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Two previously undescribed coumarins (1-2) were isolated from the root of Notopterygium incisum. The structures of new findings were elucidated by analyses of spectral evidences in HRESIMS, NMR, as well as ICD. The absolute configurations were further confirmed by chemical calculations. 1-2 exhibits obviously anti-inflammatory activity by inhibiting the expression of inflammatory mediators (COX-2, iNOS), as well as reducing the release of NO and the accumulation of ROS in cells. Western blotting analysis revealed that 2 could inhibit the PI3K/AKT pathway by reducing the expression of p-PI3K and p-AKT., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The major challenges in photodynamic therapy (PDT) are the neutralization of cytotoxic reactive oxygen species (ROS) by the excessive antioxidant glutathione (GSH) in tumor cells, high self-aggregation of most photosensitizers (PSs), and long time to protect from light after treatment. Thus, to develop the molecular PSs for the improved and safe PDT in clinic, a novel and versatile PS (Mal-Pc) has been designed by di-substituting maleimides to the axial positions of silicon (Ⅳ) phthalocyanine. Owning to the conjugation of maleimides, Mal-Pc can not only entry tumor cells more easily and faster, but also can react with the intracellular overexpressed GSH after entry. In addition, upon electrophilic reaction with GSH, the inhibition of self-aggregation of Mal-Pc has been demonstrated by the restoration of the fluorescence emission in aqueous media. As a result, the intracellular ROS levels and photocytotoxicity of Mal-Pc are dramatically enhanced. Finally, the high hydrophilicity of the product GS-conjugates facilitates Mal-Pc eliminate from the normal cells more rapidly. Overall, this work revealed the high potential of the versatile molecular Mal-Pc for highly efficient and safe PDT in clinical translation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Seven new coumarinolignans, walthindicins A-F ( 1a , 1b , 2 - 5 , 7 ), along with five known analogs ( 6 , 8 - 11 ), were isolated from the roots of Waltheria indica . The structures of the new compounds are determined by detailed nuclear magnetic resonance (NMR), circular dichroism (CD) with extensive computational support, and mass spectroscopic data interpretation. Compounds were tested for their antioxidant activity in Human Cervical Cancer cells (HeLa cells). Compounds 1a and 6 showed higher reactive oxygen species (ROS) inhibitory activity at 20 μg/mL when compared with other natural compound-based antioxidants such as ascorbic acid. Considering the role of ROS in nuclear-factor kappa B (NF-κB) activation, compounds 1a and 6 were evaluated for NF-κB inhibitory activity and showed a concentration-dependent inhibition in Human Embryonic Kidney 293 cells (Luc-HEK-293).

Osteoporosis is a disease, which causes huge economic and social burden. Using natural compound to treat such disease is beneficial for the fewer side effects and effectiveness. D-(-)-salicin (DSA) is a component extracted from the bark of Populus and Salix species. In our research, we discovered that DSA suppressed RANKL-induced differentiation of osteoclast in vitro in a dose-dependent manner. It was also found that the mineral resorbing activity by osteoclasts was depressed via DSA. For the mechanism, we confirmed the inhibitory effect, by which DSA suppressed osteoclast formation and function, was through the inhibition of ROS signaling, MAPK and NF-κB cascades. DSA also suppressed the expression and activity of NFATc1. Therefore, by inhibiting the ROS production, MAPK and NF-κB signal cascade, DSA inhibited the osteoclast differentiation and function in vitro., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Advanced glycation end products (AGEs) can damage voltage-gated K + (Kv) channels and attenuate coronary artery vasodilation, but the underlying mechanisms remain unclear. The aim of this study was to investigate the role and potential mechanism of PPARγ in AGEs-induced Kv 1 channels impairment. We used both primary rat coronary smooth muscle cells (CSMCs) in vitro and Zucker Diabetic Fatty (ZDF) rat model in vivo. Overexpression of the Pparg gene by lentivirus vector (LV-Pparg) was used to transfect CSMCs for upregulation PPARγ. Kv 1.2 and Kv 1.5 currents were measured by patch clamp. The vascular tone of coronary artery was evaluated by isometric force measurements. The proteins expression of Kv1.2 and Kv1.5 channel were detected by western blot. PPARγ was detected by immunofluorescence and western blot. Oxidative stress markers including superoxide dismutase (SOD), glutathione peroxidase (GPx) and malondialdehyde (MDA) were detected by enzyme linked immunosorbent assay (ELISA). The phosphorylation of p38 mitogen-activated protein kinase (MAPK) and total p38 expression were detected by western blot. The intracellular ROS levels were measured by the fluorescent dye 2',7'- dichlorofluorescein diacetate (DCFDA) and a cellular ROS assay kit. We found that activating PPARγ via LV-Pparg (100 MOI, 5 × 10 8 TU/mL) prevented AGEs (100 μg/mL) -mediated impairment of Kv 1.2 and Kv 1.5 channels activity and improved the reduction of Kv 1.2 and Kv 1.5 protein expression in CSMCs. Isometric force measurements showed that activating PPARγ by pioglitazone (10 mg/kg/d, intragastric administration) improved the impairment of coronary artery vasodilation, and western blot analysis showed that activating PPARγ increased the Kv 1.2 and Kv 1.5 protein expression, while inhibiting PPARγ by GW9662 (10 mg/kg/d, intraperitoneal injection) attenuated these effects in ZDF rats. Furthermore, LV-Pparg overexpression PPARγ attenuated NADPH oxidase activity, which was shown as the reduction of the NOX2 and p22phox expression by western blot analysis, decreased the MDA production and increased the SOD and GPx activities by ELISA, finally led to reduce AGEs-mediated ROS production. Moreover, activating PPARγ by LV-Pparg inhibited AGEs-induced phosphorylation of p38 MAPK, by which could reduce AGEs-mediated NOX2, p22phox expression and ROS production, while CSMCs treatment with SB203580 (10 μmol/L), a p38 MAPK inhibitor, attenuated these effects. Activating PPARγ plays a protective role in AGEs-induced impairment of coronary artery vasodilation by inhibiting p38 phosphorylation to attenuate NOX2 and p22phox expression and further decrease oxidative stress induced by ROS overproduction., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Stress-induced premature senescence may be involved in the pathogeneses of acute liver injury. Hexavalent chromium [Cr(VI)], a common environmental pollutant related to liver injury, likely leads to premature senescence in L02 hepatocytes. However, the underlying mechanisms regarding hepatocyte premature senility in Cr(VI) exposure remain poorly understood. In this study, we found that chronic exposure of L02 hepatocytes to Cr(VI) led to premature senescence characterized by increased β -galactosidase activity, senescence-associated heterochromatin foci, G1 phase arrest, and decreased cell proliferation. Additionally, Cr(VI)-induced senescent L02 hepatocytes showed upregulated inflammation-related factors, such as IL-6 and fibroblast growth factor 23 (FGF23), which also exhibited reactive oxygen species (ROS) accumulation derived from mitochondria accompanied with increased concentration of intracellular calcium ions (Ca 2+ ) and activity of nuclear factor kappa B (NF- κ B). Of note is that ROS inhibition by N-acetyl-Lcysteine pretreatment not only alleviated Cr(VI)-induced premature senescence but also reduced the elevated intracellular Ca 2+ , activated NF- κ B, and secretion of IL-6/FGF23. Intriguingly, the toxic effect of Cr(VI) upon premature senescence of L02 hepatocytes and increased levels of IL-6/FGF23 could be partially reversed by the intracellular Ca 2+ chelator BAPTA-AM pretreatment. Furthermore, by utilizing the NF- κ B inhibitor pyrrolidine dithiocarbamate (PDTC), we confirmed that NF- κ B mediated IL-6/FGF23 to regulate the Cr(VI)-induced L02 hepatocyte premature senescence, whilst the concentration of intracellular Ca 2+ was not influenced by PDTC. To the best of our knowledge, our data reports for the first time the role of ROS-Ca 2+ -NF- κ B signaling pathway in Cr(VI)-induced premature senescence. Our results collectively shed light on further exploration of innovative intervention strategies and treatment targeting Cr(VI)-induced chronic liver damage related to premature senescence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yujing Zhang et al.)

Alzheimer's disease severely perturbs transition metal homeostasis in the brain leading to the accumulation of excess metals in extracellular and intraneuronal locations. The amyloid beta protein binds these transition metals, ultimately causing severe oxidative stress in the brain. Metal chelation therapy is an approach to sequester metals from amyloid beta and relieve the oxidative stress. Here we have designed a mixed N/O donor Cu chelator inspired by the proposed ligand set of Cu in amyloid beta. We demonstrate that the chelator effectively removes Cu from amyloid beta and suppresses reactive oxygen species (ROS) production by redox silencing and radical scavenging both in vitro and in cellulo. The impact of ROS on the extent of oxidation of the different aggregated forms of the peptide is studied by mass spectrometry, which, along with other ROS assays, shows that the oligomers are pro-oxidants in nature. The aliphatic Leu34, which was previously unobserved, has been identified as a new oxidation site., (© 2021 Wiley-VCH GmbH.)

We performed next-generation sequencing in patients with familial steroid-sensitive nephrotic syndrome (SSNS) and identified a homozygous segregating variant (p.H310Y) in the gene encoding clavesin-1 (CLVS1) in a consanguineous family with 3 affected individuals. Knockdown of the clavesin gene in zebrafish (clvs2) produced edema phenotypes due to disruption of podocyte structure and loss of glomerular filtration barrier integrity that could be rescued by WT CLVS1 but not the p.H310Y variant. Analysis of cultured human podocytes with CRISPR/Cas9-mediated CLVS1 knockout or homozygous H310Y knockin revealed deficits in clathrin-mediated endocytosis and increased susceptibility to apoptosis that could be rescued with corticosteroid treatment, mimicking the steroid responsiveness observed in patients with SSNS. The p.H310Y variant also disrupted binding of clavesin-1 to α-tocopherol transfer protein, resulting in increased reactive oxygen species (ROS) accumulation in CLVS1-deficient podocytes. Treatment of CLVS1-knockout or homozygous H310Y-knockin podocytes with pharmacological ROS inhibitors restored viability to control levels. Taken together, these data identify CLVS1 as a candidate gene for SSNS, provide insight into therapeutic effects of corticosteroids on podocyte cellular dynamics, and add to the growing evidence of the importance of endocytosis and oxidative stress regulation to podocyte function.

Cancer is a heterogeneous disease with high morbidity and mortality rate involving changes in redox balance and deregulation of redox signalling. For decades, studies have involved developing an effective cancer treatment to combat treatment resistance. As natural products such as thymoquinone have numerous health benefits, studies are also focusing on using them as a viable method for cancer treatment, as they have minimal toxic effects compared with standard cancer treatments. Thymoquinone studies have shown numerous mechanisms of action, such as regulation of reactive species interfering with DNA structure, modulating various potential targets and their signalling pathways as well as immunomodulatory effects in vitro and in vivo. Thymoquinone's anti-cancer effect is mainly due to the induction of apoptotic mechanisms, such as activation of caspases, downregulation of precancerous genes, inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), anti-tumour cell proliferation, ROS regulation, hypoxia and anti-metastasis. Insight into thymoquinone's potential as an alternative treatment for chemoprevention and inflammation can be accomplished via compiling these studies, to provide a better understanding on how and why it works, as well as its interactions with common chemotherapeutic treatments., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: In the context of well-known inhibitory effects of Farrerol on the invasion of lung squamous cell carcinoma cells, the unexplored effect and regulatory mechanism of Farrerol on laryngeal squamous cell carcinoma (LSCC) emerged as the target in this study., Methods: After treatment with Farrerol alone, or together with MitoTempo, the viability, apoptosis, cell cycle distribution, migration, and invasion of LSCC cells were measured using MTT, flow cytometry, wound-healing, and transwell assays, respectively. Meanwhile, the levels of cytochrome C (Cyt C), Cleaved caspase-3/9, Cyclin D1, E-cadherin, N-cadherin, and Vimentin in LSCC cells were evaluated by Western blot; the reactive oxygen species (ROS) formation intensity and the disruption of mitochondrial membrane potential (MMP) of LSCC cells were assessed using flow cytometry; and the effect of Farrerol on xenograft tumor formation was evaluated in animal experiment., Results: Farrerol (10, 20, 50 μM) inhibited the viability, proliferation, cell cycle progression, migration and invasion, but promoted apoptosis, ROS formation intensity and disruption of MMP of LSCC cells. Moreover, Farrerol up-regulated Cyt C (in the cytoplasm), Cleaved caspase-3/9 and E-cadherin levels, but down-regulated Cyclin D1, N-cadherin and Vimentin levels in LSCC cells. Additionally, we uncovered that MitoTempo reversed the promoting effects of Farrerol on ROS formation intensity, apoptosis, and Cyt C and Cleaved caspase-3/9 levels in LSCC cells, while improving the disruption of MMP in Farrerol-treated LSCC cells. Also, Farrerol lessened the volume and weight of mice tumors., Conclusions: Farrerol suppressed the migration, invasion, and induced the apoptosis of LSCC cells via the mitochondria-mediated pathway., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The three discrete [Zn 6 ] complexes [Na 3 Zn 6 (cpdp) 3 (μ-Bz) 3 (CH 3 OH) 6 ][ZnCl 4 ][ZnCl 3 (H 2 O)] · 3CH 3 OH · 1.5H 2 O ( 1 ), [Na 3 Zn 6 (cpdp) 3 (μ- p -OBz) 3 (CH 3 OH) 6 ] · 2H 2 O ( 2 ), and [Na 3 Zn 6 (cpdp) 3 (μ- p -NO 2 Bz) 3 (CH 3 OH) 6 ]Cl 3 · 2H 2 O ( 3 ), supported by the carboxylate-based multidentate ligand N , N '-bis[2-carboxybenzomethyl]- N , N '-bis[2-pyridylmethyl]-1,3-diaminopropan-2-ol (H 3 cpdp), have been successfully synthesized and fully characterized (Bz = benzoate; p -OBz = dianion of p -hydroxybenzoic acid; p -NO 2 Bz = p -nitrobenzoate). The complexes have been characterized by elemental analysis, FTIR, UV-vis, NMR spectroscopy, PXRD, and thermal analysis, including single-crystal X-ray crystallography of 1 and 2 . The molecular architectures of 1 - 3 are built from the self-assembly of their corresponding [Zn 2 ] units, which are interconnected to the central [Na 3 (CH 3 OH) 6 ] 3+ core by six endogenous benzoate groups, with each linking one Zn(II) and one Na(I) ion in a μ 2 :η 1 :η 1 - syn-anti bidentate fashion. The composition of the (cpdp 3- ) 3 /(Zn 2+ ) 6 complexes in 1 - 3 has been observed to be 1:2, on the basis of the UV-vis titration and NMR spectroscopic results, which is further supported by X-ray crystallography. Systematic biological studies performed with a mice model suggested possible antidiabetic efficacy as well as anticancer activities of the complexes. When complexes 1 - 3 were administered intraperitoneally in mice, 1 showed a lowering in the blood glucose level, overall maintenance of the pancreatic tissue mass, restriction of DNA damage in pancreatic cells, and retention of lipid droplet (LD) frequency, whereas 2 and 3 showed hepatic tissue mass consistency by inhibiting the DNA damage in hepatic cells, prior to the exposure to a potent diabetic inducer, alloxan (ALX). Similar trends of results were observed in inhibiting the generation of reactive oxygen species (ROS) in the pancreatic and hepatic cells, as examined by spectrofluorometric methods. Thus, 1 seems to be a better compound for overall diabetic management and control, whereas 2 and 3 seem to be promising compounds for designing chemopreventive drugs against hepatic carcinoma.

Muscular dystrophy is a well-known genetically heterogeneous group of rare muscle disorders. This progressive disease causes the breakdown of skeletal muscles over time and leads to grave weakness. This breakdown is caused by a diverse pattern of mutations in dystrophin and dystrophin associated protein complex. These mutations lead to the production of altered proteins in response to which, the body stimulates production of various cytokines and immune cells, particularly reactive oxygen species and NFκB. Immune cells display/exhibit a dual role by inducing muscle damage and muscle repair. Various anti-oxidants, anti-inflammatory and glucocorticoid drugs serve as potent therapeutics for muscular dystrophy. Along with the above mentioned therapeutics, induced pluripotent stem cells also serve as a novel approach paving a way for personalized treatment. These pluripotent stem cells allow regeneration of large numbers of regenerative myogenic progenitors that can be administered in muscular dystrophy patients which assist in the recovery of lost muscle fibers. In this review, we have summarized gene-editing, immunological and induced pluripotent stem cell based therapeutics for muscular dystrophy treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The threat of antibiotic-resistant bacteria is an ever-increasing problem in public health. In this report, we examine the photochemical properties with a proof-of-principle biocidal assay for a novel series of regio-regular imidazolium derivative poly-(3-hexylthiophene)/sodium dodecyl sulfate (P3HT-Im/SDS) materials from ultrafast sub-ps dynamics to μs generation of reactive oxygen species (ROS) and 30 min biocidal reactivity with Escherichia coli ( E. coli ). This broad series encompassing pure P3HT-Im to cationic, neutral, and anionic P3HT-Im/SDS materials are all interrogated by a variety of techniques to characterize the physical material structure, electronic structure, and antimicrobial activity. Our results show that SDS complexation with P3HT-Im results in aggregate materials with reduced ROS generation and light-induced anti-microbial activity. However, our characterization reveals that the presence of non-aggregated or lightly SDS-covered polymer segments is still capable of ROS generation. Full encapsulation of the P3HT-Im polymer completely deactivates the light killing pathway. High SDS concentrations, near and above critical micelle concentration, further deactivate all anti-microbial activity (light and dark) even though the P3HT-Im regains its electronic properties to generate ROS.

Context: Bufadienolide compounds occur in many plants and animal species and have strong cardiac and anti-inflammatory properties. The compounds have been recently investigated for cytotoxic and antitumor activity., Objective: The cytotoxic effect of bersaldegenin-1,3,5-orthoacetate - a bufadienolide steroid occuring in plants from Kalanchoe genus (Crassulaceae), was evaluated with cervical cancer HeLa cells in vitro ., Materials and Methods: The cytotoxic activity of the compound (at 0.1-20.0 μg/mL) on the cells was determined by Real-Time Cell Analysis (RTCA) system for 24 h. The estimation of cell cycle arrest, reactive oxygen species (ROS) production, reduction of mitochondrial membrane potential (MMP), and caspases-3/7/9 activity in the HeLa cells treated with the compound was done by flow cytometry and luminometric technique. DNA damage in the cells was estimated by immunofluorescence staining and the comet assay with etoposide as a positive control., Results: The compound had strong effect on the cells (IC 50 = 0.55 μg/mL) by the suppression of HeLa cells proliferation in G2/M phase of cell cycle and induction of cell death through double-stranded DNA damage and reactive oxygen species overproduction. Furthermore, we did not observe an increase in the activity of caspase-3/7/9 in the treated cells as well as a decrease in cellular mitochondrial membrane potential. Gene expression analysis revealed the overexpression of NF-Kappa-B inhibitors genes (>2-fold higher than control) in the treated cells., Conclusions: Bersaldegenin-1,3,5-orthoacetate induces cell cycle arrest and caspase-independent cell death through double-stranded DNA damage. These results are an important step in further studies on cell death signalling pathways induced by bufadienolides.

Furazolidone (FZD) is a widely used drug in human and veterinary medicine, and has antibacterial and antiprotozoal action. Although it is widely used as a therapy in various pathological conditions, studies on the efficacy of FZD associated with immune responses are still limited. In this review, we seek to describe which immunopharmacological responses are caused by the administration of FZD. The study followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). A systematic review of clinical trials and in vitro and in vivo experimental studies was carried out, which resulted in 943 papers, of which 35 were considered eligible and, of these 35, 4 were selected for analysis. The studies listed indicated that administration of FZD can modulate pro- or anti-inflammatory pathways, with a probable increase in the expression of reactive oxygen species and a modulation of apoptotic pathways.

Nine compounds ( MO1-MO9 ) containing the morpholine moiety were assessed for their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Most of the compounds potently inhibited MAO-B; MO1 most potently inhibited with an IC 50 value of 0.030 µM, followed by MO7 (0.25 µM). MO5 most potently inhibited AChE (IC 50 = 6.1 µM), followed by MO9 (IC 50 = 12.01 µM) and MO7 most potently inhibited MAO-A (IC 50 = 7.1 µM). MO1 was a reversible mixed-type inhibitor of MAO-B ( K i = 0.018 µM); MO5 reversibly competitively inhibited AChE ( K i = 2.52 µM); and MO9 reversibly noncompetitively inhibited AChE ( K i = 7.04 µM). MO1 , MO5 and MO9 crossed the blood-brain barrier, and were non-toxic to normal VERO cells. These results show that MO1 is a selective inhibitor of MAO-B and that MO5 is a dual-acting inhibitor of AChE and MAO-B, and that both should be considered candidates for the treatment of Alzheimer's disease.

Objective: Human adipose-derived mesenchymal stem cells (ADSCs) have the potential to be applied to solid organ treatments. However, tissue regeneration is limited by the death of transplanted cells. Ischemia is the main cause of the poor outcome. This study aimed to investigate the effect of berberine (BBR) on ADSCs after fat grafting., Methods: The antioxidant BBR on apoptosis and autophagy of ADSCs in vitro ischemia model was induced by hypoxia and serum deprivation (HY/SD). The autophagy promoter rapamycin and autophagy inhibitor 3-MA were incubated separately to investigate the crosstalk between autophagy and apoptosis. Pathway inhibitors further verified whether the autophagy and apoptosis were regulated by AMPK/mTor signaling pathway. Fat survival, fibrosis, level of inflammatory cell infiltration, and the effect of angiogenesis after BBR treatment were observed in vivo., Results: BBR could reduce ROS production and reverse the decreasing cell survival rate. HY/SD would induce apoptosis and autophagy in ADSCs, and BBR could alleviate these processes. After interfering with the level of autophagy, we also proved that apoptosis was regulated by autophagy and changed accordingly. The results also indicated that BBR could protect against autophagy and apoptosis of ADSCs through AMPK/mTor pathway. The treated human-derived adipose tissue was transplanted into BALB/c nude mice, and with the intervention of BBR, the fat grafting had a higher survival rate, lower inflammatory cell infiltration and fibrosis level., Conclusion: Our present study revealed that BBR was a promising anti-autophagy and apoptosis agent for improving the survival rate of ADSCs during cell transplantation., Competing Interests: The authors declare that they have no competing interests., (© 2021 Pang et al.)

Fungicides often cause genotoxic stress and neurodevelopmental disorders such as autism (ASD). Fungicide-azoxystrobin (AZOX) showed acute and chronic toxicity to various organisms, and remained a concern for ill effects in developing neurons. We evaluated the neurotoxicity of AZOX in developing mouse brains, and observed prenatal exposure to AZOX reduced neuronal viability, neurite outgrowth, and cortical migration process in developing brains. The 50% inhibitory concentration (IC50) of AZOX for acute (24 h) and chronic (7 days) exposures were 30 and 10 μM, respectively. Loss in viability was due to the accumulation of reactive oxygen species (ROS), and inhibited neurite outgrowth was due to the deactivation of mTORC1 kinase activity. Pretreatment with ROS scavenger- N-acetylcysteine (NAC) reserved the viability loss and forced activation of mTORC1 kinase revived the neurite outgrowth in AZOX treated neurons. Intra-amniotic injection of AZOX coupled with in utero electroporation of GFP-labelled plasmid in E15.5 mouse was performed and 20 mg/kg AZOX inhibited radial neuronal migration. Moreover, the accumulation of mitochondria was significantly reduced in AZOX treated primary neurons, indicative of mitochondrial deactivation and induction of apoptosis, which was quantified by Bcl2/Bax ratio and caspase 3 cleavage assay. This study elucidated the neurotoxicity of AZOX and explained the possible cure from it.

Of all types of dementia, Alzheimer's disease is the type that has the highest proportion of cases and is the cause of substantial medical and economic burden. The mechanism of Alzheimer's disease is closely associated with the aggregation of amyloid-β protein and causes neurotoxicity and extracellular accumulation in the brain and to intracellular neurofibrillary tangles caused by tau protein hyperphosphorylation in the brain tissue. Previous studies have demonstrated that sirtuin1 downregulation is involved in the pathological mechanism of Alzheimer's disease. The decrease of sirtuin1 level would cause Alzheimer's disease by means of promoting the amyloidogenic pathway to generate amyloid-β species and thereby triggering amyloid-β cascade reaction, such as tau protein hyperphosphorylation, neuron autophagy, neuroinflammation, oxidative stress, and neuron apoptosis. Currently, there is no effective treatment for Alzheimer's disease, it is necessary to develop new treatment strategies. According to the theory of traditional Chinese medicine and based on the mechanism of the disease, tonifying the kidneys is one of the principles for the treatment of Alzheimer's disease and Epimedium is a well-known Chinese medicine for tonifying kidney. Therefore, investigating the influence of the components of Epimedium on the pathological characteristics of Alzheimer's disease may provide a reference for the treatment of Alzheimer's disease in the future. In this article, we summarise the effects and mechanism of icariin, the main ingredient extracted from Epimedium, in ameliorating Alzheimer's disease by regulating sirtuin1 to inhibit amyloid-β protein and improve other amyloid-β cascade pathogenesis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is the most common form of dementia and is characterized by memory loss and cognitive decline. Approximately 50 million people worldwide are suffering from AD and related dementias. Very recently, the first new drug targeting amyloid-β (Aβ) aggregates has been approved by the United States Food and Drug Administration, but its efficacy against AD is still debatable. Other available treatments temporarily relieve the symptoms of AD. The difficulty in discovering effective therapeutics for AD originates from its complicated nature, which results from the interrelated pathogenic pathways led by multiple factors. Therefore, to develop potent disease-modifying drugs, multiple pathological features found in AD should be fully elucidated.Our laboratory has been designing small molecules as chemical tools to investigate the individual and interrelated pathologies triggered by four pathogenic elements found in the AD-affected brain: metal-free Aβ, metal-bound Aβ, reactive oxygen species (ROS), and acetylcholinesterase (AChE). Aβ peptides are partially folded and aggregate into oligomers, protofibrils, and fibrils. Aβ aggregates are considered to be neurotoxic, causing membrane disruption, aberrant cellular signaling, and organelle dysfunction. In addition, highly concentrated metal ions accumulate in senile plaques mainly composed of Aβ aggregates, which indicates that metal ions can directly interact with Aβ. Metal binding to Aβ affects the aggregation and conformation of the peptide. Moreover, the impaired homeostasis of redox-active Fe(II/III) and Cu(I/II) induces the overproduction of ROS through Fenton chemistry and Fenton-like reactions, respectively. Dysregulated ROS prompt oxidative-stress-damaging biological components such as lipids, proteins, and nucleic acids and, consequently, lead to neuronal death. Finally, the loss of cholinergic transmission mediated by the neurotransmitter acetylcholine (ACh) contributes to cognitive deficits observed in AD.In this Account, we illustrate the design principles for small-molecule-based chemical tools with reactivities against metal-free Aβ, metal-bound Aβ, ROS, and AChE. More importantly, mechanistic details at the molecular level are highlighted with some examples of chemical tools that were developed by our group. The aggregation of metal-free Aβ can be modulated by modifying amino acid residues responsible for self-assembling Aβ or disassembling preformed fibrils. To alter the aggregation and cytotoxicity profiles of metal-bound Aβ, ternary complexation, metal chelation, and modifications onto metal-binding residues can be effective tactics. The presence and production of ROS are able to be controlled by small molecules with antioxidant and metal-binding properties. Finally, inhibiting substrate access or substrate binding at the active site of AChE can diminish its activity, which restores the levels of ACh. Overall, our rational approaches demonstrate the feasibility of developing small molecules as chemical tools that can target and modulate multiple pathological factors associated with AD and can be useful for gaining a greater understanding of the multifaceted pathology of the disease.

We report the rational design of a tunable Cu(II) chelating scaffold, 2-(((2-((pyridin-2-ylmethyl)amino)ethyl)amino)methyl)phenol, Salpyran (HL). This tetradentate ligand is predicated to have suitable permeation, has an extremely high affinity for Cu compared to clioquinol (pCu 7.4 = 10.65 vs 5.91), and exhibits excellent selectivity for Cu(II) over Zn(II) in aqueous media. Solid and solution studies corroborate the formation of a stable [Cu(II)L] + monocationic species at physiological pH values (7.4). Its action as an antioxidant was tested in ascorbate, tau, and human prion protein assays, which reveal that Salpyran prevents the formation of reactive oxygen species from the binary Cu(II)/H 2 O 2 system, demonstrating its potential use as a therapeutic small molecule metal chelator.

Aims: Experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), is characterized by immune-mediated demyelination and neurodegeneration. NOD-like receptor protein 3 (NLRP3) inflammasome activation aggravates spinal cord inflammation in EAE. Autophagy is associated with alleviation of systemic inflammation, including that encountered in EAE. However, the effects of autophagy on NLRP3 in EAE are still unclear. Here, we evaluated the effects of the autophagy activator AZD8055 on EAE., Methods: EAE model mice were established, histological examination was performed to assess the degree of inflammatory cell infiltration and demyelination. And the levels of autophagy and NLRP3-mediated pyroptosis in spinal cords were assessed. Western blotting and immunofluorescence analyses were performed to evaluate protein expression and localization., Results: AZD8055 significantly enhanced autophagy in the spinal cords of EAE model mice, coupled with decreased abnormal clinical behavior scores and increased body weights. The degree of inflammatory cell infiltration and demyelination was mild in AZD8055-treated EAE model mice.Meanwhile, the pathway of ROS/NLRP3 was downregulated, and LC3 and NLRP3 were colocalized., Conclusions: AZD8055 ameliorated EAE through anti-inflammatory and anti-pyroptosis effects via the mammalian target of mTOR/ROS/NLRP3 pathway. These findings provide insights into the interactions between autophagy and pyroptosis and may facilitate the development of novel treatments for MS., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Organoselenium compounds have attracted growing interests as promising antitumor agents over recent years. Herein, four series of novel selenium-containing chiral 1,4-diarylazetidin-2-ones were asymmetrically synthesized and biologically evaluated for antitumor activities. Among them, compound 7 was found to be about 10-fold more potent than its prototype compound 1a, and compound 9a exhibited the most potent cytotoxicity against five human cancer cell lines, including a paclitaxel-resistant human ovarian cancer cell line A2780T, with IC 50 values ranging from 1 to 3 nM. Mechanistic studies revealed that compound 9a worked by disrupting tubulin polymerization, inducing reactive oxygen species (ROS) production, decreasing mitochondrial membrane potential, blocking the cell cycle in the G 2 /M phase, inducing cellular apoptosis and suppressing angiogenesis. Additionally, compound 9a exhibited appropriate human-microsomal metabolic stability and physicochemical properties. Importantly, compound 9a was found to inhibit tumor growth effectively in a xenograft mice model with low toxicity profile, which rendered 9a a highly promising candidate for further pre-clinical development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Ferroptosis is a type of iron-dependent necrotic cell death, which is typically triggered by the depletion of intracellular glutathione (GSH), which is associated with increased lipid peroxidation. Nitric oxide (NO) is a highly reactive gaseous radical mediator with anti-oxidation properties that terminates lipid peroxidation reactions. In the current study, we report the anti-ferroptotic action of NOC18, an NO donor that spontaneously releases NO, in cells under various ferroptotic conditions in vitro. Our results indicate that, when mouse hepatoma Hepa 1-6 cells are incubated with NOC18, cell death induced by various ferroptotic stimuli such as cysteine (Cys) starvation, the inhibition of glutathione peroxidase 4 (GPX4) and treatment with tertiary-butyl hydroperoxide (TBHP) is significantly reduced. Treatment with NOC18 failed to improve the decrease in the levels of Cys or GSH and the accumulation of ferrous iron upon ferroptotic stimuli. The fluorescent intensity of C11-BODIPY 581/591 , a probe that is used to detect lipid peroxidation products, was increased somewhat by treatment with NOC18 under conditions of Cys starvation, and the accumulation of lipid peroxidation end-products, as evidenced by the levels of 4-hydroxynonenal, were effectively suppressed. The pre-incubation of TBHP with NOC7, a short-lived NO donor completely eliminated its ability to trigger ferroptosis. These collective results indicate that NO exerts a cytoprotective action against various ferroptotic stimuli by aborting the lipid peroxidation chain reaction., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a common cause of dementia that is clinically characterized by the loss of memory and cognitive functions. Currently, there is no specific cure for the management of AD, although natural compounds are showing promising therapeutic potentials because of their safety and easy availability. Herein, we evaluated the neuroprotective properties of kojic acid (KA) in an AD mouse model. Intracerebroventricular injection (i.c.v) of Aβ 1-42 (5 μL/5 min/mouse) into wild-type adult mice induced AD-like pathological changes in the mouse hippocampus by increasing oxidative stress and neuroinflammation, affecting memory and cognitive functions. Interestingly, oral treatment of kojic acid (50 mg/kg/mouse for 3 weeks) reversed the AD pathology by reducing the expression of amyloid-beta (Aβ) and beta-site amyloid precursor protein cleaving enzyme1 (BACE-1). Moreover, kojic acid reduced oxidative stress by enhancing the expression of nuclear factor erythroid-related factor 2 (Nrf2) and heme oxygenase 1 (HO1). Also, kojic acid reduced the lipid peroxidation and reactive oxygen species in the Aβ + kojic acid co-treated mice brains. Moreover, kojic acid decreased neuroinflammation by inhibiting Toll-like receptor 4, phosphorylated nuclear factor-κB, tumor necrosis factor-alpha, interleukin 1-beta (TLR-4, p-NFκB, TNFα, and IL-1β, respectively), and glial cells. Furthermore, kojic acid enhanced synaptic markers (SNAP-23, SYN, and PSD-95) and memory functions in AD model mice. Additionally, kojic acid treatment also decreased Aβ expression, oxidative stress, and neuroinflammation in vitro in HT-22 mouse hippocampal cells. To the best of our knowledge, this is the first study to show the neuroprotective effects of kojic acid against an AD mouse model. Our findings could serve as a favorable and alternative strategy for the discovery of novel drugs to treat AD-related neurodegenerative conditions., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Glioblastoma remains one of the most challenging and devastating cancers, with only a very small proportion of patients achieving 5-year survival. The current standard of care consists of surgery, followed by radiation therapy with concurrent and maintenance chemotherapy with the alkylating agent temozolomide. To date, this drug is the only one that provides a significant survival benefit, albeit modest, as patients end up acquiring resistance to this drug. As a result, tumor progression and recurrence inevitably occur, leading to death. Several factors have been proposed to explain this resistance, including an upregulated antioxidant system to keep the elevated intracellular ROS levels, a hallmark of cancer cells, under control. In this review, we discuss the mechanisms of chemoresistance -including the important role of glioblastoma stem cells-with emphasis on antioxidant defenses and how agents that impair redox balance (i.e.: sulfasalazine, erastin, CB-839, withaferin, resveratrol, curcumin, chloroquine, and hydroxychloroquine) might be advantageous in combined therapies against this type of cancer., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Astrocytes are crucial for the maintenance of brain homeostasis by actively participating in the metabolism of glucose, which is the main energy substrate for the central nervous system (CNS), in addition to other supportive functions. More specifically, astrocytes support neurons through the metabolic coupling of synaptic activity and glucose utilization. As such, diabetes mellitus (DM) and consequent glucose metabolism disorders induce astrocyte damage, affecting CNS functionality. Glioprotective molecules can promote protection by improving glial functions and avoiding toxicity in different pathological conditions, including DM. Therefore, this review discusses specific pathomechanisms associated with DM/glucose metabolism disorder-induced gliotoxicity, namely astrocyte metabolism, redox homeostasis/mitochondrial activity, inflammation, and glial signaling pathways. Studies investigating natural products as potential glioprotective strategies against these deleterious effects of DM/glucose metabolism disorders are also reviewed herein. These products include carotenoids, catechins, isoflavones, lipoic acid, polysaccharides, resveratrol, and sulforaphane., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Osteoclasts are large, multinucleated cells that are responsible for the resorption of bone. Bone degenerative diseases, such as osteoporosis, are characterized by overactive osteoclasts. Receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) binding to its receptor on osteoclast precursors will trigger osteoclast formation and resorption. The production of reactive oxygen species (ROS) is known to play a crucial role in RANKL-induced osteoclast formation and resorption. G-protein coupled receptor 120 (GPR120) signalling has been shown to affect osteoclast formation, but the exact mechanisms of action require further investigation. RAW264.7 murine macrophages were seeded into culture plates and exposed to the GPR120 agonist, TUG-891, at varying concentrations (20-100 µM) and RANKL to induce osteoclast formation. TUG-891 was shown to inhibit osteoclast formation and resorption without affecting cell viability in RAW264.7 macrophages. TUG-891 further decreased ROS production when compared to RANKL only cells. Antioxidant proteins, Nrf2, HO-1 and NQO1 were shown to be upregulated while the ROS inducing protein, Nox1, was downregulated by TUG-891. Gene silencing revealed that TUG-891 exerted its effects specifically through GPR120. This study reveals that GPR120 signalling may inhibit osteoclast formation and resorption through inhibition on ROS production.

Background: Microglial-mediated neuroinflammation plays an important role in vascular dementia, and modulating neuroinflammation has emerged as a promising treatment target. Nicotinamide adenine dinucleotide (NAD + ) shows anti-inflammatory and anti-oxidant effects in many neurodegenerative disease models, but its role in the chronic cerebral hypoperfusion (CCH) is still unclear., Methods: The bilateral common carotid artery occlusion (BCCAO) was performed to establish CCH models in Sprague-Dawley rats. The rats were given daily intraperitoneal injection of NAD + for 8 weeks. The behavioral test and markers for neuronal death and neuroinflammation were analyzed. Mitochondrial damage and ROS production in microglia were also assessed. RNA-seq was performed to investigate the mechanistic pathway changes. For in vitro studies, Sirt1 was overexpressed in BV2 microglial cells to compare with NAD + treatment effects on mitochondrial injury and neuroinflammation., Results: NAD + administration rescued cognitive deficits and inhibited neuroinflammation by protecting mitochondria and decreasing ROS production in CCH rats. Results of mechanistic pathway analysis indicated that the detrimental effects of CCH might be associated with decreased gene expression of PPAR-γ co-activator1α (PGC-1α) and its upstream transcription factor Sirt1, while NAD + treatment markedly reversed their decrease. In vitro study confirmed that NAD + administration had protective effects on hypoxia-induced neuroinflammation and mitochondrial damage, as well as ROS production in BV2 microglia via Sirt1/PGC-1α pathway. Sirt1 overexpression mimicked the protective effects of NAD + treatment in BV2 microglia., Conclusions: NAD + ameliorated cognitive impairment and dampened neuroinflammation in CCH models in vivo and in vitro, and these beneficial effects were associated with mitochondrial protection and ROS inhibition via activating Sirt1/PGC-1α pathway., (© 2021. The Author(s).)

Glioblastoma multiforme is one of the most deadly malignant tumors, with more than 10,000 cases recorded annually in the United States. Various clinical analyses and studies show that certain chronic diseases, including cancer, interact between cell-reactive radicals rise and pathogenesis. Reactive oxygen and nitrogenous sources include endogenous (physiological processes), and exogenous sources contain reactive oxygen and nitrogen (xenobiotic interaction). The cellular oxidation/reduction shifts to oxidative stress when the regulation mechanisms of antioxidants are surpassed, and this raises the ability to damage cellular lipids, proteins, and nucleic acids. OBJECTIVE: This review is focused on how phytochemicals play crucial role against glioblastoma multiforme and to combat these, bioactive molecules and their derivatives are either used alone, in combination with anticancer drugs or as nanomedicine formulations for better cancer theranostics over the conventional approach. CONCLUSION: Bioactive molecules found in seeds, vegetables, and fruits have antioxidant, anti-inflammatory, and anticancer properties that may help cancer survivors feel better throughout chemotherapy or treatment. However, incorporating them into the nanocarrier-based drug delivery for the treatment of GBMs, which could be a promising therapeutic strategy for this tumor entity, increasing targeting effectiveness, increasing bioavailability, and reducing side effects with this target-specificity, drug internalization into cells is significantly improved, and off-target organ aggregation is reduced., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The Coronavirus disease 19 (Covid-19) pandemic is devastating the public health: it is urgent to find a viable therapy to reduce the multiorgan damage of the disease. A validated therapeutic protocol is still missing. The most severe forms of the disease are related to an exaggerated inflammatory response. The pivotal role of reactive oxygen species (ROS) in the amplification of inflammation makes the antioxidants a potential therapy, but clinical trials are needed. The lecitinized superoxide dismutase (PC-SOD) could represent a possibility because of bioaviability, safety, and its modulatory effect on the innate immune response in reducing the harmful consequences of oxidative stress. In this review we summarize the evidence on lecitinized superoxide dismutase in animal and human studies, to highlight the rationale for using the PC-SOD to treat COVID-19., (Copyright © 2021. Published by Elsevier Masson SAS.)

Liver cancer is one of the most common and high recurrence malignancies. Besides radiotherapy and surgery, chemotherapy also plays an essential role in the treatment of liver cancer. Sorafenib and sorafenib-based combination therapies have been proven efficacy against tumors. However, previous clinical studies have indicated that some patients with liver cancer are resistant to sorafenib treatment and the existing strategies are not satisfactory in the clinic. Therefore, it is urgent to investigate strategies to improve the effectiveness of sorafenib for liver cancer and to explore effective drug combinations. In the present study, we found that dichloroacetate (DCA) could significantly enhance the anti-tumor effect of sorafenib on liver cancer cells, including reduced viability and dramatically promoted apoptosis in liver cancer cells. Moreover, compared to sorafenib alone, the combination of DCA and sorafenib markedly increased the degradation of anti-apoptotic protein Mcl-1 by enhancing its phosphorylation. Overexpression of Mcl-1 could significantly attenuate the synergetic effect of DCA and sorafenib on apoptosis induction in liver cancer cells. Furthermore, we found that the ROS-JNK pathway was obviously activated in the DCA combined sorafenib group. The levels of ROS and p-JNK were dramatically up-regulated in the two drug combination groups. Antioxidant NAC could alleviate the synergetic effects of DCA and sorafenib on ROS generation, JNK activation, Mcl-1 degradation, and cell apoptosis. Moreover, DCA and sorafenib's effects on Mcl-1 degradation and apoptosis could also be inhibited by JNK inhibitor 'SP'600125. Finally, the synergetic effects of DCA and sorafenib on tumor growth suppression, Mcl-1 degradation and induction of apoptosis were also validated in liver cancer xenograft in vivo. These findings indicate that DCA enhances the anti-tumor effect of sorafenib via the ROS-JNK-Mcl-1 pathway in liver cancer cells. This study may provide new insights to improve the chemotherapeutic effect of sorafenib, which may be beneficial for further clinical application of sorafenib in liver cancer treatment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Ferroptosis is a type of regulated cell death driven by iron dependent accumulation of cellular reactive oxygen species (ROS) when glutathione (GSH)-dependent lipid peroxidation repair systems are compromised. Nuclear receptor co-activator 4 (NCOA4)-mediated selective autophagy of ferritin, termed ferritinophagy, involves the regulation of ferroptosis. Emerging evidence has revealed that ferritinophagy and ferroptosis exert a significant role in the occurrence and development of cardiovascular disease. In the present review, we aimed to present a brief overview of ferritinophagy and ferroptosis focusing on the underlying mechanism and regulations involved. We summarize and discuss relevant research progress on the role of ferritinophagy and ferroptosis in cardiovascular diseases accompanied with potential applications of ferritinophagy and ferroptosis modulators in the treatment of ferroptosis-associated cardiovascular diseases., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Cisplatin (CisPT) is a chemotherapeutic drug that outcomes in adverse effects. In this study, we examined the effect of A. hydaspica ethyl acetate extract (AHE) in an animal model of cisplatin-induced acute kidney injury (AKI). 36 male Sprague Dawley rats were used in the AKI rat model, and CisPT (7.5 mg/kg BW, i.p) single dose was given. In the pretreatment module, AHE (400 mg/kgBW/day, p.o) was given for 7 days before and after CisPT injection. While in the post-treatment group AHE was administered for 7 days after a single CisPT shot. The standard group received silymarin (100 mg/kg BW, p.o) for 7 days before and after CisPT injection. In HCT 116 tumor xenografts (n = 32) two groups of mice were pretreated with 400 mg/kg AHE orally for 7 days and two groups were treated with distilled water. On day 7 of pretreatment one distilled water and one AHE pretreated group were injected i.p with 15 mg/kg bw dose followed by another dose of CisPT 2 wk later. AHE groups were additionally treated with 400 mg/kg AHE for 3 days/week for 2 weeks. CisPT significantly deteriorated renal function parameters, i.e., PH, specific gravity, total protein, albumin, urea, creatinine, uric acid, globulin and blood urea nitrogen. CisPT treatment increased oxidative stress markers, while lower renal antioxidant enzymes. AHE pretreatment ameliorates significantly (p < 0.0001) CisPT-induced alterations in serum and urine markers for kidney function. Furthermore, AHE pretreatment more efficiently (p < 0.001) decreases oxidative stress markers, attenuate NF-κB, and IL-6 protein and mRNA expression by augmenting antioxidant enzyme levels compared to post-treatment. The histological observations verified the protective effect of AHE. In tumor xenograft mice, AHE treatment significantly reduced CisPT induced oxidative stress while it did not interfere with the anticancer efficacy of cisplatin as shown by significance (p < 0.001) decrease in tumor size after treatment. A. hydaspica AHE might provide a prospective adjuvant that precludes CisPT-induced nephrotoxicity without compromising its antitumor potential., (© 2021. The Author(s).)

Carbon tetrachloride (CCl 4 ) is an abundant environmental pollutant that can generate free radicals and induce oxidative stress in different human and animal organs like the kidney, lung, brain, and spleen, causing toxicity. The present study evaluated the alleviative mechanism of the isolated polyphenolic fraction from seedless (pulp and skin) black Vitis vinifera (VVPF) on systemic oxidative and necroinflammatory stress in CCl 4 -intoxicated rats. Here, we found that the administration of VVPF to CCl 4 -intoxicated rats for ten days was obviously ameliorated the CCl 4 -induced systemic elevation in ROS, NO and TBARS levels, as well as MPO activity. Also, it upregulated the cellular activities of the enzymatic (SOD, and GPx) and non-enzymatic (TAC and GSH) antioxidants. Furthermore, the gene expression of the ROS-related necroinflammatory mediators (NF-κB, iNOS, COX-2, and TNF-α) in the kidney, brain, and spleen, as well as IL-1β, and IL-8 in the lung were greatly restored. The histopathological studies confirmed these biochemical results and showed a noticeable enhancing effect in the architecture of the studied organs after VVPF intake. Thus, this study indicated that VVPF had an alleviative effect on CCl 4 -induced necroinflammation and oxidative stress in rat kidney, lung, brain, and spleen via controlling the ROS/NF-κB pathway., (© 2021. The Author(s).)

Stent implantation is the primary method used to treat coronary heart disease. However, it is associated with complications such as restenosis and late thrombosis. Despite surface modification being an effective way to improve the biocompatibility of stents, the current research studies are not focused on changes in the vascular microenvironment at the implantation site. In the present study, an adaptive drug-loaded coating was constructed on the surface of vascular stent materials that can respond to oxidative stress at the site of vascular lesions. Two functional molecules, epigallocatechin gallate (EGCG) and cysteine hydrochloride, were employed to fabricate a coating on the surface of 316L stainless steel. In addition, the coating was used as a drug carrier to load pitavastatin calcium. EGCG has antioxidant activity, and pitavastatin calcium can inhibit smooth muscle cell proliferation. Therefore, EGCG and pitavastatin calcium provided a synergistic anti-inflammatory effect. Moreover, the coating was cross-linked using disulfide bonds, which accelerated the release of the drug in response to reactive oxygen species. A positive correlation was observed between the rate of drug release and the degree of oxidative stress. Collectively, this drug-loaded oxidative stress-responsive coating has been demonstrated to significantly inhibit inflammation, accelerate endothelialization, and reduce the risk of restenosis of vascular stents in vivo .

Bladder cancer is one of the most common malignancy in the urinary tract with high recurrence and drug resistance in clinics. Alternative treatments from existing drugs might be a promising strategy. Nitazoxanide (NTZ), an FDA-approved antiprotozoal drug, has got increasingly noticed because of its favorable safety profile and antitumor potential, yet the effects in bladder cancer and underlying mechanisms remain poorly understood. Herein, we find that NTZ induces mitochondrial damage and mitophagy initiation through PINK1-generated phospho-ubiquitin(pS65-Ub) and autophagy receptor-mediated pathway even in the absence of Atg5/Beclin1. Meanwhile, NTZ inhibits lysosomal degradation activity, leading to mitophagy flux impairment at late stage. Mitochondrial reactive oxygen species (ROS) production is critical in this process, as eliminating ROS with N-acetylcysteine (NAC) efficiently inhibits PINK1 signaling-mediated mitophagy initiation and alleviates lysosomal dysfunction. Co-treatment with NTZ and autophagy inhibitor Chloroquine (CQ) to aggravate mitophagy flux impairment promotes NTZ-induced apoptosis, while alleviation of mitophagy flux impairment with ROS scavenger reduces cell death. Moreover, we also discover a similar signaling response in the 3D bladder tumor spheroid after NTZ exposure. In vivo study reveals a significant inhibition of orthotopic bladder tumors with no obvious systemic toxicity. Together, our results uncover the anti-tumor activities of NTZ with the involvement of ROS-mediated mitophagy modulation at different stages and demonstrate it as a potential drug candidate for fighting against bladder tumors., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ferroptosis is a new mode of cell death different from cell necrosis, autophagy, apoptosis, and pyroptosis, which depends on the accumulation of reactive oxygen species (ROS) caused by iron-mediated lipid peroxidation, exhibits cellular, molecular, and gene-level characteristics distinct from other cell deaths. Since ferroptosis discovery, it has become a new target for antitumor therapy actively explored by researchers. In this review, we provide an overview of the known mechanisms that regulate the sensitivity of cancer cells to ferroptosis and the research progress of ferroptosis-related drugs (western medicine, traditional Chinese medicine, and nanomedicine), as well as the relationship between ferroptosis and cancer treatment, tumor drug resistance, and antitumor immunotherapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We have recently demonstrated the role of the Fyn-PKCδ signaling pathway in status epilepticus (SE)-induced neuroinflammation and epileptogenesis in experimental models of temporal lobe epilepsy (TLE). In this study, we show a significant disease-modifying effect and the mechanisms of a Fyn/Src tyrosine kinase inhibitor, saracatinib (SAR, also known as AZD0530), in the rat kainate (KA) model of TLE. SAR treatment for a week, starting the first dose (25 mg/kg, oral) 4 h after the onset of SE, significantly reduced spontaneously recurring seizures and epileptiform spikes during the four months of continuous video-EEG monitoring. Immunohistochemistry of brain sections and Western blot analyses of hippocampal lysates at 8-day (8d) and 4-month post-SE revealed a significant reduction of SE-induced astrogliosis, microgliosis, neurodegeneration, phosphorylated Fyn/Src-419 and PKCδ-tyr311, in SAR-treated group when compared with the vehicle control. We also found the suppression of nitroxidative stress markers such as iNOS, 3-NT, 4-HNE, and gp91 phox in the hippocampus, and nitrite and ROS levels in the serum of the SAR-treated group at 8d post-SE. The qRT-PCR (hippocampus) and ELISA (serum) revealed a significant reduction of key proinflammatory cytokines TNFα and IL-1β mRNA in the hippocampus and their protein levels in serum, in addition to IL-6 and IL-12, in the SAR-treated group at 8d in contrast to the vehicle-treated group. These findings suggest that SAR targets some of the key biomarkers of epileptogenesis and modulates neuroinflammatory and nitroxidative pathways that mediate the development of epilepsy. Therefore, SAR can be developed as a potential disease-modifying agent to prevent the development and progression of TLE., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent studies have reported that methylmercury (MeHg) induces neuronal apoptosis, which is accompanied by abnormal neurological development. Despite the important role of docosahexaenoic acid (DHA) in maintaining the structure and function of the brain, as well as improving neuronal apoptosis induced by MeHg, the exact mechanism remains unknown. The present study hypothesized that the reactive oxygen species (ROS)‑mediated JNK signaling pathway may be associated with the protective effect of DHA against MeHg‑induced PC12 cell apoptosis. Cell Counting Kit‑8, TUNEL staining, flow cytometry, ROS detection, PCR and western blot analysis were performed. The results demonstrated that MeHg inhibited the activity of PC12 cells, causing oxidative damage and promoting apoptosis; however, DHA significantly attenuated this effect. Mechanistic studies revealed that MeHg increased intracellular ROS levels and JNK protein phosphorylation, and decreased the expression levels of the anti‑apoptotic protein Bcl‑2, whereas DHA reduced ROS levels and JNK phosphorylation, and increased Bcl‑2 expression. In addition, the ROS inhibitor N‑acetyl‑l‑cysteine (NAC) was used to verify the experimental results. After pretreatment with NAC, expression levels of Bcl‑2, Bax, phosphorylated‑JNK and JNK were assessed. Bcl‑2 protein expression was increased and the Bcl‑2/Bax ratio was increased. Moreover, the high expression levels of phosphorylated‑JNK induced by MeHg were significantly decreased. Based on the aforementioned results, the present study indicated that the effects of DHA against MeHg‑induced PC12 cell apoptosis may be mediated via the ROS/JNK signaling pathway.

Objective: To investigate effects of dexmedetomidine (DEX) on miR-205-5p/HMGB1 axis in cerebral ischemic/reperfusion (I/R) injury., Methods: Both in vivo I/R rat model and in vitro hypoxia/reoxygenation (H/R) cell model using rat hippocampal neurons cells were established. miR-205-5p was overexpressed or inhibited by transfection of miR-205-5p mimics or inhibitor. HMGB1 was overexpressed by transfection overexpression plasmids (OE-HMGB1). TTC staining was used for measurement of infraction volume. Oxidative stress was evaluated by measurement of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) and inflammation was evaluated by measurement of IL-1β, IL-6 and TNF-α. Dual luciferase reporter assay was performed to confirm binding between miR-205-5p and HMGB1. The expression levels of miR-205-5p, and HMGB1 were measured using RT-qPCR. Western blotting was used to test the protein expression levels of HMGB1, nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase (GPx), glutathione reductase (GR), heme oxygenase 1 (HO-1) and catalase (CAT)., Results: Treatment of DEX significantly reduced brain infraction volume, decreased Longa's neurological function score and inhibited oxidative stress and inflammation in brain tissues of I/R rats, which were all reversed by inhibition of miR-205-5p. Both treatment of DEX or overexpression of miR-205-5p restricted oxidative stress and inflammation in H/R rat hippocampal neurons cells. The inhibition of miR-205-5p reversed the effects of DEX, while the overexpression of HMGB1 reversed the effects of miR-205-5p overexpression in H/R rat hippocampal neurons cells. Dual luciferase reporter assay showed miR-205-5p directly targeted HMGB1., Conclusion: DEX improved I/R injury by suppressing brain oxidative stress and inflammation DEX improved I/R injury by suppressing brain oxidative stress and inflammation through activating miR-205-5p/HMGB1 axis through activating miR-205-5p/HMGB1 axis.

L-arginine (Arg), a semi-essential amino acid, has recently been shown to attenuate inflammatory response during cardiovascular disease. NLRP3 inflammasome serves a central role in amplification of cellular inflammation. In this study, we aimed to confirm the modulatory effect of Arg on NLRP3 inflammasome and the underlying mechanisms in vascular endothelial cells (ECs). Arg suppressed NLRP3 inflammasome activation in ECs stimulated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP). Moreover, treatment with Arg increased the expression of the deacetylase sirtuin 1 (SIRT1) in ECs. Importantly, knockdown of SIRT1 abolished the inhibitory potential of Arg on the activation of NLRP3 inflammasome. Further study indicated that Arg also alleviated LPS plus ATP-induced the generation of reactive oxygen species (ROS) in ECs. In addition, Arg may regulate NLRP3 inflammasome activation partly through suppression of ROS production. In combination, we speculate that Arg exerts an inhibitory effect on the activation of NLRP3 inflammasome in ECs, which may be partly mediated by SIRT1 and ROS., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Berries are natural sources of anthocyanins, especially cyanidin-3-glucoside (C3G), and exhibit significant antioxidant, antidiabetic, anti-inflammatory, and cytoprotective effects against various oxidative stress-induced disorders. C3G and its metabolites possess higher absorption and bioavailability, and interaction with gut microbiota may enhance their health benefits. Various in vitro studies have shown the reactive oxygen species (ROS)-mitigating potential of C3G. However, in in vivo models, C3G exerts its cytoprotective properties by regulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant-responsive element (ARE) pathway. Despite existing reports stating various health benefits of C3G, its antioxidant potential by modulating the Nrf2 pathway remains less identified. This review discusses the Nrf2-mediated antioxidant response of C3G in modulating oxidative stress against DNA damage, apoptosis, carcinogen toxicity, and inflammatory conditions. Furthermore, we have reviewed the recent clinical trial data to establish cross talk between a berry-rich diet and disease prevention., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Cancer, a fatal disease, is also one of the main causes of death worldwide. Despite various developments to prevent and treat cancer, the side effects of anticancer drugs remain a major concern. Ascorbic acid is an essential vitamin required by our bodies for normal physiological function and also has antioxidant and anticancer activity. Although the body cannot synthesize ascorbic acid, it is abundant in nature through foods and other natural sources and also exists as a nutritional food supplement. In anticancer drug development, ascorbic acid has played an important role by inhibiting the development of cancer through various mechanisms, including scavenging reactive oxygen species (ROS), selectively producing ROS and encouraging their cytotoxicity against tumour cells, preventing glucose metabolism, serving as an epigenetic regulator, and regulating the expression of HIF in tumour cells. Several ascorbic acid analogues have been produced to date for their anticancer and antioxidant activity. The current review summarizes the mechanisms behind ascorbic acid's antitumor activity, presents a compilation of its derivatives and their biological activity as anticancer agents, and discusses delivery systems such as liposomes, nanoparticles against cancer, and patents on ascorbic acid as anticancer agents.

Morroniside, a major iridoid glycoside isolated from Cornus officinalis, has a variety of beneficial pharmacological properties. Although morroniside has recently been reported to exhibit anti-inflammatory and antioxidant effects, the detailed mechanism has not yet been fully elucidated. In this study, we investigated the inhibitory effect of morroniside on inflammatory and oxidative stress activated by lipopolysaccharide (LPS) in RAW 264.7 macrophages. Our results indicated that morroniside pretreatment significantly inhibited the LPS-induced phagocytic activity and release of pro-inflammatory factors, which was associated with blocking the expression of their regulatory genes. Morroniside also markedly suppressed the expression of myeloid differentiation factor 88 as well as Toll-like receptor 4 (TLR4), and attenuated the translocation of nuclear factor-κB (NF-κB) to the nucleus in LPS-treated RAW 264.7 macrophages. Furthermore, morroniside prevented the binding of LPS to the TLR4 on the cell surface. In addition, morroniside abolished reactive oxygen species (ROS) generation, and enhanced the expression of heme oxygenase-1 (HO-1) following activation of nuclear factor-E2-related factor 2 (Nrf2) in LPS-stimulated RAW 264.7 macrophages. However, zinc protoporphyrin, a specific inhibitor of HO-1, reversed the morroniside-mediated inhibition of inflammatory response in LPS-treated RAW 264.7 macrophages. In conclusion, our findings suggest that morroniside exerts LPS-induced anti-inflammatory and antioxidant effects by targeting the TLR4/NF-κB and Nrf2/HO-1 signaling pathways in RAW 264.7 macrophages. Taken together, our findings suggest that morroniside interacted structurally and electrochemically with TLR4/MD2 complex, consequently can be a potential functional agent to prevent inflammatory and oxidative damage., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The cluster of differentiation 36 (CD36) is a scavenger receptor present on various types of cells and has multiple biological functions that may be important in inflammation and in the pathogenesis of metabolic diseases, including diabetes. Here, we consider recent insights into how the CD36 response becomes deregulated under metabolic conditions, as well as the therapeutic benefits of CD36 inhibition, which may provide clues for developing strategies aimed at the treatment or prevention of diabetes associated with metabolic diseases. To facilitate this process further, it is important to pinpoint regulatory mechanisms that are relevant under physiological and pathological conditions. In particular, understanding the mechanisms involved in dictating specific CD36 downstream cellular outcomes will aid in the discovery of potent compounds that target specific CD36 downstream signaling cascades.

Superoxide radicals and other reactive oxygen species (ROS) are implicated in influenza A virus-induced inflammation. In this in vitro study, we evaluated the effects of TG6-44, a novel quinazolin-derived myeloperoxidase-specific ROS inhibitor, on influenza A virus (A/X31) infection using THP-1 lung monocytic cells and freshly isolated peripheral blood mononuclear cells (PBMC). TG6-44 significantly decreased A/X31-induced ROS and virus-induced inflammatory mediators in THP-1 cells (IL-6, IFN-γ, MCP-1, TNF-α, MIP-1β) and in human PBMC (IL-6, IL-8, TNF-α, MCP-1). Interestingly, TG6-44-treated THP-1 cells showed a decrease in percent cells expressing viral nucleoprotein, as well as a delay in translocation of viral nucleoprotein into the nucleus. Furthermore, in influenza A virus-infected cells, TG6-44 treatment led to suppression of virus-induced cell death as evidenced by decreased caspase-3 activation, decreased proportion of Annexin V+PI+ cells, and increased Bcl-2 phosphorylation. Taken together, our results demonstrate the anti-inflammatory and anti-infective effects of TG6-44., Competing Interests: The authors have declared that no competing interests exist.

Glomerulonephritis are renal inflammatory processes characterized by increased permeability of the Glomerular Filtration Barrier (GFB) with consequent hematuria and proteinuria. Glomerular endothelial cells (GEC) and podocytes are part of the GFB and contribute to the maintenance of its structural and functional integrity through the release of paracrine mediators. Activation of the complement cascade and pro-inflammatory cytokines (CK) such as Tumor Necrosis Factor α (TNF-α) and Interleukin-6 (IL-6) can alter GFB function, causing acute glomerular injury and progression toward chronic kidney disease. Endothelial Progenitor Cells (EPC) are bone-marrow-derived hematopoietic stem cells circulating in peripheral blood and able to induce angiogenesis and to repair injured endothelium by releasing paracrine mediators including Extracellular Vesicles (EVs), microparticles involved in intercellular communication by transferring proteins, lipids, and genetic material (mRNA, microRNA, lncRNA) to target cells. We have previously demonstrated that EPC-derived EVs activate an angiogenic program in quiescent endothelial cells and renoprotection in different experimental models. The aim of the present study was to evaluate in vitro the protective effect of EPC-derived EVs on GECs and podocytes cultured in detrimental conditions with CKs (TNF-α/IL-6) and the complement protein C5a. EVs were internalized in both GECs and podocytes mainly through a L-selectin-based mechanism. In GECs, EVs enhanced the formation of capillary-like structures and cell migration by modulating gene expression and inducing the release of growth factors such as VEGF-A and HGF. In the presence of CKs, and C5a, EPC-derived EVs protected GECs from apoptosis by decreasing oxidative stress and prevented leukocyte adhesion by inhibiting the expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin). On podocytes, EVs inhibited apoptosis and prevented nephrin shedding induced by CKs and C5a. In a co-culture model of GECs/podocytes that mimicked GFB, EPC-derived EVs protected cell function and permeselectivity from inflammatory-mediated damage. Moreover, RNase pre-treatment of EVs abrogated their protective effects, suggesting the crucial role of RNA transfer from EVs to damaged glomerular cells. In conclusion, EPC-derived EVs preserved GFB integrity from complement- and cytokine-induced damage, suggesting their potential role as therapeutic agents for drug-resistant glomerulonephritis.

Formononetin is an isoflavone, found in herbs like Trifolium pratense, which executes a variety of physiological activities including anti-neurodegenerative effect. However, the molecular mechanism of formononetin-mediated neuroprotection remains unclear. In this study, we investigated the protective effect of formononetin on hydrogen peroxide (H 2 O 2 )-induced death of human neuroblastoma SH-SY5Y cells and its underlying molecular mechanism. Formononetin suppressed H 2 O 2 -induced cytotoxicity. H 2 O 2 -induced increase in the intracellular reactive oxygen species (ROS) levels was decreased by formononetin, together with the enhanced expression of the antioxidant genes. H 2 O 2 -induced elevation of the Bax/Bcl-2 ratio and cleaved caspase-3 and caspase-7 levels were lowered by formononetin treatment. Moreover, formononetin repressed H 2 O 2 -induced phosphorylation of mitogen-activated protein kinases (MAPKs). Nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA decreased antioxidant gene expression and elevated the H 2 O 2 -induced ROS level in the formononetin-treated cells. Furthermore, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling is involved in the activation of the nuclear translocation of Nrf2. These results indicate that the neuroprotective effect of formononetin against H 2 O 2 -induced cell death is due to a decrease in the ROS level with the enhanced expression of the antioxidant genes through activation of the PI3K/Akt-Nrf2 signaling. In addition, formononetin suppressed apoptosis through inhibition of phosphorylation of MAPKs in SH-SY5Y cells. Thus, formononetin is a potential therapeutic agent for the treatment of neurodegenerative diseases., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The dysregulated host response and organ damage following systemic infection that characterizes a septic event predisposes individuals to a chronic immunoparalysis state associated with severe transient lymphopenia and diminished lymphocyte function, thereby reducing long-term patient survival and quality of life. Recently, we observed lasting production of reactive oxygen species (ROS) in mice that survive sepsis. ROS production is a potent mechanism for targeting infection, but excessive ROS production can prove maladaptive by causing organ damage, impairing lymphocyte function, and promoting inflammaging, concepts paralleling sepsis-induced immunoparalysis. Notably, we observed an increased frequency of ROS-producing immature monocytes in septic hosts that was sustained for greater than 100 days postsurgery. Recent clinical trials have explored the use of vitamin C, a potent antioxidant, for treating septic patients. We observed that therapeutic vitamin C administration for sepsis limited ROS production by monocytes and reduced disease severity. Importantly, we also observed increased ROS production by immature monocytes in septic patients both at admission and ∼28 days later, suggesting a durable and conserved feature that may influence the host immune response. Thus, lasting ROS production by immature monocytes is present in septic patients, and early intervention strategies to reduce it may improve host outcomes, potentially reducing sepsis-induced immunoparalysis., (Copyright © 2021 The Authors.)