Dataset Information

DL0410 Alleviates Memory Impairment in D-Galactose-Induced Aging Rats by Suppressing Neuroinflammation via the TLR4/MyD88/NF-κB Pathway.

ABSTRACT: Oxidative stress and neuroinflammation have been demonstrated to be linked with Alzheimer's disease (AD). In this study, we examined the protective effects of DL0410 in aging rats and explored the underlying mechanism against oxidative damage and neuroinflammation, which was then validated in LPS-stimulated BV2 microglia. We firstly investigated the improvement effects of DL0410 on learning and memory abilities and explored the potential mechanisms in D-gal-induced aging rats. An 8-week treatment with DL0410 significantly improved the learning and cognitive function of D-gal-stimulated Alzheimer's-like rats in the Morris water maze test, step-down test, and novel object recognition test, and the therapeutic effect of DL0410 at 10 mg/kg was even better than that of donepezil. What is more, the results showed that DL0410 alleviated neuron injury, increased the number of synapses, and improved the level of postsynaptic density protein 95 (PSD95) in the hippocampus and cortex. Next, we examined the protective effects of DL0410 against oxidative damage and neuroinflammation. Our observations indicated that DL0410 reduced the production of harmful oxidation products and promoted the antioxidative system, decreased the levels of proinflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6), and increased anti-inflammatory cytokines IL-10. Moreover, DL0410 inhibited the activation of astrocytes and microglia and suppressed the activation of the TLR4/MyD88/NF-κB signaling pathway. The anti-inflammation effect of DL0410 was further confirmed in LPS-stimulated BV2 cells, and the results showed that DL0410 reduced the level of inflammatory factors and inhibited the activation of the TLR4/MyD88/TRAF6/NF-κB signaling pathway in BV2 microglia. Molecular docking results indicated that DL0410 occupied the LPS recognition site in the TLR4/MD2 complex. Furthermore, the enhanced expression of claudin-1, claudin-5, occludin, CX43, and ZO-1 indicated that DL0410 protected the blood-brain barrier (BBB) integrity. Together, these results suggest that DL0410 exerts neuroprotective effects against hippocampus and cortex injury induced by D-galactose, and the possible mechanisms include antioxidative stress, antineuroinflammation, improving synaptic plasticity, and maintaining BBB integrity, which is mediated by the TLR4/MyD88/NF-κB signaling pathway inhibition. We suggest that DL0410 is a promising candidate for AD treatment.

SUBMITTER: Zhang B

PROVIDER: S-EPMC8510815 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Parkinson's disease (PD) is the second most common neurodegenerative disease, but none of the current treatments for PD can halt the progress of the disease due to the limited understanding of the pathogenesis. In PD development, the communication between the brain and the gastrointestinal system influenced by gut microbiota is known as microbiota-gut-brain axis. However, the explicit mechanisms of microbiota dysbiosis in PD development have not been well elucidated yet. FLZ, a novel squamosamide derivative, has been proved to be effective in many PD models and is undergoing the phase I clinical trial to treat PD in China. Moreover, our previous pharmacokinetic study revealed that gut microbiota could regulate the absorption of FLZ in vivo. The aims of our study were to assess the protective effects of FLZ treatment on PD and to further explore the underlying microbiota-related mechanisms of PD by using FLZ as a tool. In the current study, chronic oral administration of rotenone was utilized to induce a mouse model to mimic the pathological process of PD. Here we revealed that FLZ treatment alleviated gastrointestinal dysfunctions, motor symptoms, and dopaminergic neuron death in rotenone-challenged mice. 16S rRNA sequencing found that PD-related microbiota alterations induced by rotenone were reversed by FLZ treatment. Remarkably, FLZ administration attenuated intestinal inflammation and gut barrier destruction, which subsequently inhibited systemic inflammation. Eventually, FLZ treatment restored blood-brain barrier structure and suppressed neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra (SN). Further mechanistic research demonstrated that FLZ treatment suppressed the TLR4/MyD88/NF-κB pathway both in the SN and colon. Collectively, FLZ treatment ameliorates microbiota dysbiosis to protect the PD model via inhibiting TLR4 pathway, which contributes to one of the underlying mechanisms beneath its neuroprotective effects. Our research also supports the importance of microbiota-gut-brain axis in PD pathogenesis, suggesting its potential role as a novel therapeutic target for PD treatment.

Project description:BackgroundRed blood cells (RBCs) transfusion is related to perioperative neurocognitive disorders. The toxic effect of free heme has been identified in many pathologies. However, the underlying mechanisms of RBCs transfusion or free heme in cognitive impairment have not been clearly explored. Therefore, this research was conducted to determine the mechanism of free heme-induced neuroinflammation and cognitive impairment.MethodsRats were received intraperitoneal injection of hemin alone or combined with intracerebroventricular injection of Hemopexin (HPX), and MWM test was conducted to measure cognitive function. The amount of heme-HPX complexes was evaluated by flow cytometry for CD91 + cells. The microglial inflammatory response in rat brain was observed by immunofluorescence staining of Iba-1, and the inflammatory factors of TNF-α, IL-1β and IL-6 in rat brain and BV2 cells were detected by ELISA analysis. Furthermore, neuronal apoptosis in HT22 cells alone and in HT22 + BV2 coculture system was detected by flow cytometry and immunofluorescence staining. Finally, western blot was conducted to detect TLR4/MyD88/NF-κB proteins in rat brain and BV2 cells treated with hemin or combined with pathway inhibitors. Additionally, the M1 surface marker CD86 was observed in BV2 cells to further confirm neuroinflammation.ResultsIntraperitoneal injection of hemin induced cognitive impairment, increase of CD91 + cells, up-regulation of TNF-α and IL-1β, down-regulation of IL-6, activation of microglia, and activation of the TLR4/MyD88/NF-κB signaling pathway in rat brain. Significantly, intracerebroventricular injection of HPX reduced the above effects. Hemin induced boost of TNF-α, IL-1β and IL-6 in BV2 cells, as well as apoptosis in HT22 cells. Notably, when HT22 cells were cocultured with BV2 cells, apoptosis was significantly increased. Hemin also induced activation of the TLR4/MyD88/NF-κB signaling pathway and increased the M1 surface marker CD86 in BV2 cells, and inhibiting this pathway reduced the inflammatory responses.ConclusionsFree heme induces cognitive impairment, and the underlying mechanism may involve neuronal apoptosis and microglial inflammation via the TLR4/MyD88/NF-κB signaling pathway. HPX may have potential therapeutic effects. Video Abstract.

Project description:BackgroundJianpi Yangxue Qufeng Compound (JPYXQFC) is a Chinese medicine widely used in the clinical treatment of atopic dermatitis (AD) and has a significantly therapeutic effect. However, the mechanism of JPYXQFC in AD has been not understood clearly.ObjectiveThis study aimed to explore the effect of JPYXQFC on AD model cells and rats by regulating TLR4/MyD88/NF-κB signaling pathway.MethodsThe rats (n > 5) were given JPYXQFC decoction orally twice a day for three days, and their abdominal aortic blood was collected. HaCaT cell proliferation rate was tested by cell counting kit-8 (CCK-8) assays. We induced AD rat model through 2, 4-dinitrofluorobenzene (DNFB). AD rats were given oral JPYXQFC decoction and cetirizine (positive control). HaCaT cells were pretreated with JPYXQFC drug serum or cetirizine for 0.5 h and then stimulated with TNF-α/IFN-γ for 1 h. The mRNA levels of TLR4, MyD88, NF-κB, IL-4, IL-13, MCP1, TNF-α and TSLP were detected by quantitative real-time PCR (Q-RT-PCR), and TLR4/MyD88/NF-κB pathway protein expression was tested by Western blot. The total serum levels of immunoglobulin E (IgE), thymus and activation regulated chemokine/chemokine (C-C motif) ligand 17 (TARC/CCL17) were detected by enzyme-linked immunosorbent assay (ELISA). The epidermal thickness was detected by hematoxylin and eosin (HE) staining. The dermatitis area and score were measured by a ruler and a four-point scoring method, respectively.ResultsJPYXQFC significantly inhibited mRNA and protein expression of the TLR4/MyD88/NF-κB pathway and Histone H3 in TNF-α/IFN-γ-induced HaCaT cells and DNFB-induced rats, decreased the mRNA of IL-4, IL-13, MCP1, CCL22, TSLP and the level of AD-related genes IgE and TAEC/CCL17 of TNF-α/IFN-γ-induced HaCaT cells. Meanwhile, JPYXQFC significantly reduced the dermatitis area and dermatitis score in DNFB-induced rats, inhibited the levels of pro-inflammatory cytokines IL-6 and TNF-α, and upregulated FLG, as well as inhibited the levels of IgE and TARC/CCL17 in the serum of AD rats.ConclusionJPYXQFC alleviates AD by inhibiting the activation of TLR4/MyD88/NF-κB pathway.

Project description:Inflammatory bowel disease (namely, colitis) severely impairs human health. Isoleucine is reported to regulate immune function (such as the production of immunoreactive substances). The aim of this study was to investigate whether l-isoleucine administration might alleviate dextran sulfate sodium (DSS)-induced colitis in rats. In the in vitro trial, IEC-18 cells were treated by 4 mmol/L l-isoleucine for 12 h, which relieved the decrease of cell viability that was induced by TNF-α (10 ng/ml) challenge for 24 h (P <0.05). Then, in the in vivo experiment, a total of 44 Wistar rats were allotted into 2 groups that were fed l-isoleucine-supplemented diet and control diet for 35 d. From 15 to 35 d, half of the rats in the 2 groups drank the 4% DSS-adding water. Average daily gain, average daily feed intake and feed conversion of rats were impaired by DSS challenge (P <0.05). Drinking the DSS-supplementing water also increased disease activity index (DAI) and serum urea nitrogen level (P <0.05), shortened colonic length (P <0.05), impaired colonic enterocyte apoptosis, cell cycle, and the ZO-1 mRNA expression (P <0.05), increased the ratio of CD11c-, CD64-, and CD169-positive cells in colon (P <0.05), and induced extensive ulcer, infiltration of inflammatory cells, and collagenous fiber hyperplasia in colon. However, dietary l-isoleucine supplementation attenuated the negative effect of DSS challenge on growth performance (P <0.05), DAI (P <0.05), colonic length and enterocyte apoptosis (P <0.05), and dysfunction of colonic histology, and downregulated the ratio of CD11c-, CD64-, and CD169-positive cells, pro-inflammation cytokines and the mRNA expression of TLR4, MyD88, and NF-κB in the colon of rats (P <0.05). These results suggest that supplementing l-isoleucine in diet improved the DSS-induced growth stunting and colonic damage in rats, which could be associated with the downregulation of inflammation via regulating TLR4/MyD88/NF-κB pathway in colon.

Dataset Information

DL0410 Alleviates Memory Impairment in D-Galactose-Induced Aging Rats by Suppressing Neuroinflammation via the TLR4/MyD88/NF-κB Pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets