Search Results (1,229)

Alzheimer’s disease (AD) is the most predominant cause of dementia, considered a progressive decline in cognitive function that ultimately leads to death. AD has posed a substantial challenge in the records of medical science over the past century, representing a predominant etiology of dementia with a high prevalence rate. Neuroinflammation is a common characteristic of various central nervous system (CNS) pathologies like AD, primarily mediated by specialized brain immune and inflammatory cells, such as astrocytes and microglia. The present study aims to elucidate the potential mechanism of physcion that mitigates LPS-induced gliosis and assesses oxidative stress in mice. Physcion reduced the reactivity of Iba-1- and GFAP-positive cells and decreased the level of inflammatory cytokines like TNF-α and IL-1β. Physcion also reversed the effect of LPS-induced oxidative stress by upregulating the expression of Nrf2 and HO-1. Moreover, physcion treatment reversed LPS-induced synaptic disorder by increasing the level of presynaptic protein SNAP-23 and postsynaptic protein PSD-95. Our findings may provide a contemporary theoretical framework for clinical investigations aimed at examining the pathogenic mechanisms and therapeutic approaches for neuroinflammation and AD. Full article

Bilirubin (BR) is an important ingredient of a valuable Chinese medicine, Calculus bovis. Over recent decades, increasing evidence has confirmed that BR offers health benefits in cardiovascular health, stroke, diabetes, and metabolic syndrome. However, BR is mainly produced by extraction from pig bile. In this study, we assembled an efficient pathway for BR production by metabolic engineering of Escherichia coli. First, heme oxygenase (HO1) and biliverdin reductase were co-expressed in E. coli. HPLC and LC–MS confirmed the accumulation of BR in the recombinant E. coli cells. To improve BR production, the catalytic abilities of HO1 from different species were investigated. In addition, the outermembrane-bound heme receptor (ChuA) and the enzymes involved in heme biosynthesis were overexpressed among which ChuA, 5-aminolevulinic acid dehydratase (HemB), protoporphyrin oxidase (HemG), and ferrochelatase (HemH) were found to enhance BR accumulation in E. coli. In addition, expression of ferredoxin (Fd) was shown to contribute to efficient conversion of heme to BR in E. coli. To increase supply of NADPH, isocitrate dehydrogenase (IDH), NAD kinase (nadK), NADP-specific glutamate dehydrogenase (gdhA), and glucose-6-phosphate 1-dehydrogenase (ZWF) were overexpressed and were found to enhance BR accumulation when these proteins were expressed with a low-copy plasmid pACYCduet-1. Modular optimization of the committed genes led to a titer of 17.2 mg/L in strain M1BHG. Finally, fed-batch fermentation was performed for the strains M1BHG and M1, resulting in accumulation of 75.5 mg/L and 25.8 mg/L of BR, respectively. This is the first report on biosynthesis of BR through metabolic engineering in a heterologous host. Full article

This study investigates the composition characteristics and anti-inflammatory activity mechanisms of the essential oil from the leaves of Crossostephium chinense. C. chinense is a perennial herb commonly found in East Asia, traditionally used to treat various ailments. The essential oil extracted through water distillation, primarily contains 1,8-cineole (13.73%), santolina triene (13.53%), and germacrene D (10.67%). Three compounds were identified from the essential oil, namely 1-acetoxy-2-(2-hydroxypropyl)-5-methylhex-3,5-diene, 1-acetoxy-isopyliden-hex-5-en-4-one, and chrysanthemyl acetate, with the first two being newly discovered compounds. Then, the essential oil of C. chinense exhibits significant anti-inflammatory effects on RAW264.7 macrophages, effectively inhibiting the production of NO and ROS, with the IC50 value of 10.3 μg/mL. Furthermore, the essential oil reduces the expression of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. Mechanistic studies indicate that the essential oil affects the inflammatory response by inhibiting the expression of iNOS but has no significant impact on COX-2. Further analysis suggests that the essential oil may regulate the inflammatory response through the ERK protein in the MAPK pathway and IκBα in the NF-κB pathway, while also promoting the activity of the NRF2/HO-1 antioxidant pathway, enhancing the cell’s antioxidant capacity, thereby achieving an effect of inhibiting the inflammatory response. These results highlight the potential application value of C. chinense leaf essential oil in the medical and healthcare fields. Full article

We describe the antioxidant capability of scavenging the superoxide radical of several tea and yerba mate samples using rotating ring–disk electrochemistry (RRDE). We directly measured superoxide concentrations and detected their decrease upon the addition of an antioxidant to the electrochemical cell. We studied two varieties of yerba mate, two varieties of black tea from Bangladesh, a sample of Pu-erh tea from China, and two components, caffeic acid and chlorogenic acid. All of these plant infusions and components showed strong antioxidant activities, virtually annihilating the available superoxide concentration. Using density functional theory (DFT) calculations, we describe a mechanism of superoxide scavenging via caffeic and chlorogenic acids. Superoxide can initially interact at two sites in these acids: the H4 catechol hydrogen (a) or the acidic proton of the acid (b). For (a), caffeic acid needs an additional π–π superoxide radical, which transfers electron density to the ring and forms a HO₂⁻ anion. A second caffeic acid proton and HO₂⁻ anion forms H₂O₂. Chlorogenic acid acts differently, as the initial approach of superoxide to the catechol moiety (a) is enough to form the HO₂⁻ anion. After an additional acidic proton of chlorogenic acid is given to HO₂⁻, three well-separated compounds arise: (1) a carboxylate moiety, (2) H₂O₂, and a (3) chlorogenic acid semiquinone. The latter can capture a second superoxide in a π–π manner, which remains trapped due to the aromatic ring, as for caffeic acid. With enough of both acids and superoxide radicals, the final products are equivalent: H₂O₂ plus a complex of the type [X-acid–η–O₂], X = caffeic, chlorogenic. Chlorogenic acid (b) is described by the following reaction: 2 O₂^•− + 2 chlorogenic acid → 2 chlorogenic carboxylate + O₂ + H₂O₂, and so, it acts as a non-enzymatic superoxide dismutase (SOD) mimic, as shown via the product formation of O₂ plus H₂O₂, which is limited due to chlorogenic acid consumption. Caffeic acid (b) differs from chlorogenic acid, as there is no acidic proton capture via superoxide. In this case, approaching a second superoxide to the H4 polyphenol moiety forms a HO₂⁻ anion and, later, an H₂O₂ molecule upon the transfer of a second caffeic acid proton. Full article

Nuclear erythroid 2-related factor 2 (Nrf2) and its downstream effector heme oxygenase 1 (HO-1) are commonly activated in response to cellular stresses. The elevated expression of HO-1 has been associated with markedly accelerated peripheral nerve regeneration. This study aimed to evaluate the impact of a naturally occurring dietary Nrf2/HO-1 activator—sulforaphane (SFN)—on regeneration in a murine sciatic nerve crush model. The beneficial safety profile of SFN has been thoroughly investigated and confirmed several times. Here, SFN was administered daily, starting immediately after C57BL/6 mice were subjected to sciatic nerve crush injury. Injured sciatic nerves were excised at various time points post injury for molecular, immunohistochemical and morphometric analyses. Moreover, functional assessment was performed by grip strength analysis and electrophysiology. Following SFN treatment, the early response to injury includes a modulation of autophagic pathways and marked upregulation of Nrf2/HO-1 expression. This enhancement of HO-1 expression was maintained throughout the regeneration phase and accompanied by a significant increase in repair Schwann cells. In these cells, elevated proliferation rates were observed. Significant improvements in grip strength test performance, nerve conduction velocity and remyelination were also noted following SFN treatment. Collectively, SFN modulates cytoprotective and autophagic pathways in the injured nerve, increasing the number of repair Schwann cells and contributing to effective nerve regeneration. Given the availability of SFN as a nutritional supplement, this compound might constitute a novel regenerative approach with broad patient accessibility and further studies on this topic are warranted. Full article

Prostate cancer (PC) is a significant cause of mortality in men worldwide, hence the need for a comprehensive understanding of the molecular mechanisms underlying its progression and resistance to treatment. Heme oxygenase-1 (HO-1), an inducible enzyme involved in heme catabolism, has emerged as a critical player in cancer biology, including PC. This review explores the multifaceted role of HO-1 in PC, encompassing its function, regulation, and implications in cancer therapy. HO-1 influences cell proliferation, anti-apoptotic pathways, angiogenesis, and the tumor microenvironment, thereby influencing tumor growth and metastasis. HO-1 has also been associated with therapy resistance, affecting response to standard treatments. Moreover, HO-1 plays a significant role in immune modulation, affecting the tumor immune microenvironment and potentially influencing therapy outcomes. Understanding the intricate balance of HO-1 in PC is vital for developing effective therapeutic strategies. This review further explores the potential of targeting HO-1 as a therapeutic approach, highlighting challenges and opportunities. Additionally, clinical implications are discussed, focusing on the prognostic value of HO-1 expression and the development of novel combined therapies to augment PC sensitivity to standard treatment strategies. Ultimately, unraveling the complexities of HO-1 in PC biology will provide critical insights into personalized treatment approaches for PC patients. Full article

α-tocopherol (α-T), β-sitosterol (β-S), canolol (CA), and sinapic acid (SA) are the four main endogenous lipid phytochemicals (LP) found in Brassica napus L. seed oil, which possess the bioactivity to prevent the risk of several chronic diseases via antioxidant-associated mechanisms. Discovering the enhancer effects or synergies between LP is valuable for resisting oxidative stress and improving health benefits. The objectives of this study were to identify a potentially efficacious LP combination by central composite design (CCD) and cellular antioxidant activity (CAA) and to investigate its protective effect and potential mechanisms against H₂O₂-induced oxidative damage in HepG2 cells. Our results indicated that the optimal concentration of LP combination was α-T 10 μM, β-S 20 μM, SA 125 μM, and CA 125 μM, respectively, and its CAA value at the optimal condition was 10.782 μmol QE/100 g. At this concentration, LP combination exerted a greater amelioration effect on H₂O₂-induced HepG2 cell injury than either antioxidant (tea polyphenols or magnolol) alone. LP combination could reduce the cell apoptosis rate induced by H₂O₂, lowered to 10.06%, and could alleviate the degree of oxidative damage to cells (ROS↓), lipids (MDA↓), proteins (PC↓), and DNA (8-OHdG↓). Additionally, LP combination enhanced the antioxidant enzyme activities (SOD, CAT, GPX, and HO-1), as well as the T-AOC, and increased the GSH level in HepG2 cells. Furthermore, LP combination markedly upregulated the expression of Nrf2 and its associated antioxidant proteins. It also increased the expression levels of Nrf2 downstream antioxidant target gene (HO-1, SOD-1, MnSOD, CAT, GPX-1, and GPX-4) and downregulated the mRNA expression levels of Keap1. The oxidative-stress-induced formation of the Keap1/Nrf2 complex in the cytoplasm was significantly blocked by LP treatment. These results indicate that LP combination protected HepG2 cells from oxidative stress through a mechanism involving the activation of the Keap1/Nrf2/ARE signaling pathways. Full article

In 5G networks and beyond, managing handovers (HOs) becomes complex because of frequent user transitions through small coverage areas. The abundance of small cells (SCs) also complicates HO decisions, potentially leading to inefficient resource utilization. To optimize this process, we propose an intelligent algorithm based on a method that utilizes a fuzzy logic controller (FLC), leveraging prior expertise to dynamically adjust the time-to-trigger (TTT), and handover margin (HOM) in a 5G ultra-dense SC heterogeneous network (HetNet). FLC refines TTT based on the user’s velocity to improve the response to movement. Simultaneously, it adapts HOM by considering inputs such as the reference signal received power (RSRP), user equipment (UE) speed, and cell load. The proposed approach enhances HO decisions, thereby improving the overall system performance. Evaluation using metrics such as handover rate (HOR), handover failure (HOF), radio link failure (RLF), and handover ping-pong (HOPP) demonstrate the superiority of the proposed algorithm over existing approaches. Full article

Hydroxyapatite (HAp) is a widely used biocompatible material in orthopedic composite preparations. However, HAp composites that exhibit both anticancer and antibacterial activities through bioactive coordination complexes are relatively rare. To explore orthopedic applications, we blended several silver camphorimine compounds with HAp to create [Ag(I)] composites. All compounds [Ag(NO₃)(L)_n] (n = 1,2) based on camphorimine (L^A), camphor sulfonimine (L^B) or imine bi-camphor (L^C) ligands demonstrated significant cytotoxic activity (IC₅₀ = 0.30–2.6 μg_Ag/mL) against osteosarcoma cancer cells (HOS). Based on their structural and electronic characteristics, four complexes (1–4) were selected for antibacterial evaluation against Escherichia coli, Burkholderia contaminans, Pseudomonas aeruginosa, and Staphylococcus aureus. All complexes (1–4) revealed combined anticancer and antibacterial activities; therefore, they were used to prepare [Ag(I)]:HAp composites of 50:50% and 20:80% weight compositions and the activities of the composites were assessed. Results showed that they retain the dual anticancer and antibacterial characteristics of their precursor complexes. To replicate the clinical context of bone-filling applications, hand-pressed surfaces (pellets) were prepared. It is worth highlighting that no agglutination agent was necessary for the pellet’s consistency. The biological properties of the so-prepared pellets were assessed, and the HOS cells and bacteria spreading on the pellet’s surface were analyzed by SEM. Notably, composite 4B, derived from the bicamphor (L^C) complex [Ag(NO₃)(OC₁₀H₁₄N(C₆H₄)₂NC₁₀H₁₄O)], exhibited significant anticancer activity against HOS cells and antibacterial activity against P. aeruginosa, fostering potential clinical applications on post-surgical OS treatment. Full article

The anti-inflammatory, antiviral, and anti-cancer properties, as well as the mechanism of action of cyclo-[Pro-Pro-β³-HoPhe-Phe-] tetrapeptide (denoted as 4B8M), were recently described. The aim of this work was to synthesize and evaluate the immunosuppressive actions of the stereochemical variants of 4B8M by sequential substitution of L-amino acids by D-amino acids (a series of peptides denoted as P01–P07) using parent 4B8M as a reference compound. In addition, diverse available bioinformatics tools using machine learning and artificial intelligence were tested to find the bio-pharmacokinetic and polypharmacological attributes of analyzed stereomers. All peptides were non-toxic to human peripheral blood mononuclear cells (PBMCs) and only cyclo-[D-Pro-Pro-β³-HoPhe-Phe-] peptide (P03) was capable of inhibiting mitogen-induced PBMC proliferation. The peptides inhibited the lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha (TNF-α) to various degrees, with P04 (cyclo-[Pro-Pro-D-β³-HoPhe-Phe-]) and P03 being the most potent. For further in vivo studies, P03 was selected because it had the combined properties of inhibiting cell proliferation and TNF-α production. P03 demonstrated a comparable ability to 4B8M in the inhibition of auricle edema and lymph node cell number and in the normalization of a distorted blood cell composition in contact sensitivity to the oxazolone mouse model. In the mouse model of carrageenan-induced inflammation of the air pouch, P03 exhibited a similar inhibition of the cell number in the air pouches as 4B8M, but its inhibitory effects on the percentage of neutrophils and eosinophils in the air pouches and blood, as well as on mastocyte degranulation in the air pouches, were stronger in comparison to 4B8M. Lastly, in a mouse model of dextran sulfate-induced colitis, similar effects to 4B8M regarding thymocyte number restoration and normalization of the blood cell pictures by P03 were observed. In summary, depending on either experimental findings or in silico predictions, P03 demonstrated comparable, or even better, anti-inflammatory and bio-pharmacokinetic properties to 4B8M and may be considered as a potential therapeutic. The possibility of P00 and P03 identification by circular dichroism measurements was tested by quantum-chemical calculations. Full article

It is still unclear whether or how quercetin influences the toxic events induced by acetaldehyde in hepatocytes, though quercetin has been reported to mitigate alcohol-induced mouse liver injury. In this study, we evaluated the modulating effect of quercetin on the cytotoxicity induced by acetaldehyde in mouse hepatoma Hepa1c1c7 cells, the frequently used cellular hepatocyte model. The pretreatment with quercetin significantly inhibited the cytotoxicity induced by acetaldehyde. The treatment with quercetin itself had an ability to enhance the total ALDH activity, as well as the ALDH1A1 and ALDH3A1 gene expressions. The acetaldehyde treatment significantly enhanced the intracellular reactive oxygen species (ROS) level, whereas the quercetin pretreatment dose-dependently inhibited it. Accordingly, the treatment with quercetin itself significantly up-regulated the representative intracellular antioxidant-related gene expressions, including heme oxygenase-1 (HO-1), glutamate-cysteine ligase, catalytic subunit (GCLC), and cystine/glutamate exchanger (xCT), that coincided with the enhancement of the total intracellular glutathione (GSH) level. Tin protoporphyrin IX (SNPP), a typical HO-1 inhibitor, restored the quercetin-induced reduction in the intracellular ROS level, whereas buthionine sulphoximine, a representative GSH biosynthesis inhibitor, did not. SNPP also cancelled the quercetin-induced cytoprotection against acetaldehyde. These results suggest that the low-molecular-weight antioxidants produced by the HO-1 enzymatic reaction are mainly attributable to quercetin-induced cytoprotection. Full article

Oxidative stress (OS) is a key factor in the generation of various pathophysiological conditions. Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is a major transcriptional regulator of antioxidant reactions. Heme oxygenase-1 (HO-1), a gene regulated by Nrf2, is one of the most critical cytoprotective molecules. In recent years, Nrf2/HO-1 has received widespread attention as a major regulatory pathway for intracellular defense against oxidative stress. It is considered as a potential target for the treatment of inflammatory bowel disease (IBD). This review highlights the mechanism of action and therapeutic significance of Nrf2/HO-1 in IBD and IBD complications (intestinal fibrosis and colorectal cancer (CRC)), as well as the potential of phytochemicals targeting Nrf2/HO-1 in the treatment of IBD. The results suggest that the therapeutic effects of Nrf2/HO-1 on IBD mainly involve the following aspects: (1) Controlling of oxidative stress to reduce intestinal inflammation and injury; (2) Regulation of intestinal flora to repair the intestinal mucosal barrier; and (3) Prevention of ferroptosis in intestinal epithelial cells. However, due to the complex role of Nrf2/HO-1, a more nuanced understanding of the exact mechanisms involved in Nrf2/HO-1 is the way forward for the treatment of IBD in the future. Full article

Resolvin D5 (RvD5) is a lipid mediator that has been reported to present anti-inflammatory and pro-resolution properties. Evidence also supports its capability to enhance reactive oxygen species (ROS) production during bacterial infections, which would be detrimental in diseases driven by ROS. The biological activity of RvD5 and mechanisms against UVB irradiation skin pathology have not been investigated so far. Female hairless mice were treated intraperitoneally with RvD5 before UVB stimulus. RvD5 reduced skin edema in a dose-dependent manner as well as oxidative stress by increasing antioxidants (endogenous tissue antioxidant scavenging of cationic radical, iron reduction, catalase activity and reduced glutathione levels) and decreasing pro-oxidants (superoxide anion and lipid peroxidation). RvD5 antioxidant activity was accompanied by enhancement of Nrf2, HO-1 and NQO1 mRNA expression. RvD5 reduced the production of IL-1β, TNF-α, TGF-β, and IL-10. RvD5 also reduced the inflammatory cell counts, including mast cells and neutrophils/macrophages. The reduction of oxidative stress and inflammation resulted in diminished matrix metalloproteinase 9 activity, collagen degradation, epidermal thickening and sunburn cell development. Therefore, this study demonstrates, to our knowledge, the first body of evidence that RvD5 can be used to treat UVB skin pathology and unveils, at least in part, its mechanisms of action. Full article

Oxidative stress is associated with asthma pathobiology. We reported that oxidized phosphatidylcholines (OxPCs) are mediators of oxidative stress and accumulate in the lung in response to allergen challenge. The current study begins to unravel mechanisms for OxPC accumulation in the lung, providing the first insights about how OxPCs underpin allergic airway pathophysiology, and pre-clinical testing of selective neutralization of OxPCs in a murine model of allergic asthma. We hypothesized that intranasal delivery of E06, a natural IgM antibody that neutralizes the biological activity of OxPCs, can ameliorate allergen-induced airway inflammation and airway hyperresponsiveness. Adult BALB/c mice were intranasally (i.n.) challenged with house dust mite (HDM) (25 μg/mouse, 2 weeks). Some animals also received E06 monoclonal antibody (mAb) (10 µg) i.n. 1 hr before each HDM challenge. HDM challenge reduced mRNA for anti-oxidant genes (SOD1, SOD2, HO-1, and NFE2L2) in the lung by several orders of magnitude (p < 0.05). Concomitantly, total immune cell number in bronchoalveolar lavage fluid (BALF) increased significantly (p < 0.001). E06 mAb treatment prevented allergen-induced BALF immune cell number by 43% (p < 0.01). This included a significant blockade of eosinophils (by 48%, p < 0.001), neutrophils (by 80%, p < 0.001), macrophages (by 80%, p < 0.05), and CD4 (by 30%, p < 0.05) and CD8 (by 42%, p < 0.01) lymphocytes. E06 effects correlated with a significant reduction in TNF (by 64%, p < 0.001) and IL-1β (by 75%, p < 0.05) and a trend to diminish accumulation of other cytokines (e.g., IL-4, -10, and -33, and IFN-γ). E06 mAb treatment also inhibited HDM exposure-induced increases in total respiratory resistance and small airway resistance by 24% and 26%, respectively. In conclusion, prophylactic treatment with an OxPC-neutralizing antibody significantly limits allergen-induced airway inflammation and airway hyperresponsiveness, suggesting that OxPCs are important mediators of oxidative stress-associated allergic lung pathophysiology. Full article

Metabolic syndrome (MetS) is defined by the World Health Organisation (WHO) as a pathologic condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidaemia. The components of MetS and the associated cardiovascular risks may disrupt the vascular endothelial function and the structure of the vascular wall, increasing the risk of atherosclerosis and vascular diseases. In this study we evaluated the relationship between the carotid intima–media thickness (CIMT), the redox balance parameters of plasma asymmetric dimethylarginine (ADMA), malondialdehyde (MDA), and heme oxygenase 1 (HO-1), and the expression of oxidative stress-related nuclear factor kappa B (NF-kB), nuclear factor erythroid 2-related factor 2 (Nrf2), and HO-1 in peripheral blood mononuclear cells (PBMCs) in MetS. Significantly higher CIMT was established in MetS patients aged ≥ 55 years as compared with the control group (0.96 ± 0.29 vs. 0.74 ± 0.21, p < 0.05). Expression was higher in MetS patients aged < 55 years (83% for NF-kB, p < 0.05; 251% for Nrf2, p < 0.05, and 337% for HO-1, p < 0.05) in comparison to the control group. Similarly, expression was higher in CIMT < 0.90 mm than the control group by 80% for NF-kB, p < 0.01; 260% for Nrf2, p < 0.05, and 303% for HO-1, p < 0.05. In contrast, gene expression was under-regulated in the subgroups of MetS patients aged ≥ 55 years and MetS patients with CIMT ≥ 0.90 mm. Significantly higher plasma levels for MDA, ADMA, and HO-1 were established in the age < 55 and age ≥ 55 MetS subgroups and the CIMT < 0.90 mm and CIMT ≥ 0.90 mm subgroups. In conclusion, MetS individuals aged ≥ 55 are at higher risk of increased CIMT and impaired redox balance. Full article