at concentrations equal or higher than 0.01 μM (p<0.05), with its effect plateauing after 0.2 μM. This pre-clinical study supports the effectiveness of Panobinostat as a potential therapeutic agent for DIPG compared to ONC201, with no apparent synergistic effect observed in combination.

Background/aim

Doxorubicin (DOX) is a highly effective chemotherapy medicine commonly used to treat breast cancer; yet, despite its clinical efficacy, it usually causes chemobrain. As a result, we investigated the neuroprotective effects of Diosmin (DIOS) on DOX-induced chemobrain in male rat brains.

Animals and methods

In the experimental protocol, Rats were divided into 4 groups: group I received solvent and saline for 56 days, group II received Dios and a concomitant dose of saline for 56 days, group III received DOX intraperitoneally on 7th, 14th, 21st, 28th, 35th, 42nd, 49th and 56th days, and Group IV received DIOS (40 mg/kg P.O.) for 56 days and DOX was administered one hour after DIOS oral administration. The novel-object recognition memory test (NORT) was used to assess non-spatial memory function. Following that, brain neurochemical status were assessed.

Results

DIOS increased cognitive performance in DOX-treated rats by enhancing exploration of unfamiliar objects. DIOS protects the brain from DOX-mediated alterations in oxidative status, as well as brain metabolic enzyme indicators. It also decreased MMP-6, IL-6, IL-β1, TNF-α and COX-2 expression, reduced apoptotic markers levels, boosted mTOR protein levels, lowered beclin-1, restored brain metabolic enzyme activities, increased neurotransmitter as well as cathepsin levels, and avoided the rise in α-synuclein and PON1 enzyme activity.

Conclusion

In conclusion, DIOS protects rats' brains against DOX-induced chemobrain via oxidative stress inhibition, autophagy modulation, and down-regulation of inflammatory and apoptotic markers.

Background

Alzheimer's disease (AD) is the most common and progressive type of brain disorder that affects parts of the brain responsible for memory, speaking, thinking, and many other important functions. Apart from its common risk factors such as aging, environment, and lifestyle elements, the risk of developing AD largely depends on gene variants, which present a promising opportunity for identifying novel diagnostic and therapeutic biomarkers.

Objectives

Early studies have revealed numerous SNPs simultaneously associated with AD and other diseases such as Parkinson's disease, stroke, multiple sclerosis, and more. Therefore, it is important to conduct research on identifying single nucleotide missense mutations in certain genes specifically linked to AD to understand the prognosis and diagnosis of the disease.

Methods

In this research, we utilized multiple sequence-based computational tools and database servers to analyze specific missense single nucleotide polymorphisms and their potential effects on protein structure and stability.

Results

Our in-silico analysis revealed SNPs of 3 genes, specifically, ATP8B4, UBXN11, and TREM2, to be deleterious. The associating mutations were found to be destabilizing the protein structure and function of deleterious genes.

Conclusion

Three genes, including ATP8B4, UBXN11, and TREM2 and their associated SNPs, were found to be deleterious and are potentially linked to AD. Amino acid changes associated with these genes were found to affect their interactions, which are connected to specific biological processes and pathways that may trigger AD.

Introduction

The “borderline” pituitary tumor category between typical benign adenomas and pituitary carcinomas is a subject of ongoing controversy. Surveillance, Epidemiology, and End Results (SEER) database classifies uncertain behavior pituitary tumors (UPTs) under the “borderline” category including atypical adenomas with presumed propensity for aggressive behavior. Very little is known about UPT patient survival prognostic factors. We aimed to characterize survival risk factors of patients with UPT according to the SEER database.

Methods

SEER 17 database was queried for pituitary tumors and further separated by SEER classification of “Borderline” under the category “ICD-O-3 Hist/behav, malignant”. Patient demographics, tumor characteristic, extent of disease and treatment data were extracted and analyzed. A nomogram was built assessing survival.

Results

Three hundred and thirty-two patients diagnosed between 2004 and 2019 were included. The survival rates at 1, 5 and 10 years were 86.8 %, 78.6 % and 65.1 %, respectively. Female sex and age <65 years correlated with a better prognosis (HR 2.41, 95 % CI [1.57–3.68], p = 4.00E-05 and HR 5.47; 95 % CI [3.53–8.45], p = 3.00E-15). Patients undergoing surgery had a better prognosis than those pursuing non-surgical management (HR 0.43, 95 % CI [0.19–0.97], p = 0.02). A nomogram incorporating sex, age and surgical versus non-surgical treatment status was created. The nomogram demonstrated acceptable accuracy in estimating the survival probability at 1- and 2-years, with a C-index of 0.751 (95 % CI: 0.641–0.861).

Conclusion

Female sex, age <65 years and surgical resection are significant factors determining UPT patient survival based on SEER data. The proposed nomogram achieved good potential for predicting UPT patient survival.

Amyloidosis is associated with misfolding of protein (normal functional and cellular) into intractable aggregates, commonly known as amyloid fibrils. These amyloid fibrils contain thread-like structure with a high amount of β sheet content and their accumulation initiates the formation of toxic intermediates in the process of self-assembly. This conversion into intractable aggregates is strongly linked with disorders like Creutzfeldt-Jakob disease, Alzheimer's disease, Parkinson's disease, and lifestyle-related Type II diabetes. The exact mechanism of such normal cellular protein conversion into intractable protease-resistant amyloid aggregates has not yet been explored very well, but an agent that can degrade such amyloid fibrils can be a suitable drug candidate for such disorders. Various proteins and peptides like β-amyloid peptide, β2-microglobulin, insulin amyloids (IA), prion, and serum amyloid Aβ protein accumulate in the human body under different diseased conditions. These amyloids have mutual traits and are usually protease-resistant which makes them difficult to clear from the human body. In this review, we have discussed the history of amyloidosis, the different types of amyloids related to neurological disorders, and systemic and localized amyloidosis. A detailed description of insulin amyloids and prion amyloids has been discussed. A glimpse of the use of natural enzymes and their role is the dissociation of amyloids has been discussed.

Chronic necrotizing granulomatous meningoencephalitis is an idiopathic inflammatory disease with possible autoimmune mediated delayed type hypersensitivity response. It commonly affects the central nervous system of dogs, and on rare occasions cats. However, this inflammatory disease has rarely been reported in humans. A 69-year-old woman presented with subacute intermittent sharp headaches. Brain MRI revealed multifocal enhancing lesions and edema as well as multifocal signal abnormality throughout the supratentorial and infratentorial parenchyma. Cerebrospinal fluid showed elevated opening pressure, pleocytosis, and elevated protein. MRA head, MRV head, cerebral angiogram, extensive serum and CSF work up for infectious and autoimmune etiologies were also unremarkable. Brain biopsy revealed necrotizing granulomatous inflammation with dystrophic calcification. High dose of methylprednisolone followed by a 6-week prednisone taper resolved her headache and the brain MRI abnormalities. This case demonstrates the response of necrotizing granulomatous meningoencephalitis in humans to steroids.