A new colorimetric and fluorescence turn-on chemodosimeter for selective detection of GSH over Cys and Hcy with 34-fold enhancement in emission intensity is reported. Probe 1 exhibited ultra-sensitivity toward GSH with 0.125 nM detection limit and successfully displayed GSH detection in MCF-7 live cells. The mechanism of sensing is established by density functional theoretical calculations.

Background: Iron accumulation in organs affects iron metabolism, leading to deleterious effects on the body. Previously, it was studied that high dietary iron in various forms and concentrations influences iron metabolism, resulting in iron accumulation in the liver and spleen and cognitive impairment. However, the actual mechanism and impact of long-term exposure to high dietary iron remain unknown. As a result, we postulated that iron overload caused by chronic exposure to excessive dietary iron supplementation would play a role in iron dyshomeostasis and inflammation in the liver and brain of Wistar rats. Methods: Animals were segregated into control, low iron (FAC-Ferric Ammonium Citrate 5000 ppm), and high iron dose group (FAC 20,000 ppm). The outcome of dietary iron overload on Wistar rats was evaluated in terms of body weight, biochemical markers, histological examination of liver and brain tissue, and cognitive-behavioral studies. Also, gene expression of rat brain tissue involving iron transporters Dmt1, , TfR1, , iron storage protein Fpn1, , inflammatory markers Nf-kB, , Tnf-alpha, , Il-6, and hepcidin was performed. Results: Our data indicate that excess iron supplementation for 30 weeks leads to decreased body weight, increased serum iron levels, and decreased RBC levels in iron fed Wistar rats. Morris water maze (MWM) studies after 30 weeks showed increased escape latency in the high iron dose group compared with the control group. Histological studies of the high iron dose group showed an iron accumulation in the liver and brain loss of cellular architecture, and cellular degeneration was observed. Excess iron treatment showed upregulation of the Dmt1 gene in iron metabolism and a remarkable increase in the Nf-kB gene in rat brain tissue. Conclusion: The results show chronic excess iron supplementation leads to iron accumulation in the liver, leading to inflammation in Wistar rats.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting mental ability and interrupts neurocognitive functions. Treating multifactorial conditions of AD with a single-target-directed drug is highly difficult. Thus, a multi-target-directed ligand (MTDL) development strategy has been developed as a promising approach for the treatment of AD. Herein, we have synthesized two novel thiosemicarbazones as MTDLs and reported their bioactivities against diverse neuropathological events involved in AD. In vitro studies revealed that both compounds exhibited promising anticholinesterase activity (AChE, IC50 = 15.98 μM, MZET and IC50 = 30.23 μM, MZMT), well supported by a detailed computational study. Both analogs have shown good thermodynamic behaviour and stability through interactions with characteristic amino acid residues throughout simulation of 100 ns against acetylcholinesterase enzyme. In an electrophysiology assay, these analogs have shown a characteristic inhibitory response against the GluN1-1a + GluN2B subunit of N-methyl-D-aspartate receptors. Pre-treatment of BV-2 microglial cells with MZET effectively decreased nitrite production compared to nitrite produced by lipopolysaccharide-treated cells alone. Further, the effect of MZMT and MZET on autophagy regulation was determined using stably transfected SH-SY5Y neuroblastoma cells. MZET significantly enhanced the autophagy flux in neuroblastoma cells. A significant decrease in copper-catalysed oxidation of amyloid-β in presence of synthesized thiosemicarbazones was also observed. Collectively, our findings indicated that these analogs have potential as effective anti-AD candidates and can be used as a prototype to develop more safer multi-targeted anti-AD drugs.

Alzheimer's disease (AD) is a multifactorial brain disorder that involves several pathophysiological events, like amyloidogenesis, acetylcholine deficit, neuroinflammation, cellular oxidative stress and dysfunctional autophagy. Hence, to cure AD, it is necessary to target multiple mechanisms involved in the development and progression of AD. This study reports a novel methyl-substituted 3-acetylcoumarin thiosemicarbazone (ACT) derivative, viz. [(2E)-N-methyl-2-[1-(2-oxo-2H-1-benzopyran-3-yl) ethylidene] hydrazine-1carbothioamide], (ACMT), and the protective effect of these compounds towards acetylcholinesterase activity, inflammation and autophagy induction. The crystal structure of ACMT is solved by using singlecrystal X-ray diffraction. The molecular docking studies showed that the methyl substitution of 3acetylcoumarin thiosemicarbazone modulates its hydrophobic and hydrogen-bonding interactions with the active site of acetylcholinesterase enzyme (AChE), resulting in a better inhibition of AChE activity. Methyl-substitution of 3-acetylcoumarin thiosemicarbazone also causes better peptide aggregation inhibition as compared to the parent compound. Further, the anti-inflammatory activity of these compounds in BV-2 microglial cells was determined. Data showed that the incorporation of methyl substitution of 3-acetylcoumarin thiosemicarbazone enhances the potency of ACT to induce autophagy in SH-SY5Y neuroblastoma cells. ACT and ACMT also rescue the rough eye phenotype at 20 mu M concentration in GMR-A ss Drosophila melanogaster model of AD. (c) 2021 Elsevier B.V. All rights reserved.

The heterobimetallic Ru(II)-Pt(II) polypyridyl complexes [Ru(bpy) 2 (BPIMBp)PtCl 2 ] 2+ ( 3 ) and [Ru(phen) 2 (BPIMBp)PtCl 2 ] 2+ ( 4 ) with their parent complexes [Ru(bpy) 2 BPIMBp] 2+ ( 1 ) and [Ru(phen) 2 BPIMBp] 2+ ( 2 ) possessing bridging ligand (BPIMBp = 1,4′-Bis-{(2-pyridin-2-yl)-1H-imidazol-1-yl)methyl}-1,1′-biphenyl) were used for photocytotoxicity against MCF-7 cells.The parent ruthenium complexes (complexes 1-2 ) exhibited a negligible increase in viscosity of DNA while heterobimetallic Ru(II)-Pt(II) system exhibited a decrease in viscosity of DNA, indicating covalent interaction (through cis-PtCl 2 unit). The Ru(II)-Pt(II) system co-precipitated with CT-DNA confirmed the covalent binding. In electrophoretic mobility studies, the interaction of Ru(II)-Pt(II) system with plasmid DNA led to retardation of negative supercoiled form, followed by positive supercoiled migration in the dark that indicated the ability to form covalent adducts with DNA similar to cisplatin. The complexes 1-4 showed enhanced photocleavage of plasmid DNA on blue light (~450 nm) irradiation. In a cell-based study, all the complexes exhibited photoactivated cytotoxicity in MCF-7 cancer cells when exposed to visible light of ~450 nm as compared to low toxicity in absence of irradiation. Additionally, the complexes containing platinum showed induction of autophagy in GFP-LC3 expressing MCF-7 cells. Overall our study shows that the inclusion of photosensitizer Ru(II) polypyridyl complexes to cis-PtCl 2 moiety improves anticancer properties of complexes. Graphic abstract The effect of Ru(II)-Pt(II) polypyridyl complexes as photosensitizers was studied against MCF-7 cells. The complexes are negligibly toxic to MCF-7 cells in the dark while highly cytotoxic towards MCF-7 cells on irradiation of blue light (~450 nm). Therefore, the complexes could be potential candidates for Photodynamic Therapy.

Rhodamine-based reversible fluorescence turn-on chemosensor appended with 'N' and 'O' donor atoms as chelating moieties has been synthesized for the selective detection of Fe3+ ion over other competitive metal ions in aqueous medium. Designed probe indicated color change to pink with lower limit of detection at 1.93x10(-7) M exhibiting high sensitivity toward Fe3+ ion. Sensing mechanism was established by HRMS and NMR titration studies. The probe was successfully applied for the detection of Fe3+ ions in live MCF-7 cells.

We recently developed an oxidative intramolecular 1,2-amino-oxygenation reaction, combining gold(I)/gold(III) catalysis, for accessing structurally unique ionic pyridinium-oxazole dyads (PODs) with tunable emission wavelengths. On further investigation, these fluorophores turned out to be potential biomarkers; in particular, the one containing -NMe2 functionality (NMe2-POD) was highly selective for mitochondrial imaging. Of note, because of mitochondria's involvement in early-stage apoptosis and degenerative conditions, tracking the dynamics of mitochondrial morphology with such imaging technology has attracted much interest. Along this line, we wanted to build a library of such PODs which are potential mitochondria trackers. However, Au/Selecfluor, our first-generation catalyst system, suffers from undesired fluorination of electronically rich PODs resulting in an inseparable mixture (1:1) of the PODs and their fluorinated derivatives. In our attempt to search for a better alternative to circumvent this issue, we developed a second-generation approach for the synthesis of PODs by employing Cu(II)/PhI(OAC)(2)-mediated oxidative 1,2-amino-oxygenation of alkynes. Thes newly synthesized PODs exhibit tunable emissions as well as excellent quantum efficiency up to 0.96. Further, this powerful process gives rapid access to a library of NMe2-PODs which are potential mitochondrial imaging agents. Out of the library, the randomly chosen POD-3g was studied for cell-imaging experiments which showed high mitochondrial specificity, superior photostability, and appreciable tolerance to microenvironment changes with respect to commercially available MitoTracker green.

Four novel dimeric bis-μ-imido bridged metal-metal bonded oxidomolybdenum(V) complexes [MoV2O2L'21-4] (1-4) (where L'1-4 are rearranged ligands formed in situ from H2L1-4) and a new mononuclear dioxidomolybdenum(VI) complex [MoVIO2L5] (5) synthesized from salen type N2O2 ligands are reported. This rare series of imido-bridged complexes (1-4) have been furnished from rearranged H3L'1-4 ligands, containing an aromatic diimine (o-phenylenediamine) "linker", where Mo assisted hydrolysis followed by -C═N bond cleavage of one of the arms of the ligand H2L1-4 took place. A monomeric molybdenum(V) intermediate species [MoVO(HL'1-4)(OEt)] (Id1-4) was generated in situ. The concomitant deprotonation and dimerization of two molybdenum(V) intermediate species (Id1-4) ultimately resulted in the formation of a bis-μ-imido bridge between the two molybdenum centers of [MoV2O2L'21-4] (1-4). The mechanism of formation of 1-4 has been discussed, and one of the rare intermediate monomeric molybdenum(V) species Id4 has been isolated in the solid state and characterized. The monomeric dioxidomolybdenum(VI) complex [MoVIO2L5] (5) was prepared from the ligand H2L5 where the aromatic "linker" was replaced by an aliphatic diimine (1,2-diaminopropane). All the ligands and complexes have been characterized by elemental analysis, IR, UV-vis spectroscopy, NMR, ESI-MS, and cyclic voltammetry, and the structural features of 1, 2, 4, and 5 have been solved by X-ray crystallography. The DNA binding and cleavage activity of 1-5 have been explored. The complexes interact with CT-DNA by the groove binding mode, and the binding constants range between 103 and 104 M-1. Fairly good photoinduced cleavage of pUC19 supercoiled plasmid DNA was exhibited by all the complexes, with 4 showing the most promising photoinduced DNA cleavage activity of ∼93%. Moreover, in vitro cytotoxic activity of all the complexes was evaluated by MTT assay, which reveals that the complexes induce cell death in MCF-7 (human breast adenocarcinoma) and HCT-15 (colon cancer) cell lines.

We have reported earlier, an orally active insulin-like protein (ILP) from Costus igneus having potent hypoglycemic property in STZ-induced diabetic Swiss mice. The blood glucose level was reduced significantly within two hours after feeding ILP orally in an oral glucose tolerance test. The present study elucidates the mechanism underlying the hypoglycemic action of ILP. Mechanism of action of ILP was studied in differentiated L6 myotubes. 2-NBDG uptake stimulated by ILP was studied in differentiated L6 myotubes under normoglycemic, hyperglycemic and induced insulin resistant conditions. ILP treatment significantly increased 2-NBDG uptake in differentiated L6 myotubes. The levels of insulin signaling molecules IRS-1 and GLUT-4 were assessed in ILP treated L6 myotubes by immunoblot analysis of cytoplasmic and plasma membrane fractions respectively. Immunoblot analysis revealed an increase in cytoplasmic IRS-1 with a concomitant increase in GLUT-4 translocation to the plasma membrane in a time dependent manner. Toxicity studies of ILP were performed on normal as well as diabetic Swiss albino mice. ILP did not show any toxicity in the acute and sub-chronic toxicity studies in normal as well as diabetic Swiss albino mice. Mass spectrometry was carried out to identify ILP. MALDI TOF/TOF MS analysis of ILP revealed sequence homology with the predicted protein from Physcomitrella patens. Our study reveals that ILP acts via insulin signaling pathway and can be used as oral insulin mimetic.