Spectroscopic methodologies and molecular docking studies on the interaction of the soluble guanylate cyclase stimulator riociguat with human serum albumin

Publisher's version (útgefin grein)Abstract Interaction of riociguat with human serum albumin (HSA) is extremely important in understanding the drug's disposition and efficiency. In the current study, the binding of riociguat to HSA was explored using spectroscopic methods and molecular docking. The quenching constant, the binding constant, the number of binding sites, thermodynamic parameters, and the secondary structure of protein were determined. A fluorescence study revealed that riociguat quenched HSA fluorescence via static quenching with a binding constant of 1.55 × 104 L mol-1 at 298 K. The calculated thermodynamic parameters indicated that the binding process was spontaneous and that the main interaction force was hydrophobic interaction. Site marker competitive binding experiments and molecular docking studies suggested that riociguat was inserted into the subdomain IIA (site I) of HSA. Alterations in the protein secondary structure after drug complexation were predicted. Results indicated that the protein a-helix structure increased with an increasing concentration of riociguat. This indicated that a riociguat-HSA complex was formed and that the protein secondary structure was altered by the addition of riociguat.This work was supported by the Natural Science Foundation of China (81502921 and 81503251), the Key Research and Development Program of Shandong Province (2017GSF218049), and Young Scholars Program of Shandong University (2015WLJH50).Peer Reviewe

Antifungal effects and biocontrol potential of lipopeptide-producing Streptomyces against banana Fusarium wilt fungus Fusarium oxysporum f. sp. cubense

Fusarium wilt of banana (FWB), caused by Fusarium oxysporum f. sp. cubense (Foc), especially tropical race 4 (TR4), presents the foremost menace to the global banana production. Extensive efforts have been made to search for efficient biological control agents for disease management. Our previous study showed that Streptomyces sp. XY006 exhibited a strong inhibitory activity against several phytopathogenic fungi, including F. oxysporum. Here, the corresponding antifungal metabolites were purified and determined to be two cyclic lipopeptide homologs, lipopeptin A and lipopeptin B. Combined treatment with lipopeptin complex antagonized Foc TR4 by inhibiting mycelial growth and conidial sporulation, suppressing the synthesis of ergosterol and fatty acids and lowering the production of fusaric acid. Electron microscopy observation showed that lipopeptide treatment induced a severe disruption of the plasma membrane, leading to cell leakage. Lipopeptin A displayed a more pronounced antifungal activity against Foc TR4 than lipopeptin B. In pot experiments, strain XY006 successfully colonized banana plantlets and suppressed the incidence of FWB, with a biocontrol efficacy of up to 87.7%. Additionally, XY006 fermentation culture application improved plant growth parameters and induced peroxidase activity in treated plantlets, suggesting a possible role in induced resistance. Our findings highlight the potential of strain XY006 as a biological agent for FWB, and further research is needed to enhance its efficacy and mode of action in planta

Long non-coding RNA HOTAIR inhibits miR-17-5p to regulate osteogenic differentiation and proliferation in non-traumatic osteonecrosis of femoral head.

BACKGROUND AND AIM:The biological functions of non-coding RNAs (ncRNAs) have been widely identified in many human diseases. In the present study, the relationship between long non-coding RNA HOTAIR and microRNA-17-5p (miR-17-5p) and their roles in osteogenic differentiation and proliferation in non-traumatic osteonecrosis of femoral head (ONFH) were investigated. METHODS:The expression levels of HOTAIR and miR-17-5p in the mesenchymal stem cells (MSCs) derived from patients with non-traumatic ONFH and osteoarthritis (OA) were examined by real-time PCR. BMP-2 induced human MSCs from bone marrow (hMSC-BM) were used for osteogenic differentiation. RESULTS:It was observed that the expression level of miR-17-5p was lower and the level of HOTAIR was higher in samples of non-traumatic ONFH compared with OA. HOTAIR downregulation induced by si-HOTAIR led to the increase of miR-17-5p expression and the decrease of miR-17-5p target gene SMAD7 expression. The values of osteogenic differentiation markers, including RUNX2 and COL1A1 mRNA expression and ALP activity, were also elevated by si-HOTAIR. However, the increase of these values was canceled by miR-17-5p inhibitor or SMAD7 upregulation. CONCLUSION:HOTAIR played a role in regulating osteogenic differentiation and proliferation through modulating miR-17-5p and its target gene SMAD7 in non-traumatic ONFH

Plasma Pharmacokinetics and Tissue Distribution of Doxorubicin in Rats following Treatment with Astragali Radix

Doxorubicin (DOX) is an essential component in chemotherapy, and Astragali Radix (AR) is a widely used tonic herbal medicine. The combination of DOX and AR offers widespread, well-documented advantages in treating cancer, e.g., reducing the risk of adverse effects. This study mainly aims to uncover the impact of AR on DOX disposition in vivo. Rats received a single intravenous dose of 5 mg/kg DOX following a single-dose co-treatment or multiple-dose pre-treatment of AR (10 g/kg × 1 or × 10). The concentrations of DOX in rat plasma and six tissues, including heart, liver, lung, kidney, spleen, and skeletal muscle, were determined by a fully validated LC-MS/MS method. A network-based approach was further employed to quantify the relationships between enzymes that metabolize and transport DOX and the targets of nine representative AR components in the human protein–protein interactome. We found that short-term (≤10 d) AR administration was ineffective in changing the plasma pharmacokinetics of DOX in terms of the area under the concentration–time curve (AUC, 1303.35 ± 271.74 μg/L*h versus 1208.74 ± 145.35 μg/L*h, p > 0.46), peak concentrations (Cmax, 1351.21 ± 364.86 μg/L versus 1411.01 ± 368.38 μg/L, p > 0.78), and half-life (t1/2, 31.79 ± 5.12 h versus 32.05 ± 6.95 h, p > 0.94), etc. Compared to the isotype control group, DOX concentrations in six tissues slightly decreased under AR pre-administration but only showed statistical significance (p < 0.05) in the liver. Using network analysis, we showed that five of the nine representative AR components were not localized to the vicinity of the DOX disposition-associated module. These findings suggest that AR may mitigate DOX-induced toxicity by affecting drug targets rather than drug disposition

Ovarian microcystic stromal tumor with omental metastasis: the first case report and literature review

Abstract Background Microcystic stromal tumor (MCST) of the ovary is an extremely rare subtype of sex cord-stromal neoplasm first described by Irving and Young in 2009. Tumors from all previously reported cases (fewer than 40 total) were benign, but one was a case of ovarian MCST that reoccurred. Case presentation Herein, we present a unique single case of ovarian MCST with omental metastasis in a 47-year-old Chinese female along with its histologic and immunohistochemical profile and genetic alterations. The tumor exhibited the previously described classic microscopic features and immunoprofiles of MCST. The tumorlet in the omentum presented the same histological structures and characteristically expressed β-catenin protein (localized in the nucleus). Molecular analysis identified a point mutation (c.98C > G) in exon 3 of CTNNB1. Conclusions To the best of our knowledge, no such report has been documented for ovarian MCST with omental metastasis. The study may provide new insights into the tumor biology of MCST and provide a better understanding of this rare entity

Antiosteoporosis effect and possible mechanisms of the ingredients of Radix Achyranthis Bidentatae in animal models of osteoporosis: systematic review and meta-analysis of in vivo studies

Abstract Background The effect and mechanisms of the ingredients (IRAB) of Radix Achyranthis Bidentatae (RAB) on treating osteoporosis (OP) remains debated. We aimed to summary the evidence to evaluate the efficacy of IRAB for animal model OP and elucidate the potential mechanism of IRAB in the treatment of OP. Methods In this review and meta-analysis, we searched PubMed, EMBASE, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, Chinese Biomedical Literature Database, as well as Chinese VIP databases for targeting articles published from inception to March 2023 in English or Chinese. All randomized controlled animal trials that assessed the efficacy and safety of IRAB for OP were included. We excluded trials according to exclusion criteria. The CAMARADES 10-item quality checklist was utilized to test the risk of potential bias for each including study and modifications were performed accordingly. The primary outcome measures were bone mineral density of the femoral neck (F-BMD), serum calcium (Ca), serum phosphorus (P), serum alkaline phosphatase (ALP), bone gla protein (BGP), bone maximum stress (M-STRESS). The secondary outcome measure was the antiosteoporosis mechanisms of IRAB. Results Data from nine articles were included in the systematic review and meta-analysis, which focused on 196 animals. Egger’s test revealed the presence of publication bias in various studies regarding the primary outcome. Administration of IRAB or RAB could significantly increases the F-BMD (SMD = 2.09; 95% CI = 1.29 to 2.89; P < 0.001, I 2 = 76%), Ca (SMD = 0.86; 95% CI = 0.39to1.34; P = 0.07, I 2 = 49%); P (SMD = 1.01; 95% CI = 0.45–4.57; P = 0.08, I 2 = 50%), BGP (SMD = 2.13; 95% CI = 1.48 to 2.78; I 2 = 46%, P = 0.10), while the ALP (SMD = − 0.85; 95% CI =  − 1.38 to − 0.31; I 2 = 46%, P = 0.10) was remarkably decreased in OP model animals. Moreover, the bone biomechanical indicator M-STRESS (SMD = 2.39; 95% CI = 1.74–3.04; I 2 = 32%, P = 0.21) was significantly improved. Conclusion Collectively, the findings suggest that the RAB or IRAB could be an effective drug or an ingredient in diet for the clinical treatment of OP in future

Database of human well-being and eco-sustainability under planetary pressures of the Belt and Road 1990–2018

Abstract The Belt and Road (B&R) Initiative is considered as closely aligned with the UN’s Sustainable Development Goals by 2030 and could have a huge global impact. Its sustainable development issues have attracted worldwide attention. However, both the existing research and data accumulation on this aspect are seriously insufficient. Starting from the logic of the ultimate goal of sustainable development (namely within the ecological limitations, maximizing human well-being with minimum ecological consumption and minimizing the planetary pressures with maximum resource utilization efficiency), we have constructed a comprehensive evaluation method on sustainable development, namely the Consumption-Pressure-Output-Efficiency method in our previous study. Based on it, we provide a database with five datasets, which includes four core datasets (ecological consumption, planetary pressures, human well-being outputs and ecological well-being output efficiency) and a related dataset (biocapacity, ecological surplus/deficit, population), covering 61 B&R countries, B&R regional average and global average from 1990 to 2018. It can be used for further comprehensive research on sustainable development under planetary pressures and others of B&R

The expression levels of miR-17-5p and HOTAIR in MSCs of patients with non-traumatic necrosis of femoral head and osteoarthritis.

<p>The MSCs were isolated from patients with non-traumatic necrosis of femoral head (ONFH, n = 15), osteoarthritis (OA, n = 13) and healthy donor (n = 10), the expression levels of miR-17-5p (A) and HOTAIR (B) were detected by real-time PCR. Each sample was repeated three times. ** <i>P</i><0.01.</p

HOTAIR regulates osteogenic differentiation markers through mediating SMAD7 expression.

<p>Human mesenchymal stem cells from bone marrow (hMSC-BM) cell line was treated with co-transfection of siRNA-HOTAIR (si-HOTAIR) and Adenovirus-SMAD7 (Ad-SMAD7), with si-control and Ad-GFP acting as controls, respectively (A) or co-transfection of Ad-HOTAIR and si-SMAD7, with Ad-GFP and si-control acting as control, respectively (B) for 48h, then incubated with osteoblastic-inductive BMP-2 for six days. The mRNA and protein levels of RUNX2 and COL1A1 were detected by real-time PCR and western blot, and ALP activity was measured. n = 3, each sample was repeated three times. ** <i>P</i><0.01.</p