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Bacteria have distinctive properties that make them ideal for biomedical applications. They can self‐propel, sense their surroundings, and be externally detected. Using bacteria as medical therapeutic agents or delivery platforms opens new possibilities for advanced diagnosis and therapies. Nano‐drug delivery platforms have numerous advantages over traditional ones, such as high loading capacity, controlled drug release, and adaptable functionalities. Combining bacteria and nanotechnologies to create therapeutic agents or delivery platforms has gained increasing attention in recent years and shows promise for improved diagnosis and treatment of diseases. In this review, design principles of integrating nanoparticles with bacteria, bacteria‐derived nano‐sized vesicles, and their applications and future in advanced diagnosis and therapeutics are summarized. [ABSTRACT FROM AUTHOR]

Dysregulation of auto-reactive T cells and autoantibody-producing B cells and excessive inflammation are responsible for the occurrence and development of autoimmune diseases. The suppression of autoreactive T cell activation and autoantibody production, as well as inhibition of inflammatory cytokine production have been utilized to ameliorate autoimmune disease symptoms. However, the existing treatment strategies are not sufficient to cure autoimmune diseases since patients can quickly suffer a relapse following the end of treatments. Pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), Nod-like receptors (NLRs), RIG-I like receptors (RLRs), C-type lectin receptors (CLRs) and various nucleic acid sensors, are expressed in both innate and adaptive immune cells and are involved in the development of autoimmune diseases. Here, we have summarized advances of PRRs signaling pathways, association between PRRs and autoimmune diseases, application of inhibitors targeting PRRs and the corresponding signaling molecules relevant to strategies targeting autoimmune diseases. This review emphasizes the roles of different PRRs in activating both innate and adaptive immunity, which can coordinate to trigger autoimmune responses. The review may also prompt the formulation of novel ideas for developing therapeutic strategies against autoimmune diseases by targeting PRRs-related signals. [ABSTRACT FROM AUTHOR]

CONSTANS (CO)/CONSTANS-like (COL) genes that have been studied in annual model plants such as Arabidopsis thaliana and Oryza sativa play key roles in the photoperiodic flowering pathway. Moso bamboo is a perennial plant characterized by a long vegetative stage and flowers synchronously followed by widespread death. However, the characteristics of COL in moso bamboo remain unclear. In view of this, we performed a genome-wide identification and expression analysis of the COL gene family in moso bamboo. Fourteen nonredundant PheCOL genes were identified, and we analyzed gene structures, phylogeny, and subcellular location predictions. Phylogenetic analyses indicated that 14 PheCOLs could be clustered into three groups, and each clade was well supported by conserved intron/exon structures and motifs. A number of light-related and tissue-specific cis-elements were randomly distributed within the promoter sequences of the PheCOLs. The expression profiling of PheCOL genes in various tissues and developmental stages revealed that most of PheCOL genes were most highly expressed in the leaves and took part in moso bamboo flower development and rapid shoot growth. In addition, the transcription of PheCOLs exhibited a clear diurnal oscillation in both long-day and short-day conditions. Most of the PheCOL genes were inhibited under light treatment and upregulated in dark conditions. PheCOLs can interact with each other. Subcellular localization result showed that PheCOL14 encoded a cell membrane protein, and it bound to the promoter of PheCOL3. Taken together, the results of this study will be useful not only as they contribute to comprehensive information for further analyses of the molecular functions of the PheCOL gene family, but also will provide a theoretical foundation for the further construction of moso bamboo photoperiod regulation networks. [ABSTRACT FROM AUTHOR]

Personalized antiplatelet treatment in patients with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI) remains challenging in clinical practice. The present study aimed to explore the benefit of genotype-guided antiplatelet treatment with P2Y12 inhibitors in patients with ACS or undergoing PCI. A literature search was conducted (from inception to September 2018) in the PUBMED, EMBASE and Cochrane databases. Studies were included in which the genotype-guided P2Y12 inhibitor antiplatelet strategy was compared with the standard strategy in patients with ACS or undergoing PCI. The endpoints were high on-treatment platelet reactivity (HTPR), major adverse cardiovascular events including all-cause mortality, myocardial infarction (MI), stent thrombosis (ST), stroke and target-vessel revascularization (TVR), and major bleedings. A total of 3377 patients in 9 studies (5 RCTs and 4 non-RCTs) were included, in which 91% of the patients were diagnosed with ACS and 88.5% underwent PCI. A total of 1639 patients (48.5%) were assigned to the genotype-guided group, and 1738 (51.4%) assigned to the conventional or standard (STD) group, with an average follow-up time of 7.6 months. After the pooled analysis, significantly lower risks of HTPR (HR: 0.32, 95% CI: 0.18–0.55, P < 10−4), all-cause mortality (HR: 0.55, 95% CI: 0.37–0.83, p = 0.005), MI (HR: 0.43, 95% CI: 0.27–0.67, p = 0.0002) and ST (HR: 0.39, 95% CI: 0.16–0.97, p = 0.004) were observed in the genotype-guided group compared to the STD group. No significant between-group difference was found for the risk of stroke, TVR, and major bleedings after the pooled analysis. Genotype-guided antiplatelet treatment could decrease the risks of HTPR, all-cause mortality, MI and ST in patients with ACS or undergoing PCI. • Inadequate antiplatelet with P2Y12 inhibitor of clopidogrel is strongly predicted by CYP2C19 loss-of-function alleles. • There is controversy over the benefit of genotype-guided antiplatelet treatment with P2Y12 inhibitors. • Genotype-guided antiplatelet treatment could decrease the risks of HTPR and MACEs in ACS or PCI patients. [ABSTRACT FROM AUTHOR]

Background: Hilar cholangiocarcinoma (HCCA) is a rare tumor, usually associated with obstructive jaundice and unfavorable prognosis. Obstructive jaundice can affect the liver, kidney, heart, and the immune system of the patients. Currently, controversy exists in whether preoperative biliary drainage (PBD) is of any benefit to the patients, and the best way for PBD in patients with resectable HCCA of malignant biliary obstruction remains to be determined.Objectives: To compare the clinical outcomes and effectiveness of endoscopic biliary drainage (EBD) treatment with those of percutaneous transhepatic biliary drainage (PTBD) treatment in patients with malignant biliary obstruction caused by resectable HCCA.Materials and Methods: The databases including MEDLINE, EMBASE, PubMed, CBM (China Biological Medicine Database), and CNKI were employed to identify the clinic trials on EBD versus PTBD for malignant biliary obstruction associated with resectable HCCA from January 2008 to October 2017. A systematic review and meta-analysis were carried out.Results: Six trials were identified and included in this study. Overall, the differences in technical success rate, R0 resection, incidence of total complication after resection, postoperative hospitalization time, resection time, and recurrence were not statistically significant between the EBD group and PTBD group (all P > .05). However, the incidence of total complications after EBD treatment is higher than that after PTBD treatment (P < .05).Conclusion: For patients with obstructive jaundice associated with HCCA, current evidence indicate no superiority of PTBD over EBD regarding clinical feasibility and success rate, but data suggest a better clinical safety of PTBD compared with EBD in short-term postoperation. In long-term evaluation, the differences in clinical outcomes are not statistically significant between PTBD and EBD. [ABSTRACT FROM AUTHOR]

Plant derived flavonoids have been demonstrated to possess many valuable biological functions. In recent years, flavonoids have been successfully conjugated with polysaccharides through different graft copolymerization methods including chemical coupling, enzyme catalysis, free radical mediated grafting, and acid catalyzed condensation reactions. The successful grafting of flavonoids onto polysaccharides can be confirmed by several instrumental methods. The conjugation of flavonoids can significantly improve the antioxidant, antimicrobial, antitumor, hepatoprotective and enzyme inhibition properties of polysaccharides. Moreover, the applications of polysaccharides in food and pharmaceutical industries can be greatly broadened by grafting with flavonoids. Flavonoid-grafted polysaccharides can be developed as films for active packaging, hydrogels for controlled drug release, micelles for oral drug delivery, and emulsions for nutraceutical delivery. In general, the bioactivities and applications of conjugates are closely related to the type of flavonoid grafted, the grafting method used as well as the grafting efficiency. Recent advances in the synthesis, structural characterization, bioactivities and potential applications of flavonoid-grafted polysaccharides are summarized in this review. [ABSTRACT FROM AUTHOR]

Human telomeres undertake the structure of intra-molecular parallel G-quadruplex in the presence of K + in eukaryotic cell. Stabilization of the telomere G-quadruplex represents a potential strategy to prevent telomere lengthening by telomerase in cancer therapy. Current work demonstrates that the binding of central K + with the parallel G-quadruplex is a coordinated water directed step-wise process. The K + above the top G-tetrad is prone to leak into environment and the 5′-adenine quickly flips over the top G-tetrad, leading to the bottom gate of G-tetrads as the only viable pathway of K + binding. Present molecular dynamics studies on the two most potent stabilizers RHPS4 and BRACO-19 reveal that the central K + has little influence on the binding conformations of the bound stabilizers. But without the central K + , either RHPS4 or BRACO-19 cannot stabilize the structure of G-quadruplex. The binding strength of stabilizers evaluated by the MM-PBSA method follows the order of BRACO-19> RHPS4, which agrees with the experimental results. The difference in binding affinities between RHPS4 and BRACO-19 is probably related to the ability to form intramolecular hydrogen bonds and favorable van del Waals interactions with G-quadruplex. In the models that have one central K + located at the upper/lower binding site, the corresponding top/bottom stacked stabilizers show more favorable binding affinities, indicating the apparent promoting effect of central K + on the stabilizer binding. Our findings provide further insights into the regulatory effect of K + on the G-quadruplex targeted binding, which is meaningful to the development of G-quadruplex stabilizers. [ABSTRACT FROM AUTHOR]

The root of Cynanchum auriculatum Royle ex Wight is a traditional Chinese herbal medicine and healthy food. Although C. auriculatum has already been processed into starch for human consumption in China, the structural characterizations of C. auriculatum starch is still unknown. Therefore, the morphology, structural and physicochemical properties of C. auriculatum starch were investigated in this study. C. auriculatum starch exhibited both spherical and polygonal shapes with granule size ranging from 2 to 12 μm. Some void cavities and serpentine channels were observed in the inner of starch granules. X-ray powder diffraction pattern revealed that C. auriculatum starch was a C B -type with relative crystallinity of 25.19%. Small-angle X-ray scattering spectrum indicated C. auriculatum starch had a lamellar repeat distance of 9.21 nm. The proportions of single helix, double helix and amorphous components in C. auriculatum starch were 3.42%, 27.11% and 69.47%, respectively. The amylose content of C. auriculatum starch was 28.0% with the gelatinization temperature ranging from 59.3 to 70.1 °C. The maximum weight loss rate of C. auriculatum starch appeared at 309 °C. In addition, C. auriculatum starch showed higher swelling power than other starches tested. Our results suggest C. auriculatum starch will have wide applications in food industry. [ABSTRACT FROM AUTHOR]

Background: The amygdala is a key region in emotion processing, and studies have suggested that amygdala-frontal functional connectivity deficits could be modulated by antidepressants in major depressive disorder (MDD). Transcutaneous vagus nerve stimulation (tVNS), a non-invasive, peripheral neuromodulation method at the ear, has shown promising results in treating major depressive disorder (MDD) in several pilot studies. However, the neural mechanism underlying tVNS treatment of depression has not been fully investigated. In this study, we investigated how tVNS can modulate the amygdala-lateral prefrontal network resting state functional connectivity (rsFC) in mild or moderate major depressive disorder (MDD) patients.Methods: Forty-nine MDD patients were recruited and received tVNS or sham tVNS (stVNS) treatments for four weeks. Resting state fMRI scans were applied before and after treatments.Results: After 1 month of tVNS treatment, the 24-item Hamilton Depression Rating Scale (HAMD) scores were reduced significantly in the tVNS group as compared with the sham tVNS group. The rsFC in the tVNS group between the right amygdala and left dorsolateral prefrontal cortex was increased compared with sham tVNS. All the rsFC increases were also associated with HAMD reduction as well as reductions in the anxiety and retardation HAMD subscales.Conclusions: tVNS can significantly modulate the amygdala-lateral prefrontal rsFC of MDD patients; our results provide insights into the brain mechanism of tVNS treatment for MDD patients. [ABSTRACT FROM AUTHOR]

In this paper, we construct an HIV infection model which includes latent infection, logistic growth for healthy CD4 T-cells, and antiretroviral therapy. We obtain the global asymptotic stability of the uninfected equilibrium by constructing a Lyapunov function, and we give a sufficient condition for the local asymptotic stability of the infected equilibrium. We also use the latin hypercube sampling technique to identify the key parameters in determining the stability of the infected equilibrium. By numerical simulations, we observe that the model without logistic growth would underestimate the number of infectious virions, while the model without latent infection would overestimate the number of infectious virions. [ABSTRACT FROM AUTHOR]

Peptide based vaccine that incorporates one or several highly conserved CD8+ T cells epitopes to induce potent cytotoxic T lymphocyte (CTL) response is desirable for some infectious diseases, such as HIV-1 (human immunodeficiency virus-1), and cancers. However, the CD8+ T cells epitope is often weakly immunogenic, and thus requires a specific adjuvant or delivery system to enhance the efficiency. Here we investigated the use of self-assembling peptide EAK16-II based platform to achieve the co-delivery of CD8+ T cells epitope and TLR7/8 agonists (R848 or R837) for augmenting DCs maturation and HIV-1 specific CTL response. HIV-1 CTL epitope SL9 was conjugated with EAK16-II to obtain SL9-EAK16-II, which further spontaneously co-assembled with R848 or R837 in aqueous solution, forming co-assembled nanofibers. Fluorescence spectra and calorimetrical titration revealed the interaction between SL9-EAK16-II assemblies and R848 or R837 via hydrogen bonding and hydrophobic interaction, with the binding affinity (dissociation constant K d ) of 0.62 μM or 0.53 μM, respectively. Ex vivo generated DCs from HIV-1 + patients pulsed with the SL9-EAK16-II/R848 nanofibers stimulated significantly more polyfunctional SL9 specific CTLs, compared to the DCs pulsed with SL9 alone or the mixture of SL9 and TLR agonist. Furthermore, the nanofibers elicited stronger SL9 specific CTL response in vaccinated mice. Our findings suggest the self-assembling peptide EAK16-II might be used as a new delivery system for peptide based vaccines. [ABSTRACT FROM AUTHOR]

ObjectiveThough the median age at diagnosis is 64 years, few studies focus on elderly (≥65 years) patients with chronic myeloid leukemia (CML). This study examines healthcare outcomes among elderly Medicare beneficiaries with CML who started nilotinib or dasatinib after imatinib. Research design and methodsPatients were identified in the Medicare Research Identifiable Files (2006–2012) and had continuous Medicare Parts A, B, and D coverage. Main outcome measuresTreatment patterns, overall survival (OS), monthly healthcare resource utilization and medical costs were measured from the second-line tyrosine kinase inhibitor (TKI) initiation (index date) to end of Medicare coverage. ResultsDespite similar adherence, dasatinib patients (N = 379) were more likely to start on the recommended dose (74% vs. 53%;p < 0.001), and to have dose reductions (21% vs. 11%, adjusted hazard ratio [HR] = 1.94;p = 0.002) or dose increases (9% vs. 7%; adjusted HR = 1.81;p = 0.048) than nilotinib patients (N = 280). Fewer nilotinib patients discontinued (59% vs. 67%; adjusted HR = 0.80;p = 0.026) or switched to another TKI (21% vs. 29%; adjusted HR = 0.72;p = 0.044) than dasatinib patients. Nilotinib patients had longer median OS (>4.9 years vs. 4.0 years;p = 0.032) and 37% lower mortality risk than dasatinib patients (adjusted HR = 0.63;p = 0.008). Nilotinib patients had 23% fewer inpatient admissions, 30% fewer emergency room visits, 13% fewer outpatient visits (allp < 0.05), and lower monthly medical costs (by $513,p = 0.024) than dasatinib patients. LimitationsLack of clinical assessment (disease phase and response to first-line therapy) and retrospective nature of study (unobservable potential confounding factors, non-randomized treatment choice). ConclusionsIn the current study of elderly CML patients, initiation of second-line TKIs frequently occurs at doses lower than the recommended starting doses and, despite this, many patients require dose adjustments. Here, nilotinib patients required fewer dose adjustments than dasatinib patients. Further research focusing on elderly CML patients is warranted in order to help define future best clinical practices. [ABSTRACT FROM PUBLISHER]

Background: Depression presents a significant burden to both patients and society. One treatment that has emerged is vagus nerve stimulation (VNS), an FDA-approved physical treatment for depressive disorders. However, the application of this intervention has been limited by the involvement of surgery and potential side effects. The aim of this study is to explore the effectiveness of stimulating the superficial branches of the vagus nerve as a solo treatment for MDD.Methods: This is a nonrandomized, controlled study. The first cohort of patients (n=91) only received transcutaneous auricular VNS (taVNS) for 12 weeks. In the second cohort (n=69), patients first received 4 weeks of sham taVNS followed by 8 weeks of taVNS. All treatments were self-administered by the patients at home after they received training from the hospitals. The primary outcome measurement was the 24-item Hamilton Depression Rating Scale measured at weeks 0, 4, 8, and 12. Data analysis included a timelag analysis comparing (1) real and sham taVNS groups at week 4; (2) the real taVNS group at week 4 vs the sham taVNS group at week 8 (fourth week of real taVNS following 4 weeks of sham); and (3) the real taVNS group at week 8 vs the sham taVNS group at week 12 (eighth week of real taVNS following sham).Results: After four weeks of treatment, MDD patients in the taVNS group showed greater improvement than patients in the sham taVNS group as indicated by Hamilton score changes as well as response and remission rates at week four. In addition, we also found that the clinical improvements continued until week 12 during taVNS.Limitations: Patients were not randomized in this study.Conclusions: Our results suggest that taVNS is a promising, safe, and cost-effective therapeutic method for mild and moderate MDD. [ABSTRACT FROM AUTHOR]

Background: For unresectable or metastatic melanoma, first-line ipilimumab has demonstrated long-term survival benefits over a 7-year period. First-line treatment with BRAF inhibitors has demonstrated efficacy in clinical trials with up to 3 years of follow-up. The long-term comparative efficacy and costs of ipilimumab and BRAF inhibitors are unknown. Methods: Patient-level data from 12 clinical studies for ipilimumab were used. Survival data were extracted from included clinical trials for BRAF inhibitors based on a systematic literature review. Different parametric survival models, including exponential, Gompertz, log-normal, and Weibull models, were used to fit reported overall survival (OS) data and to project long-term survival for BRAF inhibitors. Survival benefits were measured in terms of total life-months gained as calculated by the area under the curve of OS Kaplan-Meier curves for the observed ipilimumab data and projected BRAF inhibitor data. Total life-months gained and cumulative costs per life-month gained were compared between ipilimumab and BRAF inhibitors. Results: The systematic literature review identified six randomized-controlled trials of BRAF inhibitors for subsequent analyses. With 7-year follow-up, ipilimumab was associated with a total of 28.5 life-months gained. Based on the Weibull model, the extrapolated total life-months gained for BRAF inhibitors were 26.5 months for dabrafenib, 21.3 months for trametinib, 14.3 months for vemurafenib, and 24.6 months for dabrafenib + trametinib. In sensitivity analyses, extrapolated total life-months gained varied across the three other models, ranging from 13.7 to 36.8 months across therapies. Cumulative costs per life-month gained with ipilimumab decreased steadily over time, while the costs remained constant for BRAF inhibitors due to continuous dosing. By year 3, cumulative costs per life-month gained were the lowest with ipilimumab; by year 7, the costs were $4281 for ipilimumab, compared with $8920 for dabrafenib, $10,211 for trametinib, $11,002 for vemurafenib, and $19,132 for the dabrafenib + trametinib combination therapy. Conclusions: Ipilimumab was associated with a better long-term cost-per-life month compared to BRAF agents. Long-term extrapolation of survival with BRAF agents was uncertain, and showed no evidence of prolonged survival compared to ipilimumab. [ABSTRACT FROM AUTHOR]

Licochalcone A (Lico A), a flavonoid found in licorice root ( Glycyrrhiza glabra), has been reported to have anti-inflammatory activity. However, the protective effects of Lico A on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) remains unclear. In this study, using a mouse model of LPS-induced AKI, we investigated the protective effects and mechanism of Lico A on LPS-induced AKI in mice. LPS-induced kidney injury was assessed by detecting kidney histological study, blood urea nitrogen (BUN), and creatinine levels. The production of inflammatory cytokines TNF-α, IL-6, and IL-1β in serum and kidney tissues was detected by ELISA. The activation of NF-κB was measured by western blot analysis. Our results showed that Lico A dose-dependently attenuated LPS-induced kidney histopathologic changes, serum BUN, and creatinine levels. Lico A also suppressed LPS-induced TNF-α, IL-6, and IL-1β production both in serum and kidney tissues. Furthermore, our results showed that Lico A significantly inhibited LPS-induced NF-κB activation. In conclusion, our results suggest that Lico A has protective effects against LPS-induced AKI and Lico A exhibits its anti-inflammatory effects through inhibiting LPS-induced NF-κB activation. [ABSTRACT FROM AUTHOR]

Pterostilbene (PT), an analog of resveratrol, exerts a potent anti-inflammatory effect. However, the protective effects of PT against inflammation in endothelial cells have not been elucidated. Previous studies have confirmed that endoplasmic reticulum stress (ERS) plays an important role in regulating the pathological process of endothelial cell inflammation. In this study, we explored the effect of PT on the tumor necrosis factor-α (TNF-α)-induced inflammatory response in human umbilical vein endothelial cells (HUVECs) and elaborated the role of ERS in this process. TNF-α treatment significantly upregulated the levels of inflammation-related molecules in cell culture media, increased the adhesion of monocytes to HUVECs, and enhanced the expression of the MMP9 and ICAM proteins in HUVECs. Additionally, TNF-α potently increased ERS-related protein levels, such as GRP78 and p-eIF2α. However, PT treatment reversed the increased production of inflammatory cytokines and the adhesion of monocytes to HUVECs, as well as reduced the TNF-α-induced effects exerted by ERS-related molecules. Furthermore, thapsigargin (THA), an ERS inducer, attenuated the protective effect of PT against TNF-α-induced inflammation and ERS in HUVECs. Additionally, the downregulation of ERS signaling using siRNA targeting eIF2α and IRE1 not only inhibited ERS-related molecules but also simulated the therapeutic effects of PT on TNF-α-induced inflammation. In summary, PT treatment potently attenuates inflammation in vascular endothelial cells, which at least partly depends on the reduction of ERS. [ABSTRACT FROM AUTHOR]

N,N ′-disubstituted urea-based soluble epoxide hydrolase (sEH) inhibitors are promising therapeutics for hypertension, inflammation, and pain in multiple animal models. The drug absorption and pharmacological efficacy of these inhibitors have been reported extensively. However, the drug metabolism of these inhibitors is not well described. Here we reported the metabolic profile and associated biochemical studies of an N -adamantyl urea-based sEH inhibitor 1-adamantan-1-yl-3-(5-(2-(2-ethoxyethoxy)ethoxy)pentyl)urea (AEPU) in vitro and in vivo . The metabolites of AEPU were identified by interpretation of liquid chromatography–mass spectrometry (LC–MS), liquid chromatography–tandem mass spectrometry (LC–MS/MS) and/or NMR. In vitro , AEPU had three major positions for phase I metabolism including oxidations on the adamantyl moiety, urea nitrogen atoms, and cleavage of the polyethylene glycol chain. In a rodent model, the metabolites from the hydroxylation on the adamantyl group and nitrogen atom were existed in blood while the metabolites from cleavage of polyethylene glycol chain were not found in urine. The major metabolite found in rodent urine was 3-(3-adamantyl-ureido)-propanoic acid, a presumably from cleavage and oxidation of the polyethylene glycol moiety. All the metabolites found were active but less potent than AEPU at inhibiting human sEH. Furthermore, cytochrome P450 (CYP) 3A4 was found to be a major enzyme mediating AEPU metabolism. In conclusion, the metabolism of AEPU resulted from oxidation by CYP could be shared with other N -adamantyl-urea-based compounds. These findings suggest possible therapeutic roles for AEPU and new strategies for drug design in this series of possible drugs. [ABSTRACT FROM AUTHOR]

Although selective COX-2 inhibitors have cancer-preventive effects and induce apoptosis, the mechanisms underlying these effects are not fully understood. This study investigated the effects of nimesulide, a selective COX-2 inhibitor, on apoptosis and on the JAK/STAT signaling pathway in Eca-109 human esophageal squamous carcinoma cells. The effects and mechanisms of nimesulide on Eca-109 cell growth were studied in culture and in nude mice with Eca-109 xenografts. Cells were cultured with or without nimesulide and/or the JAK2 inhibitor AG490. Cell proliferation was evaluated using the MTT assay, and apoptosis was investigated. COX-2 mRNA expression was measured using reverse transcription polymerase chain reaction, and protein expression was detected by Western blot analysis, immunohistochemistry, and flow cytometry. Nimesulide significantly inhibited Eca-109 cell viability in vitro in a dose- and time-dependent manner ( P < 0.05). Nimesulide also induced apoptosis, which was accompanied by a significant decrease in the expression of COX-2 and survivin and an increase in caspase-3 expression. Nimesulide downregulated the phosphorylation levels of JAK2 and STAT3, and JAK2 inhibition by AG490 significantly augmented both nimesulide-induced apoptosis and the downregulation of COX-2 and survivin ( P < 0.05). In vivo , nimesulide inhibited the growth of Eca-109 tumors and the expression of p-JAK2 and p-STAT3. Thus, nimesulide downregulates COX-2 and survivin expression and upregulates caspase-3 expression in Eca-109 cells, by inactivating the JAK2/STAT3 pathway. These effects may mediate nimesulide-induced apoptosis and growth inhibition in Eca-109 cells in vitro and in vivo . [ABSTRACT FROM AUTHOR]

In this study, the antioxidant activity and hepatoprotective effect of inulin and catechin grafted inulin (catechin-g-inulin) against carbon tetrachloride (CCl 4 )-induced acute liver injury were investigated. Results showed that both inulin and catechin-g-inulin had moderate scavenging activity on superoxide radical, hydroxyl radical and H 2 O 2 , as well as lipid peroxidation inhibition effect. The antioxidant activity decreased in the order of Vc > catechin > catechin-g-inulin > inulin. Administration of inulin and catechin-g-inulin could significantly reduce the elevated levels of serum aspartate transaminase, alanine transaminase and alkaline phosphatase as compared to CCl 4 treatment group. Moreover, inulin and catechin-g-inulin significantly increased the levels of hepatic superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione and total antioxidant capacity, whereas markedly decreased the malondialdehyde level when compared with CCl 4 treatment group. Notably, catechin-g-inulin showed higher hepatoprotective effect than inulin. In addition, the hepatoprotective effect of catechin-g-inulin was comparable to positive standard of silymarin. Our results suggested that catechin-g-inulin had potent antioxidant activity and potential protective effect against CCl 4 -induced acute liver injury. [ABSTRACT FROM AUTHOR]

Background: Graves' ophthalmopathy (GO) is thought to be an inflammatory disorder of autoimmune background. The aim of this study is to investigate the involvement of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF) in patients with Graves' ophthalmopathy (GO). Methods: Serum concentrations of VEGF and b-FGF of 48 GO patients, 30 Graves' hyperthyroid disease (GD) patients without ophthalmopathy, and 30 healthy controls were measured by Enzyme-Linked Immunosorbent Assay (ELISA). Patients with GO were subdivided into two groups according to clinical activity scores (CAS): a score of 3 or less is considered as inactive (CAS ≤ 3, inactive GO, n = 14), and 4 or more is considered active eye disease (CAS ≥ 4, active GO; n = 34). All of the patients with active GO underwent corticosteroid therapy. Results: The concentrations of serum VEGF and b-FGF were significantly higher in patients with GO and in those with GD than in controls. The serum levels of VEGF and b-FGF in patients with active GO were higher than those in patients with inactive GO and those in GD patients ( P < 0.05). Moreover, serum VEGF and b-FGF concentratison were significantly correlated with CAS in GO patients ( p < 0.01). Mean VEGF and b-FGF levels in corticosteroid-responsive patients (CAS decreases ≥3 after treatment) decreased significantly after corticosteroid treatment ( P < 0.05), and these changes were accompanied by a decrease of CAS ( P < 0.05). Conclusion: The results suggest that serum VEGF and b-FGF levels were increased in patients with active GO and could reflect the degree of ocular inflammatory activity. [ABSTRACT FROM AUTHOR]

Background: No specific antiviral agent against hand foot and mouth disease (HFMD) is available for clinical practice today. Objective: To evaluate the efficacy and safety of Jinzhen oral solution in treating uncomplicated HFMD. Methods: In this randomized, double-blind, placebo-controlled trial, 399 children aged 1 to 7 years with laboratory confirmed HFMD were randomized to receive Jinzhen oral liquid or placebo 3 times daily for 7 days with a 3-day follow-up. The primary outcomes were time to the first disappearance of oral ulcers and vesicles on hand or foot and time to the first normalization of temperature (fever clearance). Results: There were 199 children enrolling into the Jinzhen group including 79 with fever and 200 into the placebo group including 93 with fever. Jinzhen reduced the time to the first disappearance of oral ulcers and vesicles on hand or foot to 4.9 days (95% CI, 4.6 to 5.2 days), compared with 5.7 days (95% CI, 5.4 to 6.0 days) in the placebo group (P = 0.0036). The median time of fever clearance was shorter in the 79 children who received Jinzhen (43.41 hrs, 95% CI, 37.05 to 49.76) than that in the 93 children who received placebo (54.92 hrs, 95% CI, 48.16 to 61.68) (P = 0.0161). Moreover, Jinzhen reduced the risk of symptoms by 28.5% compared with placebo (HR, 0.7150, 95% CI, 0.5719 to 0.8940, P = 0.0032). More importantly, treatment failure rate was significantly lower in the Jinzhen group (8.04%) compared with that in the placebo group (15.00%) (P = 0.0434). The incidence of serious adverse events did not differ significantly between the two groups (9 in Jinzhen group vs. 18 in placebo, P = 0.075). Conclusions: Children with HFMD may benefit from Jinzhen oral liquid treatment as compared with placebo. Trial Registration: Chinese Clinical Trial Registry (http://www.chictr.org/en/) ChiCTR-TRC-10000937 [ABSTRACT FROM AUTHOR]

Introduction: The treatment of terrible triad injury with a poor outcome after intervention has not been successful thus far. The purpose of this study was to evaluate the efficacy of arthrolysis and reconstruction in the treatment of terrible triad injury with a poor outcome after surgical as well as conservative intervention. Materials and methods: Twelve patients (12 elbows) with the diagnosis of terrible triad injury were respectively reviewed. All the 12 patients had elbow dysfunction after conservative and surgical treatment of the terrible triad injury. Preoperatively, the flexion arc and forearm rotation were 36.7° ± 28.5° and 51.3° ± 43.4°, respectively, and the Mayo Elbow Performance Score was 56.3 points. The mean interval between the primary injury and our surgical treatment was 6.6 months. Our surgical intervention included elbow arthrolysis, ulnar nerve transposition, radial head replacement, coronoid process and ligament repair, and hinged external fixation. Patients were encouraged to participate in rehabilitation training 24 h after surgery. Results: The mean follow-up duration was 20.1 months; the flexion arc and forearm rotation were 122° ± 18° and 140° ± 20°, respectively, and the mean Mayo Elbow Performance Score was 94.6 points (9 excellent, 3 good). Concentric stability was restored in all elbows. Complications included superficial pin tract infection (1), heterotopic ossification (3), and ulnar nerve palsy (1); the ulnar nerve symptoms had improved at the last follow-up. Conclusions: The combination of open arthrolysis and reconstruction performed at a mean interval of 6-month posttrauma can restore functional mobility in cases of terrible triad injury with a poor outcome after surgical as well as conservative intervention. Thus, it may be an effective alternative for the treatment of the poor outcome terrible triad injury. We recommend early functional rehabilitation with adherence to the guidelines for hinged external fixation. [ABSTRACT FROM AUTHOR]

Study design: This study is randomized controlled trial. Purpose: To evaluate the effect of tranexamic acid (TXA) on reducing postoperative blood loss in posterior approach lumbar surgery for degenerative lumbar instability with stenosis. Methods: Sixty patients with degenerative lumbar instability with stenosis were randomized into TXA and control groups, receiving 15 mg/kg body weight of TXA or placebo (0.9 % Sodium chloride solution) intravenously, respectively, before the skin incision was made. The operation of pedicle screw system fixation was performed for all patients, and then selective laminectomy and posterior lumbar interbody fusion (PLIF) were carried out. Intraoperative and postoperative blood loss were compared between the two groups. And the complication of TXA was also investigated. Results: There were no statistically significant differences between the TXA and control groups in terms of age, sex, body mass index, and operation time. There was no significantly difference in intraoperative blood loss between the two groups. However, in the TXA group, postoperative blood loss was significantly lower than that in the control group (13.0 %). Especially, postoperative blood loss during the first 12 h was reduced by 29.9 % as compared to the control group. There were no thromboembolic events or other complications occurred in either group. Conclusions: Preoperative single-dose TXA can significantly reduce postoperative blood loss in posterior approach lumbar surgery, and there were no significant side effects. [ABSTRACT FROM AUTHOR]

The author reflects on translational medical research. He discusses the role of "Clinical & Experimental Pharmacology & Physiology (CEPP)" in serving translational medicine through publishing research, examples of previous articles on translational medicine research appearing in "CEPP," such as one by and Lv et al. on the use of the plant compound 2,3,5,6-tetramethylpyrazine (TMP) to treat myocardial ischaemia reperfusion (IR), and a chart of translational medical research centers in China.

Abstract: Ethnopharmacological relevance: Chronic gastritis is a very common disease of the digestive tract. Although herbal preparation Chaihu-Shugan-San (CSS) has been widely used as an alternative treatment for chronic gastritis in East Asia, its effectiveness is not verified. The purpose of this meta-analysis is to evaluate the effectiveness of CSS in treating various types of chronic gastritis. Materials and methods: Retrospective review of pertinent literature via Embase, China National Knowledge Infrastructure database, Wanfang Data, Vip Information and the Cochrane Library search using the keywords “Chaihushugan” or “Chaihu Shugan” or “Chai Hu Shu Gan” or “Chaihu Shu Gan”. Twenty-one trials were identified including 2572 patients (1384 in CSS group and 1188 in chemotherapy group). Each trial was independently reviewed by two assessors. Results: The risk ratios of bile reflux gastritis, chronic superficial gastritis, chronic atrophic gastritis, and chronic erosive gastritis in the CSS-treated and chemotherapy groups were 1.30, 1.20, 1.24, and 1.48, respectively. CSS had more therapeutic effect in various types of chronic gastritis patients for improving clinical response compared with the chemotherapy group. Of the 21 trials administrating CSS to patients, no adverse event was reported. Conclusions: CSS was more effective compared to chemotherapy in the treatment of chronic gastritis and no serious side-effects were identified. However, the evidence is insufficient because of the low methodological quality of the included trials. More full-scale, randomized, double-blind, placebo-controlled clinical trials are recommended to further evaluate the therapeutic benefit of CSS. [Copyright &y& Elsevier]

China–Myanmar border plays a crucial role in HIV-1 transmission in Asia. Here, we performed Bayesian phylodynamics analyses on p17 gene using BEAST to investigate HIV-1 transmission in this region. Maximum clade credibility trees of subtype C and CRF01_AE show that majority of unique recombinant forms (URFs) and pure subtype strains from Dehong and Myanmar cluster together, forming large clades with ancestral geographical states of Dehong. Bayes factor tests support the statistically significant geographic diffusion link between Dehong and Myanmar. The estimated time to the most recent common ancestor of Myanmar URFs_BC (1999.2) was later than that of Dehong URFs_BC (1998.0), but earlier than that of Myanmar URFs_01BC (2004.3). Since 1998, HIV-1 recombination between subtypes B, C and CRF01_AE has been continuously occurring in China–Myanmar border region. These results suggest that HIV-1 subtypes B, C and CRF01_AE were most likely transmitted from Dehong to Myanmar, and predict that URFs_01BC should be also prevalent in Dehong, Yunnan. [ABSTRACT FROM AUTHOR]

Abstract: Inflammation is a multi-staged process whose expansive phase is thought to be driven by acutely released arachidonic acid (AA) and its metabolites. Inhibition of cyclooxygenase (COX), lipoxygenase (LOX), or soluble epoxide hydrolase (sEH) is known to be anti-inflammatory. Inhibition of sEH stabilizes the cytochrome P450 (CYP450) products epoxyeicosatrienoic acids (EETs). Here we used a non-selective COX inhibitor aspirin, a 5-lipoxygenase activation protein (FLAP) inhibitor MK886, and a sEH inhibitor t-AUCB to selectively modulate the branches of AA metabolism in a lipopolysaccharide (LPS)-challenged murine model. We used metabolomic profiling to simultaneously monitor representative AA metabolites of each branch. In addition to the significant crosstalk among branches of the AA cascade during selective modulation of COX, LOX, or sEH, we demonstrated that co-administration of t-AUCB enhanced the anti-inflammatory effects of aspirin or MK886, which was evidenced by the observations that co-administration resulted in favorable eicosanoid profiles and better control of LPS-mediated hypotension as well as hepatic protein expression of COX-2 and 5-LOX. Targeted disruption of the sEH gene displayed a parallel profile to that produced by t-AUCB. These observations demonstrate a significant level of crosstalk among the three major branches of the AA cascade and that they are not simply parallel pathways. These data illustrate that inhibition of sEH by both pharmacological intervention and gene knockout enhances the anti-inflammatory effects of aspirin and MK886, suggesting the possibility of modulating multiple branches to achieve better therapeutic effects. [Copyright &y& Elsevier]

1. Telomeres (ends of chromosomes) undergo constant remodelling during cell development, proliferation and differentiation, as well as in neoplastic cell immortalization and transformation. How the cellular microenvironment influences telomere remodelling (lengthening or shortening) remains largely unknown. 2. Recently, studies from our laboratories and others have indicated that growth factors and cytokines have significant roles in regulating telomere remodelling and thus influence cell functions and properties. Cancer cells must maintain their already short telomeres either by the enzyme telomerase or, more rarely, through alternative lengthening of telomeres, which functions independently of cellular regulation. 3. However, application of transforming growth factor-β family cytokines induces transcriptional inhibition of telomerase in cancer cells, leading to telomere shortening, cell senescence (ageing) and apoptosis (death) by mechanisms dependent on telomerase inhibition. Furthermore, selective gene silencing of vascular endothelial growth factor and/or the telomerase catalytic subunit (i.e. telomerase reverse transcriptase) potently inhibits the growth of cervical cancer and laryngeal squamous cancer in mice. 4. The present paper summarizes our current understanding of the negative regulation by cytokines of telomere maintenance and thus cancer cell proliferation in cultured cells and mouse models. [ABSTRACT FROM AUTHOR]

Abstract: Background: Iron deficiency anemia (IDA) is a common nutritional disease worldwide. Iron supplementation is an efficient method for treating patients with IDA. Polysaccharide iron complex is an oral iron supplement that is associated with generally good tolerability and good bioavailability. Objective: The aim of this study was to evaluate the bioequivalence of 2 branded formulations of polysaccharide iron complex in healthy adult male Chinese volunteers by determining the pharmacokinetic parameters after single-dose oral admi ni strati on. Methods:This sequence-randomized, double-blind, 2-way crossover study was carried out in the Affiliated Hospital, Institute of Medical Sciences of Qingdao University, Qingdao, China. Healthy adult male Chinese volunteers were enrolled and evenly randomized to receive 1 of 2 formulations on day 1. Subjects received an oral dose of 150 mg (1 capsule) of polysaccharide iron complex with 150 mL of warm water in the morning. Capsules were of similar size, shape, and color to ensure blinding. Four hours after administration, the subjects were given standardized meals. After a 1-week washout period, the subjects were crossed over to receive the other formulation in a similar manner. The serum iron concentration 12 hours after study drug administration was determined using atomic-absorption spectrometry. The pharmacokinetic parameters Cmax, Tmax, AUC0−t, and AUC0−∞ were obtained and analyzed using the Schuir mann 2 one-sided t test. The 2 formulations were considered bioequi valent if the test/reference ratios of Cmax, AUC0−t, and their 90% CIs were within the range of 70% to 143% for Cmax and within 80% to 125% for AUC0−t. Tolerability was monitored by inquiring whether the subjects had experienced adverse events (AEs), with a focus on gastrointestinal AEs, during the clinic visits during the 24-hour period after drag administration and subsequently via telephone throughout the study. Results: Thirty adult male Chinese volunteers were assessed for inclusion. Twenty healthy male volunteers (10 in each group) (mean [SD] age, 21.5 [2.9] years [range, 19–23 years]; weight, 66.2 [5–8] kg [range, 56–80 kg]; height, 172.5 [5.1] cm [range, 162–180 cm]) were enrolled and completed the study. The pharmacokinetic parameters of the test and reference formulations were as follows: AUCO−t, 6.58 (2.09) and 6.58 (1.91) μg/mL · h−1; Cmax, 1.10 (0.28) and 1.07 (0.25) μg/mL; Tmax, 3.93 (0.37) and 3–93 (0.37) hours; t½, 8.33 (0.36) and 8.38 (0.41) hours; and AUC0−∞, 6.93 (2.23) and 6.95 (2.13) μg/mL · h−1, respectively. There were no statistically significant differences in AUC0−∞ or Tmax by formulation, period, or subject between the test and reference formulations. Similarly, there were no statistically significant differences in Cmax by period; however, a significant difference was found in Cmax by formulation (P = 0.012). No clinically significant AEs were reported with either formulation. Conclusions: In these healthy adult male Chinese volunteers, the test formulation of polysaccharide iron complex was found to be bioequivalent to the reference formulation according to the Chinese regulatory definition. A significant difference by formulation was found in Cmax. The sample size was smaller than that recommended by the US Food and Drug Administration for a bioequivalence study, and additional studies with larger sample sizes are needed. [Copyright &y& Elsevier]

Most cancer therapeutics fails to eradicate cancer because cancer cells rapidly develop resistance to its proapoptotic effects. The underlying mechanisms remain incompletely understood. Here we show that three representative apoptotic stimuli, that is, serum starvation, a mitochondrial toxin, and a DNA-damaging agent (etoposide), rapidly induce several distinct classes of prosurvival molecules, in particular, Bcl-2/Bcl-XL and superoxide dismutase (SOD; including both MnSOD and Cu/ZnSOD). At the population level, the induction of these prosurvival molecules occurs prior to or concomitant with the induction of proapoptotic molecules such as Bim and Bak. Blocking the induction using siRNAs of the prosurvival or proapoptotic molecules facilitates or inhibits apoptosis, respectively. One master transcription factor, FOXO3a, is involved in the transcriptional activation of some of these prosurvival (e.g., MnSOD) and proapoptotic (e.g., Bim) molecules. Interestingly, in all three apoptotic systems, FOXO3a itself is also upregulated at the transcriptional level. Mechanistic studies indicate that reactive oxygen species (ROS) are rapidly induced upon apoptotic stimulation and that ROS inhibitors/scavengers block the induction of FOXO3a, MnSOD, and Bim. Finally, we show that apoptotic stimuli also upregulate prosurvival molecules in normal diploid human fibroblasts and at subapoptotic concentrations. Taken together, these results suggest that various apoptotic inducers may rapidly mobilize prosurvival mechanisms through ROS-activated master transcription factors such as FOXO3a. The results imply that effective anticancer therapeutics may need to combine both apoptosis-inducing and survival-suppressing strategies.Oncogene (2005) 24, 2020-2031. doi:10.1038/sj.onc.1208385 Published online 24 January 2005 [ABSTRACT FROM AUTHOR]

Neuropathic pain after spinal cord injury (SCI) represents a difficult problem that is commonly refractory to conventional medical management. To determine if spinal release of γ-amino butyric acid (GABA) could reduce below-level central neuropathic pain after SCI, we constructed a replication-incompetent herpes simplex virus (HSV)-based vector encoding one isoform of human glutamic acid decarboxylase (GAD67). Dorsal root ganglion (DRG) neurons transduced in vitro or in vivo by subcutaneous inoculation produced GAD and released GABA constitutively. T13 spinal cord hemisection resulted in central neuropathic pain manifested by mechanical allodynia and thermal hyperalgesia. Subcutaneous inoculation of the vector into both feet reduced both manifestations of below-level SCI pain; the vector-mediated effect was partially reversed by intrathecal bicuculline or phaclofen at doses that did not affect thresholds in normal or injured uninoculated animals. Vector-mediated GABA release attenuated the increase in spinal calcitonin gene-related peptide immunoreactivity caused by cord hemisection. These results suggest that HSV-mediated gene transfer to DRG could be used to treat below-level central neuropathic pain after incomplete SCI. [Copyright &y& Elsevier]

Background: Although fisetin may exist widely in many natural herbs, its anti-OP mechanism is still unclear. The aim of this study is to explore the molecular anti-osteoporosis (OP) mechanism of fisetin based on network pharmacology and cell experiments. Methods: The target of fisetin was extracted by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The targets of OP were obtained by DisGeNET, GeneCards and the Comparative Toxicogenomics Database, and the targets of fisetin in OP were screened by cross-analysis. The protein–protein interaction (PPI) network was constructed by STRING, and the core targets were obtained. We performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses on common targets via the Database for Annotation, Visualization and Integrated Discovery. Finally, an in vitro cell experiment was used to verify the anti-OP effect and mechanism of fisetin. Results: There are 44 targets of fisetin related to the treatment of OP. The PPI results suggest that CTNNB1, CCND1, TP53, JUN, and AKT1 are the core targets. A total of 259 biological process, 57 molecular function and 26 cell component terms were obtained from GO enrichment analysis. The results of KEGG pathway enrichment analysis suggested that fisetin treatment of OP may be related to the Wnt signaling pathway, estrogen signaling pathway, PI3K-Akt signaling pathway and other signaling pathways. In vitro cell experiments showed that fisetin significantly increased the expression levels of ALP, collagen I, osteopontin and RUNX2 in bone marrow mesenchymal stem cells (BMSCs) (p < 0.05). Fisetin also increased the gene expression levels of Wnt3 and β-catenin (CTNNB1) in BMSCs, which indicates that fisetin can regulate the Wnt/β-catenin signaling pathway and promote the osteogenic differentiation of BMSCs. Conclusions: Fisetin acts on multiple targets and pathways in the treatment of OP; mechanistically, it regulates the Wnt/β-catenin signaling pathway, which promotes the osteogenic differentiation of BMSCs and maintains bone homeostasis. The results of this study provide a theoretical basis for further study on the complex anti-OP mechanism of fisetin. [ABSTRACT FROM AUTHOR]

Long‑term sorafenib treatment triggers resistance to chemotherapy in patients with hepatocellular carcinoma (HCC). In order to investigate the mechanisms of sorafenib resistance in HCC, the aim of the present study was to develop a resistant human liver cell line via long‑term exposure to sorafenib. The cytotoxicity cell counting kit‑8 assay was used to evaluate drug sensitivity. Reverse transcription‑quantitative polymerase chain reaction and western blotting were used to examine the molecular mechanisms underpinning sorafenib resistance. Migratory and invasive properties in resistant cells were assessed using Transwell assays. The results from the present study revealed that resistant cells became insensitive to sorafenib treatment and exhibited increased migratory and invasive capacities. Activation of the phosphatidylinositol‑3‑kinase (PI3K)/Akt signaling pathway and epithelial‑mesenchymal transition was characteristic of resistant cells. The use of LY294002, a PI3K inhibitor, was able to suppress the activation of Akt and extracellular signal‑regulated kinase 1/2, attenuated the migratory and invasive capacities of resistant cells. Data from the present study indicates that inhibition of the PI3K signaling pathway with LY294002 exerts suppressive effects on sorafenib resistance and provides an attractive novel therapeutic regime in patients with advanced HCC. [ABSTRACT FROM AUTHOR]

Objective: To investigate the epidemiological features of child and adolescent (≤18 years old) patients managed for traumatic skull fractures (TSKFs) and associated traumatic brain injury (TBI).Design: 393 Patients who were children and adolescent who had TSKFs admitted to our university affiliated hospitals between January 2003 and December 2010. The incidence and patterns were summarized with respect to different age group, admission time and etiology.Setting: Two university-affiliated hospitals from January 2003 to May 2010.Results: The most common etiologies were motor vehicle collisions (MVCs) (166, 42.2%) and high fall (101, 25.7%). The most common skull fracture sites were parietal fractures (n=111, 28.2%) and basilar skull fracture (n=111, 28.2%). A total of 300 (76.3%) patients suffered TBI and 23 (5.9%) patients suffered OCI. The most common intracranial hemorrhage was epidural hemorrhage (n=94, 23.9%). The frequencies of emergency admission, medical insurance and associated injuries were 56.2% (n=221), 22.4% (n=88) and 37.2% (n=146). The frequencies of TBI and associated injuries were significantly increased from 53.45% to 76.3% and from 6.9% to 41.6% with age, respectively.Conclusions: MVCs were the most common etiologies. Parietal and basilar skull fractures, epidural hemorrhages were the most common fracture sites and intracranial hemorrhage. [ABSTRACT FROM AUTHOR]

The progression of pulmonary fibrosis (PF) entails a complex network of interactions between multiple classes of molecules and cells, which are closely related to the vagus nerve. Stimulation of the vagus nerve increases fibrogenic cytokines in humans, therefore, activation of the nerve may promote PF. The hypothesis was tested by comparing the extent and severity of fibrosis in lungs with and without vagal innervation in unilaterally vagotomized mice. The results show that in vagotomized lungs, there were less collagen staining, less severe fibrotic foci (subpleural, peri-vascular and peri-bronchiolar lesions) and destruction of alveolar architecture; decreased collagen deposition (denervated vs intact: COL1α1, 19.1 ± 2.2 vs 22.0 ± 2.6 ng/mg protein; COL1α2, 4.5 ± 0.3 vs 5.7 ± 0.5 ng/mg protein; p < 0.01, n = 21) and protein levels of transforming growth factor beta and interleukin 4; and fewer myofibroblast infiltration (denervated vs intact: 1.2 ± 0.2 vs 3.2 ± 0.6 cells/visual field; p < 0.05, n = 6) and M2 macrophages [though the infiltration of macrophages was increased (denervated vs intact: 112 ± 8 vs 76 ± 9 cells/visual field; p < 0.01, n = 6), the percentage of M2 macrophages was decreased (denervated vs intact: 31 ± 4 vs 57 ± 9%; p < 0.05, n = 5)]. It indicated that the vagus nerve may influence PF by enhancing fibrogenic factors and fibrogenic cells. [ABSTRACT FROM AUTHOR]

With the aim of finding more potential inhibitors against NADH-fumarate reductase (specific target for treating helminthiasis and cancer) from natural resources, Talaromyces wortmannii was treated with the epigenome regulatory agent suberoylanilide hydroxamic acid, which resulted in the isolation of four new wortmannilactones derivatives (wortmannilactones I–L, 1 – 4 ). The structures of these new compounds were elucidated based on IR, HRESIMS and NMR spectroscopic data analyses. These four new compounds showed potent inhibitory activity against NADH-fumarate reductase with the IC 50 values ranging from 0.84 to 1.35 μM. [ABSTRACT FROM AUTHOR]

Tourette syndrome (TS) is a neuropsychiatric disorder that affects both children and adults. We searched for randomised controlled trials (RCTs) using acupuncture to treat TS written in English or Chinese without restrictions on publication status. Study selection, data extraction, and assessment of study quality were conducted independently by two reviewers. Meta-analyses were performed using Review Manager (RevMan) 5.3 software from the Cochrane Collaboration. Data were combined with the fixed-effect model based on a heterogeneity test. Results were presented as risk ratios for dichotomous data and mean differences (MDs) for continuous data. This review included 7 RCTs with a total of 564 participants. The combined results showed that acupuncture may have better short-term effect than Western medicine for TS and that acupuncture may be an effective adjuvant therapy in improving the effect of Western medicine on TS, but the evidence is limited because of existing biases. Rigorous high-quality RCTs are needed to verify these findings. [ABSTRACT FROM AUTHOR]

Curcumin is capable of promoting peripheral nerve regeneration in normal condition. However, it is unclear whether its beneficial effect on nerve regeneration still exists under diabetic mellitus. The present study was designed to investigate such a possibility. Diabetes in rats was developed by a single dose of streptozotocin at 50 mg/kg. Immediately after nerve crush injury, the diabetic rats were intraperitoneally administrated daily for 4 weeks with curcumin (50 mg/kg, 100 mg/kg and 300 mg/kg), or normal saline, respectively. The axonal regeneration was investigated by morphometric analysis and retrograde labeling. The functional recovery was evaluated by electrophysiological studies and behavioral analysis. Axonal regeneration and functional recovery was significantly enhanced by curcumin, which were significantly better than those in vehicle saline group. In addition, high doses of curcumin (100 mg/kg and 300 mg/kg) achieved better axonal regeneration and functional recovery than low dose (50 mg/kg). In conclusion, curcumin is capable of promoting nerve regeneration after sciatic nerve crush injury in diabetes mellitus, highlighting its therapeutic values as a neuroprotective agent for peripheral nerve injury repair in diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background and Purpose: Psoriasis is a chronic inflammatory skin disease associated with both innate and adaptive immune responses. The stimulator of interferon genes (STING) protein engages in sensing of cytosolic DNA to initiate dsDNA‐driven immune responses. In vitro and in vivo anti‐psoriasis effects of STING antagonist H‐151 were explored. Experimental Approach We analysed the gene expression profile of STING and related downstream targets in the skin samples of healthy people and psoriasis patients from the GEO database. Cellular inhibitory activity of H‐151 on STING pathway was confirmed via qPCR and western blotting. The preventive effect of topical application of H‐151 on imiquimod‐induced psoriatic mice was examined through histological, immunohistochemical, immunofluorescent, flow cytometric analysis, ELISA Kits and other approaches. Preliminary mechanistic studies were also performed. Key Results: Gene expressions of STING and its downstream target were up‐regulated in lesional skin samples from psoriasis patients. Topical administration of H‐151 attenuated the skin lesions in imiquimod‐induced psoriatic mouse model, while the secretion of pro‐inflammatory cytokines (IL‐17, IL‐23 and IL‐6), infiltration of M1 macrophages and differentiation of Th17 cells were significantly suppressed by H‐151 treatment. Mechanistically, H‐151 inhibited STING/NF‐κB signalling in both keratinocytes and immune cells. Conclusion and Implications: H‐151 displayed anti‐inflammatory activity in both keratinocytes and immune cells, and decreased the severity of psoriatic response in vivo. Inhibition of STING signalling pathway may represent a novel therapeutic approach to psoriasis and related complications. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Arginine (Arg) is known to possess numerous useful physiological properties and immunomodulatory effects. Th17 cells are a unique T-helper cell lineage. Regulation of Th17 cells plays a significant role in the pathogenesis of inflammatory disorders. This study investigated the effect of Arg on the exogenous advanced glycosylation end product (AGE)-induced Th17-mediated immune response. Methods: Rats were randomly divided into three groups. The control BSA (CB) group was fed a common diet and given a tail vein injection of non-glycated bovine serum albumin (BSA). The control AGE (CA) group was fed the common diet and injected with 2 mg AGE-BSA. Arg-AGE (AA) group was fed the Arg-supplemented diet and injected with 2 mg AGE-BSA. The experimental diets were identical in energy and nutrient distributions except for the amino acid content. Arg provided 2% of the total energy. Tail vein injections and diets were given daily. After 10 d, all rats were sacrificed, and blood samples were collected for further analysis. Results: The AA group had the highest inducible nitric oxide (NO) synthase expression and plasma NO levels. The percentage of Foxp3 T-regulatory cells in the AA group was lower than those of the CA and CB groups. Transforming growth factor-β1, interleukin (IL)-6, and IL-17A gene expression was higher in the AGE-administered groups. The AA group had higher TGF-β1 and IL-17A expression than did the CA group. Conclusion: These results suggest that in a condition of exogenous AGE administration, supplemental dietary Arg resulted in a more pronounced IL-23/IL-17 immune response, possibly by increasing NO secretion. [Copyright &y& Elsevier]

Abstract: Objectives: Antrodia camphorata (AC) is a traditional Chinese medicine, and the polysaccharides contained within AC (AC-PSs) are reported to possess various biological functions. This study extracted AC-PSs from mycelia and fruiting bodies and evaluated their influences on inflammatory mediator expressions in septic mice. Methods: There were one normal control (NC) and three experimental groups. The normal control group underwent a sham operation, whereas the experimental groups underwent cecal ligation and puncture (CLP) to induce sepsis. Mice in the experimental groups were further divided into saline, mycelia, and fruiting body treatment groups. Saline or AC-PSs were injected intraperitoneally twice at 0.5 and 1 h after CLP and the mice were sacrificed at 6 or 16 h after sepsis for further analysis. Results: Compared with the normal control group, interleukin (IL)-6, tumor necrosis factor-α, IL-10, and monocyte chemotactic protein-1 levels in plasma and/or peritoneal lavage fluid in the septic mice dramatically increased after CLP. The increased levels of these inflammatory mediators in the two AC-PS–treated groups had decreased by 16 h after CLP. Messenger RNA expressions of tumor necrosis factor-α, IL-6, and IL-10 in the splenocytes were lower in the 2 AC-PS–treated groups than in the saline group. Consistent with the results, lung nuclear factor-κB expressions decreased and less severe interstitial inflammation was observed in the histologic finding after CLP in mice that had received AC-PSs. The fruiting body group had higher white blood cell counts and lower IL-6 levels in the peritoneal lavage fluid 6 h after CLP, whereas the interferon-γ level was higher 16 h after CLP than in the saline group. These alterations were not found in mice injected with the mycelia extract. Conclusion: The administration of AC-PSs from mycelia or fruiting bodies decreased the inflammatory mediator expressions at the location of injury and in the circulation, especially in the late stage of sepsis. AC-PSs from fruiting bodies seemed to be more effective in decreasing the inflammatory response than those from mycelia. These findings suggest that AC-PSs from mycelia and fruiting bodies have potential protective effects against polymicrobial sepsis. [Copyright &y& Elsevier]

Abstract: Hippuristanol is a natural product that has recently been shown to inhibit eukaryotic translation initiation and tumor cell proliferation. To investigate the structure and activity relationship of hippuristanol, we synthesized a series of analogs by expanding the size of its F ring and determined their effects on the proliferation of cancer cell lines. All changes to the F-ring of hippuristanol resulted in 3-fold to >100-fold decrease in activity. [Copyright &y& Elsevier]

Abstract: A novel series of 2-cyclopropyl-4-thiophenyl quinoline-based mevalonolactones were synthesized from the substituted anilines by several reactions. Among them, (4R,6S)-6-[(E)-2-(2-cyclopropyl-6-fluoro-4-(4-fluoro-thiophenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (1d), (4R,6S)-6-[(E)-2-(2-cyclopropyl-6-fluoro-4-(3-methoxy-thiophenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (1f) and (4R,6S)-6-[(E)-2-(2-cyclopropyl-6-fluoro-4,7-di(3-methoxy-thiophenyl)-quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (1q) showed potent HMG-CoA reductase inhibitory activity comparable with pitavastatin. [Copyright &y& Elsevier]

Abstract: During the development of protein therapeutics, characterization of the active pharmaceutical ingredient is performed extensively to ensure the stability, safety, and efficacy of the drug. Little is known, however, about the characteristics of protein drugs circulating in the blood. The recent availability of a fluorescence detection system (FDS) in analytical ultracentrifugation (AUC) instruments enables the characterization of fluorescently labeled proteins in biological fluids. AUC provides information about protein size, shape, self-association, and binding while avoiding many limitations associated with size exclusion chromatography. Furthermore, with the specificity and sensitivity of FDS, measurements can be performed at physiological concentrations directly in serum. In the current study, we used omalizumab, an anti-immunoglobulin E (IgE) monoclonal antibody, to demonstrate the potential of using AUC–FDS for the study of a monoclonal antibody and its complexes directly in human serum. Omalizumab properties were essentially unaltered after labeling with the fluorescent dye Alexa Fluor 488. In addition, omalizumab and IgE formed different complexes in serum than in phosphate-buffered saline in terms of both size and affinity. [Copyright &y& Elsevier]

Background and Purpose: The protein V‐domain immunoglobulin suppressor of T‐cell activation (VISTA) is a novel immune‐checkpoint molecule that belongs to the B7 family and regulates a broad spectrum of immune responses. So far, low MW compounds targeting VISTA for the treatment of autoimmune diseases or inflammation, have not been identified. Experimental Approach We developed a homology modelling for VISTA 3D structure and subsequent virtual screening for low MW ligands binding to VISTA. Visualization of the binding postures of docked ligands with protein VISTA indicated that compound M351‐0056 targeted VISTA. The biological activities of compound M351‐0056 targeting VISTA were investigated in vitro using monocytes and T cells and in vivo, using mice with imiquimod‐induced dermatitis. Key Results: The KD value of M351‐0056 for human VISTA‐extracellular domain was 12.60 ± 3.84 μM as assessed by microscale thermophoresis. M351‐0056 decreased cytokine secretion from PBMCs or human CD4+ T cells, suppressed proliferation of PBMCs and enhanced expression of Foxp3+ T cells. These effects of M351‐0056 modulating VISTA involved the JAK2–STAT2 pathway. Daily administration of M351‐0056 ameliorated imiquimod‐induced psoriasis‐like dermatitis. Expression of mRNA and protein of inflammatory cytokines in psoriatic lesions was decreased after M351‐0056 treatment. Conclusion and Implications: The compound M351‐0056 showed high affinity for VISTA and may modulate its immune function in vitro and in vivo. Our finding provides a lead compound for therapeutically enhancing VISTA‐mediated pathways to benefit the treatment of autoimmune diseases or inflammation. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) were initially regarded as by‐products of aberrant splicing. But now, there are substantial evidence on their various roles in the regulation of genes during the development of organs and diseases. Consistent with these breakthroughs, it is experiencing rapid growth that circRNAs function as the important checkpoints during the osteogenesis. Therefore, characterizing the roles of circRNAs is useful and critical to better understanding the process of osteogenic differentiation, which could provide new avenues for the diagnosis and treatment of bone diseases, such as bone defects and osteoporosis. In this review, we presented a map of the interaction between circRNAs and the molecules of signaling pathways associated with osteogenesis, summarized the current knowledge of the biological functions of circRNAs during the osteogenic differentiation, figured out the limits of existing research works, and provided a novel look on the diagnostic and therapeutic methods of bone diseases based on circRNAs. [ABSTRACT FROM AUTHOR]

In this study, the purified water-soluble polysaccharide (ALP-1) from Arctium lappa was used to intervene lipopolysaccharide-induced RAW264.7 macrophage and systemic inflammatory mice. Our results showed that ALP-1 could effectively accommodate the levels of inflammatory cytokines in macrophages and serum of mice, including increased anti-inflammatory cytokine (interleukin-10) and down-regulated pro-inflammatory cytokines (interleukin-1β, interleukin-6 and Tumor Necrosis Factor-α). Moreover, according to our data from 16 s high-throughput sequencing, as compared with LPS model group, the composition of gut microbiota in mice was ameliorated in ALP-1 treatment group. There were higher levels of several probiotics in the stools of ALP-1 treatment group, such as Lactobacillius, Alistipes, Odoribacter, and Phascolarctobacterium. Simultaneously, symbiotic bacteria like Bacteroides were inhibited by ALP-1. Besides, ALP-1 could significantly enhance the production of short chain fatty acids (SCFAs) in gut. • The water-soluble polysaccharide from Arctium lappa (ALP-1) could alleviate inflammation in RAW264.7 cells. • ALP-1 regulated the inflammatory cytokines in systemic inflammatory mice. • ALP-1 could ameliorate gut microbiota in inflammatory mice. • ALP-1 could accommodate the levels of SCFAs in gut of inflammatory mice. [ABSTRACT FROM AUTHOR]