Emodin attenuates inflammation and demyelination in experimental autoimmune encephalomyelitis.

Emodin, a substance extracted from herbs such as rhubarb, has a protective effect on the central nervous system. However, the potential therapeutic effect of emodin in the context of multiple sclerosis remains unknown. In this study, a rat model of experimental autoimmune encephalomyelitis was established by immune induction to simulate multiple sclerosis, and the rats were intraperitoneally injected with emodin (20 mg/kg/d) from the day of immune induction until they were sacrificed. In this model, the nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and the microglia exacerbated neuroinflammation, playing an important role in the development of multiple sclerosis. In addition, silent information regulator of transcription 1 (SIRT1)/peroxisome proliferator-activated receptor-alpha coactivator (PGC-1α) was found to inhibit activation of the NLRP3 inflammasome, and SIRT1 activation reduced disease severity in experimental autoimmune encephalomyelitis. Furthermore, treatment with emodin decreased body weight loss and neurobehavioral deficits, alleviated inflammatory cell infiltration and demyelination, reduced the expression of inflammatory cytokines, inhibited microglial aggregation and activation, decreased the levels of NLRP3 signaling pathway molecules, and increased the expression of SIRT1 and PGC-1α. These findings suggest that emodin improves the symptoms of experimental autoimmune encephalomyelitis, possibly through regulating the SIRT1/PGC-1α/NLRP3 signaling pathway and inhibiting microglial inflammation. These findings provide experimental evidence for treatment of multiple sclerosis with emodin, enlarging the scope of clinical application for emodin.

Biology of Pellino1: a potential therapeutic target for inflammation in diseases and cancers.

Pellino1 (Peli1) is a highly conserved E3 Ub ligase that exerts its biological functions by mediating target protein ubiquitination. Extensive evidence has demonstrated the crucial role of Peli1 in regulating inflammation by modulating various receptor signaling pathways, including interleukin-1 receptors, Toll-like receptors, nuclear factor-κB, mitogen-activated protein kinase, and phosphoinositide 3-kinase/AKT pathways. Peli1 has been implicated in the development of several diseases by influencing inflammation, apoptosis, necrosis, pyroptosis, autophagy, DNA damage repair, and glycolysis. Peli1 is a risk factor for most cancers, including breast cancer, lung cancer, and lymphoma. Conversely, Peli1 protects against herpes simplex virus infection, systemic lupus erythematosus, esophageal cancer, and toxic epidermolysis bullosa. Therefore, Peli1 is a potential therapeutic target that warrants further investigation. This comprehensive review summarizes the target proteins of Peli1, delineates their involvement in major signaling pathways and biological processes, explores their role in diseases, and discusses the potential clinical applications of Peli1-targeted therapy, highlighting the therapeutic prospects of Peli1 in various diseases.

The therapeutic potential of triptolide and celastrol in neurological diseases.

Neurological diseases are complex diseases affecting the brain and spinal cord, with numerous etiologies and pathogenesis not yet fully elucidated. Tripterygium wilfordii Hook. F. (TWHF) is a traditional Chinese medicine with a long history of medicinal use in China and is widely used to treat autoimmune and inflammatory diseases such as systemic lupus erythematosus and rheumatoid arthritis. With the rapid development of modern technology, the two main bioactive components of TWHF, triptolide and celastrol, have been found to have anti-inflammatory, immunosuppressive and anti-tumor effects and can be used in the treatment of a variety of diseases, including neurological diseases. In this paper, we summarize the preclinical studies of triptolide and celastrol in neurological diseases such as neurodegenerative diseases, brain and spinal cord injury, and epilepsy. In addition, we review the mechanisms of action of triptolide and celastrol in neurological diseases, their toxicity, related derivatives, and nanotechnology-based carrier system.

Dietary Restriction against Parkinson's Disease: What We Know So Far.

Dietary restriction (DR) is defined as a moderate reduction in food intake while avoiding malnutrition. The beneficial effects of DR are being increasingly acknowledged in aging and in a series of age-related neurodegenerative disorders, for example, Parkinson's disease (PD). To date, the pathogenesis of PD remains elusive and there is no cure for it in spite of intensive research over decades. In this review, we summarize the current knowledge on the efficacy of DR on PD, focusing on the underlying mechanisms involving general metabolism, neuroendocrinolgy, neuroinflammation, gut microbiome, and so on. We anticipate that this review will provide future perspectives for PD prevention and treatment.

Focus on the Role of the NLRP3 Inflammasome in Multiple Sclerosis: Pathogenesis, Diagnosis, and Therapeutics.

Neuroinflammation is initiated with an aberrant innate immune response in the central nervous system (CNS) and is involved in many neurological diseases. Inflammasomes are intracellular multiprotein complexes that can be used as platforms to induce the maturation and secretion of proinflammatory cytokines and pyroptosis, thus playing a pivotal role in neuroinflammation. Among the inflammasomes, the nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome is well-characterized and contributes to many neurological diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD), and ischemic stroke. MS is a chronic autoimmune disease of the CNS, and its hallmarks include chronic inflammation, demyelination, and neurodegeneration. Studies have demonstrated a relationship between MS and the NLRP3 inflammasome. To date, the pathogenesis of MS is not fully understood, and clinical studies on novel therapies are still underway. Here, we review the activation mechanism of the NLRP3 inflammasome, its role in MS, and therapies targeting related molecules, which may be beneficial in MS.

Emerging Role of Ferroptosis in the Pathogenesis of Ischemic Stroke: A New Therapeutic Target?

Ischemic stroke is one of the main causes of high morbidity, mortality, and disability worldwide; however, the treatment methods are limited and do not always achieve satisfactory results. The pathogenesis of ischemic stroke is complex, defined by multiple mechanisms; among them, programmed death of neuronal cells plays a significant role. Ferroptosis is a novel type of regulated cell death characterized by iron redistribution or accumulation and increased lipid peroxidation in the membrane. Ferroptosis is implicated in many pathological conditions, such as cancer, neurodegenerative diseases, and ischemia-reperfusion injury. In this review, we summarize current research findings on ferroptosis, including possible molecular mechanisms and therapeutic applications of ferroptosis regulators, with a focus on the involvement of ferroptosis in the pathogenesis and treatment of ischemic stroke. Understanding the role of ferroptosis in ischemic stroke will throw some light on the development of methods for diagnosis, treatment, and prevention of this devastating disease.

Cerebrospinal fluid cells immune landscape in multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is a potentially devastating autoimmune neurological disorder, which characteristically induces demyelination of white matter in the brain and spinal cord. METHODS: In this study, three characteristics of the central nervous system (CNS) immune microenvironment occurring during MS onset were explored; immune cell proportion alteration, differential gene expression profile, and related pathways. The raw data of two independent datasets were obtained from the ArrayExpress database; E-MTAB-69, which was used as a derivation cohort, and E-MTAB-2374 which was used as a validation cohort. Differentially expressed genes (DEGs) were identified by the false discovery rate (FDR) value of < 0.05 and |log2 (Fold Change)|> 1, for further analysis. Then, functional enrichment analyses were performed to explore the pathways associated with MS onset. The gene expression profiles were analyzed using CIBERSORT to identify the immune type alterations involved in MS disease. RESULTS: After verification, the proportion of five types of immune cells (plasma cells, monocytes, macrophage M2, neutrophils and eosinophils) in cerebrospinal fluid (CSF) were revealed to be significantly altered in MS cases compared to the control group. Thus, the complement and coagulation cascades and the systemic lupus erythematosus (SLE) pathways may play critical roles in MS. We identified NLRP3, LILRB2, C1QB, CD86, C1QA, CSF1R, IL1B and TLR2 as eight core genes correlated with MS. CONCLUSIONS: Our study identified the change in the CNS immune microenvironment of MS cases by analysis of the in silico data using CIBERSORT. Our data may assist in providing directions for further research as to the molecular mechanisms of MS and provide future potential therapeutic targets in treatment.

Identifying the pattern of immune related cells and genes in the peripheral blood of ischemic stroke.

BACKGROUND: Ischemic stroke (IS) is the second leading cause of death worldwide which is a serious hazard to human health. Evidence suggests that the immune system plays a key role in the pathophysiology of IS. However, the precisely immune related mechanisms were still not been systematically understood. METHODS: In this study, we aim to identify the immune related modules and genes that might play vital role in the occurrence and development of IS by using the weighted gene co-expression network analysis (WGCNA). Meanwhile, we applied a kind of deconvolution algorithm to reveal the proportions of 22 subsets of immune cells in the blood samples. RESULTS: There were total 128 IS patients and 67 healthy control samples in the three Gene Expression Omnibus (GEO) datasets. Under the screening criteria, 1082 DEGs (894 up-regulated and 188 down-regulated) were chosen for further analysis. A total of 11 clinically significant modules were identified, from which immune-related hub modules and hub genes were further explored. Finally, 16 genes were selected as real hub genes for further validation analysis. Furthermore, these CIBERSORT results suggest that detailed analysis of the immune subtype distribution pattern has the potential to enhance clinical prediction and to identify candidates for immunotherapy. More specifically, we identified that neutrophil emerge as a promising target for IS therapies. CONCLUSIONS: In the present study, we investigated the immune related gene expression modules, in which the SLAMF1, IL7R and NCF4 may be novel therapeutic targets to promote functional and histological recovery after ischemic stroke. Furthermore, these hub genes and neutrophils may become important biological targets in the drug screening and drug designing.

Potential Roles of Exosomes in Parkinson's Disease: From Pathogenesis, Diagnosis, and Treatment to Prognosis.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease in the world, after Alzheimer's disease (AD), affecting approximately 1% of people over 65 years of age. Exosomes were once considered to be cellular waste and functionless. However, our understanding about exosome function has increased, and exosomes have been found to carry specific proteins, lipids, functional messenger RNAs (mRNAs), high amounts of non-coding RNAs (including microRNAs, lncRNAs, and circRNAs) and other bioactive substances. Exosomes have been shown to be involved in many physiological processes in vivo, including intercellular communication, cell migration, angiogenesis, and anti-tumor immunity. Moreover, exosomes may be pivotal in the occurrence and progression of various diseases. Therefore, exosomes have several diverse potential applications due to their unique structure and function. For instance, exosomes may be used as biological markers for the diagnosis and prognosis of various diseases, or as a natural carrier of drugs for clinical treatment. Here, we review the potential roles of exosomes in the pathogenesis, diagnosis, treatment, and prognosis of PD.