Gastrodin (GAS), a phenolic glucoside derived from Gastrodiaelata Blume, has been reported to have anti-inflammatory effect. The aim of this study was to investigate the effects of GAS on LPS-induced acute lung injury in mice. ALI was induced by the intranasal administration of LPS and GAS was given 1 h or 12 h after LPS treatment. The results indicated that GAS treatment markedly attenuated the damage of lung injury induced by LPS. GAS attenuated the activity of myeloperoxidase (MPO) and down-regulated the levels of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β in BALF. LPS-induced lung edema and lung function were also reversed by GAS. Furthermore, GAS was found to inhibit LPS-induced inflammatory cells infiltration. In addition, treatment of GAS inhibited LPS-induced NF-κB activation and up-regulated the expression of Nrf2 and HO-1. In conclusion, our results indicated that GAS had anti-inflammatory effects on LPS-induced acute lung injury. The anti-inflammatory mechanism of GAS was through the inhibition of NF-κB and activation of Nrf2 signaling pathways.
Background: Increased consumption of fruit and vegetables has been shown to be associated with a reduced risk of cognitive impairment and dementia in many epidemiological studies. The purpose of this study was to assess the strength of this association in a meta-analysis. Methods: We identified relevant studies by searching Medline, Embase, and Cochrane Library electronic databases (from 1970 to January 2016). Study were included if they reported relative risks and corresponding 95% confidence intervals (CIs) of cognitive impairment and dementia with respect to frequency of fruit and vegetable intake. Results: Nine studies (five cohort studies and four cross-sectional studies) met the inclusion criteria and were included in the meta-analysis. There were a total of 31,104 participants and 4,583 incident cases of cognitive impairment and dementia. The meta-analysis showed that an increased consumption of fruit and vegetables was associated with a significant reduction in the risk of cognitive impairment and dementia (OR = 0.80, 95% CI 0.71-0.89). Subgroup analysis indicated this inverse association was only found among participants with mean age over 65 years and combined sexes. Dose-response meta-analysis showed that an increment of 100 g per day of fruit and vegetable consumption was related to an approximately 13% (OR = 0.87, 95% CI 0.77-0.99) reduction in cognitive impairment and dementia risk. There was no potential publication bias in the meta-analysis and the dose-response meta-analysis. Conclusion: The increased consumption of fruit and vegetables is associated with a reduced risk of cognitive impairment and dementia.
Alzheimer`s disease (AD) is a very common progressive neurodegenerative disorder with the highest incidence in the world. Dysfunction of the blood brain barrier (BBB) may be responsible for the pathogenesis and pathology of AD for abnormally transporting amyloid-β (Aβ, the main component of the senile plaques) from the sera into the central nervous system. Aβ peptides induce apoptosis in human brain microvascular endothelial cells (hBMECs), the main component of BBB. Apoptosis in neuronal cells plays a critical role in the pathogenesis of AD. Asiaticoside, a natural glycoside extracted from Centella asiatica (L.) Urban, has an anti-apoptotic effect on hBMECs but the molecule mechanism remains unclear. Therefore, we investigate the protective effect of asiaticoside on Aβ1-42-induced cytotoxicity and apoptosis as well as associated mechanism in hBMECs with commonly used in vitro methods for clinical development of asiaticoside as a novel anti-AD agent. In the present study, we investigated the effects of asiaticoside on cytotoxicity by Cell Counting Kit-8 assay, mitochondrial membrane potential by JC-1 fluorescence analysis, anti-apoptosis by Hoechst 33258 staining and Annexin V-FITC (fluorescein isothiocyanate) and propidium iodide (PI) analyses, the expressions of TNF-α and IL-6 by enzyme-linked immunosorbent assay (ELISA) and TLR4, MyD88, TRAF6, p-NF-κB p65, and total NF-κB p65 by Western blotting, and nuclear translocation of NF-κB p65 by immunofluorescence analysis in hBMECs. The results showed that pretreatment of asiaticoside (25, 50, and 100 μM) for 12 h significantly attenuated cell growth inhibition and apoptosis, and restored declined mitochondrial membrane potential induced by Aβ1-42 (50 μM) in hBMECs. Asiaticoside also significantly down-regulated the elevated expressions of TNF-α, IL-6, TLR4, MyD88, TRAF6, and p-NF-κB p65, as well as inhibited NF-κB p65 translocation from cytoplasm to nucleus induced by Aβ1-42 in hBMECs in a concentration-dependent manner. The possible underlying molecular mechanism of asiaticoside may be through inhibiting the TLR4/NF-KB signaling pathway. Therefore, asiaticoside may be developed as a novel agent for the prevention and/or treatment of AD clinically.
Human umbilical vein endothelial cells (HUVECs) serve a critical role in maintaining normal vascular function. Lipopolysaccharide (LPS), which is released from pathogenic bacteria in the blood, induces HUVEC apoptosis and injury to cause vascular dysfunction and infectious vascular diseases. Procyanidin B2 (PB2) possesses numerous functions, including antioxidant, antitumor, anti‑inflammatory and antiapoptosis effects, but the molecular mechanism is not completely understood. The present study investigated the effects of PB2 on LPS‑induced cytotoxicity and apoptosis in HUVECs, as well as the underlying mechanisms. The effects of PB2 on LPS‑mediated alterations to cytotoxicity, mitochondrial membrane potential, apoptosis were assessed by performing Cell Counting Kit‑8, JC‑1 fluorescence, Hoechst 33258 staining assays, respectively. IL‑1β, IL‑6 and TNF‑α mRNA expression and protein levels were measured by performing reverse transcription‑quantitative PCR and ELISAs, respectively. Bcl‑2, Bax, cleaved caspase‑3, cleaved caspase‑7, cleaved caspase‑9, phosphorylated (p)‑IκB‑α, p‑IκB‑β, p‑NF‑κB‑p65 and total NF‑κB p65 protein expression levels were determined via western blotting. NF‑κB p65 nuclear translocation was assessed via immunofluorescence. PB2 pretreatment markedly attenuated LPS‑induced cytotoxicity and apoptosis in HUVECs. PB2 also significantly downregulated the expression levels of IL‑1β, IL‑6, TNF‑α, Bax, cleaved caspase‑3, cleaved caspase‑7, cleaved caspase‑9 and p‑NF‑κB‑p65, but upregulated the expression levels of Bcl‑2, p‑IκB‑α and p‑IκB‑β in LPS‑induced HUVECs. Moreover, PB2 markedly inhibited LPS‑induced NF‑κB p65 nuclear translocation in HUVECs. The results suggested that the potential molecular mechanism underlying PB2 was associated with the Bax/Bcl‑2 and NF‑κB signalling pathways. Therefore, PB2 may serve as a useful therapeutic for infectious vascular diseases.
Aims: The present study is to investigate the effect of Asiaticoside (AS) on the expression of hippocampal Peroxisome Proliferator Activated Receptor Gamma (PPARγ) and inflammatory factors such as Interleukin (IL)-6 and Tumor Necrosis Factor (TNF)-α in rats after intracerebral injection of Aβ1-42. Methods: A total of 40 specific pathogen-free Sprague-Dawley rats were evenly divided into shamoperation (control) group, model group, model+AS (15 mg/kg) group and model+AS (45 mg/kg) group. Condensed β-amyloid protein (Aβ)-1-42 was slowly injected into the CA1 region in hippocampus of rats to simulate Alzheimer’s disease. Morris water maze test was used to examine the ability of spatial learning and memory of rats. Immunohistochemistry was performed to detect the deposition of Aβ1-42 in hippocampal tissues. Enzyme-linked immunosorbent assay was carried out to determine the contents of IL-6 and TNF-α in hippocampal tissues. Western blotting was employed to measure the protein expression of PPARγ. Results: Treatment with AS enhanced the spatial learning and memory, reduced the expression of Aβ1-42 in hippocampal region, decreased the contents of IL-6 and TNF-α in hippocampal tissues, and elevated the protein expression of PPARγ in hippocampal tissues of AD model rats. Conclusions: The present study demonstrates that AS improves spatial learning and memory abilities of AD model rats by promoting the expression of PPARγ and inhibiting the contents of inflammatory factors.
Atractylodes is the dry root of atractylodes macrocephala koidz and has been commonly used as a traditional Chinese medicine (TCM). Atractylenolide III, a main component of atractylodes, has displayed significant effects on anti-inflammation and anticancer. However, the effects of atractylenolide III on growth inhibition and apoptosis induction in colon cancer remain unclear. The results showed that atractylenolide III significantly inhibited the cell growth and induce cellular apoptosis in HCT-116 cells in a concentration dependence manner in vitro. Mechanistic studies further showed that atractylenolide III could regulate the Bax/Bcl-2 apoptotic signaling pathway through promoting the expression of proapoptotic related gene/proteins Bax, caspase-9 and caspase-3 but inhibiting the expression of antiapoptotic related gene/protein Bcl-2 in HCT-116 cells. Furthermore, atractylenolide III also significantly inhibited the tumor growth of HCT-116 tumor xenografts bearing in nude mice through inducing apoptosis by upregulation of the expressions of Bax, cleaved caspase-3 and p53 but downregulation of the expressions of Bcl-2 in HCT-116 tumor tissues in vivo. The studies may provide the scientific rationale for the understanding of the anticancer effect of atractylenolide III. Therefore, atractylenolide III may have the potential to be developed as a promising novel anticancer agent for the treatment of colorectal cancer clinically.
T cell exclusion is crucial in enabling tumor immune evasion and immunotherapy resistance. However, the key genes driving this process remain unclear. We uncovered a notable increase of insulin-like growth factor 2 (IGF2) in immune-excluded tumors, predominantly secreted by cancer-associated fibroblasts (CAFs). Using mice with systemic or fibroblast-specific deletion of IGF2, we demonstrated that IGF2 deficiency enhanced the infiltration and cytotoxic activity of CD8+ T cells, leading to a reduction in tumor burden. Integration of spatial and single-cell transcriptomics revealed that IGF2 promoted interaction between CAFs and T cells via CXCL12 and programmed death ligand 1 (PD-L1). Mechanistically, autocrine IGF2 activated PI3K/AKT signaling by binding to the IGF1 receptor (IGF1R) on CAFs, which was required for the immunosuppressive functions of CAFs. Furthermore, genetic ablation of IGF2 or targeted inhibition of the IGF2/IGF1R axis with the inhibitor linsitinib markedly boosted the response to immune checkpoint blockade. Clinically, elevated levels of IGF2 in tumors or plasma correlated with an adverse prognosis and reduced efficacy of anti–programmed death 1 treatment. Together, these results highlight the pivotal role of IGF2 in promoting CAF-mediated immunoevasion, indicating its potential as a biomarker and therapeutic target in immunotherapy.
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