Cefminox sodium alleviates the high-fat high-sugar-fed mice's hepatic fatty accumulation via multiple pathways.

The increasing global prevalence of nonalcoholic fatty liver disease (NAFLD) starves for effective therapy, but no agent has been approved yet. We sought to evaluate the therapy of cefminox sodium (CMNX) on fatty accumulation in animal and cell models and explore the underlying mechanisms. The results revealed that CMNX reduced the gain of the liver and alleviated fatty accumulation both in high-fat high-sugar diet (HFHSD) mice's livers and WRL-68 cells. In HFHSD mice's livers and FFAs exposure hepatic cells, ACC1, SREBP-1c, and CYP2E1 were enhanced expression, which were reversed by CMNX treatment. In addition, PPARγ, PPARα, PCK1, and ACSL4 expressions were increased in CMNX-treated WRL-68 cells. These findings suggest that CMNX improves fatty accumulation in HFHSD mice/hepatic cells by restraining fatty acid synthesis and facilitating fatty acid oxidation.

Natural Targeting Potent ROS-Eliminating Tungsten-Based Polyoxometalate Nanodots for Efficient Treatment of Pulmonary Hypertension.

Pulmonary hypertension (PH) is a disease of pulmonary artery stenosis and blockage caused by abnormal pulmonary artery smooth muscle cells (PASMCs), with high morbidity and mortality. High levels of reactive oxygen species (ROS) in pulmonary arteries play a crucial role in inducing phenotypic switch and abnormal proliferation of PASMCs. However, antioxidants are rarely approved for the treatment of PH because of a lack of targeting and low bioavailability. In this study, the presence of an enhanced permeability and retention effect (EPR)-like effect in the pulmonary arteries of PH is revealed by tissue transmission electron microscopy (TEM). Subsequently, for the first time, tungsten-based polyoxometalate nanodots (WNDs) are developed with potent elimination of multiple ROS for efficient treatment of PH thanks to the high proportion of reduced W5+ . WNDs are effectively enriched in the pulmonary artery by intravenous injection because of the EPR-like effect of PH, and significantly prevent the abnormal proliferation of PASMCs, greatly improve the remodeling of pulmonary arteries, and ultimately improve right heart function. In conclusion, this work provides a novel and effective solution to the dilemma of targeting ROS for the treatment of PH.

Plasma exosomes confer hypoxic pulmonary hypertension by transferring LOX-1 cargo to trigger phenotypic switching of pulmonary artery smooth muscle cells.

The pulmonary vascular remodeling (PVR), the pathological basis of pulmonary hypertension (PH), entails pulmonary artery smooth muscle cells (PASMCs) phenotypic switching, but appreciation of the underlying mechanisms is incomplete. Exosomes, a novel transfer machinery enabling delivery of its cargos to recipient cells, have been recently implicated in cardiovascular diseases including PH. The two critical questions of whether plasma-derived exosomes drive PASMCs phenotypic switching and what cargo the exosomes transport, however, remain unclear. Herein, by means of transmission electron microscopy and protein detection, we for the first time, characterized lectin like oxidized low-density lipoprotein receptor-1 (LOX-1) as a novel cargo of plasma-derived exosomes in PH. With LOX-1 knockout (Olr1-/-) rats-derived exosomes, we demonstrated that exosomal LOX-1 could be transferred into PASMCs and thus elicited cell phenotypic switching. Of importance, Olr1-/- rats exhibited no cell phenotypic switching and developed less severe PH, but administration of wild type rather than Olr1-/- exosomes to Olr1-/- rats recapitulated the phenotype of PH with robust PASMCs phenotypic switching. We also revealed that exosomal LOX-1 triggered PASMCs phenotypic switching, PVR and ultimately PH via ERK1/2-KLF4 signaling axis. This study has generated proof that plasma-derived exosomes confer PH by delivering LOX-1 into PASMCs. Hence, exosomal LOX-1 represents a novel exploitable target for PH prevention and treatment.

Consideration of the Management of Pediatric Fever Clinics During the Novel Coronavirus Pneumonia Outbreak.

Since the outbreak of 2019 novel coronavirus (2019-nCoV) infection in Wuhan City, China, pediatric cases have gradually increased. It is very important to prevent cross-infection in pediatric fever clinics, to identify children with fever in pediatric fever clinics, and to strengthen the management of pediatric fever clinics. According to prevention and control programs, we propose the guidance on the management of pediatric fever clinics during the nCoV pneumonia epidemic period, which outlines in detail how to optimize processes, prevent cross-infection, provide health protection, and prevent disinfection of medical staff. The present consideration statement summarizes current strategies on the pre-diagnosis, triage, diagnosis, treatment, and prevention of 2019-nCoV infection, which provides practical suggestions on strengthening the management of pediatric fever clinics during the nCoV pneumonia epidemic period.

Protection of ripasudil, a Rho kinase inhibitor, in lipopolysaccharides-induced acute pneumonia in mice.

Pneumonia is a major cause of morbidity and mortality of infectious diseases, especially in children. Ripasudil (K-115), a selective ROCK inhibitor, is a promising emerging drug against glaucoma, and reported to have anti-inflammatory activity. However, the anti-inflammatory effect of ripasudil still remains unclear in pneumonia. The goal of this study is to investigate the role and the underlying mechanism of ripasudil in pneumonia. BALB/c mice were used to establish an acute pneumonia model of mice by injection of lipopolysaccharide (LPS) intraperitoneally. Ripasudil (0.5 mg, 1 mg, 2 mg) was administrated 1 h before the induction of LPS. The histoligical change of lung tissue was evaluated by hematoxylin-eosin staining and lung wet/dry ratio. Inflammatory cytokines secretion, oxidant-antioxidant factors levels were measured. Cell apoptosis was examined using TNUEL assay. Western blot and qRT-PCR was used to determine gene expressions. Results showed that ripasudil significantly attenuated LPS-induced histological changes, reduced the production of pro-inflammatory cytokines, and alleviated LPS-induced oxidative stress in mice. LPS-induced cell apoptosis and associated protein expression changes were attenuated by ripasudil. Besides, ripasudil reduced the expression of RhoA, and decreased the activity of RhoA/ROCK signaling. Finally, the level of RhoA and eNOS from pneumonia patients exhibited negatively correlated, whereas the level of RhoA was higher while eNOS level was lower than that in the healthy control. The results of the present study indicate that ripasudil attenuate LPS-induced pneumonia in BALB/c mice by ameliorating inflammation, oxidative stress and apoptosis through inhibiting RhoA/ROCK signaling pathway. Ripasudil might be a novel and effective drug for the treatment of pneumonia.

Calotropin activates YAP through downregulation of LATS1 in colorectal cancer cells.

Objectives: Calotropin (CTP), a natural product isolated from Calotropis gigantea, has been identified as a potential anticancer agent. In this study, we aimed to investigate the effect CTP on colorectal cancer and the role of Yes-associated protein (YAP) in CTP-inhibited cell proliferation. Methods: Cell viability and cell proliferation were detected by MTT and BrdU assay. Western blotting and immunofluorescence were performed to determine CTP-induced YAP dephosphorylation and nuclear localization. Western blotting, siRNA transfection and RT-PCR analysis were carried out to investigate the mechanisms of CTP-mediated YAP activation. The anti-tumor activities of CTP were observed in mice tumor models. Results: We demonstrated that CTP inhibits the proliferation of colorectal cancer cells both in vitro and in vivo. Moreover, we showed that CTP activates YAP in colorectal cancer cells. Mechanistically, CTP promotes LATS1 degradation via the ubiquitination/proteasome pathway, resulting in YAP dephosphorylation and nuclear localization, leading to induce YAP target genes expression in colorectal cancer cells. Inhibition of YAP activity enhances CTP-mediated inhibition of cell proliferation, suggesting that YAP plays a protective role in CTP-induced antiproliferative effect. Conclusion: Our results demonstrate that CTP markedly inhibits tumor growth and activates a protective role of YAP in colorectal cancer cells, indicating that combination of CTP and YAP targeting drugs may be a promising strategy for colorectal cancer treatment.

Sodium butyrate and panobinostat induce apoptosis of chronic myeloid leukemia cells via multiple pathways.

PURPOSE: Histone deacetylase inhibitor (HDACI) is a novel therapeutic option for cancer. However, the effects of HDACIs on chronic myeloid leukemia (CML) and the underlying mechanisms are still unknown. The aim of this study was to investigate the effect and the mechanism-of-action of two HDACI members, sodium butyrate (NaBu) and panobinostat (LBH589) in K562 and the adriamycin-resistant cell line K562/ADR. METHODS: Cell viability was assessed using MTT assay. Cell apoptosis was detected with flow cytometry. Cell cycle analysis and western blot were performed to explore the possible molecules related to HDACIs effects. RESULTS: The effect of NaBu was more powerful on K562/ADR than on K562 cells. LBH589 triggered apoptosis and inhibited the growth of K562 cells. Both HDACIs inhibited K562 and K562/ADR cells via activation of intrinsic/extrinsic apoptotic pathways and inhibition of AKT-mTOR pathway while NaBu also activated endoplasmic reticulum stress (ERS) mediated apoptotic pathway in K562/ADR cells. LBH589 reduced the expression of drug-resistant related proteins in K562 cells. However, neither NaBu nor LBH589 could significantly influence the expression of the drug-resistant related proteins in K562/ADR cells. CONCLUSION: The combination of HDACI and other therapeutic strategies are likely required to overcome drug resistance in CML therapy.

Genetically engineered drug rhCNB induces apoptosis and cell cycle arrest in both gastric cancer cells and hepatoma cells.

OBJECTIVES: Calcineurin B (CNB) is a regulatory subunit of calcineurin, and it has antitumor activity. In this study, we aimed to investigate the effect of recombinant human calcineurin B (rhCNB) on the proliferation of gastric cancer cells and hepatoma cells both in vitro and in vivo. MATERIALS AND METHODS: Cell viability and cell proliferation were detected by MTT and BrdU assay. Flow cytometry, Western blot and immunohistochemistry were performed to determine rhCNB-induced apoptosis and cell cycle arrest. The antitumor activities of rhCNB were observed in mice tumor models. RESULTS: We demonstrated that rhCNB inhibits the proliferation of gastric cancer cells and hepatoma cells both in vitro and in vivo. We showed that the inhibition of cell proliferation by rhCNB is associated with apoptosis and cell cycle arrest in both tumor cell lines. Furthermore, we indicated that rhCNB promotes p53 protein expression, a potent proapoptotic factor. Meanwhile, we also exhibited that rhCNB decreases the expression of both cyclin B1 and CDK1 proteins, two proteins associated with G2/M arrest. CONCLUSION: Together, these findings suggest that rhCNB markedly inhibits tumor growth and provides guidance for its drug development.

Effect of curcumin on expressions of NF-κBp65, TNF-α and IL-8 in placental tissue of premature birth of infected mice.

OBJECTIVE: To observe the effect of curcumin on expressions of nuclear transcription factor-kappa Bp65 (NF-κBp65), TNF-α and IL-8 in placental tissue of premature birth of infected mice induced by lipopolysaccharide (LPS). METHODS: A total of 60 C57BL/6 mice pregnant with 15 d were collected and randomly divided into control group, model group, treatment group and preventative group. LPS was repeatedly injected in abdominal cavity to construct infected premature birth model, while mice of control group were given with 100 mg/kg of vitamin C through abdominal cavity injection and mice of treatment group and preventative group were given curcumin of 100 mg/kg through abdominal cavity injection after modeling operation and before 1 d of modeling operation, respectively. A total of 5 mice of four groups respectively were executed by cervical dislocation after 6 h, 12 h and 24 h after constructing model. Placental tissues were collected and the immunohistochemical method SABC of immunologic tissue was used to detect the expression of NF-κBp65, TNF-α and IL-8 and peripheral blood of executed mice after 24 h was collected to detect the concentrations of IL-8, malondialdehyde (MDA) and superoxide dismutase (SOD), meanwhile live birth rate of four groups was contrasted. RESULTS: Staining intensity of NF-κBp65, TNF-α and IL-8 in placental tissue of treatment group and preventative group was significantly higher than control group but lower than model group (P < 0.05). Level of serum IL-8 and MDA of control group was significantly lower than the other three groups (P < 0.05) and level of blood of SOD in model group was significantly lower than control group (P < 0.05). Levels of serum IL-8 and MDA of treatment group and preventative group were significantly lower than model group (P < 0.05) while level of SOD was significantly higher than model group (P < 0.05). Live birth rate of treatment group and preventative group was significantly higher than model group (P < 0.05). CONCLUSIONS: Curcumin can effectively prevent the active pathway of NF-κB in pregnant tissue of premature birth of infected mice, reduce the expression of TNF-α and IL-8 and relieve the damage of lipid peroxide of oxidative stress of LPS on mother-fetus and further to achieve the objective of preventing and curing premature birth induced with infection.

Evaluation of the effects of active fractions of chinese medicine formulas on IL-1ß, IL-6, and TNF-α release from ANA-1 murine macrophages.

ETHNOPHARMACOLOGICAL RELEVANCE: Yaotongning (YTN) is a traditional Chinese Medicine (TCM) that contains ten component medicinal materials (CMMs) and uses Chinese rice wine as a vehicle to enhance its efficacy. YTN has been used for rheumatoid arthritis (RA) treatment in China for decades and has been reported to have anti-inflammatory and analgesic effects, as well as to strengthen the immune system. AIM OF THE STUDY: The present work quantitatively evaluated the in vitro effects of active fractions from the ten CMMs that make up YTN and eight additional herbs commonly used in TCM formulas for RA treatment, as well as different combinations of these active fractions, on cellular immune response; the findings were used to determine which active fractions are responsible for promoting an immune response, and to assess whether YTN is superior to other similar formulas and whether YTN can be improved by simplifying its formula from the point of its cellular immunomodulatory activity. MATERIALS AND METHODS: Using the YTN formulation principles and some concepts in combinatorial chemistry, 27 TCM samples were designed by combining some or all of the active fractions of YTN and other eight herbs used for RA treatment. Release of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) from ANA-1 murine macrophages was measured using an enzyme-linked immunosorbent assay (ELISA). The immunoregulatory effects of the TCM samples were evaluated by comparing their half-effective concentrations (EC50) for stimulating the release of these cytokines. RESULTS: Among the investigated active fractions, the flavonoids from Carthamus tinctorius (Fct), Davallia mariesii (Fdm), and Cinnamomum cassia Twig volatile oils (Vca) from the eight selected herbs effectively promoted IL-1ß and IL-6 release from ANA-1 cells. Saponins from the YTN CMM Glycyrrhiza uralensis (Sgu) were the most potent promoters of IL-1ß and TNF-α release. The aqueous extract of YTN CMM Eupolyphaga sinensis (Ves) strongly enhanced the release of IL-1ß, IL-6, and TNF-α from ANA-1 cells. The EC50 values for stimulating the secretion of IL-1ß, IL-6, and TNF-α could be determined for only six samples. The full YTN formula and the sample containing 50% Glycyrrhiza uralensis saponins, 25% of the mixture of alkaloids, and 25% of the mixture of all flavonoids exhibited good comprehensive cellular immunomodulatory activity. The immunomodulatory activity of the complete YTN formula was better than that of the sample containing all active fractions of YTN without Chinese rice wine (the YTN vehicle). CONCLUSIONS: Sgu and Ves are the primary active fractions of YTN involved in stimulating immune responses. The YTN prescription was reasonably effective at promoting cellular immune responses. Chinese rice wine, the YTN vehicle, strengthened the immunoregulatory activity of YTN. The results of this study demonstrate that the YTN recipe could be improved by reducing the number of CMMs and altering some active fractions without reducing its activity to promote cellular immune responses.

A novel method to predict protein-protein interactions based on the information of protein-protein interaction networks and protein sequence.

Protein-protein interactions (PPIs) are crucial to most biochemical processes in human beings. Although many human PPIs have been identified by experiments, the number is still limited compared to the available protein sequences of human organisms. Recently, many computational methods have been proposed to facilitate the recognition of novel human PPIs. However the existing methods only concentrated on the information of individual PPI, while the systematic characteristic of protein-protein interaction networks (PINs) was ignored. In this study, a new method was proposed by combining the global information of PINs and protein sequence information. Random forest (RF) algorithm was implemented to develop the prediction model, and a high accuracy of 91.88% was obtained. Furthermore, the RF model was tested using three independent datasets with good performances, suggesting that our method is a useful tool for identification of PPIs and investigation into PINs as well.