rhEGF Treatment Improves EGFR Inhibitors-Induced Skin Barrier and Immune Defects

Abstract Background: The mechanisms of epidermal growth factor (EGF) effects EGF receptor inhibitor (EGFRI)-related skin toxicities are as yet unknown. We investigated which mechanisms are involved in EGF’s positive effects. Methods: Two types of EGFRIs, cetuximab and gefitinib, were used to treat the cells or 3d-cultured human skin tissue with recombinant human EGF (rhEGF). The expression levels of skin barrier related proteins, inflammatory cytokines, and antimicrobial peptides (AMPs) were measured by using RT qPCR, ELISA, immunohistochemical (IHC) stain, or immunofluorescence..Results: Using western blot assay, cetuximab decreased EGFR and phosphorylated EGFR (pEGFR) expression. In contrast, rhEGF increased EGFR and pEGFR expression. Also, rhEGF induces EGFR signaling by pAKT and pPI3K expression in gefitinib and rhEGF co-treated cells. Expressions of proliferation and differentiation proteins, both ki-67 and filaggrin, were decreased in EGFRIs -treated tissue. However, in rhEGF and EGFRIs co-treated tissue, those expressions were increased. Pro-inflammatory cytokines, including IL-1α, IL-8, and TNF-α expression, were increased by EGFRIs, and down-regulated by rhEGF. In patients’ tissue evaluation, compared with control, patients’ Ki-67 and EGFR expression were decreased (P=0.015, P=0.001). Patients’ IL-17 and TNF-α expression intensity was higher than that of control group (P=0.038, P=0.037). After treatment with EGF ointment, average values of Ki-67, EGFR, and Melan-A were changed to normal values. Oppositely patients’ proportions of IL-17 and TNF-α were decreased to low stain level.Conclusions: Treatment of rhEGF improved EGFRIs-induced skin eruption via normalizing the proliferation and differentiation of keratinocytes, reducing inflammatory cytokines by the affected EGFRIs.

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rhEGF Treatment Improves EGFR Inhibitor-Induced Skin Barrier and Immune Defects

Cancers ◽

10.3390/cancers12113120 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3120

Author(s):

Ji Min Kim ◽

Jun Ho Ji ◽

Young Saing Kim ◽

Suee Lee ◽

Sung Yong Oh ◽

...

Keyword(s):

Egf Receptor ◽

Skin Barrier ◽

Control Group ◽

Ki 67 ◽

Positive Effects ◽

Egfr Expression ◽

Tnf Α ◽

Proliferation And Differentiation ◽

Gefitinib Treatment ◽

Immune Defects

The mechanisms of epidermal growth factor (EGF) affecting EGF receptor inhibitor (EGFRI)-related skin toxicities are as yet unknown. We investigated which mechanisms are involved in EGF’s positive effects. Two types of EGFRIs, cetuximab and gefitinib, were used to treat the cells or 3d-cultured human skin tissue with recombinant human EGF (rhEGF). As a result, rhEGF increased EGFR and pEGFR expression. Furthermore, rhEGF induces EGFR signaling by pAKT and pPI3K expression in gefitinib and rhEGF co-treated cells. In addition, rhEGF bound to EGFR after than cetuximab, but cetuximab bound to EGFR more strongly than rhEGF. Moreover, expressions of proliferation and differentiation proteins, both ki-67 and filaggrin, were decreased in EGFRI-treated tissue. However, in rhEGF and EGFRI co-treated tissue, those expressions were increased. Expression of IL-1α, IL-8, and TNF-α was increased by EGFRIs and down-regulated by rhEGF. Furthermore, hBD-2 and hBD-3 protein expressions were inhibited by cetuximab or gefitinib treatment, and those decrements were increased by rhEGF treatment. In patients’ tissue evaluation, compared with controls, patients’ Ki-67 and EGFR expression were decreased (p = 0.015, p = 0.001). Patients’ IL-17 and TNF-α expression intensity was higher than that of the control group (p = 0.038, p = 0.037). After treatment with EGF ointment, average values of Ki-67, EGFR, and Melan-A were changed to normal values. Oppositely, patients’ proportions of IL-17 and TNF-α were decreased to low stain level. In conclusion, treatment of rhEGF improved EGFRI-induced skin eruption via normalizing the proliferation and differentiation of keratinocytes, reducing inflammatory cytokines by the affected EGFRIs.

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The effect of zinc supplementation on pro-inflammatory cytokines (TNF-α, IL-1 AND IL-6) in mice with Escherichia coli LPS-induced diarrhea

Iranian Journal of Microbiology ◽

10.18502/ijm.v11i5.1960 ◽

2019 ◽

Author(s):

Sulaiman Yusuf ◽

Yati Soenarto ◽

Muhammad Juffrie ◽

Wiryatun Lestariana

Keyword(s):

Inflammatory Cytokines ◽

Zinc Supplementation ◽

Controlled Trial ◽

Control Group ◽

Once Daily ◽

E Coli ◽

Positive Effects ◽

Tnf Α ◽

Positive Effect ◽

Pro Inflammatory Cytokines

Background and Objectives: Inflammation in the intestine causes diarrhea due to an increased release of pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6. These are triggered by the exposure of E. coli-LPS to epithelial cells of the intestinal mucosa as well as low concentration of zinc in plasma such as in infants or children who are experiencing diarrhea. This paper aims to determine the effects of zinc supplementation on pro-inflammatory cytokines (TNF-α, IL-1 and IL-6) in mice with E. coli-LPS-induced diarrhea. Materials and Methods: This study used a controlled trial experimental design in the laboratory. A sample size of 20 mice were randomly divided into 4 groups: 1) Control group was given standard foods, 2) Trial group was given E. coli-LPS 2.5 mg/kg/oral once on day1, 3) Prevention group was given E. coli-LPS + 30 mg/kg/oral of zinc once daily for 12 days, 4) Therapeutic group was given E. coli-LPS, and were then given 30 mg/kg/oral of zinc once daily for 12 days if diarrhea occurred. Blood samples of mice were taken through the orbital sinus on the 0, 5th, 10th hour, and on the 4th, 8th and 12th days. Results: Positive effects of zinc supplementation on levels of pro-inflammatory cytokines were observed, in which the higher levels of zinc were present, the lower levels of pro-inflammatory cytokines, especially TNF-α were observed. However, there was an increase of IL-1 and IL-6 levels on the 8th day in the prevention and therapeutic groups. Conclusion: Oral zinc supplementation had a significant positive effect on the levels of pro-inflammatory cytokines. Where there were higher levels of zinc, lower levels of pro-inflammatory cytokines TNF-α were present.

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Ascorbic Acid, Inflammatory Cytokines (IL-1β/TNF-α/IFN-γ), or Their Combination’s Effect on Stemness, Proliferation, and Differentiation of Gingival Mesenchymal Stem/Progenitor Cells

Stem Cells International ◽

10.1155/2020/8897138 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Karim M. Fawzy El-Sayed ◽

Nhung Nguyen ◽

Christof E. Dörfer

Keyword(s):

Ascorbic Acid ◽

Progenitor Cells ◽

Inflammatory Cytokines ◽

Cellular Proliferation ◽

Basic Medium ◽

Control Group ◽

Multilineage Differentiation ◽

Positive Effects ◽

Proliferation And Differentiation ◽

The Impact

Objective. Ascorbic acid (AA) and controlled inflammatory stimuli are postulated to possess the ability to independently exert positive effects on a variety of proliferative, pluripotency, and differentiation attributes of gingival mesenchymal stem/progenitor cells (G-MSCs). The current study’s objective was to explore and compare for the first time the impact of the major inflammatory cytokines (IL-1β/TNF-α/IFN-γ), AA, or their combination on multipotency/pluripotency, proliferative, and differentiation characteristics of G-MSCs. Design. Human G-MSCs (n=5) were isolated and cultured in basic medium (control group), in basic medium with major inflammatory cytokines; 1 ng/ml IL-1β, 10 ng/ml TNF-α, and 100 ng/ml IFN-γ (inflammatory group), in basic medium with 250 μmol/l AA (AA group) and in inflammatory medium supplemented by AA (inflammatory/AA group). All media were renewed three times per week. In stimulated G-MSCs intracellular β-catenin at 1 hour, pluripotency gene expression at 1, 3, and 5 days, as well as colony-forming units (CFUs) ability and cellular proliferation over 14 days were examined. Following a five-days stimulation in the designated groups, multilineage differentiation was assessed via qualitative and quantitative histochemistry as well as mRNA expression. Results. β-Catenin significantly decreased intracellularly in all experimental groups (p=0.002, Friedman). AA group exhibited significantly higher cellular counts on days 3, 6, 7, and 13 (p<0.05) and the highest CFUs at 14 days [median-CFUs (Q25/Q75); 40 (15/50), p=0.043]. Significantly higher Nanog expression was noted in AA group [median gene-copies/PGK1 (Q25/Q75); 0.0006 (0.0002/0.0007), p<0.01, Wilcoxon-signed-rank]. Significant multilineage differentiation abilities, especially into osteogenic and chondrogenic directions, were further evident in the AA group. Conclusions. AA stimulation enhances G-MSCs’ stemness, proliferation, and differentiation properties, effects which are associated with a Wnt/β-catenin signaling pathway activation. Apart from initially boosting cellular metabolism as well as Sox2 and Oct4A pluripotency marker expression, inflammation appeared to attenuate these AA-induced positive effects. Current results reveal that for AA to exert its beneficial effects on G-MSCs’ cellular attributes, it requires to act in an inflammation-free microenvironment.

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Analysis of the physical activity effects and measurement of pro-inflammatory cytokines in irradiated lungs in rats

Acta Cirurgica Brasileira ◽

10.1590/s0102-86502012000300004 ◽

2012 ◽

Vol 27 (3) ◽

pp. 223-230 ◽

Cited By ~ 1

Author(s):

Renata Cristiane Gennari Bianchi ◽

Eduardo Rochete Ropelle ◽

Carlos Kiyoshi Katashima ◽

José Barreto Campello Carvalheira ◽

Luiz Roberto Lopes ◽

...

Keyword(s):

Physical Activity ◽

Western Blotting ◽

Inflammatory Cytokines ◽

Lower Lobe ◽

Whole Body ◽

Control Group ◽

Western Blotting Analysis ◽

Blotting Analysis ◽

Tnf Α ◽

Pro Inflammatory Cytokines

PURPOSE: To study if the pre-radiotherapy physical activity has radio-protective elements, by measuring the radio-induced activation of pro-inflammatory cytokines as interleukin-6 (il-6), transforming growth factor -β (tgf -β), tumor necrosis factor -α (tnf-α) and protein beta kinase β (ikkβ), through western blotting analysis. METHODS: A randomized study with 28 Wistar hannover rats, males, with a mean age of 90 days and weighing about 200 grams. The animals were divided into three groups: (GI, GII and GIII). GIII group were submitted to swimming for eight weeks (zero load, three times a week, about 30 minutes). Then, the groups (except the control group) were submitted to irradiation by cobalt therapy, single dose of 3.5 gray in the whole body. All animals were sacrificed by overdose of pentobarbital, according to the time for analysis of cytokines, and then a fragment of the lower lobe of the right lung went to western blotting analysis. RESULTS: The cytokines IKK β, TNF-α and IL-6 induced by radiation in the lung were lower in the exercised animals. However, exercise did not alter the radiation-induced increase in tgf-β. CONCLUSION: The results show a lower response in relation to inflammatory cytokines in the group that practiced the exercise pre-radiotherapy, showing that exercise can protect tissues from tissue damage due to irradiation.

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Pro- and Anti-Inflammatory Cytokines in the First Trimester—Comparison of Missed Miscarriage and Normal Pregnancy

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18168538 ◽

2021 ◽

Vol 18 (16) ◽

pp. 8538

Author(s):

Maciej Kwiatek ◽

Tomasz Gęca ◽

Anna Kwaśniewska

Keyword(s):

Immune Response ◽

Inflammatory Cytokines ◽

First Trimester ◽

Normal Pregnancy ◽

Control Group ◽

Study Group ◽

Tnf Α ◽

Cytokine Levels ◽

Anti Inflammatory ◽

Tgf Β1

The advantage in response of Th2 over Th1 is observed in normal pregnancy in peripheral blood. A disturbance of this balance can lead to symptoms of miscarriage and pregnancy loss. The aim of this study was to evaluate the pro- and anti-inflammatory cytokines in sera of women who were diagnosed with missed miscarriage in the first trimester and to compare this systemic immune response to the response in women with normal pregnancy. The study group consisted of 61 patients diagnosed with missed miscarriage. In total, 19 healthy women with uncomplicated first trimester created the control group. Cytokines were determined in the maternal serum by ELISA. The analysis included INF-γ, TNF-α, Il-1β, Il-4, Il-5, Il-6, Il-9, Il-10, Il-13 and TGF-β1. Th1 cytokine levels in the study group reached slightly higher values for INF-γ, Il-1β and slightly lower for IL-6 and TNF-α. In turn, Th2 cytokine levels in the study group were slightly higher (Il-9, Il-13), significantly higher (Il4, p = 0.015; Il-5, p = 0.0003) or showed no differences with the control group (Il-10). Slightly lower concentration involved only TGF-β1. Analysis of the correlation between levels of pro- and anti-inflammatory cytokines resulted in some discrepancies, without showing predominance of a specific immune response. The results did not confirm that women with missed miscarriage had an advantage in any type of immune response in comparison to women with normal pregnancy.

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Mechanical Growth Factor Promotes FOXP3 Expression in Regulatory T Cells and Enhances Its Function in Treating Ankylosing Spondylitis

10.21203/rs.3.rs-238795/v2 ◽

2021 ◽

Author(s):

Hongyu Qin ◽

Shuangshuang Yuan ◽

Hao Zeng ◽

Hao Li ◽

Jinsong Yang

Keyword(s):

Ankylosing Spondylitis ◽

Growth Factor ◽

Bone Destruction ◽

Foxp3 Expression ◽

Treg Cells ◽

Control Group ◽

Related Factors ◽

Cell Proliferation And Differentiation ◽

Tnf Α ◽

Proliferation And Differentiation

Abstract Objective: We aimed to verify whether mechanical growth factor (MGF) may be an effective target for treating ankylosing spondylitis. Methods: FOXP3 expression was measured in Treg cells from healthy male subjects administered MGF. A rat model of ankylosing spondylitis was established, and the level of ankylosing spondylitis-related factors (tumor necrosis factor [TNF]-α, interleukin [IL]-2, and IL-10) was measured. Results: We found that the proliferation and total number of Treg cells, as well as FOXP3 expression, significantly increased in the MGF-treated groups compared with those in the control. The level of inflammation, bone destruction, and new bone formation significantly decreased in rats treated with MGF compared with those in the control group. TNF-α expression significantly decreased, whereas the IL-2 and IL-10 levels significantly increased in the MGF group compared with those in the control. Conclusions: MGF may delay disease progression in ankylosing rats by inducing FOXP3 expression, promoting FOXP3+ Treg cell proliferation and differentiation, reducing TNF-α expression, and increasing IL-10 and IL-2 expression.

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Effects of Decursin and Angelica gigas Nakai Root Extract on Hair Growth in Mouse Dorsal Skin via Regulating Inflammatory Cytokines

Molecules ◽

10.3390/molecules25163697 ◽

2020 ◽

Vol 25 (16) ◽

pp. 3697

Author(s):

Tae-Kyeong Lee ◽

Bora Kim ◽

Dae Won Kim ◽

Ji Hyeon Ahn ◽

Hyejin Sim ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Hair Growth ◽

Hair Follicles ◽

Control Group ◽

Root Extract ◽

Dorsal Skin ◽

Angelica Gigas ◽

Angelica Gigas Nakai ◽

Tnf Α ◽

Anti Inflammatory

This current study investigates the facilitative effects and mechanisms of decursin, a major component of Angelica gigas Nakai (AGN), and AGN root extract on hair growth in mice. We perform high-performance liquid chromatography on AGN extract to show it contains 7.3% decursin. Hairs in mouse dorsal skin are shaved distilled in water, 0.15% decursin, and 2% AGN root extract (0.15% decursin in the diluted extract) and topically applied twice a day for 17 days. Hematoxylin and eosin staining are done to examine the morphological changes in the hair follicles. To compare the effects of decursin and AGN extract on inflammatory cytokines in the dorsal skin, Western blot analysis and immunohistochemistry for tumor necrosis factor α (TNF-α) and interleukin (IL)-1β as pro-inflammatory cytokines, and IL-4 and IL-13 as anti-inflammatory cytokines are conducted. The results show that the application of decursin and AGN extract confer effects on hair growth. Hair growth is significantly facilitated from seven days after the treatments compared to that in the control group, and completely grown hair was found 17 days after the treatments. The protein levels and immunoreactivity of TNF-α and IL-1β in this case are significantly decreased, whereas the IL-4 and IL-13 levels and immunoreactivity are significantly increased compared to those in the control group. Additionally, high-mobility group box 1, an inflammatory mediator, is elevated by the topical application of decursin and AGN extract. Taken together, the treatment of mouse dorsal skin with AGE root extract containing decursin promotes hair growth by regulating pro- and/or anti-inflammatory cytokines. We, therefore, suggest that AGN root extract as well as decursin can be utilized as materials for developing hair growth-facilitating treatments.

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Acute lung injury inhibition by juglone in LPS induced sepsis mouse model involves Sirt1 activation

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i5.14 ◽

2020 ◽

Vol 19 (5) ◽

pp. 1001-1007

Author(s):

Qiong Hu ◽

Chunai Yang ◽

Fenshuang Zheng ◽

Hongdan Duan ◽

Yangshan Fu ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Mouse Model ◽

Inflammatory Cytokines ◽

Alveolar Epithelial Cells ◽

Control Group ◽

Western Blot Assay ◽

Edema Formation ◽

Sirt1 Expression ◽

Treatment Groups

Purpose: To investigate the effect of juglone on LPS induced lung injury in a mouse model and in TC 1cell line.Methods: Edema formation in lungs were measured by determination of lung wet/dry weight. Expressions of various proteins were assessed by western blot assay, while Sirt1 level was assessed using immunohistochemistry. Mice were randomly assigned to nine groups of 10 mice each: normal control, untreated and seven juglone treatment groups. Acute lung injury was induced in mice by injecting LPS (10 mg/kg) via intraperitoneal route (ip). The treatment groups were given 10, 20, 30, 40, 50, 60 and 100 μM of juglone, ip, respectively.Results: The levels of MMP-9, IL-6, IL-1β and iNOS were significantly higher in acute lung injury induced mice compared than the control group (p < 0.05). Treatment of the mice with juglone significantly decreased LPS-induced up-regulation of inflammatory cytokines in a dose-dependentmanner. The production of inflammatory cytokines was almost completely inhibited in the mice treated with 100 mg/kg dose of juglone, while treatment of the LPS-stimulated TC 1 cells with juglone upregulated the expression of Sirt1 mRNA. Down-regulation of Sirt1 expression by siRNA inhibited the effect of juglone on LPS-induced increase in inflammatory cytokine production.Conclusion: Juglone prevents lung injury in mice via up-regulation of Sirt1 expression. Therefore, juglone might be useful for the development of a treatment strategy for lung injury. Keywords: Inflammatory, Sirtuin, Edema, Cytokines, Lung injury, TC 1 lung alveolar epithelial cells, Sirt1

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Topical Wound Healing Activity of Myricetin Isolated from Tecomaria capensis v. aurea

Molecules ◽

10.3390/molecules25214870 ◽

2020 ◽

Vol 25 (21) ◽

pp. 4870

Author(s):

Abdelsamed I. Elshamy ◽

Naglaa M. Ammar ◽

Heba A. Hassan ◽

Walaa A. El-Kashak ◽

Salim S. Al-Rejaie ◽

...

Keyword(s):

Wound Healing ◽

Inflammatory Cytokines ◽

Group Treatment ◽

Wound Closure ◽

Burn Injury ◽

Control Group ◽

Albino Rats ◽

Large Area ◽

Blood Capillaries ◽

Tnf Α

Wounds and burn injury are major causes of death and disability worldwide. Myricetin is a common bioactive flavonoid isolated naturally from the plant kingdom. Herein, a topical application of naturally isolated myricetin from the shoots of Tecomaria capensis v. aurea on excisional wound healing that was performed in albino rats. The wounded rats were treated every day with 10 and 20% myricetin for 14 days. During the experiment, the wound closure percentage was estimated at days 0, 7, and 14. Effects of myricetin on the inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and cluster of differentiation 68 (CD68) in the serum were evaluated using immunosorbent assay kits. The percentage of wound closure and contraction was delayed in wounded rats (67.35%) and was remarkably increased after treatment of wounded rats with myricetin; the treatment with 20% myricetin was the most potent (98.76%). Histological findings exhibited that 10% myricetin caused the formation of a large area of scarring at the wound enclosure and stratified squamous epithelium without the formation of papillae as in the control group. Treatment with 20% myricetin exhibited less area of scarring at the wound enclosure as well as re-epithelialization with a high density of fibroblasts and blood capillaries in the wound. Level elevations of serum pro-inflammatory cytokines, IL-1β, and TNF-α and macrophage CD68 were decreased in wounded rats treated with myricetin. Thus, it can be suggested that the enhancements in inflammatory cytokines as well as systemic reorganization after myricetin treatment may be recommended to play a crucial part in the promotion of wound healing. The findings suggest that treatment with a higher dose of myricetin was better in improving wound curing in rats. It could serve as a potent anti-inflammatory agent and can be used as an adjunctive or alternative agent in the future.

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The content of cytokines IL-6, IL-8, TNF-α, IL-4 and the level of expression in macrophages CD86 and CD163 in peritoneal fluid has a reverse correlation with the degree of severity of external genital endometriosis

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20196505432 ◽

2019 ◽

Vol 65 (5) ◽

pp. 432-436

Author(s):

A.M. Krasnyi ◽

A.A. Sadekova ◽

T.G. Sefihanov ◽

V.V. Vtorushina ◽

E.G. Krechetova ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Peritoneal Fluid ◽

Inflammatory Marker ◽

Inflammatory Activity ◽

Control Group ◽

Reverse Correlation ◽

Tnf Α ◽

Ifn Γ ◽

Anti Inflammatory ◽

Degree Of Severity

Concentrations of eight different cytokines and the level of expression of CD86 and CD163 macrophages were studied in peritoneal fluid in women with endometriosis. It was found that the concentration of both inflammatory (IL-6, IL-8, TNF-α) and anti-inflammatory cytokines (IL-4) as well as the level of macrophage expression of the proinflammatory marker CD86 and anti-inflammatory marker CD163 increased in women with mild external genital endometriosis (1-2 stage), and did not differ from the control group in women with severe endometriosis (3-4 stage). The content of IL-2, IL-10, CM-CSF and IFN-γ in the peritoneal fluid of women with endometriosis did not differ significantly from the control group. The results of the study indicate that the development of external genital endometriosis may be based on insufficient both inflammatory and anti-inflammatory activity of macrophages in the peritoneal fluid.

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