Microchannel-embedded implantable device with fibrosis suppression for prolonged controlled drug delivery.

For the prolonged, controlled delivery of systemic drugs, we propose an implantable drug-delivery chip (DDC) embedded with pairs of a microchannel and drug-reservoir serving as a drug diffusion barrier and depot, respectively. We pursued a DDC for dual drugs: a main-purpose drug, diclofenac (DF), for systemic exposure, and an antifibrotic drug, tranilast (TR), for local delivery. Thus, the problematic fibrotic tissue formation around the implanted device could be diminished, thereby less hindrance in systemic exposure of DF released from the DDC. First, we separately prepared DDCs for DF or TR delivery, and sought to find a proper microchannel length for a rapid onset and sustained pattern of drug release, as well as the required drug dose. Then, two distinct DDCs for DF and TR delivery, respectively, were assembled to produce a Dual_DDC for the concurrent delivery of DF and TR. When the Dual_DDC was implanted in living rats, the DF concentration in blood plasma did not drop significantly in the later periods after implantation relative to that in the early periods before fibrotic tissue formation. When the Dual_DDC was implanted without TR, there was a significant decrease in the blood plasma DF concentration as the time elapsed after implantation. Biopsied tissues around the Dual_DDC exhibited a significant decrease in the fibrotic capsule thickness and collagen density relative to the Dual_DDC without TR, owing to the effect of the local, sustained release of the TR.

Effects of Tranilast on Inflammasome and Macrophage Phenotype in a Mouse Model of Myocardial Infarction.

Acute myocardial infarction (AMI) has been a devastating actuality and accounts for half of cardiovascular emergency department visits. Nucleotide oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome participates in the mediation of myocardial inflammation during AMI. Therefore, this study aimed to reveal the therapeutic function of tranilast, an agent targeting NLRP3, for AMI. AMI mouse model was first established by transient myocardial ischemia. Western blot and quantitative reverse transcription polymerase chain reaction assay were performed to estimate the expression levels of related genes. Flow cytometry was used to analyze the macrophage types, and the therapeutic effects of tranilast were estimated by echocardiographic analysis and Masson's trichrome stain. We demonstrated that AMI induced the activation of NLRP3 inflammasome in the heart tissues of mice with AMI. Tranilast decreased the expression of interleukin-1ß and cleaved caspase-1 in bone marrow-derived macrophages and thus re-educated M1-macrophages toward the M2-phenotype both in vitro and in vivo. Tranilast inhibited the activation in the heart tissues of AMI mice and thus improved cardiac functional recovery in the AMI mouse model. In conclusion, we revealed that tranilast ameliorated myocardial infarction by inhibiting NLRP3 inflammasome and re-educating macrophage phenotype in this study.

Clinical safety and efficacy of neoadjuvant combination chemotherapy of tranilast in advanced esophageal squamous cell carcinoma: Phase I/II study (TNAC).

BACKGROUND: Transient receptor potential vanilloid 2 (TRPV2) was previously shown to play an important role in the maintenance of cancer stem cells, and its specific inhibitor, tranilast, also has potential as a targeted therapeutic agent for esophageal squamous cell carcinoma (ESCC). The present study is being conducted to confirm the safety and efficacy of the additional use of tranilast with conventional preoperative adjuvant chemotherapy for patients with advanced ESCC. PATIENTS AND METHODS: Between 56 and 59 patients aged between 20 and 74 years with clinically diagnosed Stage II or Stage III ESCC will be enrolled. Eligible patients will receive preoperative adjuvant chemotherapy, 2 cycles of combination therapy with cisplatin, 5-fluorouracil, and tranilast. Recruitment started in November 2019, with the final follow-up being planned for March 2029. One subject has been enrolled since October 21, 2020. The pathological therapeutic effect is the primary endpoint. The objective response rate, safety of preoperative adjuvant chemotherapy, recurrence-free survival (RFS), and overall survival (OS) are the secondary endpoints. RFS and OS will be calculated as the time from surgery to first recurrence and all-cause death, respectively. ETHICS AND DISSEMINATION: This protocol has been approved by the Institutional Review Boards of Kyoto Prefectural University of Medicine and all participating hospitals in August 30, 2019 (Number: CRB5180001). Written informed consent will be obtained from all patients before their registration, which is in accordance with the Declaration of Helsinki. The results of the present study will be disseminated via publication in peer-reviewed journals. TRIAL REGISTRATION: Trial registration number jRCTs051190076.

Effect of dose on the intravenous pharmacokinetics of tolfenamic acid in goats.

The objective of this study was to determine the pharmacokinetics of tolfenamic acid (TA) following intravenous (IV) administration at doses of 2 and 4 mg/kg in goats. In this study, six healthy goats were used. TA was administered intravenously to each goat at 2 and 4 mg/kg doses in a cross-over pharmacokinetic design with a 15-day washout period. Plasma concentrations of TA were analyzed using the high performance liquid chromatography with ultraviolet detector, and pharmacokinetic parameters were assigned by noncompartmental analysis. Following IV administration at dose of 2 mg/kg, area under the concentration-time curve (AUC0-∞ ), elimination half-life (t1/2ʎz ), total clearance (ClT ) and volume of distribution at steady state (Vdss ) were 6.64 ± 0.81 hr* µg/ml, 1.57 ± 0.14 hr, 0.30 ± 0.04 L h-1  kg-1 and 0.40 ± 0.05 L/kg, respectively. After the administration of TA at a dose of 4 mg/kg showed prolonged t1/2ʎz , increased dose-normalized AUC0-∞ , and decreased ClT . In goats, TA at 4 mg/kg dose can be administered wider dose intervals compared to the 2 mg/kg dose. However, further studies are needed to determine the effect of different doses on the clinical efficacy of TA in goats.

Avenanthramide supplementation reduces eccentric exercise-induced inflammation in young men and women.

BACKGROUND: Avenanthramides (AVA) are a group of di-phenolic acids found only in oats and have shown antioxidant and anti-inflammatory effects in vitro and in vivo. Eccentric muscle contraction is intimately involved in rigorous exercise that activates systemic and local inflammatory responses. The objective of the study is to evaluate whether chronic AVA supplementation could attenuate peripheral inflammatory and immunological markers in human subjects in response to an acute bout of downhill running (DR). METHODS: Eleven male and thirteen female subjects voluntarily participated in this double-blinded, randomized controlled study and were randomly divided into AVA-supplemented (AVA) or control (C) groups. All subjects conducted a DR protocol at - 10% grade with an intensity equivalent to 75% of their maximal heart rate. Blood samples were collected at rest and various time points (0-72 h) after DR (PRE). After an 8-week washout period, participants received two cookies daily containing either 206 mg/kg (AVA) or 0 mg/kg (C) AVA for 8 weeks. Following the oat supplementation regimen, the DR and blood sampling protocols were repeated (POST). Plasma inflammatory and immunological markers were measured using Multiplex immunoassay and muscle soreness was evaluated with pain rating scale. RESULTS: DR increased plasma creatine kinase (CK) activity (P < 0.01) during PRE, but the response was reduced at 24 and 48 h during POST vs. PRE regardless of AVA status (P < 0.05). Neutrophil respiratory burst (NRB) levels were elevated at 4 and 24 h (P < 0.05) during PRE but were significantly decreased at 0-48 h during POST vs. PRE (P < 0.05 or 0.01). Granulocyte-colony stimulating factor (G-CSF), the neutrophil stimulating cytokine, was also increased in response to DR but showed lower levels in AVA compared to C during POST vs. PRE (P < 0.05). Plasma interleukin-6 (IL-6) content showed an increase at 0 and 4 h during PRE and 0 h during POST (P < 0.01), whereas during POST there was a trend toward a lower IL-6 level in AVA vs. C (P = 0.082). Plasma levels of anti-inflammatory agent interleukin-1 receptor antagonist (IL-1Ra) showed an increase at 4 h during PRE, and was significantly elevated in AVA vs. C during POST. Both soluble vascular cell adhesion molecule-1 (sVCAM-1) and monocyte chemoattractant protein-1 (MCP-1) contents increased at 0 and 24 h post DR during PRE as well as POST sessions, however, sVCAM-1 content was lower in AVA vs. C during POST (P < 0.05) and MCP-1 levels were below resting level at 24, 48 and 72 h during POST (P < 0.05). DR increased muscle pain at all post-DR time points (P < 0.01), but the pain level was alleviated by oat supplementation at 48 and 72 h during POST regardless of AVA treatment (P < 0.05). CONCLUSIONS: Oat AVA supplementation reduced circulatory inflammatory cytokines and inhibited expression of chemokines and cell adhesion molecules induced by DR. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02584946 . Registered 23 October 2015.

Pharmacokinetics of tolfenamic acid in green sea turtles (Chelonia mydas) after intravenous and intramuscular administration.

The present study aimed to evaluate the pharmacokinetic features of tolfenamic acid (TA) in green sea turtles, Chelonia mydas. Green sea turtles were administered single either intravenous (i.v.) or intramuscular (i.m.) injection of TA, at a dose of 4 mg/kg body weight (b.w.). Blood samples were collected at preassigned times up to 168 hr. The plasma concentrations of TA were measured using a validated liquid chromatography tandem mass spectrometry method. Tolfenamic acid plasma concentrations were quantifiable for up to 168 hr after i.v. and i.m. administration. The concentration of TA in the experimental green sea turtles with respect to time was pharmacokinetically analyzed using a noncompartment model. The Cmax values of TA were 55.01 ± 8.34 µg/ml following i.m. administration. The elimination half-life values were 32.76 ± 4.68 hr and 53.69 ± 3.38 hr after i.v. and i.m. administration, respectively. The absolute i.m. bioavailability was 72.02 ± 10.23%, and the average binding percentage of TA to plasma protein was 19.43 ± 6.75%. Based on the pharmacokinetic data, the i.m. administration of TA at a dosage of 4 mg/kg b.w. might be sufficient to produce a long-lasting anti-inflammatory effect (7 days) for green sea turtles. However, further studies are needed to determine the clinical efficacy of TA for treatment of inflammatory disease after single and multiple dosages.

Influences of tolfenamic acid and flunixin meglumine on the disposition kinetics of levofloxacin in sheep.

The pharmacokinetics of levofloxacin (4 mg/kg), administered both alone and in combination with tolfenamic acid (2 mg/kg) and flunixin meglumine (2.2 mg/kg), was established after intravenous administration in sheep. Plasma levofloxacin concentrations were assayed by high-performance liquid chromatography and analysed according to the two-compartment open model. Following the administration of levofloxacin alone, the mean distribution half-life, elimination half-life, total clearance, volume of distribution at steady state and area under the plasma concentration-time curve were 0.20 h, 1.82 h, 0.39 L/h/kg, 0.96 L/kg and 10.40 h × µg/mL, respectively. Tolfenamic acid and flunixin meglumine caused a slow elimination and increased plasma concentrations of levofloxacin in combination administration. Levofloxacin, with an alteration in the dosage regimen, can be used effectively with tolfenamic acid and flunixin meglumine for the therapy of infections and inflammatory conditions in sheep.

Phototoxic risk assessment of dermally-applied chemicals with structural variety based on photoreactivity and skin deposition.

Combined use of photochemical and pharmacokinetic (PK) data for phototoxic risk assessment was previously proposed, and the system provided reliable phototoxic risk predictions of chemicals in same chemical series. This study aimed to verify the feasibility of the screening system for phototoxic risk assessment on dermally-applied chemicals with wide structural diversity, as a first attempt. Photochemical properties of test chemicals, 2-acetonaphthalene, 4'-methylbenzylidene camphor, 6-methylcoumarin, methyl N-methylanthranilate, and sulisobenzone, were evaluated in terms of UV absorption and reactive oxygen species (ROS) generation, and PK profiles of the test chemicals in rat skin were characterized after dermal co-application. All test chemicals showed strong UVA/B absorption with molar extinction coefficients of over 3000 M-1⋅cm-1, and irradiated 2-acetonaphthalene, 6-methylcoumarin, and methyl N-methylanthranilate exhibited significant ROS generation. Dermally-applied 2-acetonaphthalene and 4'-methylbenzylidene camphor indicated high and long-lasting skin deposition compared with the other test chemicals. Based on the photochemical and PK data, 2-acetonaphthalene was predicted to have potent phototoxic risk. The predicted phototoxic risk of the test chemicals by integration of obtained data was mostly consistent with their in vivo phototoxicity observed in rat skin. The screening strategy employing photochemical and PK data would have high prediction capacity and wide applicability for photosafety evaluation of chemicals.

TGF-ß inhibition combined with cytotoxic nanomedicine normalizes triple negative breast cancer microenvironment towards anti-tumor immunity.

Tumor normalization strategies aim to improve tumor blood vessel functionality (i.e., perfusion) by reducing the hyper-permeability of tumor vessels or restoring compressed vessels. Despite progress in strategies to normalize the tumor microenvironment (TME), their combinatorial antitumor effects with nanomedicine and immunotherapy remain unexplored. Methods: Here, we re-purposed the TGF-ß inhibitor tranilast, an approved anti-fibrotic and antihistamine drug, and combined it with Doxil nanomedicine to normalize the TME, increase perfusion and oxygenation, and enhance anti-tumor immunity. Specifically, we employed two triple-negative breast cancer (TNBC) mouse models to primarily evaluate the therapeutic and normalization effects of tranilast combined with doxorubicin and Doxil. We demonstrated the optimized normalization effects of tranilast combined with Doxil and extended our analysis to investigate the effect of TME normalization to the efficacy of immune checkpoint inhibitors. Results: Combination of tranilast with Doxil caused a pronounced reduction in extracellular matrix components and an increase in the intratumoral vessel diameter and pericyte coverage, indicators of TME normalization. These modifications resulted in a significant increase in tumor perfusion and oxygenation and enhanced treatment efficacy as indicated by the notable reduction in tumor size. Tranilast further normalized the immune TME by restoring the infiltration of T cells and increasing the fraction of T cells that migrate away from immunosuppressive cancer-associated fibroblasts. Furthermore, we found that combining tranilast with Doxil nanomedicine, significantly improved immunostimulatory M1 macrophage content in the tumorigenic tissue and improved the efficacy of the immune checkpoint blocking antibodies anti-PD-1/anti-CTLA-4. Conclusion: Combinatorial treatment of tranilast with Doxil optimizes TME normalization, improves immunostimulation and enhances the efficacy of immunotherapy.

Avenanthramide-C Restores Impaired Plasticity and Cognition in Alzheimer's Disease Model Mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and dementia with no effective treatment. Here, we investigated a novel compound from oats named avenanthramide-C (Avn-C), on AD-related memory impairment and behavioral deficits in transgenic mouse models. Acute hippocampal slices of wild-type or AD transgenic mice were treated with Avn-C in the presence or absence of oligomeric Aß42. LTP analyses and immunoblotting were performed to assess the effect of Avn-C on Aß-induced memory impairment. To further investigate the effect of Avn-C on impaired memory and Aß pathology, two different AD transgenic mice (Tg2576 and 5XFAD) models were orally treated with either Avn-C or vehicle for 2 weeks. They were then assessed for the effect of the treatment on neuropathologies and behavioral impairments. Avn-C reversed impaired LTP in both ex vivo- and in vivo-treated AD mice hippocampus. Oral administration (6 mg/kg per day) for 2 weeks in AD mice leads to improved recognition and spatial memory, reduced caspase-3 cleavage, reversed neuroinflammation, and to accelerated glycogen synthase kinase-3ß (pS9GSK-3ß) and interleukin (IL-10) levels. Avn-C exerts its beneficial effects by binding to α1A adrenergic receptors to stimulate adenosine monophosphate-activated kinase (AMPK). All of the beneficial effects of Avn-C on LTP retrieval could be blocked by prazosin hydrochloride, a specific inhibitor of α1A adrenergic receptors. Our findings provide evidence, for the first time, that oats' Avn-C reverses the AD-related memory and behavioral impairments, and establish it as a potential candidate for Alzheimer's disease drug development.

Efficacy of a detergent combined with a moisturizer for the treatment of pruritus associated with xerosis in an elderly population affected by Kaposi's sarcoma.

BACKGROUND: Xerosis is common among patients with Kaposi's sarcoma (KS). The aim of our study was to evaluate the efficacy of a detergent containing dihydroavenanthramide D 5% combined with a moisturizer containing 1% of menthol for the treatment of chronic pruritus associated with xerosis in elderly KS patients. METHODS: We conducted a prospective, open-label, intra-individual, right/left comparative study. During the 4-week treatment study, patients used the test products on the right lower limb, and a basic skin cleanser plus basic cream on their left lower limb, in a predefined protocol. A 10 cm visual analogue scale (VAS), the hydration index (HI) of the stratum corneum and the overall dry skin score (ODSS) were used to assess pruritus and xerosis severity on admission, at 2 and 4 weeks. RESULTS: Thirty patients (24 males, 6 females, mean age: 76.6±6.8 years) were enrolled. At the end of 4 weeks, the mean pruritus VAS score declined from 4.2±2.2 to 1.7±1.4 on the right side, and from 4.2±2.2 to 2.3±1.5 on the left side. The HI score increased from 25.6±15.0 to 46.1±12.3 on the right side, and from 26.0±15.2 to 35.4±12.6 on the left side. Differences between the right and left limbs were significant for VAS score (P=0.0064), HI (P<0.0001) and ODSS values (P=0.0049). There was no adverse reaction to the test products. CONCLUSIONS: Daily use of a detergent containing dihydroavenanthramide D 5% combined with a moisturizer containing 1% of menthol improves chronic pruritus associated with xerosis in elderly adults with KS.

The combined effect of tranilast 8% liposomal gel on the final cosmesis of acne scarring in patients concomitantly treated by isotretinoin: prospective, double-blind, split-face study.

BACKGROUND: Tranilast [N-(3,4-dimethoxycinnamoyl) anthranilic acid] has never been investigated for the prevention and treatment of acne scars. AIM: To evaluate the efficacy and safety of tranilast 8% gel in improving the final appearance of patients with acne scarring concomitantly treated by isotretinoin. METHODS: This was a prospective, double-blind, split-face study, which enrolled 40 otherwise healthy participants (aged 18-49 years) with facial acne scars. For each patient, one half of the face were treated with tranilast 8% liposomal gel and the other half with a water-based placebo. Using the Global Aesthetic Improvement Scale (GAIS), acne scars were evaluated by two dermatologists and by the patients, and the patients also rated their satisfaction with the treatment and reported adverse effects. RESULTS: In total, 32 participants completed the trial. The mean GAIS scores at 5 months post-treatment were significantly lower (better outcome) for the tranilast-treated side than the placebo-treated areas in patients concomitantly treated with isotretinoin (P < 0.001). All the isotretinoin-treated patients reported greater satisfaction and better general improvement in the skin's appearance and texture, and also greater improvement of pigment and redness on the tranilast 8% gel-treated side compared with the control side. CONCLUSION: Combined topical application of tranilast 8% gel twice daily with oral isotretinoin treatment in the active phase of acne vulgaris may result in fewer scars, finer skin texture and enhanced appearance.

Pharmacokinetics of tolfenamic acid in Hawksbill turtles (Eretmochelys imbricata) after single intravenous and intramuscular administration.

To the best of our knowledge, limited pharmacokinetic information to establish suitable therapeutic plans is available for Hawksbill turtles. Therefore, the present study aimed to assess the pharmacokinetic features of tolfenamic acid (TA) in Hawksbill turtles, Eretmochelys imbricata, after single intravenous (i.v.) and intramuscular (i.m.) administration at dosage 4 mg/kg body weight (b.w.). The study (parallel design) used 10 Hawksbill turtles randomly divided into equal groups. Blood samples were collected at assigned times up to 144 hr. The concentrations of TA in plasma were quantified by a validated liquid chromatography tandem mass spectrometry (LC-ESI-MS/MS). The concentration of TA in the experimental turtles with respect to time was pharmacokinetically analyzed using a noncompartment model. The Cmax values of TA were 89.33 ± 6.99 µg/ml following i.m. administration. The elimination half-life values were 38.92 ± 6.31 hr and 41.09 ± 9.32 hr after i.v. and i.m. administration, respectively. The absolute i.m. bioavailability was 94.46%, and the average binding percentage of TA to plasma protein was 31.39%. TA demonstrated a long half-life and high bioavailability following i.m. administration. Therefore, the i.m. administration is recommended for use in clinical practice because it is both easier to perform and provides similar plasma concentrations to the i.v. administration. However, further studies are needed to determine the clinical efficacy of TA for treatment of inflammatory disease after single and multiple dosages.

Chlorantraniliprole against the black cutworm Agrotis ipsilon (Lepidoptera: Noctuidae): From biochemical/physiological to demographic responses.

Agrotis ipsilon (Lepidoptera: Noctuidae) is a major underground pest that damages many agricultural crops in China and other countries. A diet-incorporation-based bioassay was conducted to evaluate the sublethal effects of the novel anthranilic diamide chlorantraniliprole on the nutritional physiology, enzymatic properties and population parameters of this cutworm. Chlorantraniliprole exhibited signs of active toxicity against third instar larvae of A. ipsilon, and the LC50 was 0.187 µg.g-1 of artificial diet after treatment for 72 h. The development time of the larval, pupal and adult stages was significantly affected after chlorantraniliprole exposure, compared to the control treatment. Relative to the control treatment, chlorantraniliprole decreased pupal and adult emergence rates, fecundity and fertility and increased the proportions of developmental deformities, the adult preoviposition period (APOP) and the total preoviposition period (TPOP). Furthermore, compared to those treated with the control, A. ipsilon larvae treated with low doses of chlorantraniliprole decreased food utilization and nutrient content (protein, lipid, carbohydrate, trehalose), showed lower pupal weights and growth rates. Compared with the control treatment, chlorantraniliprole significantly reduced digestive enzyme activities and observably increased detoxifying and protective enzyme activities and hormone titers. Importantly, these chlorantraniliprole-induced changes affected life table parameters of the cutworm. These results suggest that chlorantraniliprole at low concentrations can impair A. ipsilon development duration, normal food consumption and digestion process, enzymatic properties, hormone levels, fecundity and population levels. Chlorantraniliprole exhibit the potential to be exploited as a control strategy for this cutworm.

Tranilast enhances the effect of anticancer agents in osteosarcoma.

Tranilast [N­(3',4'­dimethoxycinnamoyl)­anthranilic acid], initially developed as an antiallergic drug, also exhibits a growth inhibitory effect on various types of cancer. Osteosarcoma is treated mainly with high­dose methotrexate, doxorubicin, cisplatin and ifosfamide; however, 20­30% of patients cannot be cured of metastatic disease. We investigated whether tranilast enhances the anticancer effects of chemotherapeutic drugs and analyzed its mechanism of action in osteosarcomas. Tranilast inhibited proliferation of HOS, 143B, U2OS and MG­63 osteosarcoma cells in a dose­dependent manner, as well as enhancing the effects of cisplatin and doxorubicin. The average combination index at effect levels for tranilast in combination with cisplatin was 0.57 in HOS, 0.4 in 143B, 0.39 in U2OS and 0.51 in MG­63 cells. Tranilast and cisplatin synergistically inhibited the viability of osteosarcoma cells. In flow cytometric analysis, although tranilast alone did not induce significant apoptosis, the combination of tranilast and cisplatin induced early and late apoptotic cell death. Expression of cleaved caspase­3, cleaved poly(ADP­ribose) polymerase and p­H2AX was enhanced by tranilast in combination with cisplatin. Tranilast alone increased expression of p21 and Bim protein in a dose­dependent manner. Cell cycle analysis using flow cytometry demonstrated that the combination of tranilast and cisplatin increased the number of cells in the G2/M phase. Compared with cisplatin alone, the combination increased levels of phospho­cyclin­dependent kinase 1 (Y15). In the 143B xenograft model, tumor growth was significantly inhibited by combined tranilast and cisplatin compared with the controls, whereas cisplatin alone did not significantly inhibit tumor growth. In conclusion, tranilast has a cytostatic effect on osteosarcoma cells and enhances the effect of anticancer drugs, especially cisplatin. Enhanced sensitivity to cisplatin was mediated by increased apoptosis through G2/M arrest. Since tranilast has been clinically approved and has few adverse effects, clinical trials of osteosarcoma chemotherapy in combination with tranilast are expected.

Avenanthramide A Induces Cellular Senescence via miR-129-3p/Pirh2/p53 Signaling Pathway To Suppress Colon Cancer Growth.

Cellular senescence is the state of irreversible cell cycle arrest that provides a blockade during oncogenic transformation and tumor development. Avenanthramide A (AVN A) is an active ingredient exclusively extracted from oats, which possesses antioxidant, anti-inflammatory, and anticancer activities. However, the underlying mechanism(s) of AVN A in the prevention of cancer progression remains unclear. In the current study, we revealed that AVN A notably attenuated tumor formation in an azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model. AVN A treatment triggered cellular senescence in human colon cancer cells, evidenced by enlarging cellular size, upregulating ß-galactosidase activity, γ-H2AX positive staining, and G1 phase arrest. Moreover, AVN A treatment significantly increased the expression of miR-129-3p, which markedly repressed the E3 ubiquitin ligase Pirh2 and two other targets, IGF2BP3 and CDK6. The Pirh2 silencing by miR-129-3p led to a significant increase in protein levels of p53 and its downstream target p21, which subsequently induced cell senescence. Taken together, our data indicate that miR-129-3p/Pirh2/p53 is a critical signaling pathway in AVN A induced cellular senescence and AVN A could be a potential chemopreventive strategy for cancer treatment.

Distribution of methyl and isopropyl N-methylanthranilates and their metabolites in organs of rats treated with these two essential-oil constituents.

Two volatile alkaloids, methyl (MMA) and isopropyl N-methylanthranilates (IMA), identified in the essential oil of Choisya ternata Kunth (Rutaceae), have been proven to possess polypharmacological properties (antinociceptive, anti-inflammatory, gastro-, hepato-, nephroprotective activities, anxiolytic and antidepressant properties, and likewise an effect on diazepam-induced sleep). In the continuation of our investigation of their urinary-metabolite profiles, we performed GC-MS analyses of the diethyl-ether extracts of selected tissues (liver, kidneys, heart, brain, lungs, quadriceps femoris muscle, and spleen) of rats intraperitoneally treated with MMA or IMA (2 g kg-1). Organ-metabolite profiles of MMA and IMA were qualitatively mutually analogous (varying only in the alcohol moiety of the metabolites), and generally analogous to their urinary-metabolite profiles. The greatest diversity and the highest overall amount of anthranilate metabolites was found in the hepatic tissue. The principal anthranilate-related compounds in the organs of rats treated with MMA, among 12 detected, were the products of ester hydrolysis, N-methylanthranilic and anthranilic acids. In the tissues of IMA-treated rats, among 16 compounds, the most abundant ones were the unmetabolized IMA and N-methylanthranilic acid. A collection of the compositional data regarding the anthranilate-related metabolites was statistically treated by multivariate statistical analysis that provided a better insight into the possible biotransformation pathways.

Changes in novel gastrointestinal and renal injury markers in the blood plasma of sheep following increasing intravenous doses of tolfenamic acid.

The administration of high doses of non-steroidal anti-inflammatory drugs (NSAID), such as tolfenamic acid (TA), has undesirable effects on different organs. Some novel biomarkers have been reported that can determine the gastrointestinal and renal injury caused by a high dose of NSAIDs or other toxic substances. This study was aimed at determining the changes in gastrointestinal (TFF2 and HYP), renal (NGAL and KIM-1) and cardiac (cTn-I, CK-MB) injury markers after the use of increasing intravenous doses of TA in sheep. TA was administered intravenously to groups of six sheep each, at the dose levels of 0 (Group 0, i.e., G0), 2 (G2), 4 (G4), 8 (G8) and 16 (G16) mg/kg. The concentrations of the studied biomarkers were measured at 3, 9, 18 and 36 h after administration of TA. The TFF2 and NGAL concentrations in G16 were found to be significantly higher (P < 0.05) than in the other groups except for G8 at different sampling times. HYP concentration in G16 was observed to be significantly (P < 0.05) lower than that in all other groups at 36 h. KIM-1 level in G16 was significantly (P < 0.05) higher than in all other groups at different sampling times. An increase in the renal markers, KIM-1 and NGAL, in G8 was observed before any change in plasma creatinine and urea. The cardiac marker cTn-I in G16 was significantly (P < 0.05) higher than in other groups at different sampling times. The results showed that the novel biomarkers (HYP, TFF2, NGAL, and KIM-1) can be used to determine gastric and renal injury in sheep.

Clinical and confocal evaluation of avenanthramides-based daily cleansing and emollient cream in pediatric population affected by atopic dermatitis and xerosis.

BACKGROUND: Xerosis and atopic dermatitis (AD) are chronic skin conditions that occur in children and adults which can result in scaling, flaking and itching. Risk factors for xerosis include sunlight, friction, low humidity and use of soaps. Xerosis is also a symptom of cutaneous conditions such as psoriasis, dermatitis and ichthyosis. AD has a complex pathogenesis but there is increased evidence that a genetically-impaired skin barrier plays a primary role in its development. METHODS: The aim of this study is to evaluate the efficacy of the combination of a product for topical application to be used for daily cleansing and an emollient cream with colloidal oatmeal, avenanthramides, shea butter and oat oil in patients with xerosis and AD. Indeed, emollients play a key role in the treatment of xerosis and of mild to moderate AD because help to restore and maintain the skin barrier function. Topical emollients are considered first-line treatment in those conditions. Outcomes included Investigators' Global Assessment (IGA) (0=clear, 5=very severe), Eczema Area and Severity Index (EASI) composite score, Itch severity (0=none, 4=severe), and Infant's Dermatitis Quality of Life Index (IDQOL). The evaluation of the response to treatment was also measured through the use of photographic documentation and examination by Reflectance Confocal Microscopy (RCM) performed at baseline and after therapy. RESULTS: The evaluation of the response to treatment was also measured through the use of photographic documentation and examination by reflectance confocal microscopy (RCM) performed at baseline and after therapy. Our results showed improvement in epidermal thickness, skin dryness, itching and cracking after one month of use of the oat cleanser and lotion. CONCLUSIONS: Colloidal oatmeal has been shown to safely reduce itching and irritation associated with AD and the severity of dry skin. These benefits, mediated by colloidal oatmeal's natural components, help to restore and maintain skin barrier function. This compound is safe, well tolerated, and can be effective as adjuvant treatment in AD. Moisturizers can reduce the dependency on topical corticosteroids and their potential adverse effects.

Tranilast Treatment Attenuates Cerebral Ischemia-Reperfusion Injury in Rats Through the Inhibition of Inflammatory Responses Mediated by NF-κB and PPARs.

Ischemia-reperfusion injury (IRI) occurs when blood supply returns to tissue after interruption, which is associated with life-threatening inflammatory response. Tranilast is a widely used antiallergic agent in the treatment against bronchial asthma and keloid. To study the function of tranilast, we used IRI in rat models. The brain tissues of IRI rats with or without tranilast treatment were collected. Neuronal apoptosis in the brain was detected by terminal deoxynucleotidyl transferase nick end labeling assay, and proinflammatory cytokine levels were measured by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. The expression levels of nuclear factor-kappa B (NF-κB), inhibitor of κB (IκB) and peroxisome proliferator-activated receptors (PPARs) were detected by Western blot. The results showed that tranilast treatment reduced neuronal apoptosis in the brain of IRI rats. Tranilast enhanced the short-term memory and long-term memory to novel object recognition paradigm. Tranilast treatment decreased the messenger RNA (mRNA) and protein levels of multiple proinflammatory cytokines, and affected NF-κB and inhibitor of kappa B protein expressions. Tranilast promoted the expressions of PPAR-α and PPAR-γ. Our findings demonstrate that tranilast treatment could attenuate cerebral IRI by regulating the inflammatory cytokine production and PPAR expression. Tranilast is a potential drug for IRI treatment in the clinic.