Search

Fibrosis of the liver is a degenerative alteration that occurs in the majority of chronic liver disorders. Further progression can lead to cirrhosis, liver failure, and hepatocellular carcinoma, which can seriously affect the health and lives of patients. The field of liver fibrosis research has flourished in the last 20 years, with approximately 9,000 articles retrieved from the Web of Science Core Collection database alone. In order to identify future research hotspots and potential paths in a thorough and scientifically reliable manner, it is important to organize and visualize the research on this topic from a holistic and very general perspective. This study used bibliometric analysis with CiteSpace and VOSviewer software to provide a quantitative analysis, hotspot mining, and commentary of articles published in the field of liver fibrosis over the last 20 years. This bibliometric analysis contains a total of 8,994 articles with 45,667 authors from 6,872 institutions in 97 countries, published in 1,371 journals and citing 156,309 references. The literature volume has steadily increased over the last 20 years. Research has focused on gastroenterologyhepatology, pharmacologypharmacy, and medicine, researchexperimental areas. We found that the pathological mechanisms, diagnostic and quantitative methods, etiology, and anti-fibrotic strategies constitute the knowledge structure of liver fibrosis. Finding mechanisms for liver fibrosis regression, identifying precise non-invasive diagnostic and prognostic biomarkers, and creating efficient liver fibrosis patient treatments are the main goals of current research.

Bone cancer pain (BCP) is a difficult-to-treat pathologic condition that impairs the patient's quality of life. The effective therapy options for BCP are restricted due to the unknown pathophysiology. Transcriptome data were obtained from the Gene Expression Omnibus (GEO) database and differentially expressed gene (DEGs) extraction was performed. Differentially expressed genes analysis (DEGs) integrated with pathological targets found 68 genes in the study. Butein was discovered as a possible medication for BCP after the 68 genes were submitted to the Connectivity Map (CMap) 2.0 database for drug prediction. To collect the butein targets, we used the CTD, SEA, TargetNet, and Super-PRED databases. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed butein's pharmacological effects, indicating that butein may aid in treating BCP by altering the hypoxia-inducible factor, NF-kappa B, angiogenesis, and sphingolipid signaling pathways. Moreover, the pathological targets integrated with drug targets were obtained as the shared gene set A (GSA), which was analyzed by ClueGO and MCODE. Biological process analysis and MCODE algorithm further analyzed that BCP related targets were mainly involved in signal transduction process and ion channel-related pathways. Next, we integrated targets related to network topology parameters and targets of core pathways, identified PTGS2, EGFR, JUN, ESR1, TRPV1, AKT1 and VEGFA as butein regulated hub genes by molecular docking, which play a critical role in its analgesic effect. This study lays the scientific groundwork for elucidating the mechanism underlying butein's success in the treatment of BCP.

Objective The purpose of this study is to explore whether combining the power analysis of covariates and the machine learning (ML) analysis of correlated covariates can improve the model’s predictive performance. Methods Two drugs were selected to explore the methodology of population pharmacokinetics. The parameter-covariate relationships were estimated by the SCM and COSSAC methods. The different covariates for each parameter selected by the SCM and COSSAC methods implement the power analysis. And then the highly correlated covariates were analyzed to select a significant covariate by the ML method. The performance of the calibrated model developed by the above process was compared with the performance of two other predictive models: the SCM model and the COSSAC model. Relative error was used to evaluate the different models. The non-compartment analysis (NCA) was used to calculate individual reference AUC. The AUC obtained by population pharmacokinetic models was compared with the reference AUC to evaluate these models’ predictive performance. Result The performance of the calibrated model is similar to the SCM and COSSAC models known from the relative error, the R2of all models is more than 97%. However, the performance predicting the AUC of the calibrated model is better than the SCM and COSSAC models. Conclusion The power analysis can reduce the redundancy of covariate information, and the ML method can provide a criterion to select a covariate from these highly correlated covariates. There combining the two methods may be beneficial for improving individual prediction.

Aim: To characterize two plasmids p13294-KPC and pA1966-NR from clinical Klebsiella pneumoniae strains. Materials & methods: Plasmids p13294-KPC and pA1966-NR were fully sequenced and then detailed genomic analysis was performed in this work. The antimicrobial resistance phenotypes were determined. Results: p13294-KPC and pA1966-NR displayed IncpA1763-KPC:IncFIIK7 dual-replicon structures. The backbone of these two plasmids were closely related to each other. p13294-KPC contained two accessory modules, namely ΔIS Kpn25 and blaKPC-2 region, and the blaKPC-2 region carried a range of mobile elements and resistance gene blaKPC-2. while pA1966-NR contained four individual IS elements in its backbone and carried no resistance genes. Conclusion: This study provided a deeper insight into the genomic characterization of IncpA1763-KPC: IncFIIK7 type plasmids p13294-KPC and pA1966-NR.

Liver fibrosis is a chronic liver disease that can lead to cirrhosis, liver failure, and hepatocellular carcinoma, and it is associated with long-term adverse outcomes and mortality. As a primary resource for complementary and alternative medicine, traditional Chinese medicine (TCM) has accumulated a large number of effective formulas for the treatment of liver fibrosis in clinical practice. However, studies on how to systematically optimize TCM formulas are still lacking.To provide a methodological reference for the systematic optimization of TCM formulae against liver fibrosis and explored the underlying molecular mechanisms; To provide an efficient method for searching for lead compounds from natural sources and developing from herbal medicines; To enable clinicians and patients to make more reasonable choices and promote the effective treatment toward those patients with liver fibrosis.TCM formulas related to treating liver fibrosis were collected from the Web of Science, PubMed, the China National Knowledge Infrastructure (CNKI), Wan Fang, and the Chinese Scientific Journals Database (VIP). Furthermore, the TCM compatibility patterns were mined using association analysis. The core TCM combinations were found by designing an optimized formulas algorithm. Finally, the hub target proteins, potential molecular mechanisms, and active compounds were explored through integrative pharmacology and docking-based inverse virtual screening (IVS) approaches.We found that the herbs for reinforcing deficiency, activating blood, removing blood stasis, and clearing heat were the basis of TCM formulae patterns. Furthermore, the combination of Salviae Miltiorrhizae (Salvia miltiorrhiza Bunge; Chinese salvia/Danshen), Astragali Radix (Astragalus membranaceus (Fisch.) Bunge; Astragalus/Huangqi), and Radix Bupleuri (Bupleurum chinense DC.; Bupleurum/Chaihu) was identified as core groups. A total of six targets (TNF, STAT3, EGFR, IL2, ICAM1, PTGS2) play a pivotal role in TCM-mediated liver fibrosis inhibition. (-)-Cryptotanshinone, Tanshinaldehyde, Ononin, Thymol, Daidzein, and Formononetin were identified as active compounds in TCM. And mechanistically, TCM could affect the development of liver fibrosis by regulating inflammation, immunity, angiogenesis, antioxidants, and involvement in TNF, MicroRNAs, Jak-STAT, NF-kappa B, and C-type lectin receptors (CLRs) signaling pathways. Molecular docking results showed that key components had good potential to bind to the target genes.In summary, this study provides a methodological reference for the systematic optimization of TCM formulae and exploration of underlying molecular mechanisms.

Cell mechanics plays an important role in cellular physiological and pathological processes. During the formation and progression of tumors, the alterations in the mechanics of cancerous cells and tumor micro-environment promote the growth and migration of cancerous cells. Hence, investigating cell mechanics is of crucial significance in understanding the underlying mechanisms regulating life activities and diseases. The advent of atomic force microscopy (AFM) provides a powerful tool for detecting the mechanical properties of single cells. Compared with other single-cell mechanical analysis techniques, the advantage of AFM is that AFM is able to simultaneously obtain the topography and mechanics of cells, which is particularly useful for investigating the correlation between cell structures and cell mechanics. The biomedical applications of AFM in single-cell mechanics provide considerable novel insights into how cell and tissue mechanics affect tumor development and metastasis, contributing much to the communities of biomechanics and biophysics. However, current AFM single-cell mechanical experiments are commonly performed on measuring the elastic properties of cells and studies about the viscoelastic properties of cells are still scarce. In this work, AFM was utilized to measure and analyze the viscoelastic properties of cells. First, the detailed procedure of detecting the viscoelasticity of cells based on AFM indentation technique was established. AFM probe was controlled to perform approach-dwell-retract movement on cells in the vertical direction. During the approach-dwell-retract process, the deflection of AFM cantilever versus time was recorded, which yielded the force-time (F-T) curves. The original F-T curves were then normalized and fitted by two-order Maxwell model, which gave two cellular relaxation times (the first relaxation time τ 1 and the second relaxation time τ 2). The fitting results showed that the theoretical curve matched the experimental relaxation curve well, indicating that the two-order Maxwell model was suited for characterizing the relaxation behaviors of cells. Second, the established procedure was used to measure the relaxation time of six different types of cells, including mammalian adherent cells, mammalian suspended cells, normal cells, cancerous cells, cell lines cultured in vitro and primary cells prepared from bone marrow and peripheral blood of healthy volunteers. The fitting curves were consistent with the experimental relaxation curves for all of the six types of cells used here, indicating the effectiveness of the presented method for detecting the viscoelastic properties of cells. Besides, the results showed the various cellular relaxation times for the different types of cells. The statistical results showed that the first cellular relaxation times were in the range 0.01−0.03 s, which might correspond to the behaviors of cytoplasm. The second cellular relaxation time was in the range 0.2−0.4 s, which might correspond to the behaviors of the cytoskeleton. Finally, regression analysis was performed on the measured cellular relaxation times, showing the linear relationship between the first cellular relaxation time τ 1 and the second cellular relaxation time τ 2, and the regression coefficients were variable for different types of cells. The research improves our understanding of cellular viscoelasticity and also provides a novel idea to measure the viscoelastic properties of cells, which will have potential impacts on cell mechanics and biomedicine.

Hepatitis B (HB) is a globally prevalent infectious disease caused by the HB virus. Xiaochaihu decoction (XCHD) is a classic herbal formula with a long history of clinical application in treating HB. Although the anti-HB activity of XCHD has been reported, systematic research on the exact mechanism of action is lacking. Here, a network pharmacology-based approach was used to predict the active components, important targets, and potential mechanism of XCHD in HB treatment. Investigation included drug-likeness evaluation; absorption, distribution, metabolism, and elimination (ADME) screening; protein-protein interaction (PPI) network construction and cluster analysis; Gene Ontology (GO) analysis; and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation. Molecular docking was adopted to investigate the interaction between important target proteins and active components. Eighty-seven active components of XCHD and 155 anti-HB targets were selected for further analysis. The GO enrichment and similarity analysis results indicated that XCHD might perform similar or the same GO functions. Glycyrrhizae Radix (GR), one of the seven XCHD herbs, likely exerts some unique GO functions such as the regulation of interleukin-12 production, positive regulation of interleukin-1 beta secretion, and regulation of the I-kappaB/NF-kappaB complex. The PPI network and KEGG pathway analysis results showed that XCHD affects HB mainly through modulating pathways related to viral infection, immunity, cancer, signal transduction, and metabolism. Additionally, molecular docking verified that the active compounds (quercetin, chrysin, and capsaicin) could bind with the key targets. This work systematically explored the anti-HB mechanism of XCHD and provides a novel perspective for future pharmacological research.

Background: COVID-19 has become one of the most serious global epidemics in the 21st Century. This study aims to explore the distribution of research capabilities of countries, institutions, and researchers, and the hotspots and frontiers of coronavirus research in the past two decades. In it, references for funding support of urgent projects and international cooperation among research institutions are provided. Method: the Web of Science core collection database was used to retrieve the documents related to coronavirus published from 2003 to 2020. Citespace.5.6.R2, VOSviewer1.6.12, and Excel 2016 were used for bibliometric analysis. Results: 11,036 documents were retrieved, of which China and the United States have contributed the most coronavirus studies, Hong Kong University being the top contributor. Regarding journals, the Journal of Virology has contributed the most, while in terms of researchers, Yuen Kwok Yung has made the most contributions. The proportion of documents published by international cooperation has been rising for decades. Vaccines for SARS-CoV-2 are under development, and clinical trials of several drugs are ongoing. Conclusions: international cooperation is an important way to accelerate research progress and achieve success. Developing corresponding vaccines and drugs are the current hotspots and research directions.

Although there are many different methods of treating type 2 diabetes (T2D), it is still difficult to draw coincident conclusions concerning the efficacy and safety of different classes of new drugs, and the recommendation level of them has still kept uncertain as second anti-diabetic agents. Therefore, the aim of this study was to summarize evidence on the efficacy and safety of DPP-4is, GLP-1RAs and SGLT-2is as monotherapy or add-on to metformin (Met) for treatment of T2D. We searched PubMed, Embase, Cochrane library and ClinicalTrials.gov for relevant articles in keeping with established methods using terms associated with anti-diabetic agents up to February, 2020, with no start date restriction. Weighted mean difference and risk ratios with 95% confidence intervals were calculated within traditional and network meta-analysis. Primary outcomes were the mean change in hemoglobin A1c (HbA1c), fasting plasma glucose (FPG) change and the frequency of hypoglycemic events from baseline after 12 weeks of treatment. In total, 64 eligible studies comprising 37,780 patients and 7 treatment strategies were included. The results of primary outcomes showed that GLP-1RAs were significantly more effective than DPP-4is or SGLT-2is in reducing HbA1c when add-on to Met. For FPG, both GLP-1RAs and SGLT-2is significantly reduced FPG compared with DPP-4is whether add-on to Met or not. For hypoglycemia, monotherapy has a lower risk than combination therapy except for SGLT-2is. Ranking probability analysis indicated that GLP-1RAs and SGLT-2is, respectively, reduced HbA1c and FPG most when add-on to Met. Meanwhile, GLP-1RAs took the lowest risk to induce the hypoglycemia, whereas GLP-1RAs plus Met the highest. Both GLP-1RAs and SGLT-2is have their own advantages in efficacy and safety. Monotherapy is beneficial for reducing the risk of hypoglycemia. The recommendation should be a patient-centered approach when selecting treatment choices.

Aims To compare the efficacy and safety of dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) as monotherapy or add-on to metformin (Met) in patients with type 2 diabetes mellitus (T2DM). Materials and Methods PubMed, Embase and ClinicalTrials.gov sites were systematically searched for randomized controlled trials to assess the efficacy and safety of DPP-4is and SGLT-2is in patients with T2DM. Risk ratio (RR) and weighted mean difference (WMD) were used to evaluate outcomes. Results In the analysis of 25 randomized trials, which involved 14 619 patients, SGLT-2is were associated with a significantly stronger reduction in haemoglobin A1c (HbA1c) (WMD 0.13%, 95% credible interval [CI], 0.04%-0.22%, P = .005) and fasting plasma glucose (FPG) (WMD 0.80 mmol/L, 95% CI, 0.58-1.01 mmol/L, P

The purpose of this study was to explore the feasibility of combining fused deposition modeling (FDM) 3D printing technology with hot melt extrusion (HME) to fabricate a novel controlled-release drug delivery device. Glipizide used in the treatment of diabetes was selected as model drug, and was successfully loaded into commercial polyvinyl alcohol (PVA) filaments by HME method. The drug-loaded filaments were printed through a dual-nozzle 3D printer, and finally formed a double-chamber device composed by a tablet embedded within a larger tablet (DuoTablet), each chamber contains different contents of glipizide. The drug-loaded 3D printed device was evaluated for drug release under in vitro dissolution condition, and we found the release profile fit Korsmeyer-Peppas release kinetics. With the double-chamber design, it is feasible to design either controlled drug release or delayed drug release behavior by reasonably arranging the concentration distribution of the drug in the device. The characteristics of the external layer performed main influence on the release profile of the internal compartment such as lag-time or rate of release. The results of this study suggest the potential of 3D printing to fabricate controlled-release drug delivery system containing multiple drug concentration distributions via hot melt extrusion method and specialized design configurations.

Pseudoginsenoside-F11 (PF11), an ocotillol-type saponin, has been reported to have anti-inflammatory properties, but the effects of PF11 on acute lung inflammation were unknown. The present study aimed to investigate the protective effects and potential mechanisms of PF11 on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in male BALB/c mice. After being treated with PF11 (3, 10, and 30 mg/kg, intravenous) once a day for 3 consecutive days, the mice were challenged by intratracheal instillation of LPS, and then their lung tissues and bronchoalveolar lavage fluid (BALF) were collected for further analysis. The results showed that PF11 attenuated LPS-induced ALI, with alleviated histopathological damage, decreased lung wet/dry weight ratio, and reduced protein concentration and inflammatory cells number in BALF. Moreover, PF11 reversed the LPS-induced increases of mRNA expression and protein levels of interleukin-6, tumor necrosis factor-α, and interleukin-1β. Meanwhile, PF11 decreased LPS-induced myeloperoxidase activity and neutrophil infiltration in lung tissue by reducing the expression of macrophage inflammatory protein-2 and intercellular adhesion molecule-1, as well as enhanced neutrophil clearance by accelerating neutrophils apoptosis and their phagocytosis by alveolar macrophages. In conclusion, these results indicated that PF11 significantly attenuated LPS-induced ALI through suppressing neutrophil infiltration and accelerating neutrophil clearance, suggesting its potential in the treatment of ALI.

Valsartan, an angiotensin II receptor antagonist, is widely used to treat high blood pressure in the clinical setting. However, its poor water solubility results in the low oral bioavailability. The aim of this study was to improve dissolution rate and oral bioavailability by developing a self-nanoemulsifying drug delivery system. Saturation solubility of valsartan in various oils, surfactants, and cosurfactants was investigated, and the optimized formulation was determined by central composite design-response surface methodology. The shape of resultant VAL-SNEDDS was spherical with an average diameter of about 27 nm. And the drug loading efficiency is approximately 14 wt%. Differential scanning calorimetry and XRD studies disclosed the molecular or amorphous state of valsartan in VAL-SNEDDS. The dissolution study indicated that the self-nanoemulsifying drug delivery systems (SNEDDS) exhibited significantly enhanced dissolution compared with market capsules (Diovan®) in various media. Furthermore, the stability of formulation revealed that valsartan SNEDDS was stable under low temperature and accelerated test condition. Furthermore, the pharmacokinetics demonstrated that C max and AUC(0-∞) of SNEDDS capsules were about three- and twofold higher than Diovan® in beagle dogs, respectively. Meanwhile, the safety evaluation implied that VAL-SNEDDS was innocuous to beagle dogs during 15 days of continuous administration. Our results suggested that VAL-SNEDDS was a potential and safe delivery system with enhanced dissolution rate and oral bioavailability, as well as offered a strategy for the engineering of poorly water-soluble drugs in the clinical setting.

This paper aims to identify lung adenocarcinoma biomarkers through WGCNA and machine learning and construct a clinical diagnosis model for lung adenocarcinoma. We used the lung cancer protein expression data from the CPTAC database to conduct differentiation analysis, built a WGCNA network of lung adenocarcinoma samples and a WGCNA network of lung tumor samples and normal samples, and assessed the overlapped module of these two networks using machine learning. GO and KEGG abundance analysis was conducted to find proteins related to lung tumor, a correlation network for proteins in the overlapped module was created to mine the target protein biomarkers, and machine learning was used to create and analyze a screening model. Therewere2317 differentially expressed proteins obtained from 213 lung tumor samples from the CPTAC database; the lung tumor network and the lung tumor para-carcinoma tissue joint network had two overlapping modules; through PPI network optimization, we mined 11 protein biomarkers related to lung adenocarcinoma. Through verification based on data outside TCGA, we found that the lung adenocarcinoma diagnosis model constructed based on the 11 protein biomarkers had high accuracy and stability, showing clinical and biological significance.

The study aimed at increasing the skin retention of 3-O-ethyl-ascorbic acid (EA) and potassium 4-methoxysalicylate (4-MSK) via topical administration for effective skin-whitening. To achieve this goal, EA and 4-MSK were formulated into lamellar liquid crystalline (LLC) cream, and response surface methodology (RSM) was employed to optimize the formulation. Polarized light microscopy (PLM), differential scanning calorimetry (DSC), and rheological experiments were performed to confirm the presence of the LLC structure in the base of cream. In addition, a comparison analysis of the skin retention of the two drugs between the LLC cream and the common o/w (COW) cream was made through in vitro permeation and in vivo drug distribution experiments. As a result, the optimal formulation was defined as 1.2% of EA, 1.48% of 4-MSK, 14.05% of Schercemol™ DISM Ester (DISM) as the oil, 4.0% of Emulium® Delta as the emulsifier, and 3.0% of stearyl alcohol as the co-emulsifier. In comparison with the COW cream, the LLC cream significantly increased the skin retention of EA and 4-MSK both in vitro and in vivo. In conclusion, the LLC carrier serves as a promising choice for topical preparation by enhancing skin retention and providing desirable rheological characteristics.

To achieve the synchronous skin permeation of indapamide (IND) and bisoprolol (BSP) in their compound patch, the techniques of ion-pair complexation and chemical enhancers were combined to dual-directionally regulate drug permeating amounts. Ion-pair complexes of BSP and various organic acids were formed by the technique of ion-pair complexation. Among the complexes formed, bisoprolol tartrate (BSP.T) down-regulated the permeating amount of BSP to the same extent as that of IND. Then, to simultaneously up-regulate the amounts of the two drugs, an enhancer combination of 15.8% Span80 (SP), 6.0% Azone (AZ) and 2.2% N-methyl pyrrolidone (NMP) was obtained by central composite design and exhibited an outstanding and simultaneous enhancement on IND and BSP with enhancing ratio (ER) of 4.52 and 3.49, respectively. The effect of the dual-directional regulation was evaluated by in vitro permeation experiments and in vivo pharmacokinetic studies. For IND and BSP, their observed permeation profiles were comparable and their MAT (mean absorption time) showed no significant difference, which both demonstrated these two drugs achieved the synchronous skin permeation in their compound patch by the dual-directional regulation strategy of combining the technique of ion-pair complexation with chemical enhancers.

Uridine, a potential endogenous neuromodulator, has been demonstrated to interact with the dopaminergic system and to regulate dopamine-related behaviors. The present study investigated the effects of uridine on morphine-induced hyperactivity and behavioral sensitization and on modulating dopaminergic neurotransmission in mice, which may help to understand how uridine and its metabolites act as modulators of the GABAA receptors. The results showed that either systemic (30 or 100mg/kg) or central (30, 100 or 300nM) uridine administration significantly attenuated the hyperactivity induced by acute morphine treatment in mice. Intracerebroventricular administration of uracil and β-alanine also inhibited morphine-induced hyperactivity. Uridine, a known modulator of the GABA receptors, increased the extracellular levels of GABA in the brain. In addition, the GABAA receptors antagonist bicuculline significantly attenuated the effects of uridine on morphine-induced hyperactivity, suggesting that the GABAA receptors potentially mediate the effects of uridine and its metabolites on morphine-related activity. It was also observed that morphine-induced locomotor sensitization was abolished after chronic uridine treatment. In vivo microdialysis demonstrated that uridine reversed morphine-induced dopamine release in the dorsal striatum of morphine-sensitized mice. In conclusion, these data suggest that the therapeutic effects of uridine and its metabolites on morphine-induced hyperactivity and established behavioral sensitization may be mediated in part by interfering with the dopaminergic system possibly via agonistic effects at GABAA receptors.

Ethnopharmacological relevance Niuhuang Jiedu Tablet (NJT), composed of Realgar (As 2 S 2 ), Bovis Calculus Artificialis , Borneolum Synthcticum , Gypsum Fibrosum , Rhei Radix et Rhizoma ( RR ), Scutellariae Radix ( SR ), Platycodonis Radix ( PR ) and Glycyrrhizae Radix et Rhizoma ( GR ), is an effective formula of traditional Chinese medicine (TCM) used in treating acute tonsillitis, pharyngitis, periodontitis and mouth ulcer. In the formula, significant level of realgar (As 2 S 2 ) as a potentially toxic element is contained. In our pervious experiments, NJT was significantly less toxic than realgar (As 2 S 2 ), and the material bases of toxicity alleviation effect to realgar (As 2 S 2 ) were RR , SR , PR and GR . However, the toxicity alleviation effect of each above mentioned four herbs to realgar (As 2 S 2 ) and their synergistic detoxification effects to realgar (As 2 S 2 ) were still obscure. Materials and methods Male Wistar rats were divided into 11 groups: control, group R (treated with Realgar ), group RRSPG (treated with Realgar , RR , SR , PR and GR ), group RRSP (treated with Realgar , RR , SR and PR ), group RRSG (treated with Realgar , RR , SR and GR ), group RRPG (treated with Realgar , RR , PR and GR ), group RSPG (treated with Realgar , SR , PR and GR ), group RR (treated with Realgar and RR ), group RS (treated with Realgar and SR ), group RP (treated with Realgar and PR ) and group RG (treated with Realgar and GR ). Based on 1 H NMR spectra of urine and serum from rats, PCA and PLS-DA were performed to identify different metabolic profiles. Liver and kidney histopathology examinations and serum clinical chemistry analysis were also performed. Results The metabolic profiles of groups RR , RS , RP and RG were similar to those of group R , while the metabolic profiles of groups RRSPG , RRSP , RRSG , RRPG and RSPG were almost in line with those of control group. Statistics results were confirmed by the histopathological examination and biochemical assay. Conclusion The present work suggested that the toxicity alleviation effects of RR , SR , PR and GR to realgar (As 2 S 2 ) were not obvious when combined with realgar (As 2 S 2 ) respectively, but they had synergistic detoxification effects on realgar (As 2 S 2 ) mutually.

Neutrophils have been traditionally considered as the major mediators of harmful inflammatory responses in ischemic stroke, whereas accumulating evidence indicates that neutrophils can be polarized into an N2 phenotype. Similar to M2 microglia, N2 neutrophils contribute to resolution of inflammation and may participate in neuroprotection. However, it remains unclear whether N2 neutrophils protect ischemic neurons and whether they are associated with long-term outcomes after transient cerebral ischemia in rats. The present study proved that N2 neutrophils protected against oxygen glucosedeprivation/re-oxygenation (OGD/R)-induced primary cortical neuron injury via brain-derived neurotrophic factor/tropomyosin-related kinase B (BDNF/TrkB) signaling. In addition, in vivo studies revealed that transient middle cerebral artery occlusion (tMCAO)-induced injury exhibited spontaneous recovery over time in rats. Moreover, neutrophils could infiltrate the ipsilateral brain parenchyma from the periphery after transient cerebral ischemia. Pearson's correlation analysis indicated that the proportion of N2 neutrophils in ipsilateral brain parenchyma was negatively correlated with the number of degenerating neurons, modified Neurological Severity Score (mNSS), brain water content and infarct volume, and positively correlated with the number of surviving neurons and grip strength. In summary, the present study shows that N2 neutrophils likely participate in spontaneous recovery after transient cerebral ischemia by inhibiting ischemic neuron damage in rats, which indicates that N2 neutrophils may represent promising therapeutic target for promoting recovery after ischemic stroke.

Human effective intestinal membrane permeability (Peff) is one of the two important indicators for drug classification according to the Biopharmaceutical Classification System (BCS), and contributes greatly to the performance of oral drug absorption. Here, a structure-based in silico predictive model of Peff was developed successfully to facilitate in silico BCS classification in the early stage of drug discovery, even before the compound was synthesized. The quantitative structure–Peff relationship for 30 drugs was constructed based on seven structural parameters. Then the model was built by the multiple linear regression method and internally validated by the residual analysis, the normal probability–probability plot and the Williams plot. For the entire data set, the R2 and adjusted R2 values were 0.782 and 0.712, respectively. The results indicated that the fitted model was robust, stable and satisfied all the prerequisites of the regression models. As for the 102 tested drugs, the predicted Peff values had a good correlation with the experimental human absorbed fraction (Fa). This model was also used to perform high/low Peff classification for 57 drugs that have been classified according to the BCS, and 72% of drugs could be classified correctly, indicating that the developed model can be used for rapid BCS classification in the early stages of drug discovery. Copyright © 2013 John Wiley & Sons, Ltd.

Ethnopharmacological relevance Niuhuang Jiedu Tablet (NJT) is an effective prescription of traditional Chinese medicine (TCM) used in treating acute tonsillitis, pharyngitis, periodontitis and mouth ulcer. NJT is prepared from Xionghuang ( Realgar , As 2 S 2 ), Rengong Niuhuang ( Bovis Calculus Artificialis ), Bingpian ( Borneolum Synthcticum ), Shigao ( Gypsum Fibrosum ), Dahuang ( Rhei Radix et Rhizoma ), Huangqin ( Scutellariae Radix ), Jiegeng ( Platycodonis Radix ) and Gancao ( Glycyrrhizae Radix et Rhizoma ). In the prescription, significant level of realgar (As 2 S 2 ) as a potentially toxic element is contained. Aim of the study In this study, 1 H NMR-based metabonomics approach has been used to investigate the toxicity of realgar (As 2 S 2 ) after being counterbalanced by other TCMs in NJT. Materials and methods Male Wistar rats were divided into five groups: control, group I (treated with Realgar ), group II (treated with Realgar , Bovis Calculus Artificialis , Borneolum Synthcticum , Gypsum Fibrosum , Rhei Radix et Rhizoma , Scutellariae Radix , Platycodonis Radix and Glycyrrhizae Radix et Rhizoma ), group III (treated with Realgar , Bovis Calculus Artificialis , Borneolum Synthcticum and Gypsum Fibrosum ) and group IV (treated with Realgar , Rhei Radix et Rhizoma , Scutellariae Radix , Platycodonis Radix and Glycyrrhizae Radix et Rhizoma ). Based on 1 H–NMR spectra of urine and serum from rats, PCA and PLS-DA were performed to identify different metabolic profiles. Liver and kidney histopathology examinations and serum clinical chemistry analysis were also performed. Results PLS-DA scores plots demonstrated that the cluster of group I was separated from that of control rats, while group II was located close to control rats, indicating that metabolic profiles of group II were restored toward those of control rats. The metabolic profiles of group III were similar to those of group I, while the metabolic profiles of group II were almost in line with those of group II. Statistics results were confirmed by the histopathological examination and biochemical assay. Conclusion Our results indicated that it was more secure and much less toxic for counterbalanced realgar (As 2 S 2 ) in NJT. The effective material bases of toxicity alleviation to realgar (As 2 S 2 ) were Dahuang ( Rhei Radix et Rhizoma ), Huangqin ( Scutellariae Radix ), Jiegeng ( Platycodonis Radix ) and Gancao ( Glycyrrhizae Radix et Rhizoma ), which regulated energy metabolism, choline metabolism, amino acid metabolism and gut flora disorder affected by realgar (As 2 S 2 ) exposure.

Hyponatremia, defined as a nonartifactual serum sodium level

Uridine, a pyrimidine nucleoside, has been proposed to be a potential signaling molecule in the central nervous system. The understanding of uridine release in the brain is therefore of fundamental importance. The present study was performed to determine the characteristics of basal and morphine-induced uridine release in the striatum of freely moving mice by using the microdialysis technique. To ascertain whether extracellular uridine was derived from neuronal release, the following criteria were applied: sensitivity to (a) K(+) depolarization, (b) Na(+) channel blockade and (c) removal of extracellular Ca(2+). Uridine levels were not greatly affected by infusion of tetrodotoxin (TTX) and were unaffected by either Ca(2+)-free medium or in the presence of EGTA (a calcium chelator), suggesting that basal extracellular uridine levels were maintained mainly by non-vesicular release mechanisms. In addition, both systemic and local application of morphine increased striatal uridine release. The morphine-induced release was reversed by naloxone pretreatment, but was unaffected by TTX or EGTA infusion. Moreover, co-administration of morphine and nitrobenzylthioinosine (NBTI, an inhibitor of nucleotide transporter) produced increases of uridine levels similar to that produced by NBTI or morphine alone, suggesting a nucleotide transporter mechanism involved. Taken together, these findings suggest that morphine produces a μ-opioid receptor-mediated uridine release via nucleoside transporters in a TTX- and calcium-independent manner.

Methamphetamine (METH) abuse is a serious social and health problem worldwide. At present, there are no effective medications to treat METH addiction1. Here, we report that aggregated single-walled carbon nanotubes (aSWNTs) significantly inhibited METH self-administration, METH-induced conditioned place preference and METH- or cue-induced relapse to drug-seeking behaviour in mice. The use of aSWNTs alone did not significantly alter the mesolimbic dopamine system, whereas pretreatment with aSWNTs attenuated METH-induced increases in extracellular dopamine in the ventral striatum. Electrochemical assays suggest that aSWNTs facilitated dopamine oxidation. In addition, aSWNTs attenuated METH-induced increases in tyrosine hydroxylase or synaptic protein expression. These findings suggest that aSWNTs may have therapeutic effects for treatment of METH addiction by oxidation of METH-enhanced extracellular dopamine in the striatum.

In order to regulate the skin permeation rate (flux) of escitalopram (ESP), ion-pair strategy was used in our work. Five organic acids with different physicochemical properties, benzoic acid (BA), ibuprofen (IB), salicylic acid (SA), benzenesulfonic acid (BSA), and p-aminobenzoic acid (PABA), were employed as counter-ions to regulate the permeation rate of ESP across the rabbit abdominal skin in vitro. The interaction between ESP and organic acids was characterized by FTIR and 13C NMR spectroscopy. Results showed that all organic acids investigated in this study performed a controlling effect on ESP flux. To further analyze the factors concerned with the permeation capability of ESP-acid complex, a multiple linear regression model was used. It is concluded that the steady-state flux (J) of ESP-acid complexes had a positive correlation with log K o/w (the n-octanol/water partition coefficient of ion-pair complex) and pK a (the acidity of organic acid counter-ion), but a negative correlation with MW (the molecular weight of ion-pair complex). The logK o/w of ion-pair complex is the primary one in all the factors that influence the skin permeation rate of ESP. The results demonstrated that organic acid with appropriate physicochemical properties can be considered as suitable candidate for the transdermal drug delivery of escitalopram.

Objective: To understand the current situation of network pharmacology, and to analyze external and internal characteristics of literature, is of great significance for the development of network pharmacology in the future and its application in the modernization of Chinese medicine. Methods: Bibliometrics were adapted to perform visual analysis on the research status of network pharmacology with Citespace and SPSS for windows 22.0 version (IBM, Armonk, New York, USA). Knowledge map was used to analyze the knowledge system in the field, to identify the research hotspots and dynamic frontiers, and to elaborate the research status and development trend of domestic network pharmacology. Results: The research on network pharmacology in China is at the stage of the formation and construction of basic theories. At present, we focuses on the solution of actual disease problems and basic theoretical research, while the application in the research field of traditional Chinese medicine is a new hot spot and trend in the future development. Conclusions: It is important to pay attention to the connection and communication among the knowledge groups, so that a systematic knowledge system can be formed in the field of network pharmacology in domestic as soon as possible.

To improve the bioavailability of orally administered drugs, we synthesized a pH-sensitive polymer (poly(ethylene glycol)-poly(2-methyl-2-carboxyl-propylene carbonate)-vitamin E, mPEG-PCC-VE) attempting to integrate the advantages of enteric coating and P-glycoprotein (P-gp) inhibition. The aliphatic polycarbonate chain was functionalized with carboxyl groups and vitamin E via postpolymerization modification. Optimized by comparison and central composite design, mPEG113-PCC32-VE4 exhibited low critical micelle concentration of 1.7 × 10(-6) mg/mL and high drug loading ability for tacrolimus (21.2% ± 2.7%, w/w). The pH-responsive profile was demonstrated by pH-dependent swelling and in vitro drug release. Less than 4.0% tacrolimus was released under simulated gastric fluid after 2.5 h, whereas an immediate release was observed under simulated intestinal fluid. The mPEG113-PCC32-VE4 micelles significantly increased the absorption of P-gp substrate tacrolimus in the whole intestine. The oral bioavailability of tacrolimus micelles was 6-fold higher than that of tacrolimus solution in rats. This enteric polymer therefore has the potential to become a useful nanoscale carrier for oral delivery of drugs.

Niuhuang Jiedu Tablet (NJT), composed of Realgar (As₂S₂), Bovis Calculus Artificialis, Borneolum Synthcticum, Gypsum Fibrosum, Rhei Radix et Rhizoma (RR), Scutellariae Radix (SR), Platycodonis Radix (PR) and Glycyrrhizae Radix et Rhizoma (GR), is an effective formula of traditional Chinese medicine (TCM) used in treating acute tonsillitis, pharyngitis, periodontitis and mouth ulcer. In the formula, significant level of realgar (As₂S₂) as a potentially toxic element is contained. In our pervious experiments, NJT was significantly less toxic than realgar (As₂S₂), and the material bases of toxicity alleviation effect to realgar (As₂S₂) were RR, SR, PR and GR. However, the toxicity alleviation effect of each above mentioned four herbs to realgar (As₂S₂) and their synergistic detoxification effects to realgar (As₂S₂) were still obscure.Male Wistar rats were divided into 11 groups: control, group R (treated with Realgar), group RRSPG (treated with Realgar, RR, SR, PR and GR), group RRSP (treated with Realgar, RR, SR and PR), group RRSG (treated with Realgar, RR, SR and GR), group RRPG (treated with Realgar, RR, PR and GR), group RSPG (treated with Realgar, SR, PR and GR), group RR (treated with Realgar and RR), group RS (treated with Realgar and SR), group RP (treated with Realgar and PR) and group RG (treated with Realgar and GR). Based on (1)H NMR spectra of urine and serum from rats, PCA and PLS-DA were performed to identify different metabolic profiles. Liver and kidney histopathology examinations and serum clinical chemistry analysis were also performed.The metabolic profiles of groups RR, RS, RP and RG were similar to those of group R, while the metabolic profiles of groups RRSPG, RRSP, RRSG, RRPG and RSPG were almost in line with those of control group. Statistics results were confirmed by the histopathological examination and biochemical assay.The present work suggested that the toxicity alleviation effects of RR, SR, PR and GR to realgar (As₂S₂) were not obvious when combined with realgar (As₂S₂) respectively, but they had synergistic detoxification effects on realgar (As₂S₂) mutually.

In order to investigate the influence of drug physicochemical properties on bioavailability of water insoluble drug nanosuspensions, five drug nanosuspensions were prepared using high pressure homogenization. These nanosuspensions were similar in particle size and same in stabilizer. Differential scanning calorimetry and powder X-ray diffraction analysis showed the crystalline state of the freeze dried nanocrystals did not change. In vitro dissolution test in fasted state simulated intestinal fluid (FaSSIF) and in vivo bioavailability study in rats demonstrated that the nanosuspensions had higher dissolution rate and higher AUC0-t and the ratios of dissolvednano/dissolvedmicro in 120 min were well correlated with the ratios of AUC0-t nano/AUC0-t micro. Correlation analysis between drug physicochemical properties and AUC0-t nano was performed and four-grid interpolation method was employed for interpolation and smooth surface fitting to give a visible trend. The results revealed that drug with smaller melting point, logP value around 5 and polar surface area value in the range of 50-60 would gain higher AUC0-t nano and accordingly better absorption of its nanosuspension. Melting point, logP and polar surface area were factors that influence the absorption of drug nanosuspensions in this study.

In this paper, we use the state-space realization of discrete-time descriptor system to solve the inner-outer and spectral factorization problems. The algorithm is based on finding two orthogonal matrices to decompose the pole separated realization of transfer function matrix, to get a stabilizing solution by sloving a algebraic Riccati equation which order usually smaller than the McMillan degree of the transfer function. We give a theorem to discuss the relation of inner-outer and spectral factorization and get the inner-outer factor of the system. Thus, the inner-outer factor is the spectral factor of the system. Finally, a simple numerical example is also illustrated.

In this paper, we use the state-space realization of discrete-time descriptor system to solve the inner-outer and spectral factorization problems. The algorithm is based on finding two orthogonal matrices to decompose the pole separated realization of transfer function matrix, to get a stabilizing solution by sloving a algebraic Riccati equation which order usually smaller than the McMillan degree of the transfer function. We give a theorem to discuss the relation of inner-outer and spectral factorization and get the inner-outer factor of the system. Thus, the inner-outer factor is the spectral factor of the system. Finally, a simple numerical example is also illustrated.

Human effective intestinal membrane permeability (Peff) is one of the two important indicators for drug classification according to the Biopharmaceutical Classification System (BCS), and contributes greatly to the performance of oral drug absorption. Here, a structure-based in silico predictive model of Peff was developed successfully to facilitate in silico BCS classification in the early stage of drug discovery, even before the compound was synthesized. The quantitative structure-Peff relationship for 30 drugs was constructed based on seven structural parameters. Then the model was built by the multiple linear regression method and internally validated by the residual analysis, the normal probability-probability plot and the Williams plot. For the entire data set, the R² and adjusted R² values were 0.782 and 0.712, respectively. The results indicated that the fitted model was robust, stable and satisfied all the prerequisites of the regression models. As for the 102 tested drugs, the predicted Peff values had a good correlation with the experimental human absorbed fraction (Fa). This model was also used to perform high/low Peff classification for 57 drugs that have been classified according to the BCS, and 72% of drugs could be classified correctly, indicating that the developed model can be used for rapid BCS classification in the early stages of drug discovery.

Ethnopharmacological relevance Zhusha Anshen Wan (ZSASW), a traditional Chinese medicine (TCM) prescription, composed of cinnabar (cinnabaris), Coptidis Rhizoma (Coptis chinensis French.), Angelicae Sinensis Radix (Angelica sinensis (oliv.) Diels), uncooked Rehmanniae Radix (Rehmannia glutinosa Libosch.), honey fried Glycyrrhizae Radix Et Rhizoma (Glycyrrhiza uralensis Fisch.), has been widely used for sedative therapy. Cinnabar, the chief component of ZSASW, has been proved to possess the toxicities. Aim of the study In this study, a metabonomics approach based on high-resolution 1H nuclear magnetic resonance spectroscopy was applied to investigate the protective effects of ZSASW on the toxic effects induced by cinnabar alone. Materials and methods Male Wistar rats were divided into three groups: control group, ZSASW group and cinnabar group. Partial least squares-discriminant analysis (PLS-DA) was performed to identify different metabolic profiles of urine and serum from rats. Liver and kidney histopathology examinations and serum clinical chemistry analysis were also performed. Results The significant difference in metabolic profiling of urine and serum of the rats was observed between cinnabar treated group, control group, and the changes of endogenous metabolites related to the toxicities were identified. The results were also certified by the liver and kidney histopathology examinations and biochemical analysis of blood. Conclusion Our results suggested that the four combined herbal medicines of ZSASW had the effects of protecting from the toxicity induced by cinnabar alone. This work showed that the NMR-based metabonomics approach might be a promising approach to study detoxification of Chinese medicines and reasonable combination of TCM prescriptions.

Patients with rheumatoid arthritis (RA) often bear joint destruction and symptomatic pain. The aim of this work is to develop a compound transdermal patch containing teriflunomide (TEF) and lornoxicam (LOX) to transport these drugs across the skin with the isochronous permeation rates for RA therapy and investigate intra-articular delivery of TEF and LOX following transdermal patches applied topically. The salts of TEF and LOX with organic amines diethylamine (DEtA), triethylamine (TEtA), diethanolamine (DEA), triethanolamine (TEA) and N-(2'-hydroxy-ethanol)-piperdine (NP) were prepared to improve the skin permeation of the parent drug. The optimized patch formulation is obtained from a 3-factor, 2-level central composite design. After topical application of the optimized compound patch to only one knee joint in rabbit, intra-articular delivery of TEF and LOX on the application site was compared with that on the non-application site. Anti-inflammatory and analgesic effects of the optimized compound patch were evaluated using the adjuvant arthritis model and the pain model induced by acetic acid, respectively. The in vitro experiment results showed that the amine salts of TEF and LOX, especially TEF-TEtA and LOX-TEtA, enhanced the skin permeation of TEF and LOX from the transdermal patch system. The optimal formulation successfully displayed isochronous permeation rates for TEF and LOX across rabbit skin, and was defined with 5% of TEF-TEtA, 10% of LOX-TEtA and 15% of azone. The in vivo study showed that TEF and LOX from transdermal patches were transferred into skin, ligament and fat pad on the application site by direct diffusion and on the non-application site by the redistribution of systemic blood supply, while local absorption of TEF and LOX in synovial fluid originated from the systemic blood supply rather than direct diffusion. In the RA rat model, the results of swelling inhibition on primary arthritis of bilateral hind paws further confirmed the above-mentioned point. The optimal formulation displayed a double response on joint inflammation and symptomatic pain. In conclusion, although transdermal administration applied topically can provide a local enhanced drug delivery for the superficial joint tissues by direct diffusion, it seemed unlikely to do that for the deeper tissue synovial fluid.

Classical genetic algorithm suffers heavy pressure of fitness evaluation for time-consuming optimization problems, e.g., aerodynamic design optimization, qualitative model learning in bioinformatics. To address this problem, we present a combination between genetic algorithms and clustering methods. Specifically, the clustering method used in this paper is affinity propagation. The numerical experiments demonstrate that the proposed method performs promisingly for well-known benchmark problems in the term of optimization accuracy.

A negative emotional state resulting from the withdrawal of drug addiction is thought to be an important factor that triggers and exacerbates relapse. Since the insular cortex is a key brain structure involved in the modulation of negative emotions, we investigated whether the integrity of the insular cortex was important for motivational aversion associated with morphine withdrawal as well as whether this kind of negative emotion induced neuroadaptation in the insular cortex. In this present study, a sensitive mouse conditioned place aversion (CPA) model measuring the motivational aversion of morphine withdrawal was first established. Our results showed that bilateral insular cortex lesions by kainic acid completely inhibited the expression of CPA. The expression of FosB/ΔFosB in the insular cortex was significantly increased 24 h after the CPA regime was performed, but the expression of c-Fos in the insular cortex did not changed. These findings indicate that the integrity of the insular cortex is essential to motivational aversion associated with morphine withdrawal, and that this kind of aversion induces neuroadaptation, observed as the increase of FosB/ΔFosB expression, in the insular cortex.