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The intrinsic pathway of apoptosis is regulated by the Bcl-2 family of proteins. Inhibition of the anti-apoptotic members represents a strategy to induce apoptotic cell death in cancer cells. We have measured the membrane binding properties of a series of peptides, including modified α/β-peptides, designed to exhibit enhanced membrane permeability to allow cell entry and improved access for engagement of Bcl-2 family members. The peptide cargo is based on the pro-apoptotic protein Bim, which interacts with all anti-apoptotic proteins to initiate apoptosis. The α/β-peptides contained cyclic β-amino acid residues designed to increase their stability and membrane permeability. Dual polarisation interferometry was used to study the binding of each peptide to two different model membrane systems designed to mimic either the plasma membrane or the outer mitochondrial membrane. The impact of each peptide on the model membrane structure was also investigated, and the results demonstrated that the modified peptides had increased affinity for the mitochondrial membrane and significantly altered the structure of the bilayer. The results also showed that the presence of an RRR motif significantly enhanced the ability of the peptides to bind to and insert into the mitochondrial membrane mimic, and provide insights into the role of selective membrane targeting of peptides. The membrane binding of two peptides designed to exhibit enhanced membrane permeability to allow cell entry and engagement of Bcl-2 family members shows that an RRR motif significantly enhances peptide binding and insertion into a mitochondrial membrane mimic and provides insights into selective membrane targeting of peptides. [ABSTRACT FROM AUTHOR]

The effect of carbon dots (CDs) on a model blayer membrane was studied as a means of comprehending their ability to affect cell membranes. Initially, the interaction of N-doped carbon dots with a biophysical liposomal cell membrane model was investigated by dynamic light scattering, z-potential, temperature-modulated differential scanning calorimetry, and membrane permeability. CDs with a slightly positive charge interacted with the surface of the negative-charged liposomes and evidence indicated that the association of CDs with the membrane affects the structural and thermodynamic properties of the bilayer; most importantly, it enhances the bilayer's permeability against doxorubicin, a well-known anticancer drug. The results, like those of similar studies that surveyed the interaction of proteins with lipid membranes, suggest that carbon dots are partially embedded in the bilayer. In vitro experiments employing breast cancer cell lines and human healthy dermal cells corroborated the findings, as it was shown that the presence of CDs in the culture medium selectively enhanced cell internalization of doxorubicin and, subsequently, increased its cytotoxicity, acting as a drug sensitizer. [ABSTRACT FROM AUTHOR]

Simple Summary: Renal cell carcinoma (RCC) has an extremely poor prognosis, as there are few therapeutic options. In addition, resistance often develops during the administration of cytostatic drugs, preventing further drug-based therapy. New therapeutic modalities to reduce tumor cells would therefore be an important advance in the cancer therapy of RCC. In the present research study, non-invasive physical plasma (NIPP) was used to treat RCC cells. It was found that both cell growth and cell motility of RCC cells could be significantly reduced. Furthermore, programmed cell death was induced, so that some of the cancer cells actually died. Cellular analysis of NIPP treated cancer cells indicated that exposure to NIPP resulted in increased permeability of the cytoplasmic membrane to low molecular weight substances. This may contribute to the inhibition of the physiological activities of the cancer cells. The present results suggest that treatment with NIPP may represent a promising, innovative, and non-chemical option for the therapy of RCC and cancer in general. In combination with established therapeutic modalities, therapeutic effects would be enhanced and resistance would be minimized by the simultaneous application of multiple modes of action. Renal cell carcinoma (RCC) is the third most common urological tumor and has an extremely poor prognosis after metastasis has occurred. Therapeutic options are highly restricted, primarily due to resistance to classical chemotherapeutics. The development of new, innovative therapeutic procedures is thus of great urgency. In the present study, the influence of non-invasive physical plasma (NIPP) on malignant and non-malignant renal cells is characterized. The biological efficacy of NIPP has been demonstrated in malignant renal cell lines (786-O, Caki-1) and non-malignant primary human renal epithelial cells (HREpC). The cell responses that were experimentally examined were cell growth (cell number determination, calculation of growth rate and doubling time), cell motility (scratch assay, invasiveness assay), membrane integrity (uptake of fluorescent dye, ATP release), and induction of apoptosis (TUNEL assay, caspase-3/7 assay, comet assay). A single NIPP treatment of the malignant cells significantly inhibited cell proliferation, invasiveness, and metastasis. This treatment has been attributed to the disruption of membrane functionality and the induction of apoptotic mechanisms. Comparison of NIPP sensitivity of malignant 786-O and Caki-1 cells with non-malignant HREpC cells showed significant differences. Our results suggest that renal cancer cells are significantly more sensitive to NIPP than non-malignant renal cells. Treatment with NIPP could represent a promising innovative option for the therapy of RCC and might supplement established treatment procedures. Of high clinical relevance would be the chemo-sensitizing properties of NIPP, which could potentially allow a combination of NIPP treatment with low-dose chemotherapy. [ABSTRACT FROM AUTHOR]

Decabromodiphenyl ether (BDE-209), a major component of brominated flame retardants, has been detected in considerable amounts in the soil. Given that BDE-209 is toxic, ubiquitous, and persistent, it may cause toxic effects on vegetables planted in contaminated soil. In this study, Chinese cabbage seedlings cultivated in the soil contaminated by BDE-209 (5 - 20 mg kg-1) for 60 d were investigated to evaluate the phytotoxicity of BDE-209 in terms of growth, physiological responses, photosynthetic function, and antioxidant capacity. The results showed that BDE-209-induced phytotoxicity was reflected in the growth suppression, the decrease of chlorophyll content and soluble protein content, and especially in the reduced photosynthetic parameters (net photosynthetic rate and stomatal conductance). BDE- 209 showed direct toxicities to plasma membranes causing their elevated permeability. In addition, BDE-209 induced the overproduction of reactive oxygen species (ROS), membrane lipid peroxidation and protein carbonylation, manifesting in the increased content of O2 •-, H2O2, malondialdehyde, and carbonyl. Chinese cabbage seedlings activated the antioxidant defence system (superoxide dismutase and peroxidase) to scavenge the ROS and counter-balance the oxidative stress caused by BDE-209, while the toxicity could not be effectively alleviated. Our study will provide valuable information for further understanding of the phytotoxicity of polybrominated diphenyl ethers. [ABSTRACT FROM AUTHOR]

Ultrasound with low frequency (20–100 kHz) assisted drug delivery has been widely investigated as a non-invasive method to enhance the permeability and retention effect of drugs. The functional micro/nanobubble loaded with drugs could provide an unprecedented opportunity for targeted delivery. Then, ultrasound with higher intensity would locally burst bubbles and release agents, thus avoiding side effects associated with systemic administration. Furthermore, ultrasound-mediated destruction of micro/nanobubbles can effectively increase the permeability of vascular membranes and cell membranes, thereby not only increasing the distribution concentration of drugs in the interstitial space of target tissues but also promoting the penetration of drugs through cell membranes into the cytoplasm. These advancements have transformed ultrasound from a purely diagnostic utility into a promising theragnostic tool. In this review, we first discuss the structure and generation of micro/nanobubbles. Second, ultrasound parameters and mechanisms of therapeutic delivery are discussed. Third, potential biomedical applications of micro/nanobubble-assisted ultrasound are summarized. Finally, we discuss the challenges and future directions of ultrasound combined with micro/nanobubbles. [ABSTRACT FROM AUTHOR]

Decabromodiphenyl ether (BDE-209), a major component of brominated flame retardants, has been detected in considerable amounts in the soil. Given that BDE-209 is toxic, ubiquitous, and persistent, it may cause toxic effects on vegetables planted in contaminated soil. In this study, Chinese cabbage seedlings cultivated in the soil contaminated by BDE-209 (5 - 20 mg kg-1) for 60 d were investigated to evaluate the phytotoxicity of BDE-209 in terms of growth, physiological responses, photosynthetic function, and antioxidant capacity. The results showed that BDE-209-induced phytotoxicity was reflected in the growth suppression, the decrease of chlorophyll content and soluble protein content, and especially in the reduced photosynthetic parameters (net photosynthetic rate and stomatal conductance). BDE-209 showed direct toxicities to plasma membranes causing their elevated permeability. In addition, BDE-209 induced the overproduction of reactive oxygen species (ROS), membrane lipid peroxidation and protein carbonylation, manifesting in the increased content of O2 •-, H2O2, malondialdehyde, and carbonyl. Chinese cabbage seedlings activated the antioxidant defence system (superoxide dismutase and peroxidase) to scavenge the ROS and counter-balance the oxidative stress caused by BDE-209, while the toxicity could not be effectively alleviated. Our study will provide valuable information for further understanding of the phytotoxicity of polybrominated diphenyl ethers. [ABSTRACT FROM AUTHOR]

Photodynamic therapy has always been an antibacterial tool for solving multi-drug resistant bacteria problem, but the side effects and the low efficiency due to the high aggregation and low solubility of photosensitizers limit its application. Due to the anti-inflammatory effect of caffeic acid, two novel photosensitizers (CA-1-TBO, CA-TBO) were synthesized by conjugating caffeic acid with toluidine blue O (TBO). The structures have been characterized by 1HNMR and high-resolution mass spectrometry. The UV–vis absorption, fluorescence spectra and the octanol-water partition coefficient of two photosensitizers were measured to evaluate their photophysical properties and hydrophilic/hydrophobic properties. Compared with parent TBO, the two modified photosensitizers have shown a higher quantum yield and kinetics constants of singlet oxygen, which has been supported by the simulation results of density functional theory. As drug-resistant representatives of gram-positive and gram-negative bacteria, respectively, S. aureus and P. aeruginosa have been used for in vitro antibacterial experiments. The sterilization efficiencies of the two modified photosensitizers far exceed that of parent TBO. The results of the octanol-water partition coefficient and fluorescence quantification showed that modified photosensitizers CA-1-TBO and CA-TBO could be more accumulated than parent TBO. Based on scanning electron microscopy images, protein gel electrophoresis, and the conductivity of the bacterial solution, the possible mechanism of improved antibacterial photodynamic efficiencies could be induced by membrane permeability due to the caffeic acid effect. The findings demonstrate the significant potential of natural phenolic compounds in the development of photosensitizer molecules with characteristics such as more efficient, biocompatible and less side effects. • Novel photosensitizers from caffeic acid and toluidine blue O have been prepared. • CA-1-TBO and CA-TBO can penetrate bacterial membranes. • CA-1-TBO and CA-TBO could accumulate efficiently into bacterial cells. • CA-1-TBO and CA-TBO showed the enhanced aPDT efficiency. • CA-1-TBO and CA-TBO could target intracellular proteins. [ABSTRACT FROM AUTHOR]

Apoptosis is an exquisitely controlled complex process which plays key roles in maintaining cell homeostasis. Abnormal regulation of apoptosis was directly related to severe diseases including cancer, neurodegenerative diseases, and cardiovascular diseases. Herein, we proposed a chain-engineering strategy for constructing probes to distinguish the different stages of apoptosis. Two fluorescent probes (CPI-2 and CPI-3) with very similar structure were developed to detect the late and early apoptotic stages, respectively. CPI-2 with short chain could not enter live cells due to its poor membrane permeability, and thus exclusively illuminated the nucleolus of late apoptotic cells with damaged plasma membrane. CPI-3 was permeable to biomembranes and stained mitochondria in living cells, which immigrated into the nucleolus during early apoptotic procedure due to the decrease of mitochondrial membrane potential. Furthermore, CPI-2 and CPI-3 were successfully used to monitor the different stages of apoptosis induced by different concentrations of H 2 O 2 , paclitaxel, and rotenone. Particularly, we studied the heavy metals poisoning and detoxification of cysteine by CPI-2 and CPI-3. This work provides a viable strategy for constructing probes to detect the different stages of apoptosis, which is expected to promote the development of probes to monitor apoptosis processes. [Display omitted] • A chain-engineering strategy for probes to detect the early and late apoptosis was proposed. • Two probes with similar chemical structures were developed to distinguish different apoptotic stages. • CPI-2 was impermeable to intact biomembranes which enabled detection of late apoptosis. • CPI-3 exhibited good membrane permeability which could detect early apoptosis via subcellular immigration. • Both probes were used to study heavy metal poisoning and the detoxication of cysteine. [ABSTRACT FROM AUTHOR]

It is well established that lipid aldehydes (LAs) are able to increase the permeability of cell membranes and induce their rupture. However, it is not yet clear how LAs are distributed in phase-separated membranes (PSMs), which are responsible for the transport of selected molecules and intracellular signaling. Thus, we investigate here the distribution of LAs in a PSM by coarse-grained molecular dynamics simulations. Our results reveal that LAs derived from mono-unsaturated lipids tend to accumulate at the interface between the liquid-ordered/liquid-disordered domains, whereas those derived from poly-unsaturated lipids remain in the liquid-disordered domain. These results are important for understanding the effects caused by oxidized lipids in membrane structure, properties and organization. [Display omitted] • Liquid-ordered (Lo) and liquid-disordered (Ld) phases coexist in cell membranes (lipid rafts). • The interface between the Lo/Ld domains is more susceptible to pore formation. • Lipid aldehydes (LAs) derived from mono-unsaturated lipids tend to accumulate at the interface between the Lo/Ld domains. • LAs derived from poly-unsaturated lipids remains in the Ld domain. [ABSTRACT FROM AUTHOR]