Ratiometric Fluorescent Probe Promotes Trans-differentiation of Human Mesenchymal Stem Cells to Neurons.

Development of multifunctional theranostics is challenging and crucial for deciphering complex biological phenomena and subsequently treating critical disease. In particular, development of theranostics for traumatic brain injury (TBI) and understanding its repair mechanism are challenging and highly complex areas of research. Recently, there have been interesting pieces of research work demonstrated that a small molecule-based neuroregenerative approach using stem cells has potential for future therapeutic lead development for TBI. However, these works demonstrated the application of a mixture of multiple molecules as a "chemical cocktail", which may have serious toxic effects in the differentiated cells. Therefore, development of a single-molecule-based potential differentiating agent for human mesenchymal stem cells (hMSCs) into functional neurons is vital for the upcoming neuro-regenerative therapeutics. This lead could be further extraploted for the design of theranostics for TBI. In this study, we have developed a multifunctional single-molecule-based fluorescent probe, which can image the transdifferentiated neurons as well as promote the differentiation process. We demonstrated a promising class of fluorescent probes (CP-4) that can be employed to convert hMSCs into neurons in the presence of fibroblast growth factor (FGF). This fluorescent probe was used in cellular imaging as its fluorescence intensity remained unaltered for up to 7 days of trans-differentiation. We envision that this imaging probe can have an important application in the study of neuropathological and neurodegenerative studies.

Tripodal molecular propellers perturb microtubule dynamics: indole acts as a blade and plays a crucial role in anticancer activity.

An indole-rich tripodal microtubule inhibitor is designed, which binds at the DCVJ site of tubulin and inhibits its polymerization. It causes apoptotic death of cancer cells without affecting normal cells and inhibits the growth of tumors. Finally, STD-NMR and TR-NOESY experiments reveal that the indole appendages play a crucial role in interacting with tubulin.

Power of Tyrosine Assembly in Microtubule Stabilization and Neuroprotection Fueled by Phenol Appendages.

Microtubules play a crucial role in maintenance of structure, function, axonal extensions, cargo transport, and polarity of neurons. During neurodegenerative diseases, microtubule structure and function get severely damaged due to destabilization of its major structural proteins. Therefore, design and development of molecules that stabilize these microtubule networks have always been an important strategy for development of potential neurotherapeutic candidates. Toward this venture, we designed and developed a tyrosine rich trisubstituted triazine molecule (TY3) that stabilizes microtubules through close interaction with the taxol binding site. Detailed structural investigations revealed that the phenolic protons are the key interacting partners of tubulin. Interestingly, we found that this molecule is noncytotoxic in PC12 derived neurons, stabilizes microtubules against nocodazole induced depolymerization, and increases expression of acetylated tubulin (Ac-K40), an important marker of tubulin stability. Further, results show that TY3 significantly induces neurite sprouting as compared to the untreated control as well as the two other analogues (TS3 and TF3). It also possesses anti-Aß fibrillation properties as confirmed by ThT assay, which leads to its neuroprotective effect against amyloidogenic induced toxicity caused through nerve growth factor (NGF) deprivation in PC12 derived neurons. Remarkably, our results reveal that it reduces the expression of TrkA (pY490) associated with NGF deprived amyloidogenesis, which further proves that it is a potent amyloid ß inhibitor. Moreover, it promoted the health of the rat primary cortical neurons through higher expression of key neuronal markers such as MAP2 and Tuj1. Finally, we observed that it has good serum stability and has the ability to cross the blood-brain barrier (BBB). Overall, our work indicates the importance of phenolic -OH in promoting neuroprotection and its importance could be implemented in the development of future neurotherapeutics.

A prospective antibacterial for drug-resistant pathogens: a dual warhead amphiphile designed to track interactions and kill pathogenic bacteria by membrane damage and cellular DNA cleavage.

A rationally designed bactericidal amphiphile acts on compelling targets and has the potential to disarm resistance development in pathogenic bacteria.

Synthetic amphiphiles as therapeutic antibacterials: lessons on bactericidal efficacy and cytotoxicity and potential application as an adjuvant in antimicrobial chemotherapy.

In this paper, we present a critical assessment of the therapeutic potential of low molecular weight pyridine-based synthetic amphiphiles based on structure-guided bactericidal activity and a rational evaluation of their cytotoxic potential. Fluorescence-based structure-function studies revealed that the amphiphiles were membrane-acting and displayed a hierarchical pattern of bactericidal activity, which could be correlated with their charge density and hydrophobicity. The membrane-targeting activity of the most potent cationic amphiphile (compound 6) was vindicated as it induced extensive membrane-disruption and dissipation of the transmembrane potential (ΔΨ) in pathogenic bacteria. At concentrations equivalent to the minimum inhibitory concentration (MIC) against the Gram-positive pathogen S. aureus MTCC 96, none of the amphiphiles exerted any cytotoxic effect on model human cell lines (HeLa, MCF-7 and HT-29). However, at elevated concentrations, a distinct gradation in the cytotoxic effect was manifested, which is probably accounted by the charge density and conformational flexibility of the amphiphiles. A viable therapeutic application of compound 6 is demonstrated in combinatorial assays, wherein the proclivity of the amphiphile to disrupt bacterial membranes at very low concentration is exploited to enhance the uptake and bactericidal efficacy of erythromycin against Gram-negative pathogenic bacteria.