Peptidomics-based study of antihypertensive activity: discovery of novel ACE inhibiting peptides from peanut yogurt.

Studies have confirmed that yogurt has the activity of regulating blood pressure because it is rich in probiotic-fermented food-derived active peptides. There are also studies on angiotensin-converting enzyme inhibition (ACEI) peptide milk, but the bioactive molecules in it are still unclear. Therefore, in this study, we developed a peanut yogurt with ACEI activity, analyzed 1877 differential peptides and their antihypertensive pathways before and after fermentation using peptidomics, and identified three peptides (FLPYPY, QPPPSPPPFL and APFPEVFGK) with potential antihypertensive activity using molecular docking and chemical synthesis techniques. These results first elucidated the relationship between peanut yogurt peptides and antihypertensive function, demonstrated the benefits of peanut yogurt, and provided a theoretical basis for the application of probiotic fermented plant yogurt in health care.

Paeoniflorin ameliorates lipopolysaccharide-induced acute liver injury by inhibiting oxidative stress and inflammation via SIRT1/FOXO1a/SOD2 signaling in rats.

Acute liver injury (ALI) is a poor prognosis and high mortality complication of sepsis. Paeoniflorin (PF) has remarkable anti-inflammatory effects in different disease models. Here, we explored the protective effect and underlying molecular mechanisms of PF against lipopolysaccharide (LPS)-induced ALI. Sprague-Dawley rats received intraperitoneal (i.p.) injection of PF for 7 days, 1 h after the last administration, and rats were injected i.p. 10 mg/kg LPS. PF improved liver structure and function, reduced hepatic reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA) levels, and increased superoxide dismutase (SOD) activity. Western blot analysis suggested that PF significantly inhibited expression of inflammatory cytokines (TNF-α, IL-1ß, and IL-18) and inhibited activation of the NLRP3 inflammasome. PF or mitochondrial ROS scavenger (mito-TEMPO) significantly improved liver mitochondrial function by scavenging mitochondrial ROS (mROS), restoring mitochondrial membrane potential loss and increasing level of ATP and enzyme activity of complex I and III. In addition, PF increased expression of sirtuin-1 (SIRT1), forkhead box O1 (FOXO1a) and manganese superoxide dismutase (SOD2), and increased FOXO1a nuclear retention. However, the inhibitor of SIRT1 (EX527) abolished the protective effect of PF. Taken together, PF promotes mROS clearance to inhibit mitochondrial damage and activation of the NLRP3 inflammasome via SIRT1/FOXO1a/SOD2 signaling.

Lycopene Alleviates Chronic Stress-Induced Spleen Apoptosis and Immunosuppression via Inhibiting the Notch Signaling Pathway in Rats.

Chronic stress induction in immunosuppression and splenocyte apoptosis is commonly associated with increased susceptibility to various diseases. Lycopene (LYC) is a member of the carotenoid family with immune restoration and anti-apoptotic function. However, little is known about the mechanisms underlying the protective roles of LYC against spleen injury induced by chronic stress. Herein, male Wistar rats were undergoing chronic restraint stress and/or administered LYC (10 mg/kg) for 21 days. The effective model establishment was validated by open-field tests and levels of corticosterone in serum. Histopathological staining observation displayed that LYC could reduce chronic stress-induced spleen structure damage. Furthermore, LYC treatment significantly reduced the number of apoptotic-positive splenocytes caused by chronic stress via the death receptor apoptotic pathway. We detected the interleukin 4 and interferon γ levels in serum and spleen to determine the ratio of Th1 and Th2 and found that LYC can alleviate the immunosuppression induced by chronic stress. Notably, western blot and real-time polymerase chain reaction indicated that LYC can reduce the expression of the Notch-pathway-related proteins and mRNA in rats exposed to chronic stress. Further study of the potential mechanisms by adding the Notch pathway inhibitor DAPT revealed that LYC alleviates the structure damage, apoptosis, and immunosuppression caused by chronic stress via the suppression of the Notch pathway. Overall, this study presents a strong rationale to target LYC as a treatment strategy to relieve chronic stress-induced spleen injury.

Dexmedetomidine Alleviates Lipopolysaccharide-Induced Hippocampal Neuronal Apoptosis via Inhibiting the p38 MAPK/c-Myc/CLIC4 Signaling Pathway in Rats.

Dexmedetomidine (DEX) has multiple biological effects. Here, we investigated the neuroprotective role and molecular mechanism of DEX against lipopolysaccharide (LPS)-induced hippocampal neuronal apoptosis. Sprague Dawley rats were intraperitoneally injected with LPS (10 mg/kg) and/or DEX (30 µg/kg). We found that DEX improved LPS-induced alterations of hippocampal microstructure (necrosis and neuronal loss in the CA1 and CA3 regions) and ultrastructure (mitochondrial damage). DEX also attenuated LPS-induced inflammation and hippocampal apoptosis by inhibiting the increase of interleukin-1ß, interleukin-6, interleukin-18, and tumor necrosis factor-α levels and downregulating the expression of mitochondrial apoptosis pathway-related proteins. Moreover, DEX prevented the LPS-induced activation of the c-Myc/chloride intracellular channel 4 (CLIC4) pathway. DEX inhibited the p38 MAPK pathway, but not JNK and ERK. To further clarify whether DEX alleviated LPS-induced neuronal apoptosis through the p38 MAPK/c-Myc/CLIC4 pathway, we treated PC12 cells with p38 MAPK inhibitor SB203582 (10 µM). DEX had the same effect as SB203582 in reducing the protein and mRNA expression of c-Myc and CLIC4. Furthermore, DEX and SB203582 diminished LPS-induced apoptosis, indicated by decreased Bax and Tom20 fluorescent double-stained cells, reduced annexin V-FITC/PI apoptosis rate, and reduced protein expression levels of Bax, cytochrome C, cleaved caspase-9, and cleaved caspase-3. Taken together, the findings indicate that DEX attenuates LPS-induced hippocampal neuronal apoptosis by regulating the p38 MAPK/c-Myc/CLIC4 signaling pathway. These findings provide new insights into the mechanism of Alzheimer's disease and depression and may help aid in drug development for these diseases.

Long non-coding RNA PTPRG-AS1 promotes cell tumorigenicity in epithelial ovarian cancer by decoying microRNA-545-3p and consequently enhancing HDAC4 expression.

BACKGROUND: Long non-coding RNA PTPRG antisense RNA 1 (PTPRG-AS1) deregulation has been reported in various human malignancies and identified as an important modulator of cancer development. Few reports have focused on the detailed role of PTPRG-AS1 in epithelial ovarian cancer (EOC) and its underlying mechanism. This study aimed to determine the physiological function of PTPRG-AS1 in EOC. A series of experiments were also performed to identify the mechanisms through which PTPRG-AS1 exerts its function in EOC. METHODS: Reverse transcription-quantitative polymerase chain reaction was used to determine PTPRG-AS1 expression in EOC tissues and cell lines. PTPRG-AS1 was silenced in EOC cells and studied with respect to cell proliferation, apoptosis, migration, and invasion in vitro and tumor growth in vivo. The putative miRNAs that target PTPRG-AS1 were predicted using bioinformatics analysis and further confirmed in luciferase reporter and RNA immunoprecipitation assays. RESULTS: Our data verified the upregulation of PTPRG-AS1 in EOC tissues and cell lines. High PTPRG-AS1 expression was associated with shorter overall survival in patients with EOC. Functionally, EOC cell proliferation, migration, invasion in vitro, and tumor growth in vivo were suppressed by PTPRG-AS1 silencing. In contrast, cell apoptosis was promoted by loss of PTPRG-AS1. Regarding the mechanism, PTPRG-AS1 could serve as a competing endogenous RNA in EOC cells by decoying microRNA-545-3p (miR-545-3p), thereby elevating histone deacetylase 4 (HDAC4) expression. Furthermore, rescue experiments revealed that PTPRG-AS1 knockdown-mediated effects on EOC cells were, in part, counteracted by the inhibition of miR-545-3p or restoration of HDAC4. CONCLUSIONS: PTPRG-AS1 functioned as an oncogenic lncRNA that aggravated the malignancy of EOC through the miR-545-3p/HDAC4 ceRNA network. Thus, targeting the PTPRG-AS1/miR-545-3p/HDAC4 pathway may be a novel strategy for EOC anticancer therapy.

Aluminum trichloride caused hippocampal neural cells death and subsequent depression-like behavior in rats via the activation of IL-1ß/JNK signaling pathway.

Aluminum (Al) is an inorganic pollutant that induces nerve cells apoptosis and necroptosis, thereby causing depression and neurodegenerative diseases. IL-1ß/JNK signaling pathway can regulate apoptosis and necroptosis. However, it remains unclear whether IL-1ß/JNK signaling pathway is involving in the regulation of Al-induced hippocampal neural cells apoptosis and necroptosis. To investigate the mechanism of Al on neural cells apoptosis and necroptosis, rats were orally exposed to different doses of AlCl3 for 90 days. The open-field test results showed that AlCl3 caused depressive behavior in rats. Histopathological evidence showed that AlCl3 induced hippocampal neural cells apoptosis and necrosis. Moreover, Bax/Bcl-2 mRNA expression ratio, caspase-3 activity and mRNA expression and TUNEL positive rates were upregulated, meanwhile, TNF-α mRNA and protein expression levels, TNFR1, RIP1, RIP3 and MLKL proteins levels were increased, while caspase-8 protein level was decreased in the hippocampus of Al-exposed groups. These results proved that AlCl3 induced hippocampal neural cells apoptosis and necroptosis. Combined with histopathology and correlation analysis, we deduced that hippocampal neural cells were more likely to undergo necroptosis at high doses (450 mg/kg) of AlCl3, while <150 mg/kg AlCl3 tended to induce apoptosis. Finally, AlCl3 increased the proteins level of IL-1ß, IL-1RI, IL-1RAcP, JNK and p-JNK, indicating that AlCl3 activated IL-1ß/JNK signaling pathway. However, the application of IL-1 receptor antagonist (IL-1Ra) inhibited the phosphorylation of JNK and the related genes expression of apoptosis and necroptosis caused by AlCl3. Thus, we concluded that AlCl3 induced hippocampal neural cells death and depression-like behavior in rats by activating IL-1ß/JNK signaling pathway.