Macrophage-Derived mir-155-Containing Exosomes Suppress Fibroblast Proliferation and Promote Fibroblast Inflammation during Cardiac Injury.

Inflammation plays an important role in cardiac injuries. Here, we examined the role of miRNA in regulating inflammation and cardiac injury during myocardial infarction. We showed that mir-155 expression was increased in the mouse heart after myocardial infarction. Upregulated mir-155 was primarily presented in macrophages and cardiac fibroblasts of injured hearts, while pri-mir-155 was only expressed in macrophages. mir-155 was also presented in exosomes derived from macrophages, and it can be transferred into cardiac fibroblasts by macrophage-derived exosomes. A mir-155 mimic or mir-155 containing exosomes inhibited cardiac fibroblast proliferation by downregulating Son of Sevenless 1 expression and promoted inflammation by decreasing Suppressor of Cytokine Signaling 1 expression. These effects were reversed by the addition of a mir-155 inhibitor. In vivo, mir-155-deficient mice showed a significant reduction of the incidence of cardiac rupture and an improved cardiac function compared with wild-type mice. Moreover, transfusion of wild-type macrophage exosomes to mir-155-/- mice exacerbated cardiac rupture. Finally, the mir-155-deficient mice exhibited elevated fibroblast proliferation and collagen production, along with reduced cardiac inflammation in injured heart. Taken together, our results demonstrate that activated macrophages secrete mir-155-enriched exosomes and identify macrophage-derived mir-155 as a paracrine regulator for fibroblast proliferation and inflammation; thus, a mir-155 inhibitor (i.e., mir-155 antagomir) has the potential to be a therapeutic agent for reducing acute myocardial-infarction-related adverse events.

Metoprolol decreases the plasma exposure of metformin via the induction of liver, kidney and muscle uptake in rats.

Drug interactions are one of the commonest causes of side effects, particularly in long-term therapy. The aim of the current study was to investigate the possible effects of metoprolol on the pharmacokinetics of metformin in rats and to clarify the mechanism of drug interaction. In this study, rats were treated with metformin alone or in combination with metoprolol. Plasma, urine and tissue concentrations of metformin were determined by HPLC. Western blotting and real-time qPCR were used to evaluate the expression of rOCTs and rMATE1. The results showed that, after single or 7-day repeated administration, the plasma concentrations of metformin in the co-administration group were significantly decreased compared with that in the metformin group. However, the parameter V/F of metformin in the co-administration group was markedly increased compared with that in the metformin group. The hepatic, renal and muscular Kp of metformin were markedly elevated after co-administration with metoprolol. Consistently, metformin uptake in rat kidney slices was significantly induced by metoprolol. In addition, multiple administrations of metoprolol significantly reduced the expression of rMATE1 in rat kidney as well as the urinary excretion of metformin. Importantly, after long-term administration, lactic acid and uric acid levels in the co-administration group were increased by 25% and 26%, respectively, compared with that in the metformin group. These results indicate that metoprolol can decrease the plasma concentration of metformin via the induction of hepatic, renal and muscular uptake, and long-term co-administration of metformin and metoprolol can cause elevated lactic acid and uric acid levels. Copyright © 2016 John Wiley & Sons, Ltd.

Cross talk between vascular smooth muscle cells and monocytes through interleukin-1ß/interleukin-18 signaling promotes vein graft thickening.

OBJECTIVE: Interleukin (IL)-1ß and IL-18 are key proinflammatory cytokines that play important roles in the pathophysiology of vein graft remodeling. However, the mechanism of IL-1ß/IL-18 production and its role in the development of graft remodeling remain unclear. APPROACH AND RESULTS: IL-1ß/IL-18 were rapidly expressed in venous interposition grafts. Vascular smooth muscle cell (VSMC) death and monocytic inflammasome activation occurred in grafted veins. Necrotic VSMCs induced the expression of IL-1ß, IL-18, and other inflammasome-associated proteins in monocytes, which was partially inhibited by their antagonist, recombinant IL-1ra-Fc-IL-18bp. Activated monocytes stimulated proliferation of VSMCs by activating cell growth-related signaling molecules (AKT, STAT3, ERK1/2, and mTOR [AKT/protein kinase B, signal transducer and activator of transcription 3, extracellular signal-regulated kinase 1/2, mammalian target of rapamycin]) and increasing production of platelet-derived growth factor-bb; these effects were suppressed by IL-1ra-Fc-IL-18bp. Activated monocytes also promoted migration of VSMCs, which was independent of IL-1ß/IL-18 signaling. Importantly, administration of IL-1ra-Fc-IL-18bp inhibited activation of cell growth-related signaling molecules, VSMC proliferation, and vein graft thickening in vivo. CONCLUSIONS: Our work identified an interaction among necrotic VSMCs, monocytes, and viable VSMCs through IL-1ß/IL-18 signaling, which might be exploited as a therapeutic target in vein graft remodeling.

[C825T polymorphism of G protein beta3 subunit gene and Uygur Hilit type of essential hypertension: a correlation study].

OBJECTIVE: To explore the association between C825T polymorphism of G protein beta3 subunit (GNB3) gene and different Hilit types of essential hypertension (EH) in the Uygur nationality of Xinjiang. METHODS: According to Uygur medical theories, EH patients (as the EH group) and non-EH patients (as the control group) were assigned to four Hilit groups. The C825T polymorphism of GNB3 was detected in 161 EH patients and 379 non-EH subjects of different Hilit types by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to explore the difference of the genotypes and allelic frequencies and hypertension. RESULTS: (1) In Xinjiang Uygur population, the distribution frequencies of GNB3 C825T polymorphism were in accordance with Hardy-Weinberg (chi2 = 0.871, P = 0.647). (2) There was no statistical difference in the distribution frequencies of three genotypes and two alleles of GNB3 between the EH group and the control group (P > 0.05). (3) There was statistical difference in distribution frequencies of three genotypes between the abnormal Sapra and non-abnormal Sapra group (the sum of abnormal Sewda, abnormal Kan, and abnormal Balhem) (chi2 = 6.905, P = 0.032), especially between the abnormal Sapra and abnormal Balhem groups (chi2 = 10.404, P = 0.006), but there was no statistical difference in distribution frequencies of alleles between the two groups (P > 0.05). (4) In 161 EH patients, there was statistical difference in the distribution frequencies of three genotypes and two alleles between the abnormal Sapra and non-abnormal Sapra group (chi2 = 9.034, P = 0.011; chi2 = 4.701, P = 0.03). CONCLUSIONS: Both TT genotype and T allele of GNB3 C825T polymorphism might not be associated with EH patients in Xinjiang Uygur populations. However, they were correlated with hypertension patients of non-abnormal Sapra, indicating the pathogeneses of EH with different Hilit types might be different.

Individualized antibiotic dosage regimens for patients with augmented renal clearance.

Objectives: Augmented renal clearance (ARC) is a state of enhanced renal function commonly observed in 30%-65% of critically ill patients despite normal serum creatinine levels. Using unadjusted standard dosing regimens of renally eliminated drugs in ARC patients often leads to subtherapeutic concentrations, poor clinical outcomes, and the emergence of multidrug-resistant bacteria. We summarized pharmaceutical, pharmacokinetic, and pharmacodynamic research on the definition, underlying mechanisms, and risk factors of ARC to guide individualized dosing of antibiotics and various strategies for optimizing outcomes. Methods: We searched for articles between 2010 and 2022 in the MEDLINE database about ARC patients and antibiotics and further provided individualized antibiotic dosage regimens for patients with ARC. Results: 25 antibiotic dosage regimens for patients with ARC and various strategies for optimization of outcomes, such as extended infusion time, continuous infusion, increased dosage, and combination regimens, were summarized according to previous research. Conclusion: ARC patients, especially critically ill patients, need to make individualized adjustments to antibiotics, including dose, frequency, and method of administration. Further comprehensive research is required to determine ARC staging, expand the range of recommended antibiotics, and establish individualized dosing guidelines for ARC patients.

[Isolation, purification and composition analysis of water-soluble polysaccharide from Halenia elliptica].

OBJECTIVE: To provide scientific cue for the use of Halenia elliptica. METHODS: The crude polysaccharide was extracted from Halenia elliptica with hot water and precipitated by ethanol. The crude polysaccharide has been eliminated protein and fractionated by acidic ethanol. Four fractions HM1, HM2, HM3 and HM4 were got respectively. RESULTS: By using DEAE-Sephadex A-25 gel filtration, HM1 was got. GC analysis indicated that HM1, HM2, HM3, HM4 and HM41 were composed of Rha, Ara, Xyl, Man, Gal and Glc. But their molar ratios were different. CONCLUSION: Polysaccharide HM41 is isolated from Halenia elliptica for the first time.

Hesperidin alleviates cholestasis via activation of the farnesoid X receptor in vitro and in vivo.

Cholestasis causes the intrahepatic accumulation of bile acids leading to hepatobiliary injury. Recently obeticholic acid, a farnesoid X receptor (FXR) agonist, was FDA-approved to treat cholestatic liver diseases, providing a new therapeutic strategy for cholestasis. The purpose of the current study was to characterize a novel FXR agonist and verify the anti-cholestatic effect of hesperidin (HP) in vivo and in vitro. Based on a molecular docking study that predicted that HP would bind to FXR, the hepatoprotective effect of HP against cholestasis and hepatotoxicity was evaluated in mice and in normal and FXR-suppressed HepaRG cells. HP prevented bile acid toxicity in HepaRG cells, and this effect was blocked by FXR silencing. HP appears to activate FXR to prevent cholestatic liver injury. Dynamic change analysis of bile acids revealed that HP promoted bile acid excretion into feces and reduced hepatic accumulation via the regulation of the FXR-target genes bile salt export pump, multi-drug resistance-associated protein 2, and Na+-taurocholate cotransporting polypeptide. Furthermore, HP down-regulated enzymes involved in bile acid synthesis including cholesterol 7α-hydroxylase and sterol 27-hydroxylase. HP produced a protective effect against cholestasis via FXR activation, and may be an effective approach for the prevention and treatment of cholestatic liver diseases.

Irinotecan-induced bile acid malabsorption is associated with down-regulation of ileal Asbt (Slc10a2) in mice.

Irinotecan, (CPT-11), an antitumor agent primarily used for the treatment of solid tumors, has often compromised clinical application due to the inducement of severe delay-onset diarrhea. Bile acid malabsorption (BAM) is widely accepted as the common cause of diarrhea. However, whether CPT-11-induced diarrhea has correlation with BAM is unknown. The aim of this study was to investigate the effect of CPT-11 on the bile acid homeostasis in mice. The mice were administrated with CPT-11 intravenously for four consecutive days. The total bile acids (TBAs) levels in the small intestine, colon, feces, liver, serum and gallbladder were evaluated by automatic biochemical analyzer, and the individual bile acids were also measured by LC-MS/MS. Real-time qPCR and Western blot techniques were used to evaluate the mRNA and protein expressions of Cyp7a1, Cyp27a1, Asbt, Ostα/ß. In situ loop method was carried out to evaluate the function of apical Na+-dependent bile salt transporter (Asbt). Results showed that the bile acid pool size was significantly reduced by 17%, 25%, and 40% respectively at 2, 3, and 4days post CPT-11 treatment. The fecal excretions of TBAs were significantly increased by 2.1-fold at 3 and 4days post CPT-11 treatment. The ileal expression of Asbt was significantly decreased at mRNA and protein levels, and the transport ability of Asbt was also attenuated after CPT-11 treatment. Moreover, the incidence of CPT-11-induced delay-onset diarrhea was also decreased after cholestyramine administration in CPT-11-treated mice. These results indicated that BAM may be partially responsible for CPT-11-induced delay-onset diarrhea, and the underlying mechanism may have correlation with down-regulation of the Asbt in the ileum of mice.

Strong pyro-catalysis of pyroelectric BiFeO3 nanoparticles under a room-temperature cold-hot alternation.

A strong pyro-catalytic dye degradation with an ultrahigh degradation efficiency (>99%) in hydrothermally synthesized pyroelectric BiFeO3 nanoparticles was achieved under a room-temperature cold-hot alternating excitation (between 27 °C to 38 °C). The pyro-catalysis originated from a combination of the pyroelectric effect and the electrochemical oxidation-reduction reaction. The intermediate products (hydroxyl radicals and superoxide radicals) of pyro-electro-catalysis were observed. Pyro-catalysis provides a highly efficient and reusable dye wastewater decomposition technology through utilizing environmental day-night temperature variation.

Simultaneous Determination of Metformin, Metoprolol and its Metabolites in Rat Plasma by LC-MS-MS: Application to Pharmacokinetic Interaction Study.

A simple, rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was developed and validated for the simultaneous quantitation of metformin (MTF), metoprolol (MET), α-hydroxymetoprolol (HMT) and O-desmethylmetoprolol (DMT) in rat plasma using paracetamol as an internal standard (IS), respectively. The sample preparation involved a protein-precipitation method with methanol after the addition of IS. The separation was performed on an Agilent HC-C18 column (4.6 × 250 mm, 5 µm) at a flow rate of 1.0 mL/min, using methanol-water containing 0.1% formic acid (39:61, v/v) as mobile phase, and total run time was 8.5 min. MS-MS detection was accomplished in multiple reaction monitoring mode with positive electrospray ionization. The monitored transitions were m/z 130.1 → 60.2 for MTF, m/z 268.2 → 116.1 for MET, m/z 284.2 → 116.1 for HMT, m/z 254.2 → 116.1 for DMT and m/z 152.3 → 110.1 for IS. The method was fully validated in terms of selectivity, linearity, accuracy, precision, stability, matrix effect and recovery over a concentration range of 19.53-40,000 ng/mL for MTF, 3.42-7,000 ng/mL for MET, 2.05-4,200 ng/mL for HMT and 1.95-4,000 ng/mL for DMT, respectively. The analytical method was successfully applied to drug interaction study of MTF and MET after oral administration of MTF and MET. Results suggested that the coadministration of MTF and MET results in a significant drug interaction in rat.

S100a8/a9 released by CD11b+Gr1+ neutrophils activates cardiac fibroblasts to initiate angiotensin II-Induced cardiac inflammation and injury.

Angiotensin II induces cardiovascular injury, in part, by activating inflammatory response; however, the initial factors that trigger the inflammatory cascade remain unclear. Microarray analysis of cardiac tissue exposed to systemic angiotensin II infusion revealed that extracellular heterodimeric proteins S100a8/a9 were highly upregulated. The increase in S100a8/a9 mRNA of CD11b(+)Gr1(+) neutrophils isolated from both the peripheral blood and heart was highest on day 1 of angiotensin II infusion and decreased to baseline at day 7. Immunostaining showed that S100a8/a9 was primarily present in infiltrating CD11b(+)Gr1(+) neutrophils in the heart. The receptor for advanced glycation end products, an S100a8/a9 receptor, was expressed in cardiac fibroblasts (CFs). Microarray analysis and Bio-Plex protein array showed that treatment of CFs with recombinant S100a8/a9 activated multiple chemokine and cytokines released. Luciferase reporter assay indicated S100a8/a9-activated nuclear factor-κ B pathway in CFs. Consequently, recombinant S100a8/a9-treated CFs promoted migration of monocytes and CFs, whereas neutralizing S100a9 antibody blocked S100a9 or receptor for advanced glycation end products-suppressed cellular migration. Finally, administration of a neutralizing S100a9 antibody prevented angiotensin II infusion-induced nuclear factor-κ B activation, inflammatory cell infiltration, cytokine production, subsequent perivascular and interstitial fibrosis, and hypertrophy in heart. Our findings identify neutrophil-produced S100a8/a9 as an initial proinflammatory factor needed to trigger inflammation and cardiac injury during acute hypertension.