Reactive Oxygen Species Generation Research Articles

A straightforward strategy to modulate ROS generation of AIE photosensitizers for type-I PDT

Type-I photodynamic therapy (PDT), valued for its reduced oxygen requirement, generates highly cytotoxic •OH radicals. However, conventional strategies for developing type-I photosensitizers (PSs) are complex and involve intricate organic synthesis. Herein, we present a novel strategy to alter the generation of reactive oxygen species (ROS) by simply manipulating the twisting degree of donor–acceptor (D−A) type aggregation-induced emission (AIE) PSs. Specifically, natural saturated fatty acids are employed to modulate the twisting state of AIE PSs, with higher doping ratios yielding more twisted structures and increased type-I ROS generation. In contrast, fatty acids with higher crystallinity promote planar structures and type-II ROS generation. Theoretical calculations suggest that AIE PSs with highly twisted structures lead to a prominent reduction in ΔEST and effective separation of electron−hole pairs, thereby favoring efficient intersystem crossing and charge transfer. The PDT system primarily driven by type-I ROS exhibits efficient bactericidal activity against clinically drug-resistant bacteria, which remarkably accelerates the recovery of bacteria-infected wounds in mice. This study demonstrates the first example of modulating ROS generation type by manipulating the twisting degree of D−A type AIE PSs, eliminating the need for intricate molecular design and organic synthesis. The proposed strategy opens up new avenues for advancing PDT applications.

Cellular calcium handling and electrophysiology are modulated by chronic physiological pacing in human induced pluripotent stem cell-derived cardiomyocytes.

Electric pacing of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) has been increasingly used to simulate cardiac arrhythmias in vitro and to enhance cardiomyocyte maturity. However, the impact of electric pacing on cellular electrophysiology and Ca2+ handling in differentiated hiPSC-CM is less characterized. Here we studied the effects of electric pacing for 24 h or 7 days at a physiological rate of 60 beats/min on cellular electrophysiology and Ca2+ cycling in late-stage, differentiated hiPSC-CM (>90% troponin+, >60 days postdifferentiation). Electric culture pacing for 7 days did not influence cardiomyocyte cell size, apoptosis, or generation of reactive oxygen species in differentiated hiPSC-CM compared with 24-h pacing. However, epifluorescence measurements revealed that electric pacing for 7 days improved systolic Ca2+ transient amplitude and Ca2+ transient upstroke, which could be explained by elevated sarcoplasmic reticulum Ca2+ load and SERCA activity. Diastolic Ca2+ leak was not changed in line-scanning confocal microscopy, suggesting that the improvement in systolic Ca2+ release was not associated with a higher open probability of ryanodine receptor (RyR)2 during diastole. Whereas bulk cytosolic Na+ concentration and Na+/Ca2+ exchanger (NCX) activity were not changed, patch-clamp studies revealed that chronic pacing caused a slight abbreviation of the action potential duration (APD) in hiPSC-CM. We found in whole cell voltage-clamp measurements that chronic pacing for 7 days led to a decrease in late Na+ current, which might explain the changes in APD. In conclusion, our results show that chronic pacing improves systolic Ca2+ handling and modulates the electrophysiology of late-stage, differentiated hiPSC-CM. This study might help to understand the effects of electric pacing and its numerous applications in stem cell research including arrhythmia simulation.NEW & NOTEWORTHY Electric pacing is increasingly used in research with human induced pluripotent stem cell cardiomyocytes (hiPSC-CM), for example to simulate arrhythmias but also to enhance maturity. Therefore, it is mandatory to understand the effects of pacing itself on cellular electrophysiology in late-stage, matured hiPSC-CM. This study provides an electrophysiological characterization of the effects of chronic electric pacing at a physiological rate on differentiated hiPSC-CM.

Insulin oxidation and oxidative modifications alter glucose uptake, cell metabolism, and inflammatory secretion profiles

Insulin participates in glucose homeostasis in the body and regulates glucose, protein, and lipid metabolism. Chronic hyperglycemia triggers oxidative stress and the generation of reactive oxygen species (ROS), leading to oxidized insulin variants. Oxidative protein modifications can cause functional changes or altered immunogenicity as known from the context of autoimmune disorders. However, studies on the biological function of native and oxidized insulin on glucose homeostasis and cellular function are lacking. Native insulin showed heterogenous effects on metabolic activity, proliferation, glucose carrier transporter (GLUT) 4, and insulin receptor (INSR) expression, as well as glucose uptake in cell lines of five different human tissues. Diverse ROS compositions produced by different gas plasma approaches enabled the investigations of variously modified insulin (oxIns) with individual oxidative post-translational modification (oxPTM) patterns as identified using high-resolution mass spectrometric analysis. Specific oxIns variants promoted cellular metabolism and proliferation in several cell lines investigated, and nitrogen plasma emission lines could be linked to insulin nitration and elevated glucose uptake. In addition, insulin oxidation modified blood glucose levels in the chicken embryos (in ovo), underlining the importance of assessing protein oxidation and function in health and disease.

Antibiofilm and antivirulence efficacy of Pleurotus platypus methanolic extract against Staphylococcus aureus through ROS generation and cell membrane disruption

Multi-drug resistance is recognized as a significant worldwide public health concern in the current century. Biofilm formation further exacerbates bacterial resistance to antibacterial medications, host immunological responses, and phagocytosis, resulting in long-lasting chronic illnesses. Investigating natural resources is a very potent approach for developing alternative anti-infective medications to effectively control multi-drug resistant bacterial infections. In this study, a unique mushroom species namely Pleurotus platypus had been discovered from the Terai-Duars region of West Bengal, India. The myco-chemical profiling and preliminary chemical analysis of Pleurotus platypus methanolic extract determined the significant presence of metabolites belonging to several major chemical classes such as flavonoid, alkaloid, triterpenoid, polyphenol, benzoic acids, coumarin, flavone etc. Most intriguingly, the extract possessed effective antibacterial, antibiofilm and antivirulence properties against Staphylococcus aureus and Methicillin resistant Staphylococcus aureus, one of the most notable drug-resistant opportunistic and nosocomial pathogens. Mechanistically, the mushroom extract enhanced the production of Reactive Oxygen Species (ROS) inside the targeted bacteria, causing alterations in membrane potential, damage to the cellular membrane and further release of intracellular DNA, destined to cell death. Moreover, the methanolic extract reported the eradication of pre-existing biofilms from the urinary catheter surface, hinting towards its future application in the related field. To summarize, Pleurotus platypus methanolic extract could be an excellent alternative antibacterial and antibiofilm therapeutic candidate for the effective management of Staphylococcus infections with improved outcome.

Metformin (The Miracle Drug) Kinetics in Different Diseases such as Cancer

: Metformin, a miracle drug that was introduced a century ago, could be considered for various aspects of diseases such as diabetes (type 1 and 2), cancer prevention or chemotherapy, metabolic and neurodegenerative disease. It is well known that the frequency of cancer is higher in patients with type 2 diabetes mellitus. This review aims to provide updated information regarding clinical pharmacokinetics and the mechanism of action of Metformin in different diseases such as cancer. Diabetes type 1 is another chronic autoimmune disease detected usually in early childhood due to immune-mediated devastation of insulin-producing pancreatic beta-cells. Because of the lack of effective therapeutic approaches, its prevalence is increasing. Regarding cancer, an estimated 19.3 million new cancer cases and almost 10.0 million cancer deaths were reported in 2020 worldwide. By 50-60% bioavailability, the main route of metformin excretion is through urine. Its mechanism of action is based on 1) initiation of adenosine monophosphate-activated kinase, 2) block proinflammatory paths in perivascular adipose tissue, 3) decrease in monocyte-to-macrophage differentiation in vascular tissues, and 4) improvement in endothelial function. Metformin induces adenosine monophosphate-activated protein kinase signaling and suppresses gluconeogenesis. Antitumor properties of Metformin include a decrease in reactive oxygen species generation and inducing autophagy. In addition to glucose-lowering effects, Metformin has moderate anti-inflammatory and antioxidative effects. It could improve lipid profile and reduce overweight individuals' body mass and arterial blood pressure. In type 1 diabetes, Metformin reduces the requirement for daily insulin and improves glycemia. Its long-term use decreases cardiovascular events. In addition to inhibiting the synthesis of lipids via a reduction in oxidative stress, Metformin inhibits inflammation and increases energy metabolism. Finally, by reducing micro- and macro-vascular consequences, mortality-related diabetes and cancer decline by metformin administration. Therefore, in addition to diabetes, Metformin could reduce the proliferation of cancer cells and the possibility of malignancies in different types of cancer.

Influence mechanism of divalent metals in the laminates of M2+Al-layered double hydroxides on peroxymonosulfate activation reaction pathway: Radical vs nonradical

Radical and nonradical reaction pathways have been commonly validated in peroxymonosulfate (PMS) based advanced oxidation progresses (AOPs) using layered double hydroxides (LDHs) as catalysts, but achieving efficient and selective degradation of organic pollutants remains challenging due to the unclear regulatory mechanism of laminate M2+ in PMS activation. Here, the d-orbital electrons configuration of M2+ was found to influence the degree of overlap between M−OH and O of PMS, which results in the selective dissociation of PMS to form reactive oxygen species (ROS) or achieve electron transfer pathway. Further analysis revealed that Co(II, 3d7) and Ni(II, 3d8) with filled 3d orbital electrons can serve as electron donors for PMS, leading to the cleavage of O–O bond and the efficient generation of radical-based ROS. In contrast, Mg(II, 3d0) with unfilled 3d orbital electrons and Zn(II, 3d10) with full filled 3d orbital electrons tend to act as electron shuttles, and the outermost orbitals substantially overlap with the O of PMS to form metastable complexes. Consequently, MgAl-LDH interacts with PMS to selectively degrade quinolones as electron donor through electron transfer pathway, and its performance was not inhibited by common anions and organic matter in actual water. The above results provide a basis for optimizing the design of LDH-based catalysts according to the type of laminate M2+ to achieve high selectivity and efficiency of PMS-AOPs in water purification applications.

New insights into the PFAS defluorination performance and mechanism of ultrasound-enhanced electrochemistry with peroxydisulfate electrolyte

Ultrasound (US)-assisted electrochemical oxidation (EO) has previously demonstrated its ability to degrade perfluorooctanoic acid (PFOA). However, the mechanisms of direct electron transfer and indirect oxidation by reactive oxygen species (ROS), as well as the involvement of these ROS, are unclear, particularly with the peroxydisulfate (PDS) electrolyte and the added effect of US. In this study, an US/EO/PDS system was first investigated, achieving nearly 100 % and 80.01 % defluorination for PFOA and perfluorooctane sulfonate, respectively (within 3 h). This US/EO/PDS system exhibited remarkable stability, pH tolerance, and practicality. Further experimental and theoretical studies revealed that the predominant mechanism of PFOA defluorination was indirect oxidation via ROS, rather than direct oxidation at the anode. Although none of these ROS could initiate the degradation of PFOA without additional energy, both ROS (SO4∙- ＞ •OH ＞ 1O2 ＞ O2∙-) and US/EO contributed to the initial step of PFOA defluorination. Furthermore, US enhanced the generation of ROS and the direct oxidation (electron transfer) ability of EO. The electrons were transferred from PFOA to PDS via the electrode assembly. This study clarified, for the first time, the synergistic effect of US/EO/PDS and the involvement of direct and indirect ROS oxidation in defluorination of PFOA, which shows potential for developing US and EO technology for complete degradation of polyfluoroalkyl substances.

Redox Imbalance and Cardiovascular Pathogenesis: Exploring the Therapeutic Potential of Phytochemicals

Abstract: The intriguing role of the oxidation system in cardiovascular disease lies in its contribution to chronic and acute increases in intracellular reactive oxygen species (ROS), driving the progression of cardiovascular diseases (CVDs). ROS, produced as by-products of oxidative physiological and metabolic events, act as mediators in various signaling pathways contributing to cardiovascular pathology. The delicate equilibrium between the production of free radicals and antioxidant defense shifts in favor of the former, resulting in redox imbalance and extensive cellular damage. Among CVDs, coronary artery disease (CAD) remains as the leading cause of death globally. Understanding the significance of oxidative damage in the dysfunction of endothelial cells, atherosclerosis, and other pathogenic events and pathways is crucial for preventing and managing CVD. Consequently, it is imperative to comprehend the mechanism/s underlying the pathogenic alterations of CVD due to oxidative damage to develop effective prevention strategies. Many studies have reported bioactive phytochemical/s as potential therapies against CVDs, modulating ROS generation, controlling the CVD-related inflammatory mediators and protecting the vascular system. Therefore, this review provides an update for understanding how the phytoconstituents exhibit preventive roles in oxidative stress-related CVD, thus improving the quality of life of people. This study conducted a thorough literature search on CVD, oxidative imbalance, and phytoconstituents. The search was performed using multiple search engines and the main keywords, and only English publications until June 2023 were included. However, there is a need for more research and clinical trials to fully elucidate the efficacy and safety of these phytochemicals for managing the disease.

Self-adaptive carbon nanozyme regulation of ROS balance for bacteria-infected wound therapy

Nanozymes sterilizing drug-resistant (DR) bacteria by generating reactive oxygen species (ROS) have emerged as a promising approach for treating infected wounds. However, designing biocompatible adaptive ROS balance therapeutic platform for DR bacteria-infected wounds remains a great challenge. Herein, biocompatible lignin-based carbon dot nanomaterials (LCDs-OA) with more CO and COOH functional groups on the surface were prepared by hydrothermal organic acid co-processing and used as a dual enzyme-like active nanozyme for the therapy of wounds infected by DR bacteria. Experimental and theoretical calculations demonstrated that the CO and COOH functional groups in LCDs-OA have site-switching roles in the dual enzyme-like activity, which can balance reactive oxygen species (ROS) according to the changes in microenvironmental pH at the wound site, and realize the adaptive regulation of ROS generation for bactericidal and ROS scavenging for healing. Furthermore, the performance differences between different organic acid treatments were investigated and an adaptive ROS balance therapeutic platform (LCDs-OA@CaO2) was constructed to overcome the major limitation in treating DR bacterial infected wounds. The system achieved >99.6 % in vitro antimicrobial efficiency against DR bacteria and was highly biocompatible while effectively reducing oxidative damage to normal tissues, resulting in satisfactory therapeutic results in repairing wounds infected with DR bacteria.

Molecular insights into the degradation of organic matter from secondary swine wastewater effluent: A comparative study of advanced oxidation processes

Advanced oxidation processes (AOPs) are promising for the treatment of secondary swine wastewater effluents, however, the molecular-level understanding of effluent organic matter (EfOM) removal and transformation during AOPs is limited. This study employed molecular-level characterization based on Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) and bulk characterizations to investigate these processes in various AOPs, including Cu-Fenton, UV-Cu-Fenton, Fenton, UV-Fenton, and UV/H2O2 treatments. Our findings revealed that the removal rates of dissolved organic carbon and EfOM molecules follow the sequence of UV-Fenton > Fenton > UV-Cu-Fenton > UV/H2O2 > Cu-Fenton, correlating with the rates of H2O2 decomposition during reactions. AOPs with faster H2O2 decomposition, indicative of higher reactive oxygen species generation, predominantly mineralize rather than transform EfOM. Linkage analysis highlighted oxygen addition and deamination as the primary transformation reactions, with variations in the dominance levels of these reactions across different AOPs. Recalcitrant molecule, particularly CHNO and CHO types, including low-molecular-weight carboxyl-rich alicyclic molecules, pose challenges in treatment. To enhance the efficacy of secondary effluent treatment, strategies focusing on the targeted removal of such recalcitrant EfOM should be developed. This study provided new insights into the selection and optimization of AOPs for secondary swine wastewater effluent treatment.

Oxygen-Bonded Amorphous Transition Metal Dichalcogenides with pH-Responsive Reactive Oxygen Biocatalysis for Combined Antibacterial and Anti-inflammatory Therapies in Diabetic Wound Healing.

Diabetic wound healing is a formidable challenge, often complicated by biofilms, immune dysregulation, and hindered vascularization within the wound environments. The intricate interplay of these microenvironmental factors has been a significant oversight in the evolution of therapeutic strategies. Herein, the design of an efficient and versatile oxygen-bonded amorphous transition metal dichalcogenide biocatalyst (aRuS-Or) with pH-responsive reactive oxygen biocatalysis for combined antibacterial and anti-inflammatory therapies in promoting diabetic wound healing is reported. Leveraging the incorporation of Ru─O bonds, aRuS-Or exhibits optimized adsorption/desorption behavior of oxygen intermediates, thereby enhancing both the reactive oxygen species (ROS) generation activity in acidic conditions and ROS scavenging performance in neutral environments. Remarkably, aRuS-Or demonstrates exceptional bactericidal potency within infected milieus through biocatalytic ROS generation. Beyond its antimicrobial capability, post-eradication, aRuS-Or serves a dual role in mitigating oxidative stress in inflammatory wounds, providing robust cellular protection and fostering an M2-phenotype polarization of macrophages, which is pivotal for accelerating the wound repair process. The findings underscore the multifaceted efficacy of aRuS-Or, which harmoniously integrates high antibacterial action with anti-inflammatory and pro-angiogenic properties. This triad of functionalities positions aRuS-Or as a promising candidate for the comprehensive management of complex diabetic ulcers, addressing the unmet needs in the current therapeutics.

Strength in Numbers: A Giant NIR-II AIEgen with One-for-All Phototheranostic Features for Exceptional Orthotopic Bladder Cancer Treatment.

One-for-all phototheranostics that allows the simultaneous implementations of multiple optical imaging and therapeutic modalities by utilizing a single component, is growing into a sparkling frontier in cancer treatment. Of particular interest is phototheranostic agent with emission in the second near-infrared (NIR-II) window. Nevertheless, the practical uses of those conventional NIR-II agents are severely impeded by their unsatisfactory features including insufficient stability, low synthetic yield, to be extended absorption/ emission wavelengths, and inefficient phototheranostic outcomes. Developing exceptional phototheranostic agents is thus highly desirable yet remains formidably challenging. Herein, we synthesized two novel N-heteroacenes-based NIR-II luminogens, namely 2TT-PPT and 4TT-PBPT, by respectively employing pyrene-fused phenaziothiadiazoles and pyrene-fused bisphenaziothiadiazoles as acceptor skeletons. There is strength in numbers by increasing the fusing rings in N-heteroacenes moieties and numbers of appended donors. Compared to less ring-fused 2TT-PPT, the giant molecule 4TT-PBPT shows improved photophysical characteristics, such as enhanced light absorbance, red-shifted wavelengths, higher brightness, favorable reactive oxygen species (ROS) generation, and elevated photothermal conversion efficiency, which render 4TT-PBPT nanoparticles excellent fluorescence-photoacoustic-photothermal trimodal imaging guided photodynamic-photothermal synergistic therapy for orthotopic bladder cancer.

A DNAzyme-Based Nanohybrid for Ultrasound and Enzyme Dual-Controlled mRNA Regulation and Combined Tumor Treatment.

Despite the significant potential of RNA-cleaving DNAzymes for gene regulation, their application is limited by low therapeutic efficacy and lack of cell-specific control. Here, a DNAzyme-based nanohybrid designed for ultrasound (US)-controlled, enzyme-activatable mRNA regulation is presented, enabling tumor cell-selective combination therapy. The nanohybrid is constructed by coordination-directed self-assembly of an enzymatically-triggerable therapeutic DNAzyme (En-Dz) and natural sonosensitizer hemoglobin (Hb). Controlled US exposure induces reactive oxygen species generation from Hb units, which not only facilitates efficient endosomal escape of En-Dz, but also promotes the translocation of specific enzyme from the nucleus to the cytoplasm, thereby enhancing gene regulation efficacy. Notably, the enzyme-triggered, spatiotemporally-controlled activation of En-Dz's catalytic activity results in enhanced cancer-cell selectivity in the therapeutic treatment. Furthermore, the combination of enzyme-activated mRNA regulation and sonodynamic therapy significantly enhances anti-tumor efficacy both in vitro and in vivo. This work highlights the potential of integrating a sonodynamic strategy to overcome the current limitations of DNAzyme-based gene regulators, providing a spatiotemporally-controlled approach for precise tumor treatment.

Injectable Autocatalytic Hydrogel Triggers Pyroptosis to Stimulate Anticancer Immune Response for Preventing Postoperative Tumor Recurrence.

Modulating immunosuppression while eliminating residual microscopic tumors is critical for inhibiting the postoperative recurrence of triple-negative breast cancer (TNBC). Although immunotherapy has shown potential in achieving this goal, due to multiple immunosuppression and poor immunogenicity of apoptosis, a satisfactory anti-recurrence effect still faces the challenge. Herein, an injectable hydrogel-encapsulated autocatalytic copper peroxide (CP@Gel) therapeutic platform is designed and combine it with the clinical-grade DNA methyltransferase inhibitor decitabine (DAC) to effectively inhibit TNBC growth and postoperative recurrence via pyroptosis, killing residual cancer cells that bypass apoptosis resistance while also improving immunogenicity and modulating immunosuppression to achieve an intense anti-tumor immune response. Following injection of the CP@Gel, the sustained release of CP leads to the autocatalytic generation of reactive oxygen species, resulting in caspase-3 activation, and the pre-administered DAC inhibits the methylation of Gsdme to elevate the GSDME protein levels, leading to intense pyroptosis and anti-tumor immune responses. The in vivo results show a 67% elimination of local tumor recurrence via treatment with DAC+CP@Gel, suggesting the successful integration of sustained drug release with autocatalysis and epigenetic modification. The results thus suggest great potential for pyroptosis-based and injectable hydrogel-aided strategies for preventing the postoperative recurrence of TNBC.

Programmable Plasma-Microdroplet Cascade Reactions for Multicomponent Systems.

The concept of programmable cascade reactions in charged microdroplets is introduced using carbon-carbon (C-C) bond formation via uncatalyzed Michael addition in a three-tier study culminating in programmable Hantzsch multicomponent, multistep reactions. In situ generated reactive oxygen species (ROS) from nonthermal plasma discharge are fused with charged water microdroplets (devoid of ROS) in real time for accelerated chemical reactions. This plasma-microdroplet fusion platform utilizing a coaxial spray configuration enabled product selection while avoiding unwanted side reactions. Hydrogen abstraction via ROS facilitated the formation of enolate anions without strong base use. Reaction enhancement factors >103 were calculated for plasma-microdroplet fusion versus microdroplet-only reactions. The platform programmability was showcased through (i) uncatalyzed 1,4-Michael addition of α,β-unsaturated carbonyls, (ii) novel C-C bond formation via the use of pro-electrophilic amine and alcohol substrates─activated through collisions in the microdroplet environment to serve as Michael acceptors, and (iii) selective Hantzsch cascade reaction with cross-coupling products, avoiding side reactions including N-alkylation and self-coupling product formation. Milligram quantity product collection is achieved, showcasing plasma-microdroplet fusion as an effective tool for preparative-scale synthesis. Thus, the controlled generation of ROS via plasma discharge during charged water microdroplet evolution establishes a green synthetic method for uncatalyzed C-C bond formation.

Selective Cytotoxicity and Gene Expression Profiles in Response to Methanolic Extract of Phyllanthus amarus Extract against MCF-7 Breast Cancer Cells

Background Breast cancer, a malignant tumor, is the most common cancer type among women worldwide. Conventional chemotherapy treatments for breast cancer often cause adverse side effects in normal tissues and can lead to treatment failure. Plant-derived natural compounds offer an effective alternative with fewer side effects for cancer patients. Phyllanthus amarus is a medicinal plant widely distributed in China, India, and Brazil and reported to be used for the treatment of various types of cancer. Purpose This study was aimed to investigate the anticancer efficacy of methanolic extract of P. amarus against MCF-7 breast cancer cells. Methods We probed the anticancer activity in MCF-7 breast cancer cells by isolating the methanolic extract of P. amarus leaf extract (MEPA). The standard chemotherapy drug docetaxel is combined with MEPA to increase the drug efficacy. Moreover, the intracellular reactive oxygen species (ROS), alterations in mitochondrial membrane potential (MMP), nuclear condensation, and apoptotic activation were investigated in MCF-7 cells. Additionally, the customized PCR array comprising of cell cycle, apoptosis, mTOR, and JAK-STAT-related genes was studied during different MEPA treatments. Results In the MCF-7 breast cancer cells, the MEPA and docetaxel combination demonstrated strong cytotoxicity, with IC50 values of 45 and 2.6 µg/mL, respectively. MEPA and docetaxel together exhibited enhanced alterations in MMP and increased generation of ROS in MCF-7 cells. Furthermore, the combination of docetaxel with MEPA induces nuclear condensation and apoptotic cell death. During MEPA treatment, the gene expression profiles in MCF-7 cells were accessed. The JAK-STAT, mTOR signaling pathway, apoptosis, and cell growth-related genes were strongly affected by the dose-dependent administration of MEPA. Conclusion This study suggests that MEPA could be a useful alternative treatment for breast cancer. When combined with traditional chemotherapy, MEPA might offer better results with fewer side effects. More in vivo studies are needed to confirm MEPA’s effectiveness in animal models.

MRPL44 haploinsufficient mouse spontaneously develops hypertrophic cardiomyopathy and shows systolic dysfunction after aldosterone treatment

Abstract Introduction It has been recently reported there are big differences in pathophysiological and molecular phenotypes in mouse and human hypertrophic cardiomyopathy. These differences are observed all in terms of myocyte redox, mitochondrial number and respiration, mitochondrial reactive oxygen species generation and Ca2+ handling. Therefore we should search for molecules to be able to induce similar phenotype and molecular signaling both in mice and human. Mitochondrial ribosomal large subunit 44 (MRPL44) knockout mice were embryonic lethal, for which mutations are known to cause mitochondrial infantile cardiomyopathy and hypertrophic cardiomyopathy. Purpose Our purpose is to investigate the effect of MRPL44 haploinsufficiency in mice. Methods MRPL44 haploinsufficient (MRPL44+/-) mice were generated. Mineralocorticoid receptor-associated hypertension mice were induced in MRPL44+/- and wild-type (WT, MRPL44+/+) mice with subcutaneous infusion of aldosterone(Aldo) and 8% NaCl food for 4 weeks after uninephrectomy. Systolic blood pressure was measured by tail cuffs every week. WB, qPCR, cardiac echo, and histological examinations were performed. RNA sequencing analysis, electron microscopy examinations and mitochondrial activity assay were performed to find differences between MRPL44+/- and MRPL44+/+ mice. Results MRPL44 haploinsufficient mice spontaneously developed left ventricular hypertrophy in 6 weeks old. Heart rate, blood pressure, and cardiac systolic function were normal in MRPL44 haploinsufficient mice. MRPL44 was decreased about to 70% in MRPL44 haploinsufficient mice and mitochondrial arrangement were impaired in electron microscopic analysis. After Aldo treatment, blood pressure elevation were similar, however, MRPL44 haploinsufficient mice developed left ventricular systolic dysfunction and dilation compared with MRPL44+/+ mice. WB showed mitochondrial electron transport chain protein complex IV expression was significantly decreased. Furthermore, mitochondrial activity assay showed MRPL44 haploinsufficient mice had a significant reduction in complex IV activity, whereas complex I and II activity were similar to MRPL44+/+ mice. RNA sequencing analysis showed the significant changes in the expression of ribosomal subunits coded by nucleus in addition to mitochondrial ribosomal subunits. These results indicate MRPL44 plays an important role in the cardiac function of mitochondrial electron transport chain protein complexes via the expression of ribosomal protein subunits coded by both nucleus and mitochondria. Conclusions MRPL44 haploinsufficient mice spontaneously develop left ventricular hypertrophy and shows systolic dysfunction after aldosterone treatment accompanied with oxidative phosphorylation enzyme dysfunction.

Aconitine in Synergistic, Additive and Antagonistic Approaches

Aconitine is a highly poisonous C19-diterpenoid alkaloid identified and isolated from the species of the genus Aconitum. Aconitine is indicated in the treatment of cardiovascular diseases (CVDs) and, due to its neurotoxic effects, is a very effective drug in pain release. A total of 101 relevant scientific papers were manually searched on the Web of Science, Scopus, Science Direct, Google Scholar, PubMed and Dovepress databases and in the books available in the library of the Department of Natural Sciences, the National University of Science and Technology POLITEHNICA Bucharest, Pitesti University Centre, Romania. In combination treatments, aconitine shows antiarrhythmic and anti-inflammatory activity, a synergistic antiproliferative effect and decreased reactive oxygen species (ROS) generation, an improved biodistribution and bioavailability. Additionally, the entrapment of aconitine in engineered nanoparticles represents a promising method for reducing the toxicity of this alkaloid. This review provides, for the first time, a comprehensive picture of the knowledge and research on the synergistic, additive and antagonistic effects of aconitine in combination treatments applied in vivo or in vitro. The summarized studies represent important clues in addressing the multitude of knowledge, which can find their utility in practical and clinical applications.

Aerobic exercise improves astrocyte mitochondrial quality and transfer to neurons in a mouse model of Alzheimer's disease.

Mitochondrial dysfunction is a well-established hallmark of Alzheimer's disease (AD). Despite recent documentation of transcellular mitochondrial transfer, its role in the pathogenesis of AD remains unclear. In this study, we report an impairment of mitochondrial quality within the astrocytes and neurons of adult 5 × FAD mice. Following treatment with mitochondria isolated from aged astrocytes induced by exposure to amyloid protein or extended cultivation, cultured neurons exhibited an excessive generation of reactive oxygen species and underwent neurite atrophy. Notably, aerobic exercise enhanced mitochondrial quality by upregulating CD38 within hippocampal astrocytes of 5 × FAD mice. Conversely, the knockdown of CD38 diminished astrocytic-neuronal mitochondrial transfer, thereby abolishing the ameliorative effects of aerobic exercise on neuronal oxidative stress, β-amyloid plaque deposition, and cognitive dysfunction in 5 × FAD mice. These findings unveil an unexpected mechanism through which aerobic exercise facilitates the transference of healthy mitochondria from astrocytes to neurons, thus countering the AD-like progression.

Histological and Biochemical Effects of Lutein on Paraquat-induced Renal Toxicity in Wistar Rats

Introduction: Paraquat (PQ) poisoning in humans predominantly results from the generation of reactive oxygen species (ROS). To date, no proven antidote exists for PQ poisoning, which is characterized by severe kidney injury and high mortality rates globally. However, free radical scavengers and antioxidant agents have shown potentials to mitigate PQ toxicity. Aim: The study is aimed at investigating lutein, an antioxidant, for possible mitigation of paraquat-induced renal toxicity. Study Design: Preclinical experimental study. Place and Duration of Study: Department of Anatomy, Obafemi Awolowo University (OAU), Nigeria, between 2022 and 2023. Methods: Forty wistar rats weighing 150-180 grammes were randomly grouped (A to E) for this study. Paraquat (PQ) toxicity was induced in groups B to E. Lutein was administered at graded doses of 50 mg/kg, 100 mg/kg and 150 mg/kg to groups C to E for twenty-one days respectively. Group A (positive control) was given only normal saline, while group B had paraquat only. Twenty-four hours after the last administration, urine and blood samples were collected and the animals were sacrificed before the excision of the kidneys. Results: A marked histological distortion, which was characterized by compromised Bowman's space and renal tubule dimensions, was observed in Group B. In contrast, the lutein-treated groups exhibited dose-dependent improvements, with outcomes comparable to the control group. Notably, Group B showed significant elevations in plasma creatinine (P = 0.003) and urine protein (P = 0.001), accompanied by reduced plasma protein (P = 0.004), relative to the treated groups. However, Group E, which received the highest lutein dose, demonstrated substantial improvement in histoarchitectural and biochemical findings similar to the control group." Conclusion: This study demonstrated significant alterations in the histoarchitecture and biochemical profiles of renal tissue following paraquat exposure. Notably, the lutein-treated groups exhibited substantial improvement, with results comparable to the control group. These findings suggest that lutein may possess potential therapeutic properties to mitigate paraquat-induced renal toxicity.