A model for wet-casting polymeric membranes incorporating nonequilibrium interfacial dynamics, vitrification and convection

A new model is developed for wet-casting polymeric membranes that address how the concentrations at the interface between the casting solution and nonsolvent bath adjust from initial nonequilibrium to equilibrium values on the binodal. Properly describing the evolution of the interface concentrations enables this new model to predict vitrification, which has been observed experimentally but not predicted heretofore. This new model also incorporates densification-induced convection that arises owing to density changes associated with the concentration gradients and contributes to the mass-transfer fluxes. The predictions for the cellulose acetate, acetone, and water system indicate that densificationinduced convection can increase the mass-transfer flux by nearly two orders-of-magnitude shortly after initiating wet-casting. This increased mass-transfer flux can have a marked effect on the properties of the functional layer of asymmetric membranes that is formed early in the casting process. The predictions for initial casting-solution thicknesses of 75 and 125 m are markedly different. When densification induced convection is included, the 125 m film is predicted to enter well into the metastable region, thereby allowing supersaturation that promotes macrovoid defects. Hence, this new model provides an explanation for the effect of casting-solution thickness on the occurrence of macrovoids

Nonbuoyancy density-driven convective mass and heat transfer : scaling analysis and solution methodology

Density change during mass or heat transfer can cause convection in the absence of buoyancy forces. Prior studies have shown that this convection can be significant in the determination of diffusion coefficients and in the casting of polymeric membranes. Including this effect is challenging even for advanced numerical codes. A general methodology for obtaining the mass-average velocity for unsteady-state, one-dimensional, multicomponent mass and/or heat transfer circumvents the problem of numerically solving the coupled continuity equation. Scaling analysis permits assessing the importance of this convection for a generic equation-of-state. Numerical predictions for evaporation from a liquid layer for components having density ratios of 1:1 and 0.7:1 indicate that ignoring convection results in errors of 34% and 24% in the evaporation time and final thickness, respectively. This convection also influences the evaporation in the percutaneous application of cosmetics, medications, and insecticides, curing of paints, varnishes, and lacquers, and formation of thin films

HBx Sensitizes Cells to Oxidative Stress-induced Apoptosis by Accelerating the Loss of Mcl-1 Protein via Caspase-3 Cascade

Abstract Background Oxidative stress has been implicated in the pathogenesis of a wide spectrum of human diseases, including Hepatitis B virus (HBV)-related liver disease. Hepatitis B virus X protein (HBx) is a key regulator of HBV that exerts pleiotropic activity on cellular functions. Recent studies showed that HBx alters mitochondrial membrane potential, thereby sensitizing cells to pro-apoptotic signals. However, it remains largely unknown whether susceptibility of hepatocytes could be disturbed by HBx under oxidative stress conditions. The purpose of this study is to determine the apoptotic susceptibility of HBx-expressing hepatocytes upon exposure to pro-oxidant stimuli in vitro and in vivo and explore its underlying mechanism. Results Although expression of HBx itself did not activate apoptotic signaling, it significantly enhanced oxidative stress-induced cell death both in vitro and in vivo. Interestingly, this phenomenon was associated with a pronounced reduction of protein levels of Mcl-1, but not other anti-apoptotic Bcl-2 members. Importantly, enforced expression of Mcl-1 prevented HBx-triggered cell apoptosis; conversely, specific knockdown of Mcl-1 exacerbated HBx-induced apoptosis upon exposure to oxidative stress. Furthermore, inhibition of caspase-3 not only abrogated HBx-triggered apoptotic killing but also blocked HBx-induced Mcl-1 loss. Additionally, expression of HBx and Mcl-1 was found to be inversely correlated in HBV-related hepatocellular carcinogenesis (HCC) tissues. Conclusions Our findings indicate that HBx exerts pro-apoptotic effect upon exposure to oxidative stress probably through accelerating the loss of Mcl-1 protein via caspase-3 cascade, which may shed a new light on the molecular mechanism of HBV-related hepatocarcinogenesis.</p

Hepatitis B Virus X Protein Enhances Cisplatin-Induced Hepatotoxicity via a Mechanism Involving Degradation of Mcl-1 ▿ †

Hepatitis B virus X protein (HBx) is implicated in the pathogenesis of hepatitis B virus (HBV)-associated liver diseases. However, whether HBx has the ability to disturb the susceptibility of hepatocytes to common chemotherapeutic agents remains incompletely understood. Here we demonstrate that HBx enhances cisplatin-induced hepatotoxicity by a mechanism involving degradation of Mcl-1, an antiapoptotic member of the Bcl-2 family. Ectopic expression of HBx sensitized hepatocytes to cisplatin-induced apoptosis, which was accompanied by a marked downregulation of Mcl-1 but not of Bcl-2 or Bcl-xL. Overexpression of Mcl-1 prevented HBx-induced proapoptotic and proinflammatory effects during cisplatin treatment both in vitro and in vivo. HBx-induced dysregulation of Mcl-1 resulted mainly from posttranslational degradation rather than transcription repression. Moreover, a caspase-3 inhibitor effectively abrogated HBx-enhanced Mcl-1 degradation and cell death. Importantly, antioxidants blocked activation of caspase-3 and acceleration of Mcl-1 loss, as well as cell death, in HBx-expressing hepatocytes upon cisplatin exposure in vitro and in vivo. Collectively, these data implicate oxidative stress-dependent caspase-3-mediated degradation of Mcl-1 as a mechanism contributing to HBx-mediated sensitization of cisplatin-induced hepatotoxicity. A combination of cisplatin and antioxidants might provide more advantage than cisplatin alone in the treatment of cancer patients with chronic HBV infection

Select dietary phytochemicals function as inhibitors of COX-1 but not COX-2.

Recent clinical trials raised concerns regarding the cardiovascular toxicity of selective cyclooxygenase-2 (COX-2) inhibitors. Many active dietary factors are reported to suppress carcinogenesis by targeting COX-2. A major question was accordingly raised: why has the lifelong use of phytochemicals that likely inhibit COX-2 presumably not been associated with adverse cardiovascular side effects. To answer this question, we selected a library of dietary-derived phytochemicals and evaluated their potential cardiovascular toxicity in human umbilical vein endothelial cells. Our data indicated that the possibility of cardiovascular toxicity of these dietary phytochemicals was low. Further mechanistic studies revealed that the actions of these phytochemicals were similar to aspirin in that they mainly inhibited COX-1 rather than COX-2, especially at low doses

Blockade of C5aR1 resets M1 via gut microbiota-mediated PFKM stabilization in a TLR5-dependent manner

Abstract Targeting C5aR1 modulates the function of infiltrated immune cells including tumor-associated macrophages (TAMs). The gut microbiome plays a pivotal role in colorectal cancer (CRC) tumorigenesis and development through TAM education. However, whether and how the gut flora is involved in C5aR1 inhibition-mediated TAMs remains unclear. Therefore, in this study, genetic deletion of C5ar1 or pharmacological inhibition of C5aR1 with anti-C5aR1 Ab or PMX-53 in the presence or absence of deletion Abs were utilized to verify if and how C5aR1 inhibition regulated TAMs polarization via affecting gut microbiota composition. We found that the therapeutic effects of C5aR1 inhibition on CRC benefited from programming of TAMs toward M1 polarization via driving AKT2-mediated 6-phosphofructokinase muscle type (PFKM) stabilization in a TLR5-dependent manner. Of note, in the further study, we found that C5aR1 inhibition elevated the concentration of serum IL-22 and the mRNA levels of its downstream target genes encoded antimicrobial peptides (AMPs), leading to gut microbiota modulation and flagellin releasement, which contributed to M1 polarization. Our data revealed that high levels of C5aR1 in TAMs predicted poor prognosis. In summary, our study suggested that C5aR1 inhibition reduced CRC growth via resetting M1 by AKT2 activation-mediated PFKM stabilization in a TLR5-dependent manner, which relied on IL-22-regulated gut flora

Effects of dietary phytochemicals on (A) nitric oxide (NO) production and (B) cell viability.

<p>NO concentration was measured as nitrite using the Nitrate/Nitrite colorimetric assay kit as described in “Materials and Methods”. Data are presented as means ± S.E.M. (n = 3) and the asterisk(s) indicate a significant (**, <i>p</i> < 0.01) difference versus IL-1β group. Cell viability was tested as described in “Materials and Methods”. Data are presented as means ± S.E.M. (n = 3) and the asterisk(s) indicate a significant (*, <i>p</i> < 0.05; **, <i>p</i> < 0.01; ***, <i>p</i> < 0.001) difference versus control (DMSO).</p