The effect of protocatechuic acid on nephrotoxicity induced by gentamicin in rats

doi:10.21203/rs.3.rs-5341389/v1

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The effect of protocatechuic acid on nephrotoxicity induced by gentamicin in rats

https://doi.org/10.21203/rs.3.rs-5341389/v1

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Gentamicin (GM) is an aminoglycoside antibiotic widely used in the treatment of gram-negative infections. It is known that oxidative stress plays an important role in gentamicin nephrotoxicity. Therefore, the aim of this study is to investigate the possible protective effect of protocatechuic acid (PCA), which is reported to have antioxidant properties, on GM-induced nephrotoxicity. For this purpose, 32 rats were randomly divided into four groups: Control (Physiological saline orally), PCA (20 mg/kg orally), GM (80 mg/kg/day/i.p), GM + PCA (GM 80 mg/kg/day/i.p and 20 mg/kg PCA orally). Trial period was eight days. Blood samples were taken for biochemical, kidneys were removed for immunohistochemistry and histopathological evaluations. Serum urea, creatinine, Na, K, Cl analyzes of the rats were performed in an autoanalyzer, and malondialdehyde (MDA), advanced oxidation protein products (AOPP), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) analyzes were performed in ELISA. While urea (p < 0.001), creatinine (p < 0.001), MDA (p < 0.05) and AOPP (p < 0.05) levels decreased in the GM + PCA group compared to the GM group, the GSH level (p < 0.05) and GPx activity (p < 0.05) levels increased. In conclusion; in GM-induced nephrotoxicity, PCA prevented lipid peroxidation and protein oxidation, increased GSH level and GPx activity, and according to histopathological and immunohistochemical findings, it prevented necrosis in tubular epithelium, atrophy in glomerulus and decreased 8-OHdG expression in kidney cells. With this study, it was emphasized once again that PCA is a good antioxidant agent and it can be said that PCA has a protective effect in nephrotoxicity induced by GM.

Gentamicin

nephrotoxicity

protocatechuic acid

oxidative stress

antioxidant enzymes

Gentamicin (GM) is an aminoglycoside antibiotic still widely used in the treatment of serious life-threatening infections caused by gram-negative aerobes. Despite its beneficial effects, low cost and low resistance levels, its use is limited due to serious side effects such as ototoxicity and nephrotoxicity; causes nephrotoxicity in 10–20% of patients(Ali, 1995; Cui et al., 2019). Although the mechanism of nephrotoxicity induced by GM is not fully known, oxidative stress is thought to play a central role(Abdel-Naim, Abdel-Wahab, & Attia, 1999; Randjelovic, Veljkovic, Stojiljkovic, Sokolovic, & Ilic, 2017). Both in vivo and in vitro studies have shown that treatment with GM causes oxidative stress (Juan et al., 2007; Karatas et al., 2004). The current oxidative stress is mediated by H₂O₂ and hydroxyl radicals from the superoxide anion(Basnakian, Kaushal, & Shah, 2002). GM directly increases ROS production in mitochondria(Morales et al., 2010). The ROS formed inhibit the respiratory chain and ATP production, stimulate the release of cytochrome C and other proapoptotic factors, impair cell function by damaging cellular proteins, lipids and nucleic acids, induce mesangial contraction, cause endoplasmic reticulum stress, interfere with inflammation, cell swelling and necrosis. It inhibits transmembrane sodium transport.

Many studies have reported the protective effects of treatment with substances with antioxidant properties against kidney damage caused by GM(Randjelovic, Veljkovic, Stojiljkovic, Jankovic-Velickovic, et al., 2012; Randjelovic, Veljkovic, Stojiljkovic, Velickovic, et al., 2012; Stojiljkovic et al., 2012). Possibly the protective effect of antioxidants; it is a result of actions that combine at different levels, such as mitigating the cytotoxic effect of GM, inhibiting vasoconstriction and mesangium contraction, anti-inflammatory effect, and reducing lipid peroxidation (Randjelovic et al., 2017).

Protocatechic acid (PCA, 3,4-dihydroxy benzoic acid) found in many food plants such as olives and white grapes is an important metabolite of complex polyphenols, especially anthocyanins (Semaming, Pannengpetch, Chattipakorn, & Chattipakorn, 2015). PCA is especially important in terms of nutrition, as it is the main anthocyanin metabolite that can reach tissues in amounts that may have biological effects on health (Kay, Kroon, & Cassidy, 2009). In vivo studies have shown that male balb/cA mice fed a standard diet supplemented with PCA have increased PCA levels in plasma and tissues such as brain, heart, liver and kidney (Lin, Tsai, Huang, & Yin, 2011). It has been reported to have antioxidant, anti-inflammatory, antibacterial, anticancer, antidiabetic, antiageing, antiulcer, antifibrotic, analgesic, antiviral, antiatherosclerotic, antihyperlipidemic activities and nephroprotective, neuroprotective and hepatoprotective properties (Kakkar & Bais, 2014; Mert, Kerem, Mıs, Yıldırım, & Mert, 2022). The antioxidant effects of PCA are 10 times greater than α-tocopherol (Lee et al., 2017). Its antioxidant activity has been attributed to phenolic hydroxyl groups and activation of endogenous antioxidant enzymes (Han et al., 2018).

PCA has attracted the attention of researchers in recent years due to its antioxidant activity. However, studies investigating the possible effects of PCA on kidney protection are very few (Adefegha, Omojokun, & Oboh, 2015; Lin et al., 2011; Molehin, Adeyanju, Adefegha, Oyeyemi, & Idowu, 2019; Yamabe et al., 2015; Yüksel et al., 2017). Therefore, the aim of this study is to examine the effect of protocatechuic acid on gentamicin nephrotoxicity. In particular, the antioxidant property of protocatechuic acid will be investigated with the parameters to be examined.

Animals

The animal material of this study was obtained from Yuzuncu Yil University Experimental Animals Unit. 200–300 gr. 32 female Wistar Albino rats were used. During the experiment, the rats were housed in rooms with 12 hours of dark/lighting and a temperature of 22 ± 2°C, in cages with constant feed and fresh water ad libitum.

This study was carried out with the approval of Van Yuzuncu Yıl University Animal Experiments Local Ethics Committee (27.04.2023, 2023/06–13).

Experimental application and collection of samples

The animals were randomly divided into 4 groups and the experimental period was planned as 8 days.

1-Control group (8 rats): Physiological saline was given orally for 8 days.

2-Protocatechuic acid group (PCA group) (8 rats): Protocatechuic acid was given to animals as 20 mg/kg orally (Yamabe et al., 2015) for 8 days.

3-Gentamycin group (GM group) (8 rats): Gentamicin was given as 80 mg/kg/day/i.p (Yilmaz, 2014)

for 8 days.

4-Gentamycin + Protocatechuic acid group (GM + PCA group) (8 rats): Gentamicin 80 mg/kg/day/i.p and 20 mg/kg protocatechuic acid were given orally together for 8 days.

After the experimental applications (9th day), 90 mg/kg ketamine i.p was given to all rats and blood samples were taken. The animals were sacrificed, both kidneys were immediately removed.

Biochemical analyzes

The blood taken into the tubes was centrifuged at 3000 rpm at + 4 ^oC for 10 minutes. Urea, creatinine, Na, K, Cl levels in the obtained serum samples were performed in an autoanalyzer, and MDA, AOPP, GSH, SOD, CAT, GPx analyzes were performed in the ELISA device using Sun Red ELISA kits (respectively, Catalog No: 201-11-0157, Catalog No: 201-11-2673, Catalog No: 201-11-7122, Catalog No: 201-11-0169, Catalog No: 201-11-5106, Catalog No: 201-11-5104).

Histopathological examination

Tissue samples taken at the end of the evaluation were fixed in 10% formaldehyde solution for 48 hours and embedded in paraffin blocks at the end of routine tissue follow-up procedures. Sections of 4 µm thickness were taken from each block, and the preparations prepared for histopathological examination were stained with hematoxylin-eosin (HE) and examined with a light microscope (Olympus BX 51, Japan). Sections were evaluated as absent (-), mild (+), moderate (++) and severe (+++) according to their histopathological features.

Immunohistochemical examination

Tissue sections taken on adhesive (poly-L-lysin) slides for immunoperoxidase examination were deparaffinized and dehydrated. Then 10 minutes in 3% H₂O₂ endogenous peroxidase was inactivated. Then the tissues were boiled in 1% antigen retrieval (citrate buffer (pH + 6.1) 100X) solution and allowed to cool at room temperature. In order to avoid nonspecific background staining in tissues, sections were washed with protein block for 5 min. left for incubation. Then, primary antibody (8-OHdG Cat No: sc-66036, dilution ratio: 1/100. USA) was dripped onto the tissues and incubated in accordance with the instructions for use. 3–3' Diaminobenzidine (DAB) chromogen was used as chromogen in tissues. The stained sections were examined with a light microscope (Zeiss Axio, Germany).

Statistical analysis

“SPSS Statistic 20” package program was used in the analysis of biochemical data. Descriptive statistics for the featured features expressed as Mean and Standard Deviation. One-Way ANOVA analysis was performed in the statistical analysis of all parameters. Tukey test was used to compare different groups. The statistical significance level was taken as 5% in the calculations.

The nonparametric Kruskal-Wallis test was used for the analysis of the differences between the groups in the semiquantitative data obtained in the histopathological examination, and the Mann Whitney U test was used for the comparison of the paired groups. SPSS 13.0 package program was used for these statistical analyses.

Findings of biochemical parameters

The mean serum urea, creatinine, Na, K, Cl levels of control, PCA, GM, GM + PCA group rats are given in Table 1.

Table 1

Average values of serum urea, creatinine, Na, K and Cl levels of control, PCA, GM, GM + PCA group rats
	n	Control X ± SD	PCA X ± SD	GM X ± SD	GM + PCA X ± SD	p
Urea (mg/dl)	8	42.37 ± 9.43^a	38.07 ± 7.71^a	158.11 ± 34.12^c	74.28 ± 14.21^b	p < 0.001
Creatinine (mg/ dl)	8	0.42 ± 0.04^a	0.36 ± 0.04^a.	2.67 ± 0.40^c	0.63 ± 0.20^b	p < 0.001
Na (mmol/L)	8	143.2 ± 2.0^a	141.3 ± 3.2^a	146.5 ± 5.2^a	144.7 ± 3.8^a	p > 0.05
K (mmol/L)	8	5.9 ± 0.6^a	5.8 ± 0.2^a	5.0 ± 0.6^a	5.4 ± 0.9^a	p > 0.05
Cl (mmol/L)	8	102.2 ± 1.9^a	99.0 ± 1.9^a	98.5 ± 6.9^a	101.2 ± 6.9^a	p > 0.05

a, b, c: The difference between the group means with different letters on the same line is statistically significant.

While serum urea and creatinine levels were highest in animals in the GM group, urea and creatinine levels were found to decrease significantly in the GM + PCA group at the level of p < 0.001. In addition, statistical significance was not found between the groups in terms of serum Na, K and Cl levels (p > 0.05).

The mean serum MDA, AOPP, GSH levels and SOD, CAT, GPx activities of the rats in the control, PCA, GM, GM + PCA groups are given in Table 2.

Table 2

Oxidative stress parameters and antioxidant enzyme activities of control, PCA, GM and GM + PCA group rats
	Control X ± SD		PCA Group X ± SD		GM Group X ± SD		GM + PCA Group X ± SD
	n	X ± Sx	n	X ± Sx	n	X ± Sx	n	X ± Sx	P
MDA (nmol/ml)	8	1.27 ± 0.35^ab	8	1.2 ± 0.23^a	8	1.96 ± 0.81^b	8	0.76 ± 0.4^a	p < 0.05
AOPP (nmol/ml)	8	12.2 ± 2.59^ab	8	12.0 ± 1.73^ab	8	15.46 ± 4.51^b	8	11.48 ± 1.73^a	p < 0.05
GSH (mg/L)	8	260.91 ± 53.26^b	8	244.24 ± 57.45^b	8	101.85 ± 16.57^a	8	215.85 ± 53.15^b	p < 0.05
SOD (ng/ml)	8	9.5 ± 4.23^b	8	7.77 ± 1.56^ab	8	4.61 ± 0.74^a	8	6.19 ± 1.29^a	p < 0.05
CAT (ng/ml)	8	19.71 ± 5.68^a	8	20.58 ± 5.42^a	8	15.3 ± 4.74^a	8	18.65 ± 5.76^a	p > 0.05
GPx (ng/ml)	8	76.52 ± 0.9^b	8	70.54 ± 8.38^ab	8	58.89 ± 2.64^a	8	71.55 ± 14.98^b	p < 0.05

a, b: The difference between the group means with different letters on the same line is statistically significant.

While MDA (p < 0.05) and AOPP (p < 0.05) levels decreased in the GM + PCA group compared to the GM group, it was observed that the GSH level (p < 0.05) and GPx activity (p < 0.05) increased statistically. Again, there was no statistical significance between these two groups in terms of SOD and CAT activities (p > 0.05).

Histopathological Findings

Control Group

In the histopathological examination of kidney tissues, it was observed that they were in normal histological structure (Fig. 1).

PCA Group

In the histopathological examination of the kidney tissues, it was determined to have a normal histological appearance (Fig. 1).

GM Group

In the histopathological examination of kidney tissues, severe hydropic degeneration and necrosis in the renal tubular epithelium, moderate atrophy in the glomerulus, moderate dilatation in the Bowman capsule, and severe hyperemia in the vessels were observed (Fig. 1).

GM + PCA Group

In the histopathological examination of kidney tissues, mild degeneration of tubular epithelium, mild dilatation of Bowman's capsule, and hyperemia of vessels were observed (Fig. 1). A statistically significant difference (p˂0.05) was found when compared with the GM group. Histopathological findings are summarized in Table 3.

Immunohistochemical Findings

When the kidney tissues were examined immunohistochemically;

Control Group

It was evaluated as negative 8-OHdG expression (Fig. 1).

PCA Group

It was evaluated as negative 8-OHdG expression (Fig. 1).

GM Group

Severe cytoplasmic 8-OHdG expression was detected in tubular epithelium (Fig. 1).

GM + PCA Group

Mild 8-OHdG expression was observed in tubular epithelium (Fig. 1). A statistically significant difference (p˂0.05) was found when compared with the GM group. Immunohistochemical findings are summarized in Table 3.

Table 3

Scoring of histopathological and immunohistochemical findings in kidney tissues and statistical finding
	Control	PCA	GM	GM + PCA
Degeneration of tubular epithelium	-	-	+++	+
Necrosis of tubular epithelium	-	-	+++	-
Atrophy of the glomeruli	-	-	++	-
Dilatation of Bowman's capsule	-	-	++	+
Hyperemia in the veins	-	-	+++	++
8-OHdG expression	20.14 ± 2.10^a	21.03 ± 2.74^a	81.87 ± 4.27^c	42.25 ± 3.07^b

a,b,c: different letters on the same line represent statistically significant difference (p < 0.05).

Kidney is an essential organ that performs many important functions, including maintenance of homeostasis, regulation of the extracellular environment such as detoxification, and excretion of toxic metabolites and drugs (Ferguson, Vaidya, & Bonventre, 2008; Kim & Moon, 2012). Therefore, the kidney can be considered as the main target organ for exogenous toxic substances. It not only has a rich blood supply that takes 25% of cardiac output, but also helps to remove these toxins through glomerular filtration and tubular secretion (Patel Manali, Deshpande, & Shah, 2011). Kidneys are prone to drug-induced damage due to this high relative blood flow. Gentamicin, an aminoglycoside-type antibiotic, is one of the main causes of drug-induced nephrotoxicity.

Nephrotoxicity is a kidney-specific feature in which excretion does not go smoothly due to toxic chemicals or drugs (Finn & Porter, 2003; Galley, 2000; Kim & Moon, 2012). Serum urea and creatinine levels are considered traditional biomarkers of nephrotoxicity and renal dysfunction (Al-Naimi, Rasheed, Hussien, Al-Kuraishy, & Al-Gareeb, 2019). In many studies, creatinine and urea levels were found to increase in animals treated with GM (Ataman, Mert, Yıldırım, & Mert, 2018; Botros, Matouk, Anter, Khalifa, & Heeba, 2022; Erseckin, Mert, İrak, Yildirim, & Mert, 2022; Sarwar et al., 2022; Yilmaz, 2014). Adefegha et al. (Adefegha et al., 2015) suggested that the elevated urea, uric acid and creatinine levels, which were in Cd-induced nephrotoxicity, were also decreased due to the renal protective effect of PCA. In this study, it was determined that the serum urea and creatinine levels increased in animals in the GM group, and decreased with the administration of PCA (p < 0.001), which indicates an improvement in kidney functions. Indeed, in the histopathological examination of the kidney tissues of the GM group, severe hydropic degeneration and necrosis of the renal tubular epithelium and moderate atrophy of the glomeruli were observed, while in the GM + PCA group, necrosis of the tubular epithelium and atrophy of the glomeruli weren’t observed. In addition, according to immunohistochemical findings, 8-OHdG expression in kidney cells was decreased with PCA administration.

Kidneys have a very important role in regulating body fluid and electrolyte balance, therefore, when kidney failure develops, disturbances in fluid, electrolyte and acid-base balance may occur. Kidney diseases are often associated with hypervolemia, hyperkalemia, hypocalcemia, hyperphosphatemia, hyponatremia, hypermagnesemia, and metabolic acidosis. The severity of these electrolyte disturbances reflects the catabolic state of the patient and the degree of kidney damage (ÇALIŞKAN & YILDIZ, 2010; Medineli, Mert, İrak, & Mert, 2021).

Changes in urinary excretion of some ions are observed in renal damage after treatment with gentamicin. The decrease in the activity of Na, K-ATPase in the proximal tubules in rats given GM may be due to GM-induced nephrotoxicity. Because, this enzyme is responsible for regulating intracellular electrolyte and cell volume transport (Ali, 1995). It has been reported that aminoglycoside nephrotoxicity causes a decrease in serum potassium levels in experimental animals and humans (Cronin & Thompson, 1991; Silan et al., 2007). In addition, glomerular dysfunction due to GM has been associated with increased sodium levels in plasma (Cuzzocrea et al., 2002) Medineli et al. (Medineli et al., 2021) found that Na and K levels did not change and Cl levels increased in the rat group treated only with GM compared to controls. Noorani et al. (Noorani, Gupta, Bhadada, & Kale, 2011) also found that serum Na level changes in rats in nephrotoxicity caused by gentamicin were insignificant compared to controls, and potassium and chlorine levels were higher than the control group (p < 0.05). Yilmaz et al. (Yilmaz, 2014) on the other hand, found that Na and K levels increased in the GM group compared to the controls, but it was not significant, and the Cl level did not change. In this study, serum Na, K and Cl levels were examined. There was no statistical significance between the groups in terms of serum Na, K and Cl levels. Despite changes in renal electrolyte distribution with GM administration to animals, changes in plasma electrolytes induced by aminoglycosides have occasionally been observed. This may be due to the presence of excess electrolytes in standard feeds for laboratory animals or the absence of other factors that predispose to electrolyte imbalance(Bach & Lock, 2012).

Details on the mechanisms of GM-induced nephrotoxicity are still not completely known. Various mechanisms such as oxidative stress, apoptosis, tubular necrosis, phospholipidosis, increased endothelin I and leukocyte infiltrations have been suggested by different studies(Ahmadvand, Nouryazdan, Nasri, Adibhesami, & Babaeenezhad, 2020; Balakumar et al., 2008; Lopez-Novoa, Quiros, Vicente, Morales, & Lopez-Hernandez, 2011). GM is absorbed by renal tubular cells via the anion transport system. GM accumulation in these cells ultimately leads to morphological changes, functional impairments, and an increase of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the kidney (Ahmadvand et al., 2020; Balakumar et al., 2008). During nephrotoxicity, these free radicals promote the inflammatory process, apoptosis, and necrosis (Ahmadvand et al., 2020; Lopez-Novoa et al., 2011). Free radicals also suppress the renal antioxidant system through protein oxidation (Sener et al., 2002) and lipid peroxidation (LPO) (Nitha & Janardhanan, 2008).

Since oxidative stress plays a role in the pathogenesis of chronic inflammatory diseases, modulating the cellular redox state by enhancing endogenous antioxidant defenses may be an effective mechanism in the prevention of the disease. In this context, dietary polyphenols generally act as antioxidant compounds, albeit to varying degrees. Polyphenols exert indirect antioxidant effects through the induction of genes involved in the endogenous defense system (Masella et al., 2004; Varì et al., 2011). The endogenous defense system, consisting of enzymatic antioxidants such as superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase, and non-enzymatic antioxidants such as GSH, plays an important role in protecting cells against oxidative damage caused by electrophiles and reactive oxidants (Varì et al., 2011). PCA showed a particularly high capacity to induce gene expression of antioxidant enzymes. In a study using the macrophage cell line J774 A.1, it was found that PCA increased the expression of GPx and GR, mainly by inducing JNK-mediated phosphorylation of the transcription factor Nrf2, which is the main regulator of antioxidant/detoxification (Varì et al., 2011). Again, PCA has been shown to mediate hepatoprotection by increasing SOD, CAT, GST and NQO-1 activities via Akt and PI3K (Ibitoye & Ajiboye, 2020).

It has been shown that the antioxidant potential of PCA is ten times greater than that of α-tocopherol (Song et al., 2020). PCA gives the hydroxyl groups in its chemical structure as a hydrogen atom donor for the reduction of peroxyl radicals, stopping their harmful effects on the cellular membrane and cellular components (Owumi, Ajijola, & Agbeti, 2019). PCA; in addition to stimulating the activities of endogenous antioxidant enzymes such as CAT, SOD, GST, GR and GPx, they also reduce ROS and MDA levels (Li et al., 2021; Song et al., 2020). In PCA-mediated hepatorenal protection, the level of GSH rises significantly and thus increases the bioavailability of cellular GSH to scavenge the produced free radicals (Kassab et al., 2022; Owumi et al., 2019).

Masella et al. (Masella et al., 2004) found that extra virgin olive oil biophenols, namely PCA and oleuropein, completely prevent J774 A.1-mediated oxidation of LDL, inhibit O2•- and H₂O₂ production and decrease in GSH content, thereby neutralizing time-dependent variations in intracellular redox balance, re-regulated GR and GPx activities, thereby restoring mRNA expression of γGCS, GR and GPx to control values. They reported that activation of mRNA transcription of GSH-related enzymes represents an important mechanism in the phenolic antioxidative effect. Again, recent studies strongly suggest that dietary polyphenols can stimulate antioxidant transcription and detoxification defense systems through antioxidant responsive elements (ARE) (Masella, Di Benedetto, Varì, Filesi, & Giovannini, 2005).

In this study, MDA and AOPP levels were examined as oxidative stress parameters. It was determined that the MDA and AOPP levels, which were increased in the GM group, decreased significantly with the administration of PCA. The fact that the obtained values are even lower than the control group can be interpreted as the fact that PCA behaves like an antioxidant compound due to its chemical structure. Because; the antioxidant capacity of a phenolic compound depends on some factors such as the structure of the phenolic compound, the number of aromatic and hydroxyl groups in its structure, and the distribution of these groups within the structure (Adefegha et al., 2015; Balasundram, Sundram, & Samman, 2006). Again in this study, the decreased GSH level and antioxidant enzyme GPx activity in the GM group increased significantly with the administration of PCA (p < 0.05). It can be said that PCA increases the bioavailability of GSH (Kassab et al., 2022; Owumi et al., 2019) and induces antioxidant enzyme synthesis by increasing GPx activity. Indeed, modulatory effects of PCA on GSH-related enzymes have been identified in previous in vitro studies(Masella et al., 2004).

In conclusion; in this study, the protective effect of PCA on GM-induced nephrotoxicity was investigated. In GM-induced nephrotoxicity, PCA prevented lipid peroxidation and protein oxidation, increased GSH level and GPx activity, and according to histopathological and immunohistochemical findings, it prevented necrosis in tubular epithelium, atrophy in glomerulus and decreased 8-OHdG expression. With this study, it was emphasized once again that PCA is a good antioxidant agent and it can be said that PCA has a protective effect in nephrotoxicity induced by GM.

Acknowledgements

We would like to thank to Van YYU Directory of Scientific Research Project Unit who supported to this project (Project Number: TAP-TYL-2022-9401).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Funding

This research was supported by the Van YYU Directory of ScientificResearch Project under project number TAP- TYL-2022-9401

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The effect of protocatechuic acid on nephrotoxicity induced by gentamicin in rats

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