Cholangiocarcinoma(CHOL)is one of the most aggressive tumors worldwide and cannot be effectively treated by conventional and novel treatments,including immune checkpoint blockade therapy.The mRNA vaccine-based immunot...Cholangiocarcinoma(CHOL)is one of the most aggressive tumors worldwide and cannot be effectively treated by conventional and novel treatments,including immune checkpoint blockade therapy.The mRNA vaccine-based immunotherapeutic strategy has attracted much attention for various diseases,however,its application in CHOL is limited due to the thoughtlessness in the integration of vaccine design and patient selection.A recent study established an integrated path for identifying potent CHOL antigens for mRNA vaccine development and a precise stratification for identifying CHOL patients who can benefit from the mRNA vaccines.In spite of a promising prospect,further investigations should identify immunogenic antigens and onco-immunological characteristics of CHOL to guide the clinical application of CHOL mRNA vaccines in the future.展开更多
Five novel cationic lipids, the polar head group of which was attached to the cholesterol backbone via a tertiary carbamate linker, were synthesized and their physicochemical properties were compared to their transfec...Five novel cationic lipids, the polar head group of which was attached to the cholesterol backbone via a tertiary carbamate linker, were synthesized and their physicochemical properties were compared to their transfection efficiencies. Transfection activity of the primary amine analog was highest among the series, while the quaternary ammonium iodide salt was essentially transfection incompetent. Contrary to DC-Chol, methyl and ethyl carbamoyl derivatives of DC-Chol mediated high levels of transfection in the absence of DOPE. Ionization of the cationic assemblies in 40 mM Tris buffer pH 7.2 exactly correlated with the competitive nature of the inductive and steric effects of the methyl groups on the aliphatic nitrogen of the lipids’ polar moiety. Interestingly, the pH interaction zone of all lipid dispersions at 25°C was extended by ± 2 pH units from the pKa, while the pKa of the cationic lipids determined in mixed vesicles composed of 90 % DOPC and cholesterol was approximately 1.3 to 1.5 times higher than that of pure cationic assemblies. The interaction of cationic lipids with plasmid DNA was correlated with pKa, but not the transfection activity.展开更多
Morphology of dipalmitoyl phosphatidyl choline (DPPC)-cholesterol (Chol) mixed monolayer formed on water surface by dropping method was investigated using surface tension measurement (STm), Brewster angle microscopy (...Morphology of dipalmitoyl phosphatidyl choline (DPPC)-cholesterol (Chol) mixed monolayer formed on water surface by dropping method was investigated using surface tension measurement (STm), Brewster angle microscopy (BAM), and fluorescence microscopy (FM). STm showed strong condensation effect of Chol in fluidic DPPC monolayer. Excess area (S<sub>ex</sub>) from mean mixing state of DPPC and Chol was about twice larger than that by general compression method in the range from xC = 0.2 to 0.4 (xC: mole fraction of Chol). BAM and FM images showed clearly that the fluidic DPPC monolayer changed to condensed rigid monolayer due to the condensation effect of Chol. At more than xC = 0.3 DPPC-Chol mixed monolayer changed to condensed state similar to the Chol monolayer. These results support previous reports by compression method that Chol molecule demonstrates the strong condensation effect to the fluidic monolayer and also indicate that dropping method enables to form unique monolayer on the water surface.展开更多
Aurein is a cationic antimicrobial peptide, rich in phenylalanine residues. Although the peptide has been extensively studied, its mechanism of action is not fully understood and has not been established. This project...Aurein is a cationic antimicrobial peptide, rich in phenylalanine residues. Although the peptide has been extensively studied, its mechanism of action is not fully understood and has not been established. This project is focused on studying the interactions of aurein with model biological membranes and antimalarials using Fourier Transform Infrared (FTIR), fluorescence, dynamic light scattering (DLS), atomic force microscopy (AFM), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) techniques. FTIR data revealed conformational changes to the secondary structure of the peptide in the presence of the model membranes. The strongest interactions of aurein were found with DOPC and lipid raft systems. Fluorescence data revealed some differences in the mechanism of interaction between aurein and lipid rafts. Topographical analysis was performed using atomic force microscopy (AFM). AFM images of the peptide with its lipid rafts showed a change in surface roughness suggesting a different mechanism of interaction. DLS data in agreement with FTIR confirmed that aurein interacts differently with the lipid rafts. The results gathered from this study provided new insights on the interaction of aurein. On the other hand, drug-drug interaction issues continue to present a major dilemma for the clinician caring for complex patients such as those infected with infectious disease. This study has examined the interaction of aurein with quinine, primaquine, and chloroquine. Significant interactions between aurein and antimalarials occured at a higher concentration of antimalarials. Interactions between aurein and anti-malarials reveal a strong interaction between aurein and primaquine. Interactions between aurein and quinine or chloroquine were found to be weak and negligible. FTIR, TGA, and DSC may be used in a complementary way to gain insights into the possible drug-drug interactions involving aurein. These studies are needed to initiate in vivo controlled interaction studies between antibiotics and antimalarials.展开更多
<p> <b><span>Background. </span></b><span>Hypertension (HTN) is a preventable risk factor for morbidity and mortality worldwide. Hypertensive retinopathy (HR), its ocular complicati...<p> <b><span>Background. </span></b><span>Hypertension (HTN) is a preventable risk factor for morbidity and mortality worldwide. Hypertensive retinopathy (HR), its ocular complication, is characterized by progressive metabolic disorders and structural damage of the retina. Lipids play an essential role in retina homeostasis, </span><span>so</span><span "=""><span> an alteration of lipid metabolism specific for HTN may be of great significance in the development of hypertensive retinal injury. The study aimed to investigate the association between HR, traditional lipid biomarkers changes, and the atherogenic index, as well as to highlight a possible role of lipid metabolism markers in HR diagnosis and prognosis. </span></span> </p> <p> <span "=""><b><span>Methods.</span></b><span> A total of 90 hypertensive patients from the Republic of Moldova, admitted to the Ovisus Medical Center, Chisinau, Republic of Moldova, for a vision check and firstly diagnosed with HR were recruited in our study.</span></span><span "=""> </span><span>The enrolment period </span><span>is </span><span>between February 2018 and December 2019. They were divided into three groups based on fundoscopy, using Keith-Wagner-Barker grading system of HR—GI:</span><span "=""> </span><span>36 patients;GII:</span><span "=""> </span><span>35 patients;GIII:</span><span "=""> </span><span>19 patients. </span><a name="_Hlk65664122"></a><span>The level of serum lipids: triglycerides, total cholesterol, LDL-Chol, and HDL-Chol w</span><span>as</span><span> determined, followed by the calculation of the atherogenic index of plasma. </span><span "=""><span>Results </span><span>are displayed as the median and interquartile range (IQR). Kolmogorov-Smirnov</span><span> and Shapiro-Wilk normality tests were used, followed by Levene’s homogeneity of variance test. The groups were compared using the non-parametric Kruskal-Wallis and Mann-Whitney tests. The Spearman correlation coefficient was calculated (SPSS 23.0)</span></span><span>: </span><span "=""><span>p < 0.05—statistically significant. </span></span> </p> <p> <span "=""><b><span>Results. </span></b></span><span "=""><span>It</span><b> </b></span><span "=""><span>was attested a statistically significant increase of serum total cholesterol levels between the groups as the HR advanced (p = 0.017). In paired group comparisons, the total cholesterol level in GII significantly enhanced compared to GI 5.63 (IQR 0.69) mM/L vs. 5.49 (IQR 0.51) mM/L, p = 0.05 and in GIII compared to GI 5.76 (IQR 0.82) μM/L vs. 5.49 (IQR 0.51) mM/L, p = 0.04, showing a significant weak positive correlation with the degree of HR (r = 0.292**, p = 0.005). A resembled tendency to increase was highlighted also in serum TAG levels between groups (p = 0.061), with a significant weak and positive correlation with the degree of HR (r = 0.249*, p = 0.018). The results for HDL-Chol, LDL-Chol and atherogenic index were insignificant. </span></span> </p> <p> <span "=""><b><span>Conclusion. </span></b><span>The study revealed statistically conclusive changes associated with the HR degree of the TAG and total cholesterol levels and the </span><span>absence of changes in plasma lipoprotein content</span><span>—</span><span>LDL-Chol and HDL-Chol. </span><span>Extended research is mandatory to conclude the role of lipid metabolism in the advancement of HR and to ascertain the potential diagnostic importance of the presented lipid status changes.</span></span> </p>展开更多
基金supported by the National Natural Science Foundation of China(31970696,81502975,81830089,U20A20378,82188102)the Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholar(LR22H160010)+2 种基金the National Key Research and Development Program(2019YFC1316000)the Zhejiang Provincial Key Research and Development Program(2019C03019)the Zhejiang Provincial College Student Science and Technology Innovation Activity Plan-College Student Innovation and Entrepreneurship Incubation Program(Young Talent Program)(2022R40122)。
文摘Cholangiocarcinoma(CHOL)is one of the most aggressive tumors worldwide and cannot be effectively treated by conventional and novel treatments,including immune checkpoint blockade therapy.The mRNA vaccine-based immunotherapeutic strategy has attracted much attention for various diseases,however,its application in CHOL is limited due to the thoughtlessness in the integration of vaccine design and patient selection.A recent study established an integrated path for identifying potent CHOL antigens for mRNA vaccine development and a precise stratification for identifying CHOL patients who can benefit from the mRNA vaccines.In spite of a promising prospect,further investigations should identify immunogenic antigens and onco-immunological characteristics of CHOL to guide the clinical application of CHOL mRNA vaccines in the future.
文摘Five novel cationic lipids, the polar head group of which was attached to the cholesterol backbone via a tertiary carbamate linker, were synthesized and their physicochemical properties were compared to their transfection efficiencies. Transfection activity of the primary amine analog was highest among the series, while the quaternary ammonium iodide salt was essentially transfection incompetent. Contrary to DC-Chol, methyl and ethyl carbamoyl derivatives of DC-Chol mediated high levels of transfection in the absence of DOPE. Ionization of the cationic assemblies in 40 mM Tris buffer pH 7.2 exactly correlated with the competitive nature of the inductive and steric effects of the methyl groups on the aliphatic nitrogen of the lipids’ polar moiety. Interestingly, the pH interaction zone of all lipid dispersions at 25°C was extended by ± 2 pH units from the pKa, while the pKa of the cationic lipids determined in mixed vesicles composed of 90 % DOPC and cholesterol was approximately 1.3 to 1.5 times higher than that of pure cationic assemblies. The interaction of cationic lipids with plasmid DNA was correlated with pKa, but not the transfection activity.
文摘Morphology of dipalmitoyl phosphatidyl choline (DPPC)-cholesterol (Chol) mixed monolayer formed on water surface by dropping method was investigated using surface tension measurement (STm), Brewster angle microscopy (BAM), and fluorescence microscopy (FM). STm showed strong condensation effect of Chol in fluidic DPPC monolayer. Excess area (S<sub>ex</sub>) from mean mixing state of DPPC and Chol was about twice larger than that by general compression method in the range from xC = 0.2 to 0.4 (xC: mole fraction of Chol). BAM and FM images showed clearly that the fluidic DPPC monolayer changed to condensed rigid monolayer due to the condensation effect of Chol. At more than xC = 0.3 DPPC-Chol mixed monolayer changed to condensed state similar to the Chol monolayer. These results support previous reports by compression method that Chol molecule demonstrates the strong condensation effect to the fluidic monolayer and also indicate that dropping method enables to form unique monolayer on the water surface.
文摘Aurein is a cationic antimicrobial peptide, rich in phenylalanine residues. Although the peptide has been extensively studied, its mechanism of action is not fully understood and has not been established. This project is focused on studying the interactions of aurein with model biological membranes and antimalarials using Fourier Transform Infrared (FTIR), fluorescence, dynamic light scattering (DLS), atomic force microscopy (AFM), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) techniques. FTIR data revealed conformational changes to the secondary structure of the peptide in the presence of the model membranes. The strongest interactions of aurein were found with DOPC and lipid raft systems. Fluorescence data revealed some differences in the mechanism of interaction between aurein and lipid rafts. Topographical analysis was performed using atomic force microscopy (AFM). AFM images of the peptide with its lipid rafts showed a change in surface roughness suggesting a different mechanism of interaction. DLS data in agreement with FTIR confirmed that aurein interacts differently with the lipid rafts. The results gathered from this study provided new insights on the interaction of aurein. On the other hand, drug-drug interaction issues continue to present a major dilemma for the clinician caring for complex patients such as those infected with infectious disease. This study has examined the interaction of aurein with quinine, primaquine, and chloroquine. Significant interactions between aurein and antimalarials occured at a higher concentration of antimalarials. Interactions between aurein and anti-malarials reveal a strong interaction between aurein and primaquine. Interactions between aurein and quinine or chloroquine were found to be weak and negligible. FTIR, TGA, and DSC may be used in a complementary way to gain insights into the possible drug-drug interactions involving aurein. These studies are needed to initiate in vivo controlled interaction studies between antibiotics and antimalarials.
文摘<p> <b><span>Background. </span></b><span>Hypertension (HTN) is a preventable risk factor for morbidity and mortality worldwide. Hypertensive retinopathy (HR), its ocular complication, is characterized by progressive metabolic disorders and structural damage of the retina. Lipids play an essential role in retina homeostasis, </span><span>so</span><span "=""><span> an alteration of lipid metabolism specific for HTN may be of great significance in the development of hypertensive retinal injury. The study aimed to investigate the association between HR, traditional lipid biomarkers changes, and the atherogenic index, as well as to highlight a possible role of lipid metabolism markers in HR diagnosis and prognosis. </span></span> </p> <p> <span "=""><b><span>Methods.</span></b><span> A total of 90 hypertensive patients from the Republic of Moldova, admitted to the Ovisus Medical Center, Chisinau, Republic of Moldova, for a vision check and firstly diagnosed with HR were recruited in our study.</span></span><span "=""> </span><span>The enrolment period </span><span>is </span><span>between February 2018 and December 2019. They were divided into three groups based on fundoscopy, using Keith-Wagner-Barker grading system of HR—GI:</span><span "=""> </span><span>36 patients;GII:</span><span "=""> </span><span>35 patients;GIII:</span><span "=""> </span><span>19 patients. </span><a name="_Hlk65664122"></a><span>The level of serum lipids: triglycerides, total cholesterol, LDL-Chol, and HDL-Chol w</span><span>as</span><span> determined, followed by the calculation of the atherogenic index of plasma. </span><span "=""><span>Results </span><span>are displayed as the median and interquartile range (IQR). Kolmogorov-Smirnov</span><span> and Shapiro-Wilk normality tests were used, followed by Levene’s homogeneity of variance test. The groups were compared using the non-parametric Kruskal-Wallis and Mann-Whitney tests. The Spearman correlation coefficient was calculated (SPSS 23.0)</span></span><span>: </span><span "=""><span>p < 0.05—statistically significant. </span></span> </p> <p> <span "=""><b><span>Results. </span></b></span><span "=""><span>It</span><b> </b></span><span "=""><span>was attested a statistically significant increase of serum total cholesterol levels between the groups as the HR advanced (p = 0.017). In paired group comparisons, the total cholesterol level in GII significantly enhanced compared to GI 5.63 (IQR 0.69) mM/L vs. 5.49 (IQR 0.51) mM/L, p = 0.05 and in GIII compared to GI 5.76 (IQR 0.82) μM/L vs. 5.49 (IQR 0.51) mM/L, p = 0.04, showing a significant weak positive correlation with the degree of HR (r = 0.292**, p = 0.005). A resembled tendency to increase was highlighted also in serum TAG levels between groups (p = 0.061), with a significant weak and positive correlation with the degree of HR (r = 0.249*, p = 0.018). The results for HDL-Chol, LDL-Chol and atherogenic index were insignificant. </span></span> </p> <p> <span "=""><b><span>Conclusion. </span></b><span>The study revealed statistically conclusive changes associated with the HR degree of the TAG and total cholesterol levels and the </span><span>absence of changes in plasma lipoprotein content</span><span>—</span><span>LDL-Chol and HDL-Chol. </span><span>Extended research is mandatory to conclude the role of lipid metabolism in the advancement of HR and to ascertain the potential diagnostic importance of the presented lipid status changes.</span></span> </p>
