Why metalloenzymes often show dramatic changes in their catalytic activity when subjected to chemically similar but non-native metal substitutions is a long-standing puzzle. Here, we report on the catalytic roles of metal ions in a model metalloenzyme system, human carbonic anhydrase II (CA II). Through a comparative study on the intermediate states of the zinc-bound native CA II and non-native metal-substituted CA IIs, we demonstrate that the characteristic metal ion coordination geometries (tetrahedral for Zn2+, tetrahedral to octahedral conversion for Co2+, octahedral for Ni2+, and trigonal bipyramidal for Cu2+) directly modulate the catalytic efficacy. In addition, we reveal that the metal ions have a long-range (~10 Å) electrostatic effect on restructuring water network in the active site. Our study provides evidence that the metal ions in metalloenzymes have a crucial impact on the catalytic mechanism beyond their primary chemical properties.
Aim:To test the potential of orally administered citrate functionalized Mn3O4 nanoparticles (C-Mn3O4 NPs) as a therapeutic agent against hepatic fibrosis and associated chronic liver diseases.Materials & methods:C-Mn3O4 NPs were synthesized and the pH dependent antioxidant mechanism was characterized by in vitro studies. CCl4 intoxicated mice were orally treated with C-Mn3O4 NPs to test its in vivo antioxidant and antifibrotic ability.Results:We demonstrated ultrahigh efficacy of the C-Mn3O4 NPs in treatment of chronic liver diseases such as hepatic fibrosis and cirrhosis in mice compared with conventional medicine silymarin without any toxicological implications.Conclusion:These findings may pave the way for practical clinical use of the NPs as safe medication of chronic liver diseases associated with fibrosis and cirrhosis in human subjects.
Ubiquitousness in
the target organs and associated oxidative stress
are the most common manifestations of heavy-metal poisoning in living
bodies. While chelation of toxic heavy metals is important as therapeutic
strategy, scavenging of increased reactive oxygen species, reactive
nitrogen species and free radicals are equally important. Here, we
have studied the lead (Pb) chelating efficacy of a model flavonoid
morin using steady-state and picosecond-resolved optical spectroscopy.
The efficacy of morin in presence of other flavonoid (naringin) and
polyphenol (ellagic acid) leading to synergistic combination has also
been confirmed from the spectroscopic studies. Our studies further
reveal that antioxidant activity (2,2-diphenyl-1-picrylhydrazyl assay)
of the Pb–morin complex is sustainable compared to that of
Pb-free morin. The metal–morin chelate is also found to be
significantly soluble compared to that of morin in aqueous media.
Heavy-metal chelation and sustainable antioxidant activity of the
soluble chelate complex are found to accelerate the Pb-detoxification
in the chemical bench (in vitro). Considering the synergistic effect
of flavonoids in Pb-detoxification and their omnipresence in medicinal
plants, we have prepared a mixture (SKP17LIV01) of flavonoids and
polyphenols of plant origin. The mixture has been characterized using
high-resolution liquid chromatography assisted mass spectrometry.
The mixture (SKP17LIV01) containing 34 flavonoids and 76 other polyphenols
have been used to investigate the Pb detoxification in mouse model.
The biochemical and histopathological studies on the mouse model confirm
the dual action in preclinical studies.
The potentiality of nano‐enzymes in therapeutic use has directed contemporary research to develop a substitute for natural enzymes, which are suffering from several disadvantages including low stability, high cost, and difficulty in storage. However, inherent toxicity, inefficiency in the physiological milieu, and incompatibility to function in cellular enzyme networks limit the therapeutic use of nanozymes in living systems. Here, it is shown that citrate functionalized manganese‐based biocompatible nanoscale material (C‐Mn3O4 NP) efficiently mimics glutathione peroxidase (GPx) enzyme in the physiological milieu and easily incorporates into the cellular multienzyme cascade for H2O2 scavenging. A detailed computational study reveals the mechanism of the nanozyme action. The in vivo therapeutic efficacy of C‐Mn3O4 nanozyme is further established in a preclinical animal model of Huntington's disease (HD), a prevalent progressive neurodegenerative disorder, which has no effective medication to date. Management of HD in preclinical animal trial using a biocompatible (non‐toxic) nanozyme as a part of the metabolic network may uncover a new paradigm in nanozyme based therapeutic strategy.
Centers for Disease Control and Prevention (CDC) warns the use of one-way valves or
vents in face masks for potential threat of spreading COVID-19 through expelled
respiratory droplets. Here, we have developed a nanoceutical cotton fabric duly
sensitized with non-toxic zinc oxide nanomaterial for potential use as a membrane filter
in the one-way valve for the ease of breathing without the threat of COVID-19 spreading.
A detailed computational study revealed that zinc oxide nanoflowers (ZnO NFs) with
almost two-dimensional petals trap SARS-CoV-2 spike proteins, responsible to attach to
ACE-2 receptors in human lung epithelial cells. The study also confirmed significant
denaturation of the spike proteins on the ZnO surface, revealing removal of the virus
upon efficient trapping. Following the computational study, we have synthesized ZnO NF
on a cotton matrix using a hydrothermal-assisted strategy. Electron-microscopic,
steady-state, and picosecond-resolved spectroscopic studies confirm attachment of ZnO NF
to the cotton (i.e., cellulose) matrix at the atomic level to develop the nanoceutical
fabric. A detailed antimicrobial assay using
Pseudomonas aeruginosa
bacteria (model SARS-CoV-2 mimic) reveals excellent antimicrobial efficiency of the
developed nanoceutical fabric. To our understanding, the nanoceutical fabric used in the
one-way valve of a face mask would be the choice to assure breathing comfort along with
source control of COVID-19 infection. The developed nanosensitized cloth can also be
used as an antibacterial/anti CoV-2 washable dress material in general.
Nanomedicine, the offspring born from the marriage of nanotechnology and medicine, has already brought momentous advances in the fight against a plethora of unmet diseases from cardiovascular and neurodegenerative to diabetes and cancer. Here, we review a conceptual framework that will provide a basic understanding about the molecular mechanism of action of a therapeutic nanomaterial inside biological milieu. In this review, we highlight how the catalytic nature of a transition metal oxide nanomaterial influences the cellular redox homeostasis, supports the cellular antioxidant defence system and reactivates the reactive oxygen species (ROS) mediated signalling to perform normal cell functions like cell cycle, differentiation, apoptosis, inflammation, toxicity, and protein interactions. With numerous examples, we describe the redox modulatory nature of d-block metal oxide nanomaterials and their biomimetic nanozyme activities to protect the mitochondria, the cellular redox mediator which prevents an organism from various diseases. This knowledge will be useful to design new nanomaterials capable of intracellular redox modulation, which in turn can be effective therapeutic agents for treatment of various unmet diseases that are beyond the ability of modern synthetic medicine.
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