Antioxidant Signaling Pathway Research Articles

Everolimus alleviates CD4+ T cell inflammation by regulating autophagy and cellular redox homeostasis.

Aging is associated with the onset and progression of multiple diseases, which limit health span. Chronic low-grade inflammation in the absence of overt infection is considered the simmering source that triggers age-associated diseases. Failure of many cellular processes during aging is mechanistically linked to inflammation; however, the overall decline in the cellular homeostasis mechanism of autophagy has emerged as one of the top and significant inducers of inflammation during aging, frequently known as inflammaging. Thus, physiological or pharmacological interventions aimed at improving autophagy are considered geroprotective. Rapamycin analogs (rapalogs) are known for their ability to inhibit mTOR and thus regulate autophagy. This study assessed the efficacy of everolimus, a rapalog, in regulating inflammatory cytokine production in T cells from older adults. CD4+ T cells from older adults were treated with a physiological dose of everolimus (0.01µM), and indices of autophagy and inflammation were assessed to gain a mechanistic understanding of the effect of everolimus on inflammation. Everolimus (Ever) upregulated autophagy and broadly alleviated inflammatory cytokines produced by multiple T cell subsets. Everolimus's ability to alleviate the cytokines produced by Th17 subsets of T cells, such as IL-17A and IL-17F, was dependent on autophagy and antioxidant signaling pathways. Repurposing the antineoplastic drug everolimus for curbing inflammaging is promising, given the drug's ability to restore multiple cellular homeostasis mechanisms.

S-Nitrosoglutathione Attenuates Oxidative Stress and Improves Retention Memory Dysfunctions in Intra-Cerebroventricular-Streptozotocin Rat Model of Sporadic Alzheimer's Disease via Activation of BDNF and Nuclear Factor Erythroid 2-Related Factor-2 Antioxidant Signaling Pathway.

The brain-derived neurotrophic factor (BDNF) and transcription nuclear factor erythroid 2-related factor-2 (NRF-2) play an important role in Alzheimer's disease (AD). However, the interactive involvement of BDNF and NRF-2 in respect to antioxidant mechanisms in different parts of the AD brain is still unclear. Considering the above condition, used S-nitrosoglutathione (GSNO) to examine whether it modulates the BDNF and NRF-2 levels to activate signaling pathway to promote antioxidant levels in AD brains. AD was induced by intracerebroventricular infusion of streptozotocin (ICV-STZ, 3 mg/kg) in Wistar rats. The effect of GSNO was analyzed by evaluating the retention of memory in months 1, 2, and 3. After the behavior study, rats were sacrificed and accessed the amyloid beta (Aβ)-40, Aβ42, glutathione (GSH), BDNF, and NRF-2 levels in the hippocampus, cortex, and amygdala tissue. Pretreatment with GSNO (50 µg/kg/intraperitoneal/day) restored the BDNF, and NRF-2 levels toward normalcy as compared with ICV-STZ + saline-treated animals. Also, GSNO treatment reversed the oxidative stress and increased the GSH levels toward normal levels. Further, reduced Aβ levels and neuronal loss in different brain regions. As a result, GSNO treatment improved the cognitive deficits in ICV-STZ-treated rats. The results showed that endogenous nitric oxide donor GSNO improved the cognitive deficits and ICV-STZ-induced AD pathological conditions, possibly via attenuating the oxidative stress. Hence, the above finding supported that GSNO treatment may activate BDNF and NRF-2 antioxidant signaling pathways in the AD brain to normalize oxidative stress, which is the main causative factor for ICV-STZ-induced AD pathogenesis.

New insights into the potential cardioprotective effects of telmisartan and nanoformulated extract of Spirulina platensis via regulation of oxidative stress, apoptosis, and autophagy in an experimental model.

Cardiotoxicity is one of the limiting side effects of the commonly used anticancer agent cyclophosphamide (Cyclo). The possible protective effects of telmisartan and nanoformulated Spirulina platensis (Sp) methanolic extract against Cyclo-induced cardiotoxicity were examined in this study. Experimental groups of rats were randomly divided into nine groups as control vehicle, control polymer, telmisartan (TEL, 10mg/kg), free Sp extract (300mg/kg), nano Sp extract (100mg/kg), Cyclo (200mg/kg), TEL + Cyclo, free Sp + Cyclo, and nano Sp + Cyclo. The groups with Cyclo combinations were treated in the same manner as their corresponding ones without Cyclo, with a single dose of Cyclo on day 18. The results indicate that Cyclo causes significant cardiotoxicity, manifesting in the form of notable increases of 155.49%, 105.74%, 451.76%, and 826.07% in the serum levels of glutamic oxaloacetic transaminase (SGOT), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), and cardiac troponin I (cTnI) enzyme activities, respectively, as compared to the control. In addition, the cardiac glutathione (GSH) content and activity of glutathione peroxidase-1 (GPX-1) enzyme decreased by 65.94% and 73.85%, respectively. Treatment with nano Sp extract showed the most prominent restorations of the altered biochemical, histopathological, and immunohistochemical features as compared with those by TEL and free Sp; moreover, reductions of 30.64% and 43.02% in the p-AKT content as well as 60.43% and 75.30% of the endothelial nitric oxide synthase (eNOS) immunoreactivity were detected in the TEL and free Sp treatment groups, respectively. Interestingly, nano Sp boosted the autophagy signal via activation of beclin-1 (36.42% and 153.4%), activation of LC3II (69.13% and 195%), downregulation of p62 expressions (39.68% and 62.45%), and increased gene expressions of paraoxonase-1 (PON-1) (90.3% and 225.9%) compared to the TEL and free Sp treatment groups, respectively. The findings suggest the protective efficiency of telmisartan and nano Sp extract against cardiotoxicity via activations of the antioxidant, antiapoptotic, and autophagy signaling pathways.

Cyperus peptide SFRWQ inhibits oxidation and inflammation in RAW264.7 cell model

Oxidative stress can induce many diseases. Antioxidant peptides from food sources have the advantages of good safety, high activity, and good absorbability. In this study, a pentapeptide (SFRWQ; SER-PHE-ARG-TRP-GLN) was identified in a protein hydrolysate of Cyperus (Cyperus esculentus L.). Enzyme-linked immunosorbent assay (ELISA), real-time quantitative (qPCR), immunofluorescence and other techniques were used to evaluate the anti-inflammatory and antioxidant effects of SFRWQ. SFRWQ was found to have 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical-scavenging ability, help increase superoxide dismutase (SOD) and catalase (CAT) levels in RAW264.7 cells, reduce reactive oxygen species (ROS) levels, and decrease tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) gene expression and secretion. The binding score of SFRWQ to recombinant Kelch-like ECH-associated protein 1 (Keap1) was greater than that of TX6. These findings suggest that SFRWQ activates the Keap1-Nrf2 cellular antioxidant signaling pathway. According to metabolomics studies, SFRWQ increased glutathione (GSH), glutathione disulfide (GSSG), and γ-glutamylcysteine levels and decreased the levels of Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), and Prostaglandin H2 (PGH2), which are involved in arachidonic acid metabolism, to protect cells from LPS-induced damage. By elucidating the mechanism of action of SFRWQ, we provide a reference for the development of dietary antioxidant peptides.

Fisetin Alleviates Inflammation and Oxidative Stress in Deep Vein Thrombosis via MAPK and NRF2 Signaling Pathway.

Oxidative stress and inflammation play pivotal roles in the progression of deep vein thrombosis (DVT). Fisetin has demonstrated promising pharmacological features; however, its underlying mechanisms in DVT remain elusive. In our study, we investigated the effects and underlying mechanisms of Fisetin on a DVT mouse model. The protective effects of Fisetin on DVT were evaluated by comparing the size of thrombosis and detecting the mRNA expression levels of pro-inflammatory cytokines. After that, the biological processes were studied via transcriptomics after Fisetin administration. The antioxidant effect was evaluated and explained via NRF2 signaling pathway. Finally, the anti-inflammatory effect was explained according to KEGG analysis and the final mechanism was verified via Western blot. Our results found that the mRNA expression levels of pro-inflammatory cytokines were inhibited by Fisetin. Moreover, transcriptomic studies suggested that MAPK signaling pathway may be associated with the anti-inflammatory activity of Fisetin. Then, we confirmed that Fisetin administration significantly inhibited the activation of typical pro-inflammatory signaling pathways via Western blot. Finally, the results of Western blot showed that Fisetin significantly activated NRF2 signaling pathway and induced the expression of downstream antioxidant enzymes. Our findings suggested that Fisetin exhibits potential therapeutic effects on DVT through its ability to attenuate inflammation and oxidative stress. The underlying mechanism may involve the suppression of MAPK-mediated inflammatory signaling pathway and activation of NRF2-mediated antioxidant signaling pathway.

Abstract 4563: Ferroptotic mechanism of drug induced toxicity of PARPi and AurKi in prostate cancer

Abstract BACKGROUND: Cancer is typically treated with a combination of drugs rather than monotherapy stratagems, but identification of synergistic drug combinations for the treatment of cancers is challenging. Here we present the combination of PARP and Aurora Kinase inhibitors synergize through induction of the ferroptosis pathway of cell death. METHODS: We identified these drugs through an unbiased screen of enriched drug class response correlations. We then validated a synergistic cell killing effect of multiple drugs of each class by in vitro drug screening. Next, we performed reversal experiments using a ferroptosis inhibitor and lipid peroxide staining to confirm ferroptosis is a relevant cell death pathway. We performed Western immunoblot analysis in cells overexpressing putative Aurora Kinase phospho-substrates in the relevant pathway of interest, and performed site directed mutagenesis experiments to show the relevant amino acid altered by kinase activity. We also performed a series of qPCR and co-IP experiments to show PARPi effect on the antioxidant signaling pathway. RESULTS: We validated and identified synergy in a prostate cancer specific context. Next, we found Talazoparib and Alisertib induced ferroptosis after synergy was reduced with a ferroptosis inhibitor and lipid peroxides increased accumulation. We found a novel mechanism action for Alisertib, wherein Aurora Kinase inhibitors can alter the phospho-status and activity of the iron reduction enzyme Steap3.We also found that PARP inhibitors can affect the Nrf2-driven antioxidant signaling pathway on a transcriptional level. CONCLUSION: Aurora Kinase inhibitors and PARP inhibitors for the treatment of prostate cancer was identified and was validated as synergistic, which revealed new functional roles of both drugs in the context of cell killing. These findings represent a new clinical combination of drugs in prostate cancer and reveal a novel role for this drug class in ferroptosis. Citation Format: August John, Kuntian Luo, Zhenkun Lou, Liewei Wang. Ferroptotic mechanism of drug induced toxicity of PARPi and AurKi in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4563.

Platycodon D protects human nasal epithelial cells from pyroptosis through the Nrf2/HO-1/ROS signaling cascade in chronic rhinosinusitis

BackgroundPyroptosis has been demonstrated being closely associated with the inflammatory progression in chronic rhinosinusitis (CRS). However, platycodon D (PLD) has emerged as a key anti-inflammatory mediator in the inflammatory progression of various respiratory diseases. This study aims at investigating whether PLD could reduce inflammatory progression of CRS by inhibiting pyroptosis.MethodsNasal mucosal tissues from patients with CRS and the control group (simple nasal septal deviation) were analyzed for morphological difference using hematoxylin & eosin staining and for the expression of pyroptosis-related makers by immunofluorescence (IF). Human nasal epithelial cells (HNEpCs) were cultured and co-stimulated with lipopolysaccharide (LPS)/adenosine triphosphate (ATP) to construct an in vitro cellular model simulating CRS. After pretreatment with PLD, EthD-I staining, TUNEL staining, transmission electron microscopy (TEM), and GSDMD-NT detection were performed to evaluate pyroptosis markers. The NLRP3 inflammasome was detected by IF and western blotting (WB). Reactive oxygen species (ROS) were detected by H2DCFDA staining, and mitochondrial membrane potential was evaluated by JC-1 staining. Mitochondrial morphology and structure were observed using TEM. The Nrf2/HO-1 antioxidant signaling pathway was detected using WB.ResultsThe nasal mucosa structure of patients with CRS exhibited significant damage, with a marked increase in the expression of pyroptosis-related proteins compared with the control group. LPS/ATP co-stimulation resulted in an increased expression of IL-18 and IL-1β in HNEpCs, causing significant damage to nuclear and cell membranes, GSDMD-NT accumulation around the cell membrane, and intracellular NLRP3 inflammasome activation. Furthermore, it led to increased ROS expression, significantly decreased mitochondrial membrane potential, and damaged mitochondrial structure. However, pretreatment with PLD significantly reversed the aforementioned trends and activated the Nrf2/HO-1 antioxidant signaling pathway.ConclusionsThe results of this study confirm that NLRP3-mediated pyroptosis plays a crucial role in the pathological process of nasal mucosal impairment in patients with CRS. PLD inhibits NLRP3-mediated pyroptosis, preventing inflammatory damage in HNEpCs of patients with CRS by activating the Nrf2/HO-1 antioxidant signaling pathway, which in turn reduces ROS production and ameliorates mitochondrial damage.

Is there a Place for Klotho in Alzheimer’s disease?

Alzheimer’s disease, a major healthcare concern, lacks an effective pharmacological therapy to change its irreversible progression. In this work, we present Klotho, a protein associated with aging that is involved in the regulation of numerous physiological processes and is a serious candidate to be a pharmacological target to act on. Klotho’s mRNA has been found in neurons of a variety of brain regions (cortex, hippocampus). The best studied and prominent function of Klotho is as the co-receptor of fibroblast growth factor 23 (FGF23), through which Klotho controls renal phosphate excretion and vitamin D metabolism. Reduced serum levels of Klotho in mice have been associated with a shorter life expectancy and with numerous pathological conditions such as renal disease, vascular calcification, neurodegeneration, and others. Moreover, overexpression of Klotho leads to opposite effects resulting in increased survival rates. In this review we address different signaling pathways in which Klotho is involved in one way or another, focusing on those pathways that could serve as pharmacological targets to modify the evolution of Alzheimer’s disease. We describe how Klotho inhibits signaling cascades involved in cellular senescence, fibrosis, inflammation, and apoptosis all of which are mediated by tumor growth factor β (TGF- β), nuclear factor kappa K (NF- κ B), insulin-like growth factor 1 (IGF-1) or Wnt. We also highlight how Klotho is able to activate anti-inflammatory and antioxidant signaling pathways. Although there are no drugs that act specifically on Klotho, compounds currently on the market such as hormone-based drugs, pravastatin, losartan, fosinopril, and rapamycin have been shown to increase the expression of this protein and are also discussed.

Chitosan oligosaccharide improves intestinal homeostasis to achieve the protection for the epithelial barrier of female Drosophila melanogaster via regulating intestinal microflora.

The epithelial barrier plays an important role in the organism's health. Chitosan oligosaccharide (COS), a new potential prebiotic, exhibits excellent antioxidant capacity and anti-inflammatory effects. Our study elucidated the protective mechanisms of COS on the intestinal barrier of Drosophila melanogaster under oxidative stress, which could provide new insights into COS application in various industries, such as food, agriculture, and medicine.

Hepatoprotective Effect of Annulohypoxylon stygium Melanin on Acute Alcoholic Liver Injury in Mice.

Annulohypoxylon stygium melanin (AsM) has various functional properties such as antioxidant and anti-radiation, but its biological activity in vivo has not been fully investigated. In this study, we researched the effects of AsM on the protection against acute liver injury in mice and its mechanism. The results showed that AsM had no significant effect on body weight in mice but reduced the liver index. It was able to significantly decrease the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), the contents of triglyceride (TG) and total cholesterol (TC) in mice. Simultaneously, it raised the levels of superoxide dismutase (SOD), peroxidase (CAT), and glutathione peroxidase (GSH-Px), which obviously exceeded those of the EtOH group. AsM could significantly lower the levels of inflammatory factors, with inhibition rates of 68.30%, 29.0%, and 19.50% for IL-1β, IL-6, and TNF-α, respectively. H&E and Oil red O staining also showed that AsM ameliorated liver damage and lipid accumulation in mice. The protective mechanism of AsM may be associated to the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant signaling pathway, which could activate the downstream antioxidant enzymes heme oxygenase-1 (HO-1), glutamate-cysteine ligase modifier subunit (GCLM), and glutamate-cysteine ligase catalytic subunit (GCLC). These findings confirmed that AsM had an alleviating effect on alcoholic liver injury and provided new thoughts for the development of natural product.

Involvement of the Keap1-Nrf2-ARE pathway in the antioxidant activity of sinomenine

Sinomenine is a pure alkaloid isolated from Sinomenium acutum. This study is aimed to investigate the critical role of the nuclear factor erythroid 2-related factor 2 (Nrf2)-kelch-like ECH-associated protein-1(Keap1)-antioxidant response element (ARE) antioxidative signaling pathway in protecting sinomenine against H2O2-induced oxidative injury. Cytotoxicity and antioxidant experiments to initially determine the protective effects of sinomenine show that sinomenine has no effect on the decreased cell viability and presents similar potency in scavenging all three free radicals. The binding affinity between sinomenine and Keap1 was determined via fluorescence polarization assay, with IC50 of 13.52 μM. Quantum chemical calculation and theoretical simulation illustrated that sinomenine located into the Nrf2-binding site of Keap1 via hydrophobic and hydrogen interactions, showing high stability and binding affinity. On the basis of the stable binding of sinomenine with Keap1, sinomenine efficiently induced nuclear translocation of Nrf2, and increased in ARE activity in a concentration-dependent manner. Quantitative polymerase chain reaction provided further evidences that sinomenine-induced protection upregulated ARE-dependent genes, such as NAD(P)H quinone oxidoreductase 1, hemeoxygenase-1, and glutamate-cysteine ligase modifier subunit. Western blot confirmed that sinomenine increased the expressions of these antioxidative enzymes. Taken together, in vitro and in silico evaluations demonstrate that sinomenine inhibits the binding of Keap1 to Nrf2, promotes the nuclear accumulation of Nrf2 and thus leads to the upregulated expressions of Nrf2-dependent antioxidative genes. Our findings also highlight the use of sinomenine for pharmacological or therapeutic regulation of the Nrf2-Keap1-ARE system, which is a novel strategy to prevent the progression of oxidative injury.

The Ameliorative Role of Lico A on Aflatoxin B1-Triggered Hepatotoxicity Partially by Activating Nrf2 Signal Pathway.

Aflatoxin B1 (AFB1) is one of the most harmful and toxic mycotoxins in foods and feeds, posing a serious health risk to both humans and animals, especially its hepatotoxicity. Nuclear factor-erythroid 2-related factor 2 (Nrf2), an important nuclear transcription factor, is generally recognized as a potential target for phytochemicals to ameliorate liver injury. The current study sought to elucidate the molecular processes by which licochalcone A (Lico A), a compound derived from Xinjiang licorice Glycyrrhiza inflate, protects against AFB1 toxicity. In vivo, male wild-type (WT) and Nrf2 knockout (Nrf2-/-) C57BL/6 mice were orally administered AFB1 at 1.5 mg/kg body weight (BW) with or without Lico A at 5 mg/kg. In vitro, AML12 cells were utilized to evaluate the protective effect and mechanism of Lico A against the AFB1-induced hepatotoxicity. Our findings demonstrated that AFB1 caused severe hepatotoxicity, while Lico A treatment successfully relieved the toxicity. Meanwhile, Lico A effectively improved liver injury, inflammatory mediators, oxidative insults, apoptosis, liver fibrosis, and pyroptosis, which contributed to the inhibition of toll receptor 4 (TLR4)-NF-κB/MAPK and NOD-like receptors protein 3 (NLRP3)/caspase-1/GSDMD signaling pathway activation. Furthermore, Lico A was able to enhance the Nrf2 antioxidant signaling pathway. Intriguingly, Lico A still had a protective effect on AFB1-caused liver injury in mice via the inhibition of inflammation and pyroptosis, while apoptosis and liver fibrosis were blocked in the absence of Nrf2. To sum up, the present study first elucidated that Lico A ameliorated AFB1-induced hepatotoxic effects and its main mechanism involved the inhibitory effects on oxidative stress, apoptosis, liver fibrosis, inflammation, and pyroptosis, which might be partially dependent on the regulation of Nrf2. The work may enrich the role and mechanism of Lico A's resistance to liver injury caused by various factors, and its application is promising.

Armillariella tabescens polysaccharide treated rats with oral ulcers through modulation of oral microbiota and activation of the Nrf2/HO-1 pathway

We identified Armillariella tabescens polysaccharide (PAT-W), a compound isolated from a Chinese medicinal mushroom, as a potential novel oral ulcer (OU) drug. In treating OU rats with PAT-W, especially in the high-dose group, oral mucous tissue TNF-α, IL-1β, and IL-6 levels were markedly reduced, and pathological morphology and oxidative stress were effectively improved. Western blot analysis showed that the PAT-W channel ameliorated OU mucous tissue damage, which depends on the activation of the Nrf2/HO-1 antioxidant signaling pathway. Furthermore, high-throughput sequencing results showed that PAT-W regulated the maladjustment of the oral microbiota caused by OU. Therefore, based on the new viewpoint of activating the Nrf2/HO-1 pathway and regulating oral microbiota, PAT-W is expected to become a new natural drug for treating oral ulcers and improving patients' quality of life.

Inactivation of Mst/Nrf2/Keap1 signaling flexibly mitigates MAPK/NQO-HO1 activation in the reproductive axis of experimental fluorosis

Fluoride induced reprotoxicity through oxidative stress-mediated reproductive cell death. Hence, the current study evaluated the importance of the MST/Nrf2/MAPK/NQO-HO1 signaling pathway in fluorosis-induced reproductive toxicity. For this purpose, the reproductive toxicity of sodium fluoride (NaF) at physiological, biochemical, and intracellular levels was evaluated. In-vivo, NaF at 100 mg/L instigated physiological dysfunction, morphological, stereological, and structural injuries in the gut-gonadal axis of fluorosis mice through weakening the antioxidant signaling, Nrf2/HO-1/NQO1signaling pathway, causing the gut-gonadal barrier disintegrated via oxidative stress-induced inflammation, mitochondrial damage, apoptosis, and autophagy. Similar trends were also observed in-vitro in the isolated Leydig cells (LCs) challenging with 20 mg/L NaF. Henceforth, activating the cellular antioxidant signaling pathway, Nrf2/HO-1/NQO1, inactivating autophagy and apoptosis, or attenuating lipopolysaccharide (LPS) can be the theoretical basis and valuable therapeutic targets for coping with NaF-induced reproductive toxicity.

Cytoprotective effects of iridoids from Gaultheria spp. berries in gastric and intestinal epithelial cells after in vitro digestion

Reactive oxygen species may induce oxidation of macromolecules in foods and during digestion in the gastrointestinal tract, negatively impacting human health. Antioxidants present in plant foods, including carotenoids, tocochromanols, ascorbic acid, as well as (poly)phenols and iridoids, may counteract oxidation of macromolecules. The aims of the present study were to determine the contents of carotenoids, tocochromanols, ascorbic acid from Gaultheria spp. berries and to investigate the cytoprotective and antioxidant activities of the fruit extracts and monotropein esters present in the berries. Moreover, the underlying mechanisms of action in gastrointestinal epithelial cells after in vitro digestion was also investigated. The content of ascorbic acid ranged from 3 to 24 mg/100 g fw, carotenoids from 9 to 56 μg/100 g fw, and total tocochromanols from 0.29 to 0.45 mg/100 g fw. The pre-incubation of gastric (AGS) and intestinal (Caco-2) cells with Gaultheria fruit extracts significantly increased viability of cells stressed with 10 mM H2O2 and 100 mM AAPH, respectively, compared to control cells. Furthermore, digested Gaultheria fruit extracts and monotropein esters increased the relative mRNA of the Nrf2/Keap1/ARE antioxidant signaling pathway and enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPX) and reductase, and catalase (CAT). The pre-incubation of Caco-2 cells with digested monotropein and monotropein esters increased the protein expression of GPX, CAT, Keap1, and Nrf2, and incremented the SOD activity in Caco-2 cells. In conclusion, Gaultheria spp. fruit extracts and monotropein esters may protect gastrointestinal epithelial cells against oxidative stress during digestive processes.

Global Remodeling of Host Proteome in Response to Leishmania Infection.

The protozoan parasite Leishmania possesses an intrinsic ability to modulate a multitude of pathways in the host, toward aiding its own proliferation. In response, the host reprograms its cellular, immunological, and metabolic machinery to evade the parasite's lethal impact. Besides inducing various antioxidant signaling pathways to counter the elevated stress response proteins like heme oxygenase-1 (HO-1), Leishmania also attempts to delay host cell apoptosis by promoting anti-apoptotic proteins like Bcl-2. The downstream modulation of apoptotic proteins is regulated by effector pathways, including the PI3K/Akt survival pathway, the mitogen-activated protein kinases (MAPKs) signaling pathway, and STAT phosphorylation. In addition, Leishmania assists in its infection in a time-dependent manner by modulating the level of various proteins of autophagic machinery. Immune effector cells, such as mast cells and neutrophils, entrap and kill the pathogen by secreting various granular proteins. In contrast, the host macrophages exert their leishmanicidal effect by secreting various cytokines, such as IL-2, IL-12, etc. An interplay of various signaling pathways occurs in an organized network that is highly specific to both pathogen and host species. This Review analyzes the modulation of expression of proteins, including the cytokines, providing a realistic approach toward understanding the pathophysiology of disease and predicting some prominent markers for disease intervention and vaccine support strategies.

Aureusidin ameliorates 6-OHDA-induced neurotoxicity via activating Nrf2/HO-1 signaling pathway and preventing mitochondria-dependent apoptosis pathway in SH-SY5Y cells and Caenorhabditis elegans

Movement disorder Parkinson's disease (PD) is the second most common neurodegenerative disease in the world after Alzheimer's disease, which severely affects the quality of patients' lives and imposes an increasingly heavy socioeconomic burden. Aureusidin is a kind of natural flavonoid compound with anti-inflammatory and anti-oxidant activities, while its pharmacological action and mechanism are rarely reported in PD. This study aimed to explore the neuroprotective effects and potential mechanisms of Aureusidin in PD. The present study demonstrated that Aureusidin protected SH-SY5Y cells from cell damage induced by 6-hydroxydopamine (6-OHDA) via inhibiting the mitochondria-dependent apoptosis and activating the Nrf2/HO-1 antioxidant signaling pathway. Additionally, Aureusidin diminished dopaminergic (DA) neuron degeneration induced by 6-OHDA and reduced the aggregation toxicity of α-synuclein (α-Syn) in Caenorhabditis elegans (C. elegans.) In conclusion, Aureusidin showed a neuroprotective effect in the 6-OHDA-induced PD model via activating Nrf2/HO-1 signaling pathway and prevented mitochondria-dependent apoptosis pathway, and these findings suggested that Aureusidin may be an effective drug for the treatment of PD.

Dietary Co-supplements attenuate the chronic unpredictable mild stress-induced depression in mice

Does it make a difference what we eat when it comes to our mental health? Food and nutrients are essential not only for human biology and physical appearance but also for mental and emotional well-being. There has been a significant increase in the favourable effects of dietary supplements in the treatment of depressive state in the latest days. Co-supplements which can be a great contribution in the management of depression from the future perspective and might help to reduce standard anti-depressant drug doses, which can be a strategic way to reduce the side effect of standard anti-depressants drugs. This study was designed to evaluate and compare the anti-depressant effects of cholecalciferol-D3 (V.D3), n-3 polyunsaturated fatty acid (PUFA), and a combination of V.D3 + n-3 PUFA with fluoxetine treatment in chronic unpredictable mild stress (CUMS) induced depression in the mice model. We established CUMS depressant mice model and treated CUMS mice with V.D3, n-3 PUFA, and a combination of V.D3 + n-3 PUFA with fluoxetine. Behavioral changes were measured by the forced swim and tail suspension test. Oxidative stress markers and anti-depressant activity were assessed through parameters such as superoxide dismutase, reduced glutathione, lipid peroxidation, and serum corticosterone levels. Additionally, we measured the levels of neurotransmitters dopamine and serotonin. CUMS induced mice displayed depressive-like behaviours. Moreover, cholecalciferol-D3, n-3 PUFA, and a combination of Cholecalciferol-D3 + n-3 PUFA with fluoxetine treatment attenuated the depressive-like behaviour in CUMS mice accompanied with suppression of oxidative stress markers by up-regulated the expression of an antioxidant signalling pathway. The results suggested that treatment of cholecalciferol-D3, n-3 PUFA, and a combination of Cholecalciferol-D3 + n-3 PUFA with fluoxetine significantly ameliorated depressive-like behaviours in CUMS induced depression in mice. To delve further into the implications of these findings, future studies could explore the specific molecular mechanisms underlying the observed effects on oxidative stress markers and the antioxidant signaling pathway. This could provide valuable insights into the potential of dietary supplements in the management of depression and help in reducing the reliance on conventional antidepressant medications, thus improving the overall quality of treatment for this prevalent mental health condition.

Polyphenols in Inner Ear Neurobiology, Health and Disease: From Bench to Clinics.

There is substantial experimental and clinical interest in providing effective ways to both prevent and slow the onset of hearing loss. Auditory hair cells, which occur along the basilar membrane of the cochlea, often lose functionality due to age-related biological alterations, as well as from exposure to high decibel sounds affecting a diminished/damaged auditory sensitivity. Hearing loss is also seen to take place due to neuronal degeneration before or following hair cell destruction/loss. A strategy is necessary to protect hair cells and XIII cranial/auditory nerve cells prior to injury and throughout aging. Within this context, it was proposed that cochlea neural stem cells may be protected from such aging and environmental/noise insults via the ingestion of protective dietary supplements. Of particular importance is that these studies typically display a hormetic-like biphasic dose-response pattern that prevents the occurrence of auditory cell damage induced by various model chemical toxins, such as cisplatin. Likewise, the hormetic dose-response also enhances the occurrence of cochlear neural cell viability, proliferation, and differentiation. These findings are particularly important since they confirmed a strong dose dependency of the significant beneficial effects (which is biphasic), whilst having a low-dose beneficial response, whereas extensive exposures may become ineffective and/or potentially harmful. According to hormesis, phytochemicals including polyphenols exhibit biphasic dose-response effects activating low-dose antioxidant signaling pathways, resulting in the upregulation of vitagenes, a group of genes involved in preserving cellular homeostasis during stressful conditions. Modulation of the vitagene network through polyphenols increases cellular resilience mechanisms, thus impacting neurological disorder pathophysiology. Here, we aimed to explore polyphenols targeting the NF-E2-related factor 2 (Nrf2) pathway to neuroprotective and therapeutic strategies that can potentially reduce oxidative stress and inflammation, thus preventing auditory hair cell and XIII cranial/auditory nerve cell degeneration. Furthermore, we explored techniques to enhance their bioavailability and efficacy.

Dietary Chito-oligosaccharide attenuates LPS-challenged intestinal inflammation via regulating mitochondrial apoptotic and MAPK signaling pathway

To investigate the regulatory effects of Chito-oligosaccharide (COS) on the anti-oxidative, anti-inflammatory, and MAPK signaling pathways. A total of 40 28-day-old weaned piglets were randomly allotted to 4 equal groups [including the control group, lipopolysaccharide (LPS) group, COS group, and COS*LPS group]. On the morning of d 14 and 21, piglets were injected with saline or LPS. At 2 h post-injection, whole blood samples were collected on d 14 and 21, and small intestine and liver samples were collected and analyzed on d 21. The results showed that COS inhibited the LPS-induced increase of malondialdehyde (MDA) concentration and hepatic TNF-α cytokines. COS significantly increased the serum total antioxidant capability (T-AOC) value on d 14, and total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-PX) activities in both serum and liver on d 21. Furthermore, it increased hepatic catalase (CAT) activity. COS also increased the LPS-induced decrease in serum IgG concentrations. Immunohistochemical analysis results showed that COS significantly increased the jejunal and ileal Caspase 3, and ileal CD4+ values challenged by LPS. Dietary COS decreased the LPS-induced jejunal and ileal BAX and CCL2 mRNA levels, markedly decreased ileal COX2 and SOD1 mRNA levels, while increasing ileal iNOS. Furthermore, COS significantly increased the LPS-induced jejunal and ileal p-P38 and MyD88, as well as jejunal P38, while it effectively suppressed jejunal JNK1, and jejunal and ileal JNK2, p-JNK1, and p-JNK2 protein expressions. These results demonstrated that COS could be beneficial by attenuating LPS-challenged intestinal inflammation via regulating mitochondrial apoptotic and MAPK signaling pathways.