Seshu Vardhan

Skeletal muscle experiences large fluctuations in ATP demand and redox state during contraction, ischaemia and chronic disease, requiring rapid adaptations in substrate selection, mitochondrial workload, vascular coupling, regeneration and protein homeostasis. Hypoxia‐inducible factor‐1a (HIF1a) is classically viewed as an oxygen‐responsive transcription factor that mediates rapid adaptation to hypoxia. Accumulating evidence across tissues, including skeletal muscle, indicates that HIF1a is also responsive to physiological and pathological inputs, such as exercise, circadian timing, redox perturbations and endogenous/exogenous cytotoxins, even when tissue hypoxia is not detectable. During hypoxia, including transient mismatches between oxygen demand and supply during muscle contraction, HIF1a activation shifts metabolism from oxidative to non‐oxidative energy production, suppresses non‐essential energy‐consuming processes, including protein homeostasis, and promotes vascular responses that improve oxygen delivery. Under normoxic conditions, persistent HIF1a activation promotes maladaptive responses, including impaired mitochondrial remodelling, reduced anabolic responsiveness, defective regeneration, fibrosis, and atrophy‐ and senescence‐associated reprogramming. Current evidence shows that this shift from adaptive to maladaptive signalling is determined in part by post‐translational mechanisms that regulate signalling duration and target gene engagement, as well as by fibre type, circadian state and the nature of the upstream stressor. Unlike the robust responses in muscle tissue observed in preclinical models, human muscle biopsies often show modest or transient HIF1a accumulation, yet transcriptional responses indicate meaningful pathway activation, suggesting that biologically relevant signalling occurs even when total protein levels appear low. Genetic models, multiomics, and human studies support HIF1a as a context‐dependent regulator of metabolic reprogramming that balances short‐term adaptation with long‐term energetic cost. image

A series of novel Ru(II)/Ir(III)/Re(I)-based organometallic complexes [Ru₂L1, Ru₂L2, Ir₂L1, Ir₂L2, Re₂L1, and Re₂L2] have been synthesized to assess their potency and selectivity against multiple cancer cells A549, HCT-116, and HCT-116 colon CSCs. The cytotoxic screening of the synthesized complexes has revealed that complex Ru₂L1 and Ir₂L2 are two proficient complexes among all, but Ru₂L1 is the most potent complex. A significant binding constant value was observed for DNA and BSA in all complexes. Significant lipophilic properties allow them to penetrate cancer cell membranes, and substantial quantum yield (ϕ_f) values support bioimaging potential. Again, these complexes are particular for mitochondrial localization and produce a profuse amount of ROS to damage the mitochondrial DNA and then G1 phase cell-cycle arrest. Protein expression analysis unveiled that pro-apoptotic Bax protein overexpressed in Ru₂L1-treated cells, whereas antiapoptotic Bcl-2 protein was expressed twofold in Ir₂L2-treated cells, which correlated with autophagy reticence.

Chronic kidney disease (CKD) poses a global health challenge, engendering various physiological and metabolic shifts that significantly impact health and escalate the susceptibility to severe illnesses. This comprehensive review delves into the intricate complexities of CKD, scrutinizing its influence on cellular growth homeostasis, hormonal equilibrium, wasting, malnutrition, and its interconnectedness with inflammation, oxidative stress, and cardiovascular diseases. Exploring the genetic, birth-related, and comorbidity factors associated with CKD, alongside considerations of metabolic disturbances, anemia, and malnutrition, the review elucidates how CKD orchestrates cellular growth control. A pivotal focus lies on the nexus between CKD and insulin resistance, where debates persist regarding its chronological relationship with impaired kidney function. The prevalence of insulin abnormalities in CKD is emphasized, contributing to glucose intolerance and raising questions about its role as a precursor or consequence. Moreover, the review sheds light on disruptions in the growth hormone and insulin-like growth factor axis in CKD, underscoring the heightened vulnerability to illness and mortality in cases of severe growth retardation. Wasting, a prevalent concern affecting up to 75% of end-stage renal disease (ESRD) patients, is analyzed, elucidating the manifestations of cachexia and its impact on appetite, energy expenditure, and protein reserves. Taste disturbances in CKD, affecting sour, umami, and salty tastes, are explored for their implications on food palatability and nutritional status. Independent of age and gender, these taste alterations have the potential to sway dietary choices, further complicating the management of CKD. The intricate interplay between CKD, inflammation, oxidative stress, and cardiovascular diseases is unraveled, emphasizing the profound repercussions on overall health. Additionally, the review extends its analysis to CKD’s broader impact on cognitive function, emotional well-being, taste perception, and endothelial dysfunction. Concluding with an emphasis on dietary interventions as crucial components in CKD management, this comprehensive review navigates the multifaceted dimensions of CKD, providing a nuanced understanding essential for developing targeted therapeutic strategies.

Triple-negative breast cancer (TNBC) is an extremely vicious subtype of human breast cancer having the worst prognosis along with strong invasive and metastatic competency. Hence, it can easily invade into blood vessels, and presently, no targeted therapeutic approach is available to annihilate this type of cancer. Metal complexes have successfully stepped into the anticancer research and are now being applauded due to their anticancer potency after the discovery of cisplatin. Many of these metal complexes are also well recognized for their activity toward breast cancer. As the TNBC is a very dangerous subtype and has long been a challenging ailment to treat, we have intended to develop a few brand new mixed metallic Ru(II)/Ir(III)/Re(I)-2,2'-bipyrimidine complexes [L'Re2], [L'RuRe], and [L'IrRe] to abate the unbridled proliferation of TNBC cells. The potency of the complexes against TNBC cells has been justified using MDA-MB-468 TNBC cell lines where complex [L'IrRe] has displayed significant potency among all the three complexes with an IC₅₀ value of 24.12 μM. The complex [L'IrRe] has been competent to cause apoptosis of TNBC cells through inhibition of the G2/M phase in the cell cycle in association with a profuse amount of ROS generation and mitochondrial depolarization.

Due to a number of unpleasant considerations, marketed drugs have steadily lost their importance in the treatment of cancer. In order to find a viable cancer cell diagnostic agent, we therefore focused on metal complexes that displayed target adequacy, permeability to cancer cells, high standard water solubility, cytoselectivity, and luminescent behavior. In this aspect, luminescent 11-{naphthalen-1-yl} dipyrido [3,2-a:2',3'-c] phenazine based Ru(II)/Ir(III)/Re(I) complexes have been prepared for HCT-116 colorectal cancer stem cell therapy. Our study successfully established the possible cytotoxicity of IrL complex at different doses on HCT-116 colorectal cancer stem cells (CRCSCs). Additionally, an immunochemistry analysis of the complex IrL showed that the molecule was subcellularly localized in the nucleus and other regions of the cytoplasm, where it caused nuclear DNA damage and mitochondrial dysfunction. The level of BAX and Bcl-2 was further quantified by qRT-PCR. The expression of proapoptotic BAX showed increased expression in the complex IrL-treated cell compared to the control, indicating the potential of complex IrL for apoptotic induction. Upon further validation, complex IrL was developed as an inhibitor of autophagy for the eradication of cancer stem cells.

DNA-targeting half-sandwich [Ru(η⁶-p-cymene)(N^O 8-hydroxyquinoline)(PTA)] complexes have been developed for human brain cancer cell therapy.

GSH-resistant, hypoxia active iridium( iii )–Cp*-(imidazo[4,5- f ][1,10]phenanthrolin-2-yl)phenol complexes were developed as highly cytoselective anticancer agents and mitochondria-targeting CSC therapeutic agents.