Sinoporphyrin Sodium-Mediated Sonodynamic Therapy Inhibits RIP3 Expression and Induces Apoptosis in the H446 Small Cell Lung Cancer Cell Line

Background/Aims: Sonodynamic therapy (SDT) is expected to be a new method to solve the clinical problems caused by advanced metastasis in patients with lung cancer. The use of ultrasound has the advantage of being noninvasive, with deep-penetration properties. This study explored the anti-tumor effect of SDT with a new sonosensitizer, sinoporphyrin sodium (DVDMS), on the human small cell lung cancer H446 cell line in vitro and in vivo. Methods: Absorption of DVDMS was detected by a fluorescence spectrophotometer, and DVDMS toxicity was determined using a Cell Counting Kit-8. Mitochondrial membrane potential (MMP) was assessed using the JC-1 fluorescent probe. Cell apoptosis was measured by flow cytometry, and apoptosis-related proteins were detected by western blotting. The expression of cytokines was measured using an enzyme-linked immunosorbent assay and quantitative real-time PCR. To verify the in vitro results, we detected tumor volumes and weight changes in a xenograft nude mouse model after DVDMS-SDT. Hematoxylin and eosin staining was used to observe changes to the tumor, heart, liver, spleen, lung, and kidney of the mice, and immunohistochemistry was used to examine changes in the expression of tumor CD34 and receptor-interacting protein kinase-3 (RIP3), while terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling was used to observe apoptosis in tumor tissues. Results: DVDMS-SDT-treated H446 cells increased the rate of cellular apoptosis and the levels of reactive oxygen species (ROS), cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, and caspase-10, and decreased the levels of MMP, RIP3, B-cell lymphoma 2, vascular endothelial growth factor, and tumor necrosis factor-α. The sonotoxic effect was mediated by ROS and was reduced by a ROS scavenger (N-acetyl-L-cysteine). In the in vivo mouse xenograft model, DVDMS-SDT showed efficient anti-cancer effects with no visible side effects. Conclusion: DVDMS-SDT induced apoptosis in H446 cells, in part by targeting mitochondria through the mitochondria-mediated apoptosis signaling pathway, and the extrinsic apoptosis pathway was also shown to be involved. Both apoptosis and changes in RIP3 expression were closely related to the generation of ROS. DVDMS-SDT will be advantageous for the management of small cell lung cancer due to its noninvasive characteristics

The Mineral Chemistry of Chlorites and Its Relationship with Uranium Mineralization from Huangsha Uranium Mining Area in the Middle Nanling Range, SE China

The Huangsha uranium mining area is located in the Qingzhangshan uranium-bearing complex granite of the Middle Nanling Range, Southeast China. This uranium mining area contains three uranium deposits (Liangsanzhai, Egongtang, and Shangjiao) and multiple uranium occurrences, showing favorable mineralization conditions and prospecting potential for uranium mineral resources. Chloritization is one of the most important alteration types and prospecting indicators in this mining area. This study aims to unravel the formation environment of chlorites and the relationship between chloritization and uranium mineralization, based on detailed field work and petrographic studies of the wallrock and ore samples from the Huangsha uranium mining area. An electron probe microanalyzer (EPMA) was used in this study to analyze the paragenetic association, morphology, and chemical compositions of chlorite, to classify chemical types and to calculate formation temperatures and n(Al)/n(Al + Mg + Fe) values of chlorite. The formation mechanism and the relationship with uranium mineralization of the uranium mining area are presented. Some conclusions from this study are: (1) There are five types of chlorites, including the chlorite formed by the alteration of biotite (type-I), by the metasomatism of feldspar with Fe–Mg hydrothermal fluids (type-II), chlorite vein/veinlet filling in fissures (type-III), chlorite closely associated with uranium minerals (type-IV), and chlorite transformed from clay minerals by adsorbing Mg- and Fe-components (type-V). (2) The chlorite in the Huangsha uranium mining area belongs to iron-rich chlorite and is mainly composed of chamosite, partly clinochlore, which are the products of multiple stages of hydrothermal action. The original rocks are derived from argillite, and their formation temperatures vary from 195.7 °C to 283.0 °C, with an average of 233.2 °C, suggesting they formed under a medium to low temperature conditions. (3) The chlorites were formed under reducing conditions with low oxygen fugacity and relatively high sulfur fugacity through two formation mechanisms: dissolution–precipitation and dissolution–migration–precipitation; (4) The chloritization provided the required environment for uranium mineralization, and promoted the activation, migration, and deposition of uranium

Twin structure of the lath martensite in low carbon steel

It has been well accepted that the martensites in quenched carbon steels exhibit two typical morphologies which are closely dependent on the carbon content, i.e. lath martensite in low carbon steels and lenticular martensite in high carbon steels. Based on conventional belief, the lath martensites in low carbon steels are with high density dislocations as the substructure, in contrast to twin substructure in lenticular high carbon martensite. In the present work, an intensive transmission electron microscopy investigation was made to characterize the microstructures of the lath martensite in a low carbon steel of 0.2 wt%C. It was found that lots of lath martensites consist of twin as their substructure, rather than high density dislocations. In addition, nanoscale precipitates cohering with ferrite matrix were found at the twin interfaces. The orientation relationships between the precipitates and the ferrite matrix are in good agreement with that of primitive hexagonal ω phase in titanium alloys and other bcc metals or alloys

Regulating the Polarization of Macrophages: A Promising Approach to Vascular Dermatosis

Macrophages, a kind of innate immune cells, derive from monocytes in circulation and play a crucial role in the innate and adaptive immunity. Under the stimulation of the signals from local microenvironment, macrophages generally tend to differentiate into two main functional phenotypes depending on their high plasticity and heterogeneity, namely, classically activated macrophage (M1) and alternatively activated macrophage (M2). This phenomenon is often called macrophage polarization. In pathological conditions, chronic persistent inflammation could induce an aberrant response of macrophage and cause a shift in their phenotypes. Moreover, this shift would result in the alteration of macrophage polarization in some vascular dermatoses; e.g., an increase in proinflammatory M1 emerges from Behcet’s disease (BD), psoriasis, and systemic lupus erythematosus (SLE), whereas an enhancement in anti-inflammatory M2 appears in infantile hemangioma (IH). Individual polarized phenotypes and their complicated cytokine networks may crucially mediate in the pathological processes of some vascular diseases (vascular dermatosis in particular) by activation of T cell subsets (such as Th1, Th2, Th17, and Treg cells), deterioration of oxidative stress damage, and induction of angiogenesis, but the specific mechanism remains ambiguous. Therefore, in this review, we discuss the possible role of macrophage polarization in the pathological processes of vascular skin diseases. In addition, it is proposed that regulation of macrophage polarization may become a potential strategy for controlling these disorders

Proanthocyanidins as a Potential Novel Way for the Treatment of Hemangioma

Hemangioma, the most common benign vascular tumor, not only affects the appearance and psychology but also has a life-threatening potential. It is considered that clonal vascular endothelial cell proliferation and excessive angiogenesis are responsible for hemangioma pathogenesis, in which abnormal cytokines/pathways are closely implicated, primarily including high expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) as well as their downstream pathways, especially phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt). These further stimulate the migration and proliferation of vascular endothelial cells and promote the formation of new vessels, ultimately leading to the occurrence and development of hemangioma. Proanthocyanidins are naturally active substance from plants and fruits. They possess multiple functions like antiproliferation, antiangiogenesis, and antitumor. It has been demonstrated that proanthocyanidins effectively work in various diseases via inhibiting the expression of various factors, e.g., HIF-1α, VEGF, PI3K, and Akt. Considering the pathogenesis of hemangioma and the effect of proanthocyanidins, we hold a hypothesis that proanthocyanidins would be applied in hemangioma via downregulating cytokine/pathway expression, suppressing vascular cell proliferation and arrest abnormal angiogenesis. Taken together, proanthocyanidins may be a potential novel way for the treatment of hemangioma

Assembly and Reassembly of Polyelectrolyte Complex Formed by Poly(ethylene glycol)-<i>block</i>-poly(glutamate sodium) and S₅R₄ Peptide

The structure and stability of polyelectrolyte complex are controlled not only by electrostatic interaction but also by hydrogen bonding and hydrophobic interaction if they are present. The complexes formed by such multiple interactions should exhibit different responses to the environmental changes, such as ionic strength and pH. In this work, we designed a positively charged peptide S₅R₄, which can interact with poly­(ethylene glycol)-<i>block</i>-poly­(glutamate sodium) (PEG₁₁₄-PGlu₆₄) via electrostatic interaction, hydrogen bonding, and hydrophobic interaction. In deionized water at pH 7.1, the complexes formed by PEG₁₁₄-PGlu₆₄ and S₅R₄ assemble into wormlike micelles, spheres, and even hierarchical “wool balls”, depending on mixing ratio. However, a distinct dissociation–reassembly process is observed when 30 mM NaCl is added to screen the electrostatic interaction. The spheres transform into loose clusters after reassembly. This process is caused by the switch of driving force from electrostatic interaction to hydrogen bonding. Similarly, when the driving force is switched from electrostatic interaction to hydrophobic interaction by increasing solution pH to above 8.7, the original structure quickly dissociates and reassembles into dense aggregates. The rich structures formed by polyelectrolyte complexes and their drastic and sensitive responses to environmental changes are helpful to understand the working mechanism of biomolecules regulated by pH or ion strength

Shear Effects on Stability of DNA Complexes in the Presence of Serum

The behavior of nanocarriers, even though they are well-defined at equilibrium conditions, is unpredictable in living system. Using the complexes formed by plasmid DNA (pDNA) and K₂₀ (K: lysine), protamine, or polylysine (PLL) as models, we studied the dynamic behavior of gene carriers in the presence of fetal bovine serum (FBS) and under different shear rates, a condition mimicking the internal physical environment of blood vessels. Without shear, all the positively charged complexes bind to the negatively charged proteins in FBS, leading to the formation of large aggregates and even precipitates. The behaviors are quite different under shear. The shear generates two effects: a mechanical force to break down the complex into smaller size particles above a critical shear rate and a stirring effect leading to secondary aggregation of complexes below the critical shear rate. In the studied shear rate from 100 to 3000 s^–1, the mechanical force plays a key role in K₂₀/pDNA and protamine/pDNA, while the stirring effect is dominant in PLL/pDNA. A model study shows that the interfacial tension, the chain density, and the elasticity of the complexes determine their responsiveness to shear force. This study is helpful to understand the fate of drug/gene carriers under physiological conditions. It also gains insight in designing drug/gene carriers with desirable properties for in vivo applications

Effects of Structural Flexibility on the Kinetics of DNA Y‑Junction Assembly and Gelation

The kinetics of DNA assembly is determined not only by temperature but also by the flexibility of the DNA tiles. In this work, the flexibility effect was studied with a model system of Y-junctions, which contain single-stranded thymine (T) loops in the center. It was demonstrated that the incorporation of a loop with only one thymine prominently improved the assembly rate and tuned the final structure of the assembly, whereas the incorporation of a loop of two thymines exhibited the opposite effect. These observations could be explained by the conformation adjustment rate and the intermotif binding strength. Increasing DNA concentration hindered the conformational adjustment rate of DNA strands, leading to the formation of hydrogels in which the network was connected by ribbons. Therefore, the gel can be treated as a metastable state during the phase transition