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Conditioned medium from human adipose-derived mesenchymal stem cells attenuates cardiac injury induced by Movento in male rats: role of oxidative stress and inflammation

BMC Pharmacology and Toxicology volume 26, Article number: 13 (2025) Cite this article

Abstract

Movento an insecticide containing spirotetramat, has been shown to cause severe toxicity in humans and rats. Due to the widespread use of the Movento in agriculture, and since the cardiac effects of this toxin have not been investigated in any study so far, in this study, for the first time, the effect of movento on the structure and function of the heart in rats was investigated. 24 adults’ male Wistar rats randomly divided to 4 experimental groups: 1- control (CTL), 2- Movento (M) 3- M + Basal media (BM) 4- M + Conditioned medium (CM). Animals were subjected to deep anesthesia to record the ECG and blood pressure. H&E staining was performed to determine the degree of damage. Oxidative stress markers and inflammatory factors were investigated with related kits. In rats that received Movento’s insecticide, mean arterial pressure (MAP), amplitude of the P wave and total antioxidant capacity (TAC) decreased compared to the control group and treatment with CM increased them significantly compared to M and M + BM group. Also, Movento increased histological score, MDA, TNF-α and IL-6 compared to the control group and CM significantly decreased them compared to M and M + BM groups. CM derived from mesenchymal stem cells (MSC) can be used as a therapy for heart disorders caused by movento toxin in the heart of rats. Also, it seems that this treatment could be a promising way to improve heart complications in farmers exposed to this toxin in the future.

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Introduction

Spirotetramat, a novel cyclic ketoenol compound derived from tetramic acid, has recently emerged as a widely used pesticide product, targeting whiteflies, aphids, and various other agricultural pests [1]. Movento an insecticide containing spirotetramat, has been shown to cause severe toxicity in humans when ingested orally. Additionally, It has been reported to induce acute toxicity in rats through mouth, skin, and inhalation exposures [2]. It has been shown that the consumption of movento in humans can cause ischemic changes in the heart, which shows itself as an increase in the height of the ST segment (ST elevation) in the electrocardiograms [3]. On the other hand, it seems that one of the mechanisms by which movento exerts its destructive effects is through the increase in oxidative stress [4]. It has been shown that spirotetramat can induce liver damage in zebrafish by increasing the expression of proinflammatory cytokines such as TNFα and IL-10 [5].

Mesenchymal stem cells (MSCs) can be mentioned among the most important stem cells that have attracted the attention of most researchers these days. These pluripotent somatic stem cells have been specified in different tissues including umbilical cord blood, bone marrow, skeletal muscles, brain, adipose tissue, peripheral blood, and skin graft tissues [6, 7]. The therapeutic effects of MSCs are generally mediated by various secreted cytokines, growth factors, extracellular matrix proteins, and factors involved in matrix regeneration, as well as different types of extracellular vesicles. The conditioned medium derived from MSCs includes products secreted from the cell and therapeutic benefits for the treatment of neurodegenerative diseases, lung damage, myocardial infarction and stroke [8].

MSCs are derived from various sources, including adipose tissue. The important advantage of mesenchymal stem cells derived from adipose tissue compared to other sources is that they can be easily and repeatedly cultured using less invasive techniques and with minimal complications, making them more resistant compared to other sources [9]. The culture medium derived from adipose tissue stem cells is rich in growth factors such as FGF, BEGF and VEGF [10].

It has been reported that the conditioned media (CM) caused by MSCs increases the survival of neurons in conditions of glutamate toxicity and oxygen-glucose deprivation. The secreted factors from the CM derived from MSCs may play a role in cell renewal and immune regulation. MSCs secrete bioactive factors into the CM, which may be a new treatment method for heart damage [11].

Many studies have shown the therapeutic effects of administration of stem cells and CM derived from them on various heart disorders such as heart attack [12] and cardiac ischemia-reperfusion injury [13]. The antioxidant effects of stem cells and the CM derived from them have been well demonstrated and it seems to be one of their protective mechanisms [14]. Also, it has been shown that CM can shift the immune system from a pro-inflammatory state (M1 macrophages, Th1 cells) to an anti-inflammatory state (M2 macrophages, Tregs) [15]. CM has been shown to inhibit the NF-κB pathway, a central regulator of inflammation. This reduces the production of pro-inflammatory cytokines [16].

Given the expanding use of movento in agriculture (especially in pistachio cultivation in Kerman province), this study aims to investigate for the first time the effects of this poison on the histological and functional aspects of the heart tissue in rats.

Materials and methods

Animals and experimental design

In this research, 24 adults’ male Wistar rats within the weight range of 250 to 300 g were employed. Animals were purchased from the animal farm of Kerman University of Medical Sciences, were kept in a controlled environment with a 12-hour light-dark cycle, maintained at a constant temperature of 22 ± 1.4 °C and humidity 50 ± 4, and provided unrestricted access to both food and water. All methods were performed in accordance with the ARRIVE guidelines. All experiments were performed in accordance with relevant guidelines and regulations. The Animal Ethics Committee at Kerman University of Medical Sciences reviewed and approved all procedures involving animal experimentation (IR.KMU.AEC.1402.067).

The rats were allocated randomly to 4 experimental groups:1- control (CTL), 2- Movento (M), the animals of this group receive Movento at a dose of 1000 mg/kg every three days (on days 1, 4, and 7) through gavage with a volume of 1 cc, 3- M + BM, animals in this group, received tail vein injections of 150 µl basal medium ( M + BM) 4- M + CM (conditioned medium), animals in this group, received tail vein injections of 150 µl MSC-CM for 10 days (except days 1, 4, and 7 that receive Movento).

Preparation of MSCs conditioned medium (MSCs-CM)

Conditioned media collection utilized Adipose Tissue-derived Mesenchymal Stem Cells (MSCs) from the fourth passage. When the cells reached approximately 80% confluence, they were cultured for a duration of 48 h in serum-free DMEM (Dulbecco’s Modified Eagle’s Medium). Subsequently, the collected conditioned media was subjected to centrifugation at 1800 rpm for 20 min at 4 °C to eliminate cell debris. It was then filtered through a 0.22 μm syringe filter. Subsequently, supernatants from the MSCs were gathered. The collected media were concentrated by subjecting them to centrifugation at 6000 g using an Amicon Ultra-10 device from (Millipore Corporation, Bedford, MA, USA). The protein concentration of MSC-CM was determined to be within the range of 700–1400 µg/ml using the Pierce™ BCA protein assay kit from Thermo Fisher Scientific. Following concentration, the media were stored at -80 °C for future use [17].

Recording of ECG and measurement of physiological indicators

After 10 days of the start of the experiment, the animals were subjected to deep anesthesia using ketamine (80 mg/kg) and xylazine (20 mg/kg). Subsequently, to record the ECG based on the 2nd derivation, needle electrodes are placed under the skin of rats and connected to the Powerlab system (ADInstruments, Australia). In derivation 2, the positive electrode is connected to the left leg and the negative electrode is connected to the right hand, and the third electrode, which is the reference, is connected to the left hand. 10 min after recording the ECG, the electrodes are removed from under the animal’s skin and after a surgical incision in the neck area and by removing the tissues, the right carotid artery is found for cannulation. Then, a polyethylene catheter is sent into the right carotid artery to record the mean arterial pressure to transmit the pressure changes to the Powerlab device. Average arterial pressure is recorded for at least 10 min.

Then, after ensuring deep anesthesia, the chest of the animal is split open and the heart is removed from the body. After humidification, the total weight of the heart is measured with a digital scale. Then half of the heart is quickly transferred to a freezer at -80 for the assessment of oxidative stress markers. Another part of the heart was dissected for histological evaluation.

Assessment of oxidative stress markers in the heart

The heart tissue was dissected and subsequently homogenized in cold PBS (with a pH of 7.4). The specimens were subjected to centrifugation at 10,000 times the force of gravity (at 4 °C). Afterward, the resulting supernatants were gathered and preserved at -80 °C until they were ready for subsequent examination.

The concentration of malondialdehyde (MDA) was determined using the thiobarbituric acid reactive substance method (TBARS) and with related assay kits (Kiazist Life Sciences, CN: KMDA96, Iran). Total antioxidant capacity (TAC) levels were measured using commercially available assay kits (Kiazist Life Sciences, CN: KTAC96, Iran) employing the colorimetric method. To determine the protein content in the tissue, the BCA (bicinchoninic acid) Protein Quantification Kit from Parstous, Iran, was employed [18].

Assessment of inflammatory factors in the heart

To evaluate the inflammation in the heart tissue in the studied groups, the amount of TNF-α (KPG, CN: KPG-TNF-α, Iran) and IL-6 (KPG, CN: KPG-MIL6, Iran) was checked by ELISA method. Heart tissue was homogenized in phosphate-buffered saline, supernatant and standard solutions were added to the wells and then the detection antibody and horseradish peroxidase were added. After incubation at 378 C for 1 h, the plate was washed using the appropriate solution. Afterward, chromogens A and B were added to the well to react with the enzyme and form a colored solution. Finally, the plate was incubated at 378 C for 10 min, the stop solution was added, and absorption was read using an ELISA reader (Eliza MAT 2000, DRG instruments, GmbH) at 450 nanometers [19].

Histological studies

The other half of the heart is fixed in formaldehyde, and after embedding in paraffin and sectioning, H&E staining will be performed to determine the degree of damage [20].

Based on four indices of leukocyte infiltration, congestion and hemorrhage, hypereosinophilic bundles, and cardiomyocyte necrosis, histopathological scores were calculated by a blind pathologist and divided into four scors: severe (+++), moderate (+++), mild (+) and normal (0). one point was assigned to each animal, with a total of 12 histological points.

Statistical analysis

The data underwent statistical analysis using Prism (version 8). To assess the normality of data distribution, the Shapiro-Wilk test or K-S test will be employed. For data analysis, a variety of statistical tests were applied, including parametric tests such as one-way ANOVA with Tukey’s post hoc, as well as non-parametric tests like the Kruskal-Wallis test followed by Dunn’s multiple comparisons test. The data were presented in the format of mean ± standard error of the mean (SEM), and a significance level of P < 0.05 was established as the threshold for statistical significance.

Results

Effect of CM on heart weight and mean arterial pressure

The ratio of heart weight to body weight did not show a significant change in any of the groups (Fig. 1A). In rats that received Movento’s insecticide, mean arterial pressure (MAP) decreased compared to the control group (p < 0.01). Also, basal media treatment showed a significant decrease in MAP when compared with the control group, but could not to reverse Movento’s effects on MAP, in M + BM group. In rats treated with CM, MAP increased compared to the movento group (p < 0.01) (Fig. 1B).

Fig. 1
figure 1

Investigation of the effect of CM on the ratio of heart weight to body weight (HW/BW) (A) and MAP (B) in studied groups. n = 6, **P < 0.01 vs. the control group, ##P < 0.01 vs. the M + BM group. Data are means ± SEM. CTL: control; M: Movento; BM: basal medium, CM: condition medium, MAP: mean arterial pressure

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Effect of CM on ECG parameters

Among the parameters of the ECG, only the amplitude of the P wave decreased under the influence of M and M + BM groups versus control group, however the treatment with CM increased this amplitude compared to control group (p < 0.01). Other parameters did not show significant changes (Table 1).

Table 1 Effect of CM on ECG parameters
Full size table

Effect of CM on heart histopathology

The total histological score in the M group was 5.6 ± 1.1 and in M + BM was 5.2 ± 1.09 which showed a significant increase compared to the control group (p < 0.001) (Fig. 2A-E). CM decreased histological score to 2.6 ± 1 compared to the M group (p < 0.001) (Fig. 2A-E).

Fig. 2
figure 2

Histological assessment of the heart tissue in normal rats (A), under the influence of Movento (B) and treatment with BM (C), CM (D) and histopathological score in studied groups (E). H&E staining was performed to determine the degree of damage. n = 6, *** P < 0.001 vs. the control group, ### P < 0.001 vs. the M + BM group. Data are means ± SEM. CTL: control; M: Movento; BM: basal medium, CM: condition medium

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Effect of CM on oxidative stress

Total antioxidant capacity (TAC) was decreased in M and M + BM rats compared to the control group (p < 0.001). CM increased TAC to the normal level, which is significant compared to the M + BM group (p < 0.001) (Fig. 3A). MDA in M and M + BM rats increased compared to the control group and CM decreased it significantly (p < 0.001) (Fig. 3B).

Fig. 3
figure 3

Oxidative stress alterations under the influence of Movento and treatment with CM in studied groups. MDA (A) and TAC (B) levels were measured using thiobarbituric acid reactive substance method (TBARS) and colorimetric method respectively. n = 6, ***P < 0.001 vs. the control group, ###P < 0.001 vs. the M + BM group. Data are mens ± SEM. CTL: control; M: Movento; BM: basal medium, CM: condition medium, TAC: total antioxidant capacity, MDA: malondialdehyde

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Effect of CM on inflammation

In rats that received movento insecticide, inflammatory factors have increased significantly compared to the control group (p < 0.001) (Fig. 4A, B). CM significantly decreased TNF-α (p < 0.001) and IL-6 (p < 0.05) levels compared to M and M + BM groups (Fig. 4A, B).

Fig. 4
figure 4

Inflammatory factors alterations under the influence of movento and treatment with CM in studied groups. TNF-α (A) and IL-6 (B) levels were measured by ELISA method. n = 6, ***P < 0.001 vs. the control group, ###P < 0.001 and #P < 0.05 vs. the movento group. Data are means ± SEM. CTL: control; M: Movento; BM: basal medium, CM: condition medium, TNF-α: Tumor necrosis factor, IL-6: Interleukin 6

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Discussion

Though the various type of pesticide has been studied extremely, limited data are available regarding movento effects. Therefore, the present research needs to consider the effect of movento on the histological and functional aspects of the heart tissue in rats.

The data indicated that movento gavage (dosage of 1000 mg/kg) can cause heart failure and CM obtained from undifferentiated mesenchymal stem derived from adipose tissue cells can improve this deficiency. The main findings of this article were as follows: The average body weight and the heart relative weight were stable during the experiment, without differences between treatments. In the histological evaluation the heart tissue showed relatively medial pathological changes in the exposed rats, which decreased to a moderate degree after 10 days of treatment with CM. Also, MAP and TAC decreased in M and M + BM rats and treatment with CM restored these changes. Also, MDA as oxidative indicator and the amount of TNF-α and IL-6 as inflammatory factors increased in M and M + BM rats, and treatment with CM decreased them. Among the parameters of the ECG, the amplitude of the P wave decreased, and treatment with CM can compensate for this decrease. Treatment with basal medium had no therapeutic effect on rats with movento.

In the current study movento was given to animals by gavage. The previous studies have shown that the components of this poison are absorbed from the gastrointestinal system and reach their maximum amount in the plasma after a few hours [2]. It can be noted that the breed and species of the animal has always been effective in responding to this dangerous insecticide [21]. Our previous research has been also revealed that gavage of a dose 1000 mg/kg movento in rats can induce damage the areas related to memory and learning in the brain and interfere with the learning of rats by reducing the expression of BDNF protein [22].

For the first time, our study examines the effect of movento insecticide on cardiac disorders, and so far, no study has been reported in this field, only one case report study reported a man consuming 100 ml of Movento. In this study, it is stated that there is an ST elevation in the ECG of this person. Current findings from the effect of movento insecticide on heart structure and function in our animals showed that movento weakens cardiac function so that MAP decreases in rats. Also in ECG, amplitude of the P wave decreased. Reduced P wave amplitude can indicate a disorder in electrolytes such as potassium (K+) and has been considered as one of the hyperkalemic ECG indicators [23]. Laboratory and clinical experiments indicate that K+ ion plays an important role in the regulation of blood pressure [24]. Our results suggested a relationship between movento taking and the kalmia level in rats with movento gavage. However, as a limitation, the potassium level should have been measured.

We hypothesized that inflammation and stress oxidative, important players involved in cardiovascular disorders, may be another part of insecticide target in this scenario. In intact condition, low level of myocardial TNF-α and normal contractile function observed [25]. In the normal individual the existence of this factor and transcripts is much more restricted microvasculature [26]. Our study showed that heart tissue TNF-α and IL6 levels as pro inflammatory cytokines increased after movento gavage, also our rats had moderate to severe heart pathological injury, it is not surprising to observe that levels of TNF-α were increased after movento gavage, thereby initiating inflammatory effects. In fact, there was such an expectation. These changes were mitigated by CM treatment, suggesting its restorative potential. The reduction in inflammatory markers such as TNF-α and IL6 in the CM group further supports this observation. On the other hands, low blood pressure following movento gavage and TAC reduction in this group can be consistent with previous studies. Eichacker PQ et al., showed that administrating the inflammatory cytokine tumor necrosis factor -alpha to dogs, resulted in a fatal cardiovascular collapse [27]. The blood pressure lowering effect of TNF-α is caused by an excessive production of the signaling molecule nitric oxide as vasodilator factor as well as reactive oxygen species [28]. These effects lead to disruption of the contractility of the heart muscle and excessive dilation of blood vessels. A more detailed investigation of biochemical changes in NO production pathways and the role of reactive oxygen species can provide more evidence.

In contrast to hypotensive effect of high level of TNF-α, a constant low-level increase in TNF-α production activates various pathways that lead to vasoconstriction in vessels. These compensatory vasoconstriction pathway can counteract the decrease in blood pressure caused by excessive TNF-α [29], which can be somewhat consistent with our results after using the CM. Researchers showed that the uptake of calcium (Ca2+) into the sarcoplasmic reticulum and the sensitivity of the myofilaments to calcium were both dependent on the dose of TNF-α. As the dose of TNF-α was reduced, these calcium-related processes were also diminished [30], The effect of TNF-α reducing cardiac contractility is mediated by the p38 MAPK signaling pathway, which is a negative regulator of cardiac contractility. TNF-α suppresses intracellular calcium handling by inhibiting the expression and activity of the sarcoplasmic reticulum calcium ATPase, which is responsible for uptake of calcium into the sarcoplasmic reticulum [31]. In normal physiological states, the renin-angiotensin system and the TNF-α signaling pathway show a complex regulatory relationship with one another. Studies have demonstrated that TNF-α inhibits the expression of the renin mRNA in adrenal cells [32] as well as in the juxtaglomerular cells of the kidney [33]. on the other hand, activation of the cardiac RAS within the heart was found to increase, leading to enhance of left ventricular remodeling, increase of collagen content leading to increased stiffness and impaired function, and apoptosis of cardiac myocytes [34]. According to these documents, inflammation condition following movento gavage can be justified.

Additionally, we focused on the TAC and MDA contents. In fact, the relationship between movento intake and MDA content and proinflammatory cytokines confirmed in our study. In the M + CM group, we also found the inverse relationship between CM and MDA concentration, which was revealed in the movento group.

The results demonstrate a correlation between the severity of total histological score in movento group and low TAC as antioxidant marker. The two groups had comparable values for parameters such as TAC and MDA content.

Our data are partially in agreement with the findings reported by Keith et al., who showed a relationship between the score of heart failure and increased levels of MDA, an oxidative stress marker in both patient with ischemic cardiac injury and dilated cardiomyopathy who had end-stage heart failure [35]. Similar outcomes are achieved from the other study. An elevated concentration of MDA was determined in the circulation blood of patients with mild sign of congestive heart failure [36]. Additionally, we observed that MDA and TAC in CM group was interestingly similar to control group. Furthermore, there was a similar level between MDA and TAC in both the movento and movento + BM groups that has been suppose treatment with BM had no therapeutic effect on rats with movento. In fact the decrease in MDA levels following treatment with CM suggests a reduction in oxidative stress. Investigating the direct correlation between the reduction in MDA levels and the improvement in cardiac function could provide deeper insights into the therapeutic efficacy of CM.

However, we found an increase in TAC in M + CM, which is an important factor of oxidative stress as it helps protect cells by enhancing antioxidant capability. Overall, the results indicate that the compound CM exerts an anti-oxidative effect during Movento gavage by enhancing the level of both anti inflammation and antioxidants factors in rats. The results also suggest that CM may be more effective for human mesenchymal stem cells from adipose tissue (hMSCA) rather than BM. An important point to consider is that it remains uncertain whether that CM can outperform or surpass the effect of chemical antioxidant compounds.

However, to the best of our knowledge, a direct comparison between Movento effects and MSC-CM has not been carried out. Using chemical antioxidants or anti-inflammatory drugs as a comparison to assess the efficacy of MSC-CM would add value to the findings. Long term studies are suggested to evaluate the sustainability of MSC-CM positive effects, which is essential for its potential clinical applications.

Conclusions

Taken together, this study clearly demonstrated that first, oral administration of movento can cause lowering the blood pressure. Second, histological evaluation the heart tissue showed relatively medial pathological changes in movento group rats. Third, the effect of CM was prominent than BM in improving the antioxidant factors. These effects may emanate from the fact that the oxidant process induces disturbance in molecular and physiological functions and some interventions such as conditioned medium can become more effective. Although this is a basic study, its results could potentially be useful for future human studies (for example, in people exposed to various pesticides).

Study limitations

In this study, ketamine and xylazine were used for anesthesia, which may affect cardiac parameters.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

Not applicable.

Funding

This work was supported by the Kerman University of Medical Sciences under grant number [402000333].

Author information

Author notes

  1. Iman Zangiabadi and Majid Askaripour contributed equally to this work and were considered as the first authors.

Authors and Affiliations

  1. Department of Basic Sciences, School of Medicine, Bam University of Medical Sciences, Bam, Iran

    Iman Zangiabadi

  2. Department of anatomy, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran

    Iman Zangiabadi, Ali Shamsara & Golnaz Shafiei

  3. Department of Physiology, School of Medicine, Bam University of Medical Sciences, Bam, Iran

    Majid Askaripour

  4. Endocrinology and Metabolism Research Center, Kerman University of Medical Sciences, Kerman, Iran

    Mohammad Amin Rajizadeh

  5. Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Jehad Blvd, Ebn Sina Avenue, Kerman, 76198-13159, Iran

    Mohammad Amin Rajizadeh & Soodeh Rajabi

  6. Behbahan Faculty of Medical Sciences, Behbahan, Iran

    Firuzeh Badreh

  7. Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran

    Mohammad Mehdi Bagheri

  8. Pathology and Stem Cell Research Center, Department of Pathology, Kerman University of Medical Sciences, Kerman, Iran

    Elham Jafari

  9. Institute of Neuropharmacology, Kerman Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran

    Ali Shamsara

  10. Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran

    Golnaz Shafiei

Authors
  1. Iman Zangiabadi
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  2. Majid Askaripour
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  3. Mohammad Amin Rajizadeh
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  4. Firuzeh Badreh
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  5. Mohammad Mehdi Bagheri
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  6. Elham Jafari
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  7. Ali Shamsara
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  8. Golnaz Shafiei
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  9. Soodeh Rajabi
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Contributions

S.R, I.Z, M.A: Conceptualization, Methodology, Validation, Investigation, Writing—original draft, Visualization. M.A.R, F.B, M.M.B, E.J, A.SH, G.SH: Methodology, Formal analysis, Investigation, Visualization. S.R, I.Z, M.A: Resources, Formal analysis, Validation, Supervision, Project administration. All authors have approved the final version of the manuscript.

Corresponding author

Correspondence to Soodeh Rajabi.

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Ethical approval

The study was approved by the ethics committee of the Kerman University of Medical Sciences (IR.KMU.AEC.1402.067).

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Not Applicable.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Zangiabadi, I., Askaripour, M., Rajizadeh, M.A. et al. Conditioned medium from human adipose-derived mesenchymal stem cells attenuates cardiac injury induced by Movento in male rats: role of oxidative stress and inflammation. BMC Pharmacol Toxicol 26, 13 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40360-025-00847-w

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40360-025-00847-w

Keywords

BMC Pharmacology and Toxicology

ISSN: 2050-6511

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