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Effect of an Aqueous Garlic Extract on Kidney Damage in an Experimental Model of Sepsis

Authors:
Eect of an Aqueous Garlic Extract on Kidney Damage in an
Experimental Model of Sepsis
Sulu Sarımsak Ekstresinin Deneysel Sepsis Modelinde Böbrek Hasarı Üzerine Etkisi
Hazal İpekçi1, Tuğba Tunalı Akbay1, Göksel Şener2
1Department of Biochemistry, Marmara University School of Dentistry, İstanbul, Turkey
2Department of Pharmacology, Marmara University School of Pharmacy, İstanbul, Turkey
Correspondence Author/Sorumlu Yazar: Tuğba Tunalı Akbay E-mail/E-posta: ttunali@marmara.edu.tr
Received/Geliş Tarihi: 29.07.2016 Accepted/Kabul Tarihi: 27.09.2016 Available Online Date/Çevrimiçi Yayın Tarihi: 24.02.2017 DOI: 10.5152/clinexphealthsci.2017.140
©Copyright by 2017 Journal of Marmara University Institute of Health Sciences - Available online at www.clinexphealthsci.com
©Telif Hakkı 2017 Marmara Üniversitesi Sağlık Bilimleri Enstitüsü - Makale metnine www.clinexphealthsci.com web sayfasından ulaşılabilir
INTRODUCTION
Sepsis is a condition characterized by a disseminated inammatory response triggered by a bacterial, viral, or fungal infection. In sepsis,
kidney injury frequently occurs as a complication (1). In this condition, kidney function decreases and the ion–water balance becomes
impaired (2).
It has been demonstrated that free radicals and the resultant oxidative stress play an important role in sepsis-induced multiorgan dam-
age (3, 4). Proinammatory markers of oxidative stress include cell and DNA damage, neutrophil recruitment, lipid peroxidation, and
protein oxidation (5). Therefore, antioxidant usage may increase survival rates by decreasing oxidative stress in sepsis (6).
Various studies have been conducted to understand the progression of septic kidney damage using animal models of sepsis. The cecal
ligation and perforation (CLP) model of polymicrobial peritonitis is frequently used in rats (7). To date, successful treatment strategies
have not been developed against sepsis-induced kidney damage. In the present study, the eect of prolonged 15 days AGE usage and
Öz
Amaç: Sepsis, patojenlere veya onların salgıladığı maddelere karşı verilen
sistemik inamatuvar bir yanıttır. Bu çalışmada sepsiste oluşan böbrek ha-
sarına karşı sulu sarımsak ekstresinin olası koruyucu etkisi incelenmiştir.
Yöntemler: Çalışmamızda sıçanlar; ‘kontrol’, ‘sepsis’, ‘sepsis+sarımsak’ ve
‘sepsis+ön-tedavili sarımsak’ grupları olmak üzere 4 gruba ayrılmıştır.
Sepsis modeli çekal ligasyon ve perforasyon yöntemi ile oluşturulmuştur.
‘Sepsis+ön-tedavili sarımsak’ grubuna sepsis oluşumundan 15 gün önce
başlanarak, 250 mg/kg/gün dozunda sulu sarımsak ekstresi oral yoldan uy-
gulanmıştır. ‘Sepsis+sarımsak’ grubunda ise tedavi sepsis uygulamasından
hemen sonra tek doz (250 mg/kg) olarak yapılmıştır. Sepsis oluşumundan
12 saat sonra bütün gruplardaki sıçanlar dekapite edilerek, böbrek dokula-
rı alınmıştır. Böbrek dokusunda, glutatyon (GSH) ve malondialdehit (MDA)
seviyeleri, süperoksit dismutaz (SOD), doku faktörü (TF), katalaz (CAT) ve
miyeloperoksidaz (MPO) aktivitesi tayin edilmiştir.
Bulgular: Sepsise bağlı olarak böbrek dokusunda artan MDA düzeyleri ve
MPO aktivitesi ile azalan GSH düzeyleri ve SOD ve CAT aktiviteleri sulu sa-
rımsak ekstresi ile geri çevrilmiştir. TF aktivitesi sepsiste değişmemiştir. Kı-
salmış pıhtı oluşum zamanı, artmış TF aktivitesini göstermektedir. Bu doğ-
rultuda ön-tedavili sepsis sarımsak grubunda TF aktivitesi artmıştır.
Sonuç: Sulu sarımsak ekstresi kullanımının yeni sepsis tedavi yöntemleri
geliştirilirken oksidan-antioksidan dengesi açısından dikkate alınması ge-
rektiğini düşünmekteyiz.
Anahtar Kelimeler: Sepsis, böbrek, sulu sarımsak ekstresi, oksidatif stres,
doku faktörü
Abstract
Objective: Sepsis is a systemic inammatory response against pathogens
or substances secreted by pathogens. In this study, the potential protec-
tive eect of an aqueous garlic extract (AGE) against sepsis-induced kidney
injury.
Methods: Rats were divided into four groups: control, sepsis, sepsis+AGE-
garlic, and sepsis+pretreated garlic. Sepsis was induced using cecal ligation
and perforation. An AGE was orally administered to rats in the sepsis+pre-
treated garlic group at a dose of 250 (mg/kg/day) for 15 days prior to sepsis
induction. In rats in the sepsis+garlic group, the AGE was administered at a
single dose (250 mg/kg) immediately after sepsis induction. Twelve hours
after sepsis induction, all rats were decapitated and kidney tissues were
taken. Glutathione (GSH) and malondialdehyde (MDA) levels and super-
oxide dismutase (SOD), tissue factor (TF), catalase (CAT), and myeloperoxi-
dase (MPO) activities were determined in the kidney issue.
Results: Increased MDA levels and MPO activity and decreased GSH lev-
el and SOD and CAT activities due to sepsis were reversed by the AGE. TF
activity did not change in sepsis. Shortened clot formation time shows in-
creased TF activity. Accordingly, kidney TF activity signicantly increased in
mice in the pre-treated garlic group.
Conclusion: AGE usage should be considered in developing new sepsis
treatment strategies in terms of oxidant and antioxidant balance.
Keywords: Sepsis, kidney, aqueous garlic extract, oxidative stress, tissue
factor
This study was presented as a poster at the 6th event of the Institute of Experimental Medicine (DETAE), 24-25 November, 2014, İstanbul, Turkey.
Bu çalışma 6. Deneysel Tıp Araştırma Enstitüsü (DETAE) Günleri’nde poster bildiri olarak sunulmuştur, 24-25 Kasım 2014, İstanbul, Türkiye.
Original Article /
Özgün Araştırma
single-dose aqueous garlic extract (AGE) against sepsis-induced
damages in kidney tissue was investigated.
Garlic, Allium sativum, has been widely used as a traditional medi-
cine for many years worldwide. It contains 1–3% of sulfur-containing
compounds (8). Allicin is the main sulfur-containing compound in
garlic (9). It has the ability to penetrate through membranes rapid-
ly, and it can react with thiol-containing proteins and enzymes (10).
There are many reports that show the antioxidant activity of garlic
and its constituents in vivo and in vitro, but its role in sepsis-induced
kidney damage has not been studied (11-14).
METHODS
Animals
Wistar albino rats (200 to 250 g, either sex) were kept in a room where
the temperature was set to 22±2°C and relative humidity to 65–70%.
Light cycles were set as 12 h: 12 h light: dark. Standard rat chow was
used for feeding. The experimental protocol was approved by the
Marmara University Animal Care and Ethics Committee (Protocol
Number: 10.2015.mar)
AGE Preparation
Garlic was acquired from Kastamonu, Turkey. It was stored in dry and
light protected conditions. It means that standard controlled condi-
tions for plant. In a mortar, peeled garlic (30 g) was crushed with dis-
tilled water. It was decanted by pressing, and 60 mL of aqueous garlic
was extracted. One milliliter of AGE contained material from 500 mg
of garlic (1 mL of AGE extract contains 500 mg garlic, 500 mg/mL) (15,
16). The AGE was stored at 4°C.
Experimental Protocol and Sepsis Induction
Forty rats were equally divided into four groups: control (C), sepsis
(S), sepsis+garlic (S+AGE), and sepsis+pretreated garlic (S+pre-AGE).
Rats in the C and S groups were supplemented with saline and those
in the S+pre-AGE group were supplemented with AGE (250 mg/kg/
day orally) for 15 days prior to CLP. In rats in the sepsis+AGE group, a
single dose of garlic extract (250 mg/kg/day orally) was given imme-
diately after sepsis induction. In the sham-operated control groups
YES, after laparotomy, the cecum was manipulated but left intact
(without ligation or perforation). In the S group, rats underwent CLP
according to the method described by Fujimura et al. (17).
Minimal dissection was used for midline laparotomy; then, the ce-
cum was ligated just below the ileocecal valve with 3-0 silk ligatures.
Using an 18-gauge needle, the cecum was perforated at two loca-
tions and, the cecum was gently compressed until the feces were
entirely extruded. After feces extrusion, the incision was closed. All
rats were resuscitated with saline (3 mL/100 g body weight, subcu-
taneous.) at the end of the operation. Twenty-four hours after sepsis
induction, the rats were decapitated, and kidney tissues were taken.
Malondialdehyde (MDA) and glutathione (GSH) levels and superox-
ide dismutase (SOD), myeloperoxidase (MPO), catalase (CAT), and
tissue factor (TF) activities were determined in kidney tissue homog-
enates by the methods by Yagi (18), Beutler (19), Mylorie et al. (20),
Hillegas et al. (21), Aebi (22), and Ingram (23) respectively.
Statistical Analysis
Statistical analysis was performed using GraphPad Prism 5.0 (Graph-
Pad Software, San Diego, CA, USA), and all data were expressed as
mean±standard deviation. Data groups were compared with analysis
of variance (ANOVA) followed by Tukey ’s multiple comparison tests. A
p value of less than 0.05 was considered signicant.
RESULTS
MDA and GSH Levels
Kidney MDA levels signicantly increased in the S group in compari-
son with those in C group (Table 1). The increase seen in the S group
was in the S+pre-AGE group (Table 1). However, a single dose of AGE
administration did not signicantly change the MDA level in the S
group.
Kidney GSH levels signicantly decreased in the S group in compar-
ison with those in the control group. Pre-AGE administration signi-
cantly increased GSH levels in the S group (Table 1).
Kidney SOD, CAT, and MPO Activities
Kidney SOD activity decreased in the S group in comparison to that
in the control group (Figure 1). A single dose of AGE administration
signicantly increased SOD activity in the S group (Figure 1).
Kidney CAT activity decreased in the S group but, this decrease was
not statistically signicant (Figure 2). Both AGE administrations sig-
nicantly increased CAT activity in S group (Figure 2). Kidney MPO
activity insignicantly increased in the S group (Figure 3). Both AGE
administrations signicantly decreased MPO activity in the S group
(Figure 3).
Kidney TF Activity
Tissue factor activity was expressed in seconds. Shortened clot for-
mation time shows increased TF activity. TF activity did not signi-
cantly change in the S group, but in S+pre-AGE group, TF activity sig-
nicantly increased (Table 2). A single dose of AGE administration did
not signicantly change TF activity in the S group (Table 2).
Clin Exp Health Sci 2017İpekçi et al. Garlic and Kidney Injury in Sepsis
C S S+pre-AGE S+AGE
(n=8) (n=8) (n=8) (n=8)
MDA (nmol MDA/g tissue) 63.41±3.32 112.3±8.,75 +++, ++ 67.92±8.04 95.65±3.83
GSH (µg GSH/g tissue) 138.0±8.30 105.3±3.82 +++, + 129.70±2.57 126.2±4.54
Values are given as mean±standard deviation (SD)
C: control; S: sepsis; S+pre-AGE: AGE administration 15 days prior to sepsis induction; S+AGE: single dose of AGE administration after sepsis induction; (èèè ): p<0.001
versus control group; (+): p<0.05 versus S+pre-AGE group
(++): p<0.01 versus S+pre-AGE group
Table 1. Malondialdehyde and glutathione levels in all groups
DISCUSSION
Garlic-derived allium derivatives have been shown to exert antibi-
otic, anticancer, antithrombotic, and lipid-lowering cardiovascular
eects (24). In the present study, renal pathologic changes induced
by oxidative damage due to experimental sepsis and the putative
protective roles of AGE against this damage were investigated. In
kidney tissue, AGE administration alleviated the sepsis-induced ox-
idative damage by signicantly decreasing the MDA level and MPO
activity and increasing the GSH level and SOD and CAT activities. Fur-
thermore, TF activity, which did not change in sepsis, increased by
AGE administration that was given 15 days prior to sepsis induction.
Sepsis-associated oxidative damage in kidney tissue was prevented
by the antioxidant properties of garlic.
Sepsis is an inammatory response that aects various organs and
systems; it also contributes to an inammatory response, microvas-
cular hypoperfusion, organ dysfunction, and increased mortality. In
sepsis, the kidney is subjected to inammatory cytokines and isch-
emia. Sepsis also causes widespread tubular cell apoptosis (25).
In sepsis, an increase in the production of ROS leads to multiorgan
dysfunction, mostly in the kidneys, lungs, liver, heart, and intestines.
These dysfunctions are known to result from bacterial toxins and en-
zymes, the eects of mediators, impaired perfusion, and disseminat-
ed intravascular coagulation (26).
Clin Exp Health Sci 2017 İpekçi et al. Garlic and Kidney Injury in Sepsis
C S S+pre-AGE S+AGE
(n=6) (n=8) (n=8) (n=8)
TF activity (sec.) 44.67±1.51 42.83±1.60 + 39.75±2.49 44.20±3.03
Values are given as mean±standard deviation (SD)
C: Control; S: sepsis; S+pre-AGE: AGE administration 15 days prior to sepsis induction; S+AGE: single dose of AGE administration after sepsis induction; TFa: tissue
factor activity; sec.: seconds (+): p<0.05 versus the S+pre-AGE group
Table 2. Kidney tissue factor activities in all groups
Figure 1. Superoxide dismutase activities in all groups
C: control; S: Sepsis; S+pre-AGE: AGE administration 15 days prior to
sepsis induction; S+AGE: Single dose of AGE administration after sepsis
induction; (ééé ): p<0.001 versus the control group, (•): p<0.05 versus
the S+AGE group
Figure 3. Myeloperoxidase activities in all groups
C: Control; S: Sepsis, S+pre-AGE: AGE administration 15 days prior to
sepsis induction; S+AGE: Single dose of AGE administration after sepsis
induction; (+): p<0.05 versus S+pre-AGE group; (•••): p<0.0001 versus
the S+AGE group
Figure 2. Catalase activities in all groups
C: Control; S: Sepsis; S+pre-AGE: AGE administration 15 days prior to
sepsis induction; S+AGE: single dose of AGE administration after sepsis
induction; (+): p<0.05 versus the S+pre-AGE group; (•): p<0.05 versus
S+AGE group
In the present study, the MDA level was signicantly increased in
kidney tissue. AGE administration prior to sepsis induction inhibit-
ed MDA elevations in kidney tissue, but single dose of AGE adminis-
tration did not signicantly change the increased kidney MDA level.
Restored control levels might be related to the maintained cellular
integrity that was achieved by AGE administration.
As an enzymatic antioxidant, SOD is particularly important for the
intracellular destruction of phagocytized bacteria and granulocyte
function (27). GSH, which is also a non-enzymatic antioxidant, pro-
tects tissues against oxidative stress (28). In our study, kidney tissue
GSH level and SOD and CAT activities decreased in the S group in
comparison to those in the control group. Pre-AGE administration
increased GSH level and CAT activity, while a single dose of AGE ad-
ministration was eective in increasing only SOD activity.
The heme enzyme MPO, found in neutrophils, uses a superoxide an-
ion to produce hypochlorous acid, which is the major oxidant for its
immune function (29). Thus, tissue-associated MPO activity is con-
sidered to correlate to the degree of inammatory damage. In the
present study, the increase in kidney MPO activity in the S group
compared to that in the C group might be related to neutrophil accu-
mulation in sepsis-induced oxidative injury. However, the decrease in
kidney MPO activity in both the S+AGE and S+pre-AGE groups might
be considered to explain the anti-inammatory eect of AGE.
Due to its receptor activity for factor VII, TF is the primary initiator of
the blood coagulation cascade, while also ensuring rapid hemosta-
sis in the case of organ damage (30). TF activity did not signicant-
ly change in the S group. As a shortened clot formation time shows
increased TF activity, AGE administration prior to sepsis induction
signicantly increased kidney TF activity. Increase in kidney TF activ-
ity with pre-treated AGE administration may help eliminate the sep-
sis-induced risk of bleeding in kidney tissues.
CONCLUSION
In conclusion, long-term AGE administration has great potential for
preventing the oxidation and inammation of the kidneys seen after
sepsis induction. The mechanism of this eect might be the mainte-
nance of cellular integrity by the AGE during sepsis.
Ethics Committee Approval: Ethics committee approval was received for
this study from the ethics committee on Research Animals of Marmara Uni-
versity (10.2015.mar).
Peer-review: Externally peer-reviewed.
Author contributions: Concept - T.A., G.Ş.; Design - T.A., G.Ş.; Supervision - T.A.,
G.Ş.; Resource - T.A., G.Ş., H.İ.; Materials - T.A., G.Ş., H.İ.; Data Collection and/or
Processing - T.A., G.Ş., H.İ.; Analysis and/or Interpretation - T.A., G.Ş., H.İ.; Liter-
ature Search - T.A., G.Ş., H.İ.; Writing - T.A., G.Ş., H.İ.; Critical Reviews - T.A., G.Ş.
Acknowledgements: The authors thanks to Marmara University Scientic
Research Project Department for supporting this study.
Conict of Interest: No conict of interest was declared by the authors.
Financial Disclosure: This study was supported by the Marmara University
Scientic Research Project Department (03.01.2014, SAG-C-YLP-030114-0008).
Etik Komite Onayı: Bu çalışma için etik komite onayı Marmara Üniversitesi
Hayvan Deneyleri Yerel Etik Kurulu’ndan alınmıştır (10.2015.mar).
Hakem Değerlendirmesi: Dış Bağımsız.
Yazar Katkıları: Fikir - T.A., G.Ş.; Tasarım - T.A., G.Ş.; Denetleme - T.A., G.Ş.; Kay-
naklar - T.A., G.Ş., H.İ.; Malzemeler - T.A., G.Ş., H.İ.; Veri Toplanması ve/veya işle-
mesi - T.A., G.Ş., H.İ.; Analiz ve/veya Yorum - T.A., G.Ş., H.İ.; Literatür taraması
- T.A., G.Ş., H.İ.; Yazıyı Yazan - T.A., G.Ş., H.İ.; Eleştirel İnceleme - T.A., G.Ş.
Teşekkür: Yazarlar, bu çalışmaya destek olduğu için Marmara Üniversitesi
Bilimsel Araştırma Projeleri Birimi’ne teşekkür ederler.
Çıkar Çatışması: Yazarlar çıkar çatışması bildirmemişlerdir.
Finansal Destek: Bu çalışma Marmara Üniversitesi Bilimsel Araştırma Projeleri
Birimi tarafından desteklenmiştir (03.01.2014, SAG-C-YLP-030114-0008).
REFERENCES
1. Mayeux PR, MacMillan-Crow LA. Pharmacological targets in the renal
peritubular microenvironment: implications for therapy for sepsis-in-
duced acute kidney injury. Pharmacol Ther 2012; 134: 139-55. [CrossRef]
2. Ricci Z, Polito A, Ronco C. The implications and management of septic
acute kidney injury. Nat Rev Nephrol 2011; 7: 218-25. [CrossRef]
3. Macdonald, J, Galley HF, Webster NR. Oxidative stress and gene expres-
sion in sepsis. Br J Anaesth 2003; 90: 221-32. [CrossRef]
4. Goode HF, Cowley HC, Walker BE, Howdle PD, Webster NR. Decreased an-
tioxidant status and increased lipid peroxidation in patients with septic
shock and secondary organ dysfunction. Crit Care Med 1995; 23: 646-51.
[CrossRef]
5. Zimmermann JJ. Dening the role of oxyradicals in the pathogenesis of
sepsis. Crit Care Med 1995; 23: 616-7. [CrossRef]
6. Ritter C, Andrades M, Frota Júnior ML, Bonatto F, Pinho RA, Polydoro M, et
al. Oxidative parameters and mortality in sepsis induced by cecal ligation
and perforation. Intensive Care Med 2003; 29: 1782-9. [CrossRef]
7. Rittirsch D, Huber-Lang MS, Flierl MA, Ward PA. Immunodesign of exper-
imental sepsis by cecal ligation and puncture. Nat Protoc 2009; 4: 31-6.
[CrossRef]
8. B Darbyshire, RJ Henry. Dierences in fructan content and synthesis in
some Allium species. New Phytol 1981; 87: 249-56. [CrossRef]
9. Cutler RR, Wilson P. Antibacterial activity of a new, stable, aqueous ex-
tract of allicin against methicillin-resistant Staphylococcus aureus. Br J
Biomed Sci 2004; 61: 71-4. [CrossRef]
10. Ankri S, Mirelman D. Antimicrobial properties of allicin from garlic. Mi-
crobes Infect 1999; 1: 125-9. [CrossRef]
11. Augusti KT, Sheela CG. Antiperoxide eect of S-allyl cysteine sulfoxide,
an insulin secretagogue, in diabetic rats. Experimentia 1996; 52: 115-20.
[CrossRef]
12. Iqbal M, Athar M. Attenuation of iron-nitrilotriacetate (Fe-NTA)-mediat-
ed renal oxidative stress, toxicity and hyperproliferative response by the
prophylatic treatment of rats with garlic oil. Food Chem Toxicol 1998; 36:
485-95. [CrossRef]
13. Prasad K, Laxdal VA, Yu M, Raney BL. Evaluation of hydroxyl radical-scav-
enging property of garlic. Mol Cell Biochem 1996; 154: 55-63. [CrossRef]
14. Rabinkov A, Miron T, Konstantinovski L, Wilchek M, Mirelman D, Weiner
L. The mode of action of allicin: trapping of radicals and interaction with
thiol containing proteins. Biochem Biophys Acta 1998; 1379: 233-44.
[CrossRef]
15. Sener G, Satiroglu H, Ozer Sehirli A, Kaçmaz A. Protective eect of aque-
ous garlic extract against oxidative organ damage in a rat model of ther-
mal injury. Life Sci 2003; 73: 81-91. [CrossRef]
16. Batirel HF, Aktan S, Aykut C, Yeğen BC, Coşkun T. The eect of aqueous
garlic extract on the levels of arachidonic acid metabolites (leukotriene
C4 and prostoglandin E2) in rat forebrain after ischemia- reperfusion
injury. Prostaglandins Leukot Essent Fatty Acids 1996; 54: 289-92.
[CrossRef]
17. Fujimura N, Sumita S, Aimono M, Masuda Y, Shichinohe Y, Narimatsu E, et
al. Eect of free radical scavengers on diaphragmatic contractility in sep-
tic peritonitis. Am J Respir Crit Care Med 2000; 162: 2159-65. [CrossRef]
18. Yagi K. Assay for blood plasma or serum. Method Enzymol 1984; 105:
328-37. [CrossRef]
Clin Exp Health Sci 2017İpekçi et al. Garlic and Kidney Injury in Sepsis
19. Beutler E. Gluthatione: red cell metabolism. In: A manual biochemical
methods. New York: Grune and Stratton; 1975. p.112-4.
20. Mylroie AA, Collins H, Umbles C, Kyle J. Erythrocyte superoxide
dismutase activity and other parameters of copper status in rats
ingesting lead acetate. Toxicol Appl Pharmacol 1986; 82: 512-20.
[CrossRef]
21. Hillegass LM, Griswold DE, Brickson B, Albrightson-Winslow C. Assess-
ment of myeloperoxidase activity in whole rat kidney. J Pharmacol Meth-
ods 1990; 24: 285-95. [CrossRef]
22. Aebi H. Catalase in vitro. In: Bergmeye HU, editor. Methods of enzymatic
analysis. Wenheim: Verlag Chemie; 1974. p.121-6. [CrossRef]
23. Ingram GI, Hills M. Reference method for the one-stage prothrombin
time test on human blood. International committee for standardization
in hematology. Thromb Haemost 1976; 36: 237-8.
24. Borek C. Antioxidant health eects of aged garlic extract. J Nutr 2001;
131: 1010S-5S.
25. Parmar A, Langenberg C, Wan L, May CN, Bellomo R, Bagshaw SM. Epide-
miology of septic acute kidney injury. Curr Drug Targets 2009; 10: 1169-
78. [CrossRef]
26. Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J
Med 1999; 340: 207-14. [CrossRef]
27. Johnston RB Jr, Keele BB Jr, Misra HP, Lehmeyer JE, Webb LS, Baehner RL,
et al. The role of superoxide anion generation in phagocytic bactericidal
activity. Studies with normal and chronic granulomatous disease leuko-
cytes. J Clin Invest 1975; 55: 1357-72. [CrossRef]
28. Ross D. Glutathione, free radicals and chemotherapeutic agents. Mech-
anisms of free-radical induced toxicity and glutathione-dependent pro-
tection. Pharmacol Ther 1988; 37: 231-49. [CrossRef]
29. Klebano SJ. Myeloperoxidase. Proc Assoc Am Physicians 1999; 111: 383-9.
30. Witkowski M, Landmesser U, Rauch U. Tissue factor as a link between
inammation and coagulation. Trends Cardiovasc Med 2016; 26:
297-303.[CrossRef]
Clin Exp Health Sci 2017 İpekçi et al. Garlic and Kidney Injury in Sepsis
... 107 Moreover, in CLP-induced septic rats, aqueous garlic extract demonstrated ameliorative effects on kidney injury, because the garlic extract reversed the increased levels of MDA and MPO activity, as well as reversed the decreased levels of GSH and SOD and CAT activity that normally occur in sepsis. 108 It has also been previously reported that the extract of aged black garlic alleviates sepsis by suppressing the LPS-induced activation of MAPKs (ERK, JNK, and p38) and NF-κB, as well as downregulating the expression of COX-2, TNF-α, IL-6, and iNOs in LPSchallenged macrophages. 109 Allicin, a sulfide compound extracted from garlic bulbs, exerts its ameliorative effects on LPS-induced ALI by inhibiting the TLR4/MyD88/NF-kB signaling pathway, in addition to inhibiting the activity of caspase-3 and caspase-9 in the lung tissue of LPSchallenged rats. ...
... Moreover, in a study evaluating the effects of glycyrrhizin on LPS-activated macrophage-like RAW 264.7 cells, glycyrrhizin was reported to inhibit two major signaling pathways involved in the development of sepsis; specifically, the p38 MAPK/AP-1 and TLR4/ MD2-NF-κB signaling pathways. Blocking the TLR4/ MD2-NF-κB signaling pathway suppressed the release of TNF-α and IL-6, while blocking the p38 MAPK/AP-1 signaling pathway resulted in inhibition of HMGB1 in vivo secretion of TNFα, IL-6, and IL-1β attenuating the in vitro production of IL-Reduced the increased level of glutathione 2-Reduced the activity of CAT and SOD 3-Increased the level of MDA, tissue factor, and activity of MPO[108] LPS-challenged RAW 264.7 cells LPS-induced septicemia mice Suppressed the activation ERK, JNK, p38, and NF-κB decreased the expression of COX-2, TNF-α, IL-6, and iNOs[109] ...
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... SOD, an enzymatic antioxidant, is especially important in the intracellular destruction and phagocytosis of bacteria by granulocytes. GSH, a non-enzymatic antioxidant, plays an important role in protecting protein and lipid integrity and protecting tissues against oxidative stress [31,33]. Previous studies have determined that UF can modulate the antioxidant defense system by affecting antioxidant/oxidant parameters [19,34]. ...
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