Enhanced Insecticidal Effect and Interface Behavior of Nicotine Hydrochloride Solution by a Vesicle Surfactant.

Nicotine hydrochloride (NCT) has a good control effect on hemiptera pests, but its poor interfacial behavior on the hydrophobic leaf leads to few practical applications. In this study, a vesicle solution by the eco-friendly surfactant, sodium diisooctyl succinate sulfonate (AOT), was prepared as the pesticide carrier for NCT. The physical chemical properties of NCT-loaded AOT vesicles (NCT/AOT) were investigated by techniques such as dynamic light scattering (DLS), small-angle X-ray scattering (SAXS), and cryogenic transmission electron microscopy (cryo-TEM). The results showed that the pesticide loading and encapsulation efficiency of NCT/AOT were 10.6% and 94.8%, respectively. The size of NCT/AOT vesicle was about 177 nm. SAXS and surface tension results indicated that the structure of the NCT/AOT vesicle still existed with low surface tension even after being diluted 200 times. The contact angle of NCT/AOT was always below 30°, which means it could wet the surface of the cabbage leaf well. Consequently, NCT/AOT vesicles could effectively reduce the bounce of pesticide droplets. In vitro release experiments showed that NCT/AOT vesicles had sustained release properties; 60% of NCT in NCT/AOT released after 24 h, and 80% after 48 h. Insecticidal activity assays against aphids revealed that AOT vesicles exhibited insecticidal activity and could have a synergistic insecticidal effect with NCT after the loading of NCT. Thus, the NCT/AOT vesicles significantly improved the insecticidal efficiency of NCT, which has potential application in agricultural production activities.

Single-Molecule Study of Peptides with the Same Amino Acid Composition but Different Sequences by Using an Aerolysin Nanopore.

Nanopores are original sensors employed for highly sensitive peptides/proteins detection. Herein, we describe the use of an aerolysin nanopore to identify two similar model peptides, YEQYEQQDDDRQQQ (YEQ2Q3) and QDDDRQQQYEQYEQ (Q3YEQ2), with the same amino acid composition but different sequences. All-atom molecular dynamics (MD) simulations reveal that YEQ2Q3 possesses fewer hydrogen bonds and a more extended conformation than Q3YEQ2. These two peptides, which fold differently, exhibit obviously distinct mass-independent current blockades with characteristic dwell times when entering the aerolysin nanopore. Typically, at +60 mV, the statistical dwell time of 0.630±0.018 ms for peptide Q3YEQ2 is four times longer than the value of 0.160±0.001 ms for peptide YEQ2Q3, and yet peptide YEQ2Q3 induces ∼1.9 % larger blockade current amplitude than peptide Q3YEQ2. The obtained results show the remarkable potential of aerolysin nanopore for peptides/proteins identification, characterization, sequencing and also demonstrate that the mass identification of nonuniformly charged peptides/proteins by using the nanopore technique could be complicated by their folded structure and complex analyte-pore interaction.

pH Responsiveness of Hexosomes and Cubosomes for Combined Delivery of Brucea javanica Oil and Doxorubicin.

We report pH-responsive liquid crystalline lipid nanoparticles, which are dual-loaded by Brucea javanica oil (BJO) and doxorubicin hydrochloride (DOX) and display a pH-induced inverted hexagonal (pH = 7.4) to cubic (pH = 6.8) to emulsified microemulsion (pH = 5.3) phase transition with a therapeutic application in cancer inhibition. BJO is a traditional herbal medicine that strongly inhibits the proliferation and metastasis of various cancers. Doxorubicin is an antitumor drug, which prevents DNA replication and hampers protein synthesis through intercalation between the base pairs of the DNA helices. Its dose-dependent cardiotoxicity imposes the need for safe delivery carriers. Here, pH-induced changes in the structural and interfacial properties of designed multicomponent drug delivery (monoolein-oleic acid-BJO-DOX) systems are determined by synchrotron small-angle X-ray scattering and the Langmuir film balance technique. The nanocarrier assemblies display good physical stability in the studied pH range and adequate particle sizes and ζ-potentials. Their interaction with model lipid membrane interfaces is enhanced under acidic pH conditions, which mimic the microenvironment around tumor cells. In vitro cytotoxicity and apoptosis studies with BJO-DOX dual-loaded pH-switchable liquid crystalline nanoparticles are performed on the human breast cancer Michigan Cancer Foundation-7 (MCF-7) cell line and MCF-7 cells with doxorubicin resistance (MCF-7/DOX), respectively. The obtained pH-sensitive nanomedicines exhibit enhanced antitumor efficacy. The performed preliminary studies suggest a potential reversal of the resistance of the MCF-7/DOX cells to DOX. These results highlight the necessity for further understanding the link between the established pH-dependent drug release profiles of the nanocarriers and the role of their pH-switchable inverted hexagonal, bicontinuous cubic, and emulsified microemulsion inner organizations for therapeutic outcomes.

Insights into the interactions among Surfactin, betaines, and PAM: surface tension, small-angle neutron scattering, and small-angle X-ray scattering study.

The interactions among neutral polymer polyacrylamide (PAM) and the biosurfactant Surfactin and four betaines, N-dodecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (SDDAB), N-tetradecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (STDAB), N-hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (SHDAB), and N-dodecyl-N,N-dimethyl-2-ammonio-acetate (C12BE), in phosphate buffer solution (PBS) have been studied by surface tension measurements, small-angle neutron scattering (SANS), small-angle X-ray scattering (SAXS), and rheological experiments. It has been confirmed that the length of alkyl chain is a key parameter of interaction between betaines and PAM. Differences in scattering contrast between X-ray and neutrons for surfactants and PAM molecules provide the opportunity to separately follow the changes of structure of PAM and surfactant aggregates. At concentrations of betaines higher than CMC (critical micelle concentration) and C2 (CMC of surfactant with the presence of polymer), spherical micelles are formed in betaines and betaines/PAM solutions. Transition from spherical to rod-like aggregates (micelles) has been observed in solutions of Surfactin and Surfactin/SDDAB (αSurfactin = 0.67 (molar fraction)) with addition of 0.8 wt % of PAM. The conformation change of PAM molecules only can be observed for Surfactin/SDDAB/PAM system. Viscosity values follow the structural changes suggested from scattering measurements i.e., gradually increases for mixtures PAM → Surfactin/PAM → Surfactin/SDDAB/PAM in PBS.

Mixture of nonionic/ionic surfactants for the formulation of nanostructured lipid carriers: effects on physical properties.

The objective of the present work was to investigate the effects of the mixture of nonionic/ionic surfactants on nanostructured lipid carriers (NLCs). Nonionic surfactant (polyethylene-poly(propylene glycol), Pluronic F68) and ionic surfactant (octenylsuccinic acid modified gum arabic, GA-OSA) were chosen as emulsifier for NLCs. The NLCs systems, which were composed of lipid matrix, modified 4-dedimethylaminosancycline (CMT-8), and various emulsifier agents, were characterized with dynamic light scattering (DLS), high performance liquid chromatography (HPLC), transmission electron microscopy (TEM), small-angle X-ray scattering (SAXS), differential scanning calorimetry (DSC), in vitro release, and phagocytosis assay. This mixture of nonionic/ionic surfactants showed significant effects on physical properties including particle size, polydispersity index (PDI), entrapment efficiency, and particle morphology. Compared with single stabilizer, this mixed nonionic/ionic surfactant system provided NLCs with better drug carrier properties including prolonged release profile and low phagocytosis by phagocyte. We expect that these explorations can provide a new strategy for the development of lipid nanoparticles as drug delivery.

Enhanced fungicidal efficacy and improved interfacial properties with the co-delivery of prothioconazole and tebuconazole using polylactic acid microspheres.

BACKGROUND: Prothioconazole (PTC) is one of the leading fungicide products worldwide. However, excessive use of PTC facilitates the development of resistance. Pesticide compounding technology plays an important role in reducing pesticide resistance. Microspherization technology for the construction of pesticide dual-loaded systems has recently provided a new direction for researching novel and efficient pesticide formulations. In this study, prothioconazole-tebuconazole@polylactic acid microspheres (PTC-TBA@PLA MS) were constructed by combining these two technologies. RESULTS: The final PTC-TBA@PLA MS were selected by an orthogonal method, which were uniformly spherical with smooth surface. The resultant drug loading (DL) and average particle size of PTC-TBA@PLA MS were 31.34% and 22.3 µm, respectively. A PTC-TBA@PLA MS suspending agent (SC) with a high suspension rate of 94.3% was prepared according to the suspension rate, dumping ability and stability. Compared with a commercial SC, the PTC-TBA@PLA MS SC had a larger cumulative release and better interfacial properties. Biological experiments showed that PTC-TBA@PLA MS SC had an obviously improved bactericidal effect than the commercial SC. CONCLUSION: The constructed PTC-TBA@PLA MS system detailed here is expected to reduce the risk of resistance and the frequency of pesticide use while enhancing fungal control. © 2023 Society of Chemical Industry.

Layer-by-layer assembled decomposable nanocapsules for light-responsive release of pesticide imidacloprid on Aphis craccivora Koch.

BACKGROUND: Conventional pesticide formulations are often inefficient because of low biological uptake after spraying. Controlled release nanopesticides can release pesticides precisely in response to specific stimuli, thereby killing pests and pathogens using the least effective concentration. This study aims to develop nanocapsule-based photo-decomposable nanopesticides for efficient pesticide control. RESULTS: The target nanopesticides were successfully fabricated using layer-by-layer assembly of the negative azobenzene-grafted hyaluronic acid (azo-HA) and positive polydimethyldiallylammonium chloride (polyDADMAC), confirmed by UV-visible, dynamic light scattering, Zeta potential and transmission electron microscopy measurements. The particle size and Zeta potential of the fabricated nanocapsules were 220 nm and +46.1 mV, respectively, and the nanocapsules were found to remain stable for up to 30 days. The optimized drug loading and encapsulation ratio of imidacloprid (IMI) in IMI/azo-HA@polyDADMAC were 21.5% and 91.3%, respectively. Cumulative release of IMI from the nanopesticides increased from ~50% to ~95% upon UV light irradiation (365 nm). The half lethal concentration (LC50) value of the nanopesticides toward Aphis craccivora Koch decreased from 2.22 to 0.55 mg L-1 upon UV light irradiation. CONCLUSION: The trans to cis transformation of the azo group in HA decomposed IMI/azo-HA@polyDADMAC nanopesticides upon UV irradiation, thus facilitating the release of IMI, resulting in a decrease in the concentration of pesticides required for efficient pesticide control. Our work demonstrated the great potential of light-responsive nanocapsules as a controlled release nanocarrier for efficient and eco-friendly pesticide control in sustainable agriculture. © 2024 Society of Chemical Industry.

Interaction of the biosurfactant, Surfactin with betaines in aqueous solution.

The interactions between the lipopeptide Surfactin and four betaines, N-dodecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (SDDAB), N-tetradecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (STDAB), N-hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (SHDAB), and N-dodecyl-N,N-dimethyl-2-ammonio-acetate (C12BE) are studied by surface tension and small-angle neutron scattering (SANS). SDDAB, STDAB, and SHDAB have the same headgroup but different hydrophobic chains. C12BE has different headgroup but the same hydrophobic chain with SDDAB. According to the interfacial parameters calculated from surface tension, the synergism between Surfactin and betaine is relevant with the molecule structure of betaine and the mole ratio of them. For betaines, the optimum alkyl chain length (STDAB) and long enough separation between positive charge and negative charge in headgroup are responsible for highest synergetic interaction with Surfactin. The aggregates of individual Surfactin and the mixtures of Surfactin and sulfopropyl betaines are predicted to be spherical based on the packing parameter (pp) and the average packing parameter (P(av)), which is in close qualitative agreement with SANS data analysis, while Surfactin/C12BE forms ellipsoidal micelles due to the smaller headgroup of C12BE.

An integrative method for evaluating the biological effects of nanoparticle-protein corona.

BACKGROUND: Nanoplastics in the environment can enter the human body through gastrointestinal intake, dermal contact, and pulmonary inhalation, posing a threat to human health. Protein molecules in body fluids will quickly adsorb on the surfaces of the nanoplastics, forming a protein corona, which has implications for the interaction of the nanoplastics with cells and the metabolic pathways of the nanoplastic within cells. For years, practical tools such as dynamic light scattering, transmission electron microscopy, and liquid chromatography have been developed to understand the protein corona of nanoparticles (NPs), either in vitro or in cellular or molecular level. However, an integrated approach to understand the nanoparticles-protein corona is still lacking. METHODS: Using the most frequently observed environmental nanoplastics, polystyrene nanoplastics (PS), as a standard, we established an integrative structural characterization platform, a biophysical and biochemical evaluation method to investigate the effect of surface charge on protein corona composition. The cellular and molecular mechanisms were also explored through in vitro cellular experiments. RESULTS: The first integrative method for characterizing biological properties of NPs-protein corona has been established. This method comprehensively covers the critical aspects to understand NPs-protein corona interactions, from structure to function. CONCLUSIONS: The integrative method for nanoplastics microstructure characterization can be applied to the structural characterization of nanoparticles in nanoscale, which is of universal significance from in vitro characterization to cellular experiments and then to molecular mechanism studies. GENERAL SIGNIFICANCE: This strategy has high reliability and repeatability and can be applied both in environment and nanomedicine safety assessment.

Conformationally-restricted cyclic sulfones as potent and selective mTOR kinase inhibitors.

Novel conformationally-restricted mTOR kinase inhibitors with cyclic sulfone scaffold were designed. Synthesis and structure-activity relationship (SAR) studies are described with emphasis on optimization of the mTOR potency and selectivity against class I PI3Kα kinase. PF-05139962 was identified with excellent mTOR biochemical inhibition, cellular potency, kinase selectivity and in vitro ADME properties.

KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients.

Most gastrointestinal stromal tumors (GISTs) exhibit aberrant activation of the receptor tyrosine kinase (RTK) KIT. The efficacy of the inhibitors imatinib mesylate and sunitinib malate in GIST patients has been linked to their inhibition of these mutant KIT proteins. However, patients on imatinib can acquire secondary KIT mutations that render the protein insensitive to the inhibitor. Sunitinib has shown efficacy against certain imatinib-resistant mutants, although a subset that resides in the activation loop, including D816H/V, remains resistant. Biochemical and structural studies were undertaken to determine the molecular basis of sunitinib resistance. Our results show that sunitinib targets the autoinhibited conformation of WT KIT and that the D816H mutant undergoes a shift in conformational equilibrium toward the active state. These findings provide a structural and enzymologic explanation for the resistance profile observed with the KIT inhibitors. Prospectively, they have implications for understanding oncogenic kinase mutants and for circumventing drug resistance.

Efficient oral delivery of water-soluble CT contrast agent using an W1/O/W2 alginate hydrogel matrix.

HYPOTHESIS: Iohexol (IOH) is a commonly used second-generation nonionic iodinated contrast agent. However, low gastrointestinal mucosal adherence and high downstream speed limit its application in intestinal Computed tomography (CT) imaging. We hypothesize that oral IOH delivery carriers composed of environmentally responsive materials enable the intestinal targeted delivery and prolong the intestinal residence time of IOH, enhancing the intestinal disease detection efficiency. EXPERIMENTS: An emulsion-filled alginate hydrogel system was developed as the intestinal targeting vehicle for IOH. The formulation optimization was determined by response surface analysis. After a thorough study of the physicochemical properties of this hydrogel matrix, the pH sensitivity and the ability to control release were investigated, followed by a vitro cell experiment evaluating its bioactivity and CT imaging capability. FINDINGS: This alginate hydrogel matrix was sparsely structured and rapidly released IOH at pH 7.4. Meanwhile the swelling degree was 4.4 times higher than that at pH 1.2, indicating a good selective responsiveness to the gastrointestinal simulated environment. It improved the CT visual contrast of A549 cells without affecting cell morphology, suggesting that it would be an effective oral administration for water-soluble nonionic contrast agents and a potential candidate for intestinal disease detection tools.

Imidacloprid-loaded mesoporous silica nanoparticles simultaneously coated with myristyl alcohol and polydopamine for NIR-triggered delivery on Aphis craccivora Koch.

The stimuli-responsive degradation of coating layer on pesticide-loaded mesoporous silica nanoparticles (MSNs) can realize on-demand release of pesticides. Herein, we report the simultaneously coating of imidacloprid (IMI)-loaded MSNs with phase change materials (PCMs) and polydopamine (PDA) to realize NIR-triggered release of IMI. To balance good thermal stability and sensitive thermal responsiveness, myristyl alcohol (MA) was selected as optimal PCM for IMI@MSNs@MA-PDA nanocomposites. The successful preparation of IMI@MSNs@MA-PDA nanocomposites was confirmed by FT-IR, small angle XRD, SEM, TEM, TGA and BET. MSNs@MA-PDA nanocomposites exhibited concentration and irradiation power dependent stable photothermal conversion ability, with the maximum temperature increase of 23.3 â„ƒ (808 nm, 2 W/cm2, 300 µg/mL). The drug loading and encapsulation efficiency of IMI were 30.1% and 43.0%, respectively. The cumulative release of IMI from IMI@MSNs@MA-PDA was increased by ∼30% when the temperature was increased from 25 â„ƒ to 38 â„ƒ. Meanwhile, initial burst release of IMI from MSNs was inhibited. Finally, in vivo insecticidal activity of IMI@MSNs@MA-PDA was evaluated on Aphis craccivora Koch. The LC50 value was decreased from 5.01 mg/L to 3.73 mg/L, resulted from photothermal-boosted release of IMI. Our facile and effective method to prepare MSNs-based photothermal-responsive pesticide delivery system can be generalized to prepare other nanomaterials-based delivery systems for efficient and eco-friendly pesticide-control in agriculture.

Mitochondria-specific peptide amphiphiles induce mitochondrial dysfunction and peripheral T-cell lymphomas (PTCL) damage.

Background: Peripheral T-cell lymphomas (PTCL) are aggressive lymphomas with poor prognosis, and therefore, there is a pressing need to explore new targets or compounds. Mitochondria may serve as a potential therapeutic target for PTCL. A designed positively-charged segment (pKV) is anchored to the specific 15 amino acid sequence (MIASHLLAYFFTELN) to yield a cell-penetrating peptide (pHK-pKV) and a lipid chain (Pal) is conjugated to the N-terminus of pHK-pKV (Pal-pHK-pKV) are bioactive amphiphilic peptide assemblies targeting the interaction between mitochondrial voltage dependent anion channel 1 (VDAC1) and hexokinase II (HKII). Methods: PTCL cell line H9 was treated with Pal-pHK-pKV and pHK-pKV, respectively. Cell proliferation in each group was measured by detecting cell viability and the corresponding marker Ki-67. Apoptosis was detected by immunofluorescence, flow cytometry and western blot. We also measured mitochondrial membrane potential, adenosine triphosphate (ATP) production, the cytochrome c distribution and the expression levels of B cell lymphoma 2 (BCL-2) and BCL-2 associated X protein (BAX). Western blot was used to detect the activation of the extracellular regulated protein kinases (ERK) signaling pathway. Results: Pal-pHK-pKV and pHK-pKV with 20 µM blocked the interaction between VDAC1 and HKII, and detached HKII from mitochondria, which depolarized the mitochondrial membrane potential, induced mitochondria dysfunction, and decreased ATP production. The decreased ATP subsequently inhibited the activation of the ERK/BCL-2 pathway and increased the BAX/BCL-2 ratio. Cytochrome c was then released from the mitochondria and induced capase-3 activation and subsequently apoptosis. Additionally, decreased ATP induced the expression of FAS and then apoptosis. Conclusions: Mitochondria specific peptide amphiphiles induce mitochondrial dysfunction and provide a new approach for the treatment of PTCL.

Quinazolines with intra-molecular hydrogen bonding scaffold (iMHBS) as PI3K/mTOR dual inhibitors.

Intra-molecular hydrogen bonding was introduced to the quinazoline motif to form a pseudo ring (intra-molecular H-bond scaffold, iMHBS) to mimic our previous published core structures, pyrido[2.3-D]pyrimidin-7-one and pteridinone, as PI3K/mTOR dual inhibitors. This design results in potent PI3K/mTOR dual inhibitors and the purposed intra-molecular hydrogen bonding structure is well supported by co-crystal structure in PI3Kγ enzyme. In addition, a novel synthetic route was developed for these analogs.

A Lipidated Peptide with Mitochondrial Membrane Localization in Human A549 Lung Cells: From Enhanced Cell-Penetrating Properties to Biological Activity Mechanism.

Here, a lipidated peptide Pal-pHK-pKV with self-assembly properties and the ability to provoke the disruption of the mitochondrial voltage-dependent anion channel-1 protein (VDAC1)-hexokinase-II (HK-II) complex is reported. The effects of the peptide pHK (N-terminal 15-amino acid fragment of HK-II that specifically binds VDAC1) are compared to those of a designed biomimetic amphiphilic pHK-pKV conjugate (pHK coupled with a cell-penetrating peptide pKV) and Pal-pHK-pKV (a lipidated conjugate modified with a hydrophobic palmitic (Pal) alkyl chain). The Pal-pHK-pKV exhibits a stronger interaction with the membrane as compared to pHK-pKV, which is demonstrated by the Langmuir-Blodgett technique and two-photon excitation microscopy. The amphiphilic peptide derivatives are cytotoxic to the A549 cells, but Pal-pHK-pKV is more cytotoxic. The inhibitory effects of the pHK derivatives on the A549 cells growth are investigated through induced apoptosis pathway, depolarized mitochondrial membrane potential, inhibited glycolysis, and activated caspase. The results of the immunofluorescence evidence the specific mitochondrial targeting by those derivatives.

Construction and characterization of a temperature-responsive nanocarrier for imidacloprid based on mesoporous silica nanoparticles.

Nanopesticides have great potential applications due to their stability enhancement, sustained release and target affinity. In this work, a temperature-responsive nanocarrier for imidacloprid (IMI) was constructed using mesoporous silica nanoparticles (MSNs) as the core and paraffin wax (PW) as the outer layer. IMI was loaded into MSNs by screening the drug/carrier mass ratios to obtain the optimized IMI/MSNs formulation with a high drug loading (27.47 %). IMI/MSNs were functionalized with octadecyltrimethoxysilane (C18TMS) and further coated with a temperature-responsive trigger (PW) through hydrophobic interactions. Thus, a temperature-responsive nanocarrier for IMI (PW/IMI/MSNs) was constructed. Fourier transforms infrared (FT-IR), thermogravimetric analysis (TGA) and N2 adsorption-desorption isotherm measurements confirmed the successful loading of IMI into MSNs and the coating of PW on the surface of the IMI/MSNs. X-ray diffraction (XRD) and transmission electron microscopy (TEM) analyses indicated that PW/IMI/MSNs with diameters approximately 100 nm had an ordered hexagonal mesoporous structure with a surface coating of approximately 6 nm. In addition, an in vitro release experiment showed that PW/IMI/MSNs displayed a temperature-responsive sustained release property. Correspondingly, the bioactivity assay of the PW/IMI/MSNs showed that the insecticidal activity greatly increased with temperature. This formulation is expected to have potential applications in some high-temperature areas, such as Turpan in Xinjiang Province, for improving the utilization efficiency of IMI.

Mitochondrial Voltage-Dependent Anion Channel 1-Hexokinase-II Complex-Targeted Strategy for Melanoma Inhibition Using Designed Multiblock Peptide Amphiphiles.

Targeted therapies of melanoma are of urgent need considering the resistance of this aggressive type of cancer to chemotherapeutics. The voltage-dependent anion channel 1 (VDAC1)-hexokinase-II (HK-II) complex is an emerging target for novel anticancer therapies based on induced mitochondria-mediated apoptosis. The low cell membrane permeability of the anticancer 12-mer peptide N-Ter (RDVFTKGYGFGL) derived from the N-terminal fragment of the VDAC1 protein impedes the intracellular targeting. Here, novel multiblock VDAC1-derived cationic amphiphilic peptides (referred to as Pal-N-Ter-TAT, pFL-N-Ter-TAT, and Pal-pFL-N-Ter-TAT) are designed with a self-assembly propensity and cell-penetrating properties. The created multiblock amphiphilic peptides of partial α-helical conformations form nanoparticles of ellipsoid-like shapes and are characterized by enhanced cellular uptake. The amphiphilic peptides can target mitochondria and dissociate the VDAC1-HK-II complex at the outer mitochondrial membrane, which result in mitochondria-mediated apoptosis. The latter is associated with decrease of the mitochondrial membrane potential, cytochrome c release, and changes of the expression levels of the apoptotic proteins in A375 melanoma cells. Importantly, the mitochondrial VDAC1-derived amphiphilic peptides have a comparable IC50 value for melanoma cells to a small-molecule drug, sorafenib, which has been previously used in clinical trials for melanoma. These results demonstrate the potential of the designed peptide constructs for efficient melanoma inhibition.

Interaction between the natural lipopeptide [Glu1, Asp5)] surfactin-C15 and hemoglobin in aqueous solution.

The interaction between natural lipopeptide [Glu(1), Asp(5)] surfactin-C15 (surfactin) and hemoglobin (Hb) has been studied. Surface tension measurements show that the critical micelle concentration (cmc) of surfactin increases from 1.54 x 10(-5) to 3.86 x 10(-5) mol/L with Hb. The UV spectra display that the effect of surfactin on Hb exhibits strong concentration-dependent fashion and the aquometHb convert to hemichrome at high surfactin concentration. Small-angle neutron scattering (SANS) and freeze-fracture transmission electron microscopy (FF-TEM) measurements show that surfactin result in the formation of a fractal structure representing a "necklace model" of micelle-like clusters randomly distributed along the protein polypeptide chain at high surfactin concentration. Far-UV circular dichroism (CD) results confirmed that surfactin can disrupt the helical structure of protein at high concentrations, although the enhanced native-like behavior of protein by low concentration of surfactin was observed. The microenvironment change around Phe amino residues and disulfide bonds of Hb was obtained from near-UV CD spectra.

4-methylpteridinones as orally active and selective PI3K/mTOR dual inhibitors.

Pteridinones were designed based on a non-selective kinase template. Because of the uniqueness of the PI3K and mTOR binding pockets, a methyl group was introduced to C-4 position of the peteridinone core to give compounds with excellent selectivity for PI3K and mTOR. This series of compounds were further optimized to improve their potency against PI3Kα and mTOR. Finally, orally active compounds with improved solubility and robust in vivo efficacy in tumor growth inhibition were identified as well.