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15 pages, 1980 KiB

Open AccessArticle

The Unexplored Role of Mitochondria-Related Oxidative Stress in Diverticular Disease

by Martina Cappelletti, Lucia Pallotta, Rosa Vona, Antonella Tinari, Annalinda Pisano, Giovanni Casella, Daniele Crocetti, Dominga Carlomagno, Ivan Tattoli, Carla Giordano, Paola Matarrese and Carola Severi

Int. J. Mol. Sci. 2024, 25(17), 9680; https://doi.org/10.3390/ijms25179680 - 6 Sep 2024

Viewed by 867

Abstract

The pathophysiology of diverticular disease (DD) is not well outlined. Recent studies performed on the DD human ex vivo model have shown the presence of a predominant transmural oxidative imbalance whose origin remains unknown. Considering the central role of mitochondria in oxidative stress, [...] Read more.

The pathophysiology of diverticular disease (DD) is not well outlined. Recent studies performed on the DD human ex vivo model have shown the presence of a predominant transmural oxidative imbalance whose origin remains unknown. Considering the central role of mitochondria in oxidative stress, the present study evaluates their involvement in the alterations of DD clinical phenotypes. Colonic surgical samples of patients with asymptomatic diverticulosis, complicated DD, and controls were analyzed. Electron microscopy, protein expression, and cytofluorimetric analyses were performed to assess the contribution of mitochondrial oxidative stress. Functional muscle activity was tested on cells in response to contractile and relaxant agents. To assess the possibility of reverting oxidative damages, N-acetylcysteine was tested on an in vitro model. Compared with the controls, DD tissues showed a marketed increase in mitochondrial number and fusion accompanied by the altered mitochondrial electron transport chain complexes. In SMCs, the mitochondrial mass increase was accompanied by altered mitochondrial metabolic activity supported by a membrane potential decrease. Ulteriorly, a decrease in antioxidant content and altered contraction–relaxation dynamics reverted by N-acetylcysteine were observed. Therefore, the oxidative stress-driven alterations resulted in mitochondrial impairment. The beneficial effects of antioxidant treatments open new possibilities for tailored therapeutic strategies that have not been tested for this disease. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Human Diseases)

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Figure 1

Figure 1
Transmission Electron Microscopy (TEM) analyses (bar = 1 µm). Ultrastructural analyses in CTR (control), DIV (diverticulosis), and cDD (complicated diverticular disease) of LM (longitudinal muscle) and CM (circular muscle) layers. Arrows indicate points of mitochondrial membrane fusion and elongated mitochondria. Full article ">Figure 2
Mitochondrial respiratory chain complex investigation. (a) Mitochondrial respiratory chain—complex II (SDHA) (n = 4–8). (b) Mitochondrial respiratory chain—complex IV (COX) (n = 5–8). Data are expressed as mean ± SEM. β-actin (ACTB) was used as the internal control for normalization. Both analyses were performed in tissues by Western blot. (c) Representative Western blot. CTR: control, DIV: diverticulosis, cDD: complicated diverticular disease, CM: circular muscle, LM: longitudinal muscle. Full article ">Figure 3
Cellular mitochondrial and oxidative parameter analyses. (a) Mitochondrial mass evaluation (n = 3–6). (b) Mitochondrial membrane potential (n = 4–6). (c) Total glutathione content evaluation (n = 8–10). Data are expressed as mean ± SEM. All analyses were performed in smooth muscle cells by cytofluorimetric analyses (* p ≤ 0.05 vs. control). CTR: control, DIV: diverticulosis, cDD: complicated diverticular disease, CM: circular muscle, LM: longitudinal muscle, ΔΨm: mitochondrial membrane potential. Full article ">Figure 4
Functional effects of N-acetylcysteine. Samples were evaluated before and after 2 h of NAC incubation and compared with untreated samples. (a) Modulation of glutathione content in smooth muscle cells evaluated by cytofluorimetric analyses (n = 4–5). (b) Modulation of cellular functional activity in smooth muscle cells evaluated by micrometric assay (n = 2–4). Data are expressed as mean ± SEM. * p ≤ 0.05 vs. untreated samples. CTR: control, DIV: diverticulosis, cDD: complicated diverticular disease, NT: untreated samples, NAC: N-acetylcysteine. Full article ">Figure 5
Mitochondrial electron transport chain (ETC). The ETC consists of protein complexes able to transfer electrons coming from oxidizable substrates from donors to acceptors with the final goal of producing adenosine triphosphate. In physiologic conditions during aerobic respiration, oxygen acts as the final electron acceptor and each complex of ETC includes specific sites for reactive oxygen species (ROS) release. Moreover, in pathological conditions, the overproduction of ROS negatively influence the ETC activity that in turn favors an ulterior ROS release. N-acetylcysteine is an antioxidant compound able to increase glutathione content by providing cysteine, a key precursor for its synthesis. IM: mitochondrial inner membrane, OM: mitochondrial outer membrane, ADP: adenosine diphosphate, ATP: adenosine triphosphate, NAC: N-acetylcysteine, Cyt C: cytochrome c, Cys: cysteine, Glu: glutamic acid. Full article ">

14 pages, 2479 KiB

Open AccessArticle

Prevention of UVB-Induced Photoaging by an Ethyl Acetate Fraction from Allomyrina dichotoma Larvae and Its Potential Mechanisms in Human Dermal Fibroblasts

by Kyong Kim, Chae-Eun Kim, Dong-Jae Baek, Eun-Young Park and Yoon Sin Oh

Int. J. Mol. Sci. 2024, 25(14), 7850; https://doi.org/10.3390/ijms25147850 - 18 Jul 2024

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Abstract

Allomyrina dichotoma larvae (ADL) is an insect type that is used ethnopharmacologically to treat various diseases; however, its use as an antiaging treatment has not been widely studied. Previously, we found that an ethyl acetate (EA) fraction derived from an ADL extract (ADLE) [...] Read more.

Allomyrina dichotoma larvae (ADL) is an insect type that is used ethnopharmacologically to treat various diseases; however, its use as an antiaging treatment has not been widely studied. Previously, we found that an ethyl acetate (EA) fraction derived from an ADL extract (ADLE) has a high polyphenol content and antioxidant properties. In this study, we identified the underlying molecular mechanism for the protective effect of the EA fraction against UVB-induced photodamage in vitro and ex vivo. UVB treatment increased intracellular reactive oxygen species levels and DNA damage; the latter of which was significantly decreased following cotreatment with the EA fraction. Biological markers of aging, such as p16^INK4a, p21^WAF1, and senescence-associated β-gal levels, were induced by UVB treatment but significantly suppressed following EA-fraction treatment. UVB-induced upregulation of matrix metalloproteinase (MMP)-1 and downregulation of COL1A1 were also reversed by EA-fraction treatment in both cells and a 3D skin model, which resulted in increased keratin and collagen deposition. Moreover, EA-fraction treatment inhibited the phosphorylation of MAPKs (p38, ERK, and JNK) and nuclear factor (NF-)-kB and decreased the levels of inflammatory cytokines in UVB-treated cells. The results indicate that an EA fraction from ADLE ameliorates UVB-induced degradation of COL1A1 by inhibiting MMP expression and inactivating the MAPK/NF-κB p65/AP-1 signaling pathway involved in this process. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Human Diseases)

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Figure 1
Cytoprotective effects of the ethyl acetate fraction on UVB-irradiated HDF cells. The cells were treated for 24 h with 100 µg/mL of ADLE, 100 µg/mL of EA, and 10 µM of vitamin C, after 100 mJ/cm2 UVB irradiation. Cell viability was measured using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay (A). Intracellular ROS levels were assayed by detecting the fluorescence intensity of the oxidant-sensitive fluorescent probe DCFH-DA at 485/535 nm (B). HO-1 and NQO1 protein expression levels were measured using Western blotting. The band intensity was measured using C.S. analyzer 4 version 2.4.5 software, and the relative quantity was calculated over <math display="inline"><semantics> <mrow> <mi>α</mi> </mrow> </semantics></math>-tubulin (C). Luciferase-based luminescence assay for cytosolic ATP content (D), JC-1 staining for mitochondrial membrane potential (ΔΨm) (E), and quantification of apoptosis via fragmented DNA analysis using a Cell Death Detection ELISA kit (F). Data are presented as the mean ± SD (n = 3–5). *** p < 0.001 versus control (CON, untreated). # p < 0.05, ## p < 0.01, and ### p < 0.001 versus UVB treatment alone. Full article ">Figure 2
Anti-aging effects of the EA fraction on senescence-associated secretory phenotype-based biomarkers in UVB-irradiated HDF cells. Cells were treated for 24 h with 100 µg/mL of ADLE, 100 µg/mL of EA, and 10 µM of vitamin C after 100 mJ/cm2 UVB irradiation. Beta-galactosidase activity was assayed using a mammalian β-galactosidase assay kit (A). The mRNA levels of p21, p16, and p53 were determined using qRT-PCR. The mRNA levels were normalized with those of cyclophilin (B). The mRNA levels of TNFα, IL-1β, and IFNγ were determined using qRT-PCR. The mRNA levels were normalized with those of cyclophilin (C). COX2 protein expression was measured using Western blotting. The band intensity was measured using C.S. analyzer 4 version 2.4.5 software, and the relative quantity was calculated over α-tubulin (D). Data are presented as the mean ± SD (n = 3–5). *** p < 0.001 versus CON (nontreated). # p < 0.05, ## p < 0.01, and ### p < 0.001 versus UVB treatment alone. Full article ">Figure 3
Regulation of COL1A1 and MMP-1 expression using the EA fraction in UVB-irradiated HDF cells. Cells were treated for 24 h with 100 µg/mL of ADLE, 100 µg/mL of EA, and 10 µM of vitamin C after 100 mJ/cm2 UVB irradiation. The mRNA expression levels of COL1A1 and MMPs were measured using qRT-PCR (A,C). Extracellular MMP-1 production was measured using an ELISA kit (B). The expression levels of COL1A1 and MMP-1 proteins were determined using Western blotting (D). COLIA1 and MMP-1 intensities were measured using C.S. analyzer 4 version 2.4.5 software, and relative quantities were calculated over α-tubulin (E,F). Data are presented as the mean ± SD (n = 3–5). * p < 0.05 and *** p < 0.001 versus CON. # p < 0.05, ## p < 0.01, and ### p < 0.001 versus UVB treatment alone. UVB cells were irradiated with 100 mJ/cm2 UVB alone; UVB + ADLE cells were treated with 100 μg/mL of ADLE after UVB irradiation; UVB + EA cells were treated with 100 μg/mL of EA fraction of ADLE after UVB irradiation; UVB + vitamin C cells were treated with 10 μM of ascorbic acid as a positive control. Full article ">Figure 4
Effects of the EA fraction on the activation of MAPK and NF-κB/AP-1 signaling pathways in UVB-irradiated HDF cells. Cells were treated for 24 h with 100 µg/mL of ADLE, 100 µg/mL of EA, and 10 µM of vitamin C after 100 mJ/cm2 UVB irradiation. The protein levels of MAPK pathway signals were analyzed using Western blotting (A), the band intensities were measured using C.S. analyzer 4 version 2.4.5 software, and relative quantities were calculated over α-tubulin (B). The protein levels of NF-κB related signaling and AP-1 (C) were analyzed using Western blotting (D), the band intensity was measured using C.S. Analyzer 4 version 2.4.5 software, and the relative quantity was calculated over β-actin and lamin B (E). Data are presented as mean ± SD (n = 3–5). * p < 0.05 and *** p < 0.001 versus CON. # p < 0.05, ## p < 0.01, and ### p < 0.001 versus UVB treatment alone. UVB cells were irradiated with 100 mJ/cm2 of UVB alone; UVB + ADLE cells were treated with 100 μg/mL of ADLE after UVB irradiation; UVB + EA cells were treated with 100 μg/mL of the EA fraction of ADLE after UVB irradiation; UVB + vitamin C cells were treated with 10 μM of ascorbic acid as a positive control. Full article ">Figure 5
Inhibitory effects of the EA fraction on UVB-induced collagen degradation in a 3D reconstructed human skin model. Collagen deposition in the artificial epidermis model was observed at 400× magnification after Masson’s trichrome staining (A). This staining method produces red keratin, blue collagen, light-red or pink cytoplasm, and dark brown-to-black cell nuclei. Thickness of the stratum corneum (SC) was measured in the red- and blue-stained areas at the top of the membrane in three randomly selected fields in each epidermis (B). MMP-1 (C) and COL1A1 (D) mRNA levels were determined using qRT-PCR. The mRNA levels were normalized with those of cyclophilin. Data are presented as the mean ± SD (n = 3). ** p < 0.01 and *** p < 0.001 versus CON. # p < 0.05 and ## p < 0.01 versus UVB alone. SC, stratum corneum layer; VE, viable epidermis layer; CON, nonirradiated control. UVB cells were irradiated with 100 mJ/cm2 of UVB alone; UVB + ADLE cells were treated with 100 μg/mL of ADLE after UVB irradiation; UVB + EA cells were treated with 100 μg/mL of the EA fraction of ADLE after UVB irradiation; UVB + vit. c cells were treated with 10 μM of ascorbic acid as a positive control. Full article ">Figure 6
Scheme of the anti-aging mechanism of the EA fraction of ADLE on UVB-induced HDF cells. Red cross indicates that EA fraction of ADLE inhibits the pathways induced by UVB. Full article ">

14 pages, 2133 KiB

Open AccessArticle

The Potential of Twendee X^® as a Safe Antioxidant Treatment for Systemic Sclerosis

by Fukka You, Carole Nicco, Yoshiaki Harakawa, Toshikazu Yoshikawa and Haruhiko Inufusa

Int. J. Mol. Sci. 2024, 25(5), 3064; https://doi.org/10.3390/ijms25053064 - 6 Mar 2024

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Abstract

Systemic sclerosis (SSc) is an autoimmune disease characterized by systemic skin hardening, which combines Raynaud’s phenomenon and other vascular disorders, skin and internal organ fibrosis, immune disorders, and a variety of other abnormalities. Symptoms vary widely among individuals, and personalized treatment is sought [...] Read more.

Systemic sclerosis (SSc) is an autoimmune disease characterized by systemic skin hardening, which combines Raynaud’s phenomenon and other vascular disorders, skin and internal organ fibrosis, immune disorders, and a variety of other abnormalities. Symptoms vary widely among individuals, and personalized treatment is sought for each patient. Since there is no fundamental cure for SSc, it is designated as an intractable disease with patients receiving government subsidies for medical expenses in Japan. Oxidative stress (OS) has been reported to play an important role in the cause and symptoms of SSc. HOCl-induced SSc mouse models are known to exhibit skin and visceral fibrosis, vascular damage, and autoimmune-like symptoms observed in human SSc. The antioxidant combination Twendee X^® (TwX) is a dietary supplement consisting of vitamins, amino acids, and CoQ10. TwX has been proven to prevent dementia in humans with mild cognitive impairment and significantly improve cognitive impairment in an Alzheimer’s disease mouse model by regulating OS through a strong antioxidant capacity that cannot be achieved with a single antioxidant ingredient. We evaluated the effectiveness of TwX on various symptoms of HOCl-induced SSc mice. TwX-treated HOCl-induced SSc mice showed significantly reduced lung and skin fibrosis compared to untreated HOCl-induced SSc mice. TwX also significantly reduced highly oxidized protein products (AOPP) in serum and suppressed Col-1 gene expression and activation of B cells involved in autoimmunity. These findings suggest that TwX has the potential to be a new antioxidant treatment for SSc without side effects. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Human Diseases)

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Figure 1
Effect of Twendee X® on sera redox status. Concentrations of advanced oxidation protein products (AOPP) in the sera from mice (mM of chloramine T equivalent). Each box represents mean ± SD from n = 10 individual mice. Kruskal–Wallis test with Dunn’s multiple comparison test was used for statistical analysis). * p < 0.05. Full article ">Figure 2
Effect of Twendee X® on fibrosis parameters. (A) Change in skin fold thickness in millimeters from day 1 to day 36, measured weekly (n = 10). **: p < 0.01, ***: p < 0.001 (PBS vs. HOCl), †: p < 0.05 (HOCl vs. HOCl + TwX). (B) Collagen type I levels in skin (mg/punch biopsy) and (C) in lung (mg/lobe biopsy) were evaluated by hydroxyproline dosage. Each box represents mean ± SD from n = 10 individual mice. * p < 0.05; ** p < 0.01; *** p < 0.001. (D) Relative mRNA level of Collagen-1. Results were standardized by GAPDH. Each box represents mean ± SD from n = 10 individual mice. ** p < 0.01; *** p < 0.001. (E) Representative H&E dyed skin sections of 6 μm, showing enhanced fibrosis in mice. Photographs were taken with a Nikon Eclipse 80i microscope (Nikon Instruments, Inc., Melville, NY, USA). Original magnification ×20. The scale represents 500 μm. All data are expressed as the mean ± SD. Kruskal–Wallis test with Dunn’s multiple comparison test was used for all statistical analysis. Full article ">Figure 3
Effect of Twendee X® on fibroblast differentiation. (A) α-SMA and (B) H-Ras in skin were evaluated by Western blot. Results were normalized to tubulin. Each box represents mean ± SD from n = 10 individual mice. Kruskal–Wallis test with Dunn’s multiple comparison test was used for all statistical analysis. * p < 0.05. Full article ">Figure 4
Effect of Twendee X® on Collagen and cytokines expression. Relative mRNA level of (A) Il-6, (B) Il-33, and (C) Il-17 mRNA levels in skin evaluated by qRT-PCR. Results were normalized to GAPDH. Each box represents mean ± SD from n = 10 individual mice. Kruskal–Wallis test with Dunn’s multiple comparison test was used for all statistical analysis. No significant difference was observed. Full article ">Figure 5
Effects of Twendee X® on B and T CD4+ cells activation assessed by flow cytometry in SSc mice. The side-scatter (SSC) and the forward-scatter channels (FSC) were used to gate the leukocytes. A total of 100,000 events were accumulated for each sample. Doublets were excluded with FSC-A and FSC-H channels. (A,B) Activation of B220+ cells assessed by CD40 expression (A) and MHC II expression (B). (C,D) Activation of CD4+ T cells assessed by CD69 (C) and CD44 (D) expression. Each box represents mean ± SD from n = 10 individual mice. Kruskal–Wallis test with Dunn’s multiple comparison test was used for all statistical analysis. * p < 0.05; ** p < 0.01; *** p < 0.001. Full article ">Figure 6
Flow cytometric analysis of the effects of Twendee X® on splenic macrophage phenotype in SSc mice. Splenic macrophages were gated on CD11b- and F4/80-positive cells among CD45-positive. A total of 100,000 events were accumulated for each sample. Doublets were excluded with FSC-A and FSC-H channels. (A) Percentage of splenic macrophages among total splenic cells. Data represent the percentage and SD. (B–D) Flow cytometric analysis of CD86, Ly6C, and CD206 expression on splenic macrophages. (E) Ratio of M1/M2 macrophages’ frequency. M1 macrophages were defined as B220-F4/80+CD11b+Ly6CHighCD206- and M2 macrophages as B220-F4/80+CD11b+Ly6cLowCD206+. Each box represents mean ± SD from n = 10 individual mice. Kruskal–Wallis test with Dunn’s multiple comparison test was used for all statistical analysis. * p < 0.05; ** p < 0.01; *** p < 0.001. Full article ">

14 pages, 4383 KiB

Open AccessArticle

Hepatoprotective and Antioxidant Effects of Nanopiperine against Cypermethrin via Mitigation of Oxidative Stress, Inflammations and Gene Expression Using qRT-PCR

by Sohail Hussain, Abdulmajeed M. Jali, Saeed Alshahrani, Khairat H. M. Khairat, Rahimullah Siddiqui, Mohammad Intakhab Alam, Raisuddin Ali, Manal Mohammed, Andleeb Khan, Hamad Al Shahi, Ali Hanbashi, Marwa Qadri and Mohammad Ashafaq

Int. J. Mol. Sci. 2023, 24(20), 15361; https://doi.org/10.3390/ijms242015361 - 19 Oct 2023

Cited by 3 | Viewed by 1794

Abstract

Cypermethrin (Cyp) is a pyrethroid that has been associated with the toxicity of various organs. The aim of our study was to evaluate the hepatoprotective and antioxidant activities of nano-piperine (NP) against Cyp toxicity. Cyp (50 mg/kg) was administered orally in all animals [...] Read more.

Cypermethrin (Cyp) is a pyrethroid that has been associated with the toxicity of various organs. The aim of our study was to evaluate the hepatoprotective and antioxidant activities of nano-piperine (NP) against Cyp toxicity. Cyp (50 mg/kg) was administered orally in all animals of groups III–VI for 15 days. Groups IV–VI each received three doses of NP (125, 250, and 500 µg/kg/day) for 10 days after receiving the Cyp dosage, which was given after 1 h. A rise in serum biomarkers (ALT, AST, ALP, total protein, and albumin), which are indicators of toxicity alongside anomalous oxidative stress indices (lipid peroxidation (LPO), glutathione (GSH), superoxide dismutase (SOD) and catalase), was detected. After Cyp treatment, we observed upregulated cytokines, caspase expression, and histological analysis that the showed distortion of cell shape. However, the administration of NP dramatically reversed all of the Cyp-induced alterations, inducing reductions in serum marker levels, stress level, the production of cytokines, and caspase expression. Additionally, all of the histopathological alterations were minimized to values that were comparable to normal levels. The present findings suggested that NP exhibits potent antioxidant and anti-inflammatory activities that can protect rats’ livers against Cyp-induced liver damage through hepatoprotective activities. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Human Diseases)

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14 pages, 1848 KiB

Open AccessArticle

Serum Total Antioxidant Capacity (TAC) and TAC/Lymphocyte Ratio as Promising Predictive Markers in COVID-19

by Zoltán Horváth-Szalai, Rita Jakabfi-Csepregi, Balázs Szirmay, Dániel Ragán, Gerda Simon, Zoltán Kovács-Ábrahám, Péter Szabó, Dávid Sipos, Ágnes Péterfalvi, Attila Miseta, Csaba Csontos, Tamás Kőszegi and Ildikó Tóth

Int. J. Mol. Sci. 2023, 24(16), 12935; https://doi.org/10.3390/ijms241612935 - 18 Aug 2023

Cited by 3 | Viewed by 1484

Abstract

SARS-CoV-2 infection might cause a critical disease, and patients’ follow-up is based on multiple parameters. Oxidative stress is one of the key factors in the pathogenesis of COVID-19 suggesting that its level could be a prognostic marker. Therefore, we elucidated the predictive value [...] Read more.

SARS-CoV-2 infection might cause a critical disease, and patients’ follow-up is based on multiple parameters. Oxidative stress is one of the key factors in the pathogenesis of COVID-19 suggesting that its level could be a prognostic marker. Therefore, we elucidated the predictive value of the serum non-enzymatic total antioxidant capacity (TAC) and that of the newly introduced TAC/lymphocyte ratio in COVID-19. We included 61 COVID-19 (n = 27 ward, n = 34 intensive care unit, ICU) patients and 29 controls in our study. Serum TAC on admission was measured by an enhanced chemiluminescence (ECL) microplate assay previously validated by our research group. TAC levels were higher (p < 0.01) in ICU (median: 407.88 µmol/L) than in ward patients (315.44 µmol/L) and controls (296.60 µmol/L). Besides the classical parameters, both the TAC/lymphocyte ratio and TAC had significant predictive values regarding the severity (AUC-ROC for the TAC/lymphocyte ratio: 0.811; for TAC: 0.728) and acute kidney injury (AUC-ROC for the TAC/lymphocyte ratio: 0.747; for TAC: 0.733) in COVID-19. Moreover, the TAC/lymphocyte ratio had significant predictive value regarding mortality (AUC-ROC: 0.752). Serum TAC and the TAC/lymphocyte ratio might offer valuable information regarding the severity of COVID-19. TAC measured by our ECL microplate assay serves as a promising marker for the prediction of systemic inflammatory diseases. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Human Diseases)

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Serum total antioxidant capacity levels (A), absolute lymphocyte counts (B), and total antioxidant capacity (TAC)/lymphocyte ratios (C) in controls, ward, and intensive care unit COVID-19 patients; receiver operating characteristic (ROC) curves of admission laboratory and clinical parameters for differentiating ICU from ward COVID-19 patients (D). * p < 0.05, ** p < 0.01, *** p < 0.001. SOFA score: Sequential organ failure assessment score. Full article ">Figure 2
TAC/lymphocyte ratios in COVID-19 patients suffering from mild to no (Horowitz Index > 200 mmHg) and moderate-severe (Horowitz Index ≤ 200 mmHg) acute respiratory distress syndrome (ARDS) (A) and diagnostic capacity of the studied markers regarding ARDS investigated by ROC analysis (B). ** p < 0.01. SOFA score—sequential organ failure assessment score. Full article ">Figure 3
TAC/lymphocyte ratios in COVID-19 patients with and without acute kidney injury (AKI) (A); diagnostic capacity of the studied parameters regarding AKI (B). ** p < 0.01. Full article ">Figure 4
TAC/lymphocyte ratios in survivor vs. non-survivor COVID-19 patients (A) and receiver operating characteristic curves of admission laboratory and clinical parameters for predicting hospital mortality in COVID-19 patients (B). *** p < 0.001. SOFA score—sequential organ failure assessment score. Full article ">

16 pages, 4315 KiB

Open AccessArticle

Synergistic Effects of Vitis vinifera L. and Centella asiatica against CCl₄-Induced Liver Injury in Mice

by Suvesh Munakarmi, Yamuna Gurau, Juna Shrestha, Prabodh Risal, Ho Sung Park, Geum-Hwa Lee and Yeon Jun Jeong

Int. J. Mol. Sci. 2023, 24(14), 11255; https://doi.org/10.3390/ijms241411255 - 9 Jul 2023

Cited by 1 | Viewed by 2449

Abstract

Liver injury can be acute or chronic, resulting from a variety of factors, including viral hepatitis, drug overdose, idiosyncratic drug reaction, or toxins, while the progression of pathogenesis in the liver rises due to the involvement of numerous cytokines and growth factor mediators. [...] Read more.

Liver injury can be acute or chronic, resulting from a variety of factors, including viral hepatitis, drug overdose, idiosyncratic drug reaction, or toxins, while the progression of pathogenesis in the liver rises due to the involvement of numerous cytokines and growth factor mediators. Thus, the identification of more effective biomarker-based active phytochemicals isolated from medicinal plants is a promising strategy to protect against CCl₄-induced liver injury. Vitis vinifera L. (VE) and Centella asiatica (CE) are well-known medicinal plants that possess anti-inflammatory and antioxidant properties. However, synergism between the two has not previously been studied. Here, we investigated the synergistic effects of a V. vinifera L. (VE) leaf, C. asiatica (CE) extract combination (VCEC) against CCl₄-induced liver injury. Acute liver injury was induced by a single intraperitoneal administration of CCl₄ (1 mL/kg). VCEC was administered orally for three consecutive days at various concentrations (100 and 200 mg/kg) prior to CCl₄ injection. The extent of liver injury and the protective effects of VCEC were evaluated by biochemical analysis and histopathological studies. Oxidative stress was evaluated by measuring malondialdehyde (MDA) and glutathione (GSH) levels and Western blotting. VCEC treatment significantly reduced serum transaminase levels (AST and ALT), tumor necrosis factor-α (TNF-α), and reactive oxygen species (ROS). CCl₄- induced apoptosis was inhibited by VCEC treatment by reducing cleaved caspase-3 and Bcl2-associated X protein (Bax). VCEC-treated mice significantly restored cytochrome P450 2E1, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) expression in CCl4-treated mice. In addition, VCEC downregulated overexpression of proinflammatory cytokines and hepatic nuclear factor kappa B (NF-κB) and inhibited CCl4-mediated apoptosis. Collectively, VCEC exhibited synergistic protective effects against liver injury through its antioxidant, anti-inflammatory, and antiapoptotic ability against oxidative stress, inflammation, and apoptosis. Therefore, VCEC appears promising as a potential therapeutic agent for CCl₄-induced acute liver injury in mice. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Human Diseases)

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Figure 1
Potential antioxidant properties of VE, CE, and VCEC in comparison with vitamin C. The antioxidant activities of VE, CE, and VCEC were evaluated by DPPH radical scavenging assay. Full article ">Figure 2
VCEC pretreatment ameliorates CCl4-induced acute liver injury in mice. (A) Serum levels of alanine aminotransferase (ALT) and (B) aspartate aminotransferase (AST) were analyzed 24 h after CCl4 injection. Values are presented as mean ± SD (n = 7). (C) Protein expression of cytochrome P450 2E1 (CYP2E1) 24 h after CCl4 injection. (D) Quantification of relative protein expression normalized to β-actin. Data are expressed as mean ± SD (n = 3). ### p < 0.001 denotes a significant difference compared to the control group; * p < 0.05, ** p < 0.01, and *** p < 0.001 indicates significant differences compared to the CCl4-treated group. Full article ">Figure 3
VCEC reduces the histopathological changes caused by CCl4 in liver tissues. (A) Representative H&E-stained liver sections from the indicated groups with necrotic areas and liver damage as indicated by black arrows. (B) Quantitative assessment of (%) area score of liver damage in the indicated groups. The H&E-stained tissues were observed under light microscope at magnification of ×100. The white bar in figure represents the scale bar of 50 µmm, respectively. The values presented are expressed as the mean ± SD (n = 7). ### p < 0.001 denotes significancy compared with the control group; * p < 0.05 and *** p < 0.001 indicates significant differences compared with the CCl4-treated group. Full article ">Figure 4
VCEC enhanced antioxidant activity by regulating the Nrf2/HO-1 pathway and inhibiting oxidative stress in CCl4-induced acute liver injury in mice. (A) Reduced glutathione (GSH) levels. Data presented are expressed as mean ± SD (n = 7). (B) Western blot analysis determining the protein expression of antioxidant-related markers GPx4, Nrf2, HO-1, and Cu/Zn SOD. (C) Quantification of relative protein expression normalized to β-actin. The values presented are expressed as mean ± SD (n = 3). ### p < 0.001 denotes significancy compared with the control group; * p < 0.05, ** p < 0.01, and *** p < 0.001 indicates significant differences compared with the CCl4-treated group. Full article ">Figure 5
Effects of VCEC extracts on levels of MDA, ROS/RNS, and protein expression level of inflammatory cytokine in CCl4-induced acute liver injury. (A) Lipid peroxidation as determined by MDA content; (B) ROS/RNS level. Data presented are expressed as mean ± SD (n = 7). (C) Protein expression level of inflammatory cytokines. (D) Quantification of relative protein expression normalized to β-actin. Data are expressed as mean ± SD (n = 3). ### p < 0.001 denotes significancy compared with the control group; * p < 0.05, ** p < 0.01, and *** p < 0.001 indicates significant differences compared with the CCl4-treated group. Full article ">Figure 6
VCEC pretreatment ameliorates the CCl4-induced apoptotic response. (A) Immunoblot analyses showing the levels of apoptotic proteins (cleaved caspsase-3, 9, and cleaved parp), proapoptotic protein Bax, and antiapoptotic protein Bcl2. (B) Quantification of relative protein expression normalized to β-actin. The values represent the mean ± SD (n = 3). ### p < 0.001 denotes significancy compared with the control group; * p < 0.05, ** p < 0.01, and *** p < 0.001 indicates significant differences compared with the CCl4-treated group. Full article ">Figure 7
An experimental procedure involved the establishment of a CCl4-induced acute liver injury model and subsequent treatment. (A) A diagram illustrates the drug administration route and time points at which the animals were sacrificed following CCl4 administration. (B) A table outlining the different groups along with their corresponding doses of CCl4. Full article ">Figure 8
A schematic diagram of the proposed mechanism by which VCEC exerts its effects on CCl4-induced acute liver injury through multiple pathways. CCl4 exposure leads to a decrease in antioxidant capacity, represented by reduced levels of SOD, GSH, and Nrf2, indicated by downward red arrows. Additionally, CCl4 administration increases inflammatory responses, oxidative stress, and apoptotic protein levels, depicted by upward red arrows. However, VCEC pretreatment counteracts these effects. Full article ">

13 pages, 4002 KiB

Open AccessArticle

Thymoquinone Ameliorates Carfilzomib-Induced Renal Impairment by Modulating Oxidative Stress Markers, Inflammatory/Apoptotic Mediators, and Augmenting Nrf2 in Rats

by Marwa M. Qadri, Mohammad Firoz Alam, Zenat A. Khired, Reem O. Alaqi, Amani A. Khardali, Moudi M. Alasmari, Ahmad S. S. Alrashah, Hisham M. A. Muzafar and Abdullah M. Qahl

Int. J. Mol. Sci. 2023, 24(13), 10621; https://doi.org/10.3390/ijms241310621 - 25 Jun 2023

Cited by 4 | Viewed by 1928

Abstract

Chemotherapy-induced kidney damage is an emerging problem that restricts cancer treatment effectiveness. The proteasome inhibitor carfilzomib (CFZ) is primarily used to treat multiple myeloma and has been associated with severe renal injury in humans. CFZ-induced nephrotoxicity remains an unmet medical need, and there [...] Read more.

Chemotherapy-induced kidney damage is an emerging problem that restricts cancer treatment effectiveness. The proteasome inhibitor carfilzomib (CFZ) is primarily used to treat multiple myeloma and has been associated with severe renal injury in humans. CFZ-induced nephrotoxicity remains an unmet medical need, and there is an urgent need to find and develop a nephroprotective and antioxidant therapy for this condition. Thymoquinone (TQ) is a bioactive compound that has been isolated from Nigella sativa seeds. It has a wide range of pharmacological properties. Therefore, this experimental design aimed to study the effectiveness of TQ against CFZ-induced renal toxicity in rats. The first group of rats was a normal control (CNT); the second group received CFZ (4 mg/kg b.w.); the third and fourth groups received TQ (10 and 20 mg/kg b.w.) 2 h before receiving CFZ; the fifth group received only TQ (20 mg/kg b.w.). This experiment was conducted for 16 days, and at the end of the experiment, blood samples and kidney tissue were collected for biochemical assays. The results indicated that administration of CFZ significantly enhanced serum marker levels such as BUN, creatinine, and uric acid in the CFZ group. Similarly, it was also noticed that CFZ administration induced oxidative stress by reducing antioxidants (GSH) and antioxidant enzymes (CAT and SOD) and increasing lipid peroxidation. CFZ treatment also enhanced the expression of IL-1β, IL-6, and TNF-α production. Moreover, CFZ increased caspase-3 concentrations and reduced Nrf2 expression in the CFZ-administered group. However, treatment with 10 and 20 mg/kg TQ significantly decreased serum markers and increased antioxidant enzymes. TQ treatment considerably reduced IL-1β, IL-6, TNF-α, and caspase-3 concentrations. Overall, this biochemical estimation was also supported by histopathological outcomes. This study revealed that TQ administration significantly mitigated the negative effects of CFZ treatment on Nrf2 expression. Thus, it indicates that TQ may have utility as a potential drug to prevent CFZ-induced nephrotoxicity in the future. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Human Diseases)

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Impact of thymoquinone treatment on kidney function markers. Data were displayed as mean ± standard error mean (n = 6) along with significant value **** p < 0.0001 (CFZ vs. CNT; TQ10 + CFZ vs. CFZ; TQ20 + CFZ vs. CFZ) and ns p > 0.05 (TQ20 vs. CNT) in (A,B). The significant value in (C) was **** p < 0.0001(CFZ vs. CNT; TQ20 + CFZ vs. CFZ) and * p < 0.01 (TQ10 + CFZ vs. CFZ and TQ20 vs. CNT). Abbreviations—CNT: control, CFZ: carfilzomib, and TQ: thymoquinone. Full article ">Figure 2
Impact of thymoquinone treatment on lipid peroxidation (MDA). Data were displayed as mean ± standard error mean (n = 6) along with significant value **** p < 0.0001 (CFZ vs. CNT; TQ20 + CFZ vs. CFZ), ** p < 0.001 (TQ10 + CFZ vs. CFZ), and ns p > 0.05 (TQ20 vs. CNT). Abbreviations—CNT: control, CFZ: carfilzomib, and TQ: thymoquinone. Full article ">Figure 3
Impact of thymoquinone treatment on antioxidant enzymes. Data were displayed as mean ± standard error mean (n = 6) along with significant value **** p < 0.0001 (CFZ vs. CNT) (TQ20 + CFZ vs. CFZ), *** p < 0.001 (TQ10 + CFZ vs. CFZ), ** p < 0.001 (TQ20 vs. CNT) in (A) The significant value in (B,C) was **** p < 0.0001 (CFZ vs. CNT), (TQ10 + CFZ vs. CFZ), (TQ20 + CFZ vs. CFZ); ns p > 0.05 (TQ20 vs. CNT). Abbreviations—CNT: control, CFZ: carfilzomib, and TQ: thymoquinone. Full article ">Figure 4
Impact of thymoquinone treatment on IL-1β and IL-6 gene expression. The cycle threshold (Ct) value of target genes was normalized to the Ct value of β-actin in the same sample. Data were displayed as mean ± standard error mean (n = 6) along with significant value *** p < 0.001 (CFZ vs. CNT; TQ20 + CFZ vs. CFZ), ** p < 0.001 (TQ10 + CFZ vs. CFZ), and ns p > 0.05 (TQ20 vs. CNT) in (A) and (B). Abbreviations—CNT: control, CFZ: carfilzomib, and TQ: thymoquinone. Full article ">Figure 5
Impact of thymoquinone treatment on tumor necrosis factor (TNF-α). Data were displayed as mean ± standard error mean (n = 6) along with significant value **** p < 0.0001 (CFZ vs. CNT; TQ10 + CFZ vs. CFZ; TQ20 + CFZ vs. CFZ) and ns p > 0.05 (TQ20 vs. CNT). Abbreviations—CNT: control, CFZ: carfilzomib, and TQ: thymoquinone. Full article ">Figure 6
Impact of thymoquinone treatment on apoptotic marker (caspase3). Data were displayed as mean ± standard error mean (n = 6) along with significant value **** p < 0.0001 (CFZ vs. CNT; TQ10 + CFZ vs. CFZ; TQ20 + CFZ vs. CFZ) and ns p > 0.05 (TQ20 vs. CNT). Abbreviations—CNT: control, CFZ: carfilzomib, and TQ: thymoquinone. Full article ">Figure 7
Impact of thymoquinone treatment on Nrf2 gene expression following CFZ treatment. The cycle threshold (Ct) value of the Nrf2 gene was normalized to the Ct value of β-actin in the same sample. Data were displayed as mean ± standard error mean (n = 6) along with significant value; *** p < 0.001 (TQ20 + CFZ vs. CFZ; TQ20 vs. CNT) and ns p > 0.05 (CFZ vs. CNT; TQ10 + CFZ vs. CFZ). Data represent mean ± S.E M. of 6 animals per treatment group. Abbreviations—CNT: control, CFZ: carfilzomib, and TQ: thymoquinone. Full article ">Figure 8
Histological analysis of the normal control indicated without any abnormalities in the glomeruli basement membrane and renal tubules with zero score (A). TQ-treated group revealed healthy kidney structure devoid of pathological abnormalities, including unaltered glomeruli basement membrane and renal tubules with zero score (E). However, the CFZ group indicated arrow tubular vacuolization, necrosis, as well as degenerative alterations in the glomerular basement membrane with renal injury score = 4 (B). Degenerative kidney alterations caused by CFZ were reduced with TQ treatment (10 and 20 mg/kg) with renal injury score = 2 and score = 1 for (C) and (D), respectively. ** p < 0.01 (TQ10 + CFZ vs. CFZ), **** p < 0.0001 (TQ20 + CFZ vs. CFZ), and nsp > 0.05 (TQ20 vs. CNT). Arrow (<img alt="Ijms 24 10621 i001" src="ijms/ijms-24-10621/article_deploy/html/images/ijms-24-10621-i001.png"/>) indicates the glomerular basement membrane degeneration, tubular vacuolization and necrosis, etc. Full article ">Figure 9
Male Wistar albino rats grouping and dosing scheme. Full article ">

15 pages, 2861 KiB

Open AccessArticle

Generation and Characterization of CYP2E1-Overexpressing HepG2 Cells to Study the Role of CYP2E1 in Hepatic Hypoxia-Reoxygenation Injury

by Nouf Alwadei, Mamunur Rashid, Devaraj Venkatapura Chandrashekar, Simin Rahighi, Jennifer Totonchy, Ajay Sharma and Reza Mehvar

Int. J. Mol. Sci. 2023, 24(9), 8121; https://doi.org/10.3390/ijms24098121 - 1 May 2023

Cited by 6 | Viewed by 2894

Abstract

The mechanisms of hepatic ischemia/reperfusion (I/R) injury, which occurs during liver transplantation or surgery, are poorly understood. The purpose of the current study was to generate and characterize a HepG2 cell line with a stable overexpression of CYP2E1 to investigate the role of [...] Read more.

The mechanisms of hepatic ischemia/reperfusion (I/R) injury, which occurs during liver transplantation or surgery, are poorly understood. The purpose of the current study was to generate and characterize a HepG2 cell line with a stable overexpression of CYP2E1 to investigate the role of the enzyme in hypoxia/reperfusion (H/R) injury in an ex vivo setting. GFP-tagged CYP2E1 and control clones were developed, and their gene expression and protein levels of GFP and CYP2E1 were determined using RT-PCR and ELISA/Western blot analysis, respectively. Additionally, the CYP2E1 catalytic activity was determined by UPLC-MS/MS analysis of 6-hydroxychlorzoxazone formed from the chlorzoxazone substrate. The CYP2E1 and control clones were subjected to hypoxia (10 h) and reoxygenation (0.5 h), and cell death and reactive oxygen species (ROS) generation were quantitated using LDH and flow cytometry, respectively. Compared with the control clone, the selected CYP2E1 clone showed a 720-fold increase in CYP2E1 expression and a prominent band in the western blot analysis, which was associated with a 150-fold increase in CYP2E1 catalytic activity. The CYP2E1 clone produced 2.3-fold more ROS and 1.9-fold more cell death in the H/R model. It is concluded that the constitutive CYP2E1 in the liver may play a detrimental role in hepatic I/R injury. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Human Diseases)

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The percentages of cells showing GFP fluorescence for the clones transfected with the control (GFP only) (A) or CYP2E1 (GFP plus CYP2E1) (B) plasmids. The columns and bars, respectively, represent the mean and standard deviations of the three measurements. The confocal fluorescence images for two clones from each group are also shown (green: GFP; blue: DAPI for nuclear staining). Full article ">Figure 2
The mRNA expressions (A,B) and protein contents (C,D) of GFP in the six control (A,C) and six CYP2E1 (B,D) clones of stably transfected HepG2 cells. Each column represents the average of two replicates. Full article ">Figure 3
The mRNA expressions of CYP2E1 in the six control (A) and six CYP2E1 (B) clones of stably transfected HepG2 cells, and the fold change in the mRNA expression of CYP2E1 in the CYP2E1 clones relative to the geometric mean of the expressions in the control clones (C). Each column represents the average of two replicates. Full article ">Figure 4
Western blot images of three CYP2E1 clones of stably transfected HepG2 cells with relatively high mRNA expression of CYP2E1 (Clones 2, 5, and 6), and three control clones of stably transfected HepG2 cells (clones 1, 3, and 6) using CYP2E1 (left panel), or GFP (right panel) antibodies. For comparison, the band for human recombinant CYP2E1 is also shown with the CYP2E1 antibody (left panel). Full article ">Figure 5
CYP2E1 activities of three control and three CYP2E1 clones of stably transfected HepG2 cells determined by the LC-MS/MS method (A) and the chromatograms of 6-hydroxychlorzoxazone metabolite formed by the microsomes of control (clone 6) and CYP2E1 (clone 5), which showed the highest CYP2E1 activities (B). The columns and bars, respectively, represent the mean and standard deviations of three replicate measurements. ****, p < 0.0001; based on the one-way ANOVA, followed by the Tukey’s multiple comparison test. Full article ">Figure 6
The effects of CYP2E1 overexpression on cell death during hypoxia, reoxygenation, and hypoxia/reoxygenation in the control and CYP2E1 clones. Cell death was quantitated by LDH release. The columns and bars, respectively, represent the mean and standard deviations of twelve measurements in three separate experiments. ***, p < 0.001; ****, p < 0.0001; based on the two-way ANOVA, followed by the Bonferroni’s multiple comparison test. Full article ">Figure 7
The effects of CYP2E1 overexpression on ROS generation determined by mean fluorescence intensity of CellROX deep red dye using flow cytometry after subjecting the control and CYP2E1 clones of stably transfected HepG2 cells to normoxia (basal) or hypoxia/reoxygenation (H/R). (A) Histograms for cell frequencies at each CellRox intensity for different conditions (indicated by histogram color) from a representative sample (B) the columns and bars, respectively, represent the mean and standard deviations of 25 measurements in 3 separate experiments. *, p < 0.05; ****, p < 0.0001; based on the two-way ANOVA, followed by the Bonferroni’s multiple comparison test. Full article ">

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17 pages, 682 KiB

Open AccessReview

Role of Oxidative Stress in Sensorineural Hearing Loss

by Masato Teraoka, Naohito Hato, Haruhiko Inufusa and Fukka You

Int. J. Mol. Sci. 2024, 25(8), 4146; https://doi.org/10.3390/ijms25084146 - 9 Apr 2024

Cited by 6 | Viewed by 3082

Abstract

Hearing is essential for communication, and its loss can cause a serious disruption to one’s social life. Hearing loss is also recognized as a major risk factor for dementia; therefore, addressing hearing loss is a pressing global issue. Sensorineural hearing loss, the predominant [...] Read more.

Hearing is essential for communication, and its loss can cause a serious disruption to one’s social life. Hearing loss is also recognized as a major risk factor for dementia; therefore, addressing hearing loss is a pressing global issue. Sensorineural hearing loss, the predominant type of hearing loss, is mainly due to damage to the inner ear along with a variety of pathologies including ischemia, noise, trauma, aging, and ototoxic drugs. In addition to genetic factors, oxidative stress has been identified as a common mechanism underlying several cochlear pathologies. The cochlea, which plays a major role in auditory function, requires high-energy metabolism and is, therefore, highly susceptible to oxidative stress, particularly in the mitochondria. Based on these pathological findings, the potential of antioxidants for the treatment of hearing loss has been demonstrated in several animal studies. However, results from human studies are insufficient, and future clinical trials are required. This review discusses the relationship between sensorineural hearing loss and reactive oxidative species (ROS), with particular emphasis on age-related hearing loss, noise-induced hearing loss, and ischemia–reperfusion injury. Based on these mechanisms, the current status and future perspectives of ROS-targeted therapy for sensorineural hearing loss are described. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Human Diseases)

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16 pages, 338 KiB

Open AccessReview

Insights into the Management of Chronic Hepatitis in Children—From Oxidative Stress to Antioxidant Therapy

by Ileana Ioniuc, Ancuta Lupu, Irina Tarnita, Alexandra Mastaleru, Laura Mihaela Trandafir, Vasile Valeriu Lupu, Iuliana Magdalena Starcea, Mirabela Alecsa, Ionela Daniela Morariu, Delia Lidia Salaru and Alice Azoicai

Int. J. Mol. Sci. 2024, 25(7), 3908; https://doi.org/10.3390/ijms25073908 - 31 Mar 2024

Viewed by 1212

Abstract

Recent research has generated awareness of the existence of various pathophysiological pathways that contribute to the development of chronic diseases; thus, pro-oxidative factors have been accepted as significant contributors to the emergence of a wide range of diseases, from inflammatory to malignant. Redox [...] Read more.

Recent research has generated awareness of the existence of various pathophysiological pathways that contribute to the development of chronic diseases; thus, pro-oxidative factors have been accepted as significant contributors to the emergence of a wide range of diseases, from inflammatory to malignant. Redox homeostasis is especially crucial in liver pathology, as disturbances at this level have been linked to a variety of chronic diseases. Hepatitis is an umbrella term used to describe liver inflammation, which is the foundation of this disease regardless of its cause. Chronic hepatitis produces both oxidative stress generated by hepatocyte inflammation and viral inoculation. The majority of hepatitis in children is caused by a virus, and current studies reveal that 60–80% of cases become chronic, with many young patients still at risk of advancing liver damage. This review intends to emphasize the relevance of understanding these pathological redox pathways, as well as the need to update therapeutic strategies in chronic liver pathology, considering the beneficial effects of antioxidants. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Human Diseases)

17 pages, 688 KiB

Open AccessReview

Bioactive Compounds for Combating Oxidative Stress in Dermatology

by Delia Turcov, Anca Zbranca-Toporas and Daniela Suteu

Int. J. Mol. Sci. 2023, 24(24), 17517; https://doi.org/10.3390/ijms242417517 - 15 Dec 2023

Cited by 4 | Viewed by 1698

Abstract

There are extensive studies that confirm the harmful and strong influence of oxidative stress on the skin. The body’s response to oxidative stress can vary depending on the type of reactive oxygen species (ROS) or reactive nitrogen species (RNS) and their metabolites, the [...] Read more.

There are extensive studies that confirm the harmful and strong influence of oxidative stress on the skin. The body’s response to oxidative stress can vary depending on the type of reactive oxygen species (ROS) or reactive nitrogen species (RNS) and their metabolites, the duration of exposure to oxidative stress and the antioxidant capacity at each tissue level. Numerous skin diseases and pathologies are associated with the excessive production and accumulation of free radicals. title altered Both categories have advantages and disadvantages in terms of skin structures, tolerability, therapeutic performance, ease of application or formulation and economic efficiency. The effect of long-term treatment with antioxidants is evaluated through studies investigating their protective effect and the improvement of some phenomena caused by oxidative stress. This article summarizes the available information on the presence of compounds used in dermatology to combat oxidative stress in the skin. It aims to provide an overview of all the considerations for choosing an antioxidant agent, the topics for further research and the answers sought in order to optimize therapeutic performance. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Human Diseases)

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27 pages, 3569 KiB

Open AccessReview

The Role of the Oxidative State and Innate Immunity Mediated by TLR7 and TLR9 in Lupus Nephritis

by Raquel Echavarria, Ernesto Germán Cardona-Muñoz, Pablo Ortiz-Lazareno, Jorge Andrade-Sierra, Luis Francisco Gómez-Hermosillo, Jorge Casillas-Moreno, Tannia Isabel Campos-Bayardo, Daniel Román-Rojas, Andrés García-Sánchez and Alejandra Guillermina Miranda-Díaz

Int. J. Mol. Sci. 2023, 24(20), 15234; https://doi.org/10.3390/ijms242015234 - 16 Oct 2023

Cited by 6 | Viewed by 3573

Abstract

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) and is considered one of the leading causes of mortality. Multiple immunological pathways are involved in the pathogenesis of SLE, which makes it imperative to deepen our knowledge about this disease’s [...] Read more.

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) and is considered one of the leading causes of mortality. Multiple immunological pathways are involved in the pathogenesis of SLE, which makes it imperative to deepen our knowledge about this disease’s immune-pathological complexity and explore new therapeutic targets. Since an altered redox state contributes to immune system dysregulation, this document briefly addresses the roles of oxidative stress (OS), oxidative DNA damage, antioxidant enzymes, mitochondrial function, and mitophagy in SLE and LN. Although adaptive immunity’s participation in the development of autoimmunity is undeniable, increasing data emphasize the importance of innate immunity elements, particularly the Toll-like receptors (TLRs) that recognize nucleic acid ligands, in inflammatory and autoimmune diseases. Here, we discuss the intriguing roles of TLR7 and TLR9 in developing SLE and LN. Also included are the essential characteristics of conventional treatments and some other novel and little-explored alternatives that offer options to improve renal function in LN. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Human Diseases)

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Factors in SLE development. Microvascular inflammation with the development of autoantibodies, pathogenic immune complexes, and autoreactive T cell activation against ubiquitous nuclear antigens are characteristic of SLE. Oxidative stress (OS), antioxidant capacity, DNA damage and repair, mitochondrial function, mitophagy, and innate immunity mechanisms mediated by the toll-like receptors TLR7 and TLR9 influence the induction of systemic autoimmunity and tissue damage. Full article ">Figure 2
Oxidative stress, neutrophils, and NETs in APS and SLE. Neutrophils’ immune functions, including NETosis, are primarily mediated by ROS. Neutrophil–platelet interactions augment ROS production and ease NET release. Autoantibodies against phospholipids and DNA are typical of APS and SLE, and components released by NETs often contribute to the antigenic load. Full article ">Figure 3
LN and its damage mechanism. Glomerular damage in LN features endothelial injury, glomerular membrane damage, and podocytes dysfunction mediated by autoantibodies, immune complexes, complement system activation, inflammation, autophagy, NETs, and redox imbalances. In patients with LN, a robust self-renewal and repair system of the glomerular filtration membrane results in instability regarding the degrees of renal injury and proteinuria. In early LN, it is possible to repair pathological damage to the filtration membrane caused by complement proteins and cytokines through autoregulation. However, tissue damage cannot be repaired as the disease progresses, leading to severe proteinuria, increased risk of cardiovascular disease, and high mortality. Full article ">Figure 4
Influence of OS, DNA damage, antioxidants, mitochondrial function and mitophagy on the development of LN. Oxidation leads to organic damage characteristic of SLE, especially in LN. Increases in LPO due to OS, limited antioxidant defense, and low NO availability contribute to the injury observed in LN. The balance between oxidation and DNA repair is altered in patients with LN, accumulating the marker of oxidative DNA damage (8-OHdG), genomic instability, and cellular dysfunction. Additionally, metabolic abnormalities influence the nature and state of activation of the kidney’s immune cell infiltrate, highlighting the importance of mitochondrial function in developing diseases such as LN through Danger-Associated Molecular Patterns (DAMPs), TLR activation, and the production of autoantibodies. Finally, aberrant or defective mitophagy is central to the pathology of LN as it facilitates the release of mitochondrial antigens, promotes their processing by major histocompatibility complex (MHC) molecules, and contributes to mitochondrial dysfunction. Full article ">Figure 5
Participation of innate immunity and TLRs in the development of LN. Some TLRs, such as TLR3, TLR7, and TLR9, are in the endosomal compartment, where they detect endogenous ligands such as RNA, DNA, hypo-methylated self-DNA within immune complexes, chromatin released from NETs, oxidized mitochondrial nucleoids, and other chromatin formats. Dendritic and B cells can process antigens and present antigens to T cells. In LN, TLR7 and TLR9 allow the persistent activation of dendritic and B cells by autoantigens, thereby promoting autoantibody production, systemic autoimmunity, and glomerulonephritis mediated by immune complexes. In addition, the nucleic acid component of the immune complexes also activates intra renal inflammation via TLR7 and TLR9 in intra renal macrophages, resulting in the activation of glomerular endothelium and mesangial cells that are characteristic of LN. Full article ">Figure 6
Therapeutic objectives and management of LN in SLE. The goal of therapy for LN was established with a reduction in proteinuria by ≥25% with a stable glomerular filtration rate (GFR, ±10% of baseline) in the first three months after the start of treatment, a reduction in ≥50% proteinuria at six months and a rate of proteinuria <0.5–0.7 g/24 h at 12–24 months (all with stable GFR). Immunosuppressive therapies, immunomodulatory drugs, and vitamin D are currently used to control disease activity, prevent relapses, reduce the use of glucocorticoids, and lessen inflammation and fibrosis. Voclosporin, tacrolimus, rituximab, belimumab, and cyclophosphamide limit damage to target organs, including the kidney, in patients with SLE. However, new therapies focused on reducing the effect of endogenous nucleic acids mediated by TLR7 and TLR9 present promising results in preclinical studies, suggesting that their translation to the clinic could significantly benefit the quality of life, survival, and management of comorbidities in patients with SLE and LN. Full article ">

24 pages, 2997 KiB

Open AccessReview

COVID-19 Complications: Oxidative Stress, Inflammation, and Mitochondrial and Endothelial Dysfunction

by Ekaterina Georgieva, Julian Ananiev, Yovcho Yovchev, Georgi Arabadzhiev, Hristo Abrashev, Despina Abrasheva, Vasil Atanasov, Rositsa Kostandieva, Mitko Mitev, Kamelia Petkova-Parlapanska, Yanka Karamalakova, Iliana Koleva-Korkelia, Vanya Tsoneva and Galina Nikolova

Int. J. Mol. Sci. 2023, 24(19), 14876; https://doi.org/10.3390/ijms241914876 - 4 Oct 2023

Cited by 38 | Viewed by 3845

Abstract

SARS-CoV-2 infection, discovered and isolated in Wuhan City, Hubei Province, China, causes acute atypical respiratory symptoms and has led to profound changes in our lives. COVID-19 is characterized by a wide range of complications, which include pulmonary embolism, thromboembolism and arterial clot formation, [...] Read more.

SARS-CoV-2 infection, discovered and isolated in Wuhan City, Hubei Province, China, causes acute atypical respiratory symptoms and has led to profound changes in our lives. COVID-19 is characterized by a wide range of complications, which include pulmonary embolism, thromboembolism and arterial clot formation, arrhythmias, cardiomyopathy, multiorgan failure, and more. The disease has caused a worldwide pandemic, and despite various measures such as social distancing, various preventive strategies, and therapeutic approaches, and the creation of vaccines, the novel coronavirus infection (COVID-19) still hides many mysteries for the scientific community. Oxidative stress has been suggested to play an essential role in the pathogenesis of COVID-19, and determining free radical levels in patients with coronavirus infection may provide an insight into disease severity. The generation of abnormal levels of oxidants under a COVID-19-induced cytokine storm causes the irreversible oxidation of a wide range of macromolecules and subsequent damage to cells, tissues, and organs. Clinical studies have shown that oxidative stress initiates endothelial damage, which increases the risk of complications in COVID-19 and post-COVID-19 or long-COVID-19 cases. This review describes the role of oxidative stress and free radicals in the mediation of COVID-19-induced mitochondrial and endothelial dysfunction. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Human Diseases)

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23 pages, 1377 KiB

Open AccessReview

Salivary Alterations of Myeloperoxidase in Patients with Systemic Diseases: A Systematic Review

by Kacper Nijakowski, Jakub Jankowski, Dawid Gruszczyński and Anna Surdacka

Int. J. Mol. Sci. 2023, 24(15), 12078; https://doi.org/10.3390/ijms241512078 - 28 Jul 2023

Cited by 6 | Viewed by 1910

Abstract

Salivary myeloperoxidase (MPO) is a key mediator of the oral immune system, acting as an enzyme that utilises H₂O₂ to generate molecules with high bactericidal activity. While MPO determination in plasma is quite common, the use of saliva is still [...] Read more.

Salivary myeloperoxidase (MPO) is a key mediator of the oral immune system, acting as an enzyme that utilises H₂O₂ to generate molecules with high bactericidal activity. While MPO determination in plasma is quite common, the use of saliva is still rare. Our systematic review was designed to answer the question “Are salivary levels of myeloperoxidase altered in patients with systemic diseases?”. Following the inclusion and exclusion criteria, we included twenty-six studies. Altered MPO levels in saliva were most commonly found in patients with cardiovascular and gastrointestinal diseases. Most studies concerned unstimulated whole saliva, and only a few of them stimulated, mainly by chewing paraffin. Enzyme-linked immunosorbent assay (ELISA) was the most common method for determination of MPO concentrations in saliva. Increased salivary MPO levels were more often observed for inflammatory diseases, except patients with inflammatory bowel diseases who were eligible for biologic therapy. In conclusion, MPO could be altered in the saliva of patients with systematic diseases, especially cardiovascular or gastrointestinal diseases. However, further investigations are recommended to validate these outcomes. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Human Diseases)

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