Reyanning mixture inhibits M1 macrophage polarization through the glycogen synthesis pathway to improve lipopolysaccharide-induced acute lung injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Reyanning (RYN) mixture is a traditional Chinese medicine composed of Taraxacum, Polygonum cuspidatum, Scutellariae Barbatae and Patrinia villosa and is used for the treatment of acute respiratory system diseases with significant clinical efficacy. AIM OF THE STUDY: Acute lung injury (ALI) is a common clinical disease characterized by acute respiratory failure. This study was conducted to evaluate the therapeutic effects of RYN on ALI and to explore its mechanism of action. MATERIALS AND METHODS: Ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to analyze the chemical components of RYN. 7.5 mg/kg LPS was administered to induce ALI in rats. RYN was administered by gavage at doses of 2 ml/kg, 4 ml/kg or 8 ml/kg every 8 h for a total of 6 doses. Observations included lung histomorphology, lung wet/dry (W/D) weight ratio, lung permeability index (LPI), HE staining, Wright-Giemsa staining. ELISA was performed to detect the levels of TNF-α, IL-6, IL-10, Arg-1,UDPG. Immunohistochemical staining detected IL-6, F4/80 expression. ROS, MDA, SOD, GSH/GSSG were detected in liver tissues. Multiple omics techniques were used to predict the potential mechanism of action of RYN, which was verified by in vivo closure experiments. Immunofluorescence staining detected the co-expression of CD86 and CD206, CD86 and P2Y14, CD86 and UGP2 in liver tissues. qRT-PCR detected the mRNA levels of UGP2, P2Y14 and STAT1, and immunoblotting detected the protein expression of UGP2, P2Y14, STAT1, p-STAT1. RESULTS: RYN was detected to contain 1366 metabolites, some of the metabolites with high levels have anti-inflammatory, antibacterial, antiviral and antioxidant properties. RYN (2, 4, and 8 ml/kg) exerted dose-dependent therapeutic effects on the ALI rats, by reducing inflammatory cell infiltration and oxidative stress damage, inhibiting CD86 expression, decreasing TNF-α and IL-6 levels, and increasing IL-10 and Arg-1 levels. Transcriptomics and proteomics showed that glucose metabolism provided the pathway for the anti-ALI properties of RYN and that RYN inhibited lung glycogen production and distribution. Immunofluorescence co-staining showed that RYN inhibited CD86 and UGP2 expressions. In vivo blocking experiments revealed that blocking glycogen synthesis reduced UDPG content, inhibited P2Y14 and CD86 expressions, decreased P2Y14 and STAT1 mRNA and protein expressions, reduced STAT1 protein phosphorylation expression, and had the same therapeutic effect as RYN. CONCLUSION: RYN inhibits M1 macrophage polarization to alleviate ALI. Blocking glycogen synthesis and inhibiting the UDPG/P2Y14/STAT1 signaling pathway may be its molecular mechanism.

Nrf2-Dependent Protective Effect of Paeoniflorin on α-Naphthalene Isothiocyanate-Induced Hepatic Injury.

The pathological mechanism of cholestatic hepatic injury is associated with oxidative stress, hepatocyte inflammation, and dysregulation of hepatocyte transporters. Paeonia lactiflora Pall. and its compound can improve hepatic microcirculation, dilate bile duct, and promote bile flow, which is advantageous to ameliorate liver damage. Paeoniflorin (PEA), as the main efficacy component of Paeonia lactiflora Pall., has multiple pharmacological effects. PEA improves liver injury, but it remains obscure whether the protective action on [Formula: see text]-naphthalene isothiocyanate (ANIT)-induced cholestatic liver injury is dependent on the NF-E2 p45-related Factor 2 (Nrf2) signaling pathway. In this study, C57BL/6 mice were administrated with 80 mg⋅kg[Formula: see text]⋅d[Formula: see text] ANIT followed by PEA (75, 150, and 300 mg⋅kg[Formula: see text]⋅d[Formula: see text]) orally for 10 days, respectively. Tissue histology and liver function were detected, including serum enzymes, gallbladder (GB) weight, phenobarbital-induced sleeping time (PEN-induced ST), hepatic uridine di-phosphoglucuronosyltransferase (UDPG-T), malondialdehyde (MDA), and glutathione (GSH). The expressions of protein Nrf2, sodium taurocholate cotransporting polypeptide (Ntcp), and NADPH oxidase 4 (Nox4) were evaluated. Nrf2 plasmid or siRNA-Nrf2 transfection on LO2 cells and Nrf2-/- mice were used to explore the liver protective mechanism of PEA. Compared to ANIT-treated mice, PEA decreased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), direct bilirubin (DBIL), total bile acid (TBA), and phenobarbital-induced sleeping time. The bile secretion, hepatic UDPG-T, MDA, GSH, and liver histology were improved. The expressions of protein Nrf2 and Ntcp in liver tissues increased, but Nox4 decreased. After Nrf2 plasmid or small interfering RNA (siRNA)-Nrf2 transfection, the protective effects of PEA on LO2 cells were, respectively, strengthened or weakened. Moreover, PEA had no significant effects on ANIT-treated Nrf2-/- mice. Our results suggest that Nrf2 is essential for PEA protective effects on ANIT-induced liver injury.

The purinergic P2Y14 receptor axis is a molecular determinant for organism survival under in utero radiation toxicity.

In utero exposure of the embryo and fetus to radiation has been implicated in malformations or fetal death, and often produces lifelong health consequences such as cancers and mental retardation. Here we demonstrate that deletion of a G-protein-coupled purinergic receptor, P2Y14, confers potent resistance to in utero radiation. Intriguingly, a putative P2Y14 receptor ligand, UDP-glucose, phenocopies the effect of P2Y14 deficiency. These data indicate that P2Y14 is a receptor governing in utero tolerance to genotoxic stress that may be pharmacologically targeted to mitigate radiation toxicity in pregnancy.

[Effect of single or combined application of UDP-glucose, GDNF and memantine on improvement of white matter injury in neonatal rats assessed with light and electron microscopy pathologically].

OBJECTIVE: To evaluate pathologically the effect of the single or combined application of UDP-glucose, GDNF and memantine on the improvement of white matter injury in neonatal rats with periventricular leukomalacia (PVL) under light and electron microscopy. METHODS: A five-day-old neonatal rat model for PVL was established by ligation of the lateral common carotid artery following 120-minute hypoxia. Rats were randomly divided into six groups (30 rats in each group): sham-operated, PVL, UDP-glucose (UDP-glucose 2000 mg/kg intraperitoneally after PVL), GDNF (GDNF 100 µg/kg intracerebrally after PVL), tmemantine (memantine 20 mg/kg intraperitoneally after PVL), and a combination administration of three drugs (UDP-glucose, GDNF and memantine). The rats were sacrificed 7 or 21 days after PVL for assessment of pathological changes in the white matter under both light and electron microscopy. The number and thickness of the myelin sheath in the white matter were measured under electron microscopy, and both of pathological grading and scoring were undertaken under light microscopy. RESULTS: There was rare and sparse myelinogenesis with a loose arrangement of nerve fibers in the white matter under electron microscopy in the PVL group at 7 and 21 days after PVL. The number and thickness of the myelin sheath in the PVL group were significantly less than in the sham-operated, UDP-glucose, GDNF, memantine and combination administration groups (P<0.01). The results of pathological grading of white matter under light microscopy showed that all rats in the PVL group manifested either mild injury (38%-50%) or severe injury (50%-62%) at 7 and 21 days after PVL. The majority of rats (50%-88%) in the four drug administration groups had normal white matter at 7 and 21 days after PVL. The pathological scores at 7 and 21 days after PVL in the PVL group were the highest, and they were significantly higher than in the other five groups (P<0.05). CONCLUSIONS: The single or combined application of UDP-glucose, GDNF and memantine may significantly improve pathological changes in the white matter of rats with PVL. The favorable effect is inferred to be closely correlated with the improvement of brain microenvironment and the enhancement of nerve regeneration promoted by the three drugs.

Antihepatotoxic properties of uridine-diphosphoglucose in liver fluke infection. Experimental fascioliasis in the rat.

The antihepatotoxic properties of uridine-diphosphoglucose (UDPG, Toxepasi) have been evaluated in a well-established model of liver damage, the liver fluke infection (experimental fascioliasis in the rat), which causes a dramatic loss of the microsomal drug-metabolizing monooxygenase (MFO) and glucuronosyltransferase (GT) enzyme systems as a consequence of peroxidative damage to microsomal membrane lipids. Administration of 100 mg/kg UDPG i.p. to the infested rat for the entire course of the infection (40 days) positively affects the parameters reflecting the integrity of the liver cell (serum glutamate-pyruvate, GPT and glutamate-oxaloacetate, GOT, transaminases) and the detoxifying capacity of the liver (cytochrome P-450, cytochrome b5, cytochrome P-450-dependent p-nitroanisole O-demethylase and aniline hydroxylase activities, and the p-nitrophenol glucuronidation) and greatly reduces the lipid peroxidative phenomen in membranes from whole liver (tissue malonic dialdehyde content) and in membranes of the microsomal fraction (conjugated diene absorption). As a consequence of this, the total lipid and phospholipid contents of the liver are restored, there is minimal loss of latency of GT enzyme(s), cytochrome P-450 conversion to cytochrome P-420 is fairly negligible and total liver glutathione content is also restored. Therefore, UDPG restores liver function by protecting the endoplasmic reticulum membranes from the oxidative stress resulting from activation of the CN-insensitive respiratory burst of the phagocytic cells consequent to Fasciola hepatica invasion, migration and growth. It is very likely that UDPG acts as an effective antilipoperoxidative agent through both direct (as demonstrated by our in vitro experiments) and indirect mechanisms (stimulation of the glycolytic pathway, and hence of the reducing equivalents----glutathione----vitamin E supply).(ABSTRACT TRUNCATED AT 250 WORDS)

[Uridine diphosphate glucose in acute viral hepatitis]. / L'uridin-5'-difosfoglucosio in corso di epatite virale acuta.

200 mg UDPG or placebo respectively were administered after an observation period of 1 week to two randomly constructed groups of patients aged 15-35 yr with acute viral hepatitis but no prior history of disease. In the treated patients, mean decreases were most marked and most rapid in the case of SGOT, SGPT, alkaline phosphatase and total bilirubinaemia. These results offer good reason for supposing that UDPG can be usefully employed in the management of acute viral hepatitis.

[The use of different liver-protective substances in the course of antitubercular chemotherapy and their effectiveness in preventing and countering the appearance of metabolic and functional liver changes Clinico-statistical studies]. / Impiego di differenti sostanze di pertinenza epatica in corso di chemioterapia antitubercolare e loro efficacia nel prevenire e contrastare l'insorgenza di alterazioni metabolico-funzionali. Ricerca clinico-statistica.

An open study was run on three groups of hospitalised 40 patients with medium to serious lung TB to evaluate the effectiveness of generic liver protector drugs, UDPG, and an association of UDPG-GSH in the prevention a nd hindrance of organic and metabolic-functional liver alterations in the course of chemotherapy. It was found that UDPG--particularly in association with GSH--gave highly significant results by comparison with generic protector drugs.

[Evaluation of the changes in some laboratory parameters in liver disease patients treated with Toxepasi Complex]. / Valutazione delle modificazioni di alcuni parametri di laboratorio in epato-pazienti sottoposti a trattamento con Toxepasi Complex

Toxepasi Complex (UDPG, glutathione and vitamin B12) was administered to patients with aggressive chronic hepatitis and a second group with severe cirrhosis. Changes in laboratory enzymological data indicative of the overall extent of liver damage due to cell necrosis, cholostasis and impairment of protein synthesis were evaluated. Decreases tending to normalisation were noted two weeks after the commencement of treatment, particularly in the first group. The results suggest that the complex may be usefully employed in the management of aggressive chronic hepatitis and cirrhosis of the liver.

[Clinical studies of the effect of a phosphorylated glycoderivative in acute viral hepatitis]. / Ricerca clinica sull'effetto di un glicoderivato fosforilato nell'epatite acuta da virus

Experimentation of two i.v. doses of a uridine-5-diphosphoglucose (UDPG) in 30 cases of acute viral hepatitis is reported. The therapeutic efficacy of the drug was assessed on qualitative and quantitative parameters indicative of liver distress. Statistically significant evidence was obtained of the efficacy of UDPG in acute and serious liver disease, and of the greater effectiveness of one of the two doses used. Excellent local and general tolerance was noted.