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Aim: The primary aim of this study was to develop biomimetic nanocarriers for specific homologous targeting of the anticancer drugs ammonium pyrrolidine dithiocarbamate (PDTC) and doxorubicin. Methods: Membranous nanovesicles were synthesized from a breast cancer cell line (MCF7) by syringe extrusion process and were loaded with PDTC and doxorubicin. Besides their abilities for self-homing, the drug-loaded nanovesicles showed anti-cell proliferative effects via the generation of reactive oxygen species. Results: The nanovesicles demonstrated efficient internalization via homologous targeting. Delivery of PDTC showed a higher killing effect for homologous cell targeting than other cell types. Experimental results demonstrated increased antiproliferative potency of PDTC, which induced apoptosis via reactive oxygen species generation. Conclusion: The developed membrane-derived nanocarrier is an attractive biocompatible system for ex vivo targeted drug delivery.

Herein we report the efficacy and toxicity of three de novo designed cationic antimicrobial peptides (AMPs) LL-14, VV-14 and ββ-14, where side chains of the hydrophobic amino acids were reduced gradually. The AMPs showed broad-spectrum antimicrobial activity against three pathogens from the ESKAPE group and two fungal strains. This study showed that side chains which are either too long or too short increase toxicity and lower antimicrobial activity, respectively. VV-14 was found to be non-cytotoxic and highly potent under physiological salt concentrations against several pathogens, especially Salmonella typhi TY2. These AMPs acted via membrane deformation, depolarization, and lysis. The activity of the AMPs is related to their ability to take on amphipathic helical conformations in the presence of microbial membrane mimics. Among AMPs with the same charge, hydrophobic interactions between the side chains of the residues with cell membrane lipids determine their antimicrobial potency and cytotoxicity. Strikingly, an optimum hydrophobic interaction is the crux of generating highly potent non-cytotoxic AMPs.

Herein, we demonstrate the preparation of transferrin (TF) receptor-targeted RBC membrane coated nanoparticles (NPs) to achieve chemotherapeutic and photodynamic effects. The TF conjugated RBC memb...

Herein, a membrane-coated nanocarrier for codelivery of chemotherapeutic agents, curcumin (Cur) and the hypoxia-activated molecule, tirapazamine (TPZ), has been developed. Cur and TPZ were loaded into biodegradable poly(lactic

A charged synthetic peptide-based noncytotoxic hydrogelator was employed in encapsulation, storage, and sustainable release of different kinds of drugs, namely, ciprofloxacin (CP), an antibiotic; 5-fluorouracil (5-FU), an anticancer drug and proteins like lysozyme and bovine serum albumin (BSA). Hydrogelation of the peptide and its coassembly with the drug molecules were studied to obtain mechanistic details. All of the different cargos were capable of sustained and efficient release from the delivery platform. The drugs were found to retain their activity post release, while the proteins showed complete retention of their secondary structure. While about 80% CP was released at physiological pH over a period of 3 days, 5-FU was better released (73%) at an acidic pH (5.5) in comparison to the physiological pH (68%). Lysozyme was better released (82%) than BSA (43%) owing to the smaller size of the former and negative charge on the latter. Such biocompatible multicargo-releasing platforms from simple economically viable biomaterials, capable of sustained and tissue-specific release of cargo, are extremely promising in topical delivery of therapeutics.

Boron neutron capture therapy (BNCT) is an encouraging therapeutic modality for cancer treatment. Prostate-specific membrane antigen (PSMA) is a cell membrane protein that is abundantly overexpressed in prostate cancer and can be targeted with radioligand therapies to stimulate clinical responses in patients. In principle, a spatially targeted neutron beam together with specifically targeted PSMA ligands could enable prostate cancer-targeted BNCT. Thus, we developed and tested PSMA-targeted poly(lactide

Herein, a membrane-coated nanocarrier for codelivery of chemotherapeutic agents, curcumin (Cur) and the hypoxia-activated molecule, tirapazamine (TPZ), has been developed. Cur and TPZ were loaded i...

Combination chemotherapy, where drugs with a nonoverlapping mode of action achieve better efficacy at lower doses with reduced dose-dependent side effects, holds promise for complete remission of the tumor. Herein, we report a combination therapeutic module comprised of the folic acid receptor (FAR)-targeted SeNPs (FA-SeNPs) and MAPK-pathway inhibitor PD98059 (PD98). While aberrant signaling leading to an uncontrolled proliferation in BRAF mutation bearing cancer cells including MDAMB231 (breast cancer) and A375 (melanoma) cells was inhibited by PD98, high expression of FAR by these cells also led to selective internalization of FA-SeNPs. Consequently, the combination treatment of PD98 and FA-SeNPs demonstrated synergistic antiproliferative efficacy in MDAMB231 and A375 cells involving apoptotic modes of cell death. The selective nature of the present combination module was supported by the low off-target response in L132 noncancerous lung cells. Moreover, the size of the three-dimensional MDAMB231 spheroids was successfully reduced because of the combination therapy projecting its potential in eradicating tumors

A strategy of conformational tweaking regulates the condensed state behavior of naphthalimide skeletal isomers (NSIs) and enhances their photophysical properties, cellular uptake and prolonged imaging capability. This salient approach results in a large Stokes shift (>120 nm), rapid cellular internalization, photobleaching resistance, and efficient bioimaging of the ribbon-like nano-assembly superior to that of its electronically similar micro-flower isomer.

Nerve growth factor (NGF) is a minor and neglected component of snake venom. Present study describes the purification and characterization of a NGF isoform (RVV-NGFa) from Indian Russell’s viper venom (RVV). RVV-NGFa showed a protonated molecular ion [MH+] at m/z 17388.725 Da. The RVV-NGFa induced neuritogenesis in PC-12 cells but did not show cytotoxicity in mammalian cells, hemolytic activity, platelet modulation, and interference in blood coagulation system which are the characteristic pharmacological properties of RVV. By ELISA and immunofluorescence microplate reader assay, the RVV-NGFa showed appreciable binding to TrkA receptor expressed in breast cancer MDA-MB-231 and MCF-7 cells; nevertheless, pre-incubation of cells with anti-TrkA (and not TrkB or TrkC) or anti-p75NTR antibody significantly decreased (p

A potential strategy of conformational tweak has been developed that regulates the condensed state properties in naphthalimide skeletal isomers (NSIs) and controls the cellular uptake and prolonged imaging capability. It was observed that with identical aromatic cores and electronic properties at the molecular level, fine-tuning of condensed state photophysical and supramolecular self-assembly properties were seen in these luminogenic NSIs owing to their molecular conformation energized distinct intermolecular packing orientations and even without adding any secondary components. With characteristics such as large stokes-shift, not observed in single skeletal isomers previously, this strategy boosts rapid cellular internalization¸ photobleaching resistance, and long-term imaging ability in the ribbons-like nano-assembly to that of its electronically similar micro-flower counterpart. This study presents that a conformational tweaking strategy can provide a clear outlook for designing new generation nanodrugs with clear understanding of associated molecular events for wide biomedical and theranostic applications.

Aim: To develop selenium nanoparticles (SeNPs)-based delivery systems for paclitaxel (PTX) and assess their antiproliferative efficacy against cancer cells in vitro with potential mechanistic insight. Methods: Pluronic F-127 stabilized SeNPs were prepared and characterized. Effects of PTX-loaded SeNPs on lung (A549), breast (MCF7), cervical (HeLa) and colon (HT29) cancer cells were studied by viability assay complemented with flow-cytometric analyses of cell cycle, apoptosis, mitochondrial membrane potential, intracellular reactive oxygen species and caspase activity. Results: PTX-loaded SeNPs demonstrated significant antiproliferative activity against cancer cells. Cell cycle analyses of PTX-SeNPs treated cells established G2/M phase arrest in a dose-dependent manner leading to apoptosis. Further investigation revealed disruption of mitochondrial membrane potential orchestrated with induction of reactive oxygen species leading to the activation of caspases, key players of apoptotic cell death. Conclusion: Efficient induction of apoptosis in various cancer cells by PTX-loaded SeNPs, with appropriate future studies, might lead to potential anticancer strategies.

The widespread abuse of antibiotics has led to the use of antimicrobial peptides (AMPs) as a replacement for the existing conventional therapeutic agents for combating microbial infections. The broad-spectrum activity and the resilient nature of AMPs has mainly aggrandized their utilization. Here, we report the design of non-toxic, non-hemolytic and salt tolerant undecapeptides (AMP21-24), derived by modification of a peptide P5 (NH2-LRWLRRLCONH2) reported earlier by our group. Our results depict that the designed peptides show potency against several bacterial as well as fungal strains. Circular dichroism (CD) spectroscopy in combination with molecular dynamic (MD) simulations confirm that the peptides are unstructured. Intrinsic tryptophan fluorescence quenching as well as interaction studies using isothermal calorimetry (ITC) of these peptides in the presence of biological microbial membrane mimics establish the strong microbial membrane affinity of these AMPs. Membrane permeabilization assay and cytoplasmic membrane depolarization studies of Pseudomonas aeruginosa and Candida albicans in the presence of AMPs also hint towards the AMP-membrane interactions. Leakage of calcein dye from membrane mimic liposomes, live cell NMR and field emission scanning electron microscopy (FESEM) studies suggest that the AMPs may be primarily involved in membrane perturbation leading to release of intracellular substances resulting in subsequent microbial cell death. Confocal laser scanning microscopy (CLSM) shows localization of the peptides throughout the cell, indicating the possibility of secondary mode of actions. Electrostatic interactions seem to govern the preferential binding of the AMPs to the microbial membranes in comparison to the mammalian membranes as seen from the MD simulations.

Epithelial to mesenchymal transition (EMT) induces cell migration, invasion, and drug resistance, and consequently, contributes to cancer metastasis and disease aggressiveness. This study attempted to address crucial biological parameters to correlate EMT and drug-treated cancer cells traversing through microcapillaries, reminiscent of metastatic conditions. MDA-MB-468 breast cancer cells induced to undergo EMT by treatment with 20 ng/mL of epidermal growth factor (EGF) were initially passed through several blockages and then through a constricted microchannel, mimicking the flow of invasive metastatic cells through constricted blood microcapillaries. EMT cells acquired enhanced migratory properties and retained 50% viability, even after migration through wells 10−15 μm in size and a constricted passage of 7 μm and 150 μm in length at a constant flow rate of 50 μL/h. The hydrodynamic properties revealed cellular deformation with a deformation index, average transit velocity, and entry time of 2.45, 12.3 mm/s, and 31,000 μs, respectively for a cell of average diameter 19 μm passing through one of the 7 μm constricted sections. Interestingly, cells collected at the channel outlet regained epithelial character, undergoing reverse transition (mesenchymal to epithelial transition, MET) in the absence of EGF. Remarkably, real-time polymerase chain reaction (PCR) analysis confirmed increases of 2- and 2.7-fold in the vimentin and fibronectin expression in EMT cells, respectively; however, their expression reduced to basal level in the MET cells. A scratch assay revealed the pronounced migratory nature of EMT cells compared with MET cells. Furthermore, the number of colonies formed from EMT cells and paclitaxel-treated EMT cells after passing through a constriction were found to be 95 ± 10 and 79 ± 4, respectively, confirming that the EMT cells were more drug resistant with a concomitant two-fold higher expression of the multi-drug resistance (MDR1) gene. Our results highlight the hydrodynamic and drug-evading properties of cells that have undergone an EMT, when passed through a constricted microcapillary that mimics their journey in blood circulation.

Granulocyte macrophage colony stimulating factor (GMCSF), a therapeutically important cytokine that helps in the proliferation of macrophages, was recombinantly expressed in E. coli BL21 and purified as a GST-tagged protein. Cell viability assay demonstrated significant enhancement in proliferation of RAW 264.7 (murine macrophage) in presence of GMCSF. In vitro activation of macrophages was carried out by lipopolysaccharide (LPS) or pyrogallol and probed by the generation of reactive oxygen species (ROS). Following the induction of apoptosis in A549 lung cancer cells with anticancer drug cisplatin (at 25μM), apoptotic cancer cells were effectively phagocytosed by the recombinant GMCSF-treated and exogenously activated RAW 264.7 cells as observed in fluorescence microscopic images. The current findings attribute possible role of GMCSF as adjuvant in scavenging treated cancer cells.

Protein misfolding is an intrinsic aspect of normal folding within the complex cellular environment. Its effects are minimized in living system by the action of a range of protective mechanisms including molecular chaperones and quality control systems. According to the current growing research, protein misfolding is a recognized key feature of most neurodegenerative diseases. Extensive biochemical, neuropathological, and genetic evidence suggest that the cerebral accumulation of amyloid fibrils is the central event in the pathogenesis of neurodegenerative disorders. In the first part of this review we have discussed the general course of action of folding and misfolding of the proteins. Later part of this review gives an outline regarding the role of protein misfolding in the molecular and cellular mechanisms in the pathogenesis of Alzheimer's and Parkinson along with their treatment possibilities. Finally, we have mentioned about the recent findings in neurodegenerative diseases.

Though after a start of genome sequencing most of the protein sequences are deposited in databases, some proteins remain to be annotated and functionally characterized. Analyzing and annotating the function of Hypothetical proteins of Leptospira interrogans is very important which is a pathogenic spirochete causes various complications in human and animals. Randomly we have selected 12 sequences of hypothetical proteins and were analyzed through web tools as Pfam, CD Blast, Expasy's to determine physicochemical properties and protein family information based on conserved domains. Proteins from families AdoMetDC, LRR, and PilZ are most conserved in many microorganisms can be targeted to develop efficacious drug molecules. Ligand binding site and protein structure prediction was done by using Qsite finder and PS2 server which will help to develops therapeutic molecules in docking studies. Present study has shown intracellular interactions of proteins involved in drug resistance, transcription factors, and transport channels.