Sepsis is a major cause of death worldwide. We show that a plasma protein histidine-rich glycoprotein (HRG) was decreased significantly in septic mice with cecal ligation and puncture (CLP) and supplementary treatment of septic mice with exogenous HRG improved survival, with strong inhibition of tight attachment of neutrophils to pulmonary vasculatures, subsequent immunothrombosis, DIC state, lung inflammation, hypercytokinemia, and activation of vascular endothelial cells (VECs). In contrast, knockdown of HRG by siRNA exacerbated lethality. Purified human HRG reversibly induced morphological changes in human neutrophils in vitro; induction of spherical shape with reduced microvilli and adhesiveness to VECs. HRG maintained the passage of neutrophils through microcapillaries and abolished production of reactive oxygen species. These results suggested that the supplementary therapy with HRG may provide a novel strategy for the treatment of sepsis through suppression of excessive systemic inflammation and immunothrombosis by keeping circulating neutrophils quiescent and preventing uncontrolled activation of VECs.
Recently, coamorphous systems, composed of a drug and a guest molecule, have gained increasing interest, due to their ability to overcome limitations associated with amorphous drug alone. In this study, a single-phase coamorphous form of lurasidone hydrochloride (LH) (a water-insoluble atypical antipsychotic agent with pH-dependent solubility) with saccharin (SAC) in a 1:1 molar ratio was obtained and characterized by differential scanning calorimetry and powder X-ray diffraction. Peak shifts in the Fourier transform infrared spectra indicated the formation of charge-assisted hydrogen bonds between the N + -H group of LH and the CO group of SAC. In comparison to crystalline LH, amorphous LH showed similar solubility and temporary improvement in the intrinsic dissolution rate and supersaturated dissolution, while coamorphous LH-SAC exhibited greatly improved solubility with pH-independent solubility behavior in a pH range of 2−5.5, as well as a persistent enhanced intrinsic dissolution rate and supersaturated dissolution. In addition, coamorphous LH-SAC showed superior physical stability compared to amorphous LH under the long-term storage condition. The coamorphization effect and charge-assisted hydrogen bond in coamorphous LH-SAC were speculated to be responsible for the above phenomena by prohibiting the recrystallization of LH.
The solubility equilibrium of clopidogrel hydrogen sulfate (Form I) was set up without the nucleation of Form II, as the nucleation rate of Form II is very slow under the low supersaturation. Using the laser monitoring technique, solubilities of clopidogrel hydrogen sulfate (Form I) in ethanol, 1-propanol, 1-butanol, 1-pentanol, and 2-propanol were measured at temperatures ranging from (273.15 to 318.15) K. The experimental data were correlated by the modified Apelblat equation, and the dissolution enthalpy and entropy of Form I were determined with van't Hoff plots. Compared with those of Form II, Form I exhibits a higher solubility and a lower enthalpy of dissolution. Therefore, we can draw the conclusion that Form I was the metastable form under the conditions in this work.
Over the last few years microalgae have gained increasing interest as a natural source of valuable compounds and as bioreactors for recombinant protein production. Natural high-value compounds including pigments, long-chain polyunsaturated fatty acids, and polysaccharides, which have a wide range of applications in the food, feed, cosmetics, and pharmaceutical industries, are currently produced with nontransgenic microalgae. However, transgenic microalgae can be used as bioreactors for the production of therapeutic and industrially relevant recombinant proteins. This technology shows great promise to simplify the production process and significantly decrease the production costs. To date, a variety of recombinant proteins have been produced experimentally from the nuclear or chloroplast genome of transgenic Chlamydomonas reinhardtii. These include monoclonal antibodies, vaccines, hormones, pharmaceutical proteins, and others. In this review, we outline recent progress in the production of recombinant proteins with transgenic microalgae as bioreactors, methods for genetic transformation of microalgae, and strategies for highly efficient expression of heterologous genes. In particular, we highlight the importance of maximizing the value of transgenic microalgae through producing recombinant proteins together with recovery of natural high-value compounds. Finally, we outline some important issues that need to be addressed before commercial-scale production of high-value recombinant proteins and compounds from transgenic microalgae can be realized.
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