Redox modulator iron complexes trigger intrinsic apoptosis pathway in cancer cells.

The emergence of multidrug resistance in cancer cells necessitates the development of new therapeutic modalities. One way cancer cells orchestrate energy metabolism and redox homeostasis is through overloaded iron pools directed by iron regulatory proteins, including transferrin. Here, we demonstrate that targeting redox homeostasis using nitrogen-based heterocyclic iron chelators and their iron complexes efficiently prevents the proliferation of liver cancer cells (EC50: 340 nM for IITK4003) and liver cancer 3D spheroids. These iron complexes generate highly reactive Fe(IV)=O species and accumulate lipid peroxides to promote oxidative stress in cells that impair mitochondrial function. Subsequent leakage of mitochondrial cytochrome c activates the caspase cascade to trigger the intrinsic apoptosis pathway in cancer cells. This strategy could be applied to leverage the inherent iron overload in cancer cells to selectively promote intrinsic cellular apoptosis for the development of unique iron-complex-based anticancer therapeutics.

Diazepam-based covalent modifiers of GPX4 induce ferroptosis in liver cancer cells.

Developing new chemotherapeutics that are structurally and mechanistically unique is needed due to the rapid rise of the cancer incidence across the globe. Here, we report the identification of irreversible, thiol-reactive diazepam derivatives as GPX4 modifiers and nanomolar inducers of ferroptosis in liver cancer cells.

Mn(II) Polypyridyl Complexes: Precursors to High Valent Mn(V)=O Species and Inhibitors of Cancer Cell Proliferation.

The reaction of [(L)MnII ]2+ (L = neutral polypyridine ligand framework) in the presence of mCPBA (mCPBA = m-Chloroperoxybenzoic acid) generates a putative MnV =O species at RT. The proposed MnV =O species is capable of performing the aromatic hydroxylation of Cl-benzoic acid derived from mCPBA to give [(L)MnIII (m-Cl-salicylate)]+ , which in the presence of excess mCPBA generates a metastable [(L)MnV (O)(m-Cl-salicylate)]+ , characterized by UV/Vis absorption, EPR, resonance Raman spectroscopy, and ESI-MS studies. The current study highlights the fact that [(L)MnIII (m-Cl-salicylate)]+ formation may not be a dead end for catalysis. Further, a plausible mechanism has been proposed for the formation of [(L)MnV (O)-m-Cl-salicylate)]+ from [(L)MnIII (m-Cl-salicylate)]+ . The characterized transient [(L)MnV (O)-m-Cl-salicylate)]+ reported in the current work exhibits high reactivity for oxygen atom transfer reactions, supported by the electrophilic character depicted from Hammett studies using a series of para-substituted thioanisoles. The unprecedented study starting from a non-heme neutral polypyridine ligand framework paves a path for mimicking the natural active site of photosystem II under ambient conditions. Finally, evaluating the intracellular effect of Mn(II) complexes revealed an enhanced intracellular ROS and mitochondrial dysfunction to prevent the proliferation of hepatocellular carcinoma and breast cancer cells.

Nitroisobenzofuranone, a small molecule inhibitor of multidrug-resistant Staphylococcus aureus, targets peptidoglycan biosynthesis.

Antimicrobial resistance (AMR) is a global health concern. Targetting AMR, we present an in situ lactonization mechanism generating 4-nitroisobenzofuran-1(3H)-one (IITK2020), an exclusive S. aureus inhibitor at 2-4 µg mL-1 MIC including multidrug-resistant S. aureus clinical strains, that prevents peptidoglycan biosynthesis.

Impact of piezoelectric effect on the heterogeneous visible photocatalysis of g-C3N4/Ag/ZnO tricomponent.

In recent years, the piezophotocatalytic mechanism had been intensively recognized as a potential and promising route to sewage treatment. Here we report the piezoelectric effect improved heterogeneous photocatalysis of g-C3N4/Ag/ZnO (g-CN/A/Z) tricomponent in rhodomine B (RhB) degradation. Initially, the nanomaterials were characterized for their physico-chemical and optoelectronic properties using analytical techniques such as x-ray diffraction (XRD), scanning & transmission electron microscopes (SEM & TEM), UV-vis spectrophotometer and photoluminescence spectroscopy (PL). In addition, the photoelectrochemical activity of determining the photocurrent density and electrochemical impendence response were also been conducted. The catalytic properties of the tricomponent, g-CN/A/Z was studied with the degradation of RhB with visible photons irradiation and ultrasonication. In piezophotocatalysis, degradation up to 89% of RhB was achieved with 1.26 folds synergetic effect on par to the photocatalysis and piezocatalysis.

Differential mitochondrial genome in patients with Rheumatoid Arthritis.

BACKGROUND: Mitochondria play an important role in cell survival, function and lineage differentiation. Changes in mitochondrial DNA (mtDNA) may control mitochondrial functions and thus may impart an alternative cellular state thereby leading to a disease condition in the body. Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease wherein immune cells become self-reactive causing joint inflammation, swelling and pain in patients. The changes in mtDNA may alter cellular functions thereby directing the immune cells towards an inflammatory phenotype in RA. Therefore, it becomes pertinent to identify changes in mtDNA sequence in immune cells of RA patients to understand the pathogenesis and progression of RA. METHODS: mtDNA from peripheral blood mono-nuclear cells (PBMCs) of 23 RA patients and 17 healthy controls (HCs) were sequenced using next-generation sequencing (NGS). Further, single nucleotide polymorphisms (SNPs) and other variable changes in mtDNA hypervariable and coding regions, amino acid changes with a putative impact on disease, levels of heteroplasmy, copy number variations and haplogroup analysis in RA patients and HCs were analysed and compared to identify any association of mtDNA changes and RA disease. RESULTS: A total of 382 single nucleotide mtDNA variants were observed, 91 (23.82%) were present in hypervariable region and 291 (76.18%) in coding region of patients and HC. The variant 513 GCA > ACA, with G present in HVR-III, known to control the mitochondrial translation function, was significantly present in RA patients. The CYTB gene had larger number of SNPs in HC samples while RNR2 was more variable in RA patients. A non-synonymous heteroplasmy in ND1 gene was found at a single nucleotide position 3533 in an increased number of RA patients as compared to the controls. A significant increase in mtDNA duplication and a higher frequency of the haplogroup U was also characteristic of RA. Also, the presence of SNPs in mitochondrial tRNA genes at two positions 12308 A > G and 15924 A > G were found to be pathogenic. CONCLUSION: We herein observed an altered mtDNA sequence in immune cells of RA patients and thus a possible role of mitochondrial genome in the development of RA. The observed nucleotide changes in mtDNA control region, RNR2 gene, increased heteroplasmy and mtDNA duplication in RA patients may alter sites for transcription factor binding thereby influencing mtDNA gene expression, as well as copy numbers thereby affecting the mitochondrial proteins and their functions. These changes in mtDNA could be one of the probable reasons among many leading to the progression of RA.

Altered mitochondrial proteome and functional dynamics in patients with rheumatoid arthritis.

The autoimmune inflammatory disease, Rheumatoid arthritis (RA), has known imbalances in energy metabolism and superoxide levels thus may have an etiology associated with mitochondrial dysfunction. We thus evaluated the presence of a differential mitochondrial proteome as well as other characteristics including mitochondrial mass, membrane potential (Ψm), total cellular ATP and superoxide levels. Eighteen mitochondrial proteins were down-regulated while four were up-regulated in RA patients in comparison to the healthy controls (HC). A significant decrease in mitochondrial Ψm, superoxides and cellular ATP levels was observed in RA with constant mitochondrial mass suggesting mitochondrial dysfunction responsible for functional disparity in RA.

Managing Rheumatoid Arthritis with Dietary Interventions.

Self-help by means of dietary interventions can help in management of various disorders including rheumatoid arthritis (RA), a debilitating autoimmune disease. Dietary interventions necessitate a widespread appeal for both patients as well as clinicians due to factors including affordability, accessibility, and presence of scientific evidences that demonstrate substantial benefits in reducing disease symptoms such as pain, joint stiffness, swelling, tenderness and associated disability with disease progression. However, there is still an uncertainty among the community about the therapeutic benefits of dietary manipulations for RA. In the present review, we provide an account of different diets and their possible molecular mechanism of actions inducing observed therapeutic benefits for remission and management of RA. We further indicate food that can be a potential aggravating factor for the disease or may help in symptomatic relief. We thereafter summarize and thereby discuss various diets and food which help in reducing levels of inflammatory cytokines in RA patients that may play an effective role in management of RA following proper patient awareness. We thus would like to promote diet management as a tool that can both supplement and complement present treatment strategies for a better patient health and recovery.

Direct recognition of LPS drive TLR4 expressing CD8+ T cell activation in patients with rheumatoid arthritis.

Aberrant immune responses characterize autoimmune disorders like Rheumatoid Arthritis (RA) wherein lymphocytes are recognized as key players. Role of CD8+ T cells in RA has been less defined however we found that these cells are activated in RA patients with increased expression of cytolytic granules and inflammatory mediators thereby modulating immune responses contributing to disease severity. Though unconventional expression of different Toll Like Receptors (TLRs) on CD8+ T cells has been proposed but their expression and role in T cell activation and differentiation in RA still remains obscure. Herein we report, for the first time, an increased expression of TLR4 on peripheral CD8+ T cells of RA patients and its role in skewing CD8+ T cells towards activated and inflammatory phenotype thereby playing a significant role in pathogenesis and progression of RA. We found that the surface expression of TLR4 on CD8+ T cells directly correlates with disease severity. Moreover, these CD8+ T cells respond to the TLR4 ligand LPS and express robust amounts of cytotolytic and inflammatory molecules including TNFα and IFNγ. Our study hence identifies an important role for CD8+ T cells in orchestrating RA through TLR4 mediated activation and differentiation.

Use of High-Resolution Computed Tomography (HRCT) in Diagnosis of Sputum Negative Pulmonary Tuberculosis.

OBJECTIVES: To study the role of high-resolution computed tomography (HRCT) in the diagnosis of pulmonary tuberculosis (PTB) in sputum smear negative patients and to design HRCT criterion to forecast the threat of pulmonary tuberculosis. MATERIAL AND METHODS: We studied 69 patients having sputum smear negative for acid-fast bacilli (AFB) but still with clinical suspicion of PTB after taking written informed consent. We studied their medical characteristics, numerous separate HRCT-results and combination of HRCT findings to foresee the danger for PTB by utilizing univariate and multivariate investigation. Temporary HRCT diagnostic criteria were planned in view of these outcomes to find out the risk of PTB and tested these criteria on our patients. RESULTS: Chronic cough and night sweats were highly linked to a greater risk of PTB among clinical features. On HRCT chest presence of cavity, centrilobular nodules, consolidation, ground glass opacity (GGO), lymphadenopathy, main lesion in S1, S2, S6, lobular consolidation, other minute nodules and tree in bud appearance was significantly linked to an elevated risk of PTB in linear regression analysis. While cavity, centrilobular nodules, interlobular septal thickening, pleural effusion and tree-in-bud appearance was significantly linked to a greater threat of PTB in multivariate regression analysis. Positioning of the patients utilizing our HRCT indicative criteria uncovered reliable sensitivity and specificity for PTB patients determining that HRCT is a useful tool in sputum negative PTB patients. CONCLUSION: HRCT is useful in selecting individuals with greater chances of PTB in the sputum smear-negative setting.

Role of advanced MRI brain sequences in diagnosing neurological complications of scrub typhus.

Scrub typhus is a rare disease affecting many organs and causing vasculitis by affecting the endothelium of blood vessels. Review of literature shows that there are only a few case reports describing the neuroradiological manifestations of scrub typhus. This case report describes how newer and advanced MRI sequences are able to diagnose neurological complications of scrub typhus, such as hemorrhages, meningoencephalitis, infarctions, cranial nerve involvement, thrombosis, and hypoperfusion, that are not picked up on routine magnetic resonance imaging (MRI) sequences.

Encephalocraniocutaneous lipomatosis with calvarial exostosis - Case report and review of literature.

Encephalocraniocutaneous lipomatosis (ECCL), also known as Haberland syndrome, is a rare syndrome with unknown etiology. The syndrome is characterized by a triad of unique cutaneous, ocular, and central nervous system (CNS) manifestations. The cutaneous hallmark, nevus psiloliparus (NP), along with overlying alopecia is a constant feature. Choristoma of the eyelid is the most common ocular manifestation, while intracranial lipoma is the predominant CNS finding. Genetic counseling is required to emphasize that the disorder, although congenital, is not inheritable. We present a 21-year-old female with cutaneous, ocular, and CNS features satisfying the diagnostic criteria for ECCL. To our knowledge, this is the first case of ECCL having a large temporal exostosis. The objective of this article is to better understand the phenotypic spectrum of this syndrome whose molecular basis is still unknown.