Galactose-based polymer-containing phenylboronic acid as carriers for insulin delivery.

The galactose-based polymer is a promising drug delivery material. Herein, a new galactose-based block copolymer, termed as 6-O-vinyl sebacic acid-D-galactopyranosyl ester block 3-acrylamide phenylboric acid p(OVNG-b-AAPBA) was successfully synthesized by 'block copolymer' method. The structure of p(OVNG-b-AAPBA) was proved by nuclear magnetic hydrogen spectrum (1 HNMR) and infrared (IR), the thermal stability was observed by thermogravimetric analyzer, and the molecular weights (Mw and Mn) were demonstrated by Gel permeation chromatography (GPC). The above test results suggested that the polymer of p(OVNG-b-AAPBA) was successfully synthesized, and it had optimal molecular weight and thermal stability, which could be used for investigating the drug delivery system. Then, this block copolymer was prepared to the nanoparticle (NP), these NPs had a satisfactory morphology, and their safety was verified by MTT and chronic animal toxicology test. In addition, insulin was encapsulated by the p(OVNG-b-AAPBA) NPs, the drug loading rate and encapsulation efficiency increased with that of AAPBA in the polymer. Finally, this study confirmed that these NPs can effectively maintain the blood sugar of diabetic mice at 96 h. In conclusion, the current study suggested that the insulin-loaded galactose-based polymer-block-3-acrylamide phenylboric acid NPs had slow-release/glucose-responsive drug release performance, which might play an active role in the diabetes therapy.

Preparation and evaluation of curcumin-loaded self-assembled micelles.

OBJECTIVE: Curcumin being used to treat various chronic diseases while its poor bioavailability issue limited its wide clinical application as a therapeutic agent. The aim of this work was to prepare curcumin-loaded self-assembled micelles using soluplus and solutol®HS15 (SSCMs) to enhance curcumin's solubility and thus oral bioavailability. METHODS: Optimum formulation was investigated and the optimized ratio of drugs and excipients was obtained and the SSCMs were prepared via ethanol solvent evaporation method. The optimal SSCMs were characterized by transmission electron microscopy, drug content analysis including loading efficiency (LE%) and entrapment efficiency (EE%), and the cumulative amount of curcumin released from the micelles were all calculated using HPLC method. The in vitro cytotoxicity and the permeability of SSCMs were measured by Caco-2 cell monolayers and the oral bioavailability was evaluated by SD rats. KEY FINDINGS: The solubility of curcumin in self-assembled micelles was dramatically increased by 4200 times as compared to free curcumin. Caco-2 cells transport experiment exhibited that while soluplus and solutol®HS15 were self-assembled into micelles, it could not only promote the permeability of curcumin across membrane for better absorption, but also could restrain the curcumin pumped outside due to the role of P-gp efflux mechanism of soluplus and solutol®HS15. Furthermore, the prepared SSCMs formulation was almost nontoxic and had safety performance on Caco-2 cells model. Moreover, curcumin's oral bioavailability of SSCMs formulation in SD rats had doubled than that of free curcumin. CONCLUSIONS: The prepared SSCMs were characterized by PS, PDI, LE%, EE% data analysis. After the soluplus and solutol®HS15 were self assembled into micelles, both the solubility and membrane permeability of curcumin were evaluated to have been enhanced, as well as the effect of efflux pump of curcumin was inhibited, hence to promote oral absorption and generate an increased bioavailability.

Effect of Isomeric Structures on Photovoltaic Performance of D-A Copolymers.

Two donor-acceptor copolymers based on isomeric acceptor units, [7,7'-bithieno[2',3':4,5]thieno[2,3-d]thieno[3,2-b]pyridine]-5,5'(4H,4'H)-dione (BTTP) and [2,2'-bithieno[2',3':4,5]thieno[2,3-d]thieno[3,2-b]pyridine]-5,5'(4H,4'H)-dione (iBTTP), are developed to study the effect of isomeric structures on photovoltaic performance. Compared with PBDTBTTP, PBDTiBTTP possesses a smaller bandgap for good light harvesting and a better π-π stacking for higher hole mobility. PBDTiBTTP solar cells present balanced mobilities and good nanoscale phase separation, giving a power conversion efficiency (PCE) of 6.51%, with higher short-circuit current (Jsc ) and fill factor (FF).

[The Pharmacokinetics and Pharmacodynamics of Intravenous Uricase Multivesicular Liposomes].

OBJECTIVE: To determine and compare the pharmacokinetics and pharmacodynamics of uricase-multivesicular liposomes (UOMVLs) with free uricase (UOX) in rats. METHODS: UOMVLs were prepared by the double emulsion method and confirmed with its entrapment efficiency, size and Zeta potential. Twelve healthy rats were randomly divided into two groups: one with i. v. injection of UOMVLs, and the other with i. v. injection of UOX. Their serum activity of uricase was assayed. The pharmacokinetic parameters were calculated using software DAS 2. 1. 1. Another 24 male SD rats were enrolled, the rat model of hyperuricemia was established with hypoxanthine and potassium oxonate, while normal group (n=6) was set as control. Injection of UOMVLs (1 mL, 0. 47 U/mL), UOX (1 mL, 0. 47 U/mL) and nothiy were given 1 h later in UOMVLs group (n=6), UOX group (n=6) and model group (n=6), and their serum uric acid levels were determined 1, 2, 3, 5, 7, 9, 12, 24, 36, 48 h after the establishment of hyperuricemia model. RESULTS: The entrapment efficiency of UOMVLs was (63. 75 ± 3. 65) %, with an average particle size of (22. 56 ± 1. 70) µm and Zeta potential of (-41. 81±6. 59) mV. The pharmacokinetic parameters of UOMVLs and UOX were as follows, respectively: area under time-concentration curve from 0 to infinity time (AUC0-∞) (498. 83 ± 58. 85) U/L . h and (28. 49 ± 9. 95) U/L . h; time to peak concentration (Tmax) (1. 00±0. 00) h and (0. 00±0. 00) h; peak concentration (Cmax) (73. 04±6. 35) U/L and (31. 00±6. 03) U/L; elimination half-life (t1/2) (3. 49±0. 80) h and (1. 17±0. 33) h. The relative bioavailability of UOMVLs was (1 750. 90±206. 56) %. UOMVLs decreased serum uric to normal in 9 h; whereas it took 48 h for the UOX group and the model group to return to normal. CONCLUSION: UOMVLs can prolong tmax and t1/2 and improve the relative bioavailability. UOMVLs decrease serum uric acid levels in rats with hyperuricemia more effectively than UOX.

Posterior scleritis following a single infusion of zoledronate for osteoporosis: A case report and literature review.

The most frequently reported adverse reaction to zoledronic acid is an acute phase reaction resembling influenza. While rarer adverse events such as osteonecrosis of the jaw and atypical femoral fractures have gained significant recognition, the ocular adverse effects, particularly scleritis, are not yet fully comprehended. Here, we present the case of a 75-year-old female patient with osteoporosis who developed bilateral redness and intense eye pain 48 h after receiving a 5 mg intravenous dose of zoledronic acid. Clinical presentation suggested bilateral conjunctivitis, but treatment with levofloxacin eye drops and acyclovir ophthalmic gel exacerbated the symptoms over 2 days, predominantly affecting the left eye. Ocular ultrasonography revealed thickening of the left eyeball wall with a "T" sign, while an orbital CT scan showed increased thickness of the left sclera. Treatment with methylprednisolone 80 mg intravenous infusion twice daily led to gradual symptom improvement and eventual resolution of inflammation. This report, based on a review of relevant literature, investigates the treatment and outcomes of zoledronic acid-induced scleritis, emphasizing the importance for clinicians to promptly identify and manage this rare and serious ocular adverse reaction.

Novel taste-masked orally disintegrating tablets for a highly soluble drug with an extremely bitter taste: design rationale and evaluation.

The purpose of this study was to evaluate the taste masking potential of novel solid dispersions (SDs) using Eudragit® EPO as the excipient when incorporated into the orally disintegrating tablets (ODTs) for delivering a highly soluble drug with an extremely bitter taste. The pyridostigmine bromides (PB) SDs (PBSDs) were prepared by solvent evaporation-deposition method. The physicochemical properties of PBSDs were investigated by means of differential scanning calorimetry and Fourier transformed infrared spectroscopy. The dissolution test showed that only about 8% of PB was released from PBSDs in the simulated salivary fluid in 30 s. Therefore, PBSDs were considered taste-masked and selected for formulation of PBODTs. A central composite design was employed for process optimization. Multiple linear regression analysis for process optimization revealed that the optimal PBODTs were obtained, when the microcrystalline cellulose and crospovidone were 17.16 and 5.55 (%, w/w), respectively, and the average in vivo disintegration time was 25 s. The bitterness threshold of PB was examined by a sensory test, and the threshold value was set as 3 mg in each tablet. Taste evaluation of PBODTs in 18 volunteers revealed considerable taste masking with bitterness below the threshold value. PBODTs also revealed rapid drug release (around 99%, 2 min) in the simulated gastric fluid. The mean PB plasma concentration-time profiles of PBODTs and that of the commercial tablets were comparable, with closely similar pattern. Bioequivalence assessment results demonstrated that PBODTs and the commercial tablets were bioequivalent. In conclusion, PBODTs are prepared successfully, with taste masking and rapid disintegration in the oral cavity.

Genome sequence of Paenibacillus sp. strain Aloe-11, an endophytic bacterium with broad antimicrobial activity and intestinal colonization ability.

Paenibacillus sp. strain Aloe-11, a Gram-positive, spore-forming, facultatively anaerobic bacterium isolated from the root of Aloe chinensis in the southwest region of China, has excellent antibiotic activity and intestine colonization ability. Here, we present the 5.8-Mb draft genome sequence of Paenibacillus sp. strain Aloe-11.

Intelligent Selection Algorithm of Optimal Logistics Distribution Path Based on Supply Chain Technology.

How to realize the intelligence of logistics distribution is a hot research topic at present. How to reasonably allocate vehicles, optimize driving routes and travel time, deliver goods to customers on time at the lowest cost, and realize efficient and low-cost operation of the logistics distribution system has always been a problem in academia and industry for many years. Logistics enterprises face problems such as low efficiency of logistics operation, lack of scientific rationality of logistics resource planning, and lack of overall optimization of logistics management operation mode. These are severe tests that steel companies must accept. Under the background of logistics supply chain, the integrated service platform of logistics supply chain has become an urgent research topic. This study takes a steel enterprise as the main research background. On this basis, the two core modules of warehousing and distribution in the logistics business of iron and steel enterprises are qualitatively analyzed, the concept of business process reengineering is proposed, and the logistics supply chain of iron and steel enterprises is established. The concept of comprehensive service platform is realized through RFID technology. In addition, this study conducts a comprehensive analysis and research on the logistics distribution path optimization and vehicle scheduling problem, designs and implements a logistics vehicle scheduling management system, and then adopts the multiobjective method to solve the logistics distribution path planning problem, SMEs. Genetic algorithm and a simulation decision-making subsystem suitable for this problem are designed, which can better solve the problem of route optimization and vehicle scheduling in small-scale distribution.

Mechanical force modulates periodontal ligament stem cell characteristics during bone remodelling via TRPV4.

OBJECTIVES: Mechanical force plays an important role in modulating stem cell fate and behaviours. However, how periodontal ligament stem cells (PDLSCs) perceive mechanical stimulus and transfer it into biological signals, and thereby promote alveolar bone remodelling, is unclear. MATERIALS AND METHODS: An animal model of force-induced tooth movement and a compressive force in vitro was used. After force application, tooth movement distance, mesenchymal stem cell and osteoclast number, and proinflammatory cytokine expression were detected in periodontal tissues. Then, rat primary PDLSCs with or without force loading were isolated, and their stem cell characteristics including clonogenicity, proliferation, multipotent differentiation and immunoregulatory properties were evaluated. Under compressive force in vitro, the effects of the ERK signalling pathway on PDLSC characteristics were evaluated by Western blotting. RESULTS: Mechanical force in vivo induced PDLSC proliferation, which was accompanied with inflammatory cytokine accumulation, osteoclast differentiation and TRPV4 activation; the force-stimulated PDLSCs showed greater clonogenicity and proliferation, reduced differentiation ability, improved induction of macrophage migration, osteoclast differentiation and proinflammatory factor expression. The biological changes induced by mechanical force could be partially suppressed by TRPV4 inhibition. Mechanistically, force-induced activation of TRPV4 in PDLSCs regulated osteoclast differentiation by affecting the RANKL/OPG system via ERK signalling. CONCLUSIONS: Taken together, we show here that TRPV4 activation in PDLSCs under mechanical force contributes to changing their stem cell characteristics and modulates bone remodelling during tooth movement.

Cytomembrane-mimicking nanocarriers with a scaffold consisting of a CD44-targeted endogenous component for effective asparaginase supramolecule delivery.

Highly effective and safe delivery of therapeutic enzymes is pivotal to the success of antitumor therapy. Herein, we report on a targeted enzyme delivery system based on cytomembrane-mimicking nanocarriers (CmN) and a supramolecular technique (SmT). Specifically, each CmN had a scaffold that mainly consisted of a CD44-targeted endogenous component conjugated with polyethylene glycol 2000 (HA-g-PEG) that self-assembled with α-cyclodextrin (ACD). The CmN acted as a microbioreactor with an inner hollow space with the capacity to confine the large molecule asparaginase (Asp) in an Asp/ACD-supramolecular complex conjugated to the inner region. The supramolecular Asp loaded into the CmN (A-S-CmN) exhibited superior stability, kinetic properties, catalytic activity and antitumor effects compared to free Asp due to the dual protection of the supramolecular complex and the nanovesicle, the CD44 targeting-homing ability, the prolonged effects of HA-g-PEG, and the favorable inner microenvironment of the constructed supramolecular CmN. The A-S-CmN also showed a decrease in in vivo toxicity and immunogenicity. CmN combined with SmT therapeutics are easy to implement and extend for use in the delivery of various enzymes and for many types of cancer treatment.

Biomimetic Membrane-Structured Nanovesicles Carrying a Supramolecular Enzyme to Cure Lung Cancer.

Platforms for enzyme delivery must simultaneously have plasma stability, high catalytic activity, and low/no immunogenicity of the enzyme. Here, we designed a novel biomimetic membrane-structured nanovesicle (BNV) to efficiently carry supramolecular enzymes to meet the above requirements. We complexed l-asparaginase (Aase) with hydroxypropyl-ß-cyclodextrin (HPCD) to form a supramolecular amphiphile (AS) by self-assembly via noncovalent reversible interactions. We then used the first synthesized polyethylene glycol (PEG 2 kDa)-decorated hyaluronan (12 kDa) and HPCD to self-assemble a semipermeable biomimetic membrane-structured nanovesicle (BNV) together with AS loading. As compared to native Aase, AS@BNV exhibited superior catalytic activity preservation, improved catalytic activity, better pharmacokinetics in rats, enhanced cytotoxic effects, increased antitumor efficacy, and decreased side effects. The underlying mechanisms, such as the autophagy inhibition action against tumor cells, protein-protein docking of the interaction between Aase-serum albumin, and decreased hepatic enzymatic activity, were investigated. This approach paves the way for new types of powerful biomimetic-, supramolecular-, and nanocarrier-based enzymatic therapies.

Hyperbranched poly(ß-amino ester) based polyplex nanopaticles for delivery of CRISPR/Cas9 system and treatment of HPV infection associated cervical cancer.

Persistent high-risk HPV infection is the main factor for cervical cancer. HPV E7 oncogene plays an important role in HPV carcinogenesis. Down-regulation of E7 oncogene expression could induce growth inhibition in HPV-positive cells and thus treats HPV related cervical cancer. Here we developed a non-virus gene vector based on poly(amide-amine)-poly(ß-amino ester) hyperbranched copolymer (hPPC) for the delivery of CRISPR/Cas9 system to specifically cleave HPV E7 oncogene in HPV-positive cervical cancer cells. The diameter of polyplex nanoparticles (NPs) formed by hPPCs/linear poly(ß-amino ester) (PBAE) and plasmids were approximately 300 nm. These hPPCs/PBAE-green fluorescence protein plasmids polyplex NPs showed high transfection efficiency and low toxicity in cells and mouse organs. By cleaving HPV16 E7 oncogene, reducing the expression of HPV16 E7 protein and increasing intracellular retinoblastoma 1 (RB1) amount, hPPCs/PBAE-CRISPR/Cas9 therapeutic plasmids polyplex NPs, especially highly branched hPPC1-plasmids polyplex NPs, exhibited strong growth inhibition of cervical cancer cells in vitro and xenograft tumors in nude mice. Together, the hPPCs/PBAE polyplex NPs to deliver HPV16 E7 targeted CRISPR/Cas9 system in this study could potentially be applied to treat HPV-related cervical cancer.

An effective vaginal gel to deliver CRISPR/Cas9 system encapsulated in poly (ß-amino ester) nanoparticles for vaginal gene therapy.

BACKGROUND: Gene therapy has held promises for treating specific genetic diseases. However, the key to clinical application depends on effective gene delivery. METHODS: Using a large animal model, we developed two pharmaceutical formulations for gene delivery in the pigs' vagina, which were made up of poly (ß-amino ester) (PBAE)-plasmid polyplex nanoparticles (NPs) based two gel materials, modified montmorillonite (mMMT) and hectorite (HTT). FINDINGS: By conducting flow cytometry of the cervical cells, we found that PBAE-GFP-NPs-mMMT gel was more efficient than PBAE-GFP-NPs-HTT gel in delivering exogenous DNA intravaginally. Next, we designed specific CRISPR/SpCas9 sgRNAs targeting porcine endogenous retroviruses (PERVs) and evaluated the genome editing efficacy in vivo. We discovered that PERV copy number in vaginal epithelium could be significantly reduced by the local delivery of the PBAE-SpCas9/sgRNA NPs-mMMT gel. Comparable genome editing results were also obtained by high-fidelity version of SpCas9, SpCas9-HF1 and eSpCas9, in the mMMT gel. Further, we confirmed that the expression of topically delivered SpCas9 was limited to the vagina/cervix and did not diffuse to nearby organs, which was relatively safe with low toxicity. INTERPRETATION: Our data suggested that the PBAE-NPs mMMT vaginal gel is an effective preparation for local gene therapy, yielding insights into novel therapeutic approaches to sexually transmitted disease in the genital tract. FUNDING: This work was supported by the National Science and Technology Major Project of the Ministry of science and technology of China (No. 2018ZX10301402); the National Natural Science Foundation of China (81761148025, 81871473 and 81402158); Guangzhou Science and Technology Programme (No. 201704020093); National Ten Thousand Plan-Young Top Talents of China, Fundamental Research Funds for the Central Universities (17ykzd15 and 19ykyjs07); Three Big Constructions-Supercomputing Application Cultivation Projects sponsored by National Supercomputer Center In Guangzhou; the National Research FFoundation (NRF) South Africa under BRICS Multilateral Joint Call for Proposals; grant 17-54-80078 from the Russian Foundation for Basic Research.

Bioactive injectable polymethylmethacrylate/silicate bioceramic hybrid cements for percutaneous vertebroplasty and kyphoplasty.

Polymethylmethacrylate (PMMA) cement has been widely used to fill and stabilize hard tissue defects in clinical surgery, especially in percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP). However, the dense body of pure PMMA in defects has no ability to promote bone regeneration. We herein aim to fabricate novel PMMA/silicate bioceramic hybrid cements by adding bioactive calcium silicate (CS) particles into PMMA to endow PMMA/CS hybrid cements with bioactivity and biodegradability without losing the excellent mechanical strength and injectability. Following comprehensive characterization of the physicochemical properties and in vitro bioactivity study, our results showed compared with PMMA cement, the constructed PMMA/CS hybrid cements possessed significantly lower curing temperatures and simultaneously retained the acceptable mechanical strength and injectability. Moreover, obvious bioactive ion release and hydroxyapatite formation could be detected and observed after the PMMA/CS hybrid cements were soaked in simulated body fluid, indicating their pronounced bioactivity. A further in vivo study of the PMMA/CS hybrid cements on goat vertebral body defect models reflected that the PMMA/CS hybrid cements could be biodegraded well and could significantly promote new bone formation in defects 6 months of post-injection. Our results suggest that PMMA/CS hybrid cements may be promising candidates for PVP and PKP in clinic.

A Biomimetic Hierarchical Nanointerface Orchestrates Macrophage Polarization and Mesenchymal Stem Cell Recruitment To Promote Endogenous Bone Regeneration.

The host immune response to bone biomaterials is vital in determining scaffold fates and bone regeneration outcomes. The nanometer-scale interface of biomaterials, which independently controls physical inputs to cells, regulates osteogenic differentiation of stem cells and local immune response. Herein, we fabricated biomimetic hierarchical intrafibrillarly mineralized collagen (HIMC) with a bone-like staggered nanointerface and investigated its immunomodulatory properties and mesenchymal stem cell (MSC) recruitment during endogenous bone regeneration. The acquired HIMC potently induced neo-bone formation by promoting CD68+CD163+ M2 macrophage polarization and CD146+STRO-1+ host MSC recruitment in critical-sized bone defects. Mechanistically, HIMC facilitated M2 macrophage polarization and interleukin (IL)-4 secretion to promote MSC osteogenic differentiation. An anti-IL4 neutralizing antibody significantly reduced M2 macrophage-mediated osteogenic differentiation of MSCs. Moreover, HIMC-loaded-IL-4 implantation into critical-sized mandible defects dramatically enhanced bone regeneration and CD68+CD163+ M2 macrophage polarization. The depletion of monocyte/macrophages by clodronate liposomes significantly impaired bone regeneration by HIMC, but did not affect MSC recruitment. Thus, in emulating natural design, the hierarchical nanointerface possesses the capacity to recruit host MSCs and promote endogenous bone regeneration by immunomodulation of macrophage polarization through IL-4.

A new approach to examining the extraction process of Zhishi and Zhiqiao considering the synergistic effect of complex mixtures by PAMPA.

Zhishi (ZS) and Zhiqiao (ZQ) are two important traditional Chinese medicines (TCMs) that exert various pharmacological functions due to their active ingredients. However, the oral absorption of these ingredients requires further study. At the early drug discovery stage, the high-throughput parallel artificial membrane permeability assay (PAMPA) is one of the most frequently used to predict transcellular passive absorption in in-vitro models. This study aims to establish a new approach to examine an optimal extraction process that can take into account not only the concentration of active ingredients but also the overall absorption properties of the mixtures extracted from TCMs. A high-performance liquid chromatography triple-quadrupole mass spectrometry (HPLC-QqQ-MS/MS) method was validated for the determination of the effective permeability value (Pe) applied to the above experimental medium. The PAMPA experiment showed that certain active ingredients such as diosmin, rhoifolin, eriocitrin, narirutin, naringin, hesperidin and neohesperidin were not detected in the permeability assay of mono-constituents but were well detected and achieved a better absorption in the permeability assay of the mixture, indicating that certain unknown ingredients may act as cosolvents to improve the solubility or permeability of other ingredients. Furthermore, solid phase extraction (SPE) as an enrichment and purification process enhances absorption. In the present study, a novel in vitro approach was developed to decipher the potential role of TCMs in global absorption, and the extraction process for complex TCMs was described and systematically optimized.

Ectrodactyly in a Chinese patient born to a mother with neuromyelitis optica spectrum disorder.

NMOSD develops primarily in women of childbearing age, and several previous studies have shown that the disorder may increase the risk of miscarriage. However, there are no reports, to our knowledge, of fetal malformation, other than neonatal hydrocephalus, related to NMOSD. We report a 30-year-old woman who experienced recurrent neuritis and who was seropositive for AQP4-IgG. She became pregnant, and the fetus was found to have ectrodactyly. Histological analysis of the placenta showed moderate inflammatory infiltration; however, whether fetal malformation in NMOSD is related to inflammation and AQP4-IgG remains to be determined.

Expression of Cannabinoid Type 1 Receptors in Human Odontoblast Cells.

INTRODUCTION: The aim of this study was to investigate the functional expression of cannabinoid type 1 (CB1) receptors in human odontoblasts (HODs) and the possible internal mechanism. METHODS: In the present study, we examined the molecular and functional expression of the CB1 receptors in cultured HOD-like cells and native HODs obtained from healthy wisdom teeth. RESULTS: Immunohistochemistry and immunofluorescence revealed that CB1 receptors localize to native HODs and HOD-like cells, respectively. Both reverse-transcription polymerase chain reaction and Western blot analysis confirmed gene and protein expression of CB1 receptors. The ultrastructural distribution by immunoelectron microscopy also found that CB1 receptors labeled by colloidal gold particles distribute sparsely in the cytoplasm and odontoblastic processes. In functional assays, 2-arachidonyl glycerol, as an agonist of CB receptors, elicited the increase of intracellular fluorescence intensity that could be inhibited by a CB1-specific receptor antagonist rather than a selective CB2 receptor antagonist with fluo-3AM Ca2+ fluorescence. The source of the increase of intracellular fluorescence intensity elicited by CB1 receptors was from extracellular Ca2+ but not intracellular Ca2+ stores. The process of 2-arachidonyl glycerol activating CB1 receptors modulated transient receptor potential vanilloid 1-mediated Ca2+ entry via the cyclic adenosine monophosphate signaling pathway. CONCLUSIONS: We conclude that HODs can express functional CB1 receptors that may play an important role in mediating the physiological function in tooth pulp.

Uricase alkaline enzymosomes with enhanced stabilities and anti-hyperuricemia effects induced by favorable microenvironmental changes.

Enzyme therapy is an effective strategy to treat diseases. Three strategies were pursued to provide the favorable microenvironments for uricase (UCU) to eventually improve its features: using the right type of buffer to constitute the liquid media where catalyze reactions take place; entrapping UCU inside the selectively permeable lipid vesicle membranes; and entrapping catalase together with UCU inside the membranes. The nanosized alkaline enzymosomes containing UCU/(UCU and catalase) (ESU/ESUC) in bicine buffer had better thermal, hypothermal, acid-base and proteolytic stabilities, in vitro and in vivo kinetic characteristics, and uric acid lowering effects. The favorable microenvironments were conducive to the establishment of the enzymosomes with superior properties. It was the first time that two therapeutic enzymes were simultaneously entrapped into one enzymosome having the right type of buffer to achieve added treatment efficacy. The development of ESU/ESUC in bicine buffer provides valuable tactics in hypouricemic therapy and enzymosomal application.

Menopausal depression: comparison of hormone replacement therapy and hormone replacement therapy plus fluoxetine.

BACKGROUND: To compare the efficacy and safety of hormone replacement therapy (HRT) combined with fluoxetine, with HRT alone, in post-menopausal women suffering from depression. METHODS: A randomized, open-label, parallel trial was applied. HRT was administered to all patients for 2 cycles, with 14 days of estrogen therapy and 14 days of estrogen plus progesterone. Patients who were randomly assigned to the HRT plus fluoxetine group were given fluoxetine in combination with HRT. Hamilton Depression Rating Scale (HAMD), Kupperman Menopausal Index (KMI), and Clinical Global Impressions scale were used to measure the efficacy. RESULTS: One hundred and twenty-three post-menopausal patients with depression were enrolled in the study. Among them, 120 had at least one post-treatment visit and entered into the statistical analysis. The mean total HAMD scores were significantly lower, and the percentages of HAMD score reductions were higher in the HRT plus fluoxetine Group compared with the HRT Group, after at least 3 weeks of treatment, with an average difference of 5 points at the endpoint. The Clinical Global Impression-Severity and Clinical Global Impression-Improvement scores were significantly different in the 2 groups, in favor of the combination therapy. The mean total KMI was significantly lower in the Combination Group compared with the HRT Group, after at least 6 weeks of treatment, with an average 4.5-point difference between the groups. No statistically significant differences were found in most of the adverse events reported in the Combination Group compared with the HRT group, with the exception of 3 symptoms, i.e., dry mouth, loss of appetite, and abdominal distention. They were mild to moderate in severity. Two patients in the HRT group, but none in the combination group, dropped out due to adverse events. CONCLUSION: HRT plus fluoxetine therapy was effective in the treatment of menopausal depression with a satisfactory safety profile.