Natural Amino Acid-Bearing Carbamate Prodrugs of Daidzein Increase Water Solubility and Improve Phase II Metabolic Stability for Enhanced Oral Bioavailability.

Daidzein (DAN) is an isoflavone, and it is often found in its natural form in soybean and food supplements. DAN has poor bioavailability owing to its extremely low water solubility and first-pass metabolism. Herein, we hypothesized that a bioactivatable natural amino acid-bearing carbamate prodrug strategy could increase the water solubility and metabolic stability of DAN. To test our hypothesis, nine amino acid prodrugs of DAN were designed and synthesized. Compared with DAN, the optimal prodrug (daidzein-4'-O-CO-N-isoleucine, D-4'-I) demonstrated enhanced water solubility and improved phase II metabolic stability and activation to DAN in plasma. In addition, unlike the passive transport of DAN, D-4'-I maintained high permeability via organic anion-transporting polypeptide 2B1 (OATP2B1)-mediated transport. Importantly, D-4'-I increased the oral bioavailability by 15.5-fold, reduced the gender difference, and extended the linear absorption capacity in the pharmacokinetics of DAN in rats. Furthermore, D-4'-I exhibited dose-dependent protection against liver injury. Thus, the natural amino acid-bearing carbamate prodrug strategy shows potential in increasing water solubility and improving phase II metabolic stability to enhance the oral bioavailability of DAN.

Evaluation of the effect of a novel substrate that is composed of landfill-mined-soil-like-fractions on plant growth and heavy metal accumulation.

In the pursuit of a safe, low-cost, and sustainable method for the reuse of landfill-mined-soil-like-fractions (LFMSFs), pot experiments were conducted using seven growth substrates consisting of LFMSFs, tea residue, and peat for the cultivation of Photinia × fraseri. Six of the substrates had 40 %:60 %, 60 %:40 %, and 80 %:20 % volume ratios of LFMSFs to tea residue or peat, and one substrate consisted entirely of LFMSFs. The physicochemical properties of the substrate, growth parameters of the plants, and heavy metal content in the different pots were determined after one year of growth. The results indicated that the physicochemical properties of the substrate, that was composed of a mixture of LFMSFs and tea residue showed a significant improvement in organic matter, nitrogen, phosphorus, and potassium. However, there was also an increase in the salt and heavy metal contents when compared with those of peat. The plant growth in the LFMSF and tea residue substrate was slightly lower than that in the LFMSF and peat mixture. Notably, the best plant growth and environmentally friendly effects were observed when LFMSFs were added at 40 %. Additionally, most of the heavy metals were primarily removed from the substrate through the leaves of the seedlings, with the heavy metal contents being relatively low. In conclusion, LFMSFs as a cultivation substrate, represent a practical approach for reutilization, which could contribute to the reduction of reliance on traditional resources.

Investigating the pharmacological mechanism of Zhengyuan jiaonang for treating colorectal cancer via network pharmacology analysis and experimental verification.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhengyuan jiaonang (ZYJN) is a traditional Chinese patent medicine (CPM) used in China for adjuvant cancer therapy, which has been proved to have anti-fatigue effects. AIM OF STUDY: The study aims to investigate the antitumor effects of ZYJN and its underlying mechanisms using subcutaneous transplant CT26 model. MATERIALS AND METHODS: Fingerprint analysis of ZYJN was performed using high performance liquid chromatography. The potential targets of ZYJN were predicted using bioinformatic analysis, which were further validated by Western Blot assay. Subcutaneous transplant CT26 model was used to evaluate the antitumor effects of ZYJN. The effects of ZYJN on the tumor immune microenvironment were investigated by flow cytometry. Transparent imaging was used to investigate the effects of ZYJN on fibrosis and angiogenesis. RESULTS: ZYJN could inhibit colorectal cancer growth when administered alone or in combination with 5-FU. The combination of ZYJN and 5-FU could significantly increase the serum level of albumin (ALB) and decrease the serum level of aspartate aminotransferase (AST). In addition, the combination of ZYJN at 0.75 g/kg and 5-FU significantly decreased the serum level of vascular endothelial growth factors (VEGF) and inhibited the angiogenesis of CT26 cancer. The combination of ZYJN at 1.50 g/kg and 5-FU could promote the fibrosis process of CT26 cancer. Additionally, combination of ZYJN and 5-FU could significantly increase the percentage of tumor-infiltrating T cells and CD4+ T cells in the late stage of CT26 model, while ZYJN at 1.50 g/kg increased the percentage of NK cells as well as CD8+ T cells in the early stage of CT26 model. Western Blot analysis revealed that administration of ZYJN at 0.75 g/kg reduced the expression of PI3K-p110α, CDK1, CCNB1 and MMP-9, and inhibited the phosphorylation of Akt (Thr308). CONCLUSIONS: ZYJN could inhibit the tumor growth of CT26 colorectal cancer by promoting tumor fibrosis, suppressing angiogenesis, migration, and invasion and modulating the tumor immune microenvironment. ZYJN enhanced the efficacy and reduced the toxicity of chemotherapy drugs in combination therapy. Our findings provide evidence for the clinical application of ZYJN in cancer treatment.

SFC-MS/MS method for simultaneous determination of nimodipine and 3-n-butylphthalide in beagle plasma: application to pharmacokinetic interaction study.

Aim: Nimodipine and 3-n-butylphthalide are co-administered to treat vascular dementia, but the pharmacokinetic interaction between the two drugs is still unknown. Therefore, a robust, high-throughput and economical supercritical fluid chromatography-ESI-MS/MS method has been initially developed to simultaneously determine nimodipine and 3-n-butylphthalide in beagle plasma, in order to study the safety of co-administration. Materials & methods: After a simple protein precipitation procedure, isocratic elution with mobile phase of CO2 and methanol (containing 0.3% formic acid and 2 mM ammonium acetate) was applied to minimize run time and facilitate sensitive and high-throughput bioanalysis. The method was fully validated according to US FDA Guidance. The validated method was then successfully applied in a pharmacokinetic interaction study. Results: The results indicated there is no significant pharmacokinetic interaction between the two drugs.

Omega-3 fatty acids ameliorate cognitive dysfunction in schizophrenia patients with metabolic syndrome.

Our previous study showed that metabolic abnormalities reduced the levels of brain-derived neurotrophic factor (BDNF) and deteriorated cognitive performance in patients with schizophrenia. Inflammation may play a key role in this process. Omega-3 fatty acids have been documented to ameliorate inflammation. Therefore, we hypothesized that omega-3 fatty acids may be of value in enhancing BDNF levels and improving cognitive function in patients with schizophrenia with metabolic syndrome (MetS). We recruited 80 patients with both schizophrenia and MetS who received long-term olanzapine monotherapy. The enzyme-linked immunosorbent assay was used to measure the plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). The patients were randomly assigned to the OMG-3 group (n = 40) or the placebo group (n = 40). Of the 80 patients who consented to the study, 72 completed this 12-week RCT. The primary outcome was the changes from baseline to 12 weeks in clinical characteristics and the levels of BDNF, CRP, IL-6 and TNF-α. There was a significant correlation between omega-3 fatty acid treatment and enhanced delayed memory factor in the RBANS assessment (Fgroup×time = 6.82; df = 1, 66; P = 0.01) when the patients completed this study. Along with cognitive improvement, omega-3 fatty acids enhanced BDNF (Fgroup×time = 4.93; df = 1, 66; P = 0.03) and reduced CRP (Fgroup×time = 17.11; df = 1, 66; P < 0.01), IL-6 (Fgroup×time = 9.71; df = 1, 66; P < 0.004) and TNF-α (Fgroup×time = 6.71; df = 1, 66; P = 0.012) levels after 12 weeks of treatment. The changes in BDNF levels are negatively correlated with the changes in TNF-α levels (r = -0.37, P = 0.03) but not with the changes in CRP and IL-6 levels. Our findings provide suggestive evidence that omega-3 fatty acids have beneficial effects on cognitive function in patients with MetS, which is paralleled by enhanced BDNF levels.

(-)-Epigallocatechin-3-Gallate Protects Against Lithium-Pilocarpine-Induced Epilepsy by Inhibiting the Toll-Like Receptor 4 (TLR4)/Nuclear Factor-κB (NF-κB) Signaling Pathway.

BACKGROUND Temporal lobe epilepsy (TLE) is the most common type of intractable epilepsy in humans, and it is often accompanied by cognitive impairment. In this study, we examined the effects of (-)-Epigallocatechin-3-gallate (EGCG) after SE on behavior in the rat lithium-pilocarpine model of TLE. MATERIAL AND METHODS The rats were randomly divided into 3 groups: (1) the control group, in which 12 rats received no treatment); (2) the epilepsy (EP) group, in which 15 rats were treated with saline after status epilepticus (SE); and (3) the EP+EGCG group, in which 15 rats were treated with EGCG (25 mg/kg/d, intraperitoneal) after SE. The SE model was induced with lithium chloride-pilocarpine, and electroencephalography and a high-definition camera were used to monitor SRS. The Morris water maze test and hippocampal late-phase long-term potentiation (L-LTP) recordings were used to evaluate cognitive impairment, and TLR4, NF-kappaB, and IL-1ß levels were determined using Western blot analysis. RESULTS We concluded that EGCG treatment after SE (1) markedly reduced SRS frequency in pilocarpine-treated rats, (2) improved epilepsy-induced cognitive impairment and reversed epilepsy-induced synaptic dysfunction in L-LTP in vivo, (3) protected hippocampal neurons from damage after SRS, and (4) significantly attenuated the increase in TRL-4 and IL-1ß hippocampal levels. The above findings clearly show that EGCG exerts antiepileptogenesis and neuroprotective effects on pilocarpine-induced epilepsy. CONCLUSIONS We found that EGCG can suppress seizures and inhibit hippocampal neuronal apoptosis, as well as improving cognitive function of epileptic rats. Our findings suggest that EGCG may a novel adjuvant therapeutic approach in epilepsy by improving epileptic behavior and cognitive dysfunction.

Neuroprotective effect of astaxanthin on newborn rats exposed to prenatal maternal seizures.

Maternal epilepsy during pregnancy is associated with an increased incidence of brain damage and cognitive deficits in offspring. Oxidative stress is believed to play a critical role in this process. Astaxanthin, a natural carotenoid and dietary supplement, possesses potent antioxidant properties. This study was designed to investigate whether astaxanthin ameliorates the hippocampal damage in newborn rats induced by maternal epileptic seizures in utero and to explore the underlying mechanisms. Female Sprague-Dawley rats underwent chronic amygdalar kindling. After being fully kindled, all rats were allowed to mate, and electrical stimulation in the amygdala was performed every other day throughout the pregnancy. Astaxanthin was intraperitoneally injected at a dose of 30 mg/kg/d throughout pregnancy. Prenatal astaxanthin administration ameliorated neuronal lesions, decreased oxidative stress and induced the expression of cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus of pups. Astaxanthin also ameliorated placental ischemic damage in epileptic mothers. Based on the results of the present study, we concluded that astaxanthin might serve as a therapeutic agent for preventing brain damage in offspring exposed to prenatal maternal seizures.

Intravenous treatment of choroidal neovascularization by photo-targeted nanoparticles.

Choroidal neovascularization (CNV) is the major cause of vision loss in wet age-related macular degeneration (AMD). Current therapies require repeated intravitreal injections, which are painful and can cause infection, bleeding, and retinal detachment. Here we develop nanoparticles (NP-[CPP]) that can be administered intravenously and allow local drug delivery to the diseased choroid via light-triggered targeting. NP-[CPP] is formed by PEG-PLA chains modified with a cell penetrating peptide (CPP). Attachment of a DEACM photocleavable group to the CPP inhibits cellular uptake of NP-[CPP]. Irradiation with blue light cleaves DEACM from the CPP, allowing the CPP to migrate from the NP core to the surface, rendering it active. In mice with laser-induced CNV, intravenous injection of NP-[CPP] coupled to irradiation of the eye allows NP accumulation in the neovascular lesions. When loaded with doxorubicin, irradiated NP-[CPP] significantly reduces neovascular lesion size. We propose a strategy for non-invasive treatment of CNV and enhanced drug accumulation specifically in diseased areas of the eye.

Explosible nanocapsules excited by pulsed microwaves for efficient thermoacoustic-chemo combination therapy.

Microwave irradiation is a powerful non-invasive approach for treating deep-seated diseases in a clinical setting. Pulsed microwave-induced thermoacoustic cavitation allows precise cancer treatment with microwave-absorbing materials. This differs from the traditional continuous microwave-induced thermotherapy which may be harmful to off-target tissues. Here we first report the integration of thermocavitation and cytoplasmic drug release into highly explosible cell-penetrating nanocapsules for effective tumor inhibition under pulsed microwave irradiation. The nanocapsules were formulated from arginine-tethered reduction-responsive copolymers, P(ArgMA-co-DMA)-b-PPOPMA, microwave-absorbing AB and chemotherapeutic DOX using a double-emulsion method. The nanocapsules were internalized by cancer cells rapidly via major energy-independent pathways. Upon pulsed microwave irradiation, AB absorbed energy to generate a giant thermoacoustic shockwave, simultaneously decomposing into carbon dioxide and ammonia which enforced the cavitation damage effect. The thermoacoustic shockwave and gas burst also mechanically disrupted the intracellular organelles resulting in high-ratio cell necrosis and promoted the cytosolic release of DOX into the nucleus to initiate cell death. Importantly, in vivo results demonstrated significantly suppressed tumor growth by the pulsed microwave-triggered thermocavitation and drug release, and minimal systemic toxicity from the microwave treatment. Therefore, our study provides a new strategy for effectively engineering pulsed microwave-responsive nanomaterials for smart cancer therapy.

Effects of omega-3 fatty acids on metabolic syndrome in patients with schizophrenia: a 12-week randomized placebo-controlled trial.

RATIONALE: Individuals with schizophrenia are at increased risk of developing metabolic syndrome (MetS) due to their lifestyle and antipsychotic treatment. Our previous study showed that patients with both schizophrenia and MetS present an increased expression and production of tumor necrosis factor-alpha (TNF-alpha). Omega-3 fatty acids have a documented role in suppressing TNF-alpha; therefore, we hypothesized that they may be of value in relieving inflammation and improving metabolic disturbance in patients with both schizophrenia and MetS. OBJECTIVES: This study employed a randomized placebo-controlled trial to investigate the effects of omega-3 fatty acids on MetS in patients with schizophrenia. METHODS: We recruited 80 patients with both schizophrenia and MetS who received long-term olanzapine monotherapy. The patients were randomly assigned to the OMG-3 group (n = 40) or the placebo group (n = 40). RESULTS: Patients with both schizophrenia and MetS had significantly higher levels of TNF-alpha than the control subjects (Z = - 4.37, P < 0.01). There was a significant correlation between omega-3 fatty acid treatment and reduced triglyceride (TG) levels (Fgroup × time = 13.42; df = 1, 66; P < 0.01) when the patients completed this study. Along with metabolic improvement, omega-3 fatty acids decreased TNF-alpha levels after 12 weeks of treatment (Fgroup × time = 6.71; df = 1, 66; P = 0.012). We also found that the extent of TNF-alpha decrease was significantly correlated with that of TG decrease (r = 0.38, P = 0.001). CONCLUSIONS: Our findings provide suggestive evidence that omega-3 fatty acids have beneficial effects on TG metabolism in patients with both schizophrenia and MetS that parallel decreased inflammation levels.

A black phosphorus/manganese dioxide nanoplatform: Oxygen self-supply monitoring, photodynamic therapy enhancement and feedback.

Selecting the timing of laser treatment is an important task for improving O2-dependent photodynamic therapy (PDT) efficiency. Here, a black phosphorus-based strategy was developed for dual-mode monitoring oxygen self-supply, enhancing photodynamic therapy, and feeding back therapeutic effect. The hybridized nanoplatform (R-MnO2-FBP) was prepared by assembly of Rhodamine B (RhB)-encapsulated manganese dioxide (R-MnO2) as O2 supplier and indicator, and fluorescein isothiocyanate (FITC)-labelled peptide-functionalized black phosphorus as the theranostic agent. The time-dependent assays suggested that the O2 release was proportional to the liberation of Mn2+ and RhB in the R-MnO2-FBP system. After specific delivery into cancer cells, R-MnO2-FBP was dissociated in the acidic and H2O2-rich environment and generated oxygen to overcome hypoxia-associated PDT resistance. In the meantime, it released both Mn2+and RhB dye, leading to dual-mode (magnetic resonance imaging/fluorescence imaging) monitoring of the oxygen self-supply process. More significantly, the imaging-guided PDT in hypoxic cells displayed 51.6% of cell apoptosis at optimizing timing of laser application, which could also be confirmed by the FITC fluorescence recovery induced by the activated caspase-3 in apoptotic cells. In vivo photonic therapy by R-MnO2-FBP further demonstrated the ability of R-MnO2-FBP to choose the timing of laser application, providing an efficient approach for the enhancement of PDT process.

Gene Therapy and Photothermal Therapy of Layer-by-Layer Assembled AuNCs /PEI/miRNA/ HA Nanocomplexes.

BACKGROUND: MicroRNA (miRNA) therapy, which was widely considered to treat a series of cancer, has been confronted with numerous obstacles to being delivered into target cells because of its easy biodegradation and instability. METHODS: In this research, we successfully constructed 11-mercaptoundecanoic acid modified gold nanocages (AuNCs)/polyethyleneimine (PEI)/miRNA/hyaluronic acid (HA) complexes (abbreviated as AuNCs/PEI/miRNA/HA) using a layer-by-layer method for target-specific intracellular delivery of miRNA by HA receptor mediated endocytosis. RESULTS: The results of UV spectra, hydrodynamic diameter and zeta potential analyses confirmed the formation of AuNCs/PEI/ miRNA/HA complex with its average particle size of ca. 153 nm and surface charge of ca. -9.43 mV. Next, we evaluated the antitumor effect of the nanocomplex mediated by the combination of gene therapy and photothermal therapy (PTT) against hepatocellular carcinoma (HCC) in vitro. CONCLUSION: Our experimental results indicated that the AuNCs/PEI/miRNA/HA complex effectively delivered miRNA to the target cells and its antitumor effect was significantly enhanced by the combination of gene therapy and photothermal therapy. In addition, anti-miR-181b could promote Bel-7402 cell arrest in S phase and improve TIMP-3 mRNA expression. All these results suggested that AuNCs/PEI/miRNA/HA gene delivery system with combination of gene therapy and photothermal therapy might be exploited for HCC treatment.

Ethyl Acetate Fraction of Hemerocallis citrina Baroni Decreases Tert-butyl Hydroperoxide-Induced Oxidative Stress Damage in BRL-3A Cells.

The main purposes of this study were to screen the antioxidant activities of various fractions of Hemerocallis citrina Baroni and test their hepatoprotective effects in vitro. Antioxidant assays (2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and reducing power experiments) and tert-butyl hydroperoxide- (t-BHP-) induced BRL-3A oxidative damage experiments were performed in vitro. The H. citrina ethyl acetate fraction (HCEA) was determined to have strong antioxidant activity because of its high flavonoid and polyphenol content. Ultraperformance liquid chromatography- (UPLC-) photodiode array (PDA)/mass spectrometry (MS) analysis showed that the main components of the HCEA were flavonoids and caffeic acid derivatives. A total of 17 compounds were identified. HCEA also effectively protected the liver against t-BHP-induced oxidative stress injury and significantly reduced reactive oxygen (ROS) accumulation. Moreover, HCEA significantly reduced levels of alanine aminotransferase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH). Further studies have shown that HCEA inhibits t-BHP-induced apoptosis by increasing B-cell lymphoma-2 (BCL-2) activity and decreasing caspase-3 and caspase-9 activity. Moreover, HCEA enhanced the activity of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), as well as the total antioxidant capacity (T-AOC), and increased the antioxidant level of glutathione (GSH) in BRL-3A cells. HCEA increased the antioxidant capacity of cells by increasing the gene expression of AMP-activated protein kinase (AMPK), extracellular signal-regulated kinase (ERK), P38, nuclear factor, erythroid 2 like 2 (Nrf2), SOD, glutamate-cysteine ligase catalytic subunit (GCLC), glutamate-cysteine ligase modifier subunit (GCLM), and heme oxygenase 1 (HO-1), which are associated with antioxidant pathways to protect against oxidative stress. In conclusion, HCEA protected BRL-3A cells against t-BHP-induced oxidative stress damage via antioxidant and antiapoptosis pathways. Therefore, H. citrina Baroni may serve as a potential hepatoprotective drug.

BaTiO3-core Au-shell nanoparticles for photothermal therapy and bimodal imaging.

We report sub-100 nm metal-shell (Au) dielectric-core (BaTiO3) nanoparticles with bimodal imaging abilities and enhanced photothermal effects. The nanoparticles efficiently absorb light in the near infrared range of the spectrum and convert it to heat to ablate tumors. Their BaTiO3 core, a highly ordered non-centrosymmetric material, can be imaged by second harmonic generation, and their Au shell generates two-photon luminescence. The intrinsic dual imaging capability allows investigating the distribution of the nanoparticles in relation to the tumor vasculature morphology during photothermal ablation. Our design enabled in vivo real-time tracking of the BT-Au-NPs and observation of their thermally-induced effect on tumor vessels. STATEMENT OF SIGNIFICANCE: Photothermal therapy induced by plasmonic nanoparticles has emerged as a promising approach to treating cancer. However, the study of the role of intratumoral nanoparticle distribution in mediating tumoricidal activity has been hampered by the lack of suitable imaging techniques. This work describes metal-shell (Au) dielectric-core (BaTiO3) nanoparticles (abbreviated as BT-Au-NP) for photothermal therapy and bimodal imaging. We demonstrated that sub-100 nm BT-Au-NP can efficiently absorb near infrared light and convert it to heat to ablate tumors. The intrinsic dual imaging capability allowed us to investigate the distribution of the nanoparticles in relation to the tumor vasculature morphology during photothermal ablation, enabling in vivo real-time tracking of the BT-Au-NPs and observation of their thermally-induced effect on tumor vessels.

A54 peptide-mediated functionalized gold nanocages for targeted delivery of DOX as a combinational photothermal-chemotherapy for liver cancer.

The combination of photothermal therapy and chemotherapy (photothermal-chemotherapy) is a promising strategy for cancer therapy. Gold nanocages (AuNCs), with hollow and porous structures and unique optical properties, have become a rising star in the field of drug delivery. Here, we designed a novel targeted drug delivery system based on functionalized AuNCs and evaluated their therapeutic effects in vitro and in vivo. We then loaded doxorubicin into this promising system, designated as DHTPAuNCs consisting of hyaluronic acid-grafted and A54 peptide-targeted PEGylated AuNCs. Its formation was corroborated by ultraviolet-visible spectroscopy, transmission electron microscopy and dynamic light scattering. This delivery platform needed hyaluronidase to release encapsulated drugs, meanwhile the acidic pH and near-infrared irradiation could accelerate the release. In addition, the results of cellular uptake demonstrate that this system could bind specifically with BEL-7402 cells. In vitro, we evaluated therapeutic effects of the DHTPAuNCs in BEL-7402 cells by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide assay. Moreover, in BEL-7402 tumor-bearing nude mice, its therapy effect in vivo was also evaluated. As expected, DHTPAuNCs exhibited excellent therapeutic effect by photothermal-chemotherapy, both in vitro and in vivo. In short, DHTPAuNCs with low toxicity showed great potential as a drug delivery system for cancer therapy.

Ultrasensitive Phototriggered Local Anesthesia.

An injectable local anesthetic producing repeatable on-demand nerve block would be desirable for pain management. Here we present a phototriggerable device to achieve repeatable and adjustable on-demand local anesthesia in superficial or deep tissues, consisting of gold nanorods attached to low temperature sensitive liposomes (LTSL). The particles were loaded with tetrodotoxin and dexmedetomidine. Near-infrared light (NIR, 808 nm, continuous wave) could heat gold nanorods at low fluence (short duration and low irradiance), leading to rapid release of payload. In vivo, 1-2 min of irradiation at ≤272 mW/cm2 produced repeatable and adjustable on-demand infiltration anesthesia or sciatic nerve blockade with minimal toxicity. The nerve block intensity and duration correlated with the irradiance and duration of the applied light.

Treatment of otitis media by transtympanic delivery of antibiotics.

Otitis media is the most common reason U.S. children receive antibiotics. The requisite 7- to 10-day course of oral antibiotics can be challenging to deliver in children, entails potential systemic toxicity, and encourages selection of antimicrobial-resistant bacteria. We developed a drug delivery system that, when applied once to the tympanic membrane through the external auditory canal, delivers an entire course of antimicrobial therapy to the middle ear. A pentablock copolymer poloxamer 407-polybutylphosphoester (P407-PBP) was designed to flow easily during application and then to form a mechanically strong hydrogel on the tympanic membrane. U.S. Food and Drug Administration-approved chemical permeation enhancers within the hydrogel assisted flux of the antibiotic ciprofloxacin across the membrane. This drug delivery system completely eradicated otitis media from nontypable Haemophilus influenzae (NTHi) in 10 of 10 chinchillas, whereas only 62.5% of animals receiving 1% ciprofloxacin alone had cleared the infection by day 7. The hydrogel system was biocompatible in the ear, and ciprofloxacin was undetectable systemically (in blood), confirming local drug delivery and activity. This fast-gelling hydrogel could improve compliance, minimize side effects, and prevent systemic distribution of antibiotics in one of the most common pediatric illnesses, possibly minimizing the development of antibiotic resistance.

Salidroside protects against kainic acid-induced status epilepticus via suppressing oxidative stress.

There are numerous mechanisms by which the brain generates seizures. It is well known that oxidative stress plays a pivotal role in status epilepticus (SE). Salidroside (SDS) extracted from Rhodiola rosea L. shows multiple bioactive properties, such as neuroprotection and antioxidant activity in vitro and in vivo. This study explored the role of SDS in kainic acid (KA)-induced SE and investigated the underlying mechanism. Latency to SE increased in the SDS-pretreated mice compared to the KA group, while the percentage of incidence of SE was significantly reduced. These results suggested that pretreatment with SDS not only delayed SE, but it also decreased the incidence of SE induced by KA. KA increased MDA level and reduced the production of SOD and GSH at multiple timepoints after KA administration. SDS inhibited the change of MDA, SOD and GSH induced by KA prior to SE onset, indicating that SDS protects against KA-induced SE via suppressing oxidative stress. Based on these results, we investigated the possible molecular mechanism of SDS. Pretreatment with SDS reversed the KA-induced decrease in AMP-activated protein kinase (AMPK); increased the sirtuin 1 (SIRT1) deacetylase activity in KA-treated mice, which had no demonstrable effect on SIRT1 mRNA and protein; and suppressed the KA-induced increase in Ace-FoxO1. These results showed that AMPK/SIRT1/FoxO1 signaling is possibly the molecular mechanism of neuroprotection by SDS.

[Structure-activity relationship of gastrodin and parishins on learning and memory deficits induced by scopolamine].

Gastrodin, parishin and parishin C were purified from a water extract of GE (rhizome of Gastrodia elata, an herb medicine for treatment of neuronal disorders). In order to compare the pharmacological effects of gastrodin, parishin and parishin C on improving cognition deficits, we tested them in an animal model of cognition disorders induced by scopolamine and in a study of in vivo long-term potentiation (LTP) recordings. In the Morris water maze task, parishin C (15 and 50 mg·kg(-1), P<0.05) and parishin (150 mg·kg(-1), P<0.05), improved spatial learning and memory significantly. However, gastrodin showed no significant effects at the dose of 150 mg·kg(-1). In vivo LTP recordings showed that parishin C at 5,10 and 20 mg·kg(-1), parishin at 10, 30 and 100 mg·kg(-1) reversed the suppression of LTP by scopolamine in rats in a dose-dependent manner. However, gastrodin at 100 mg·kg(-1) showed only a modest effect. In summary, the action of parishin C in the improvement of dementia induced by scopolamine was more potent than parishin and gastrodin.

Effect of an Olive Oil-Based Lipid Emulsion Compared With a Soybean Oil-Based Lipid Emulsion on Liver Chemistry and Bile Acid Composition in Preterm Infants Receiving Parenteral Nutrition: A Double-Blind, Randomized Trial.

BACKGROUND: The pathogenesis of parenteral nutrition (PN)-associated liver dysfunction is multifactorial. Lipid emulsions may be one of the putative mechanisms. Our aim was to comparatively assess the effect of parenteral olive oil- and soybean oil-based lipid emulsions on liver chemistry and bile acid composition in preterm infants. METHODS: We performed a double-blind, randomized clinical study in which 103 preterm infants were randomly assigned to PN using either soybean oil-based lipid emulsion (SO; n = 51) or olive oil (OO)-based lipid emulsion (OO; n = 52). The primary end point was liver chemistry. The secondary end point was the plasma bile acid composition. RESULTS: One hundred infants completed this study. In the SO group, the serum direct bilirubin was significantly higher after PN for 7 days compared with the OO group. Bile acids increased over time in both treatment groups. However, specific differences in the change in bile acid composition over time were noted between groups. CONCLUSIONS: Differences in direct bilirubin and bile acid composition were observed over time between the 2 groups. Considering the long-term use of lipid emulsions in higher risk babies, these findings might be useful for understanding the pathogenesis of PN-associated liver dysfunction.