Vancomycin population pharmacokinetics analysis in Chinese paediatric patients with varying degrees of renal function and ages: development of new practical dosing recommendations.

OBJECTIVES: To describe the pharmacokinetics of vancomycin in a large Chinese paediatric cohort with varying degrees of renal function and ages and to develop practical dosing guidelines. PATIENTS AND METHODS: We conducted a retrospective population pharmacokinetic study using data from paediatric patients who received vancomycin between June 2013 and June 2022. A non-linear mixed-effect modelling approach with a one-compartment model structure was applied. Monte Carlo simulations were used to stimulate an optimal dosage regimen to achieve the target of AUC24/MIC between 400 and 650. RESULTS: We analysed a total of 673 paediatric patients and 1547 vancomycin serum concentrations. Covariate analysis revealed that physiological maturation, renal function, albumin and cardiothoracic surgery (CTS) significantly affected vancomycin pharmacokinetics. The typical clearance and volume of distribution, standardized to 70 kg, were 7.75 L/h (2.3% relative standard error, RSE) and 36.2 L (1.7% RSE), respectively. Based on the model, we proposed an optimal dosing regimen that considers the patient's age and estimate glomerular filtration rate (eGFR) to achieve a target AUC24/MIC for CTS and non-CTS patients. We also found that a loading dose of 20 mg/kg can help patients with an eGFR of <60 mL/min/1.73 m2 achieve the target AUC on the first day of treatment. CONCLUSIONS: We established vancomycin pharmacokinetic parameters in Chinese paediatric patients and proposed a dosing guideline integrating eGFR, age and CTS status, potentially improving clinical outcomes and reducing nephrotoxicity risk.

MicroRNA-638 inhibits human airway smooth muscle cell proliferation and migration through targeting cyclin D1 and NOR1.

Abnormal airway smooth muscle cell (ASMC) proliferation and migration contribute significantly to increased ASM mass associated with asthma. MicroRNA (miR)-638 is a primate-specific miRNA that plays important roles in development, DNA damage repair, hematopoiesis, and tumorigenesis. Although it is highly expressed in ASMCs, its function in ASM remodeling remains unknown. In the current study, we found that in response to various mitogenic stimuli, including platelet-derived growth factor-two B chains (PDGF-BB), transforming growth factor ß1, and fetal bovine serum, the expression of miR-638, as determined by quantitative real-time polymerase chain reaction (qRT-PCR), was significantly downregulated in the proliferative human ASMCs. Both gain- and loss-of-function studies were performed to study the role of miR-638 in ASMC proliferation and migration. We found that adenovirus-mediated miR-638 overexpression markedly inhibits ASMC proliferation and migration, while ablation of miR-638 by anti-miR-638 markedly increases cell proliferation and migration, as determined by WST-8 proliferation and scratch wound assays. Dual-luciferase reporter assay, qRT-PCR, and immunoblot analysis were used to investigate the effects of miR-638 on the expression of the downstream target genes in ASMCs. Our results demonstrated that miR-638 overexpression significantly reduced the expression of downstream target cyclin D1 and NOR1, both of which have been shown to be essential for cell proliferation and migration. Together, our study provides the first in vitro evidence highlighting the antiproliferative and antimigratory roles of miR-638 in human ASMC remodeling and suggests that targeted overexpression of miR-638 in ASMCs may provide a novel therapeutic strategy for preventing ASM hyperplasia associated with asthma.

Retrospective Analysis of Vancomycin Nephrotoxicity in Elderly Chinese Patients.

This study explored nephrotoxicity in elderly Chinese patients after exposure to vancomycin and other nephrotoxic risk factors. This was a single-center retrospective study. The patient population included those who were ≥60 years of age, had normal baseline serum creatinine values, and received vancomycin for ≥48 h between January 1, 2013 and August 30, 2014. Nephrotoxicity occurred in 29% of 124 patients. A baseline creatinine clearance ≥63.5 ml/min was more common in the nephrotoxic group. Patients with high (≥15 mg/l) rather than low (<15 mg/l) average vancomycin troughs had elevated nephrotoxicity (47.2 vs. 27.3%, p = 0.0001). Of the comorbid conditions evaluated, there were more patients with shock (p = 0.001), hypertension (p = 0.020) and congestive heart failure (p = 0.04) in the nephrotoxic group. Drugs frequently given at the same time with vancomycin, such as angiotensin receptor blockers and furosemide, were also associated with increased nephrotoxic risk. In conclusion, nephrotoxicity was frequently observed in patients with concurrent vancomycin trough concentrations ≥15 µg/ml and hypertension, shock, congestive heart failure. In addition, drugs concurrently used with vancomycin may also increase its nephrotoxicity. Therefore, renal function and vancomycin serum troughs should be closely monitored, especially in patients with other renal injury risk factors.

Analysis of bioactive components and synergistic action mechanism of ShuGan-QieZhi Capsule for treating non-alcoholic fatty liver disease.

BACKGROUND: ShuGan-QieZhi capsule (SGQZC) is a traditional Chinese preparation used to treat hyperlipidemia and obesity, even non-alcoholic fatty liver disease (NAFLD). However, its therapeutic effects, main bioactive ingredients, as well as potential mechanisms for NAFLD are still unclear. PURPOSE: To investigate the pharmacological effect, main active ingredients, and mechanisms of SGQZC against high-fat diet (HFD)-induced NAFLD in mice. METHODS: NAFLD models were established by feeding C57BL/6 J mice an HFD for 24 weeks. From the 12th week, HFD-fed mice received daily gavage of either SGQZC or silibinin for 12 weeks. Hepatic hypertrophy parameters, along with hepatic and systemic lipid metabolism changes in NAFLD mice, were assessed. Oil red O and histopathological staining techniques determined lipid accumulation and liver injury severity. qRT-PCR analysis measured the expression of genes tied to liver lipid metabolism and inflammation. HPLC-MS/MS identified the primary components of SGQZC in the serum. Human normal hepatocytes (LO2) and hepatic stellate cells (LX-2) were used to screen SGQZC's bioactive ingredients. Network pharmacological analysis, transcriptomics, and western blotting delved into SGQZC's synergistic mechanisms against NAFLD. RESULTS: SGQZC ameliorated abnormal lipid metabolism and liver hypertrophy in mice with HFD-induced NAFLD, consequently reducing hepatic lipid accumulation, inflammatory cell infiltration, and liver impairment. Eight crucial components of SGQZC were detected in serum using HPLC-MS/MS and were found to effectively attenuate lipid accumulation and inflammation in liver cells. Further investigation indicated that SGQZC modulates MAPK pathway and AKT/NF-κB pathway, subsequently improving lipid metabolism and inflammation. CONCLUSION: SGQZC alleviates NAFLD by synergistically modulating the MAPK-mediated lipid metabolism and inhibiting AKT/NF-κB pathways-mediated inflammation. Our findings reveal the enormous potential of SGQZC for the treatment of NAFLD, providing a possible new clinical therapeutic strategy.

Mitochondrial dynamics in vascular remodeling and target-organ damage.

Vascular remodeling is the pathological basis for the development of many cardiovascular diseases. The mechanisms underlying endothelial cell dysfunction, smooth muscle cell phenotypic switching, fibroblast activation, and inflammatory macrophage differentiation during vascular remodeling remain elusive. Mitochondria are highly dynamic organelles. Recent studies showed that mitochondrial fusion and fission play crucial roles in vascular remodeling and that the delicate balance of fusion-fission may be more important than individual processes. In addition, vascular remodeling may also lead to target-organ damage by interfering with the blood supply to major body organs such as the heart, brain, and kidney. The protective effect of mitochondrial dynamics modulators on target-organs has been demonstrated in numerous studies, but whether they can be used for the treatment of related cardiovascular diseases needs to be verified in future clinical studies. Herein, we summarize recent advances regarding mitochondrial dynamics in multiple cells involved in vascular remodeling and associated target-organ damage.

Epigenetic regulation of vascular smooth muscle cell phenotypic switch and neointimal formation by PRMT5.

AIMS: Phenotypic transition of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic state is involved in the development of cardiovascular diseases, including atherosclerosis, hypertension, and post-angioplasty restenosis. Arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) has been implicated in multiple cellular processes, however, its role in VSMC biology remains undetermined. The objective of this study was to determine the role of PRMTs in VSMC phenotypic switch and vascular remodelling after injury. METHODS AND RESULTS: Our results show that PRMT5 is the most abundantly expressed PRMT in human aortic SMCs, and its expression is up-regulated in platelet-derived growth factor (PDGF)-stimulated VSMCs, human atherosclerotic lesions, and rat carotid arteries after injury, as determined by western blot and immunohistochemical staining. PRMT5 overexpression inhibits the expression of SMC marker genes and promotes VSMC proliferation and migration, while silencing PRMT5 exerts the opposite effects. Mechanistically, we found that PRMT5 overexpression led to histone di-methylation of H3R8 and H4R3, which in turn attenuates acetylation of H3K9 and H4, thus limiting recruitment of the SRF/myocardin complexes to the CArG boxes of SMC marker genes. Furthermore, both SMC-specific deletion of PRMT5 in mice and local delivery of lentivirus expressing shPRMT5 to rat carotid arteries significantly attenuated neointimal formation after injury. Likewise, pharmacological inhibition of PRMT5 by EPZ015666 markedly inhibited carotid artery ligation-induced neointimal formation in mice. CONCLUSIONS: Our results identify PRMT5 as a novel regulator in VSMC phenotypic switch and suggest that inhibition of PRMT5 may represent an effective therapeutic strategy for proliferative vascular diseases.

Evaluation of in vivo antibacterial drug efficacy using Caenorhabditis elegans infected with carbapenem-resistant Klebsiella pneumoniae as a model host.

Objective: This study was developed to assess the in vivo antimicrobial activity of specific drugs using a model system consisting of Caenorhabditis elegans (C. elegans) infected with Carbapenem-resistant Klebsiella pneumoniae (CRKP) in an effort to identify promising drugs for CRKP-infected patient treatment. Methods: A C. elegans-CRKP liquid assay platform was developed and used to conduct limited in vivo screening for antimicrobial agents with potential activity against CRKP. Time curves for 10 different concentrations of tested antimicrobial agents were tested in this model system at 0, 2, 6, 8, and 12 h after treatment. The protective effects of these different antimicrobial agents were compared at different time points. Furthermore, ten CRKP strains samples were isolated from clinical specimens to demonstrate the applicability of the nematode model method, and two typical clinical cases are presented. Results: CRKP bacteria were sufficient to induce C. elegans death in a dose- and time-dependent fashion, while effective antimicrobial agents improved the survival of these nematodes in a dose-dependent manner. Notably, PB and TGC exhibited robust antibacterial protection within 12 h even at low tested concentrations, and clear efficacy remained evident for high doses of CAZ at this same time point as mediators of improved nematode survival. The results of C. elegans model method were well consistent with that using the Kirby-Bauer method in 10 CRKP strains samples, and two typical clinical cases showed applicability, reliability and efficacy of C. elegans model method. Conclusion: Overall, nematode models in drug sensitivity testing have shown advantages in clinical settings. Our results highlight the value of C. elegans model systems as tools for the simultaneous screening of different agents for in vivo antibacterial efficacy and are deserved further study.

Gandi Capsule Improved Podocyte Lipid Metabolism of Diabetic Nephropathy Mice through SIRT1/AMPK/HNF4A Pathway.

Podocyte lipid accumulation is a potential therapeutic target for diabetic nephropathy (DN). This study was aimed at clarifying the mechanism of Gandi capsule (GDC) ameliorating DN by regulating the lipid metabolism of podocytes. Network pharmacology methods were performed to screen the key molecules and potential targets of GDC for constructing the molecular-protein interaction network of GDC and conducting signal pathway enrichment analysis. GDC was predicted to ameliorate DN through SIRT1/AMPK/HNF4A pathway. Our results showed that GDC improved renal function in db/db mice. Besides, GDC exhibited effectiveness in relieving kidney tissue damage and renal lipid accumulation in db/db mice, and same effects were present in GDC-active ingredient baicalin. We further proved the new role of HNF4A in the lipid metabolism of DN mediated by SIRT1 and AMPK signaling pathways. The results suggested decreased expression of SIRT1 and p-AMPKα in the kidney tissue and increased expression of HNF4A of db/db mice compared with the control group. GDC and baicalin could reverse these expression changes. Furthermore, similar expression changes were observed in the murine podocyte cell line (MPC-5) treated with different concentrations of GDC and baicalin. Our research suggested that GDC and its active ingredient baicalin could alleviate the abnormal lipid metabolism in the kidney of db/db mice and might exert renal protection through the SIRT1/AMPK/HNF4A pathway.

Analysis of the Clinical Effect of Combined Drug Susceptibility to Guide Medication for Carbapenem-Resistant Klebsiella pneumoniae Patients Based on the Kirby-Bauer Disk Diffusion Method.

OBJECTIVE: To evaluate the in-vitro antibacterial activity of drug combinations against carbapenem-resistant Klebsiella pneumoniae (CRKP) and to explore the guiding significance of the combined drug susceptibility results for determining the clinical efficacy in patients with CRKP infection. METHODS: Antimicrobial susceptibility testing was performed using the Kirby-Bauer disk diffusion method. The clinical data of CRKP-infected patients and the drug susceptibility results of sample cultures were gathered and retrospectively analyzed. RESULTS: All 16 CRKP patients had underlying diseases, of which the bloodstream infection was the most common one. Intensive care unit admission history, invasive operation history, and poor nutritional status were recorded to be the high-risk factors. The in-vitro drug susceptibility results indicated that CRKP exhibited 100%, 75.0%, and 66.7% susceptibilities to tigecycline, polymyxin, and ceftazidime/avibatan, respectively. In case of two-drug combinations, polymyxin+tigecycline, ceftazidime avibatan+tigecycline or (aztreonam, polymyxin B, fosfomycin), fosfomycin+polymycin, imipenem+tigecycline, and fosfomycin+tigecycline exhibited 100%, 87.5% (81.3%, 75.0%, 75.0%), 68.8%, 68.8%, and 62.5%, respectively, synergistic and/or cumulative antibacterial effects. Three-drug combinations such as imipene+tigecycline+polymyxin, imipenem+fosfomycin+tigecycline, imipenem+fosfomycin+polymyxin, and ceftazidime avibatan+polymyxin+fosfomycin demonstrated 75.0%, 68.8%, 62.5%, and 62.5% synergistic effects, respectively. The clinical efficacy results revealed that the combination of imipenem+tigecycline+fosfomycin showed the best results, followed by meropenem+fosfomycin, imipenem+tigecycline, ceftazidime avibatan, and ceftazidime+amikacin. CONCLUSION: The combined drug susceptibility results can facilitate guidance of the adjustment of antibacterial drug treatment regimens in patients with CRKP infection. For controlling the CRKP infection, it was found that treatment with carbapenems or ceftazidime avibatan demonstrated better antibacterial activity when combined with tigecycline and/or fosfomycin and/or polymyxin B.

Prediction of Prognosis in Adult Patients With Carbapenem-Resistant Klebsiella pneumoniae Infection.

OBJECTIVE: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections are associated with poor patient outcomes. We aimed to analyze the clinical information of adult patients with CRKP infection in order to establish a nomogram for mortality risk as well as to determine the treatment effectiveness of different antimicrobial regimens. METHODS: Adult patients diagnosed with CRKP infection in a tertiary hospital in Shanghai between September 2019 and March 2021 were included. The clinical characteristics and clinical outcomes of these patients were analyzed. RESULTS: A total of 199 cases of CRKP infection were examined. Five factors, namely age ≥65 years, respiratory failure, Sequential Organ Failure Assessment score, serum procalcitonin ≥5 ng/mL, and appropriate treatments in 3 days, were found to be associated with 30-day mortality. Upon incorporating these factors, the nomogram achieved good concordance indexes of 0.85 (95% confidence interval [CI]: 0.80-0.90) and well-fitted calibration curves. Receiver-operating characteristic curves for 7-, 15-, and 30-day survival had areas under the curve of 0.90, 0.87, and 0.88, respectively. Three-drug combination therapy was observed to be associated with lower mortality in the high-risk group (adjusted hazard ratio = 0.24, 95% CI: 0.06-0.99) but not in the low-risk group. Ceftazidime-avibactam, fosfomycin, and amikacin were effective against infections caused by CRKP. Tigecycline improved the treatment efficiency in 7 days, but a trend toward increased mortality was seen (HR, 1.69; 95% CI: 0.98-2.94; P = 0.061). CONCLUSION: The antimicrobial regimen efficacy data and the predictive nomogram established in this study can help clinicians in identifying high-risk adult patients with CRKP infection, improving the therapeutic effect, and reducing mortality.

Active-Ingredient Screening and Synergistic Action Mechanism of Shegan Mixture for Anti-Asthma Effects Based on Network Pharmacology in a Mouse Model of Asthma.

BACKGROUND: Shegan Mixture (SGM) is a traditional Chinese medicine that has anti-inflammatory and therapeutic effects on asthma. However, its active ingredients and combined action mechanism have not been fully elucidated so far. The purpose of this study was to screen the effective ingredients and targets and elucidate the synergistic action mechanism of SGM in asthma mice using the network pharmacological approach. METHODS: A mouse model of asthma model was used in this study. Mice were orally administered SGM at three doses for 4 weeks and the effect of SGM on asthma was evaluated. The active ingredients and their targets of SGM were identified by searching databases, such as Traditional Chinese Medicine Systems Pharmacology Database (TCMSP). The main active ingredients were selected with parameters OB and DL. The synergistic action mechanisms of SGM in asthma were studied through key active ingredient-target interaction network and verified using surface plasmon resonance assay (SPR). RESULTS: SGM exerts anti-asthmatic effects by reducing lung tissue damage and inflammatory factors (IFN-γ, IL-4, IL-5, and IL-13) in asthmatic mice. Twenty ingredients and 45 related proteins were selected as potential nodes using enrichment analysis and network analysis. Inflammation and smooth muscle regulation-related pathways were considered to be the main pharmacological mechanisms of SGM in the treatment of asthma. Especially, 5 molecule-target pairs (including 3 ingredients and 4 proteins) were well docked with each other and the SPR assay revealed that glabridin-PTGS2 had good binding with 44.5 µM Kd value. CONCLUSION: SGM exerts the synergistic anti-asthma effects by virtue of reducing lung-tissue damage and inflammatory factors in asthmatic mice, which explains the theoretical basis for the traditional Chinese medicine, SGM, to treat asthma. Our study thus sheds light on a variety of options including Chinese medicine that could potentially be used in the clinical treatment of asthma.

[Joint administration of acupuncture, western and herbal medicines and bamboo-jar-cupping for stroke patients of wind-phlegm obstructing collateral type in acute stage].

OBJECTIVE: To observe the curative effect of joint administration of acupuncture, western and herbal medicines and bamboo-jar-cupping in the treatment of locomotor dysfunction in patients with apoplexy (acute phase) of wind-phlegm blocking meridian-collateral type in acute stroke patients, and its influence on some relevant laboratory indexes. METHODS: A total of 100 cases of acute stroke patients of wind-phlegm blocking meridian-collateral type were recruited, and equally and randomly divided into control group and treatment group according to the random number table. The patients of both groups received treatment of conventional western medicines (for anti-platelet aggregation, blood-lipid regulation, arterial plaque-stabilization, cerebral cell protection and blood pressure-lowering), Chinese herbal medicines (for promoting blood circulation to dredge the meridian-collaterals), and acupuncture of Neiguan (PC6), Chize (LU5), Zusanli (ST36), Binao (LI14) and Sanyinjiao (SP6); and in addition, the patients of the treatment group also treated by cupping with bamboo-jar (kept for 10 min). The treatment was conducted once a day for 2 weeks. After the treatment, the National Institute of Health Stroke Scale (NIHSS), Fugl-Meyer assessment (FMA), Barthel Index (BI), and traditional Chinese medicine (TCM) syndrome score were used to assess the state of neurofunction, locomotor function, daily living ability, and TCM symptoms. The contents of serum C-reactive protein, D-dimer and blood homocysteine were detected using radical immunodiffusion, immunoturbidimetry, and enzymic methods, respectively. RESULTS: After the treatment, of the 50 and 50 cases in the control and treatment groups, 5 and 6 were cured, 7 and 18 experienced marked improvement, 23 and 20 were effective, and 15 and 6 ineffective, with the effective rate being significantly higher in the treatment group (88.0%) than in the control group (70.0%, P<0.05). Self-comparison showed that the FMA and BI scores were significantly increased (P<0.01), and the NIHSS score and TCM syndrome score notably decreased in both groups ( P<0.01) in comparison with their own pre-treatment. Comparison between the two groups showed that the FMA and BI scores were obviously higher in the treatment group than in the control group (P<0.05), whereas the NIHSS score and TCM syndrome score as well as the C-reaction protein content evidently lower in the treatment group than in the control group (P<0.05, P<0.01). CONCLUSION: Joint administration of acupuncture, western and Chinese herbal medicines and cupping can promote the recovery of nerve function, improve locomotor function, activities of daily living and quality of life, and reduce inflammatory state in acute stroke patients with wind-phlegm blocking collaterals.

Lipopolysaccharide exposure induces oxidative damage in Caenorhabditis elegans: protective effects of carnosine.

BACKGROUND: The present study was designed to investigate the protective effects and mechanisms of carnosine on lipopolysaccharide (LPS)-induced injury in Caenorhabditis elegans. METHODS: C. elegans individuals were stimulated for 24 h with LPS (100 µg/mL), with or without carnosine (0.1, 1, 10 mM). The survival rates and behaviors were determined. The activities of superoxide dismutase (SOD), glutathione reductase (GR), and catalase (CAT) and levels of malondialdehyde (MDA) and glutathione (GSH) were determined using the respective kits. Reverse transcription polymerase chain reaction (RT-PCR) was performed to validate the differential expression of sod-1, sod-2, sod-3, daf-16, ced-3, ced-9, sek-1, and pmk-1. Western blotting was used to determine the levels of SEK1, p38 mitogen-activated protein kinase (MAPK), cleaved caspase3, and Bcl-2. C. elegans sek-1 (km2) mutants and pmk-1 (km25) mutants were used to elucidate the role of the p38 MAPK signaling pathway. RESULTS: Carnosine improved the survival of LPS-treated C. elegans and rescued behavioral phenotypes. It also restrained oxidative stress by decreasing MDA levels and increasing SOD, GR, CAT, and GSH levels. RT-PCR results showed that carnosine treatment of wild-type C. elegans up-regulated the mRNA expression of the antioxidant-related genes sod-1, sod-2, sod-3, and daf-16. The expression of the anti-apoptosis-related gene ced-9 and apoptosis-related gene ced-3 was reversed by carnosine. In addition, carnosine treatment significantly decreased cleaved caspase3 levels and increased Bcl-2 levels in LPS-treated C. elegans. Apoptosis in the loss-of-function strains of the p38 MAPK signaling pathway was suppressed under LPS stress; however, the apoptotic effects of LPS were blocked in the sek-1 and pmk-1 mutants. The expression levels of sek-1 and pmk-1 mRNAs were up-regulated by LPS and reversed by carnosine. Finally, the expression of p-p38MAPK and SEK1 was significantly increased by LPS, which was reversed by carnosine. CONCLUSION: Carnosine treatment protected against LPS injury by decreasing oxidative stress and inhibiting apoptosis through the p38 MAPK pathway.

Genomic Characteristics and Selection Signatures in Indigenous Chongming White Goat (Capra hircus).

The Chongming white goat (CM) is an indigenous goat breed exhibits unique traits that are adapted to the local environment and artificial selection. By performing whole-genome re-sequencing, we generated 14-20× coverage sequences from 10 domestic goat breeds to explore the genomic characteristics and selection signatures of the CM breed. We identified a total of 23,508,551 single-nucleotide polymorphisms (SNPs) and 2,830,800 insertion-deletion mutations (indels) after read mapping and variant calling. We further specifically identified 1.2% SNPs (271,713) and 0.9% indels (24,843) unique to the CM breed in comparison with the other nine goat breeds. Missense (SIFT < 0.05), frameshift, splice-site, start-loss, stop-loss, and stop-gain variants were identified in 183 protein-coding genes of the CM breed. Of the 183, 36 genes, including AP4E1, FSHR, COL11A2, and DYSF, are involved in phenotype ontology terms related to the nervous system, short stature, and skeletal muscle morphology. Moreover, based on genome-wide F ST and pooled heterozygosity (Hp) calculation, we further identified selection signature genes between the CM and the other nine goat breeds. These genes are significantly associated with the nervous system (C2CD3, DNAJB13, UCP2, ZMYND11, CEP126, SCAPER, and TSHR), growth (UCP2, UCP3, TSHR, FGFR1, ERLIN2, and ZNF703), and coat color (KITLG, ASIP, AHCY, RALY, and MC1R). Our results suggest that the CM breed may be differentiated from other goat breeds in terms of nervous system owing to natural or artificial selection. The whole-genome analysis provides an improved understanding of genetic diversity and trait exploration for this indigenous goat breed.

Mangiferin attenuates bleomycin-induced pulmonary fibrosis in mice through inhibiting TLR4/p65 and TGF-ß1/Smad2/3 pathway.

OBJECTIVES: Investigating the antipulmonary fibrosis effect of mangiferin from Mangifera indica and the possible molecular mechanism. METHODS: In vivo, bleomycin (BLM)-induced pulmonary fibrosis experimental model was used for evaluating antipulmonary fibrosis effect of mangiferin. Histopathologic examination and collagen deposition were investigated by HE and Masson staining as well as detecting the content of hydroxyproline. The expression of transforming growth factor-ß1 (TGF-ß1), α-smooth muscle actin (α-SMA), TLR4 and p-P65 in lung tissue was analysed through immunofluorescence. Leucocytes and inflammatory cytokines including IL-1ß, IL-6, TNF-α and MCP-1 in bronchoalveolar lavage fluid were detected by cell counting and enzyme-linked immunosorbent assay. In vitro, TGF-ß1-induced A549 epithelial-mesenchymal transition (EMT) cell model was used for investigating the possible molecular mechanism. Reactive oxygen species (ROS) generation was detected by DCFH-DA assay. Expression of all proteins was examined by Western blot. KEY FINDINGS: Oral administration of mangiferin could attenuate the severity of BLM-induced pulmonary fibrosis through increasing the survival rate, improving histopathological lesion and body weight loss as well as decreasing pulmonary index visibly. Pulmonary hydroxyproline content, TGF-ß1, and α-SMA levels were reduced significantly. The molecular mechanism of mangiferin for inhibiting pulmonary fibrosis is that it could obviously inhibit the occurrence of inflammation and the secretion of inflammatory cytokine through inhibiting activation of TLR4 and phosphorylation of p65. Meanwhile, EMT process was suppressed obviously by mangiferin through blocking the phosphorylation of Smad2/3 and reducing MMP-9 expression. Besides, mangiferin could significantly inhibit the process of oxidant stress through downregulating the intracellular ROS generation. CONCLUSIONS: Mangiferin attenuates BLM-induced pulmonary fibrosis in mice through inhibiting TLR4/p65 and TGF-ß1/Smad2/3 pathway.

Effect of physical therapy for chronic obstructive pulmonary disease: A protocol for an updated systematic review of randomized controlled trial.

BACKGROUND: Previous studies have reported that physical therapy (PT) can be used for the treatment of chronic obstructive pulmonary disease (COPD). However, its effectiveness is still inconclusive. This systematic review will aim to assess its effectiveness and safety for the treatment of patients with COPD. METHODS: All randomized controlled trials (RCTs) literatures of PT for COPD will be searched from the databases of Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, MEDILINE, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, VIP Information, and Wanfang Data from inception to the present without any language restrictions. Two reviewers will independently perform the study selection, data extraction, and methodological quality assessment. A third reviewer will be invited to resolve any disagreements occurred between 2 reviewers. RESULTS: The primary outcome is lung function. The secondary outcomes include symptoms, health-related quality of life, mortality, and adverse events. The outcome data will be pooled by using the models of random-effects or fixed-effects according to the detected heterogeneity. CONCLUSION: The findings of this study will provide up-todated summary evidence for assessing the effectiveness and safety of PT for COPD.

Porcine alpha interferon inhibit Japanese encephalitis virus replication by different ISGs in vitro.

Japanese encephalitis virus (JEV) causes serious zoonosis in South Asia, Southeast Asia and other areas. Pigs are an important reservoir for this virus in nature. The treatment of JEV infection in pigs is important for controlling the prevalence of JEV in humans and economic losses in pig farming. In this study, we selected a high activity porcine alpha-interferon to inhibit JEV replication in porcine kidney cell lines (PK-15). Alpha interferon exhibited high antiviral activity against JEV; the expression of three interferon-stimulated genes (ISGs), ISG15, Mx2 and OAS L, increased significantly after interferon treatment. Furthermore, we verified the anti-JEV effect of these ISGs by RNAi and overexpression. Mx2 and OAS L exhibited strong anti-JEV effects in PK-15 cells. Based on these novel results, alpha interferon (IFN-α) should be considered to be a potential drug against JEV in pigs.

Preparation and evaluation of a novel gastric floating alginate/poloxamer inner-porous beads using foam solution.

In the present study, a simple and rapid method was developed to prepare a novel kind of inner-porous floating beads. The beads were prepared by dripping the foam solution into CaCl(2) solution using disposable syringe needle, where the foam solution consisting numerous of microbubbles with poloxamer 188 as foaming agents, alginate as foaming stablizer. Foamability and foam stability of different polymer ratios were evaluated. The SEM cross-section pictures of the beads showed that the beads were inner-porous and composed of bubbles with very thin wall bubbles stacked together. The visual observation result and the resultant-weight method confirmed that the floating beads showed good buoyancy, most beads could float in the stomach for more than 6 h. The floating beads release behavior in vitro showed that drug release from the beads in a sustained-release fashion for 10 h. Gamma scintigraphic images and pharmacokinetic studies in vivo showed that the beads can retained in the stomach for over 6 h and can improve the bioavailability of drug with narrow absorption window.