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Neutrophils play a vital role in the innate immunity by perform effector functions through phagocytosis, degranulation, and forming extracellular traps. However, over-functioning of neutrophils has been associated with sterile inflammation such as Type 2 Diabetes, atherosclerosis, cancer and autoimmune disorders. Neutrophils exhibiting phenotypical and functional heterogeneity in both homeostatic and pathological conditions suggests distinct signaling pathways are activated in disease-specific stimuli and alter neutrophil functions. Hence, we examined mass spectrometry based post-translational modifications (PTM) of neutrophil proteins in response to pathologically significant stimuli, including high glucose, homocysteine and bacterial lipopolysaccharides representing diabetes-indicator, an activator of thrombosis and pathogen-associated molecule, respectively. Our data revealed that these aforesaid stimulators differentially deamidate, citrullinate, acetylate and methylate neutrophil proteins and align to distinct biological functions associated with degranulation, platelet activation, innate immune responses and metabolic alterations. The PTM patterns in response to high glucose showed an association with neutrophils extracellular traps (NETs) formation, homocysteine induced proteins PTM associated with signaling of systemic lupus erythematosus and lipopolysaccharides induced PTMs were involved in pathways related to cardiomyopathies. Our study provides novel insights into neutrophil PTM patterns and functions in response to varied pathological stimuli, which may serve as a resource to design therapeutic strategies for the management of neutrophil-centred diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

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 (EC 50 : 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., Competing Interests: The authors declare no competing interests., (© 2024 Published by Elsevier Inc.)

Metabolic and inflammatory pathways are highly interdependent, and both systems are dysregulated in Type 2 diabetes (T2D). T2D is associated with pre-activated inflammatory signaling networks, aberrant cytokine production and increased acute phase reactants which leads to a pro-inflammatory 'feed forward loop'. Nutrient 'excess' conditions in T2D with hyperglycemia, elevated lipids and branched-chain amino acids significantly alter the functions of immune cells including neutrophils. Neutrophils are metabolically active cells and utilizes energy from glycolysis, stored glycogen and β-oxidation while depending on the pentose phosphate pathway for NADPH for performing effector functions such as chemotaxis, phagocytosis and forming extracellular traps. Metabolic changes in T2D result in constitutive activation and impeded acquisition of effector or regulatory activities of neutrophils and render T2D subjects for recurrent infections. Increased flux through the polyol and hexosamine pathways, elevated production of advanced glycation end products (AGEs), and activation of protein kinase C isoforms lead to (a) an enhancement in superoxide generation; (b) the stimulation of inflammatory pathways and subsequently to (c) abnormal host responses. Neutrophil dysfunction diminishes the effectiveness of wound healing, successful tissue regeneration and immune surveillance against offending pathogens. Hence, Metabolic reprogramming in neutrophils determines frequency, severity and duration of infections in T2D. The present review discusses the influence of the altered immuno-metabolic axis on neutrophil dysfunction along with challenges and therapeutic opportunities for clinical management of T2D-associated infections., (© 2023. The Author(s).)

Neutrophils display functional heterogeneity upon responding diversely to physiological and pathological stimulations. During type 2 diabetes (T2D), hyperglycemia constitutively activates neutrophils, leading to reduced response to infections and on the other hand, elevated metabolic intermediates such as homocysteine induce bidirectional activation of platelets and neutrophils leading to thrombosis. Hence, in the context of T2D-associated complications, we examined the influence of high glucose, homocysteine, and LPS representing effector molecules of hyperglycemia, thrombosis, and infection, respectively, on human neutrophil activation to identify distinct signaling pathways by quantitative phosphoproteomics approach. High glucose activated C-Jun-N-Terminal Kinase, NTRK1, SYK, and PRKACA kinases associated with Rho GTPase signaling and phagocytosis, whereas LPS induced AKT1, SRPK2, CSNK2A1, and TTN kinases involved in cytokine signaling and inflammatory response. Homocysteine treatment led to activatation of  LRRK2, FGR, MAPK3, and PRKCD kinases which are associated with neutrophil degranulation and cytoskeletal remodeling. Diverse inducers differentially modulated phosphorylation of proteins associated with neutrophil functions such as oxidative burst, degranulation, extracellular traps, and phagocytosis. Further validation of phosphoproteomics data on selected kinases revealed neutrophils pre-cultured under high glucose showed impeded response to LPS to phosphorylate p-ERK1/2 Thr202/Tyr204 , p-AKT Ser473 , and C-Jun-N-Terminal Kinase Ser63 kinases. Our study provides novel phosphoproteome signatures that may be explored to understand neutrophil biology in T2D-associated complications., (© 2022. The Author(s).)