Osteopontin Depletion in Non-haematopoietic Cells Improves Outcomes in Septic Mice by Enhancing Antimicrobial Peptide Production.

Osteopontin (Opn) depletion can improve septic outcomes, but the underlying mechanism remains unknown. In this study, we demonstrated that non-haematopoietic but not haematopoietic Opn depletion improved septic outcomes. Compared to wild-type (WT) mice, co-housed Opn-/- mice displayed enhanced production of antibacterial peptides (AMPs), decreased bacterial loads, and a distinct bacterial composition of gut microbiota. Fecal microbiota transplantation (FMT) and OPN neutralization assay showed that Opn depletion could reduce the bacterial loads and improve septic inflammation. By employing an intestinal organoid culture system, we proved that OPN neutralization in WT organoids could inactivate AKT and decrease FOXO3a phosphorylation, resulting in enhanced AMP production, whereas OPN treatment in OPN deficient organoids could activate AKT and increase FOXO3a phosphorylation, leading to reduced AMP production. Our findings identified OPN as a novel regulatory factor of AMP production to modulate bacterial loads and composition of gut microbiota, in turn affecting sepsis outcomes.

Study on the action mechanism of the Polygonum perfoliatum L. on non-alcoholic fatty liver disease, based on network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine (TCM) holds that non-alcoholic fatty liver disease (NAFLD) belong to the category of "thoracic fullness". Polygonum perfoliatum L. (PPL), a Chinese medicinal herb with the effect of treating thoracic fullness, was recorded in the ancient Chinese medicine book "Supplements to Compendium of Materia Medica". It has been used since ancient times to treat NAFLD. However, the underlying mechanism and active components of PPL against NAFLD remains unclear. AIM OF STUDY: To identify the main active components and the anti-NAFLD mechanism of PPL. MATERIALS AND METHODS: Network pharmacology, UPLC/QE-HFX analysis, and molecular docking were employed to determine the main bioactive compounds and key targets of PPL for the NAFLD treatment. This effect was further validated with administration of PPL (200 mg/kg and 400 mg/kg) to NAFLD model mice for 5 weeks. Systemic signs of obesity, biochemical parameters, and histological changes were characterized. Immunohistochemistry, western blot, and PCR analysis were conducted to elucidate the mechanistic pathways through which PPL exerts its effects. RESULTS: Network pharmacology revealed 77 crossover genes between the PPL and NAFLD. The kyoto encyclopedia of genes and genomes (KEGG) analysis show that PPL treat NAFLD mainly regulating glucose-lipid metabolism mediated by PI3K/AKT signal pathway. The Gene Ontology (GO) enrichment analysis show that PPL treat NAFLD mainly regulating inflammation mediated by cytokine-mediated signaling pathway. In accordance with the anticipated outcomes, administration of PPL in a dose-dependent manner effectively mitigated insulin resistance induced by a high-fat diet (HFD) by activating the PI3K/AKT signaling pathway. Histopathological evaluation corroborated the hepatoprotective effects of PPL against HFD-induced hepatic steatosis, as evidenced by the inhibition of de novo fatty acid synthesis and promotion of fatty acid ß-oxidation (FAO). Further research showed that PPL blocked cytokine production by inhibiting the NF-κB pathway, thereby reducing immune cell infiltration. Furthermore, five flavonoids from PPL, including quercetin, baicalein, galangin, apigenin, and genistein were identified as key compounds based on ingredient-target-pathway network analysis. Molecular docking show that these active compounds have favorable binding interactions with AKT1, PIK3R1, and MAPK1, further confirming the impact of PPL on the PI3K/AKT pathway. CONCLUSIONS: Through the combination of network pharmacology prediction and experimental validation, this work determined that therapeutic effect of PPL on NAFLD, and such protective effect is mediated by activating PI3K/AKT-mediated glucolipid metabolism pathway and hepatic NF-κB-mediated cytokine signaling pathway.

Quantitative proteomics reveals Polygonum perfoliatum L. ameliorates hepatic steatosis by promoting PPARs/CPT1A/CPT2-mediated fatty acid ß-oxidation.

Non-alcoholic fatty liver disease (NAFLD) is a predominant contributor to end-stage liver disease in the forthcoming decades. Polygonum perfoliatum L. (PPL) is an herbal medicine with anti-lipid peroxidation and anti-inflammatory properties. However, detailed hepatoprotective effects of PPL against NAFLD and its underlying mechanisms are not fully understood. Here, we found that PPL protects against high fat diet (HFD)-induced hepatic steatosis, lipid peroxidation, and glucose-lipid metabolism dysfunction in NAFLD mice. We therefore performed a label-free quantitative proteomic profiling analysis to determine the effect of PPL treatment on liver tissue proteomics and identified that activated PPARs/CPT1A/CPT2-mediated hepatic fatty acid ß-oxidation (FAO) process was significantly altered. In vitro treatment of hepatocytes with PPL confirmed this altered process and FAO inhibitor etomoxir (ETO) attenuated the lipid-lowering activity of PPL in hepatocytes. Ultra-high-performance liquid chromatography/Q Exactive-HFX (UPLC/QE-HFX) was used to determine the material basis of anti-NAFLD activity of PPL. Our results have demonstrated the efficacy and potential mechanisms of PPL as an effective pharmacological therapy of NAFLD.

Expression of STING Is Increased in Monocyte-Derived Macrophages and Contributes to Liver Inflammation in Hepatic Ischemia-Reperfusion Injury.

Ischemia/reperfusion (I/R) injury, aggravated by innate immune cell-mediated inflammatory response, is a major problem in liver transplantation. Stimulator of interferon gene (STING) is a crucial regulatory signaling molecule in the DNA-sensing pathway, and its activation can produce strong innate immunity. However, the STING-mediated innate immune pathway in hepatic I/R injury has not been fully elucidated. In this study, we first examined the STING expression changes in the liver tissues of mice after hepatic I/R injury by using quantitative polymerase chain reaction and Western blot assays. We then investigated the role of STING in I/R injury by using a murine hepatic I/R model. STING up-regulation in mouse liver tissues in response to I/R injury and STING deficiency in myeloid cells was found to significantly ameliorate I/R-induced liver injury and inflammatory responses. STING inhibitors were also able to ameliorate hepatic I/R injury. Mechanically, STING may have a protective effect on hepatic I/R injury by the inhibition of hypoxia-inducible factor-1 alpha and enhancement of phosphorylated AMP-activated protein kinase to reduce macrophage activation. These findings show the potential regulatory effects of STING in hepatic I/R and suggest a new method for clinical protection of hepatic I/R injury.

Investigation of the Relationship Between Flatfoot and Patellar Subluxation in Adolescents.

Patellar subluxation is common in adolescents, and a variety of factors are related to this condition, with valgus of the knee joint an important factor. The results of many studies suggest that flatfoot can cause an abnormality of the lower limb power line. Structural abnormalities of the foot caused by the high stresses exerted by body weight can lead to structural deformity of the knee and can also cause knee valgus. Screening for foot problems can help determine the risk of patellar subluxation, and early intervention can lessen the incidence of this condition. The purpose of the present study was to investigate the effects of flatfoot on the structure and function of the knees and, especially, the risk of patellar subluxation. A total of 72 participants were recruited for this cross-sectional study. The mean age at examination was 15.4 ± 4.0 (range 9 to 22) years. The measured parameters were heel valgus angle, arch index, and quadriceps angle (Q-angle). Overall, the mean values of the heel valgus angle, arch index, and Q-angle were 5.9° ± 2.4° (range 1° to 11°), 0.33 ± 0.07 (range 0.23 to 0.46), and 19.1° ± 3.5° (range 9° to 26°), respectively. The Q-angle was directly associated with the heel valgus angle (r = 0.818, p < .001) and arch index (r = 0.655, p < .001). We found that flatfoot can affect the morphology of the knee joint and increase the risk of patellar subluxation.

Solar tracking error analysis of Fresnel reflector.

Depending on the rotational structure of Fresnel reflector, the rotation angle of the mirror was deduced under the eccentric condition. By analyzing the influence of the sun tracking rotation angle error caused by main factors, the change rule and extent of the influence were revealed. It is concluded that the tracking errors caused by the difference between the rotation axis and true north meridian, at noon, were maximum under certain conditions and reduced at morning and afternoon gradually. The tracking error caused by other deviations such as rotating eccentric, latitude, and solar altitude was positive at morning, negative at afternoon, and zero at a certain moment of noon.

Unbiased photoelectrochemical water splitting in Z-scheme device using W/Mo-doped BiVO4 and Zn(x)Cd(1-x)Se.

Photoelectrochemical water splitting to generate H2 and O2 using only photon energy (with no added electrical energy) has been demonstrated with dual n-type-semiconductor (or Z-scheme) systems. Here we investigated two different Z-scheme systems; one is comprised of two cells with the same metal-oxide semiconductor (W- and Mo-doped bismuth vanadate), that is, Pt-W/Mo-BiVO4, and the other is comprised of the metal oxide and a chalcogenide semiconductor, that is, Pt-W/Mo-BiVO4 and Zn(0.2)Cd(0.8)Se. The redox couples utilized in these Z-scheme configurations were I(-)/IO3(-) or S(2-)/S(n)(2-), respectively. An electrochemical analysis of the system in terms of cell components is shown to illustrate the behavior of the complete photoelectrochemical Z-scheme water-splitting system. H2 gas from the unbiased photolysis of water was detected using gas chromatography-mass spectroscopy and using a membrane-electrode assembly. The electrode configuration to achieve the maximum conversion efficiency from solar energy to chemical energy with the given materials and the Z-scheme is discussed. Here, the possibilities and challenges of Z-scheme unbiased photoelectrochemical water-splitting devices and the materials to achieve practical solar-fuel generation are discussed.

AMPK activation enhances PPARα activity to inhibit cardiac hypertrophy via ERK1/2 MAPK signaling pathway.

Activation of adenosine monophosphate-activated protein kinase (AMPK) has been shown to inhibit cardiac hypertrophy through peroxisome proliferators-activated receptor-α (PPARα) signaling pathway, but the detailed mechanism remains unclear. A rat model of cardiac hypertrophy created by transaortic constriction (TAC) was used to investigate the mechanism involved in regulation of PPARα activity by AMPK. It was observed that treatment with AICAR (5-aminoimidazole 1 carboxamide ribonucleoside), an AMPK activator, significantly inhibited cardiac hypertrophy in vivo and in vitro. Phosphorylated extracellular signal regulated protein kinase (phospho-ERK1/2) and phospho-p38 mitogen-activated protein kinase (MAPK) protein levels were significantly up-regulated, while PPARα protein level was down-regulated in TAC rats. AICAR treatment reversed the changes of PPARα and phospho-ERK1/2, but increased phospho-p38 MAPK protein level in TAC rats. Similar changes of PPARα and phospho-ERK1/2 protein levels were observed in the hypertrophied cardiomyocytes induced by phenylephrine treatment. Epidermal growth factor (EGF, ERK1/2 activator), but not SB203580 (p38 inhibitor) blocked the up-regulation of PPARα protein level induced by AICAR. Luciferase assay showed that AICAR increased PPARα transcriptional activity which was abrogated by EGF, but not by SB203580. These results demonstrate that AMPK activation enhances the activity of PPARα to inhibit cardiac hypertrophy through ERK1/2, but not p38 MAPK, signaling pathway.

[Reactive oxygen species and mitochondrial membrane potential changes in leukemia cells during 6-gingerol induced apoptosis].

OBJECTIVE: To observe the effects of 6-gingerol on reactive oxygen species (ROS) and mitochondrial membrane potential(deltapsim) of chronic myeloid leukemia K562 cells and human acute T lymphoblastic leukemia MOLT4 cells, to investigate the role of mitochondrial pathway in the signal transduction of leukemia cell. METHODS: With different concentrations of 6-gingerol treatment, using 2,7-dichloro fluoresceinciactate (DCFH-DA) as ROS probe, rhodamine-123 as deltapsim probe, the levels of ROS and deltapsim of K562 cells and MOLT4 cells were tested by flow cytomentry. RESULTS: After treated with 6-gingerol, the ROS levels of K562 cells were significantly higher than control group (P < 0.01), while the deltapsim were significantly lower than control group (P < 0.01), and the ROS levels of MOLT4 cells were significantly higher than control group (P < 0.05). CONCLUSIONS: 6-gingerol can significantly increase ROS levels of K562 cells and MOLT4 cells, decrease deltapsim of K562 cells,induce apoptosis of leukemia cells by mitochondrial pathway.