Abstract: Paclitaxel (PTX), a BCS class IV drug that is characterized by its poor solubility and is a substrate for P-glycoprotein, is one of the most widely used antineoplastic agents. However, oral administration of PTX for chemotherapy is highly challenging. The aim of this study was to develop bile-salt liposomes (BS-Lips) to enhance the absorption of PTX and thus improve its therapeutic outcome. The BS-Lips were prepared by the thin-film hydration method and characterized in terms of particle size and morphology. Drug release and in vitro stability in simulated gastrointestinal fluids and in media of different pH values were evaluated, as well as in vivo performance, including antitumor activity and pharmacokinetics in rats, with the plasma concentrations determined by a HPLC method. The PTX-loaded BS-Lips were successfully prepared with a diameter of approximately 150 nm and an entrapment efficiency of greater than 90 percent. Moreover, the BS-Lips were not affected by gastrointestinal enzymes or pH alternation, as evident from the unchanged particle size and the drug retained in BS-Lips after 6 h incubation. The insertion of bile salt into the lipid layer of liposomes increased the lymphatic transport of PTX by twofold. Importantly, BS-Lips increased the oral bioavailability of PTX by 2.5 and 4-fold, respectively, compared with conventional liposomes (Lips) and Taxol (free drug), thereby displaying a better inhibition of tumor growth that was similar to the group injected intravenously with Taxol. In conclusion, the BS-Lips represent promising vehicles for the oral delivery of PTX, thereby enabling an intravenous-to-oral switch for cancer chemotherapy.

Abstract: Dexamethasone acetate (DEX) and polymyxin B sulfate (polymyxin B) were formulated as a cationic nanoemulsion for the treatment of ophthalmic infections. As novel concept, the positive charge to achieve mucoadhesion was not generated by toxicologically and regulatorily problematic cationic lipids or polymers, but by using a positively charged drug in combination with positively charged preservatives. The preservative also acts as co-surfactant to stabilize the emulsion. Nanoemulsions with the lipid phase Eutanol G-Lipoid S 100 (70%:30%) containing 0.05% (w/w) DEX were produced by high pressure homogenization, followed by dissolving the hydrophilic molecules in the water phase, e.g. polymyxin B (0.1%, w/w), cetylpyridinium chloride (0.01%, w/w) and glycerol (2.6%, w/w) to yield a combination product. The particles were below 200 nm with narrow size distribution. The osmolality (374 mOsm/kg), pH (5.31) and viscosity (2.45 mPa s at 37 degrees C) were compatible to the ocular administration. The zeta potential of the optimized formulation was shifted from approx. +9 mV to -11 mV after mucin incubation. The in vitro test revealed no potential cytotoxicity. The final products were stable after 180 days of storage at 4 degrees C and room temperature. The developed product is a viable alternative to the commercial ophthalmic suspensions. Moreover, this concept of generating the positive charge by cationic drug and/or preservative addition can be transferred to other ophthalmic products.

Abstract: Curcumin diethyl disuccinate (CDD) is a succinate prodrug of curcuminoids that has better stability in human plasma and improved in vitro cytotoxicity compared to curcumin. Therefore, CDD has the potential for further development as an anticancer agent. In this study, we focused on optimization of the formulation of CDD-loaded chitosan/alginate nanoparticles using Box-Behnken statistical design to enhance the therapeutic efficacy of CDD. Oil-in-water emulsification followed by ionotropic gelification was used to prepare the CDD-loaded chitosan/ alginate nanoparticles. A formulation with a 0.05:1 chitosan/alginate mass ratio, 0.65% (w/v) Pluronic F127 and 1.5 mg/ml CDD was found to be optimal. FTIR, TGA and XRD confirmed the encapsulation of CDD molecules in the nanoparticles. In vitro cytotoxicity and cellular uptake studies showed that CDD-loaded chitosan/alginate nanoparticles had significantly higher cytotoxicity and cellular uptake in human breast adenocarcinoma MDA-MB-231 cells, compared to free CDD. Physical and chemical stability studies indicated that the optimally formulated CDD-loaded chitosan/alginate nanoparticles were stable at 4 °C for 3 months.

Abstract: This randomized, placebo-controlled, double-blind trial was conducted to assess the efficacy and safety of ivy leaves cough liquid in the treatment of acute cough. A total of 181 adult patients with acute cough were treated with either ivy leaves cough liquid containing EA 575® or with placebo three times a day for one week. The primary efficacy outcome was cough severity (CS) assessed by Visual Analogue Scale (VAS) over the whole treatment period (area-under-the-curve (AUC0-168 h) over 7 days (visit (V)1, V2, V3, V4, and V5). The secondary endpoints were defined as the CS assessed by VAS over the whole observation period (V1 - V6) and by Bronchitis Severity Score (BSS) and Verbal Category Descriptive (VCD) score. The evaluation of the VAS, BSS and VCD score revealed that subjects treated with ivy leaves cough liquid showed statistically significant and clinically relevant reductions in CS, severity of symptoms associated with cough and bronchitis compared to the placebo group. Furthermore, a remarkable early onset of efficacy was observed as significant reductions of cough severity were detected within 48 hours after the first drug intake. At all following visits and even 7 days after the end of treatment (V6) this significant treatment advantage was detected in comparison to placebo. All adverse events (AEs) in this clinical trial were non-serious, mild or of moderate severity and not drug-related. This clinical trial proved consistent superiority of the ivy leaves cough liquid treatment versus placebo and confirmed the EA 575® preparation to be a safe and efficacious option for the treatment of acute cough.

Abstract: UNLABELLED The aim of this study was to explore the effects of oxymatrine in treating breast cancer patients using biomolecular methodology. Human breast cancer MCF-7 cells were treated with oxymatrine at concentrations of 0 (control), 25, 50 and 100 µg/mL. Apoptosis assay by Annexin/PI staining was performed to examine the effects of oxymatrine on apoptotic rates of MCF-7 cells at time points of 24 h, 48 h, and 72 h after treatment. Real-time PCR was performed for the mRNA abundance of Bax and Bcl-2 after the cells were treated with oxymatrine at concentration of 0, 25, 50, and 100 µg/mL at the time points of 24, 48, and 72 h. Western blotting was performed when the cells were treated with oxymatrine at various concentrations for 72h. High concentration of oxymatrine at 100 µg/mL enhanced apoptosis by 6.4-fold at 72 h compared with control (33.16% vs. 4.47%; t= 9.82, p< 0.001). Oxymatrine at 100 µg/mL up regulated Bax mRNA abundance by 169 % at 72 h (t = 18.32, p = 0.001), and reduced Bcl-2 mRNA abundance by 24 % at 72 h (t = 6.30, p = 0.001) compared with control. Oxymatrine enhanced the expression of Bax protein while reduced the expression of Bcl-2 protein. Oxymatrine treatment showed pro-apoptotic effects in breast cancer MCF-7 cells, and these effects correlated with the up regulation of Bax transcription and protein expression and the down regulation of Bcl-2 transcription and protein expression in a time- and dose-dependent manner. CONCLUSION Oxymatrine had effects in promoting apoptosis in human breast cancer MCF-7 cells by mediating the mRNA and protein expression levels of Bax and Bcl-2.

Abstract: Isoliquiritigenin, a flavonoid found in licorice, has been considered as an antioxidive and hepato-protective agent. Recent studies have shown that a possible mechanism for triptolide-induced hepatotoxicity is related to oxidative damage induced by reactive oxygen species. This study was done to investigate the protection effect of isoliquiritigenin against triptolide-induced hepatotoxicity and the mechanism involved. An acute liver injury model was established by intraperitoneal injection of triptolide (1.0 mg · kg-1) in mice. Different doses of isoliquiritigenin (12.5, 25 and 50 mg · kg-1) were employed as protection. The activities of AST, ALT, ALP and LDH in serum and levels of GSH, GPx, SOD, CAT and MDA in liver tissue were detected. The histopathological changes of liver tissues were observed after HE staining. The protein expression of Nrf2 was detected by western blot. Pretreatment with isoliquiritigenin significantly prevented the triptolide-induced hepatotoxicity indicated by reduced activities of AST, ALT, ALP and LDH. Moreover, isoliquiritigenin pretreatment also prevented from triptolide-induced hepatotoxicity by inhibiting MDA and restoring the levels of GSH, GPx, SOD and CAT. In addition, isoliquiritigenin could attenuate histopathological changes induced by triptolide. Furthermore, the results indicated that isoliquiritigenin pretreatment caused an increase in the protein expression of Nrf2. These results indicated that isoliquiritigenin could protect against triptolide-induced hepatotoxicity via activation of the Nrf2 pathway.

Abstract: Drug resistance remains a major unresolved obstacle for gastric cancer (GC) treatment. Recently, increasing studies have showen that microRNAs (miRNAs) are involved in cancer chemotherapeutic resistance and can potentially be applied to reverse drug resistance in cancers. The relationship between miRNA-149 expression and cisplatin (DDP) resistance in GC cells is still unknown. Here, we detected miR-149 expression by using RT-PCR and found that expression of miR-149 was downregulated in SGC7901/DDP cells compared with SGC7901cells, indicating a role of miR-149 in determining cisplatin-resistance of GC cells. Then, SGC7901/DDP cells were tansfected with miR-149 mimics, MTT assay was performed to determine SGC7901/DDP cell viability, and showed that overexpression of miR-149 inhibited the cell viability after cisplatin treatment, suggesting that up-regulation of miR-149 enhanced SGC7901/DDP cell sensitivity to cisplatin. Furthermore, we confirmed that Forkhead box M1 (FoxM1) is a direct target of miR-149 in SGC7901/DDP cells by using luciferase reporter assay. Besides, we also demonstrated that miR-149 enhances SGC7901/DDP cell sensitivity to cisplatin by downregulating FoxM1 expression. In summary, our data provide new insights that miR-149 plays an important role in determining sensitivity of cisplatin-resistant GC cells by targeting FoxM1 and suggest that miR-149 could be a potential target for reversing drug resistance in GC.

Abstract: Glabridin, a polyphenolic flavonoid from licorice, has inspired great interest for its antioxidant, anti-inflammatory and skin-lightening activities. However, low water solubility and poor stability of glabridin impedes its topical application in cosmetic products and therapies of dermal diseases. The purpose of this study was to develop a nanosuspension formulation of glabridin to improve its skin permeation. Glabridin nanosuspensions were prepared using anti-solvent precipitation-homogenization method, and Box-Behnken design was adopted to investigate the effects of crucial formulation variables on particle size and to optimize the nanosuspension formulation. The optimal formulation consisted of 0.25% glabridin, 0.47% Poloxamer 188 and 0.11% Polyvinylpyrrolidone K30, and the obtained nanosuspension showed an average particle size of 149.2 nm with a polydispersity index of 0.254. Furthermore, the nanosuspension exhibited significantly enhanced drug permeation flux of glabridin through rat skin with no lag phase both in vitro and in vivo, compared to the coarse suspension and physical mixture. The glabridin nanosuspension showed no significant particle aggregates and a drug loss of 5.46% after storage for 3 months at room temperature. With its enhanced skin penetration, the nanosuspension might be a more preferable formulation for topical administration of poorly soluble glabridin.

Abstract: Cisplatin-based chemotherapy has been found to improve the prognosis of patients with tongue squamous cell carcinoma (TSCC), the most common oral cancer with a poor prognosis. Chemoresistance to cisplatin appears to be an important clinical problem for cisplatin-based TSCC chemotherapy. Long noncoding RNAs (lncRNAs) play important roles in regulating tumor cells' sensitivity to chemotherapeutic agents. A recent study has shown that the expression of lncRNA UCA1 is significantly enhanced in TSCCs, suggesting that UCA1 may play a role in TSCC progression. In the present study, we explored the effects and the underlying mechanisms of UCA1 on cisplatin chemosensitivity/chemoresistance and apoptosis in TSCC cells. Transient transfection of siRNA was used to knock down UCA1 in human TSCC cell lines CAL 27 and SCC-9, where UCA1 was highly overexpressed compared to normal human tongue tissues. Knockdown of UCA1 markedly increased cisplatin-induced caspase 3 activity and apoptosis in CAL 27 and SCC-9 cells. On the other hand, it decreased cisplatin-induced phosphatidylinositol 3-kinase (PI3K) activity and activation phosphorylation of Akt. UCA1 knockdown resulted in one magnitude decrease in the half maximal inhibitory concentration (IC50) of cisplatin in CAL 27 and SCC-9 cells, from 8.9 mM and 20.7 mM down to 0.6 mM and 1.7 mM, respectively. In conclusion, this study has shown that UCA1 knockdown markedly increased cisplatin-induced apoptosis and chemosensitivity in TSCC cells, likely through inhibiting cisplatin-activated PI3K/Akt signaling. It provides new insights into the functional role of UCA1 in cancer cells and suggests that UCA1 knockdown could be a new strategy to increase cisplatin chemosensitivity and thereby improve the therapeutic outcomes of cisplatin-based chemotherapy for TSCC.

Abstract: The main purpose of this study was to examine if naringin contributed to the regulation of cholesterol homeostasis and inflammatory cytokine expressions in cholesterol and 25-OH-cholesterol-treated HepG2 cells and TNF-α-treated HUVECs. The gene and protein expressions related to cholesterol homeostasis and inflammation were determined by quantitative real-time reverse transcription-polymerase chain reaction and Western blotting. We obtained the following results: (1) A concentration-dependent increase of LDLR and CYP7A1 expressions was observed, through activating expressions of SREBP2 and PPARy in HepG2 cells after exposure to naringin; (2) EL gene and protein expressions in HUVECs were inhibited by naringin; (3) the expressions of inflammatory factors such as CRP, TNF-α, ICAM-1 and VCAM-1 in HepG2 cells, ICAM-1 and VCAM-1 in HUVECs restrained by naringin were confirmed; (4) NF-κB and ERK1/2 activities were quenched by naringin. In summary, naringin might not only effectively reduce cholesterol levels by stimulating cholesterol metabolism but also inhibit inflammatory response through reducing inflammatory cytokine expressions. The effects of naringin were achieved via modulating NF-κB and ERK signaling pathways.

Abstract: Aim Neuropathic pain is a common clinical complication of nerve injury, and the effective treatment of neuropathic pain is still challenging. Ligustrazine is mainly used for the treatment of cardiovascular disease and its role in neuropathic pain is less investigated. The purpose of our study was to explore the effects of ligustrazine on neuropathic pain, as well as the underlying molecular mechanism. Methods Neuropathic pain was induced by chronic constriction injury (CCI) of the right sciatic nerve in Sprague-Dawley (SD) rats. After CCI, rats received ligustrazine, IL-6, or both. Mechanical withdrawal threshold (MWT) and paw withdrawal thermal latency (PWTL) were assessed on days 1, 3, 7, and 14 after surgery. Expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-β, IL-2, and phosphorylation of Signal Transducer and Activator of Transcription (STAT) 3 were analyzed. Results Our results showed that both MWT and PWTL were significantly decreased by CCI on days 1, 3, 7 and 14 compared to sham group, however, ligustrazine reversed this effects. Additionally, the elevated levels of TNF-α, IL-1β, and IL-2 in CCI spinal cord were inhibited by ligustrazine. Quantitative real-time (qRT-PCR) and Western blotting analysis showed that the test substance reduced the elevated expression of pSTAT3 in the spinal cord induced by CCI, and while IL-6 administration reversed the levels as well as the behavior responses. Conclusion Our results suggest that ligustrazine could effectively attenuate neuropathic pain by inhibition of Janus Kinase (JAK)/STAT3 pathway in CCI rats.

Abstract: Oral drug administration to children poses specific pharmaceutical challenges that are often not seen to the same extent in adults, and whose occurrence may also be age dependent. When an age-appropriate dosage form is not available, manipulation of adult dosage forms (e.g., splitting and crushing of tablets or opening of capsules) has been reported as a means to facilitate administration to children. To enhance swallowability and/or mask an unpleasant taste of the dosage form to be administered, crushed/split tablets or the contents of capsules are often mixed with food or drinks or suspended in a vehicle prior to administration. However, it seems that the risks and benefits of an approach whereby the dosage form is modified prior to administration in this manner are everything but clear. The aim of the present study was to gain an overview of the physicochemical properties of a number of fluids, soft foods and suspension vehicles that are commonly reported to be mixed with oral medications before administration to children to improve patient acceptability. For this purpose, physicochemical parameters of 15 different fluids, soft foods and suspension vehicles were measured. These included pH, buffer capacity, osmolality, surface tension and viscosity. Results of the study clearly show the differences in physicochemical properties of the test candidates. It is thus obvious that the type of fluid/food mixed with a drug product before administration may have a significant impact on bioavailability of the drug administered. Therefore, a risk-based assessment of such practices considering API properties, formulation features and physicochemical properties of the fluids and foods intended to be co-administered with the dosage form, in conjunction with the anatomical and physiological maturity of the gastro-intestinal tract in the intended paediatric population, should be an essential part of paediatric oral formulation development.

Abstract: Ginkgolide A (GA) is a one of the active components of Ginkgo biloba. We aimed to detect the effects GA on the lipopolysaccharide (LPS)-induced inflammatory response in human coronary artery endothelial cells (HCAECs) and whether the effects are associated with the inhibition of toll-like receptor 4 (TLR4)-NF-κB signaling through PI3K/Akt pathway. HCAECs were stimulated with LPS and treated with GA or TLR4 inhibitor CLI-095. A PI3K/Akt inhibitor LY294002 was used to block the PI3K/Akt pathway. The toxic effects of GA, LPS and LY294002 on HCAEC were evaluated using MTT assay. Levels inflammatory mediators, TLR4 mRNA, NF-κB signaling activity were valuated. We found LPS stimulation significantly increased the release of IL-6, IL-8, MCP-1 and TNF-α from HCAECs, elevated the TLR4 mRNA expression and activated the NF-κB signaling. GA and CLI-095 abolished the LPS-induced inflammatory mediator release and NF-κB signaling activation, and GA reduced the TLR4 mRNA expression without affecting cell viability. However, PI3K/Akt blocking abolished the effects of GA on HCAECs. We conclude that GA could attenuate the LPS-induced inflammatory response in HCAECs and the anti-inflammatory activity might be associated with the inhibition of TLR4-NF-κB signaling through PI3K/AKT pathway. These findings suggest a therapeutic potential of GA in endothelial inflammation.

Abstract: Lipid based nanoparticles have become a major research object in topical drug delivery to enable drugs to pass the stratum corneum and reach the desired skin layer. The present investigation deals with the encapsulation of lidoacine into nanostructured lipid carriers (NLCs) and nanoethosomes for improving its dermal delivery and consequently local anesthetic efficacy. Concurrently these two topical delivery systems were compared. Lidocaine-loaded NLCs and nanoethosomes were characterized by various techniques and used for an in vitro skin penetration study using excised rat skin and Franz diffusion cells. The nanoparticles were tracked in the skin by following the Rhodamine-labled nanocarriers under fluorescent microscopy. Optimized lidocaine-loaded NLCs (size 96 nm, zeta potential -13.7 mV, encapsulation efficiency (EE) % 69.86% and loading capacity (LC) % 10.47%) and nanoethosomes (size 105.4 nm, zeta potential -33.6 mV, EE 40.14% and LC 8.02%) were chosen for a skin drug delivery study. Higher skin drug deposition of NLCs and nanoethosomal formulations compared to lidocaine hydroalcoholic solution represented a better localization of the drug in the skin. NLC formulation showed the lowest entered drug in the receptor phase of Franz diffusion cell in comparison with nanoethosomes and hydroalcoholic solution confirming the highest skin accumulation of drug. Both colloidal systems showed superiority over the drug solution for dermal delivery of lidocaine, however, NLC exhibited more promising characteristics than nanoethosomes regarding drug loading and skin targeted delivery.

Abstract: The novel flavonoids, 2",2"'-di-O-α-rhamnopyranosyl-vicenin II, a di-C-glycosyl flavone, and herbacetin 3-O-β-xylopyranosyl- (1"' --> 2")-O-β-glucopyranoside, were isolated from the leaves of Beta vulgaris subspecies cicla L. var. flavescens, an edible plant which is consumed in the Mediterranean areas, additional to the known flavonoids, 6-C-glucosyl isoscutellarein, vitexin-(1"' --> 2")-O-β-xylopyranosyl, vitexin-(1'" --> 2")-O-α-rhamnopyranosyI and vitexin. All metabolites were established by conventional methods of analysis and their structures were confirmed by spectroscopic analysis, including 1 D and 2D-NMR and by HR-ESIMS, as well. The extract of the plant leaves shows hepatoprotective effects in rats intoxicated by administration of acetaminophen and exhibits hypolipidemic activity in rats with high-fat-diet induced hypercholesterolemia. The evaluation was done through measuring the liver function enzymes (aspartate and alanine aminotransferases and alkaline phosphatase, the lipid profile (total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides) and histopathological analysis of liver slides.

Abstract: The present study aimed to develop a continuous single-step manufacturing platform to prepare a porous, low-density, and floating multi-particulate system (mini-tablet, 4 mm size). This process involves injecting inert, non-toxic pressurized CO₂gas (P-CO₂) in zone 4 of a 16-mm hot-melt extruder (HME) to continuously generate pores throughout the carrier matrix. Unlike conventional methods for preparing floating drug delivery systems, additional chemical excipients and additives are not needed in this approach to create minute openings on the surface of the matrices. The buoyancy efficiency of the prepared floating system (injection of P-CO₂) in terms of lag time (0 s) significantly improved (P < 0.05), compared to the formulation prepared by adding the excipient sodium bicarbonate (lag time 120 s). The main advantages of this novel manufacturing technique include: (i) no additional chemical excipients need to be incorporated in the formulation, (ii) few manufacturing steps are required, (iii) high buoyancy efficiency is attained, and (iv) the extrudate is free of toxic solvent residues. Floating mini-tablets containing acetaminophen (APAP) as a model drug within the matrix-forming carrier (Eudragit® RL PO) have been successfully processed via this combined technique (P-CO₂/HME). Desired controlled release profile of APAP from the polymer Eudragit® RL PO is attained in the optimized formulation, which remains buoyant on the surface of gastric fluids prior to gastric emptying time (average each 4 h).

Abstract: Resistance to chemotherapy is a main obstacle for effective treatment of gastric cancer, the mechanism of which is still poorly understood. Forkhead box M1 (FoxM1) plays an important role in chemo-resistance of various tumors. This study aimed to explore whether FoxM1 mediated resistance of the gastric cancer cell line SGC7901 to the chemotherapy agent cisplatin (DDP). In the study, we detected FoxM1 and Mcl-1 expression via real time-PCR and western blot and demonstrated that FoxM1 is overexpressed in cisplatin-resistance GC cells and Mcl-1 expression is regulated by FoxM1. We examined SGC7901/DDP cell viability by MTT assay, which revealed that suppression of the FoxM1/Mcl-1 pathway impaired cell viability and thus increased sensitivity to cisplatin in gastric cancer cells. Taken together, the study implied that the FoxM1/Mcl-1 pathway may overcome cispaltin resistance of gastric cancer and provide a new therapeutic target for the treatment of gastric cancer.

Abstract: Although recent studies have shown the important role and overexpression of miR-224 in several tumors, its function in gastric cancer has not yet been defined. In the present study, we tried to confirm the result of microRNAs microarray and further investigated the functions of miR-224 in gastric cancer, and tried to find new downstream targets of miR-224. In this study, the level of miR-224 was measured in gastric cancer cells with the normal human gastric epithelial cell. The effects of miR-224 of on proliferation, migration, and target protein expression were evaluated by CCK8 assay, colony assay, transwell migration assay, western blotting. In addition, luciferase reporter plasmid was constructed to demonstrate the direct target of miR-224. Overexpression of miR-224 was detected in the gastric cancer cells, especially in SCG-7901. Exogenous miR-224 expression promoted the proliferation and migration of gastric cells and abrogating expression of miR-224 suppressed proliferation, and migration of SCG-7901 cells in vitro. Luciferase assays revealed that miR-224 directly targeted the 3'UTR of p21-activated kinase 4 (PAK4). The present study provides an experimental foundation for miR-224 as a potential tumor suppressor that may decrease PAK4 expression to inhibit gastric cancer cells and that in the future, targeting of this miRNA may provide a novel strategy for the diagnosis and treatment of patients with this lethal disease.

Abstract: Angelica keiskei Koidzumi (Ashitaba) is a traditional folk medicine that is also regarded in Japan as a health food with potential antithrombotic properties. The ability of the major chalcones, xanthoangelol (XA) and 4-hydroxyderricin (4-HD) extracted from Ashitaba roots to inhibit platelet aggregation activity in vitro was recently determined. However, the anti-platelet activities of Ashitaba chalcones in vivo have remained unclear. The present study examines the anti-platelet effects of Ashitaba exudate and its constituent chalcones using mouse tail-bleeding models that reflect platelet aggregation in vivo. Ashitaba exudate and the major chalcone subtype XA, suppressed the lipopolysaccharide (LPS)-induced shortening of mouse tail bleeding. However, trace amounts of other Ashitaba chalcone subtypes including xanthoangelols B (XB), D (XD), E (XE) and F (XF) did not affect tail bleeding. These results suggest that the major chalcone subtype in Ashitaba, XA, has anti-platelet-activities in vivo.

Abstract: One water-soluble polysaccharide (ASPS), with four molecular weight distributions of 74, 3.8, 4.5, 2.3 x 10(4) Da, was isolated from the root of Acanthopanax senticosus and the yield was 4.8% (w/w). ASPS was composed of arabinose (51.4%), glucose (24.5%), galactose (10.2%), xylose (5.7) and galacturonic acid (4.9%). Effects of ASPS on the proliferation, apoptosis and Wnt/β-catenin signaling pathway were investigated in human hepatocellular carcinoma cell line HepG2 cells. The study showed that ASPS could inhibit the proliferation, increase the apoptosis rate in HepG2 cells; meanwhile, ASPS could increase the proportion of cells in G0/G1 phase, decrease the proportion of cells in S phase and G2/M phase, and elevate the expression level of β-catenin, C-myc and Cyclin D1 proteins in HepG2 cells. These results indicate that ASPS has a certain inhibition on the proliferation, can induce the apoptosis and G0/G1 phase arrest in HepG2 cells, and the mechanism may be related to the inhibition of ASPS on the activation of Wnt/β-catenin pathway HepG2 cells.

Abstract: Accumulating evidence suggests that microRNAs (miRNAs) play an important role in regulating the pathways in adipose tissue that control processes such as adipogenesis, insulin resistance, and inflammation. Adipogenic differentiation of preadipocytes is a complex process regulated by various factors including miRNAs and cytokines. MiR-455 is a well-known miRNA that enhances adipogenesis. Uncoupling protein-1 (UCP-1), a heparinbinding growth factor, plays a negative role in adipogenesis. In this investigation, we demonstrate that UCP-1 is a target gene of miR-455 during adipogenic differentiation in 3T3-L1 preadipocytes. MiR-455 downregulates UCP-1 expression through interaction with a target site of miR-455 in the coding region of mouse UCP-1. The rare codons upstream of the target site regulate miR-455-induced translational knockdown of UCP-1, which provides more insight into the mechanism of adipogenic differentiation. Thus, these results suggest that the acceerative adipogenic effect of miR-455 in 3T3-L1 cells is due, at least in part, to suppression of UCP-1.

Abstract: The present study explored the involvement and role of miR-301a in the adipose tissues. For the first time we identified the expression of miR-301a in the white adipose tissues of mice. A decreased level of miR-301a was correlated to increased chronic inflammation in the 3T3-L1 cells and circula- tion in an obese mouse model. Mechanistically, we demonstrated that miR-301a attenuated saturated free fatty acid-induced activation of peroxisome proliferator-activated receptor gamma (PPARy) and production of proinflammatory cytokines in 3T3-L1 cells. Target gene reporter assays showed that miR-301a directly targeted the 3'-untranslated region (3'UTR) of PPARγ, resulting in a decrease of PPARy protein expression. The miR-301a inhibition of adipocyte differentiation was reversed by PPARγ overexpression.

Abstract: Post-operative endophthalmitis is an infection and an inflammation of the eye following a surgical procedure. Its treatment is based on drug injections into the eye. However, this treatment can lead to ocular complications. Intraocular implants could substitute the conventional therapy. Poly(lactic-co-glycolic acid) (PLGA) implants comprising on vancomycin and dexamethasone were evaluated as drug delivery system to treat endophthalmitis after cataract surgery. Implants were characterized by drug content uniformity, Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), Wide Angle X-ray Scattering (WAXS), Scanning Electron Microscopy (SEM) and in vitro drug release. The bactericidal effect of vancomycin, eluted from the implants, was demonstrated against Staphylococcus aureus and Staphylococcus epidermidis. The drugs were uniformly distributed in the polymer. The analytical techniques revealed the chemical integrity of the drugs incorporated into the polymer and the modification of dexamethasone semi-crystalline nature. Drugs were controlled released from implants; and the eluted vancomycin showed bactericidal effects. In conclusion, PLGA implants containing vancomycin and dexamethasone may represent a therapeutic alternative to treat post-operative endophthalmitis.

Abstract: RNA-based effector molecules (nucleic acid effectors) are important tools in molecular medicine because they offer a strategy to address therapeutically interesting targets that are not "druggable" with classic small molecule inhibitors. However, for in vivo applications, RNA-based effectors require specific chemical modifications to improve their stability and pharmacokinetic properties, as well as to minimize toxic and unspecific off-target effects.

Abstract: 5-Fluorouracil (5-FU) is a pyrimidine analog widely used for the treatment of various cancers, but often causes hepatic damage in clinical practice. In this study, we examined the influence of taurine on 5-FU-induced hepatotoxicity in mice with respect to changes in oxidative stress. Elevations in the aspartate aminotransferase and alanine aminotransferase serum levels after 5-FU administration were significantly suppressed in a dosedependent manner by concurrent treatment with taurine. The activity of superoxide dismutase and reduced glutathione content in the liver were significantly decreased following treatment with 5-FU alone, but these changes were markedly inhibited by the administration of taurine. Our findings suggest that taurine protects against 5-FU-induced hepatotoxicity by suppressing oxidative stress.

Abstract: Chemoresistance in cancer is one of the major hindrances in cisplatin (DPP) treatment for nasopharyngeal carcinoma (NPC). The mechanism of such resistance remains unknown. Therefore, the present study aimed to clarify the mechanism of DDP resistance and attempted to reduce chemoresistance. Here, we found that miR-132, as a tumor suppressor, was poorly expressed in a cisplatin resistant CNE2 cell line (CNE2/DPP) accompanied with a decreased expression of miR-132 and an increased expression of FOXA1 compared with the parental cells CNE2. Exogenous overexpression of miR-132 in CNE2/DPP could sensitize their reaction to the treatment of cisplatin. In addition, FOXA1 knockdown in CNE2/DPP cells increased the chemosensitivity to DPP, suggesting the dependence of FOXA1 regulation in miR-132 activity. Moreover, miR-132 can restore cisplatin treatment response in cisplatin-resistant xenografts in vivo, while FOXA1 protein levels were decreased. In summary, our results provide novel mechanistic insights into the role of miR-132/FOXA1 signaling in the cisplatin resistance of NPC cells. Targeting of miR-132 is a potential therapeutic approach for NPC.

Abstract: TAK-242 (resatorvid), a novel small-molecule cyclohexene derivative, inhibits TLR4 signaling selectively. TAK-242 blocked the Toll-like receptor (TLR) 4-triggered inflammatory signaling by binding directly to a specific amino acid Cys747 in the intracellular domain of TLR4. The present study was designed to examine the effects of TAK-242 on vascular inflammatory responses in human coronary artery endothelial cells (HCAECs) challenged by lipopolysaccharide (LPS, a TLR4 ligand). The results show that TAK-242 attenuated the LPS-induced expression of interleukin (IL)-6, IL-8 and monocyte chemoattractant protein 1 both at the transcription and translation levels in HCAECs. LPS-induced endothelial cell adhesion molecules, intercellular adhesion molecular-1 and vascular cell adhesion molecule-1 expressions were also reduced by treatment with TAK-242. In addition, coincubation with TAK-242 did not effect the expression of TLR4 in LPS-activated HCAECs. Furthermore, TAK-242 efficiently suppressed LPS-induced phosphorylation of nuclear factor κB (NF-κB) and IL-1 associated kinase-1 (IRAK-1) in HCAECs. These findings show that TAK-242 can suppress endothelial cell inflammation, suggesting that TAK-242 might be suitable for development as a therapeutic agent for inflammatory cardiovascular disease.

Abstract: Non-metastatic melanoma glycoprotein B (Gpnmb), a type I transmembrane glycoprotein, was first cloned and described in low-metastatic human melanoma and xenografts in 1995 Up to now a growing number of studies have confirmed that Gpnmb is expressed not only in numerous normal tissues but also at pathological sites and malignant tissues and often connected with the invasive and metastatic phenotypes, including breast cancer Nowadays, immunotherapeutic approaches for cancer therapy, by which monoclonal antibodies (Mabs) target tumor specific antigens, have shown great potential Glembatumumabvedotin, also called CR011-vcMMAE, is a Mab-drug conjugate which was developed for the treatment of Gpnmb-expressing cancers Several phase I/II studies have confirmed the safety and activity of glembatumumabvedotin in patients with advanced/metastatic breast cancer and unresectable cutaneous melanoma Moreover, increasing numbers of studies have supported the potential roles of targeting Gpnmb with glembatumumabvedotin in patients with recurrent osteosarcoma, uveal melanoma, ALS, Gaucher disease, pancreatic ductal adenocarcinoma etc This review will summarize the latest understanding of Gpnmb in the aspects of diagnosis, progression and prognosis of pathological disorders and neoplasms, emphasizing the clinical advances in targeting Gpnmb-expressing malignancies

Abstract: A challenge with compounding oral liquid formulations is the limited availability of data to support the physical, chemical and microbiological stability of the formulation. This poses a patient safety concern and a risk for medication errors. The objective of this study was to evaluate the compatibility of the following active pharmaceutical ingredients (APIs) in 10 oral suspensions, using SyrSpend SF PH4 (liquid) as the suspending vehicle: cholecalciferol 50,000 IU/mL, haloperidol 0.5 mg/mL, imipramine hydrochloride 5.0 mg/mL, levodopa/carbidopa 5.0/1.25 mg/mL, lorazepam 1.0 mg/mL, minocycline hydrochloride 10.0 mg/mL, tacrolimus monohydrate 1.0 mg/mL, terbinafine 25.0 mg/mL, tramadol hydrochloride 10.0 mg/mL and valsartan 4.0 mg/mL. The suspensions were stored both refrigerated (2 - 8 degrees C) and at controlled room temperature (20 - 25 degrees C). This is the first stability study for these APIs in SyrSpend SF PH4 (liquid). Further, the stability of haloperidol,ilmipramine hydrochloride, minocycline, and valsartan in oral suspension has not been previously reported in the literature. Compatibility was assessed by measuring percent recovery at varying time points throughout a 90 days period. Quantification of the APIs was performed by high performance liquid chromatography (HPLC-UV). Given the percentage of recovery of the APIs within the suspensions, the beyond-use date of the final preparations was found to be at least 90 days for most suspensions both refrigerated and at room temperature. Exceptions were: Minocycline hydrochloride at both storage temperatures (60 days), levodopa/carbidopa at room temperature (30 days), and lorazepam at room temperature (60 days). This suggests that compounded suspensions of APIs from different pharmacological classes in SyrSpend SF PH4 (liquid) are stable.