Endoplasmic reticulum associated degradation preserves neurons viability by maintaining endoplasmic reticulum homeostasis.

Endoplasmic reticulum-associated degradation (ERAD) is a principal quality-control mechanism responsible for targeting misfolded ER proteins for cytosolic degradation. Evidence suggests that impairment of ERAD contributes to neuron dysfunction and death in neurodegenerative diseases, many of which are characterized by accumulation and aggregation of misfolded proteins. However, the physiological role of ERAD in neurons remains unclear.

The physiological role of the unfolded protein response in the nervous system.

The unfolded protein response (UPR) is a cellular stress response pathway activated when the endoplasmic reticulum, a crucial organelle for protein folding and modification, encounters an accumulation of unfolded or misfolded proteins. The UPR aims to restore endoplasmic reticulum homeostasis by enhancing protein folding capacity, reducing protein biosynthesis, and promoting protein degradation. It also plays a pivotal role in coordinating signaling cascades to determine cell fate and function in response to endoplasmic reticulum stress.

Ursolic acid alleviates paclitaxel-induced peripheral neuropathy through PPARγ activation.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) reduces the overall quality of life and leads to interruption of chemotherapy. Ursolic acid, a triterpenoid naturally which presents in fruit peels and in many herbs and spices, can function as a peroxisome proliferator-activated receptor γ (PPARγ) agonist, and has been widely used as an herbal medicine with a wide spectrum of pharmacological activities, including anti-cancer, anti-inflammatory and neuroprotective effect.

Methods: We used a phenotypic drug screening approach to identify ursolic acid as a potential neuroprotective drug in vitro and in vivo and carried out additional biochemical experiments to identify its mechanism of action.

Assessing multiple factors affecting the gut microbiome structure of very preterm infants.

The composition and diversity of the gut microbiota are essential for the health and development of the immune system of infants. However, there is limited information on factors that influence the gut microbiota of very preterm infants. In this study, we analyzed factors that affect the gut microbiota of very preterm infants.

Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis.

Cyclophilin D (CypD) is a mitochondrial matrix peptidyl prolidase that regulates the mitochondrial permeability transition pore. Inhibition of CypD was suggested as a therapeutic strategy for acute pancreatitis. Peptide inhibitors emerged as novel binding ligand for blocking receptor activity.

Endoplasmic reticulum associated degradation is essential for maintaining the viability or function of mature myelinating cells in adults.

Endoplasmic reticulum associated degradation (ERAD) is responsible for recognition and degradation of unfolded or misfolded proteins in the ER. Sel1L is essential for the ERAD activity of Sel1L-Hrd1 complex, the best-known ERAD machinery. Using a continuous Sel1L knockout mouse model (CNP/Cre; Sel1L mice), our previous studies showed that Sel1L knockout in myelinating cells, oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS), leads to adult-onset myelin abnormalities in the CNS and PNS.

The Integrated UPR and ERAD in Oligodendrocytes Maintain Myelin Thickness in Adults by Regulating Myelin Protein Translation.

Myelin proteins, which are produced in the endoplasmic reticulum (ER), are essential and necessary for maintaining myelin structure. The integrated unfold protein response (UPR) and ER-associated degradation (ERAD) are the primary ER quality control mechanism. The adaptor protein Sel1L (Suppressor/Enhancer of Lin-12-like) controls the stability of the E3 ubiquitin ligase Hrd1 (hydroxymethylglutaryl reductase degradation protein 1), and is necessary for the ERAD activity of the Sel1L-Hrd1 complex.

Endoplasmic reticulum associated degradation is required for maintaining endoplasmic reticulum homeostasis and viability of mature Schwann cells in adults.

The integrated unfolded protein response (UPR) and endoplasmic reticulum associated degradation (ERAD) is the principle mechanisms that maintain endoplasmic reticulum (ER) homeostasis. Schwann cells (SCs) must produce an enormous amount of myelin proteins via the ER to assemble and maintain myelin structure; however, it is unclear how SCs maintain ER homeostasis. It is known that Suppressor/Enhancer of Lin-12-like (Sel1L) is necessary for the ERAD activity of the Sel1L- hydroxymethylglutaryl reductase degradation protein 1(Hrd1) complex.

NF-κB Activation Accounts for the Cytoprotective Effects of PERK Activation on Oligodendrocytes during EAE.

Previous studies demonstrate that activation of pancreatic ER kinase (PERK) protects oligodendrocytes against inflammation in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Interestingly, data indicate that the cytoprotective effects of PERK activation on oligodendrocytes during EAE are not mediated by activating transcription factor 4 (ATF4) but are accompanied by activation of nuclear factor κB (NF-κB). NF-κB plays a critical role in MS and EAE; however, the effects of NF-κB activation on oligodendrocytes in these diseases remain elusive.

The UPR preserves mature oligodendrocyte viability and function in adults by regulating autophagy of PLP.

Maintaining cellular proteostasis is essential for oligodendrocyte viability and function; however, its underlying mechanisms remain unexplored. Unfolded protein response (UPR), which comprises 3 parallel branches, inositol requiring enzyme 1 (IRE1), pancreatic ER kinase (PERK), and activating transcription factor 6α (ATF6α), is a major mechanism that maintains cellular proteostasis by facilitating protein folding, attenuating protein translation, and enhancing autophagy and ER-associated degradation. Here we report that impaired UPR in oligodendrocytes via deletion of PERK and ATF6α did not affect developmental myelination but caused late-onset mature oligodendrocyte dysfunction and death in young adult mice.

Neuron-specific PERK inactivation exacerbates neurodegeneration during experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are chronic inflammatory demyelinating and neurodegenerative diseases of the CNS. Although neurodegeneration is the major contributor to chronic disability in MS, mechanisms governing the viability of axons and neurons in MS and EAE remain elusive. Data indicate that activation of pancreatic endoplasmic reticulum kinase (PERK) influences, positively or negatively, neuron and axon viability in various neurodegenerative diseases through induction of ATF4.

Activating transcription factor 6α deficiency exacerbates oligodendrocyte death and myelin damage in immune-mediated demyelinating diseases.

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) play a critical role in immune-mediated demyelinating diseases, including multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), by regulating the viability of oligodendrocytes. Our previous studies show that activation of the PERK branch of the UPR protects myelinating oligodendrocytes against ER stress in young, developing mice that express IFN-γ, a key pro-inflammatory cytokine in MS and EAE, in the CNS. Several studies also demonstrate that PERK activation preserves oligodendrocyte viability and function, protecting mice against EAE.

Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins.

A series of gossypol Schiff bases that were derived from unnatural linear amino acid methyl esters were identified and found to be much more potent than gossypol and ABT-199 in terms of anticancer activity. This is the first example of gossypol Schiff bases with increased activity. The investigation of the Schiff base side chain of gossypol revealed that the unique anticancer effect was achieved by the introduction of hydrophobic ester groups.

Myricetin alleviates cuprizone-induced behavioral dysfunction and demyelination in mice by Nrf2 pathway.

Multiple sclerosis (MS) is a demyelinating disease occurring in the central nervous system. In the present study, we evaluated the function of myricetin on the alleviation of behavioral dysfunction and myelin protection in the cuprizone-induced demyelination model. Mice were daily fed with fodder including 0.

Myricetin ameliorates brain injury and neurological deficits via Nrf2 activation after experimental stroke in middle-aged rats.

The aim of our study was to investigate the protective effects and underlying mechanisms of myricetin, a bioactive food compound, on brain injury and neurological deficits after ischemic stroke. Treatment of myricetin significantly attenuated oxygen-glucose deprivation (OGD)-induced cell death in SHSY5Y cells in vitro. In a rat model of cerebral ischemia, myricetin was administered intragastrically at 2 h before and every day after middle cerebral artery occlusion (MCAO).

Procyanidin B2 attenuates neurological deficits and blood-brain barrier disruption in a rat model of cerebral ischemia.

Scope: Disruption of the blood-brain barrier (BBB) is a major pathogenic mechanism of neurological dysfunction and death after ischemic stroke. The aim of our study was to investigate the effect of procyanidin B2 (PB), a bioactive food compound, on BBB disruption induced by ischemic stroke and explore the underlying mechanism.

Methods And Results: PB was administrated intragastrically once a day starting at 3 h after transient middle cerebral artery occlusion (MCAO).

Wild jujube polysaccharides protect against experimental inflammatory bowel disease by enabling enhanced intestinal barrier function.

Dietary polysaccharides provide various beneficial effects for our health. We investigated the protective effects of wild jujube (Ziziphus jujuba Mill. var.

A disposable electrochemical sensor for simultaneous determination of norepinephrine and serotonin in rat cerebrospinal fluid based on MWNTs-ZnO/chitosan composites modified screen-printed electrode.

A new electrochemical sensor for simultaneous determination of norepinephrine (NE) and serotonin (5-HT) was fabricated. The electrochemical behavior of NE and 5-HT were investigated using CV and SWV at the MWNTs-ZnO/chitosan composites modified screen-printed electrode (MWNTs-ZnO/chitosan SPE). The results showed that the current responses of NE and 5-HT greatly enhanced due to the high catalytic activity of composites.

Protective effects of aloe-emodin on scopolamine-induced memory impairment in mice and H₂O₂-induced cytotoxicity in PC12 cells.

Aloe-emodin (AE) is one of the most important active components of Rheum officinale Baill. The present study aimed to investigate that AE could attenuate scopolamine-induced cognitive deficits via inhibiting acetylcholinesterase (AChE) activity and modulating oxidative stress. Kunming (KM) mice were received intraperitoneal injection of scopolamine (2 mg/kg) to induce cognitive impairment.

Characterization and hepatoprotective effect of polysaccharides from Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chou sarcocarp.

The polysaccharides from Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H.

Selective tumor cell killing by triptolide in p53 wild-type and p53 mutant ovarian carcinomas.

Triptolide is a traditional Chinese medicinal herb-derived antineoplastic agent. However, its antitumor activity against gynecologic carcinomas has not yet been well described. It is the purpose of this article to investigate the effect and mechanism of triptolide in human ovarian cancer using both A2780 (p53 wild) and OVCAR-3 (p53 mutated) cells.

Tramiprosate protects neurons against ischemic stroke by disrupting the interaction between PSD95 and nNOS.

Tramiprosate, a small aminosulphonate compound, is present in various species of red marine algae. In this study, we examined whether tramiprosate protects neurons and improves functional recovery following ischemic stroke in rats subjected to the intraluminal filament model of MCAO and further explored the underlying mechanisms. Tramiprosate dose-dependently reduced the infarct volume after MCAO, and the therapeutic time window of tramiprosate (50 mg/kg) for cerebral ischemia was at least 6 h.

[Inhibitory effect of a novel histone deacetylases inhibitor FK228 on human colon cancer HCT-116 cells in vitro and in vivo].

Objective: To investigate the inhibitory effects of a novel histone deacetylases inhibitor FK228 on human colon cancer HCT-116 cells in vitro and in vivo, and evaluate its toxicity and side effects.

Methods: The in vitro growth inhibitions of HCT-116 cells by different concentrations of FK228 and 5-Fu for 24, 48 and 72 h were assessed by CCK-8 assay. BALB/c nude mouse models of tumor xenografts were prepared by subcutaneous implantation of tumor tissue, and 4 mg/kg FK228 and 50 mg/kg 5-Fu were i.

A high-throughput method for the simultaneous determination of multiple mycotoxins in human and laboratory animal biological fluids and tissues by PLE and HPLC-MS/MS.

A high-throughput method for the determination of 28 mycotoxins involving pressurised liquid extraction (PLE) coupled with liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) has been optimised and validated for determination in various biological fluids and tissues of human and laboratory animals. High-throughput analysis was achieved using PLE pre-treatment and without the need for any cleanup. The extraction solvent was acetonitrile/water/acetic acid (80/19/1, v/v/v).

Carthamus red from Carthamus tinctorius L. exerts antioxidant and hepatoprotective effect against CCl(4)-induced liver damage in rats via the Nrf2 pathway.

Ethnopharmacological Relevance: Carthamus red isolated from safflower (Carthamus tinctorius L., a Chinese traditional medicine) is evaluated for antioxidant and hepatoprotective activity.

Materials And Methods: Carthamus red was isolated from a Na2CO3 extract of safflower and its analysis was carried out by HPLC/MS.