Mitochondrial Targeting Research Articles

Combined Photosensitive Gene Therapy Effective Against Triple-Negative Breast Cancer in Mice Model.

Tumor hypoxia and invasion present significant challenges for the efficacy of photodynamic therapy (PDT) in triple-negative breast cancer (TNBC). This study developed a mitochondrial targeting strategy that combined PDT and gene therapy to promote each other and address the challenges. The positively charged amphiphilic material triphenylphosphine-tocopherol polyethylene glycol succinate (TPP-TPGS, TPS) and the photosensitizer chloride e6 (Ce6) formed TPS@Ce6 nanoparticles (NPs) by hydrophobic interaction. They electrostatically condensed microRNA-34a (miR-34a) to form stable TPS@Ce6/miRNA NPs. Firstly, Ce6 disrupted the lysosomal membrane, followed by successful delivery of miR-34a by TPS@Ce6/miRNA NPs. Meanwhile, miR-34a reduced ROS depletion and further enhanced the effectiveness of PDT. Consequently, the mutual promotion between PDT and gene therapy led to enhanced anti-tumor effects. Furthermore, the TPS@Ce6/miRNA NPs promoted apoptosis by down-regulating Caspase-3 and inhibited tumor cell migration and invasion by down-regulating N-Cadherin. In addition, in vitro and in vivo experiments demonstrated that the TPS@Ce6/miRNA NPs achieved excellent anti-tumor effects. These findings highlighted the enhanced anticancer effects and reduced migration of tumor cells through the synergistic effects of PDT and gene therapy. Taken together, the targeted co-delivery of Ce6 and miR-34a will facilitate the application of photodynamic and genic nanomedicine in the treatment of aggressive tumors, particularly TNBC.

Curcumin-conjugated Nanoparticles: An Approach to Target Mitochondria

Background: Unconjugated nanoparticles used in the treatment of cancer and various metabolic and neurodegenerative disorders exhibit extended blood circulation time, inhibition of enzymatic degradation, and increased chemical stability of the encapsulated therapeutic molecules. However, the unconjugated nanoparticles often show off-target effects and lack of specificity, which limit their applications in the healthcare system. Objective: Curcumin, a polyphenolic compound known for its proficiency to scavenge reactive oxygen species attributed to antioxidant activity and anticancer effects associated with mitochondrial dysfunction, is one of the most effective therapeutic agents. Therefore, with respect to chemotherapeutic strategies, the development of mitochondrial targeting curcumin nanoparticles for target-specific drug delivery has been extensively studied. Conclusion: The present review has focused on diverse curcumin-loaded nanoparticles targeting mitochondria along with their improved delivery potential, enhanced localization and biodistribution profile.

Mitophagy in plants: Emerging regulators of mitochondrial targeting for selective autophagy.

The degradation and turnover of mitochondria is fundamental to Eukaryotes and is a key homeostatic mechanism for maintaining functional mitochondrial populations. Autophagy is an important pathway by which mitochondria are degraded, involving their sequestration into membrane-bound autophagosomes and targeting to lytic endosomal compartments (the lysosome in animals, the vacuole in plants and yeast). Selective targeting of mitochondria for autophagy, also known as mitophagy, distinguishes mitochondria from other cell components for degradation and is necessary for the regulation of mitochondria-specific cell processes. In mammals and yeast, mitophagy has been well characterised and is regulated by numerous pathways with diverse and important functions in the regulation of cell homeostasis, metabolism and responses to specific stresses. In contrast, we are only just beginning to understand the importance and functions of mitophagy in plants, chiefly as the proteins that target mitochondria for autophagy in plants are only recently emerging. Here, we discuss the current progress of our understanding of mitophagy in plants, the importance of mitophagy for plant life and the regulatory autophagy proteins involved in mitochondrial degradation. In particular, we will discuss the recent emergence of mitophagy receptor proteins that selectively target mitochondria for autophagy, and discuss the missing links in our knowledge of mitophagy-regulatory proteins in plants compared to animals and yeast.

Mitochondrial HER2 stimulates respiration and promotes tumorigenicity.

Amplification of HER2, a receptor tyrosine kinase and a breast cancer-linked oncogene, is associated with aggressive disease. HER2 protein is localised mostly at the cell membrane, but a fraction translocates to mitochondria. Whether and how mitochondrial HER2 contributes to tumorigenicity is currently unknown. We enriched the mitochondrial (mt-)HER2 fraction in breast cancer cells using an N-terminal mitochondrial targeting sequence and analysed how this manipulation impacts bioenergetics and tumorigenic properties. The role of the tyrosine kinase activity of mt-HER2 was assessed in wild type, kinase-dead (K753M) and kinase-enhanced (V659E) mtHER2 constructs. We document that mt-HER2 associates with the oxidative phosphorylation system, stimulates bioenergetics and promotes larger respiratory supercomplexes. mt-HER2 enhances proliferation and invasiveness invitro and tumour growth and metastatic potential invivo, in a kinase activity-dependent manner. On the other hand, constitutively active mt-HER2 provokes excessive mitochondria ROS generation, sensitises to cell death, and restricts growth of primary tumours, suggesting that regulation of HER2 activity in mitochondria is required for the maximal pro-tumorigenic effect. mt-HER2 promotes tumorigenicity by supporting bioenergetics and optimal redox balance.

Organotin(IV)-tetraphenylethylene acylhydrazone compounds with aggregation-induced emission property and application in anticancer therapy

Organotin (IV)-tetraphenylethylene (TPE) acylhydrazone compounds with aggregation-induced emission (AIE) property were prepared and characterized. The organotin (IV) compounds showed a conspicuous fluorescence improvement with a high absolute fluorescence quantum yield of 25.2 % (ClSnTPE) in the aggregation state, and restriction of intramolecular rotation (RIR) contributed to this AIE property. Using suitable fluorescence, confocal tests verified that these compounds could accumulate in the mitochondria of A549 cancer cells and decrease the mitochondrial membrane potential. Meanwhile, compounds could improve the intracellular reactive oxygen species (ROS) levels and inhibit the cell cycle (G1/G0 phase), then contributing to apoptosis. In addition to favorable in-vitro anti-proliferative activity (the similar to cisplatin), these compounds could also suppress A549 cancer cell migration. Above all, organotin (IV)-TPE acylhydrazone compounds show the promise as the mitochondrial targeting anticancer drugs for further study.

Multi-targeting inulin-based nanoparticles with cannabidiol for effective prevention of ulcerative colitis

The pathogenesis of ulcerative colitis (UC) is closely related to severe inflammation, damaged colonic mucosal barrier, increased oxidative stress and intestinal ecological imbalance. However, due to the nonspecific distribution and poor bioavailability of drugs, UC treatment is still a serious challenge. Here, a mitochondria/colon dual targeted nanoparticles based on redox response was developed to effectively alleviate UC. Cannabidiol nanoparticles (CBD NPs) with a particle size of 143.2 ± 3.11 nm were prepared by self-assembly using polymers (TPP–IN–LA) obtained by modifying inulin with (5-carboxypentyl) triphenyl phosphonium bromide (TPP) and α-lipoic acid (α-LA). Excitingly, the constructed CBD NPs showed excellent mitochondrial targeting, with a Pearson correlation coefficient of 0.76 at 12 h. The results of animal imaging in vivo showed that CBD NPs could be effectively accumulated in colon tissue. Not only that, CBD showed significant glutathione stimulated release in the presence of 10 mM glutathione at pH 7.4. The results of in vivo animal experiments showed that CBD NPs significantly ameliorated DSS-induced colonic inflammation by modulating the TLR4-NF-κB signaling pathway. Moreover, CBD NPs significantly improved the histological damage of colon in UC mice, increased the expression level of tight junction protein ZO-1, and effectively restored the intestinal mucosal barrier function and intestinal mucosal permeability. More importantly, CBD NPs significantly improved the species composition, abundance and amount of short chain fatty acids of intestinal flora in UC mice, thus effectively maintaining the balance of intestinal flora. The dual-targeted and glutathione-responsive nanoparticles prepared in this study provide a promising idea for achieving targeted delivery of CBD for effective treatment of UC.

Rescuing Nucleus Pulposus Cells from ROS Toxic Microenvironment via Mitochondria-Targeted Carbon Dot-Supported Prussian Blue to Alleviate Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is invariably accompanied by excessive accumulation of reactive oxygen species (ROS), resulting in progressive deterioration of mitochondrial function and senescence in nucleus pulposus cells (NPCs). Significantly, the main ROS production site in non-immune cells is mitochondria, suggesting mitochondria is a feasible therapeutic target to reverse IVDD. Triphenylphosphine (TPP), which is known as mitochondrial-tropic ligands, is utilized to modify carbon dot-supported Prussian blue (CD-PB) to scavenge superfluous intro-cellular ROS and maintain NPCs at normal redox levels. CD-PB-TPP can effectively escape from lysosomal phagocytosis, permitting efficient mitochondrial targeting. After strikingly lessening the ROS in mitochondria via exerting antioxidant enzyme-like activities, such as superoxide dismutase, and catalase, CD-PB-TPP rescues damaged mitochondrial function and NPCs from senescence, catabolism, and inflammatory reaction in vitro. Imaging evaluation and tissue morphology assessment in vivo suggest that disc height index, mean grey values of nucleus pulposus tissue, and histological morphology are significantly improved in the IVDD model after CD-PB-TPP is locally performed. In conclusion, this study demonstrates that ROS-induced mitochondrial dysfunction and senescence of NPCs leads to IVDD and the CD-PB-TPP possesses enormous potential to rescue this pathological process through efficient removal of ROS via targeting mitochondria, supplying a neoteric strategy for IVDD treatment.

Multiplex Quantitative PCR Assay for Detection of Spinach and Lettuce Downy Mildews Using Spore Trapping

Downy mildews are major constraints on spinach and lettuce production globally. Disease management can be achieved with fungicides, but routine applications are costly and can lead to pathogen resistance. Detection of airborne spores could guide sustainable fungicide application, and, considering that spinach and lettuce are often grown in the same cycles, simultaneous detection of both pathogens is practical. Here, a multiplex hydrolysis probe quantitative PCR assay was designed using single copy mitochondrial DNA targets for spinach downy mildew ( Peronospora effusa) and lettuce downy mildew ( Bremia lactucae). To quantify P. effusa and B. lactucae sporangia, a standard curve was developed for each pathogen using the multiplex qPCR to amplify DNA obtained from known dilutions of sporangia. Analysis of these curves revealed a greater sensitivity for B. lactucae, indicating that the sporangia of B. lactucae may harbor more mitochondria than those of P. effusa, providing insight into the biology of these pathogens. The multiplex qPCR assay was partnered with two different spore trap types: a cyclone spore trap and an impaction spore trap. Results from air sampling revealed that the cyclone spore traps collect significantly more sporangia compared with impaction traps. Exposure of P. effusa sporangia to desiccation was performed to assess the environmental impact on the assay, and although detection levels were reduced, they were still apparent. This detection and quantification tool will be useful in efforts to improve the accuracy of downy mildew forecasting, which in return may reduce fungicide usage or improve its efficiency. [Formula: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 “No Rights Reserved” license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law, 2024.

A Less-is-More Strategy for Mitochondria-Targeted Photodynamic Therapy of Rheumatoid Arthritis.

Conventional photodynamic therapy (PDT) of rheumatoid arthritis (RA) faces a dilemma: low-power is insufficient to kill pro-inflammatory cells while high-power exacerbates inflammation. Herein, mitochondrial targeting is introduced in PDT of RA to implement a "less-is-more" strategy, where higher apoptosis in pro-inflammatory cells are achieved with lower laser power. In arthritic rats, chlorine 6-loaded and mitochondria-targeting liposomes (Ce6@M-Lip) passively accumulated in inflamed joints, entered pro-inflammatory macrophages, and actively localized to mitochondria, leading to enhanced mitochondrial dysfunction under laser irradiation. By effectively disrupting mitochondria, pro-inflammatory macrophages are more susceptible to PDT, resulting in increased apoptosis initiation. Additionally, it identifies that high-power irradiation caused cell rupture and release of endogenous danger signals that recruited and activated additional macrophages. In contrast, under low-power irradiation, mitochondria-targeting Ce6@M-Lip not only prevented inflammation but also reduced pro-inflammatory macrophage infiltration and pro-inflammatory cytokine secretion. Overall, targeting mitochondria reconciled therapeutic efficacy and inflammation, thus enabling efficacious yet inflammation-sparing PDT for RA. This highlights the promise of mitochondrial targeting to resolve the dilemma between anti-inflammatory efficacy and inflammatory exacerbation in PDT by implementing a "less-is-more" strategy.

Role of mitochondria in neonatal hypoxic-ischemic encephalopathy.

Neonatal hypoxic-ischemic encephalopathy, an important cause of death as well as long-term disability in survivors, is caused by oxygen and glucose deprivation, and limited blood flow. Following hypoxic-ischemic injury in the neonatal brain, three main biochemical damages (excitotoxicity, oxidative stress, and exacerbated inflammation) are triggered. Mitochondria are involved in all three cascades. Mitochondria are the nexus of metabolic pathways to offer most of the energy that our body needs. Hypoxic-ischemic injury affects the characteristics of mitochondria, including dynamics, permeability, and ATP production, which also feed back into the process of neonatal hypoxic-ischemic encephalopathy. Mitochondria can be a cellular hub in inflammation, which is another main response of the injured neonatal brain. Some treatments for neonatal hypoxic-ischemic encephalopathy affect the function of mitochondria or target mitochondria, including therapeutic hypothermia and erythropoietin. This review presents the main roles of mitochondria in neonatal hypoxic-ischemic encephalopathy and discusses some potential treatments directed at mitochondria, which may foster the development of new therapeutic strategies for this encephalopathy.

Nanoparticle-based therapeutic strategies for mitochondrial dysfunction in cardiovascular disease.

Although cardiovascular diseases (CVD) are the leading cause of global mortality, there is a lack of therapies that target and revert underlying pathological processes. Mitochondrial dysfunction is involved in the pathophysiology of CVD, and thus is a potential target for therapeutic development. To target the mitochondria and improve therapeutic efficacy, nanoparticle-based delivery systems have been proposed as promising strategies for the delivery of therapeutic agents to the mitochondria. This review will first discuss how mitochondrial dysfunction is related to the progression of several CVD and then delineate recent progress in mitochondrial targeting using nanoparticle-based delivery systems including peptide-based nanosystems, polymeric nanoparticles, liposomes, and lipid nanoparticles. In addition, we summarize the advantages of these nanocarriers and remaining challenges in targeting the mitochondria as a therapeutic strategy for CVD treatment.

Mitochondrial-related microRNAs and their roles in cellular senescence.

Aging is a natural aspect of mammalian life. Although cellular mortality is inevitable, various diseases can hasten the aging process, resulting in abnormal or premature senescence. As cells age, they experience distinctive morphological and biochemical shifts, compromising their functions. Research has illuminated that cellular senescence coincides with significant alterations in the microRNA (miRNA) expression profile. Notably, a subset of aging-associated miRNAs, originally encoded by nuclear DNA, relocate to mitochondria, manifesting a mitochondria-specific presence. Additionally, mitochondria themselves house miRNAs encoded by mitochondrial DNA (mtDNA). These mitochondria-residing miRNAs, collectively referred to as mitochondrial miRNAs (mitomiRs), have been shown to influence mtDNA transcription and protein synthesis, thereby impacting mitochondrial functionality and cellular behavior. Recent studies suggest that mitomiRs serve as critical sensors for cellular senescence, exerting control over mitochondrial homeostasis and influencing metabolic reprogramming, redox equilibrium, apoptosis, mitophagy, and calcium homeostasis-all processes intimately connected to senescence. This review synthesizes current findings on mitomiRs, their mitochondrial targets, and functions, while also exploring their involvement in cellular aging. Our goal is to shed light on the potential molecular mechanisms by which mitomiRs contribute to the aging process.

Mitochondrial DNA editing in potato through mitoTALEN and mitoTALECD: molecular characterization and stability of editing events

BackgroundThe aim of this study was to evaluate and characterize the mutations induced by two TALE-based approaches, double-strand break (DSB) induction by the FokI nuclease (mitoTALEN) and targeted base editing by the DddA cytidine deaminase (mitoTALECD), to edit, for the first time, the mitochondrial genome of potato, a vegetatively propagated crop. The two methods were used to knock out the same mitochondrial target sequence (orf125).ResultsTargeted chondriome deletions of different sizes (236–1066 bp) were induced by mitoTALEN due to DSB repair through ectopic homologous recombination of short direct repeats (11–12 bp) present in the target region. Furthermore, in one case, the induced DSB and subsequent repair resulted in the amplification of an already present substoichiometric molecule showing a 4288 bp deletion spanning the target sequence. With the mitoTALECD approach, both nonsense and missense mutations could be induced by base substitution. The deletions and single nucleotide mutations were either homoplasmic or heteroplasmic. The former were stably inherited in vegetative offspring.ConclusionsBoth editing approaches allowed us to obtain plants with precisely modified mitochondrial genomes at high frequency. The use of the same plant genotype and mtDNA region allowed us to compare the two methods for efficiency, accuracy, type of modifications induced and stability after vegetative propagation.

Modification of a natural diterpene and its antitumor mechanism: Promoting apoptosis, suppressing migration, and inhibiting angiogenesis

The synthesis or derivation of a series of structural analogues based on natural products is a common strategy for discovering antitumor drugs. As a unique natural diterpene derived from Trigonostemon howii, 3,4-seco-sonderianol (1) exhibited moderate cytotoxic effects. To improve the activity, a new diterpene derivative (1b) with a mitochondrial targeting function was synthesized by coupling triphenylphosphine to compound 1. Compared to the parent molecule, the antitumor activity of 1b increased greatly. A series of mechanistic experiments revealed that compound 1b induced cancer cell apoptosis and inhibited cancer cell migration by targeting the mitochondria and regulating the STAT3 and FAK signaling pathways. Meanwhile, 1b was found to inhibit angiogenesis in a transgenic zebrafish model. It is worth noting that 1b also demonstrated excellent antitumor effects in zebrafish tumor xenotransplantation models. All the evidence supports that compound 1b targeting mitochondria has the potential to be a candidate for an antitumor drug.

2',3' cyclic nucleotide 3' phosphodiesterase 1 functional isoform antagonizes HIV-1 particle assembly.

IFN-stimulated gene 2',3' cyclic nucleotide 3' phosphodiesterase (CNP) comprises two isoforms: the short CNP1 and the long CNP2, featuring an additional N-terminal segment of 20 amino acids (N20aa) proposed as a mitochondrial targeting sequence. Notably, CNP1 can be produced by cleaving the N20aa segment from CNP2. Although previous investigations have recognized the HIV-1 particle assembly impairment capability of CNP2, the antiviral activity of CNP1 remains ambiguous. Our study clarifies that CNP1, as opposed to CNP2, serves as the primary isoform exerting anti-HIV-1 activity. Both CNP1 and CNP2 can localize to the cell membrane, but the N20aa segment of CNP2 impedes CNP2-HIV-1 Gag interaction. Cleavage of the N20aa segment from CNP2 results in the formation of a functional, truncated form known as CNP1. Intriguingly, this posttranslational processing of CNP2 N20aa occurs within the cytoplasmic matrix rather than the mitochondria. Regulated by CTII motif prenylation, CNP1 proteins translocate to the cell membrane and engage with HIV-1 Gag. In conclusion, our findings underscore the pivotal role of posttranslational modification in governing the inhibitory potential of CNP in HIV-1 replication.

Structural determinants of mitochondrial STAT3 targeting and function

Signal transducer and activator of transcription (STAT) 3 has been found within mitochondria in addition to its canonical role of shuttling between cytoplasm and nucleus during cytokine signaling. Mitochondrial STAT3 has been implicated in modulation of cellular metabolism, largely through effects on the respiratory electron transport chain. However, the structural requirements underlying mitochondrial targeting and function have remained unclear. Here, we show that mitochondrial STAT3 partitions between mitochondrial compartments defined by differential detergent solubility, suggesting that mitochondrial STAT3 is membrane associated. The majority of STAT3 was found in an SDS soluble fraction copurifying with respiratory chain proteins, including numerous components of the complex I NADH dehydrogenase, while a minor component was found with proteins of the mitochondrial translation machinery. Mitochondrial targeting of STAT3 required the amino-terminal domain, and an internal linker domain motif also directed mitochondrial translocation. However, neither the phosphorylation of serine 727 nor the presence of mitochondrial DNA was required for the mitochondrial localization of STAT3. Two cysteine residues in the STAT3 SH2 domain, which have been previously suggested to be targets for protein palmitoylation, were also not required for mitochondrial translocation, but were required for its function as an enhancer of complex I activity. These structural determinants of STAT3 mitochondrial targeting and function provide potential therapeutic targets for disrupting the activity of mitochondrial STAT3 in diseases such as cancer.

Engineered triphenylphosphonium-based, mitochondrial-targeted liposomal drug delivery system facilitates cancer cell killing actions of chemotherapeutics.

In addition to their classical role in ATP generation, mitochondria also contribute to Ca2+ buffering, free radical production, and initiation of programmed cell death. Mitochondrial dysfunction has been linked to several leading causes of morbidity and mortality worldwide including neurodegenerative, metabolic, and cardiovascular diseases as well as several cancer subtypes. Thus, there is growing interest in developing drug-delivery vehicles capable of shuttling therapeutics directly to the mitochondria. Here, we functionalized the conventional 10,12-pentacosadiynoic acid/1,2-dimyristoyl-sn-glycero-3-phosphocholine (PCDA/DMPC)-based liposome with a mitochondria-targeting triphenylphosphonium (TPP) cationic group. A fluorescent dansyl dye (DAN) group was also included for tracking mitochondrial drug uptake. The resultant PCDA-TPP and PCDA-DAN conjugates were incorporated into a 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)-based lipid bilayer, and these modified liposomes (Lip-DT) were studied for their cellular toxicity, mitochondrial targeting ability, and efficacy in delivering the drug Doxorubicin (Dox) to human colorectal carcinoma (HCT116) and human breast (MCF7) cancer cells in vitro. This Lip-DT-Dox exhibited the ability to shuttle the encapsulated drug to the mitochondria of cancer cells and triggered oxidative stress, mitochondrial dysfunction, and apoptosis. The ability of Lip-DT-Dox to trigger cellular toxicity in both HCT116 and MCF7 cancer cells was comparable to the known cell-killing actions of the unencapsulated drug (Dox). The findings in this study reveal a promising approach where conventional liposome-based drug delivery systems can be rendered mitochondria-specific by incorporating well-known mitochondriotropic moieties onto the surface of the liposome.

Exploring mitochondrial targeting: an innovative fluorescent probe reveals Nernstian potential and partitioning combination.

This study introduces a paradigm-shifting approach to optimize mitochondrial targeting. Employing a new fluorescent probe strategy, we unravel a combined influence of both Nernst potential (Ψ) and partitioning (P) contributions. Through the synthesis of new benz[e]indolinium-derived probes, our findings redefine the landscape of mitochondrial localization by optimizing the efficacy of mitochondrial probe retention in primary cortical neurons undergoing normoxia and oxygen-glucose deprivation. This methodology not only advances our understanding of subcellular dynamics, but also holds promise for transformative applications in biomedical research and therapeutic development.

Vanadium(V) complexes derived from triphenylphosphonium and hydrazides: cytotoxicity evaluation and interaction with biomolecules.

The development of coordination compounds with antineoplastic therapeutic properties is currently focused on non-covalent interactions with deoxyribonucleic acid (DNA). Additionally, the interaction profiles of these compounds with globular plasma proteins, particularly serum albumin, warrant thorough evaluation. In this study, we report on the interactions between biomolecules and complexes featuring hydrazone-type imine ligands coordinated with vanadium. The potential to enhance the therapeutic efficiency of these compounds through mitochondrial targeting is explored. This targeting is facilitated by the derivatization of ligands with triphenylphosphonium groups. Thus, this work presents the synthesis, characterization, interactions, and cytotoxicity of dioxidovanadium(V) complexes (C1-C5) with a triphenylphosphonium moiety. These VV-species are coordinated to hydrazone-type iminic ligands derived from (3-formyl-4-hydroxybenzyl)triphenylphosphonium chloride ([AH]Cl) and aromatic hydrazides ([H2L1]Cl-[H2L5]Cl). The structures of the five complexes were elucidated through single-crystal X-ray diffraction and vibrational spectroscopies, confirming the presence of dioxidovanadium(V) species in various geometries with degrees of distortion (τ = 0.03-0.50) and highlighting their zwitterionic characteristics. The molecular structural stability of C1-C5 in solution was ascertained using 1H, 19F, 31P, and 51V-nuclear magnetic resonance. Moreover, their interactions with biomolecules were evaluated using diverse spectroscopic methodologies and molecular docking, indicating moderate interactions (Kb ≈ 104 M-1) with calf thymus DNA in the minor groove and with human serum albumin, predominantly in the superficial IB subdomain. Lastly, the cytotoxic potentials of these complexes were assessed in keratinocytes of the HaCaT lineage, revealing that C1-C5 induce a reduction in metabolic activity and cell viability through apoptotic pathways.

Metabolomics approach for the etiopathogenesis of polycystic ovarian syndrome

Polycystic ovary syndrome (PCOS) is a complex and multifaceted disorder that has been extensively studied from various angles, including genomics, metabolomics, and other multiomics approaches. This narrative review seeks to provide an updated understanding of PCOS, with a particular focus on metabolomics. PCOS encompasses four primary phenotypes: Classic PCOS with or without polycystic ovary morphology, ovulatory PCOS, and non-hyperandrogenic PCOS. Each phenotype exhibits distinct clinical and biochemical characteristics. Classic PCOS, characterized by hyperinsulinemia, insulin resistance (IR), and metabolic complications, has garnered significant attention in recent studies. In the pursuit of unraveling PCOS’s pathophysiology, researchers have embraced a multiomics approach, exploring the genome, epigenome, transcriptome, exosomes, proteome, and metabolome. The genomic landscape of PCOS includes genes related to androgen synthesis, regulation, insulin receptors, and growth factors, among others. Epigenetic mechanisms have also been investigated, revealing the roles of non-coding RNA, histone acetylation, and deacetylation. Transcriptomic biomarkers and mitochondrial RNAs targets, such as miR-9 and miR-32, have been explored in granulosa cells of PCOS patients. Metabolomics studies have identified various biomarkers and metabolic pathways that differentiate PCOS from healthy individuals. A diverse range of alterations in carbohydrate and lipid metabolism has been observed, shedding light on the underpinnings of PCOS-related metabolic dysfunction. These studies have uncovered numerous biomolecules with potential relevance to PCOS, including kininogen 1, cytoketatin 9, and many others. In addition, the intricate relationships between IR, inflammation, and metabolic factors have been elucidated. Recent research extends beyond high-end research centers, even using urine samples to identify metabolomic markers for PCOS. This approach has led to the discovery of distinct biomarker panels related to metabolic pathways that differentiate PCOS from healthy subjects. In summary, PCOS is a complex and heterogeneous condition, with multiomics studies offering promising avenues for a deeper understanding of its pathophysiology. These studies may ultimately provide valuable insights that can revolutionize the diagnosis and treatment of PCOS, ending a centurylong scientific expedition with a crescendo of discoveries.