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Impaired autophagy is a key contributor to aging and a variety of protein aggregation-linked neurodegenerative disorders.In this direction, autophagy modulation is emerging as a therapeutic approach to combat protein aggregation-related neuronal diseases.Herein, we report that nanoascorbate, a biocompatible polymeric nanoform of vitamin C, accelerates the clearance of mutant Huntingtin protein aggregates in HD150Q, the cellular model of Huntington′s disease by restoring blocked autophagy.We have confirmed that nanoascorbate induces autophagic flux in autophagy-compromised Huntington′s model cells bearing mutant Huntingtin aggregates, evident from the altered expression level of the characteristic autophagy marker protein LC3BII and rapid degradation of crucial cargo receptor SQSTM/p62.In addition, blockade of autophagy induction using a potent autophagy inhibitor causes depression/failure of clearance of protein aggregates by nanoascorbate, indicating that nanoascorbate induces autophagy-mediated degradationFurthermore, nanoascorbate-mediated upregulation of autophagic flux is ROS- and glutathione reductase-dependent.A brief incubation of 3h with a low micromolar concentration of nanoascorbate has shown an average 90% clearance of high-mol.-weight soluble aggregate of neurotoxic mutant Huntingtin protein, within 2 days.Nanoascorbate is faster, and a low micromolar concentration is sufficient compared to a high molar concentration of trehalose, a conventional autophagy inducer, that achieves only an average of 38% degradation after 96 h of prolonged incubation.In general, induced HD150Q cells bearing neurotoxic polyglutamine aggregates are prone to rapid apoptotic death.Nanoascorbate rescues mutant huntingtin aggregate-bearing cells from apoptotic insult which is evident from the lowered expression of cleaved caspase-3 manifolds, after brief incubation with nanoascorbate.In addition, dietary supplementation of nanoascorbate has shown moderate improvement in motor activity, an increase in life span, and suppression of progressive polyQ-induced eye degeneration to some extent in the transgenic Drosophila model of Huntington′s disease.Our findings manifest the remarkable neurotherapeutic potential of the nanoform of ascorbate via autophagy modulation in autophagy-compromised conditions as well as a moderate neuroprotective effect in the transgenic Drosophila model of Huntington′s disease.In addition, the current study emphasizes that modulation of autophagy can be considered as a promising therapeutic approach for proteinopathy-related neurodegenerative diseases.

24 Apr 2025·The Journal of Physical Chemistry Letters

Two- and Three-Dimensional Silver Cluster Assemblies: Effect of Argentophilic Interactions in Photoluminescence

Article

Author: Thomas, Teena ; Mandal, Sukhendu ; Varghese, Dayona Aleyamma ; Suresh, Sona Velaparambil ; Nandi, Chayan Kanti ; Salam, Abdul ; Datta, Ayan ; Chandrashekar, Priyanka ; Mondal, Pradip Kumar ; Pal, Arun K. ; Muraleedharan, Arunima ; Ghosh, Meghna

Silver nanocluster assemblies are an emerging class of fluorescent and stable solid materials by virtue of their structural tunability and stability compared to isolated clusters. The photophysical properties of the cluster nodes are influenced by an intra- or intercluster interaction. In this work, we show two-dimensional (2D) [Ag₅(C₂^tBu)₂(CF₃COO)₃(C₄H₄N₂)](CHCl₃) and three-dimensional (3D) [Ag₄(C₂^tBu)(CF₃COO)₃(C₄H₄N₂)] silver nanocluster assemblies obtained by tuning the molar ratios of the same protecting ligands and linker. The 2D assembly possesses a one-dimensional (1D) chain held together through the Ag···Ag interactions, whereas in the 3D assembly, Ag₄ units are linked through trifluoroacetate ligands to form the 1D chain with Ag₄-O-Ag₄ and Ag₄-O-C-O-Ag₄ connectivity. This varying effect of argentophilic interaction influences photoluminescence properties. In the 2D assembly, the emission was found to be dominated by the cluster-centered state owning to enhanced argentophilic interactions, whereas in 3D, the emission is from the linker. The theoretical investigations also revealed that the lowest unoccupied molecular orbitals (LUMOs) of the 3D assembly are localized on the pyrazine linker. In contrast, the LUMOs of the 2D assembly are mostly localized on the metal atoms within the cluster. This work highlights not only the importance of synthesis but also emphasizes the understanding of the cluster structure-luminescence relationship.

21 Apr 2025·Inorganic Chemistry

Functional Nonheme Diiron(II) Complexes Catalyze the Direct Reduction of Nitrite to Nitric Oxide in Relevance to the Diiron Protein YtfE

Article

Author: Mandal, Amit ; Majumdar, Amit ; Atta, Sayan ; Patra, Suman

The present work reports the functional modeling chemistry of YtfE, which features a nonheme diiron active site and mediates the direct reduction of NO₂^- to NO. The model complex, [Fe₂(HPTP)Cl₂]¹⁺ (1), reduces NO₂^- to NO in a 100% yield within 12 h and generates [Fe₄(HPTP)₂(μ-O)₃(μ-OH)]³⁺ (2). Similar to YtfE, the reaction involves stepwise oxidation of two Fe(II) centers and product (NO) inhibition, of which the latter produces [Fe₂(HPTP)(NO)₂Cl₂]¹⁺ (3). Complex 3 could also be synthesized by the reaction of [Fe₂(HPTP)(NO)₂(ClO₄)]²⁺ (4) and chloride. Complex 1 catalyzes the reduction of NO₂^- to NO in the presence of PhS^-, albeit with a low TON of 5, due to the formation of an insoluble product, [Fe₂(HPTP)(μ-SPh)Cl₂] (5). Another model complex [Fe₂(HPTP)(OPr)]¹⁺ (6), reduced NO₂^- to NO in an 80% yield after 24 h, generated [Fe₂(HPTP)(OPr)(NO)₂]¹⁺ (7), and offered a TON of 19. The third model complex, [Fe₂(HPTP)(ClO₄)₂]¹⁺ (8), could reduce NO₂^- to NO in a 100% yield but only after 48 h. A comparison of these results establishes that easy oxidation of the Fe(II) centers, easy accessibility of the Fe(II) centers for the coordination of NO₂^-, and easy release of NO from the in situ generated dinitrosyl diiron complex increase the efficiency of the functional model complexes of YtfE.

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Pipeline

Pipeline Snapshot as of 10 May 2025

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

C17 (Indian Association for the Cultivation of Science) ( Top I )	Leishmaniasis More	Preclinical
IGT Delivery Nanog siRNA ( NANOG )	Prostatic Cancer More	Preclinical
IN202331068339 ( c-Myc )	Leishmaniasis More	Discovery