Oxidative stress and alterations in redox signalling have been implicated in the pathophysiology of myocardial infarction (MI). NADPH oxidase (Nox) is an important source of reactive oxygen species (ROS) in the infarcted myocardium. Alarmin S100A8/A9 amplifies acute myocardial inflammation in MI and has been shown to be a promising therapeutic target to improve cardiac function post-MI. We aimed to elucidate the underlying mechanisms linking S100A8/A9, oxidative stress and the inflammatory response in MI. MI was induced by permanent left coronary artery ligation in C57BL/6J mice, followed by treatment with the S100A8/A9 inhibitor ABR-238901 (30 mg/kg) or PBS for 3 days. The in-vivo experiments were complemented with mechanistic studies on cultured macrophages (Mac), important cellular effectors in MI. Compared to sham-operated animals, we detected significant increases in the Nox1, Nox2, Nox4 catalytic subunits at mRNA and protein levels, and NADPH-dependent ROS production in the left ventricle of MI mice. S100A8/A9 blockade prevented the up-regulation of Nox1/2/4 expression, reduced ROS formation, suppressed NF-kB activation and prevented NLRP3 inflammasome priming and activation, leading to reduced levels of active IL-1β. In-vitro, S100A8/A9 induced gene expression of Nox catalytic subtypes and NLRP3 in Mac in a TLR4-dependent and dose-dependent manner. These effects were counteracted by pharmacological inhibition of S100A8/9, TLR4, Nox1/4 and Nox2. In conclusion, we show that Nox upregulation and ROS formation triggered by S100A8/A9 contributes to NLRP3 inflammasome priming and increased IL-1β production in the infarcted myocardium. These mechanisms can be therapeutically targeted to prevent inflammatory and oxidant myocardial damage in acute MI.

The over-stimulation of N-methyl-d-aspartate glutamate receptors causes an excitotoxic neuronal death which plays an important role in many neurodegenerative diseases. Carissa edulis, a medicinal plant used in African pharmacopeia has been shown to have many therapeutic effects. In this study, the therapeutic effects of Carissa edulis aqueous extract on L-glutamic acid-induced neurotoxicity in mice were investigated. Two-month-old mice received an intraperitoneal injection of L-glutamic acid (2 g/kg) for seven consecutive days and were treated with an aqueous extract of Carissa edulis. Mice were monitored for behavioural studies including locomotion, muscle strength, and memory. Oxidative stress was determined by measuring lipid peroxidation and the level of antioxidant enzymes. Elisa kits were used to evaluate the levels of the proinflammatory cytokines. Hippocampal histopathology was examined using cresyl violet staining. Carissa edulis administration exhibited a protective effect on L-glutamic acid-induced abnormal locomotor activity and increased the mice's muscle strength. Also, it increased the memory of treated mice. Carissa edulis aqueous extract administration decreased the malondialdehyde level and increased the catalase activity and glutathione level. Furthermore, it significantly decreased the levels of IL-1β and TNF-α compared to the L-glutamic acid group. There were no significant pathological changes in the hippocampus of the Carissa edulis-treated group compared to the L-glutamic acid group. Our results indicated that Carissa edulis aqueous extract showed therapeutic effects by alleviating memory impairment, decreasing oxidative stress, and proinflammatory cytokines in the brains of mice treated with L-glutamic acid. Therefore, Carissa edulis treatment may help reduce glutamatergic neurotoxicity in neurodegenerative diseases.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder with uncleared mechanisms. Short-chain enoyl-CoA hydratase 1 (ECHS1) is a mitochondrial enzyme critical for the β-oxidation of fatty acids and ATP production. This study aims to explore the roles of ECHS1 in PD by using rotenone-induced experimental PD models.

To evaluate the role of ECHS1 in rotenone-induced dopaminergic neurodegeneration, adeno-associated virus (AAV)-ECHS1 was stereotactically injected into the substantia nigra region of mice to overexpress ECHS1. Motor function of mice among groups was detected by rotarod test and gait analysis. Neurodegeneration, mitochondrial dysfunction and apoptosis were determined by immunohistochemistry, immunofluorescence staining, Western blot or kits, respectively.

The expression and activity of ECHS1 were decreased in PD mice and positive correlations between ECHS1 reduction and dopaminergic neurodegeneration were observed. Overexpression of ECHS1 by AAV delivery attenuated loss of dopaminergic neuron and motor deficits in PD mice. Mechanistically, ECHS1 attenuated rotenone-induced mitochondrial swelling and loss of cristae as well as decrease of ATP production, mitochondrial membrane potential, complex I/IV activities and oxygen consumption rate (OCR). Mitochondrial ROS (mtROS)-targeted antioxidant mito-TEMPO prevented ECHS1 silence-mediated mitochondrial dysfunction. Furthermore, we found that ECHS1 interacted with NADPH oxidase 4 (NOX4), resulting in decrease of NOX4 activation and subsequent reduction of mtROS production and mitochondrial dysfunction. Finally, inhibition of NOX4 by GLX351322 or mtROS production by mito-TEMPO greatly reduced ECHS1 silence-mediated apoptosis in rotenone-treated SH-SY5Y cells.

ECHS1 counteracted dopaminergic neurodegeneration through inhibition of mtROS and restoration of mitochondrial function via interaction with NOX4. Given the central role of mitochondrial dysfunction in PD pathogenesis, elucidating the role of ECHS1 holds great promise for uncovering novel therapeutic targets.

Oxidative stress is a significant cause in the occurrence of cardiac insufficiency. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase2 (NOX2)-derived reactive oxygen species (ROS) play a pivotal role in oxidative stress-induced excitation-contraction decoupling. Stachydrine hydrochloride (Sta) reduces pressure overload-induced cardiac insufficiency, which may be related to the NOX2-ROS pathway, as demonstrated by our earlier research. However, the mechanism through which Sta specifically affects NOX2 remains unknown.

In order to investigate whether Sta plays a cardioprotective role by inhibiting NOX2 activity, we explored the specific mechanism by which Sta improves cardiac function by affecting NOX2-mediated oxidative stress in this study.

Molecular docking and cellular thermal shift assay (CETSA) were performed to verify whether Sta can bind to individual subunits of NOX2. We induced models of cardiac insufficiency in the compensatory phase (cardiac hypertrophy) by phenylephrine (PE) in vivo and in vitro and treated with Sta and GSK2795039 (NOX2 inhibitor). Cardiac function and structure were observed by echocardiography analysis. We detected the expression and localization of NOX2 subunits and calcium channel proteins, also detected the activities of ROS and NOX2, SOD, and GSH, and observed intracardiac calcium homeostasis and systolic-diastolic function in cardiomyocytes. Secondly, we used adenovirus and adeno-associated virus transfection for cardiac-specific overexpression of NOX2 in vivo and in vitro respectively, and also treated with Sta to observe NOX2 activation indexes and ROS levels, cardiac function and cardiomyocyte function in mice.

Prior to our investigation, we discovered that Sta could bind to NOX2 through molecular docking and CETSA. The findings demonstrated that Sta decreased the expression levels of gp91phox and p67phox, as well as the phosphorylation levels of p47phox, and by preventing p67phox and p47phox from translocating across cell membranes. NOX2 activity inhibition by Sta suppresses ROS production. Sta reduced ROS-induced oxidation of Ca2+/calmodulin protein kinase II and modulated excitatory-contractile coupling via sarcoplasmic reticulum calcium pumps. Cardiac-specific overexpression of gp91phox promotes membrane translocation of p67phox and p47phox, increases NOX2 activity, and promotes ROS generation. Sta inhibition of gp91phox overexpression reduced the membrane translocation of p67phox and p47phox, decreased NOX2 activity and oxidative stress levels, and restored excitatory-contractor-coupled myocardial function.

Our study innovatively verified the key role of NOX2 in cardiac insufficiency. Sta downgrades NOX2's activity by suppressing the protein level of gp91phox and the membrane transport of p67phox and p47phox, thereby reducing myocardial oxidative stress and playing a cardioprotective role. This study was hoped to support the possibility of Sta as a cardiac function-enhancing drug in the future.

Electrochemistry has become a key technique for studying biomolecular reactions and dynamics of living systems by using electron-transfer reactions to probe the complex interactions between biological redox molecules and their surrounding environments. To enable such measurements, redox mediators such as ferro/ferricyanide, ferrocene methanol, and tris(bipyridine) ruthenium(II) chloride are used. However, the impact of these exogeneous redox mediators on the health of cell cultures remains underexplored. Herein, we present the effects of three common redox mediators on the health of four of the most commonly used cell lines (Panc1, HeLa, U2OS, and MDA-MB-231) in biological studies. Cell health was assessed using three independent parameters: reactive oxygen species quantification by fluorescence flow cytometry, cell migration through scratch assays, and cell growth via luminescence assays. We show that as the concentration of mediator exceeds 1 mM, ROS increases in all cell types while cell viability plumets. In contrast, cell migration was only hindered at the highest concentration of each mediator. Our observations highlight the crucial role that optimized mediator concentrations play in ensuring accuracy when studying biological systems by electrochemical methods. As such, these findings provide a critical reference for selecting redox mediator concentrations for bioanalytical studies on live cells.

Rac and Rap1A are small GTPases with the redox-sensitive GX4GK(S/T)C/ECS and NKCD motif. Of the known NADPH oxidase (NOX) isoforms, NOX1 and NOX2 function with the redox-sensitive Rac. Both exhibit an oxidative burst in which superoxide production is initially lagged but then accelerated. This burst is a reflection of NOX1 and NOX2 autoactivations occurring alongside the redox-dependent Rac autoactivation. NOX2 also contains the redox-sensitive Rap1A. However, its role in NOX2 function was unknown. In this study, we show that Rap1A is also autoactivated by its redox response, which is coupled to Rac and NOX2 autoactivations. This coupling is found to be mediated through the Rap1A-dependent recruitment of the Rac GEF P-REX1 to the NOX2 system. We further show that the initiation threshold and propagation rate of Rap1A autoactivation are lower and slower, respectively, than those of Rac and NOX2. The low-threshold Rap1A autoactivation recruits P-REX1 to the NOX2 system, resulting in the production of active Rac, thereby aiding the high-threshold initiation and propagation of Rac and NOX2 autoactivations. This results in the rapid completion of the NOX2 oxidative burst, which is specific to NOX2 because NOX1 lacks Rap1A. The redox response differences between the Rap1A NKCD motif and the Rac GX4GK(S/T)C/ECS motif appear to be the basis for the feature differences between Rap1A autoactivation and those of Rac and NOX2 autoactivations. The GX4GK(S/T)C/ECS and NKCD motifs are found in many redox-sensitive Rho/Rab and Ras family GTPases, respectively. Findings here shed light on previously unknown redox-dependent functional distinctions between these small GTPases.

Mosquitoes rely on vertebrate blood for nutrients vital for ovarian development. The enzyme serine hydroxymethyltransferase (SHMT) is crucial for amino acid and one‑carbon metabolism, playing a significant role in blood digestion and nutrient use in mosquitoes, though its functional mechanism remains further investigation. Using CRISPR/Cas9 to knock out the SHMT gene, we observed impaired blood digestion, delayed ovarian development, and inability to fly in mosquitoes. Multi-omics analysis revealed that SHMT deletion affected genes and metabolites related to amino acid metabolism. Knocking down SHMT-responsive genes mitochondrial-like serine hydroxymethyltransferase (SHMTML) and ribose-phosphate pyrophosphokinase 1 (PRPS1) also hindered blood digestion and ovarian development, mirroring SHMT-deficient mosquitoes. The interaction between SHMT, SHMTML, and PRPS1 was confirmed through various experiments, including Co-IP, GST pull-down, immunofluorescence colocalization, BiFC, molecular docking, and functional studies. Further research reveals that missing any of these proteins in mosquitoes results in ammonia and reactive oxygen species buildup, leading to mitochondrial problems, midgut cell damage, and abnormal enzyme expression. This study highlights a new molecular mechanism of SHMT and emphasizes its crucial interaction with SHMTML and PRPS1 in blood digestion and nutrient metabolism in vector mosquitoes. These findings may offer a strategic foundation for the development of innovative mosquito control measures.

The recurrent breast cancer (BC) has elicited significant concern due to its rising recurrence rates and associated mortality. However, there is currently no effective detection method to mitigate the deterioration of BC recurrence. The imbalance of HClO content could lead to oxidative stress in the body, which damaging host tissues. Additional, improper regulation of HClO may exacerbate the progression of BC and promote the metastasis of BC cells. Accurately diagnosing and monitoring the HClO levels is crucial for treating BC recurrence. Traditional fluorescent probes for HClO exhibit several limitations, including poor selectivity, susceptibility to photobleaching, a small Stokes shift, and vulnerability to disturbances from excitation and fluorescence self-absorption, which undermine the precise detection of target analytes and restrict their biological applications. Herein, rational designed hypochlorous acid-activatable fluorescent probe (QPIO) was synthesized based on phenothiazine (PZ), quinoline malononitrile (QM), and hemicyanine, which demonstrated high anti-interference capability and a significant Stokes shift for HClO detection. Under various stimuli, QPIO was able to monitor HClO levels in RAW 264.7 and 4T1 cells in the red channel. Furthermore, it elucidated the correlation between HClO concentration and the progression of BC recurrence. Consequently, QPIO was utilized to diagnose recurrent BC, track therapeutic progress, and monitor the recurrence status of breast tumors in mouse models through in vivo HClO fluorescence imaging. It was demonstrated that a close relationship exists between the dynamic changes in HClO levels and BC recurrence, potentially advancing the understanding of the early diagnosis and development of therapeutic agents for recurrent BC.

Iron and copper are essential metal ions, and maintaining their metabolic balance is critical for organismal health. The Six-Transmembrane Epithelial Antigen of the Prostate (STEAP) protein family, comprising STEAP1, STEAP2, STEAP3, and STEAP4, plays a vital role in cellular metal homeostasis. These proteins are located on the cell membrane and are characterized by six transmembrane domains. With the exception of STEAP1, the STEAP proteins function as metal oxidoreductases due to their F420H2:NADP+ oxidoreductase (FNO)-like domain. However, STEAP1 contributes to metal metabolism through its heme group and interaction with other STEAP proteins. Beyond metal metabolism, STEAP proteins are involved in critical cellular processes, including the regulation of the cell cycle, proliferation, differentiation, and apoptosis. Notably, STEAP proteins are recognized as potential biomarkers and therapeutic targets in human cancers, particularly prostate cancer. This review outlines the structural features and functional roles of STEAP proteins in various diseases, including cancers, insulin resistance, non-alcoholic fatty liver disease (NAFLD), and benign prostatic hyperplasia, with a focus on their potential for therapeutic intervention.

Entomopathogenic fungi may interact with insects' symbiotic bacteria during infection. We hypothesized that topical infection with Beauveria bassiana may alter the microbiota of the Colorado potato beetle (CPB) and that these modifications may alter the course of mycoses. We used a model with two concentrations of conidia: (1) high concentration that causes rapid (acute) pathogenesis with fast mortality followed by bacterial decomposition of insects; (2) lower concentration that leads to prolonged pathogenesis ending in conidiation on cadavers. The fungal infections increased loads of enterobacteria and bacilli on the cuticle surface and in hemolymph and midgut, and the greatest increase was detected during the acute mycosis. By contrast, stronger activation of IMD and JAK-STAT signaling pathways in integuments and fat body was observed during the prolonged mycosis. Relatively stable (nonpathogenic) conditions remained in the midgut during both scenarios of mycosis with slight changes in bacterial communities, the absence of mesh and stat expression, a decrease in reactive oxygen species production, and slight induction of Toll and IMD pathways. Oral administration of antibiotic and predominant CPB bacteria (Enterobacteriaceae, Lactococcus, Pseudomonas) led to minor and mainly antagonistic effects in survival of larvae infected with B. bassiana. We believe that prolonged mycosis is necessary for successful development of the fungus because such pathogenesis allows the host to activate antibacterial reactions. Conversely, after infection with high concentrations of the fungus, the host's resources are insufficient to fully activate antibacterial defenses, and this situation makes successful development of the fungus impossible.

The allocation of resources in animals is shaped by adaptive trade-offs aimed at maximizing fitness. At the heart of these trade-offs, lies metabolism and the conversion of food resources into energy, a process mostly occurring in mitochondria. Yet, the conversion of nutrients to utilizable energy molecules (adenosine triphosphate) inevitably leads to the by-production of reactive oxygen species (ROS) that may cause damage to important biomolecules such as proteins or lipids. The 'ROS theory of ageing' has thus proposed that the relationship between lifespan and metabolic rate may be mediated by ROS production. However, the relationship is not as straightforward as it may seem: not only are mitochondrial ROS crucial for various cellular functions, but mitochondria are also actually equipped with antioxidant systems, and many extra-mitochondrial sources also produce ROS. In this review, we discuss how viewing the mitochondrion as a regulator of cellular oxidative homeostasis, not merely a ROS producer, may provide new insights into the role of oxidative stress in the reproduction-survival trade-off. We suggest several avenues to test how mitochondrial oxidative buffering capacity might complement current bioenergetic and evolutionary studies.

Cyclosporine A (CsA) is a powerful immunosuppressant commonly used as a prophylaxis on transplant. However, it is associated with serious effects, including cardiotoxicity. Curcumin is a bioactive compound known for its anti-oxidative, anti-inflammatory, and anti-apoptotic effects. So, the present study investigated the possible protective effect of curcumin on CsA-induced heart injury in rats, focusing on oxidative stress, autophagy, and apoptosis.

A total of 32 male Wistar rats were divided into control, sham (drug solvent), CsA (30 mg/kg BW), and curcumin + CsA (40 mg/kg BW, 30 mg/kg BW, respectively) groups. After 4 weeks of treatment, the heart was isolated for molecular assays. Immunoblot detected oxidative and autophagic proteins NOX4, hsp-70, beclin-1, and LC3II. The amount of 8-OHdG was measured by ELISA and heart apoptosis was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining (TUNEL).

At the molecular levels, CSA increased the expression of NOX-4, beclin-1, LC3b, and oHdG in heart tissue. In addition, the amount of apoptosis increased in the heart tissue. However, curcumin treatment improved heart injury by significantly downregulating NOX4, LC3b, and decreasing 8-OHdG. Also, curcumin significantly reduced the rate of myocardial apoptosis.

To sum up, curcumin appears to protect against CsA-induced cardiotoxicity in rats by reducing oxidative activity, apoptosis, and regulating autophagy.

Iron metabolism of neutrophils plays a vital role in neutrophil extracellular trap (NET) formation, which presents as one of the major hurdles to the immune response in the tumor microenvironment. Here, we developed a peptide-drug conjugate (PDC)-based transformable iron nanochelator (TIN) equipped with the ability to regulate the iron metabolism of neutrophils, endowing inhibition of NET formation and the ensuing immunosuppression functions. The TIN could expose the iron-binding motifs through neutrophil elastase-mediated morphological transformation from nanoparticles to β-sheet nanofibers, which further evolve into stable α-helix nanofibers after chelation with iron(II) ions. This process enables a highly specific regulation of iron(II) ions of neutrophils, which turns into an efficient way of inhibiting NET formation and improving the immune response. Furthermore, the TIN showed an improved therapeutic effect in combination with protein arginine deiminase 4 inhibitors and synergistically boosted the anti-PD-L1 treatment. This study designates an iron-regulation strategy to inhibit NET formation, which provides an alternative approach to immune modulation from the perspective of targeting the iron metabolism of neutrophils in cancer immunotherapy.

Gastric cancer is highly correlated with Helicobacter pylori (H. pylori) infection. Approximately 50 % of the population worldwide is infected with H. pylori. However, current treatment regimens face severe challenges including drug resistance and gut microbiota disruption. An integrative treatment with slight negative influences on intestinal flora, conforming with concepts of integrative prevention of gastric cancer, is urgently needed. Non-antibiotic responsive biomaterials can respond to different stimuli, including pH, enzymes, light, ultrasound and magnetism, under which biomaterials are specifically activated to perform antibacterial capabilities, while neutral intestinal microenvironments differ from gastric microenvironments or inflammatory sites and have no or minimal irradiation via precisely controlled exogenous stimuli, which may not only overcome antibiotic resistance but also avoid gut microbiota disorders. First, the latest progress in responsive biomaterials against H. pylori without gut microbiome disturbance and their anti-H. pylori performances are profoundly summarized. Second, the mechanisms against planktonic bacteria, biofilms and intracellular bacteria are discussed respectively. Finally, the strategies of specific and targeted H. pylori elimination by responsive biomaterials are introduced. Additionally, the challenges and the focus of future research on translation into clinical application are fully proposed. Antibiotic-free responsive biomaterials for specific and targeted H. pylori eradication represent an innovative approach.

Aryl hydrocarbon receptor (AHR) and nuclear factor-erythroid 2-related factor 2 (NRF2) can regulate a series of genes encoding the detoxifying phase I and II enzymes, via a signaling crosstalk known as the "AHR-NRF2 gene battery". The chromatin transcriptional regulator Jun dimerization protein 2 (JDP2) plays a central role in thetranscription of AHR gene in response to the phase I enzyme ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin. It forms a transcriptional complex with AHR-AHR nuclear translocator (ARNT) and NRF2-small musculoaponeurotic fibrosarcoma proteins (sMAF), which are then recruited to the respective cis-elements, such as dioxin response elements and antioxidant response elements, respectively, in the AHR promoter. Here, we present a revised description of the AHR-NRF2 gene battery as the AHR-NRF2-JDP2 gene battery for transactivating the AHR promoter by phase I enzyme ligands. The chromatin regulator JDP2 was found to be involved in the movement of AHR-NRF2 complexes from the dioxin response element to the antioxidant response element in the AHR promoter, during its activation in a spatiotemporal manner. This new epigenetic and chromatin remodeling role of AHR-NRF2-JDP2 axis is useful for identifying new therapeutic targets for various diseases, including immunological response, detoxification, development, and cancer-related diseases.

Plasma-activated water (PAW) has been shown to have antimicrobial properties, making it a promising tool for surface decontamination. This study evaluated the ability of PAW generated from high voltage atmospheric cold plasma to remove Salmonella from common surfaces (stainless steel (SS), polyvinyl chloride (PVC), concrete, and wood) found in poultry houses. PAW was generated by exposing distilled water to atmospheric cold plasma in 80% humid air at 90 kV and 60 Hz for 30 min. The resulting PAW contained 1120 ppm of nitrate and 1370 ppm of hydrogen peroxide, with a pH of 1.83. PAW was then applied to coupons of SS, PVC, wood, and concrete surfaces inoculated with 7-8 log10 CFU of cocktail of Salmonella spp. (S. Typhimurium, S. Newport, S. Montevideo, and S. Enteritidis). PAW effectively reduced Salmonella levels on SS and PVC surfaces to below the detection limit within 30 s. On wood surfaces, a longer treatment time of 7.5 min was required to achieve a maximum reduction of 2.63 log10 CFU, likely due to the porosity of the wood limiting PAW contact with the bacteria. On concrete surfaces, the reduction in Salmonella levels was only 0.98 log10 CFU. This was likely due to the greater surface roughness and high alkalinity, which neutralized the PAW species.

In recent years, the introduction of sodium-glucose transporter-2 inhibitors (SGLT2is) marked a significant advancement in the treatment of cardiovascular disease (CVD). Beyond their known effects on glycemic control and lipid profile, SGLT2is demonstrate notable benefits for cardiovascular morbidity and mortality, regardless of diabetic status. These agents are currently recommended as first-line therapies in patients with heart failure, both with reduced and preserved ejection fraction, as they improve symptoms and reduce the risk of hospitalization. While several studies have demonstrated that SGLT2is can reduce the incidence of major adverse cardiovascular events (MACEs), the true impact of these agents on atherosclerosis progression and myocardial ischemia remains to be fully understood. A global beneficial effect related to improved glycemic and lipid control could be hypothesized, even though substantial evidence shows a direct impact on molecular pathways that enhance endothelial function, exhibit anti-inflammatory properties, and provide myocardial protection. In this context, this narrative review summarizes the current knowledge regarding these novel anti-diabetic drugs in preventing and treating myocardial ischemia, aiming to define an additional area of application beyond glycemic control and heart failure.

Neuropathic pain, a debilitating condition arising from somatosensory system damage, significantly impacts quality of life, leading to anxiety, self-mutilation, and depression. Oxidative and nitrosative stress, an imbalance between reactive oxygen and nitrogen species (ROS/RNS) and antioxidant defenses, plays a crucial role in its pathophysiology. While reactive species are essential for physiological functions, excessive levels can cause cellular component damage, leading to neuronal dysfunction and pain. This review highlights the complex interactions between reactive species, antioxidant systems, cell signaling, and neuropathic pain. We discuss the physiological roles of ROS/RNS and the detrimental effects of oxidative and nitrosative stress. Furthermore, we explore the potential of manganese porphyrins, compounds with antioxidant properties, as promising therapeutic agents to mitigate oxidative stress and alleviate neuropathic pain by targeting key cellular pathways involved in pain. Further research is needed to fully understand their therapeutic potential in managing neuropathic pain in human and non-human animals.

Reactive oxygen species (ROS) serve as signal molecules in plant defense responses, and the respiratory burst oxidase homolog (RBOH) enzyme plays a crucial role in their production. Although numerous RBOH family members have been identified in various plants, little is known about the RBOH genes in blueberries. In this study, we identified six VcRBOH genes from the blueberry genome. Phylogenetic analysis revealed that these VcRBOH genes can be classified into three subgroups. Conserved domain and motif analysis demonstrated high sequence similarity among VcRBOH proteins. Analysis of cis-acting elements suggested that VcRBOH genes may be involved in stress, light, and phytohormone responsiveness. Based on transcriptome data, we observed low expression levels of VcRBOHB, VcRBOHC, and VcRBOHE during the flower_at_anthesis stage. In contrast, VcRBOHA and VcRBOHD showed relatively high expression levels in various tissues. The reverse-transcription quantitative PCR (RT-qPCR) analysis indicated rapid induction of VcRBOHF by flg22 and chitin treatments. Notably, overexpression of VcRBOHF in Arabidopsis promoted PTI responses, including increased expression of marker genes, ROS production, and callose deposition. Moreover, the overexpression of VcRBOHF resulted in enhanced disease resistance against Pseudomonas syringae pv. tomato (Pst) DC3000 infection. These findings provide valuable insights into the roles of VcRBOHF genes in plant defense responses and lay the groundwork for a more comprehensive understanding of the molecular mechanisms underpinning blueberry disease resistance.

Reactive oxygen species (ROS) produced by mechanically stretching cardiomyocytes is a crucial mediator to increase contractile force in accordance with the Frank-Starling law. However, excessive ROS production leads to oxidative stress, contributing to myocardial atrophic remodeling and cellular damage. NADPH oxidase, the primary enzyme responsible for ROS production localized on the plasma membrane and organelle membranes, plays a key role in membrane-oriented ROS signaling. Two isoforms of NADPH oxidase, Nox2 (constitutive) and Nox4 (inducible), are predominantly expressed in cardiomyocytes, each playing unique roles in different contexts. Recent studies have revealed that Nox proteins form protein signaling complexes with transient receptor potential (TRP) channel proteins, amplifying ROS signaling in hearts. This review presents the putative mechanism of protein-protein interaction between TRP and Nox and their pathophysiological significance in hearts and discusses therapeutic strategies targeting TRP-Nox protein interactions for the treatment of heart failure.

Gray mould caused by Botrytis cinerea, an airborne phytopathogenic pathogen, infects many economically important fruits and vegetables. Secondary metabolic products of microorganisms are potential resources for developing fungicide alternatives. Venturicidin A (VentA) is produced by a biocontrol strain Streptomyces pratensis S10. Although a broad spectrum of antifungal activity has been reported for VentA, little is known about its antifungal mechanisms against B. cinerea.

Venturicidin A exhibited a strong hyphal inhibition of B. cinerea with an EC50 (effective concentration causing 50% growth inhibition) value of 1.08 μg mL-1 on PDA medium. Different concentrations of VentA inhibited spore germination with an inhibition rate of 49-86%. Venturicidin A also displayed protective and curative activity against the development of B. cinerea infection on tomato fruit, reducing disease incidence by ≈28-78%. Additionally, VentA effectively reduced the disease index and lesion length of gray mould on tomato plant. Meanwhile, VentA downregulated the expression levels of six genes related to pathogenicity in B. cinerea. As observed by scanning electron microscopy, B. cinerea spores and hyphae are abnormal after treatment with VentA. Propidium iodide staining revealed that VentA destroyed cell membrane integrity, causing cytoplasmic leakage. Furthermore, VentA induced accumulation of reactive oxygen species and upregulated the genes encoding subunits for NADPH oxidase in B. cinerea.

This study indicated that VentA displayed strong inhibitory activity against B. cinerea and effectively reduced gray mould disease. Thus, VentA has the potential to manage gray mould caused by B. cinerea. © 2024 Society of Chemical Industry.

Neutrophils, the most abundant circulating white blood cells, are essential for the initial immune response to infection and injury. Emerging research reveals a dualistic function of neutrophils in cancer, where they can promote or inhibit tumor progression. This dichotomy is influenced by the tumor microenvironment, with neutrophils capable of remodeling the extracellular matrix, promoting angiogenesis, or alternatively inducing cancer cell death and enhancing immune responses. An intriguing yet poorly understood aspect of neutrophil-cancer interactions is the phenomenon of neutrophil engulfment by cancer cells, which has been observed across various cancers. This process, potentially mediated by LC3-associated phagocytosis (LAP), raises questions about whether it serves as a mechanism for immune evasion or contributes to tumor cell death through pathways like ferroptosis. This review examines current knowledge on neutrophil development, their roles in cancer, and the mechanisms of LAP in neutrophil engulfment by tumor cells. We discuss how manipulating LAP impacts cancer progression and may represent a therapeutic strategy. We also explore neutrophils' potential as delivery vehicles for cancer therapeutic agents. Understanding the complex functions of tumor-associated neutrophils (TANs) and the molecular mechanisms underlying LAP in cancer may open new avenues for effective therapeutic interventions and mitigate potential risks.

The Jianpi therapeutic strategy in traditional Chinese medicine aims to enhance the spleen's digestive function and overall wellness. It has shown promise in improving cancer-related fatigue (CRF). This research systematically evaluates the effectiveness of Jianpi therapy in reducing fatigue in cancer patients through a meta-analytic review.

An exhaustive search was performed within PubMed, Embase, Web of Science, Cochrane Library, SinoMed, Wanfang Data, China Science and Technology Journal Database, and China National Knowledge Infrastructure (CNKI) for randomized controlled trials concerning the application of Jianpi therapy to address CRF. The search spanned from the commencement of each database's records to April 1, 2024. The extracted data were subjected to analysis using Stata (Version 15.1), with the selection of either a random-effects or fixed-effects model based on the heterogeneity among studies. Outcome measures were demonstrated with standardized mean differences (SMDs) or mean differences (MDs), and each complemented by a 95% confidence interval (CI). The Cochrane Risk of Bias Assessment Tool 2.0 was utilized to assess the potential biases within the studies.

A comprehensive analysis was performed on 45 eligible studies, all of which were conducted within China and encompassed a total of 3,596 participants. The meta-analysis indicated that Jianpi decoction alone exhibited the most significant improvement in the proportion of CD4 cells (SMD=1.34, 95% CI 0.54 to 2.31, P<0.001) and hemoglobin (MD=7.45, 95% CI 4.18 to 10.72, Z=4.47, P<0.001), while also more significantly reducing Piper Fatigue Scale scores (SMD=-2.05, 95% CI -2.71 to -1.39, P<0.001). The combined therapy, which integrated Jianpi therapy with standard care, demonstrated the greatest advantage in enhancing the proportion of CD3 cells (SMD=1.25, 95% CI 0.46 to 2.04, P<0.001). Furthermore, Jianpi therapy was found to be effective in lowering tumor necrosis factor-alpha levels (MD=-7.79, 95% CI -11.24 to -4.34, P<0.001) and concurrently enhancing interferon-gamma (MD=5.15, 95% CI 3.20 to 7.09, P=0.002), interleukin-2 (MD=8.37, 95% CI 6.14 to 10.59, P<0.001).

Our research indicates that Jianpi therapy effectively alleviates CRF, reduces inflammation, and strengthens immune function. However, further high-quality, multicenter randomized controlled trials are essential to confirm these findings and strengthen the evidence.

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024566739.

Normal tissues typically maintain partial oxygen pressure within a range of 3-10% oxygen, ensuring homeostasis through a well-regulated oxygen supply and responsive vascular network. However, in solid tumors, rapid growth often outpaces angiogenesis, creating a hypoxic microenvironment that fosters tumor progression, altered metabolism and resistance to therapy. Hypoxic tumor regions experience uneven oxygen distribution with severe hypoxia in the core due to poor vascularization and high metabolic oxygen consumption. Cancer cells adapt to these conditions through metabolic shifts, predominantly relying on glycolysis, and by upregulating antioxidant defenses to mitigate reactive oxygen species (ROS)-induced oxidative damage. Hypoxia-induced ROS, resulting from mitochondrial dysfunction and enzyme activation, exacerbates genomic instability, tumor aggressiveness, and therapy resistance. Overcoming hypoxia-induced ROS cancer resistance requires a multifaceted approach that targets various aspects of tumor biology. Emerging therapeutic strategies target hypoxia-induced resistance, focusing on hypoxia-inducible factors, ROS levels, and tumor microenvironment subpopulations. Combining innovative therapies with existing treatments holds promise for improving cancer outcomes and overcoming resistance mechanisms.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by lipid accumulation in the liver due to an excess in their supplies or an impairment in their management. While some patients remain stable for years, a proportion of them progress up to steatohepatitis (MASH). MASLD links with systemic pathways being associated with metabolic and non-metabolic diseases. Although liver lipid accumulation represents the first hit for MASLD, the pathophysiology of its development and progression to MASH remains not completely understood. Oxidative stress has received particular attention in recent years, as most of the oxidative process occurs in the liver, which is also the target of oxidative stress-induced damage. Growing evidence linked the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) to the increased liver production of reactive oxygen species up to liver damage and fibrosis. NOX acts both in hepatocytes and in non-parenchymal hepatic cells, contributing to hepatocyte lipotoxicity, impaired hepatic microcirculation, hepatic stellate, and mesenchymal stem cells activation and proliferation. This review aims to summarize the current knowledge on the involvement of oxidative stress in the MASLD-MASH transition, focusing on the role of NOX isoforms, and to suggest targeting NOX as a therapeutic approach in MASLD.

Bone fracture ruptures blood vessels and disrupts the bone marrow, the site of new red blood cell production (erythropoiesis). Current dogma holds that bone fracture causes severe hypoxia at the fracture site, due to vascular rupture, and that this hypoxia must be overcome for regeneration. Here, we show that the early fracture site is not hypoxic, but instead exhibits high oxygen tension (> 55 mmHg, or 8%), similar to the red blood cell reservoir, the spleen. This elevated oxygen stems not from angiogenesis but from activated erythropoiesis in the adjacent bone marrow. Fracture-activated erythroid progenitor cells concentrate oxygen through haemoglobin formation. Blocking transferrin receptor 1 (CD71)-mediated iron uptake prevents oxygen binding by these cells, induces fracture site hypoxia, and enhances bone repair through increased angiogenesis and osteogenesis. These findings upend our current understanding of the early phase of bone fracture repair, provide a mechanism for high oxygen tension in the bone marrow after injury, and reveal an unexpected and targetable role of erythroid progenitors in fracture repair.

Sustained production of reactive oxygen species (ROS) and an imbalance in the antioxidant system have been implicated in the development of cardiovascular diseases (CVD), especially when combined with diabetes, hypercholesterolemia, and other metabolic disorders. Among them, NADPH oxidases (NOX), including NOX1-5, are major sources of ROS that mediate redox signaling in both physiological and pathological processes, including fibrosis, hypertrophy, and remodeling. Recent studies have demonstrated that mitochondria produce more proteins and energy in response to adverse stress, corresponding with an increase in superoxide radical anions. Novel NOX4-mediated modulatory mechanisms are considered crucial for maintaining energy metabolism homeostasis during pathological states. In this review, we integrate the latest data to elaborate on the interactions between oxidative stress and energy metabolism in various CVD, aiming to elucidate the higher incidence of CVD in individuals with metabolic disorders. Furthermore, the correlations between NOX and ferroptosis, based on energy metabolism, are preliminarily discussed. Further discoveries of these mechanisms might promote the development of novel therapeutic drugs targeting NOX and their crosstalk with energy metabolism, potentially offering efficient management strategies for CVD.

To investigate anti-Mycobacterium tuberculosis (Mtb) influences exerted by natural killer cell-derived exosomes (NK-exo) on mice and to elucidate underlying immunologic mechanisms.

We established tuberculosis (TB) model in mouse by injecting Mtb H37Ra (1 × 106 colony counting (CFU), i.v.) into tail vein for 14 days. The survival rate of Mtb was assessed through CFU, apoptosis rates were measured utilizing flow cytometry, and inflammation relief was quantified via HE staining. Expressions of apoptosis, inflammation, and pyroptosis-related proteins were quantified by Western blotting and RT-qPCR. ELISA was utilized for detecting inflammatory cytokines production. Intracellular reactive oxygen species (ROS) levels were assessed through DCFH-DA fluorescent probe assay.

NK-exo treatment reduced Mtb load in lung and spleen tissues and alleviated inflammation in mice lung tissues. NK-exo intervention increased protein levels of markers associated with apoptosis, PARP and caspase-3/8/9, downregulating the concentrations of pro-inflammatory cytokines, comprising IL-1β, TNF-α, IL-6, along with protein expressions of biomarkers, ASC, NLRP3, GSDMD, associated to inflammation and pyroptosis. NK-exo also elevated ROS levels without affecting lactate dehydrogenase (LDH) release from macrophages.

NK-exo exhibits anti-tuberculosis activity in experimental TB mice. The underlying mechanism involve regulating caspase-dependent apoptotic signaling pathway to promote cell apoptosis, as well as modulating NLRP3 signaling pathway to suppress the inflammatory response.

Parkinson's Disease (PD) is the most common neurodegenerative disorder after Alzheimer's Disease and is clinically expressed by movement disorders, such as tremor, bradykinesia, and rigidity. It occurs mainly in the extrapyramidal system of the brain and is characterized by dopaminergic neuron degeneration. L-DOPA, dopaminergic agonists, anticholinergic drugs, and MAO-B inhibitors are currently used as therapeutic agents against PD, however, they have only symptomatic efficacy, mainly due to the complex pathophysiology of the disease. This review summarizes the main aspects of PD pathology, as well as, discusses the most important biochemical dysfunctions during PD, and presents novel multi-targeting compounds, which have been tested for their activity against various targets related to PD. This review selects various research articles from main databases concerning multi-targeting compounds against PD. Molecules targeting more than one biochemical pathway involved in PD, expected to be more effective than the current treatment options, are discussed. A great number of research groups have designed novel compounds following the multi-targeting drug approach. They include structures combining antioxidant, antiinflammatory, and metal-chelating properties. These compounds could be proven useful for effective multi-targeted PD treatment. Multi-targeting drugs could be a useful tool for the design of effective antiparkinson agents. Their efficacy towards various targets implicated in PD could be the key to the radical treatment of this neurodegenerative disorder.

Cardiovascular disorders (CVDs) are reported to occur with very high rates of incidence and exhibit high morbidity and mortality rates across the globe. Therefore, research is focused on searching for novel therapeutic targets involving multiple pathophysiological mechanisms. Oxidative stress plays a critical role in the development and progression of various CVDs, such as hypertension, pulmonary hypertension, heart failure, arrhythmia, atherosclerosis, ischemia- reperfusion injury, and myocardial infarction. Among multiple pathways generating reactive oxygen species (ROS), Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases of the NOX family as the major source of ROS generation and plays an intricate role in the development and progression of CVDs. Therefore, exploring the role of different NADPH oxidase isoforms in various cardiovascular pathologies has attracted attention to current cardiovascular research. Focusing on NADPH oxidases to reduce oxidative stress in managing diverse CVDs may offer unique therapeutic approaches to prevent and treat various heart conditions. The current review article highlights the role of different NADPH oxidase isoforms in the pathophysiology of various CVDs. Moreover, the focus is also to emphasize different experimental studies that utilized various NADPH oxidase isoform modulators to manage other disorders. The present review article considers new avenues for researchers/scientists working in the field of cardiovascular pharmacology utilizing NADPH oxidase isoform modulators.

Arsenic in the environment, such as sodium arsenic (NaAsO2), is a frequently occurring hazard that has been linked to nonalcoholic steatohepatitis (NASH). Our prior research established the involvement of ferroptosis in arsenic-induced NASH, but the precise underlying mechanisms remain elusive. Here, we found that exposure to NaAsO2 had a suppressive effect on the expression of CDGSH iron-sulfur domain-containing protein 2 (CISD2) at the protein and gene levels, and overexpression of CISD2 inhibited NaAsO2-induced ferroptosis and NASH. Additionally, administration of NaAsO2 to hepatocytes triggered mitochondrial dysfunction, manifesting as the release of cytochrome c, impairment of the mitochondrial respiratory chain, and reduction in ATP synthesis. However, these adverse effects were alleviated through overexpression of CISD2. Intracellular iron redistribution was induced by overexpression of CISD2 and inhibited NaAsO2-induced ferroptosis. This inhibition was characterized by a reduction in cytoplasmic iron levels and an increase in mitochondrial iron levels. Our study demonstrated that NaAsO2 induced intracellular iron reorganization and mitochondrial dysfunction through CISD2 inhibition, leading to ferroptosis and NASH. This may provide a novel means of treatment of nonalcoholic fatty liver disease triggered by environmental factors.

Mating exerts profound and multifaceted effects on the physiology of female insects, particularly influencing metabolic alterations and bolstering stress resilience. Drosophila melanogaster has emerged as an excellent model to investigate the mechanism of neurodegenerative diseases. However, interplay between mating and its impact on the Drosophila brain remains a tantalizing enigma, awaiting elucidation. Herein, we reported that mating significantly improved the climbing and jumping activity in mated females compared to the virgins in Drosophila. Mating also reduced oxidative stress in the brain. Based on the results, we found that, mated females exhibited better behavioral performance and fewer loss of dopaminergic (DA) neurons than unmated females in PINK1 RNAi flies, a well-established Parkinson's disease (PD) model. Further study demonstrated that mating led to decreased iron content in the brain, a process associated with decreased Transferrin 1 (Tsf1) and Malvolio (Mvl) and increased ferritin. Additionally, mating inhibited expression of Duox and Nox, two NADPH oxidases in Drosophila. Furthermore, Kr-h1, a transcription factor of JH, acted downstream of mating to regulate genes involved in iron metabolism and NADPH oxidases. Collectively, the findings suggested a pivotal role of mating in regulating iron metabolism and NADPH oxidases in the brain of Drosophila. Consequently, considering mating status is imperative in scientific research, particularly in the context of neurological disorders.

Reactive oxygen species (ROS), synthesized by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) complex, are vital molecules in biological cells, influencing various physiological processes such as fungal growth, development, and virulence. Beauveria bassiana, an entomopathogenic fungus, is a promising biopesticide for agricultural, forestry, and urban pest control. This study focuses on the characterization of NADPH oxidases (Noxs) in B. bassiana. Gene expression profiles of Noxs in B. bassiana (BbNoxs) were analysed using RT-qPCR. Knockout strains of single BbNoxA, BbNoxB, BbNoxR, and double BbNoxA and BbNoxB were constructed via homologous recombination, and their phenotypic characteristics were examined. Fungal virulence was evaluated using Galleria mellonella larvae, and infection structures formation and penetration ability were assessed on cicada wings. ROS production and actin assembly during fungal growth and infection were detected using staining and marker methods. Expression analysis revealed significant upregulation of BbNoxs during fungal growth and infection. Compared to the wild-type strain, single knockouts (ΔBbNoxA/B/R) and double knockout (ΔBbNoxAB) of BbNoxs exhibited reduced conidial yields, accelerated conidial germination rates. Deletion of BbNoxB or BbNoxR decreased fungal virulence compared to the WT strain in topical inoculation experiments. Additionally, loss of BbNoxB or BbNoxR impaired infection structures formation, penetration ability, ROS production, and actin aggregation during fungal infection. BbNoxs are crucial for fungal growth, development, and virulence in B. bassiana, playing essential roles in infection structures formation, penetration, ROS production, and actin assembly. Understanding their functions provides insights into B. bassiana's pathogenic mechanisms.

Skeletal tissue development and regeneration in mammals are intricate, multistep, and highly regulated processes. Various signaling pathways have been implicated in the regulation of these processes, including redox. Redox signaling is the signal transduction by electron transfer reactions involving free radicals or related species. Redox homeostasis is essential to cell metabolic states, as the ROS not only regulates cell biological processes but also mediates physiological processes. Following a bone fracture, redox signaling is also triggered to regulate bone healing and regeneration by targeting resident stromal cells, osteoblasts, osteoclasts and endothelial cells. This review will focus on how the redox signaling impact the bone development and bone regeneration.

The liver has a distinctive capacity to regenerate, yet severe acute injury can be life-threatening if not treated appropriately. Inflammation and oxidative stress are central processes implicated in the pathophysiology of acute livery injury. NOX isoforms are important enzymes for ROS generation, NF-κB and NLRP3 activation, its inhibition could be vital in alleviating acute liver injury (ALI). Here in our study, we used apocynin, a natural occurring potent NOX inhibitor, to exploreits potential protective effect against thioacetamide (TAA)-induced ALI through modulating crucial oxidative and inflammatory pathways. Rats were injected once with TAA (500 mg/kg/i.p) and treated with apocynin (10 mg/kg/i.p) twice before TAA challenge. Sera and hepatic tissues were collected for biochemical, mRNA expression, western blot analysis and histopathological assessments. Pretreatment with apocynin improved liver dysfunction evidenced by decreased levels of aminotransferases, ALP, GGT and bilirubin. Apocynin reduced mRNA expression of NOX1 and NOX4 which in turn alleviated oxidative stress, as shown by reduction in MDA and NOx levels, and elevation in GSH levels andcatalase and SOD activities. Moreover, apocynin significantly reduced MPO gene expression. We also demonstrate that apocynin ameliorated inflammation through activating IκBα and suppressing IKKα, IKKβ, NF-κBp65 and p-NF-κBp65, IL-6 andTNF-α. Additionally, apocynin potentiated the gene expression of anti-inflammatory IL-10 and reduced levels of hepatic NLRP3, Caspase-1 and IL-1β. These results suggest that apocynin protects against ALI in association with the inhibition of NOX1 and NOX4 and regulating oxidative and inflammatory pathways.

Invasion of microorganisms into the gut of insects triggers a cascade of immune reactions accompanied by increased synthesis of effectors (such as antimicrobial peptides, cytokines, and amino acids), leading to changes in the physiological state of the host. We hypothesized that even an inactivated bacterium can induce an immune response in an insect. The aim of this study was to compare the roles of reactive oxygen species (ROS) formation and of the response of detoxification and antioxidant systems in a Colorado potato beetle (CPB) larval model in the first hours after invasion by either an inactivated or live bacterium.

The influence of per os inoculation with inactivated entomopathogenic bacterium Bacillus thuringiensis var. tenebrionis (Bt) on the survival and physiological and biochemical parameters of CPB larvae was assessed as changes in the total hemocyte count (THC), activity of phenoloxidases (POs), glutathione-S-transferases (GSTs), nonspecific esterases (ESTs), catalase, peroxidases, superoxide dismutases (SODs) and formation of reactive oxygen species (ROS).

A series of changes occurred within the hemolymph and the midgut of CPBs inoculated with inactivated Bt at 12 h after inoculation. These physiological and biochemical alterations serve to mediate generalized resistance to pathogens. The changes were associated with an increase in the THC and a 1.4-2.2-fold enhancement of detoxification enzymatic activities (such as GST and EST) as well as increased levels of antioxidants (especially peroxidases) in hemolymph in comparison to the control group. Suppressed EST activity and reduced ROS formation were simultaneously detectable in the larval midgut. Inoculation of beetle larvae with active Bt cells yielded similar results (elevated THC and suppressed PO activity). A fundamental difference in the immune activation processes between larvae that ingested the inactivated bacterium and larvae that had consumed the active bacterium was that the inactivated bacterium did not influence ROS formation in the hemolymph but did reduce their formation in the midgut. At 24 h postinfection with active Bt, ROS levels went up in both the hemolymph and the midgut. This was accompanied by a significant 5.7-fold enhancement of SOD activity and a 5.3-fold suppression of peroxidase activity. The observed alterations may be due to within-gut toxicity caused by early-stage bacteriosis. The imbalance in the antioxidant system and the accumulation of products toxic to the "putative" pathogen can activate detoxification mechanisms, including those of an enzymatic nature (EST and GST). The activation of detoxification processes and of innate immune responses is probably due to the recognition of the "putative" pathogen by gut epithelial cells and is similar in many respects to the immune response at early stages of bacteriosis.

T lymphocytes and myeloid cells express the immunoglobulin-like glycoprotein cluster of differentiation (CD)101, notably in the gut. Here, we investigated the cell-specific functions of CD101 during dextran sulfate sodium (DSS)-induced colitis and Salmonella enterica Typhimurium infection. Similar to conventional CD101-/- mice, animals with a regulatory T cell-specific Cd101 deletion developed more severe intestinal pathology than littermate controls in both models. While the accumulation of T helper 1 cytokines in a CD101-deficient environment entertained DSS-induced colitis, it impeded the replication of Salmonella as revealed by studying CD101-/- x interferon-g-/- mice. Moreover, CD101-expressing neutrophils were capable to restrain Salmonella infection in vitro and in vivo. Both cell-intrinsic and -extrinsic mechanisms of CD101 contributed to the control of bacterial growth and spreading. The CD101-dependent containment of Salmonella infection required the expression of Irg-1 and Nox2 and the production of itaconate and reactive oxygen species. The level of intestinal microbial antigens in the sera of inflammatory bowel disease patients correlated inversely with the expression of CD101 on myeloid cells, which is in line with the suppression of CD101 seen in mice following DSS application or Salmonella infection. Thus, depending on the experimental or clinical setting, CD101 helps to limit inflammatory insults or bacterial infections due to cell type-specific modulation of metabolic, immune-regulatory, and anti-microbial pathways.

NADPH oxidases (NOXs) are a family of membrane proteins responsible for intracellular reactive oxygen species (ROS) generation by facilitating electron transfer across biological membranes. Despite the established activation of NOXs by protein kinase C (PKC), the precise mechanism through which PKC triggers NOX activation during breast cancer invasion remains unclear. The present study aimed to investigate the role of NOX1 and NOX5 in the invasion of MCF‑7 human breast cancer cells. The expression and activity of NOXs and matrix metalloprotease (MMP)‑9 were assessed by reverse transcription‑quantitative PCR and western blotting, and the activity of MMP‑9 was monitored using zymography. Cellular invasion was assessed using the Matrigel invasion assay, whereas ROS levels were quantified using a FACSCalibur flow cytometer. The findings suggested that NOX1 and NOX5 serve crucial roles in 12‑O‑tetradecanoylphorbol‑13‑acetate (TPA)‑induced MMP‑9 expression and invasion of MCF‑7 cells. Furthermore, a connection was established between PKC and the NOX1 and 5/ROS signaling pathways in mediating TPA‑induced MMP‑9 expression and cellular invasion. Notably, NOX inhibitors (diphenyleneiodonium chloride and apocynin) significantly attenuated TPA‑induced MMP‑9 expression and invasion in MCF‑7 cells. NOX1‑ and NOX5‑specific small interfering RNAs attenuated TPA‑induced MMP‑9 expression and cellular invasion. In addition, knockdown of NOX1 and NOX5 suppressed TPA‑induced ROS levels. Furthermore, a PKC inhibitor (GF109203X) suppressed TPA‑induced intracellular ROS levels, MMP‑9 expression and NOX activity in MCF‑7 cells. Therefore, NOX1 and NOX5 may serve crucial roles in TPA‑induced MMP‑9 expression and invasion of MCF‑7 breast cancer cells. Furthermore, the present study indicated that TPA‑induced MMP‑9 expression and cellular invasion were mediated through PKC, thus linking the NOX1 and 5/ROS signaling pathways. These findings offer novel insights into the potential mechanisms underlying their anti‑invasive effects in breast cancer.

The membrane-integrated NADPH oxidases DUOX1 and DUOX2 are recruited to the apical plasma membrane in epithelial cells to release hydrogen peroxide, thereby playing crucial roles in various functions such as thyroid hormone synthesis and host defense. However, it has remained unknown about the molecular mechanism for apical sorting of DUOX1 and DUOX2. Here we show that DUOX1 and DUOX2 are correctly sorted to the apical membrane via the membrane-spanning DUOX maturation proteins DUOXA1 and DUOXA2, respectively, when co-expressed in MDCK epithelial cells. Impairment of N-glycosylation of DUOXA1 results in mistargeting of DUOX1 to the basolateral membrane. Similar to DUOX1 complexed with the glycosylation-defective DUOXA1, the naturally non-glycosylated oxidase NOX5, which forms a homo-oligomer, is targeted basolaterally. On the other hand, a mutant DUOXA2 deficient in N-glycosylation is less stable than the wild-type protein but still capable of recruiting DUOX2 to the apical membrane, whereas DUOX2 is missorted to the basolateral membrane when paired with DUOXA1. These findings indicate that DUOXA2 is crucial but its N-glycosylation is dispensable for DUOX2 apical recruitment; instead, its C-terminal region seems to be involved. Thus, apical sorting of DUOX1 and DUOX2 is likely regulated in a distinct manner by their respective partners DUOXA1 and DUOXA2.

Transthyretin (ATTR) amyloidosis constitutes a spectrum of debilitating neurodegenerative diseases instigated by systemic extracellular deposition of partially unfolded/aggregated aberrant transthyretin. The homotetrameric protein, TTR, is abundant in the plasma, and to a lesser extent the cerebrospinal fluid. Rate-limiting tetramer dissociation of the native protein is regarded as the critical step in the formation of morphologically heterogenous toxic aggregates and the onset of clinical manifestations such as polyneuropathy, cardiomyopathy, disturbances in motor and autonomic functions. Over the past few decades there has been increasing evidence suggesting that in addition to destabilization in TTR tetramer structure, oxidative stress may also play an important role in the pathogenesis of ATTR amyloidosis. In this review, an update on the impact of oxidative stress in TTR amyloidogenesis as well as TTR aggregate-mediated pathologies is discussed. The counteracting effects of antioxidants and nutraceutical agents explored in the treatment of ATTR amyloidosis based on recent evidence is also critically examined. The insights unveiled could further strengthen current understanding of the mechanisms underlying ATTR amyloidosis as well as extend the range of strategies for effective management of ATTR amyloidoses.