Also published as: A Reddy, B. I. Reddy, CA Reddy, D. R. Reddy, F. Reddy, H. Reddy, J Reddy, J. J. Reddy, J. Reddy, K Laxma Reddy, K. A. Reddy, K. L. Reddy, K. Reddy, Kasi Reddy, Santhosh Reddy, M. R. Reddy, P Venkat Reddy, P. H. Reddy, P. Reddy, P. V. Reddy, Praveen Kumar K Reddy, R Reddy, R. Reddy, S. E. Reddy, S. Reddy, Santhosh Reddy Kasi Reddy, V. Venkat Reddy,
The brain’s high demand for energy necessitates tightly regulated metabolic pathways to sustain physiological activity. Glucose, the primary energy substrate, undergoes complex metabolic transformatio Show more
The brain’s high demand for energy necessitates tightly regulated metabolic pathways to sustain physiological activity. Glucose, the primary energy substrate, undergoes complex metabolic transformations, with mitochondria playing a central role in ATP production via oxidative phosphorylation. Dysregulation of this metabolic interplay is implicated in Alzheimer’s disease (AD), where compromised glucose metabolism, oxidative stress, and mitochondrial dysfunction contribute to disease progression. This review explores the intricate bioenergetic crosstalk between astrocytes and neurons, highlighting the function of mitochondrial uncoupling proteins (UCPs), particularly UCP4, as important regulators of brain metabolism and neuronal function. Predominantly expressed in the brain, UCP4 reduces the membrane potential in the inner mitochondrial membrane, thereby potentially decreasing the generation of reactive oxygen species. Furthermore, UCP4 mitigates mitochondrial calcium overload and sustains cellular ATP levels through a metabolic shift from mitochondrial respiration to glycolysis. Interestingly, the levels of the neuronal UCPs, UCP2, 4 and 5 are significantly reduced in AD brain tissue and a specific UCP4 variant has been associated to an increased risk of developing AD. Few studies modulating the expression of UCP4 in astrocytes or neurons have highlighted protective effects against neurodegeneration and aging, suggesting that pharmacological strategies aimed at activating UCPs, such as protonophoric uncouplers, hold promise for therapeutic interventions in AD and other neurodegenerative diseases. Despite significant advances, our understanding of UCPs in brain metabolism remains in its early stages, emphasizing the need for further research to unravel their biological functions in the brain and their therapeutic potential. Show less
Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical inv Show more
Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical involvement of specific mitochondrial-associated events, including mitochondrial quality control, intercellular mitochondrial transfer, and mitochondrial genetics, in potentiating the metastatic cascade of neoplastic cells. Furthermore, numerous recent studies have consistently emphasized the highly significant role mitochondria play in coordinating the regulation of tumor-infiltrating immune cells and immunotherapeutic interventions. This review provides a comprehensive and rigorous scholarly investigation of this subject matter, exploring the intricate mechanisms by which mitochondria contribute to tumor metastasis and examining the progress of mitochondria-targeted cancer therapies. Show less
Mitochondrial DNA (mtDNA) is a small, circular, double-stranded DNA inherited from the mother during fertilization. Evolutionary evidence supported by the endosymbiotic theory identifies mitochondria Show more
Mitochondrial DNA (mtDNA) is a small, circular, double-stranded DNA inherited from the mother during fertilization. Evolutionary evidence supported by the endosymbiotic theory identifies mitochondria as an organelle that could have descended from prokaryotes. This may be the reason for the independent function and inheritance pattern shown by mtDNA. The unstable nature of mtDNA due to the lack of protective histones, and effective repair systems make it more vulnerable to mutations. The mtDNA and its mutations could be maternally inherited thereby predisposing the offspring to various cancers like breast and ovarian cancers among others. Although mitochondria are considered heteroplasmic wherein variations among the multiple mtDNA genomes are noticed, mothers can have mitochondrial populations that are homoplasmic for a given mitochondrial mutation. Homoplasmic mitochondrial mutations may be transmitted to all maternal offspring. However, due to the complex interplay between the mitochondrial and nuclear genomes, it is often difficult to predict disease outcomes, even with homoplasmic mitochondrial populations. Heteroplasmic mtDNA mutations can be maternally inherited, but the proportion of mutated alleles differs markedly between offspring within one generation. This led to the genetic bottleneck hypothesis, explaining the rapid changes in allele frequency witnessed during the transmission of mtDNA from one generation to the next. Although a physical reduction in mtDNA has been demonstrated in several species, a comprehensive understanding of the molecular mechanisms is yet to be demonstrated. Despite initially thought to be limited to the germline, there is evidence that blockages exist in different cell types during development, perhaps explaining why different tissues in the same organism contain different levels of mutated mtDNA. In this review, we comprehensively discuss the potential mechanisms through which mtDNA undergoes mutations and the maternal mode of transmission that contributes to the development of tumors, especially breast and ovarian cancers. Show less
Abstract Imaging contrast agents are widely investigated in preclinical and clinical studies, among which biogenic imaging contrast agents (BICAs) are developing rapidly and playing an increasingly i Show more
Abstract Imaging contrast agents are widely investigated in preclinical and clinical studies, among which biogenic imaging contrast agents (BICAs) are developing rapidly and playing an increasingly important role in biomedical research ranging from subcellular level to individual level. The unique properties of BICAs, including expression by cells as reporters and specific genetic modification, facilitate various in vitro and in vivo studies, such as quantification of gene expression, observation of protein interactions, visualization of cellular proliferation, monitoring of metabolism, and detection of dysfunctions. Furthermore, in human body, BICAs are remarkably helpful for disease diagnosis when the dysregulation of these agents occurs and can be detected through imaging techniques. There are various BICAs matched with a set of imaging techniques, including fluorescent proteins for fluorescence imaging, gas vesicles for ultrasound imaging, and ferritin for magnetic resonance imaging. In addition, bimodal and multimodal imaging can be realized through combining the functions of different BICAs, which helps overcome the limitations of monomodal imaging. In this review, the focus is on the properties, mechanisms, applications, and future directions of BICAs. Show less
Introduction: Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity. Developing mitochondria- Show more
Introduction: Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity. Developing mitochondria-targeted modified natural compounds and US FDA-approved drugs with increased therapeutic index in cancer is discussed as an alternative strategy. Areas Covered: Triphenylphosphonium cation (TPP + )-based drugs selectively accumulate in the mitochondria of cancer cells due to their increased negative membrane potential, target the oxidative phosphorylation proteins, inhibit mitochondrial respiration, and inhibit tumor proliferation. TPP + -based drugs exert minimal toxic side effects in rodents and humans. These drugs can sensitize radiation and immunotherapies. Expert Opinion: TPP + -based drugs targeting the tumor mitochondrial electron transport chain are a new class of oxidative phosphorylation inhibitors with varying antiproliferative and antimetastatic potencies. Some of these TPP + -based agents, which are synthesized from naturally occurring molecules and FDA-approved drugs, have been tested in mice and did not show notable toxicity, including neurotoxicity, when used at doses under the maximally tolerated dose. Thus, more effort should be directed toward the clinical translation of TPP + -based OXPHOS-inhibiting drugs in cancer prevention and treatment. Show less
Abstract TFIIH is a 10‐subunit complex that regulates RNA polymerase II (pol II) transcription but also serves other important biological roles. Although much remains unknown about TFIIH function in Show more
Abstract TFIIH is a 10‐subunit complex that regulates RNA polymerase II (pol II) transcription but also serves other important biological roles. Although much remains unknown about TFIIH function in eukaryotic cells, much progress has been made even in just the past few years, due in part to technological advances (e.g. cryoEM and single molecule methods) and the development of chemical inhibitors of TFIIH enzymes. This review focuses on the major cellular roles for TFIIH, with an emphasis on TFIIH function as a regulator of pol II transcription. We describe the structure of TFIIH and its roles in pol II initiation, promoter‐proximal pausing, elongation, and termination. We also discuss cellular roles for TFIIH beyond transcription (e.g. DNA repair, cell cycle regulation) and summarize small molecule inhibitors of TFIIH and diseases associated with defects in TFIIH structure and function. Show less
Abstract Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology Show more
Abstract Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δ p or its potential component, Δ Ψ , which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1–5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling. Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δ p dissipation decreases superoxide formation dependent on Δ p . UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells. Critical Issues: A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg 2+ , or increased pyruvate accumulation may initiate UCP-mediated redox signaling. Future Directions: Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667–714. Show less
Pyridyl–tetrazole ligands 2-(5-(pyridin-2-yl)-1H-tetrazol-1-yl)acetamide (L1), 2-(5-(pyridin-2-yl)-2H-tetrazol-2-yl)acetamide (L2), 2-(5-(pyridin-2-yl)-1H-tetrazol-1-yl)acetohydrazide (L3) and 2-(5-(p Show more
Pyridyl–tetrazole ligands 2-(5-(pyridin-2-yl)-1H-tetrazol-1-yl)acetamide (L1), 2-(5-(pyridin-2-yl)-2H-tetrazol-2-yl)acetamide (L2), 2-(5-(pyridin-2-yl)-1H-tetrazol-1-yl)acetohydrazide (L3) and 2-(5-(pyridin-2-yl)-2H-tetrazol-2-yl)acetohydrazide (L4) have been prepared and coordinated with CuCl2·2H2O to furnish the corresponding complexes [Cu(L1) 2 ]–[Cu(L4) 2 ]. EPR spectra of the complexes are characteristic of square planar geometries, with nuclear hyperfine spin 3/2. DNA-binding studies using UV–Vis absorption spectroscopy, viscosity and thermal denature studies revealed that all of these complexes are avid binders of calf thymus DNA. The antioxidant properties of the free ligands and the Cu(II) complexes were investigated using the p-nitrosodimethyl aniline hydroxyl radical scavenging method, and [Cu(L4) 2 ] was found to show the highest activity. Show less
Two Ru(II) complexes [Ru(phen)2bppp](ClO4)2 (1) and [Ru(phen)27-Br-dppz](ClO4)2 (2) [phen=1,10 phenanthroline, 7-Br-dppz=7-fluorodipyrido[3,2-a:2',3'-c]phenazine, bppp=11-bromo-pyrido[2',3':5,6]pyrazi Show more
Two Ru(II) complexes [Ru(phen)2bppp](ClO4)2 (1) and [Ru(phen)27-Br-dppz](ClO4)2 (2) [phen=1,10 phenanthroline, 7-Br-dppz=7-fluorodipyrido[3,2-a:2',3'-c]phenazine, bppp=11-bromo-pyrido[2',3':5,6]pyrazino[2,3-f] [1,10]phenanthroline] have been synthesized and characterized by elemental analysis, ES-MS, (1)H-NMR, (13)C-NMR and IR. The in vitro cytotoxicity of the complexes examined against a panel of cancer cell lines (HeLa, Du145 and A549) by MTT method, both complexes show prominent anticancer activity against various cancer cells. Live cell imaging study and flow cytometric analysis demonstrate that both the complexes 1 and 2 could cross the cell membrane accumulating in the nucleus. Further, flow cytometry experiments showed that the cytotoxic Ru(II) complexes 1 and 2 induced apoptosis of HeLa tumor cell lines. Photo induced DNA cleavage studies have been performed and results indicate that both the complexes efficiently photo cleave pBR322 DNA. The binding properties of two complexes toward CT-DNA were investigated by various optical methods and viscosity measurements. The experimental results suggested that both Ru(II) complexes can intercalate into DNA base pairs. The complexes were docked into DNA-base pairs using the GOLD docking program. Show less