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Dry powder inhalers (DPIs) had been widely used in lung diseases on account of direct pulmonary delivery, good drug stability and satisfactory patient compliance. However, an indistinct understanding of pulmonary delivery processes (PDPs) hindered the development of DPIs. Most current evaluation methods explored the PDPs with over-simplified models, leading to uncompleted investigations of the whole or partial PDPs. In the present research, an innovative modular process analysis platform (MPAP) was applied to investigate the detailed mechanisms of each PDP of DPIs with different carrier particle sizes (CPS). The MPAP was composed of a laser particle size analyzer, an inhaler device, an artificial throat and a pre-separator, to investigate the fluidization and dispersion, transportation, detachment and deposition process of DPIs. The release profiles of drug, drug aggregation and carrier were monitored in real-time. The influence of CPS on PDPs and corresponding mechanisms were explored. The powder properties of the carriers were investigated by the optical profiler and Freeman Technology four powder rheometer. The next generation impactor was employed to explore the aerosolization performance of DPIs. The novel MPAP was successfully applied in exploring the comprehensive mechanism of PDPs, which had enormous potential to be used to investigate and develop DPIs.
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Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease. To advance this, we present a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity revealed cells, their inflammatory mediators and networks as potential therapeutic targets, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Tensor and matrix decomposition of the overall dataset revealed feature groupings linked with disease severity and specificity. Our systems-based integrative approach and blood atlas will inform future drug development, clinical trial design and personalised medicine approaches for COVID-19.
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An explicit illustration of pulmonary delivery processes (PDPs) was a prerequisite for the formulation design and optimization of carrier-based DPIs. However, the current evaluation approaches for DPIs could not provide precise investigation of each PDP separately, or the approaches merely used a simplified and idealized model. In the present study, a novel modular modified Sympatec HELOS (MMSH) was developed to fully investigate the mechanism of each PDP separately in real-time. An inhaler device, artificial throat and pre-separator were separately integrated with a Sympatec HELOS. The dispersion and fluidization, transportation, detachment and deposition processes of pulmonary delivery for model DPIs were explored under different flow rates. Moreover, time-sliced measurements were used to monitor the PDPs in real-time. The Next Generation Impactor (NGI) was applied to determine the aerosolization performance of the model DPIs. The release profiles of the drug particles, drug aggregations and carriers were obtained by MMSH in real-time. Each PDP of the DPIs was analyzed in detail. Moreover, a positive correlation was established between the total release amount of drug particles and the fine particle fraction (FPF) values ( = 0.9898). The innovative MMSH was successfully developed and was capable of illustrating the PDPs and the mechanism of carrier-based DPIs, providing a theoretical basis for the design and optimization of carrier-based DPIs.
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Aim To investigate the antinociception, tolerance and withdrawal abstinence of δ/μ/κ opioid receptor triple agonist KUST201 ( DPI-125 ) in rats. Methods Male Sprague-Dawley rats were used to de-termine the time course of analgesic effects and ED50 effects of co-administration of naltrindole were assessed as well. In withdrawal experiments, KUST201 was ad-ministrated twice daily for 3 d with increasing doses each day. On the 4th day, the rats were given a single dose, challenged with naloxone 3 h later, and signs of abstinence were monitored. Results The ED50 values of KUST201 were 0. 34 mg·kg-1 in tail-pinch test and 0. 68 mg · kg-1 in hot-plate test. The antinociception actions of KUST201 started to decrease 1 h after ad-ministration, and disappeared after 2 h. In chronic tol-erance experiments, the antinociception actions started to decrease on d 3 , and completely disappeared on d 7 . Naltrindole could reduce the antinociceptive action of KUST201. In withdrawal experiments, abstinence scores increased significantly in the dose range between 2~8 times of tail-pinch ED50 . Conclusion Compared with previously reported δ/μ/κ triple agonist DPI-3290 , KUST201 exhibits similar antinociceptive effects in rats. The chronic tolerance to KUST201 actions de-velops less quickly, but the abstinence scores of KUST201 are slightly higher. The activation of δ-opi-oid receptor can synergistically enhance the antinoci-ception mediated by μ-receptor.
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Tumor is a system-biology illness.Treatment of this intractable disease by any single medicine has not been realistic.In this review, we analyze the anti-tumor network of Tumor Necrosis Factor-related Apoptosis-indu-cing Ligand ( TRAIL ) by a system-biology technology and try to providecin individualized treatment strategy for TRAIL based therapy .
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Objective:To assess the effects of HEMA on the proliferation and migration of human dental pulp cells(hDPCs).Meth-ods:hDPCs were obtained using tissue explant culture technique in vitro,and then cells of the 3rd -5th passages were treated by differ-ent concentrations of HEMA for 24,48 and 72 h respectively.Cell proliferation was examined by MTT assay.Cell migration was ob-served by Transwell method.Results:The proliferation ability of hDPCs decreased when exposed to HEMA in both time and concentra-tion dependent manner(vs control,P <0.05).Cell proliferation at 24 h expossure was statistically higher than that at 48 h and 72 h(P<0.05).The migration of hDPCs was significantly reduced in HEMA groups at different concentrations(vs control,P <0.05).Con-clusion:HEMA inhibits the proliferation and migration of human dental pulp cells in vitro.
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Alzheimer′s disease ( AD) is a type of neurodegener-ative disease. Recent studies indicate that neuronal degeneration and loss triggered by tau, APP and Aβare the probable risks for AD. Neurofibrillary tangles are formed after tau truncated by ac-tivated caspases and subsequently induced tau aggregates, which causes neuronal degeneration and loss. In addition, caspases are crucial components in the biological functioning in the apoptosis pathways. Apoptosis pathway involves activation of upstream ini-tiator caspase-8 and downstream executor caspase-3/-6/-7. After the actions of β- and γ-secretase, APP transforms into sAPPβand Aβ40/42 . Aggregated Aβ42 can activate apoptosis pathway through DR4/5 interaction. C-APP is truncated into C31 frag-ments by caspases and cell apoptosis is facilitated. N-APP, a product of sAPPβhydrolysis, can promote the abnormal develop-ment of neurons mediated by DR6. Caspase activates γ-secre-tase-activating protein to regulate activity ofγ-secretase, and the production of C31 and Aβ40/42 , which, then, causes the occur-rence of AD. This brief review summarizes the specific roles of caspases and the concerning apoptosis pathways on the mecha-nisms of neuronal degeneration and loss, and how they impact the occurrence of AD in the hope of uncovering additional poten-tial therapeutic targets that can be employed in drug development and clinical therapy for AD.
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As a pro-apoptotic factor, prostate apoptosis response protein 4 (par-4) was first found in the male hormone-dependent prostate cells (AT-3). Endogenous Par-4 sensitizes cancer cells to apoptotic stimuli, but exogenous Par-4 selectively induces apoptosis in cancer cells, and these activities depends on the structure of its core domain SAC. Par-4 and SAC can specifically induce apoptosis of cancer cells but not of normal cells, and are therefore potential anti-cancer drugs. In this review we summarize the discovery, structure, and function of par-4, and its intracellular signaling pathways, then discuss the application prospects of Par-4 and SAC in the clinical treatment of cancer and the problems in its research and clinical applications.
Subject(s)
Humans , Apoptosis , Apoptosis Regulatory Proteins , Metabolism , Tumor Suppressor ProteinsABSTRACT
Many tumor cells are resistant to cell apoptosis through the expression of antiapoptotic proteins. c-FLIP is a ma-jor resistance protein of antiapoptosis. In human cells, there are three types of c-FLIP, c-FLIPL , c-FLIPS and c-FLIPR . The c-FLIP binds to FADD to prevent the formation of procaspase-8-DISC and the subsequent activation of caspase cascade. Further-more, c-FLIPL and c-FLIPS have multifunctional roles in various cellular signaling pathways, as well as up-regulating several cyto-protective signaling. Studies show that upregulation of c-FLIP has been found in various tumors, and its downregulation has been shown to restore apoptosis triggered by various chemothera-peutic agents, like the transcriptional regulating agents, trichos-tatin-A, camptothecin, cisplatin, doxorubicin, etc. or other new biotechnologies, such as the specific siRNA. Therefore, c-FLIPS are important targets of cancer therapy. This review summarizes the results on the role of c-FLIP in cancer chemotherapy of tradi-tional antitumor agents and siRNA, and to provide new ideas and rationales of searching for the antiapoptosis effective compounds that can specifically antagonize c-FLIP.
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Objective: To extract the polysaccharides of Curcuma zedoaria Rosc (PCZ) and study its bioactivities. Methods: The crude polysaccharides were extracted from herbal slice of Curcuma zedoaria Rosc with hot water ,and precipitated by ethanol and savage deproteinization and depigmentation with activated charcoal. The constituents were isolated by column chromatography and the total polysaccharides content was determined. Experiments of immune function,anti-oxidation and anti-tumor activity of KM mice and in viro were studied. Results: The content of total polysaccharides of Curcuma zedoaria Rosc was 33.12%. and the extraction rate was 1.938% . It could raise spleen cell proliferation and transformation rate of lymphocyte and SOD activity in blood of mice. A higher antitumor effect of the polysaccharides by injection was observed dose-dependently. Conclusion: PCZ could raise the immune and anti-oxidative activities and then had a higher antitumor effect.
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Objective: The chemical composition, extraction and biological activity of antioxidant substance of sweet potatoes were studied. Method: The antioxidant substance was extracted with alcohol and purified with AB-8 big-hole resin and its elimination rate of _?O 2 and OH and SOD activity were determined.Results: The content of antioxidant substance stockpiled respectively in the root tubers, stems and leaves of sweet potatoes and was different in varieties. The highest content in the root tuber was 0.324%, which accounted 70% of total content in sweet potatoes. Its extraction ratio was 85%. The major composition of the antioxidant substance was phenol acid, including chlorogenic acid,isochlorogenic acid,neochlorogenic acid and 4-0-caffeonyl quinic butyl ester. They had intense antioxidant function and their elimination rate to _?O 2 and?OH at concentration 90 mg/ml was 88.02% and 82.21% respectively. The antioxidantsubstance restrained oxidation of lipid and hemolysis of red cell induced by H2O2,and increased SOD activity in serum and skin of mice. Conclusion: Several kinds of phenol acid as antioxidant substance stockpiled in sweet potatoes were proved to have strong antioxidant activity.
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Objective: To investigate the free radical scavenging properties of six aloe species and study its protective effect on red blood cells. Methods: Free radical scavenging properties were investigated in modified chemical system. The antioxidant was purified by silica column and thin layer chromatography and analyzed by HPLC. Its protection on red blood cells was studied with red blood cells culture system in vitro. Results: The extract from A. berebihoria showed the most effective scavenging activities on O - 2? and ?OH (32.19% and 26.05% respectively) in six aloe species. The fraction A with a Rf value of 0 497 was proved to be a pure antioxidant (Rt=15.956 min). It is an anthraquinone with phenol hydroxyls. Fraction A showed strong inhibitory activity on H 2O 2 induced hemolysis of red blood cells and its IC 50 was 0.856 g/L. Conclusion: Fraction A of the extract from A. berebihoria had strong scavenging activities of O - 2? and ?OH, thereby inhibiting the peroxidation of red blood cells and maintaining their functions.
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Objective: To study the antixiodant activity of sweet-potato anthocyanin (SPAC) and its inhibiting effect on growth of cancer S180. Method: The scavenging capacity of ??O2 and?OH and the inhibitory effect of MDA were determined in vitro.The SOD activity of serum and skin, the effect on S180 growth, serum GSH-Px activity and MDA were tested in mice. Results: SPAC had antioxidant activity in vitro, with elimination rate of O2?? and?OH 30.63% and 20.57% higher than the same concerntration of VC respectively. Activity of SOD in the serum and skin of mice were raised 27.30% and 13.50% respectively after giving SPAC. The growth rate of cancer S180 in the mice was inhibited, and the highest inhibitory rate was 43.12%. The activity of serum GSH-Px, SOD of the mice was raised as compared to control, but MDA declined . Conclusion: SPAC is a perfect natural pigment with inhibitory effect on growth of cancer S180 probably through its antioxidant activity.