Limitations and Innovative Application Methods of Surfactants for Solubilization of Poorly Water-Soluble Drugs.

Poor solubility of drugs leads to poor bioavailability and therapeutic efficiency. A large proportion of drugs that are not developed and marketed for use by patients are due to their extremely low solubility. Therefore, improving the solubility of poorly water-soluble drugs is one of the most important aspects of the field of drug research. With the continuous development of more and more formulation techniques and excipient applications, the solubility of poorly water-soluble drugs can be improved to a certain extent to obtain better pharmacokinetics and pharmacodynamics, including pH microenvironment regulation technology, inclusion complex, solid dispersion, nanotechnology, and application of surfactants. However, the most widely used among them is the application of surfactants. This technique can reduce the surface tension, improve wettability, and have a remarkable solubilizing ability after forming micelles. However, surfactants have also been found to possess certain limitations in solubilization. In this review, the factors affecting the solubilization of surfactants and limiting their application have been summarized from several aspects. These factors include drugs, additives, and media. Some ideas to solve these application limitations have also been put forward, which can lay a foundation for the wider application of surfactants in the future.

Manganese(III)-mediated alkenyl C(sp2)-P bond formation from the reaction of ß-nitrostyrenes with dialkyl phosphites.

Mn(OAc)3-mediated tandem phosphonyl radical addition to ß-nitrostyrenes followed by denitration to form (E)-2-alkenyl phosphonates in good yield is described.

[DEDD decreases Smad3 activity, promotes tumor cell apoptosis and inhibits proliferation].

DEDD is a member of the death-effector domain protein family. DEDD inhibits the Smad3 mediated transcriptional activity and participates in the regulation of apoptosis. In this study, how the death-effector domain of DEDD participates in the regulation of Smad3 activity and apoptosis has been further investigated. Immunoblotting, immunofluorescence and immunoprecipitation had been used to detect the effects of the full length DEDD and its two truncated mutants, N-DEDD and C-DEDD on Smad3 subcellular distribution, phosphorylation, and interaction between Smad4. The effects of the full length DEDD and its two truncated mutants on cell apoptosis and proliferation had also been explored by flow cytometry and MTT assay. It showed that DEDD and N-DEDD inhibit TGF-beta1 induced Smad3 nuclear translocation and the formation of Smad3-Samd4 complex. DEDD and its two mutants can induce cell apoptosis and inhibit cell proliferation. These results suggested that DEDD inhibits the activity of Smad3 through its death-effector domain. Both the two truncated mutants of DEDD participate in the regulation of apoptosis and cell proliferation.

DEDD negatively regulates transforming growth factor-beta1 signaling by interacting with Smad3.

Transforming growth factor-beta1 (TGF-beta1) regulates a wide variety of cellular responses, such as proliferation, differentiation, migration and apoptosis. Here we report that death effector domain-containing DNA-binding protein (DEDD) physically interacts with Smad3. The inhibition of Smad3 by DEDD resulted in a reduction in TGF-beta1/Smad3-mediated transcription. DEDD inhibited the functions of Smad3 by preventing Smad3 phosphorylation, which led to the reduced expression of TGF-beta1/Smad3-targeted genes. TGF-beta1 inhibited DEDD expression, and DEDD inhibited TGF-beta1-mediated invasion. Therefore, our findings suggest that through its interaction with Smad3, DEDD is a novel negative regulator of the TGF-beta1 signaling pathway.

Ginsenoside Rg1 promotes glutamate release via a calcium/calmodulin-dependent protein kinase II-dependent signaling pathway.

Ginseng is one of most extensively used traditional oriental medicines worldwide with beneficial efficacy on cognitive function disorders. Pharmacological researches on its active ingredient--ginsenoside Rg1 revealed that it can improve learning and memory potentially via modulating neurotransmission in the central nervous system, whereas the specific mechanism involved has not been elucidated yet. Our previous studies have indicated that ginsenoside Rb1 could enhance glutamate release via PKA-dependent signaling pathway whereas Rg1 could enhance glutamate release via PKA-independent signaling pathway. In this work we sought to determine the role of another key mediator in neurotransmitter release--calcium/calmodulin-dependent protein kinase II (CaMKII) in the mechanism of Rg1-enhanced glutamate release. Pre-treatment with CaMKII inhibitor KN93 blocked Rg1-induced glutamate release in primary hippocampal neurons. To investigate how CaMKII was involved in this process, the effect of Rg1 on CaMKII was further studied. Rg1 activated CaMKII and subsequently increased phosphorylation level of Synapsin I (Serine(603), a substrate site of CaMKII)--an abundant phosphoprotein essential for regulating neurotransmitter release, which could be blocked by pre-treatment with CaMKII inhibitor KN93. In conclusion, the present study suggests that Rg1 promotes glutamate release potentially via a CaMKII-dependent signaling pathway in which Synapsin I may potentially act as a downstream effector. Combined with our previous study on Rb1, these two studies altogether indicated that different ginsenosides may promote neurotransmitter release via differential signaling pathways.

A new bile acid from the bile of Anser anser.

A new compound, named 3alpha-acetoxy-7alpha-hydroxy-5beta-cholan-24-oic acid (2), along with chenodeoxycholic acid (1), was isolated from the bile of Anser anser. Their structures were elucidated by means of physicochemical properties and spectroscopic methods (1D, 2D NMR and MS).

Ginsenoside Rb1 promotes neurotransmitter release by modulating phosphorylation of synapsins through a cAMP-dependent protein kinase pathway.

Ginseng, the root of Panax ginseng C.A. Meyer (Araliaceae), has been extensively used in traditional oriental medicine for the prevention and treatment of aging-related disorders for over 2000 years. Accumulating evidence suggests that ginsenosides such as Rg1 and Rb1, which are the pharmacologically active ingredients of ginseng, modulate neurotransmission. Synapsins are abundant phosphoproteins essential for regulating neurotransmitter release. All synapsins contain a short amino-terminal domain A that is highly conserved and phosphorylated by cAMP-dependent protein kinase (PKA), which plays a key role in regulating neurotransmitter release. In the present study, we demonstrated that both Rg1 and Rb1 increased neurotransmitter release in undifferentiated and differentiated PC12 cells. However, in the presence of the PKA inhibitor H89, Rg1, but not Rb1, still induced neurotransmitter release. Moreover, Rb1, but not Rg1, enhanced the phosphorylation of synapsins via PKA pathway. In summary, Rb1 promotes neurotransmitter release by increasing the phosphorylation of synapsins through the PKA pathway, whereas the similar effects observed with Rg1 are independent of the phosphorylation of synapsins.

[The mechanism of ginsenosides Rg1 and Rb1 promoting glutamic acid release from PC12 cells].

AIM: To study the mechanism of ginsenosides Rg1 and Rb1 promoting glutamic acid release from PC12 cells. METHODS: The amount of glutamic acid released from PC12 cells was measured by high performance liquid chromatography (HPLC). The effect of Rg1 and Rb1 on the phosphorylation of synapsins was detected with immunofluorescent staining and Western blotting. RESULTS: Both Rg1 (10 micromol x L(-1)) and Rb1 (10 micromol x L(-1)) increased glutamic acid release from PC12 cells. The release of glutamic acid was decreased by pre-incubating with the PKA inhibitor H89. H89 inhibited the release of glutamic acid induced by Rb1, but had no effect on the release of glutamic acid induced by Rg1. Moreover, Rb1 enhanced the phosphorylation of synapsins via PKA pathway, Rg1 was out of touch with this. CONCLUSION: Rb1 may promote release of neurotransmitters by increasing the phosphorylation of synapsins via PKA pathway, whereas the up-regulation of neurotransmitters release induced by Rg1 is independent of the phosphorylation of synapsins.