Extracellular Matrix Mimicking Wound Microenvironment Responsive Amyloid-Heparin@TAAgNP Co-Assembled Hydrogel: An Effective Conductive Antibacterial Wound Healing Material.

Bioengineered composite hydrogel platforms made of a supramolecular coassembly have recently garnered significant attention as promising biomaterial-based healthcare therapeutics. The mechanical durability of amyloids, in conjunction with the structured charged framework rendered by biologically abundant key ECM component glycosaminoglycan, enables us to design minimalistic customized biomaterial suited for stimuli responsive therapy. In this study, by harnessing the heparin sulfate-binding aptitude of amyloid fibrils, we have constructed a pH-responsive extracellular matrix (ECM) mimicking hydrogel matrix. This effective biocompatible platform comprising heparin sulfate-amyloid coassembled hydrogel embedded with polyphenol functionalized silver nanoparticles not only provide a native skin ECM-like conductive environment but also provide wound-microenvironment responsive on-demand superior antibacterial efficacy for effective diabetic wound healing. Interestingly, both the cytocompatibility and antibacterial properties of this bioinspired matrix can be fine-tuned by controlling the mutual ratio of heparin sulfate-amyloid and incubated silver nanoparticle components, respectively. The designed biomaterial platform exhibits notable effectiveness in the treatment of chronic hyperglycemic wounds infected with multidrug-resistant bacteria, because of the integration of pH-responsive release characteristics of the incubated functionalized AgNP and the antibacterial amyloid fibrils. In addition to this, the aforementioned assemblage shows exceptional hemocompatibility with significant antibiofilm and antioxidant characteristics. Histological evidence of the incised skin tissue sections indicates that the fabricated composite hydrogel is also effective in controlling pro-inflammatory cytokines such as IL6 and TNFα expressions at the wound vicinity with significant upregulation of angiogenesis markers like CD31 and α-SMA.

Next generation antimitotic ß-carboline derivatives modulate microtubule dynamics and downregulate NF-κB, ERK 1/2 and phospho HSP 27.

AIM: Exploring the efficacy of ß-carboline-based molecular inhibitors in targeting microtubules for the development of novel anticancer therapeutics. MATERIALS AND METHODS: We synthesized a series of 1-Aryl-N-substituted-ß-carboline-3-carboxamide compounds and evaluated their cytotoxicity against human lung carcinoma (A549) cells using the MTT assay. Normal lung fibroblast cells (WI-38) were used to assess compound selectivity. The mechanism of action of MJ-211 was elucidated through Western blot analysis of key pro-apoptotic and cell cycle regulatory proteins. Additionally, the inhibitory effect of MJ-211 on multicellular 3D spheroid growth of A549 cells was evaluated. KEY FINDINGS: Lead compound MJ-211 exhibited remarkable cytotoxicity against A549 cells with an IC50 of 4.075 µM at 24 h treatment and IC50 of 1.7 nM after 72 h of treatment, while demonstrating selectivity towards normal WI-38 cells. MJ-211 activated pro-apoptotic factors Bim and p53, and suppressed Cyclin B1, Phospho HSP 27, BubR1, Mad 2, ERK1/2, and NF-κB, indicating its potent antimitotic and pro-apoptotic effects. MJ-211 significantly suppressed the migration of cells and inhibited the growth of A549 cell-derived multicellular 3D spheroids, highlighting its efficacy in a more physiologically relevant model. SIGNIFICANCE: Cytotoxic effect of MJ-211 against cancer cells, selectivity towards normal cells, and ability to modulate key regulatory proteins involved in apoptosis and cell cycle progression underscore its potential as a promising template for further anticancer lead optimization. Moreover, the inhibitory effect of MJ-211 on multicellular spheroid growth suggests its efficacy in combating tumor heterogeneity and resistance mechanisms, thereby offering a promising avenue for future anticancer drug development.

Amyloid-Inspired Engineered Multidomain Amphiphilic Injectable Peptide Hydrogel─An Excellent Antibacterial, Angiogenic, and Biocompatible Wound Healing Material.

The ingrained mechanical robustness of amyloids in association with their fine-tunable physicochemical properties results in the rational design and synthesis of tailor-made biomaterials for specific applications. However, the incredible antimicrobial efficacy of these ensembles has largely been overlooked. This research work provides an insight into the interplay between self-assembly and antimicrobial activity of amyloid-derived peptide amphiphiles and thereby establishes a newfangled design principle toward the development of potent antimicrobial materials with superior wound healing efficacy. Apart from the relationship with many neurodegenerative diseases, amyloids are now considered as an important cornerstone of our innate immune response against pathogenic microbes. Impelled by this observation, a class of amphiphilic antimicrobial peptide-based biomaterial has been designed by taking Aß42 as a template. The designed AMP due to its amphipathic nature undergoes rapid self-assembly to form a biocompatible supramolecular hydrogel network having significant antibacterial as well as wound healing effectivity on both Gram-negative P. aeruginosa and MRSA-infected diabetic wounds via reduced inflammatory response and enhanced angiogenesis. Results suggest that disease-forming amyloids can be used as a blueprint for the fabrication of biomaterial-based antimicrobial therapeutics by fine-tuning both the hydrophobicity of the ß-aggregation prone zone as well as membrane interacting cationic residues.

A potent estrogen receptor and microtubule specific purine-benzothiazole-based fluorescent molecular probe induces apoptotic death of breast cancer cells.

Breast cancer is the most common malignancy in women and is a heterogeneous disease at molecular level. Early detection and specificity are the key prerequisite for the treatment of this deadly cancer. To address these issues attention on the breast cancer specific receptor protein(s) is the most realistic option. Herein estrogen (E) and progesterone (Pg) receptors(R) were considered to design fluorescent molecular probes with possible therapeutic option. We adopted QSAR technique to design a library of benzothiazole-purine hybrid molecules. Molecular docking offers us three screened molecules as most potential. Among these molecules one abbreviated as "CPIB" showed blue fluorescence and detected ER positive cancer cells at 1 nM concentration. At elevated concentration, CPIB induces apoptotic deaths of same cancer cells through targeting intracellular microtubules without affecting normal cells or ER negative cells. CPIB is one of its kind with two-in-one potential of "Detection and Destroy" ability targeting ER positive breast cancer cells.

Designed hybrid anticancer nuclear-localized peptide inhibits aggressive cancer cell proliferation.

Cell proliferation is a crucial step that might promote cancer if deregulated. Therefore, this vital segment is critically controlled by a complicated cell-cycle process in normal cells that is regulated by some regulatory proteins. It has been observed that p16 protein, playing a crucial role in cell-cycle progression/regulation, remains inactivated in different cancer cells. This inactivity of p16 protein leads to the enhancement of cancer cell proliferation by allowing uncontrolled cancer cell division. Hence, the activity of p16 protein needs to be restored using new viral vectors, small molecules as well as peptides to control/suppress this type of abnormal cell proliferation. In this work, we have taken an interesting approach to increase the efficiency and bio-availability of p16 peptide (functional part of p16 protein) to be an aggressive anti-leukemia therapeutic agent by conjugating a nuclear-localized signal (NLS) sequence and a short peptide (AVPI) with it. Moreover, this newly designed NLS attached hybrid peptide greatly affects XIAP expressing but p16 lower expressing human chronic myelogenous leukemia (CML) cell proliferation by targeting both nuclear (CDK4/cyclin D) and cellular factors (XIAP) and promoting the caspase-3 dependent apoptosis pathway.

Investigating the interference of single nucleotide polymorphisms with miRNA mediated gene regulation in pancreatic ductal adenocarcinoma: An in silico approach.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a strong genetic component and single nucleotide polymorphisms (SNPs) in key genes have been found to modulate the susceptibility of the individuals to the disease. SNPs in 3'-UTR of the target genes or in miRNA seed region has gained much importance as this may lead to impairment of miRNA-mRNA interaction. Not much information about this phenomenon is available with respect to PDAC and we wanted to predict such SNPs which could affect miRNA function in the disease using bioinformatics tools. METHODS: After identifying the deregulated miRNAs and genes in PDAC, we determined how many of those altered genes are among experimentally validated targets of those miRNAs. Subsequently, SNPs which could alter these miRNA-mRNA interactions were detected using multiple webtools following high stringent conditions. Disease relevance of the SNPs were also evaluated. RESULTS: We identified a total of 2492 experimentally validated target genes for 303 miRNAs deregulated in PDAC. Our meta-analysis from 363 PDAC patients and 162 control individuals resulted in a set of differentially expressed genes in pancreatic cancer, which was further compared with the miRNA target genes to get targets differentially expressed in pancreatic cancer. We further detected SNPs either in 'seed' region of miRNAs or 'seed-match' sequence of mRNAs either having disruption or creation of miRNA binding site, correlated the expression for each miRNA-SNP-mRNA interaction. Selected SNPs were found to be in LD with important GWAS identified SNPs. CONCLUSION: Our study, hereby, explores the probable effects of SNPs on miRNA-target mRNA interactions. Through stringent analytical methods, we have identified 3 common variants and 13other rare variants possibly interfering with miRNA mediated gene regulation in PDAC.

Cell-Derived Exosome Therapy: A Novel Approach to Treat Post-traumatic Brain Injury Mediated Neural Injury.

Traumatic brain injury (TBI) causes serious neuronal injury that often leads to death. To date there is no clinically successful treatment strategy that has been reported which offers repair of the brain injury or neural injury. Significant attempts have been made to develop effective therapies for TBI, and one of the most promising approaches is a stem cell based therapeutic approach with mesenchymal stem cells (MSCs). This approach is regarded as having the most potential in regenerative medicine. Toward this venture, the generation and release of exosomes can be attributed to the therapeutic effects of MSCs. Exosomes are nanosized vesicles, carry proteins, lipids, mRNA, and miRNA, and assist in cell-cell communication. Exosomes can interact with brain parenchyma cells and with the neurogenic niche, which can help in neurogenesis and brain remodeling. Exosomes derived from MSCs and human-induced pluripotent stem cells (hiPSCs) can be a promising approach in neuronal injury healing. In this Viewpoint, we discussed the most recent knowledge for exosome therapies for neural injuries and highlighted the major advantages of this therapy.