Using nanotechnology to progress the utilization of marine natural products in combating multidrug resistance in cancer: A prospective strategy.

Achieving targeted, customized, and combination therapies with clarity of the involved molecular pathways is crucial in the treatment as well as overcoming multidrug resistance (MDR) in cancer. Nanotechnology has emerged as an innovative and promising approach to address the problem of drug resistance. Developing nano-formulation-based therapies using therapeutic agents poses a synergistic effect to overcome MDR in cancer. In this review, we aimed to highlight the important pathways involved in the progression of MDR in cancer mediated through nanotechnology-based approaches that have been employed to circumvent them in recent years. Here, we also discussed the potential use of marine metabolites to treat MDR in cancer, utilizing active drug-targeting nanomedicine-based techniques to enhance selective drug accumulation in cancer cells. The discussion also provides future insights for developing complex targeted, multistage responsive nanomedical drug delivery systems for effective cancer treatments. We propose more combinational studies and their validation for the possible marine-based nanoformulations for future development.

NUDC is critical for rod photoreceptor function, maintenance, and survival.

NUDC (nuclear distribution protein C) is a mitotic protein involved in nuclear migration and cytokinesis across species. Considered a cytoplasmic dynein (henceforth dynein) cofactor, NUDC was shown to associate with the dynein motor complex during neuronal migration. NUDC is also expressed in postmitotic vertebrate rod photoreceptors where its function is unknown. Here, we examined the role of NUDC in postmitotic rod photoreceptors by studying the consequences of a conditional NUDC knockout in mouse rods (rNudC-/- ). Loss of NUDC in rods led to complete photoreceptor cell death at 6 weeks of age. By 3 weeks of age, rNudC-/- function was diminished, and rhodopsin and mitochondria were mislocalized, consistent with dynein inhibition. Levels of outer segment proteins were reduced, but LIS1 (lissencephaly protein 1), a well-characterized dynein cofactor, was unaffected. Transmission electron microscopy revealed ultrastructural defects within the rods of rNudC-/- by 3 weeks of age. We investigated whether NUDC interacts with the actin modulator cofilin 1 (CFL1) and found that in rods, CFL1 is localized in close proximity to NUDC. In addition to its potential role in dynein trafficking within rods, loss of NUDC also resulted in increased levels of phosphorylated CFL1 (pCFL1), which would purportedly prevent depolymerization of actin. The absence of NUDC also induced an inflammatory response in Müller glia and microglia across the neural retina by 3 weeks of age. Taken together, our data illustrate the critical role of NUDC in actin cytoskeletal maintenance and dynein-mediated protein trafficking in a postmitotic rod photoreceptor.

NUDC is critical for rod photoreceptor function, maintenance, and survival.

NUDC ( nu clear d istribution protein C) is a mitotic protein involved in nuclear migration and cytokinesis across species. Considered a cytoplasmic dynein (henceforth dynein) cofactor, NUDC was shown to associate with the dynein motor complex during neuronal migration. NUDC is also expressed in postmitotic vertebrate rod photoreceptors where its function is unknown. Here, we examined the role of NUDC in postmitotic rod photoreceptors by studying the consequences of a conditional NUDC knockout in mouse rods (r NudC -/- ). Loss of NUDC in rods led to complete photoreceptor cell death at six weeks of age. By 3 weeks of age, r NudC -/- function was diminished, and rhodopsin and mitochondria were mislocalized, consistent with dynein inhibition. Levels of outer segment proteins were reduced, but LIS1 (lissencephaly protein 1), a well-characterized dynein cofactor, was unaffected. Transmission electron microscopy revealed ultrastructural defects within the rods of r NudC -/- by 3 weeks of age. We investigated whether NUDC interacts with the actin modulator cofilin 1 (CFL1) and found that in rods, CFL1 is localized in close proximity to NUDC. In addition to its potential role in dynein trafficking within rods, loss of NUDC also resulted in increased levels of phosphorylated CFL1 (pCFL1), which would purportedly prevent depolymerization of actin. Absence of NUDC also induced an inflammatory response in Müller glia and microglia across the neural retina by 3 weeks of age. Taken together, our data illustrate the critical role of NUDC in actin cytoskeletal maintenance and dynein-mediated protein trafficking in a postmitotic rod photoreceptor. Significance Statement: Nuclear distribution protein C (NUDC) has been studied extensively as an essential protein for mitotic cell division. In this study, we discovered its expression and role in the postmitotic rod photoreceptor cell. In the absence of NUDC in mouse rods, we detected functional loss, protein mislocalization, and rapid retinal degeneration consistent with dynein inactivation. In the early phase of retinal degeneration, we observed ultrastructural defects and an upregulation of inflammatory markers suggesting additional, dynein-independent functions of NUDC.

Gut microbial metabolites of dietary polyphenols and their potential role in human health and diseases

Polyphenols contribute as one of the largest groups of compounds among all the phytochemicals. Common sources of dietary polyphenols are vegetables, fruits, berries, cereals, whole grains, etc. Owing to their original form, they are difficult to get absorbed. Dietary polyphenols after undergoing gut microbial metabolism form bioaccessible and effective metabolites. Polyphenols and derived metabolites are all together a diversified group of compounds exhibiting pharmacological activities against cardiovascular, cancer, oxidative stress, inflammatory, and bacterial diseases. The formed metabolites are sometimes even more bioavailable and efficacious than the parent polyphenols. Studies on gut microbial metabolism of dietary polyphenols have introduced new approach for the use of polyphenol-rich food in the form of supplementary diet. This review provides insights on various aspects including classification of polyphenols, gut microbiota-mediated metabolism of polyphenols, chemistry of polyphenol metabolism, and pharmacological actions of gut microbial metabolites of polyphenols. It also suggests the use of polyphenols from marine source for the microbial metabolism studies. Till date, gut microbial metabolism of polyphenols from terrestrial sources is extensively studied as compared to marine polyphenols. Marine ecosystem is a profound but partially explored source of phytoconstituents. Among them, edible seaweeds contain high concentration of polyphenols, especially phlorotannins. Hence, microbial metabolism studies of seaweeds can unravel the pharmacological potential of marine polyphenol-derived metabolites. (AU)

Gut microbial metabolites of dietary polyphenols and their potential role in human health and diseases.

Polyphenols contribute as one of the largest groups of compounds among all the phytochemicals. Common sources of dietary polyphenols are vegetables, fruits, berries, cereals, whole grains, etc. Owing to their original form, they are difficult to get absorbed. Dietary polyphenols after undergoing gut microbial metabolism form bioaccessible and effective metabolites. Polyphenols and derived metabolites are all together a diversified group of compounds exhibiting pharmacological activities against cardiovascular, cancer, oxidative stress, inflammatory, and bacterial diseases. The formed metabolites are sometimes even more bioavailable and efficacious than the parent polyphenols. Studies on gut microbial metabolism of dietary polyphenols have introduced new approach for the use of polyphenol-rich food in the form of supplementary diet. This review provides insights on various aspects including classification of polyphenols, gut microbiota-mediated metabolism of polyphenols, chemistry of polyphenol metabolism, and pharmacological actions of gut microbial metabolites of polyphenols. It also suggests the use of polyphenols from marine source for the microbial metabolism studies. Till date, gut microbial metabolism of polyphenols from terrestrial sources is extensively studied as compared to marine polyphenols. Marine ecosystem is a profound but partially explored source of phytoconstituents. Among them, edible seaweeds contain high concentration of polyphenols, especially phlorotannins. Hence, microbial metabolism studies of seaweeds can unravel the pharmacological potential of marine polyphenol-derived metabolites.

Virtual Screening of a Marine Natural Product Database for In Silico Identification of a Potential Acetylcholinesterase Inhibitor.

Alzheimer's disease is characterized by amyloid-beta aggregation and neurofibrillary tangles. Acetylcholinesterase (AChE) hydrolyses acetylcholine and induces amyloid-beta aggregation. Acetylcholinesterase inhibitors (AChEI) inhibit this aggregation by binding to AChE, making it a potential target for the treatment of AD. In this study, we have focused on the identification of potent and safe AChEI from the Comprehensive Marine Natural Product Database (CMNPD) using computational tools. For the screening of CMNPD, a structure-based pharmacophore model was generated using a structure of AChE complexed with the co-crystallized ligand galantamine (PDB ID: 4EY6). The 330 molecules that passed through the pharmacophore filter were retrieved, their drug-likeness was determined, and they were then subjected to molecular docking studies. The top ten molecules were selected depending upon their docking score and were submitted for toxicity profiling. Based on these studies, molecule 64 (CMNPD8714) was found to be the safest and was subjected to molecular dynamics simulations and density functional theory calculations. This molecule showed stable hydrogen bonding and stacked interactions with TYR341, mediated through a water bridge. In silico results can be correlated with in vitro studies for checking its activity and safety in the future.

Surface plasmon resonance: A promising approach for label-free early cancer diagnosis.

Cancer is the second leading cause of death worldwide after cardiovascular disease. The major cause of high mortality is delayed detection. Therefore, detection at an early stage followed by early treatment can mitigate morbidity as well as mortality. The utilization of biomarker-based detection tools helps in early-stage recognition. Fortunately, biomarkers indicating disease status are released in to the circulation. These include traditional marker proteins as well as exosomes, micro-RNA (miRNA) and circulating tumor DNA (ct-DNA). Biosensors are biological and chemical reaction devices that generate signals based on analyte concentration. Due to analyte binding, these devices demonstrate high sensitivity and specificity. This review examines the use of surface plasmon resonance (SPR)-based sensors in the diagnosis of various cancer including those of the breast, prostate, lung, ovary, cervix and pancreas. SPR is a label-free, real-time and non-invasive optical biosensing technology representing a novel diagnostic tool in cancer detection.