Targeted drug delivery into glial scar using CAQK peptide in a mouse model of multiple sclerosis.

In multiple sclerosis, lesions are formed in various areas of the CNS, which are characterized by reactive gliosis, immune cell infiltration, extracellular matrix changes and demyelination. CAQK peptide (peptide sequence: cysteine-alanine-glutamine-lysine) was previously introduced as a targeting peptide for the injured site of the brain. In the present study, we aimed to develop a multifunctional system using nanoparticles coated by CAQK peptide, to target the demyelinated lesions in animal model of multiple sclerosis. We investigated the binding of fluorescein amidite-labelled CAQK and fluorescein amidite-labelled CGGK (as control) on mouse brain sections. Then, the porous silicon nanoparticles were synthesized and coupled with fluorescein amidite-labelled CAQK. Five days after lysolecithin-induced demyelination, male mice were intravenously injected with methylprednisolone-loaded porous silicon nanoparticles conjugated to CAQK or the same amount of free methylprednisolone. Our results showed that fluorescein amidite-labelled CAQK recognizes demyelinated lesions in brain sections of animal brains injected with lysolecithin. In addition, intravenous application of methylprednisolone-loaded nanoparticle porous silicon conjugated to CAQK at a single dose of 0.24 mg reduced the levels of microglial activation and astrocyte reactivation in the lesions of mouse corpus callosum after 24 and 48 h. No significant effect was observed following the injection of the same dose of free methylprednisolone. CAQK seems a potential targeting peptide for delivering drugs or other biologically active chemicals/reagents to the CNS of patients with multiple sclerosis. Low-dose methylprednisolone in this targeted drug delivery system showed significant beneficial effect.

Arbuscular mycorrhizal fungi and nitric oxide alleviate cadmium phytotoxicity by improving internal detoxification mechanisms of corn plants.

Plants develop several external and internal mechanisms to increase their tolerance to heavy metals (HMs) toxicity including cadmium (Cd). Symbiosis with arbuscular mycorrhizae fungi (AMF) is one of the plants' strategies to tolerate HMs toxicity. Nitric oxide (NO), as a signaling molecule, is also involved in physiological responses of plants to various stresses. The present work was conducted as a factorial completely randomized design with three replications to study the effects of Funneliformis mosseae fungi and Sodium nitroprusside (SNP, 100 mM) as a donor of NO alone, in combination (AMF + SNP) on corn plant growth, and internal detoxification mechanisms of Cd toxicity in a Cd-contaminated calcareous soil (0, 25, 50, and 100 mg Cd kg-1). The results showed that under Cd stress, AMF inoculation and/or foliar application of SNP significantly increased plant growth (32% to 103% for shoot and 44% to 84% for root) by decreasing Cd concentration in corn plant tissues (23% to 46% for shoot and 19% to 40% for root). Cd-induced oxidative stress was mitigated by AMF and/or SNP by enhancing the activities of antioxidant enzymes, including superoxide dismutase (SOD) and catalase (CAT), and concentration of non-enzymatic antioxidants such as glutathione (GSH) and phytochelatin (PC). Increasing the tolerance index (TI) and decreasing the transfer factor (TF) in the corn plants treated with AMF and/or SNP, confirm the efficient role of SNP and AMF in stimulating the detoxification mechanisms of Cd within the plant cells, which was more pronounced at the lowest Cd level (25 mg Cd kg-1). In conclusion, symbiotic associations of corn plants with AMF alone or in combination with SNP mitigated the detrimental effect of Cd toxicity in corn grown in Cd-contaminated calcareous soil. The corn's internal detoxification mechanisms lowered the Cd concentration in plant tissue which resulted in the improvement of the corn's growth parameters.

Harmful compounds of soy milk: characterization and reduction strategies.

Soymilk is a plant based product which is a rich source of nutrients. However, various harmful compounds including allergens, anti-nutritional factors, and biogenic amines (BAs) exist in soybeans that may be transferred into soymilk. These compounds cause difficulties for consumers from mild to severe symptoms. Soymilk production is considered as a critical step in quantity of harmful compounds in final product. Common steps in soy milk manufacturing include soaking, grinding, and heating process. Allergens contents could be decreased by heating alone or in combination with structural modifiers and fermentation. BAs could be reduced by optimizing fermentation process and using suitable strains, especially BAs degradable types. Soaking, grinding and heating of soybeans in water are considered as effective methods for inactivation of antinutritional factors. Isoflavones are soy phytochemicals, which potentially leads to breast cancer in some women, can be converted to less bioavailable forms during processing. Other treatments such as high hydrostatic pressure and irradiation are also effective in harmful compounds reduction. Combination of the processes is more effective in harmful compounds removal. Considering the increasing trends in soymilk consumption, this review is focused on introduction of harmful compounds in soymilk and investigating the effects of processing condition on their concentration.

Ursolic Acid Enhances Myelin Repair in Adult Mice Brains and Stimulates Exhausted Oligodendrocyte Progenitors to Remyelinate.

In multiple sclerosis patients, long-term inflammation makes the oligodendrocyte progenitor cells (OPCs) exhausted; therefore, a new therapy that makes them responsive to insults to participate in remyelination is highly in demand. Here, we investigated the effect of ursolic acid (UA) on myelin repair after mid-term and long-term demyelination periods induced by 6 or 12 weeks of cuprizone treatment followed by 2 weeks of recovery with or without UA. Immunohistochemistry studies and myelin genes expression assessment were used to evaluate the myelination status of mouse corpora callosa and the cellular mechanisms of myelin repair. Results showed that UA significantly promoted recovery from myelin loss after discontinuing 6 or 12 weeks of cuprizone feeding, as measured by luxol fast blue (LFB), fluoroMyelin (FM), anti-myelin basic protein (MBP) staining, and oligodendrocyte progenitor cell counts. It led to reduced inflammation and gliosis as evaluated by glial fibrillary acidic protein (GFAP), Iba1, or other marker gene transcripts. Following long-term demyelination, gliosis and TNF-α were observed as potential players in lesion pathology, which were restored by UA. An increased IL-10 may contribute to UA anti-inflammatory effect and making responsive the exhausted OPCs. UA increased the number of new oligodendrocyte lineage cells and myelination. Our findings indicated that UA can enhance myelin repair after cuprizone challenge through the prevention of gliosis and increasing the newly generated myelin.

Expression pattern and clinical significance of ß-catenin gene and protein in patients with primary malignant and benign bone tumors.

This study is aimed to unravel the status of local and circulating ß-catenin in different primary bone tumors and its relevance to tumor types, severity, and chemotherapy. The ß-catenin mRNA expression level and the expression of the protein (intensity level) were evaluated in tumor tissue and peripheral blood mononuclear cells of 150 patients with different types of primary bone tumors (78 malignant and 72 benign tumors) using Real-Time PCR and immunohistochemistry. The ß-catenin mRNA expression level and the expression of the protein were increased in bone tumors which was positively correlated with the tumor malignancy. Amongst osteosarcoma, Ewing's Sarcoma, chondrosarcoma, osteochondroma, Giant Cell Tumor, and exostosis tumors, the osteosarcoma, and Giant Cell Tumor groups showed the highest level of ß-catenin expression. The ß-catenin expression in malignant bone tumors was significantly correlated with tumor grade, size, metastasis, tumor recurrent, and the level of response to chemotherapy. A similar pattern of ß-catenin gene expression and its association with tumor characteristics was detected in the patient's peripheral blood cells. The simultaneous increase in the expression of the ß-catenin gene and protein in tumor tissue and in circulating blood cells and its relationship with tumor severity indicates the possible promoting role of ß-catenin in primary bone tumor pathogenesis.

Hotair and Malat1 Long Noncoding RNAs Regulate Bdnf Expression and Oligodendrocyte Precursor Cell Differentiation.

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophins family with well-known roles in neural development, differentiation, survival, and synaptic plasticity; however, it has not been explained thoroughly how the expression of this critical gene is regulated. To reveal some aspects of Bdnf gene regulation, here it was explored whether metastasis-associated lung adenocarcinoma transcript 1 (Malat1) and HOX transcript antisense RNA (Hotair) lncRNAs play roles in the regulation of Bdnf expression level, the effect of fingolimod treatment on downstream pathways, and oligodendrocyte precursor cell (OPC) maturation. First, in rat primary glial culture, the effect of Hotair and Malat1 was investigated on Bdnf expression using downregulation by specific DNAzymes. Then, immunostaining and RT-qPCR assays were employed to assess the functions of fingolimod and lncRNAs on OPC maturation. The results demonstrated that Bdnf was significantly correlated to Hotair and Malat1 lncRNAs in glial cells. Also, a strong correlation was observed between these two lncRNAs in glial culture and isolated OPCs. Fingolimod treatment coordinated lncRNAs' role on Bdnf expression in glial cells and enhanced OPC myelination three times compared to control. Furthermore, results suggested that Malat1 may have a role in the last stages of the intrinsic oligodendrocyte (OL) myelination regardless of fingolimod treatment. As BDNF is involved in brain development, survival, and functions, understanding the regulatory mechanism behind BDNF expression leads to a better comprehension of the pathogenesis of the neurodegenerative disorder and designing more effective treatments.

Long-Term Effects of Hippocampal Low-Frequency Stimulation on Pro-Inflammatory Factors and Astrocytes Activity in Kindled Rats.

OBJECTIVE: Epilepsy is accompanied by inflammation, and the anti-inflammatory agents may have anti-seizure effects. In this investigation, the effect of deep brain stimulation, as a potential therapeutic approach in epileptic patients, was investigated on seizure-induced inflammatory factors. MATERIALS AND METHODS: In the present experimental study, rats were kindled by chronic administration of pentylenetetrazol (PTZ; 34 mg/Kg). The animals were divided into intact, sham, low-frequency deep brain stimulation (LFS), kindled, and kindled +LFS groups. In kindled+LFS and LFS groups, animals received four trains of intra-hippocampal low-frequency deep brain stimulation (LFS) at 20 minutes, 6, 24, and 30 hours after the last PTZ injection. Each train of LFS contained 200 pulses at 1 Hz, 200 µA, and 0.1 ms pulse width. One week after the last PTZ injection, the Y-maze test was run, and then the rats' brains were removed, and hippocampal samples were extracted for molecular assessments. The gene expression of two pro-inflammatory factors [interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α)], and glial fibrillary acidic protein (GFAP) immunoreactivity (as a biological marker of astrocytes reactivation) were evaluated. RESULTS: Obtained results showed a significant increase in the expression of of interleukin-6 (IL-6), tumor necrosis factor (TNF)-α, and GFAP at one-week post kindling seizures. The application of LFS had a long-lasting effect and restored all of the measured changes toward normal values. These effects were gone along with the LFS improving the effect on working memory in kindled animals. CONCLUSION: The anti-inflammatory action of LFS may have a role in its long-lasting improving effects on seizure-induced cognitive disorders.

Dendrosomal nanocurcumin promotes remyelination through induction of oligodendrogenesis in experimental demyelination animal model.

Multiple sclerosis (MS) is an autoimmune disease, associated with central nervous system (CNS) inflammation, demyelination, and axonal loss. Myelin, a multilayer membranous that covers nerve fibers, is essential for rapid impulse conduction. Oligodendrocytes that are generated either from CNS-resident oligodendrocyte progenitor cells (OPCs) or subventricular zone-derived neural stem cells (NSCs) are the myelinating cells of the CNS. The adult CNS maintains a certain endogenous potential to repair myelin damage. However, this process often fails as MS progresses. The origin of this failure is not fully understood, but it is likely to relate to progenitors/stem cells' arrestment in a quiescent state, incapable of generating new oligodendrocyte. Current treatments for MS are immunomodulatory or immunosuppressive medications, with little to no effect on myelin restoration. Recent studies have provided proof-of-principle that CNS remyelination can be promoted either via enhancing endogenous remyelination or by transplanting myelinating cells. Curcumin, a natural polyphenolic compound, has been shown to have therapeutic properties in several neurodegenerative diseases. Here, we investigated the effect of a curcumin nanoformulation, dendrosomal nanoparticles (DNC) on oligodendrogenesis and remyelination, both in vitro and in animal model of demyelination. We indicated that DNC enhanced oligodendrogenesis from NSCs and OPCs, in vitro in dose dependent manner. DNC also induced in vivo remyelination via promotion of oligodendrogenesis. Furthermore, DNC enhanced remyelination capacity of transplanted NSCs through promoting their survival and oligodendrogenesis capacity. Our findings suggest that DNC has significant beneficial effects in demyelinating conditions, either as mono-therapy or as being paired with transplantation approaches.