scholarly journals MiR-127-3p targeting CISD1 regulates autophagy in hypoxic–ischemic cortex

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Zi-Bin Zhang ◽  
Liu-Lin Xiong ◽  
Lu-Lu Xue ◽  
Yan-Ping Deng ◽  
Ruo-Lan Du ◽  
...  
Keyword(s):  
Underlying Mechanism ◽  
Perinatal Period ◽  
Neurological Injury ◽  
Neuroprotective Effects ◽  
Bioinformatics Analyses ◽  
New Treatment ◽  
Related Proteins ◽  
The Brain

AbstractNeonatal hypoxic–ischemic (HI) injury derived from asphyxia during perinatal period, is a serious complication of neonatal asphyxia and the main cause of neonatal acute death and chronic neurological injury. Aberrant autophagy occurs in many nervous system diseases, but its role and underlying mechanism in HI injury is largely unknown. Here, we successfully constructed a newborn rat model of HI brain injury, and the knockout-miR-127-3p (KO-miR-127-3p) rats were structured by using CRISPR/Cas9. Subsequently, the in vitro functional experiments, in vivo zea-longa scores, as well as bioinformatics analyses and biological experiments were applied. The expression of autophagy-related proteins, including ATG12, P62, Beclin-1, LC3II in HI cortex with miR-127-3p knockout was significantly decreased, and autophagic vacuoles were disappeared. Moreover, miR-127-3p has a specific regulatory effect on CISD1 expression, another crucial molecule in autophagy process. Accordingly, the overexpression of CISD1 effectively inhibited the autophagic cell death and physiological dysfunction in the brain of HI injury, whereas si-CISD1 reversed the neuroprotective effects of KO-miR-127-3p. Our findings explained the underlying mechanism for HI injury, and miR-127-3p targeting CISD1 signal could be supposed as a new treatment strategy to prevent and treat HI injury.

scholarly journals Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

2020 ◽  
Vol 2020 ◽  
pp. 1-27 ◽  
Author(s):  
Samuele Maramai ◽  
Mohamed Benchekroun ◽  
Moustafa T. Gabr ◽  
Samir Yahiaoui
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Event ◽  
Neuroprotective Effects ◽  
New Agents ◽  
Major Health ◽  
New Treatment ◽  
Neuronal Functions

Neurodegenerative diseases represent nowadays one of the major health problems. Despite the efforts made to unveil the mechanism leading to neurodegeneration, it is still not entirely clear what triggers this phenomenon and what allows its progression. Nevertheless, it is accepted that neurodegeneration is a consequence of several detrimental processes, such as protein aggregation, oxidative stress, and neuroinflammation, finally resulting in the loss of neuronal functions. Starting from these evidences, there has been a wide search for novel agents able to address more than a single event at the same time, the so-called multitarget-directed ligands (MTDLs). These compounds originated from the combination of different pharmacophoric elements which endowed them with the ability to interfere with different enzymatic and/or receptor systems, or to exert neuroprotective effects by modulating proteins and metal homeostasis. MTDLs have been the focus of the latest strategies to discover a new treatment for Alzheimer’s disease (AD), which is considered the most common form of dementia characterized by neurodegeneration and cognitive dysfunctions. This review is aimed at collecting the latest and most interesting target combinations for the treatment of AD, with a detailed discussion on new agents with favorable in vitro properties and on optimized structures that have already been assessed in vivo in animal models of dementia.

scholarly journals ROS-Dependent Neuroprotective Effects of NaHS in Ischemia Brain Injury Involves the PARP/AIF Pathway

2015 ◽  
Vol 36 (4) ◽  
pp. 1539-1551 ◽  
Author(s):  
Qian Yu ◽  
Zhihong Lu ◽  
Lei Tao ◽  
Lu Yang ◽  
Yu Guo ◽  
...  
Keyword(s):  
Brain Injury ◽  
Focal Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Dependent Manner ◽  
Neuroprotective Effects ◽  
Ht22 Cells ◽  
In Vivo Models ◽  
The Brain

Background/Aims: Stroke is among the top causes of death worldwide. Neuroprotective agents are thus considered as potentially powerful treatment of stroke. Methods: Using both HT22 cells and male Sprague-Dawley rats as in vitro and in vivo models, we investigated the effect of NaHS, an exogenous donor of H2S, on the focal cerebral ischemia-reperfusion (I/R) induced brain injury. Results: Administration of NaHS significantly decreased the brain infarcted area as compared to the I/R group in a dose-dependent manner. Mechanistic studies demonstrated that NaHS-treated rats displayed significant reduction of malondialdehyde content, and strikingly increased activity of superoxide dismutases and glutathione peroxidase in the brain tissues compared with I/R group. The enhanced antioxidant capacity as well as restored mitochondrial function are NaHS-treatment correlated with decreased cellular reactive oxygen species level and compromised apoptosis in vitro or in vivo in the presence of NaHS compared with control. Further analysis revealed that the inhibition of PARP-1 cleavage and AIF translocation are involved in the neuroprotective effects of NaHS. Conclusion: Collectively, our results suggest that NaHS has potent protective effects against the brain injury induced by I/R. NaHS is possibly effective through inhibition of oxidative stress and apoptosis.

Effects of Short Duration Overpressure on Astrocytes: An In Vitro Study

2007 ◽  
Author(s):  
Lai Yee Leung ◽  
Pamela J. VandeVord ◽  
Warren Hardy ◽  
Roche De Guzman ◽  
King H. Yang ◽  
...  
Keyword(s):  
Short Duration ◽  
Neuronal Degeneration ◽  
In Vitro Study ◽  
Underlying Mechanism ◽  
Blast Waves ◽  
Body Armor ◽  
The Brain ◽  
Physiological Systems

Blast wave overpressure from detonations can injure physiological systems ‘silently.’ Experimental and clinical studies have revealed the damaging effects of shock waves on different physiological systems, such as ears, lungs and gastrointestinal tracts [1, 2]. Despite the improved helmet and body armor, many veterans returning from wars suffered from neurological disorders that are being diagnosed as mild traumatic brain injury. Warden (2006) reported that most of these veterans were exposed to blast [3]. In vivo study illustrated neuronal degeneration in the brain after exposure to blast waves [4]. As with many neuronal diseases, blast-induced neuronal injury may be related to microglia and astrocyte activation. However, the underlying mechanism is not clearly understood. This study was aimed at investigating the effects of short duration overpressure on astrocytes, in terms of cell proliferation and mRNA expression of several apoptotic genes and glial fibrillary acidic protein (GFAP).

scholarly journals Effects of Red Ginseng on Neural Injuries with Reference to the Molecular Mechanisms

J ◽  
2019 ◽  
Vol 2 (2) ◽  
pp. 116-127
Author(s):  
Pengxiang Zhu ◽  
Masahiro Sakanaka
Keyword(s):  
Molecular Mechanisms ◽  
Bioactive Molecules ◽  
Red Ginseng ◽  
Promising Candidate ◽  
Neuroprotective Effects ◽  
Chemical Structures ◽  
Brain And Spinal Cord ◽  
The Brain

Red ginseng, as an effective herbal medicine, has been traditionally and empirically used for the treatment of neuronal diseases. Many studies suggest that red ginseng and its ingredients protect the brain and spinal cord from neural injuries such as ischemia, trauma, and neurodegeneration. This review focuses on the molecular mechanisms underlying the neuroprotective effects of red ginseng and its ingredients. Ginsenoside Rb1 and other ginsenosides are regarded as the active ingredients of red ginseng; the anti-apoptotic, anti-inflammatory, and anti-oxidative actions of ginsenosides, together with a series of bioactive molecules relevant to the above actions, appear to account for the neuroprotective effects in vivo and/or in vitro. Moreover, in this review, the possibility is raised that more effective or stable neuroprotective derivatives based on the chemical structures of ginsenosides could be developed. Although further studies, including clinical trials, are necessary to confirm the pharmacological properties of red ginseng and its ingredients, red ginseng and its ingredients could be promising candidate drugs for the treatment of neural injuries.

scholarly journals HDAC inhibition protects degenerating cone photoreceptors in vivo

2016 ◽  
Author(s):  
Dragana Trifunović ◽  
Blanca Arango-Gonzalez ◽  
Antonella Comitato ◽  
Melanie Barth ◽  
Ayse Sahaboglu ◽  
...  
Keyword(s):  
Cell Death ◽  
Trichostatin A ◽  
Treatment Options ◽  
Hdac Inhibition ◽  
Neuroprotective Effects ◽  
Histone Deacetylase Inhibitor Trichostatin ◽  
New Treatment ◽  
Future Therapy

AbstractRetinal diseases caused by cone photoreceptor cell death are devastating as the patients are experiencing loss of accurate and color vision. Understanding the mechanisms of cone cell death and the identification of key players therein could provide new treatment options. We studied the neuroprotective effects of a histone deacetylase inhibitor, Trichostatin A (TSA), in a mouse model of inherited, primary cone degeneration (cpfl1). We show that HDAC inhibition protects cones in vitro, in retinal explant cultures. More importantly, in vivo a single TSA injection increased cone survival for up to 10 days post-injection. In addition, the abnormal, incomplete cone migration pattern in the cpfl1 retina was significantly improved by HDAC inhibition. These findings suggest a crucial role for HDAC activity in primary cone degeneration and highlight a new avenue for future therapy developments for cone dystrophies and diseases associated with impaired cone migration.

scholarly journals Anti-inflammatory Role of GM1 and Other Gangliosides on Microglia

2021 ◽  
Author(s):  
Simonetta Sipione ◽  
Danny Galleguillos ◽  
Qian Wang ◽  
Noam Steinberg ◽  
Asifa Zaidi ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Sialic Acid Residue ◽  
Microglia Activation ◽  
Neuroprotective Effects ◽  
Bv2 Cells ◽  
Inflammatory Stimuli ◽  
Anti Inflammatory ◽  
The Brain

Abstract BackgroundGangliosides are glycosphingolipids highly enriched in the brain, with important roles in cell signaling, cell-to-cell communication, and immunomodulation. Genetic defects in the ganglioside biosynthetic pathway result in severe neurodegenerative diseases, while a partial decrease in the levels of specific gangliosides was reported in Parkinson’s disease and Huntington’s disease. In models of both diseases and other conditions, administration of GM1 - one of the most abundant gangliosides in the brain – provides neuroprotection. Most studies have focused on the direct neuroprotective effects of gangliosides on neurons, but their role in other brain cells, in particular microglia, is not known. In this study we investigated the effects of exogenous ganglioside administration and modulation of endogenous ganglioside levels on the response of microglia to inflammatory stimuli, which often contributes to initiation or exacerbation of neurodegeneration.MethodsIn vitro studies were performed using BV2 cells, mouse, rat, and human primary microglia cultures. Modulation of microglial ganglioside levels was achieved by administration of exogenous gangliosides, or by treatment with GENZ-123346 and L-t-PDMP, an inhibitor and activator of glycolipid biosynthesis, respectively. Response of microglia to inflammatory stimuli (LPS, IL-1b, phagocytosis of latex beads) was measured by analysis of gene expression and/or secretion of pro-inflammatory cytokines. The effects of GM1 administration on microglia activation were also assessed in vivo in C57Bl/6 mice, following intraperitoneal injection of LPS.ResultsGM1 decreased inflammatory microglia responses in vitro and in vivo, even when administered after microglia activation. These anti-inflammatory effects depended on the presence of the sialic acid residue in the GM1 glycan headgroup and the presence of a lipid tail. Other gangliosides shared similar anti-inflammatory effects in in vitro models, including GD3, GD1a, GD1b, and GT1b. Conversely, GM3 and GQ1b displayed pro-inflammatory activity. The anti-inflammatory effects of GM1 and other gangliosides were partially reproduced by increasing endogenous ganglioside levels with L-t-PDMP, whereas inhibition of glycolipid biosynthesis exacerbated microglial activation in response to LPS stimulation.ConclusionsOur data suggest that gangliosides are important modulators of microglia inflammatory responses and reveal that administration of GM1 and other complex gangliosides exerts anti-inflammatory effects on microglia that could be exploited therapeutically.

scholarly journals Kangfuxin Oral Liquid Attenuates Bleomycin-Induced Pulmonary Fibrosis via the TGF-β1/Smad Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Huan Yao ◽  
Shujun Wei ◽  
Yongjing Xiang ◽  
Ziqiang Wu ◽  
Weiwei Liu ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Underlying Mechanism ◽  
Protective Function ◽  
Potential Efficacy ◽  
Oral Liquid ◽  
Smad Signaling Pathway ◽  
Related Proteins

Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease with a poor prognosis characterized by transforming growth factor (TGF)-β-induced proliferation, migration, and differentiation of fibroblasts, resulting in excessive extracellular matrix (ECM) deposition. Whether Kangfuxin oral liquid (KFXOL) has a protective function in pulmonary fibrosis is largely unknown. The goal of this study was to investigate the potential efficacy of KFXOL, as well as the underlying mechanism by which KFXOL regulates pulmonary fibrosis in vivo and in vitro. We found that KFXOL dramatically attenuated intratracheal bleomycin (BLM)-induced pulmonary fibrosis in terms of both severe alveolar architecture destruction and collagen deposition. KFXOL treatment significantly inhibited the proliferation, migration, and differentiation of pulmonary fibroblasts following activation using BLM/TGF-β1 and normalized the expression of ECM deposition-related proteins, including matrix metalloproteinase (MMP)-1, MMP-9, and tissue inhibitor of metalloproteinases 1. These effects were mediated via the inhibition of TGF-β1 and phosphorylated Smad2/3 activation in vivo. Taken together, our data suggest that KFXOL attenuates the development of pulmonary fibrosis via the TGF-β1/Smad signaling pathway and thus has potential utility in the treatment of pulmonary fibrosis.

scholarly journals Minimally Invasive Delivery of Microbeads with Encapsulated, Viable and Quiescent Neural Stem Cells to the Adult Subventricular Zone

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Rita Matta ◽  
Seyoung Lee ◽  
Nafiisha Genet ◽  
Karen K. Hirschi ◽  
Jean-Leon Thomas ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Subventricular Zone ◽  
Critical Role ◽  
Neurological Injury ◽  
Cell Therapies ◽  
Neuronal Stem Cells ◽  
The Brain

AbstractStem cell therapies demonstrate promising results as treatment for neurological disease and injury, owing to their innate ability to enhance endogenous neural tissue repair and promote functional recovery. However, delivery of undifferentiated and viable neuronal stem cells requires an engineered delivery system that promotes integration of transplanted cells into the inflamed and cytotoxic region of damaged tissue. Within the brain, endothelial cells (EC) of the subventricular zone play a critical role in neural stem cell (NSC) maintenance, quiescence and survival. Therefore, here, we describe the use of polyethylene glycol microbeads for the coincident delivery of EC and NSC as a means of enhancing appropriate NSC quiescence and survival during transplantation into the mouse brain. We demonstrate that EC and NSC co-encapsulation maintained NSC quiescence, enhanced NSC viability, and facilitated NSC extravasation in vitro, as compared to NSC encapsulated alone. In addition, co-encapsulated cells delivered to an in vivo non-injury model reduced inflammatory response compared to freely injected NSC. These results suggest the strong potential of a biomimetic engineered niche for NSC delivery into the brain following neurological injury.

scholarly journals Study on the Multitarget Synergistic Effects of Kai-Xin-San against Alzheimer’s Disease Based on Systems Biology

2019 ◽  
Vol 2019 ◽  
pp. 1-15
Author(s):  
Sirui Guo ◽  
Jiahong Wang ◽  
Yunjia Wang ◽  
Ying Zhang ◽  
Kaishun Bi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Systems Biology ◽  
Synergistic Effects ◽  
Medicine Research ◽  
Related Proteins ◽  
Functional Mechanisms ◽  
The Brain

Kai-Xin-San (KXS), a classical Chinese traditional prescription, was widely applied in the treatment of Alzheimer’s disease (AD), while its functional mechanisms still remain unclear. By using systems biology approaches at animal, cellular, and molecular levels, the improvement of KXS on cognitive impairment was achieved by inhibiting abnormal acetylcholinesterase. The function on the nerve skeleton was performed by regulating the Tau phosphorylation pathway. Its antioxidant, anti-inflammatory, and antiapoptotic effects by modulating the aberrant upregulation of ROS, proinflammatory factors, and apoptosis-related proteins in the brain were studied to reveal the synergistic therapeutic efficacy of KXS. Then, formula dismantling in vitro indicated that ginseng was the principal herb, whereas three other herbs served adjuvant roles to achieve the best effect. After that, the in vivo analysis of components into plasma and brain of AD rats showed that 8 of 23 components in blood and 4 of 10 components in brain were from ginseng, respectively, further verifying the principal status of ginseng and the synergistic effects of the formula. Thus, the anti-AD effects of KXS were achieved by multitargets and multichannels. The systems biology approaches presented here provide a novel way in traditional herbal medicine research.

scholarly journals An In Vitro Verification of the Effects of Paeoniflorin on Lipopolysaccharide-Exposed Microglia

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Qiliang Chen ◽  
Yaojun Liu ◽  
Yuanyuan Zhang ◽  
Xinyu Jiang ◽  
Yuqin Zhang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Nuclear Factor Kappa B ◽  
Brain Injuries ◽  
Enzyme Linked Immunosorbent Assay ◽  
Neuroprotective Effects ◽  
Polymerase Chain ◽  
New Treatment ◽  
Culture Supernatants

Background. The neuroprotective effects of Paeoniflorin (PF) are well known. Most of the evidence was verified in vivo. We attempted to perform an in vitro verification of the effects of PF in microglia. Methods. A lipopolysaccharide- (LPS-) exposed microglia model was employed. An enzyme-linked immunosorbent assay was used to measure the levels of cytokines in the culture supernatants. A real-time polymerase chain reaction was performed to measure the mRNA expression of cytokines and M1- and M2-like genes. A western blot analysis was used to examine the expression of proteins associated with the nuclear factor-kappa B (NF-κB) signaling pathway. Results. We found that the administration of PF reversed the inflammatory response induced by LPS. It downregulated proinflammatory cytokines and upregulated anti-inflammatory cytokines. This, in turn, alleviated the oxidative injuries, downregulated the expression of M1-like genes, and upregulated the expression of M2-like genes. PF can also reverse the changes in proteins associated with the NF-κB signaling pathway induced by LPS. Conclusions. We provided evidence obtained in vitro concerning the neuroprotective effects of PF via suppressing activation of microglia, which might be associated with the NF-κB signaling pathway. These findings contribute to obtaining a deeper understanding of PF, a potential new treatment for brain injuries.

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