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A systematic review of the protective effects of silymarin/silibinin against doxorubicin-induced cardiotoxicity

Abstract

Purpose

Although doxorubicin chemotherapy is commonly applied for treating different malignant tumors, cardiotoxicity induced by this chemotherapeutic agent restricts its clinical use. The use of silymarin/silibinin may mitigate the doxorubicin-induced cardiac adverse effects. For this aim, the potential cardioprotective effects of silymarin/silibinin against the doxorubicin-induced cardiotoxicity were systematically reviewed.

Methods

In this study, we performed a systematic search in accordance with PRISMA guideline for identifying all relevant studies on “the role of silymarin/silibinin against doxorubicin-induced cardiotoxicity” in different electronic databases up to June 2022. Sixty-one articles were obtained and screened based on the predefined inclusion and exclusion criteria. Thirteen eligible papers were finally included in this review.

Results

According to the echocardiographic and electrocardiographic findings, the doxorubicin-treated groups presented a significant reduction in ejection fraction, tissue Doppler peak mitral annulus systolic velocity, and fractional shortening as well as bradycardia, prolongation of QT and QRS interval. However, these echocardiographic abnormalities were obviously improved in the silymarin plus doxorubicin groups. As well, the doxorubicin administration led to induce histopathological and biochemical changes in the cardiac cells/tissue; in contrast, the silymarin/silibinin co-administration could mitigate these induced alterations (for most of the cases).

Conclusion

According to the findings, it was found that the co-administration of silymarin/silibinin alleviates the doxorubicin-induced cardiac adverse effects. Silymarin/silibinin exerts its cardioprotective effects via antioxidant, anti-inflammatory, anti-apoptotic activities, and other mechanisms.

Introduction

Cancer, known as an uncontrolled growth of cells, is one of the leading causes of death in the world [1,2,3]. Among current mainstay treatments for cancer include surgery, chemotherapy, and radiotherapy [4,5,6]. Cancer chemotherapy is the application of drug(s) to cancer patients [7]. Advancements in chemotherapeutic drug discovery have resulted in a remarkable increase in survivorship for cancer patients [8]. However, a number of chemotherapeutic drugs cause adverse effects such as cardiovascular toxicity that may be devastating and life-threatening to cancer patients [9].

Anthracyclines are a class of chemotherapeutic agents that are administered in adult and pediatric patients for treating different cancers [10]. Doxorubicin (also known as Adriamycin) is the most common anthracycline which is widely used to treat different malignant tumors, including acute leukemia, lymphomas, ovarian, testicular, lung, thyroid, breast cancers, and so on [11,12,13,14,15]. Despite its potency, the doxorubicin-associated toxicity on various body organs (particularly the heart) limits its clinical use [16, 17]. Cardiotoxicity is defined as the deterioration of ejection fraction by more than ten percent in asymptomatic cases with a final ejection fraction of less than fifty-five percent or a reduction in ejection fraction of at least five percent in symptomatic cases with a final ejection fraction of less than fifty-five percent [18, 19]. Clinically, doxorubicin-induced cardiotoxicity is characterized by a decrease in the left ventricular ejection fraction, aberrant arrhythmias, and congestive heart failure as well as an increment in the ventricular wall thickness, which can lead to death [10, 20, 21]. This chemotherapeutic drug acutely and chronically causes cardiac adverse effects through induction of oxidative stress, apoptosis and inflammation, mitochondrial dysfunction, inhibition of nucleic acids, and other mechanisms [22,23,24]. Fortunately, previous studies have reported that the use of combination chemotherapy could alleviate the doxorubicin-induced cardiotoxicity [25, 26]; as the doxorubicin co-administration with other agents having chemoprotective capabilities can enhance the therapeutic efficacy of doxorubicin and mitigate different toxicity to normal cells/tissues at the same time [27, 28].

The use of herbal plants and their derivatives in order to alleviate the chemotherapy-associated toxicity (chemo-protectors) or increase the sensitivity of tumoral cells to chemotherapeutic drugs (chemo-sensitizers) has attracted much attention. Silymarin is a polyphenolic flavonoid mixture extracted from the seeds of Silybum marianum [29]. It is noteworthy that the standardized extract of this herbal agent contains various flavonolignans of silybin A, silybin B, silychristin A, silychristin B, isosilybin A, isosilybin B, and silydianin (approximately 65–80%), fatty acids and polyphenolic compounds (approximately 20–35%), and small amounts of flavonoids [30]. Silibinin is also a 50:50 ratio of silybin A and silybin B. It has been confirmed that silibinin is the major bioactive component of silymarin. [31, 32]. Moreover, it was shown that silymarin is one of the best pharmacologically characterized plant extracts because it is non-toxic and without side effects even at relatively high physiological dose values which can be used for treating different diseases [33, 34]. In this regard, silymarin has been used as a natural remedy for nervous system, kidney, prostate, lung, liver diseases, etc. [35, 36]. Among the protective activities of silymarin can point to antifibrotic, immunomodulatory, membrane‐stabilizing [37, 38], antioxidant [39], anti-apoptotic [40], and anti-inflammatory [41] properties. The antitumoral effects of this herbal agent have been assessed in some tumors such as lung, liver, cervical, breast, bladder, skin, and prostate cancers [42,43,44,45,46,47,48,49]. The different mechanisms for the antitumor activities of silymarin have been reported by previous studies [38, 45, 46, 50,51,52,53,54].

To the best of our knowledge, this study is the first systematic review regarding the cardioprotective potentials of silymarin/silibinin, as an adjuvant, against the doxorubicin-induced cardiac adverse effects. In this regard, it was tried to answer the following issues: (a) How does doxorubicin cause cardiotoxicity? (b) What are the underlying mechanisms of cardiac adverse effects induced by this chemotherapeutic agent? (c) What is the role of silymarin/silibinin against the doxorubicin-induced cardiotoxicity? (d) What are the cardioprotective mechanisms of silymarin/silibinin against the doxorubicin-induced cardiac adverse effects?

Methods

We performed a comprehensive and systematic search in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline [55]. In this study, we also used a PICO framework [55] for structuring the review process:

  • Participants (P): patients/animals with cardiac complications from doxorubicin (for clinical studies/in-vivo experiments) and/or cardiac cells injured by doxorubicin (for in-vitro experiments)

  • Intervention (I): cardiac cells/patients/animals treated with silymarin/silibinin plus doxorubicin

  • Comparison (C): cardiac cells/animals/patients treated with doxorubicin

  • Outcomes (O): there were two main outcomes: (1) the cardiac adverse effects induced by doxorubicin in the cardiac cells/tissue than the control groups and (2) the changes resulted in the cardiac cells/tissue following silymarin/silibinin plus doxorubicin than doxorubicin alone

Search strategy

A systematic search was carried out for obtaining all relevant scientific papers on “the cardioprotective effects of silymarin/silibinin against the doxorubicin-induced cardiotoxicity” in different electronic databases of Scopus, PubMed, and Web of Science up to June 2022 using the keywords “Silymarin” OR “Milk thistle” OR “Carduus marianus” OR “Silybum” OR “Silybum marianum” OR “Carsil” OR “Silibinin” OR “silybin” OR “Legalon” OR “Marian thistle” OR “Karsil” OR “Blessed milk thistle” OR “Scotch thistle” OR “Mary thistle” OR “variegated thistle” OR “Saint Mary's thistle” OR “Mediterranean milk thistle” AND “Doxorubicin” OR “Adriamycin” AND “Cardiac” OR “Heart” OR “Cardiomyopathy” OR “Cardiopathy” OR “Cardiac Toxicity” OR “Cardiac Toxicities” OR “Cardiopathic” OR “Arrhythmias” OR “Myocardium” OR “Cardiotoxicity” OR “Myocardial” OR “Myocyte" OR “Cardiomyocyte” in the title, abstract or keywords.

Study selection process

We initially selected all studies based on the study objective (the role of silymarin/silibinin against the doxorubicin-induced cardiotoxicity) in the title and abstract. In the next stage, the full-text papers with (a) English language, (b) adequate findings, (c) no restriction on publication year, and (d) no restriction in publications with in-vivo, in-vitro, or clinical studies were included in the present systematic review. Additionally, we excluded not related papers, book chapters, review papers, case studies, letters to the editors, posters, editorials, and oral presentations from the current study.

Data extraction

Each eligible paper was independently investigated by two authors (MS and ZHJ). When there was a discrepancy between these two authors, it was resolved by consulting the third author (BF). The following data were then extracted for each eligible study: (a) author name and publication year, (b) models (clinical study, in-vivo experiment or/and in-vitro experiment), (c) dosage, protocol of usage, and administration route of doxorubicin, (d) outcomes obtained from doxorubicin administration on the cardiac cells/tissue, (e) dosage, protocol of usage, and administration route of silymarin/silibinin, and (f) findings obtained from silymarin/silibinin co-administration on the doxorubicin-induced cardiotoxicity.

Results

Literature search and screening

We obtained sixty-one papers up to June 2022. After removing the duplicate studies (n = 29), thirty-two studies were screened in their titles and abstracts. Fourteen studies were then excluded and eighteen remaining studies were qualified for assessment of their full texts. Thirteen studies were finally included in this review. The selection process of the study is also shown in Fig. 1. Furthermore, the findings extracted from thirteen eligible studies are summarized in Table 1.

Fig. 1
figure 1

PRISMA flow diagram illustrating the selection process of studies

Table 1 The characteristics of included studies

The cardioprotective potentials of silymarin/silibinin on the doxorubicin-induced cardiac adverse effects

Cell survival and mortality

In an in-vitro experiment by Ortona et al. [56], cardiac cells (AC16 cell line) were treated with 1 μM doxorubicin for 72 h, and it was observed that cardiac cell survival following the chemotherapeutic drug administration was significantly lower than that of the untreated cells. In contrast, the findings showed that pretreated with 100 μM silibinin for 48 h could protect the cardiac cells against doxorubicin-induced reduction in cell survival [56].

Two in vivo experiments revealed that the mortality rate in the doxorubicin-treated rats/mice was higher than that in the control groups [57, 58]. However, the use of silymarin remarkably reduced the doxorubicin-induced mortality rate [57]. Patel et al. reported that a single dose of 60 mg/kg doxorubicin caused 55% death in mice, while the silymarin co-administration (16 mg/kg/day, for 14 days) decreased lethality induced by doxorubicin from 55 to 9% [57].

Body weight and heart weight changes

The results of in-vivo studies showed that the body weight and heart weight of mice/rats treated with doxorubicin were lower than those of the control groups [57,58,59,60]. A significant accumulation of ascites, pericardial, pleural, and peritoneal fluids in the animals treated with doxorubicin in comparison with the untreated group was also found [58]. Other findings indicated that the silymarin co-administration could restore the body weight and heart weight of doxorubicin-treated mice/rats [57,58,59,60].

Electrocardiography (ECG) changes

In an in-vivo experiment, it was observed that doxorubicin-treated rats had several ECG changes consisting of bradycardia and prolongation of QT and QRS interval. However, these ECG abnormalities were obviously improved in the animals receiving silymarin plus doxorubicin [58].

In a clinical study, the echocardiographic examinations of children with acute lymphoblastic leukemia were obtained before and after doxorubicin treatment alone and in combination with silymarin. According to the findings, a significant reduction in ejection fraction, tissue Doppler peak mitral annulus systolic velocity, and fractional shortening of the cancer patients were observed following doxorubicin administration. Moreover, the cancer patients receiving silymarin plus doxorubicin showed a significant increase in these parameters evaluating systolic function compared to the doxorubicin group alone [61].

Biochemical changes

The findings obtained from some studies showed that the doxorubicin administration could induce biochemical changes in the cardiac cells/tissue, as listed in Table 1. Briefly, it was shown that the lactate dehydrogenase (LDH), creatine kinase, aspartate aminotransferase (AST), creatine phosphokinase (CPK), troponin-I, creatine kinase-myocardial band (CK-MB), reactive oxygen species (ROS), malondialdehyde (MDA), thiobarbituric acid reactive substances (TBARS), nitrite, nitric oxide, hydrogen peroxide (H2O2), inducible nitric oxide synthase (iNOS), caspase-3, tumor necrosis factor-alpha (TNF-α), nuclear factor erythroid 2-related factor 2 (Nrf2), vascular endothelial growth factor A (VEGF-A), plasma cholesterol, total lipids, total cholesterol, triglycerides, low-density lipoprotein-cholesterol (LDL-c), triglyceride/high-density lipoprotein (TG/HDL), LDL/HDL, and C-reactive protein levels significantly elevated in the doxorubicin-treated groups than the untreated/control groups [56,57,58,59,60,61,62,63,64,65,66]. Additionally, the glutathione peroxidase (GPx), glutathione (GSH), superoxide dismutase (SOD), catalase, peroxidase, glutathione reductase, gamma-glutamyl transferase (γ-GT), glutathione-S-transferase (GST), HDL-c, and interleukin-10 (IL-10) levels significantly decreased following the doxorubicin treatment than the untreated/control groups [60, 64,65,66].

Other results also indicated that, for most of the cases, the silymarin/silibinin co-administration could alleviate the doxorubicin-induced biochemical alterations in the cardiac cells/tissue [34, 56,57,58,59,60,61,62,63,64,65,66,67].

Histological and ultrastructural changes

The histopathological and ultrastructural examinations of heart sections of the doxorubicin-treated mice/rats indicated the following tissue changes: necrotic muscle fibers, hypertrophy of muscle fibers, wide spaces between muscle fibers, cytoplasmic vacuole formation, highly eosinophilic cytoplasm, disturbance in cardiac trabeculae, interstitial edema, mild hyperemia, vascular congestion, myofibrillar disorganizations, infiltration of inflammatory cells, increase in number of focal necrosis and fibrosis (%), disintegration and dilatation of sarcoplasmic reticulum, vesiculated rough endoplasmic reticulum, eosinophilic degeneration, distorted blood capillaries, severe hemorrhage, retrogressive lacerations in muscle fibers, degenerated cardiac myocytes with small deeply stained pyknotic nuclei and vacuolated cytoplasm, thickening of coronary artery wall, degenerated cardiac myocytes with irregular corrugated thick basement membrane, cardiac myocytes with small shrunken fragmented nucleus, cardiac myocytes with wide intercellular space containing many fibroblasts and collage fibers, and so on [58,59,60, 62,63,64,65,66].

It was also observed that the silymarin/silibinin co-administration could mitigate the doxorubicin-induced histological/ultrastructural changes in the cardiac tissue [58,59,60, 62,63,64,65,66].

Discussion

In the current study, the effects of doxorubicin therapy alone and in combination with silymarin/silibinin on normal cardiac cells/tissue are reviewed and the findings extracted from the eligible studies are summarily presented in Table 1. Furthermore, some of the important effects of doxorubicin alone and silymarin/silibinin plus doxorubicin on the cardiac cell are shown in Fig. 2.

Fig. 2
figure 2

The molecular mechanisms of cardiac damage induced by doxorubicin. The doxorubicin administration leads to induction of oxidative damage, mitochondria damage, apoptosis, inflammation, and other mechanisms in the cardiac cell. In contrast, the silymarin/silibinin co-administration, through an opposite pattern, alleviates the doxorubicin-induced cardiac cell injury. ↓decreased by doxorubicin; ↑increased by doxorubicin; MDA, malondialdehyde; TBARS, thiobarbituric acid reactive substances; SOD, superoxide dismutase; POD, peroxidase; CAT, catalase; GR, glutathione reductase; GSH, glutathione; GPx, glutathione peroxidase; γ-GT, gamma-glutamyl transferase; GST, glutathione-S-transferase; NO, nitric oxide; ROS, reactive oxygen species; NF-κB, nuclear factor kappa B; IL, interleukin; iNOS, inducible nitric oxide synthase; TNF-α, tumor necrosis factor-alpha; TGF-β, transforming growth factor-beta; COX-2, cyclooxygenase-2; BAX, Bcl-2-associated X protein; AIF, apoptosis-inducing factor; PARP, poly (ADP-ribose) polymerase

The cardiac insult, myocardial infarction, and tissue ischemia can be detected by estimation of recognized cardiac marker enzymes, including cholesterol, creatine kinase, CPK, CK-MB, LDH, and AST present in the serum [68, 69]; hence, the activity assessment of these enzymes is important for prediction of cardiac damage. Some studies have reported that the doxorubicin administration significantly elevated the serum activities of these heart damage-associated enzymes, which were released from the damaged cardiac cells [57,58,59,60, 62, 64, 65]. It was reported that the increased serum level of troponin I shortly following chemotherapy can be considered as a powerful predictor for ventricular dysfunction and poor cardiac outcome [61, 70, 71]. Nevertheless, the co-administration of silymarin/silibinin could reduce the elevated serum levels of heart damage-associated enzymes (cholesterol, creatine kinase, CPK, CK-MB, LDH, and AST) and cardiac troponin I in the doxorubicin-treated groups [57,58,59,60,61,62, 64, 65].

It has been also shown that the doxorubicin administration might affect hematological parameters such as induction of anemia, reduction of platelet numbers, increase of lymphocyte numbers, decrease of hemoglobin concentration, etc. [60, 72, 73]. In a study by Afsar et al. it was reported that the silymarin co-administration resulted in a significant improvement in the hematological parameters of doxorubicin-treated rats [60].

Cardiac adverse effects are closely related to oxidative stress caused by excessive free radicals (such as ROS), lipid peroxidation (LPO), and antioxidant depletion [74]. The semiquinone form of doxorubicin is able to interact with molecular oxygen for ROS generation in cardiac cells [59]. The doxorubicin-generated ROS attack the cell macromolecules (such as DNA, RNA, and lysosome), leading to the malfunction of the heart tissue [75,76,77,78,79]. Moreover, the doxorubicin administration causes LPO, an interaction between doxorubicin-generated free radicals and unsaturated fatty acids normally in membrane lipids [57, 80, 81]. The TBARS and MDA levels have been reported to be a credible marker of LPO; in this regard, some studies have reported that the doxorubicin administration increased the TBARS and MDA levels of cardiac cells/tissue [60, 62, 66, 82]. Furthermore, the antioxidant endogenous system (including SOD, peroxidase, catalase, glutathione reductase, GSH, GPx, γ-GT, GST) provides defense against the oxidative damage through neutralizing additional free radicals [60, 83,84,85]; nevertheless, it was revealed that these endogenous antioxidant levels decreased in the doxorubicin-treated cardiac cells/tissue [58, 60, 64, 66, 82, 86,87,88,89,90,91,92,93]. The H2O2 level also increased in rats treated with doxorubicin [60]. Additionally, there is normally a low amount of nitric oxide in the cardiac cells [23]. It was reported that the nitric oxide level of cardiac cells increased following doxorubicin treatment and this free radical has notable roles in cellular signaling during pathological processes [94, 95]. The superoxide anion (O2) produced from an oxygen molecule following doxorubicin treatment highly interacts with nitric oxide, which can produce peroxynitrite (ONOO) [96]. Moreover, the ONOO can turn to other reactive nitrogen species (RNS), including NO2, NO3, OH, and CO3 [23]. The mitochondria injury following doxorubicin via mitochondria ROS production has been reported previously [56, 97]. Doxorubicin has also a high binding affinity to cardiolipin in the inner mitochondria membrane, directly leading to the electron transport chain disturbance, which causes excessive ROS and RNS [98,99,100]. It has been shown that silymarin through its antioxidant effects can inhibit oxidative stress by scavenging free radicals and increasing cellular antioxidant defense mechanisms [101,102,103,104,105]. Moreover, silymarin is able to decrease LPO and its anti-lipoperoxidation activity can be due to the presence of taxifolin and the ability of its polyphenols to bind transition metals and quench ROS [34]. Furthermore, the increased levels of oxidative stress markers (MDA, TBARS, nitric oxide, and H2O2) and the reduced levels of antioxidant markers (SOD, peroxidase, catalase, glutathione reductase, GSH, GPx, γ-GT, GST) in the doxorubicin-exposed cardiac cells was reversed by the silymarin/silibinin co-administration [34, 60, 62,63,64, 66]. It was also shown that the co-treatment of silibinin reduced mitochondrial ROS generation, mitochondria membrane depolarization, and cytoskeleton changes associated with doxorubicin in cardiomyocytes [56].

Doxorubicin also stimulates apoptosis via both intrinsic and extrinsic pathways [106, 107]. This chemotherapeutic agent leads to excess oxidative stress and mitochondrial damage, triggering apoptotic cell death [108,109,110,111]. Some important mediators involved in the apoptotic process are p53, B-cell lymphoma-extra large (Bcl-xL), Bcl-2, BAX, cleaved poly (ADP-ribose) polymerase (PARP), caspase enzymes, and so on [23, 112,113,114,115,116,117]. Some studies have reported that doxorubicin chemotherapy upregulates BAX, cleaved caspase-3, cleaved caspase-9, and p53 expressions and downregulates Bcl-2 and Bcl-xL expressions in the cardiac cells [75,76,77, 118,119,120,121,122,123,124]. These findings indicate that the cells are moving toward apoptotic cell death. It has been also reported that doxorubicin via activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs) pathways can trigger cardiac apoptosis [125]. The anti-apoptotic effects of silymarin/silibinin have been reported in previous studies. In this regard, it was shown that silymarin is able to prevent the release of cytochrome c, thereby inhibiting the activation of caspases [126, 127]. Additionally, the silymarin/silibinin treatment increased the Bcl-2 and Bcl-xL levels and decreased the BAX, p53, JNK and p38 MAPKs, PARP, and caspase-3 levels in the cells [29, 56, 57, 64, 105, 128,129,130,131].

The cancer chemotherapy may trigger an inflammatory process [132], leading to the incidence of various adverse effects following this therapeutic modality [133]. Some studies have reported that the cancer chemotherapy with doxorubicin can cause cardiac inflammation [89, 90, 134, 135]. The inflammatory process is positively correlated with oxidative stress in cardiotoxicity [74]. It has been reported that doxorubicin-induced oxidative stress can activate lysosomal enzymes, leading to the promotion of cardiac inflammation [23]. According to the findings obtained from some studies, it was indicated that doxorubicin treatment led to an increase in the production of pro-inflammatory mediators (iNOS, COX-2, TGF-β, IL-1β, IL-6, IL-18, NF-κB, and TNF-α) and a reduction in IL-10 level (an anti-inflammatory cytokine) of cardiac cells [64, 66, 75, 82, 120, 122, 135]. Previous studies have reported that silymarin/silibinin can be a promising anti‐inflammatory agent. It was shown that the use of silymarin/silibinin could reduce the inflammation via decreased levels of iNOS, COX-2, TGF-β, IL-1β, IL-6, IL-18, and TNF-α along with an increased level of IL-10 in different cells/tissues [64, 66, 128, 136,137,138,139,140,141]. Moreover, the anti-inflammatory effects of silymarin can mainly be because of inhibiting the NF-κB nuclear translocation/activation, resulting in preventing the aggregation of inflammatory cells as well as decreasing the expression of inflammatory cytokines and other certain inflammatory mediators [105, 128, 131, 142,143,144]. In addition, the histological findings represented in this systematic review exhibited that the doxorubicin-induced cardiac inflammation is mitigated by the silymarin/silibinin co-administration [58, 60, 62,63,64,65].

Perspective of future research and limitations

Although the doxorubicin chemotherapy is commonly applied for treating the cancer patients, its cardiotoxic adverse effects limit the clinical application of this chemotherapeutic agent. According to the data presented in this systematic review, it was shown that silymarin/silibinin can be an effective cardioprotective agent against the doxorubicin-induced cardiotoxicity. This herbal agent exerts the cardioprotective activities via the antioxidant, anti-apoptotic, anti-inflammatory effects, and other mechanisms. In addition to its chemo-protective effects, silymarin/silibinin can be used as a chemosensitizing agent on cancerous cells, mitigating the chemotherapy-induced adverse effects via reduction of the chemotherapy dose in the cancer patients.

Despite its remarkable beneficial effects, it has been reported that silymarin has very low water solubility and poor oral absorption. A number of researchers have overcome these biopharmaceutical drawbacks by using various structural modification strategies [145,146,147] and have introduced novel derivatives and analogues for silymarin [148,149,150,151,152,153,154,155,156]. Furthermore, the therapeutic/protective efficacy of novel derivatives/analogues has been investigated on tumor/normal cells [148, 150, 157, 158]. Other researchers have reported that the loading of silymarin into a delivery system improves its bioavailability; hence, they developed various formulation-based approaches such as solid lipid nanoparticles, mesoporous silica nanoparticles, biodegradable polymeric micelles, nanoemulsions, amorphous solid dispersions, nanosuspensions, and liposomes [159,160,161,162,163,164,165]. Some studies have assessed the therapeutic/protective effects of silymarin delivery systems on tumor/normal cells [166,167,168,169,170]. In view of the above, evaluating the potential cardioprotective potentials of the analogues/derivatives and the delivery systems of silymarin/silibinin against cardiotoxicity induced by chemotherapy drugs (especially doxorubicin) is suggested.

Since the data represented in this study are mostly based on in vitro and in vivo experiments, suggesting the use of silymarin/silibinin (as a potential cardioprotective agent) in the cancer patients for alleviating the cardiac adverse effects induced by doxorubicin or other chemotherapy drugs requires further clinical studies. Moreover, another point that should be evaluated with more extensive studies on the current topic is to provide more details on the type of cancer, the dose and frequency of administration of the drugs.

Conclusion

The findings reveal that the doxorubicin chemotherapy could induce echocardiographic, biochemical, and histological alterations in the cardiac cells/tissue which caused cardiotoxicity. Other results showed that the silymarin/silibinin co-administration could alleviate the doxorubicin-mediated cardiac adverse effects. Mechanically, the silymarin/silibinin exerts its cardioprotective effects via the antioxidant, anti-apoptotic, anti-inflammatory effects, and other mechanisms.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Mortezaee K, Narmani A, Salehi M, Bagheri H, Farhood B, Haghi-Aminjan H, Najafi M. Synergic effects of nanoparticles-mediated hyperthermia in radiotherapy/chemotherapy of cancer. Life Sci. 2021;269:119020.

    Article  CAS  PubMed  Google Scholar 

  2. Sheikholeslami S, Khodaverdian S, Dorri-Giv M, Mohammad Hosseini S, Souri S, Abedi-Firouzjah R, Zamani H, Dastranj L, Farhood B. The radioprotective effects of alpha-lipoic acid on radiotherapy-induced toxicities: a systematic review. Int Immunopharmacol. 2021;96:107741.

    Article  CAS  PubMed  Google Scholar 

  3. Sheikholeslami S, Aryafar T, Abedi-Firouzjah R, Banaei A, Dorri-Giv M, Zamani H, Ataei G, Majdaeen M, Farhood B. The role of melatonin on radiation-induced pneumonitis and lung fibrosis: a systematic review. Life Sci. 2021;281:119721.

    Article  CAS  PubMed  Google Scholar 

  4. Abdi Goushbolagh N, Abedi Firouzjah R, Ebrahimnejad Gorji K, Khosravanipour M, Moradi S, Banaei A, Astani A, Najafi M, Zare MH, Farhood B. Estimation of radiation dose-reduction factor for cerium oxide nanoparticles in MRC-5 human lung fibroblastic cells and MCF-7 breast-cancer cells. Artif Cells Nanomed Biotechnol. 2018;46(sup3):S1215-s1225.

    Article  CAS  PubMed  Google Scholar 

  5. Ashrafizadeh M, Farhood B, Eleojo Musa A, Taeb S, Najafi M. Damage-associated molecular patterns in tumor radiotherapy. Int Immunopharmacol. 2020;86:106761.

    Article  CAS  PubMed  Google Scholar 

  6. Ashrafizadeh M, Farhood B, Eleojo Musa A, Taeb S, Rezaeyan A, Najafi M. Abscopal effect in radioimmunotherapy. Int Immunopharmacol. 2020;85:106663.

    Article  CAS  PubMed  Google Scholar 

  7. Huang CY, Ju DT, Chang CF, Muralidhar Reddy P, Velmurugan BK. A review on the effects of current chemotherapy drugs and natural agents in treating non-small cell lung cancer. Biomedicine. 2017;7(4):23.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR, Alfano CM, Jemal A, Kramer JL, Siegel RL. Cancer treatment and survivorship statistics, 2019. CA A Cancer J Clin. 2019; 69(5):363–85.

  9. Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, MacIntyre MF, Allen C, Hansen G, Woodbrook R, Wolfe C, et al. The global burden of cancer 2013. JAMA Oncol. 2015;1(4):505–27.

    Article  PubMed  Google Scholar 

  10. Volkova M, Russell R III. Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr Cardiol Rev. 2011;7(4):214–20.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Weiss RB. The anthracyclines: Will we ever find a better doxorubicin? Semin Oncol. 1992;19(6):670–86.

    CAS  PubMed  Google Scholar 

  12. Cortés-Funes H, Coronado C. Role of anthracyclines in the era of targeted therapy. Cardiovasc Toxicol. 2007;7(2):56–60.

    Article  PubMed  Google Scholar 

  13. Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL. Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol. 2012;52(6):1213–25.

    Article  CAS  PubMed  Google Scholar 

  14. Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med. 1998;339(13):900–5.

    Article  CAS  PubMed  Google Scholar 

  15. Chatterjee K, Zhang J, Honbo N, Karliner JS. Doxorubicin cardiomyopathy. Cardiology. 2010;115(2):155–62.

    Article  CAS  PubMed  Google Scholar 

  16. Jain A, Rani V. Assessment of herb-drug synergy to combat doxorubicin induced cardiotoxicity. Life Sci. 2018;205:97–106.

    Article  CAS  PubMed  Google Scholar 

  17. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97(11):2869–79.

    Article  CAS  PubMed  Google Scholar 

  18. Jafari F, Safaei AM, Hosseini L, Asadian S, Kamangar TM, Zadehbagheri F, Rezaeian N. The role of cardiac magnetic resonance imaging in the detection and monitoring of cardiotoxicity in patients with breast cancer after treatment: a comprehensive review. Heart Fail Rev. 2021;26(3):679–97.

    Article  PubMed  Google Scholar 

  19. Chen J, Long JB, Hurria A, Owusu C, Steingart RM, Gross CP. Incidence of heart failure or cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Coll Cardiol. 2012;60(24):2504–12.

    Article  CAS  PubMed  Google Scholar 

  20. Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA. A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer. 1973;32(2):302–14.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang Q, Wu L. In vitro and in vivo cardioprotective effects of curcumin against doxorubicin-induced cardiotoxicity: a systematic review. J Oncol. 2022;2022:7277562.

    PubMed Central  PubMed  Google Scholar 

  22. McGowan JV, Chung R, Maulik A, Piotrowska I, Walker JM, Yellon DM. Anthracycline chemotherapy and cardiotoxicity. Cardiovasc Drugs Ther. 2017;31(1):63–75.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Najafi M, Hooshangi Shayesteh MR, Mortezaee K, Farhood B, Haghi-Aminjan H. The role of melatonin on doxorubicin-induced cardiotoxicity: a systematic review. Life Sci. 2020;241:117173.

    Article  CAS  PubMed  Google Scholar 

  24. Moutabian H, Ghahramani-Asl R, Mortezazadeh T, Laripour R, Narmani A, Zamani H, Ataei G, Bagheri H, Farhood B, Sathyapalan T, et al. The cardioprotective effects of nano-curcumin against doxorubicin-induced cardiotoxicity: a systematic review. BioFactors. 2022;48(3):597–610.

    Article  CAS  PubMed  Google Scholar 

  25. Specenier PM, Vermorken JB. Current concepts for the management of head and neck cancer: chemotherapy. Oral Oncol. 2009;45(4–5):409–15.

    Article  CAS  PubMed  Google Scholar 

  26. Hannouf MB, Sehgal C, Cao JQ, Mocanu JD, Winquist E, Zaric GS. Cost-effectiveness of adding cetuximab to platinum-based chemotherapy for first-line treatment of recurrent or metastatic head and neck cancer. PLoS ONE. 2012;7(6):e38557.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Higuchi T, Sugisawa N, Miyake K, Oshiro H, Yamamoto N, Hayashi K, Kimura H, Miwa S, Igarashi K, Bouvet M, et al. The combination of olaratumab with doxorubicin and cisplatinum regresses a chemotherapy-resistant osteosarcoma in a patient-derived orthotopic xenograft mouse model. Transl Oncol. 2019;12(9):1257–63.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Ruiz-González R, Milán P, Bresolí-Obach R, Stockert JC, Villanueva A, Cañete M, Nonell S. Photodynamic synergistic effect of pheophorbide a and doxorubicin in combined treatment against tumoral cells. Cancers. 2017;9(2):18.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Ahmed RF, Moussa RA, Eldemerdash RS, Zakaria MM, Abdel-Gaber SA. Ameliorative effects of silymarin on HCl-induced acute lung injury in rats; role of the Nrf-2/HO-1 pathway. Iran J Basic Med Sci. 2019;22(12):1483–92.

    PubMed Central  PubMed  Google Scholar 

  30. Comelli MC, Mengs U, Schneider C, Prosdocimi M. Toward the definition of the mechanism of action of silymarin: activities related to cellular protection from toxic damage induced by chemotherapy. Integr Cancer Ther. 2007;6(2):120–9.

    Article  CAS  PubMed  Google Scholar 

  31. de Oliveira DR, Tintino SR, Braga MF, Boligon AA, Athayde ML, Coutinho HD, de Menezes IR, Fachinetto R. In vitro antimicrobial and modulatory activity of the natural products silymarin and silibinin. Biomed Res Int. 2015;2015:292797.

    PubMed  Google Scholar 

  32. Ferenci P. Silymarin in the treatment of liver diseases: What is the clinical evidence? Clin Liver Dis. 2016;7(1):8–10.

    Article  Google Scholar 

  33. Ferenci P, Dragosics B, Dittrich H, Frank H, Benda L, Lochs H, Meryn S, Base W, Schneider B. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol. 1989;9(1):105–13.

    Article  CAS  PubMed  Google Scholar 

  34. Psotová J, Chlopcíková S, Grambal F, Simánek V, Ulrichová J. Influence of silymarin and its flavonolignans on doxorubicin-iron induced lipid peroxidation in rat heart microsomes and mitochondria in comparison with quercetin. Phytother Res. 2002;16(Suppl 1):S63-67.

    Article  PubMed  Google Scholar 

  35. Abenavoli L, Milic N. Chapter 45-silymarin for liver disease. In: Muriel P, editor, Liver pathophysiology. Boston: Academic Press; 2017. p. 621–31.

  36. Gazák R, Walterová D, Kren V. Silybin and silymarin—new and emerging applications in medicine. Curr Med Chem. 2007;14(3):315–38.

    Article  PubMed  Google Scholar 

  37. Post-White J, Ladas EJ, Kelly KM. Advances in the use of milk thistle (Silybum marianum). Integr Cancer Ther. 2007;6(2):104–9.

    Article  CAS  PubMed  Google Scholar 

  38. Hosseinabadi T, Lorigooini Z, Tabarzad M, Salehi B, Rodrigues CF, Martins N, Sharifi-Rad J. Silymarin antiproliferative and apoptotic effects: insights into its clinical impact in various types of cancer. Phytother Res. 2019;33(11):2849–61.

    Article  CAS  PubMed  Google Scholar 

  39. Taleb A, Ahmad KA, Ihsan AU, Qu J, Lin N, Hezam K, Koju N, Hui L, Qilong D. Antioxidant effects and mechanism of silymarin in oxidative stress induced cardiovascular diseases. Biomed Pharmacother. 2018;102:689–98.

    Article  CAS  PubMed  Google Scholar 

  40. Abd Eldaim MA, Barakat ER, Alkafafy M, Elaziz SAA. Antioxidant and anti-apoptotic prophylactic effect of silymarin against lead-induced hepatorenal toxicity in rats. Environ Sci Pollut Res Int. 2021;28(41):57997–8006.

    Article  CAS  PubMed  Google Scholar 

  41. Ferraz AC, Almeida LT, da Silva Caetano CC, da Silva Menegatto MB, Souza Lima RL, de Senna JPN, de Oliveira Cardoso JM, Perucci LO, Talvani A, Geraldo de Lima W, et al. Hepatoprotective, antioxidant, anti-inflammatory, and antiviral activities of silymarin against mayaro virus infection. Antiviral Res. 2021; 194:105168.

  42. Barros TMB, Lima APB, Almeida TC, da Silva GN. Inhibition of urinary bladder cancer cell proliferation by silibinin. Environ Mol Mutagen. 2020;61(4):445–55.

    Article  CAS  PubMed  Google Scholar 

  43. Féher J, Lengyel G. Silymarin in the prevention and treatment of liver diseases and primary liver cancer. Curr Pharm Biotechnol. 2012;13(1):210–7.

    Article  PubMed  Google Scholar 

  44. Kim SH, Choo GS, Yoo ES, Woo JS, Lee JH, Han SH, Jung SH, Kim HJ, Jung JY. Silymarin inhibits proliferation of human breast cancer cells via regulation of the MAPK signaling pathway and induction of apoptosis. Oncol Lett. 2021;21(6):492.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Koltai T, Fliegel L. Role of silymarin in cancer treatment: facts, hypotheses, and questions. J Evidence Based Integr Med. 2022; 27:2515690x211068826.

  46. Singh RP, Agarwal R. Flavonoid antioxidant silymarin and skin cancer. Antioxid Redox Signal. 2002;4(4):655–63.

    Article  CAS  PubMed  Google Scholar 

  47. Wu T, Liu W, Guo W, Zhu X. Silymarin suppressed lung cancer growth in mice via inhibiting myeloid-derived suppressor cells. Biomed Pharmacother. 2016;81:460–7.

    Article  CAS  PubMed  Google Scholar 

  48. Yu HC, Chen LJ, Cheng KC, Li YX, Yeh CH, Cheng JT. Silymarin inhibits cervical cancer cell through an increase of phosphatase and tensin homolog. Phytother Res. 2012;26(5):709–15.

    Article  CAS  PubMed  Google Scholar 

  49. Zhu W, Zhang JS, Young CY. Silymarin inhibits function of the androgen receptor by reducing nuclear localization of the receptor in the human prostate cancer cell line LNCaP. Carcinogenesis. 2001;22(9):1399–403.

    Article  CAS  PubMed  Google Scholar 

  50. Delmas D, Xiao J, Vejux A, Aires V. Silymarin and cancer: a dual strategy in both in chemoprevention and chemosensitivity. Molecules (Basel). 2020;25(9):2009.

    Article  CAS  Google Scholar 

  51. Kren V, Walterová D. Silybin and silymarin—new effects and applications. Biomed Pap Med Fac Univ Palacky Olomouc Czechoslovakia. 2005;149(1):29–41.

    Article  CAS  Google Scholar 

  52. Polyak SJ, Morishima C, Shuhart MC, Wang CC, Liu Y, Lee DY. Inhibition of T-cell inflammatory cytokines, hepatocyte NF-kappaB signaling, and HCV infection by standardized Silymarin. Gastroenterology. 2007;132(5):1925–36.

    Article  CAS  PubMed  Google Scholar 

  53. Saller R, Brignoli R, Melzer J, Meier R. An updated systematic review with meta-analysis for the clinical evidence of silymarin. Forschende Komplementarmedizin. 2008;15(1):9–20.

    Article  PubMed  Google Scholar 

  54. Zhong X, Zhu Y, Lu Q, Zhang J, Ge Z, Zheng S. Silymarin causes caspases activation and apoptosis in K562 leukemia cells through inactivation of Akt pathway. Toxicology. 2006;227(3):211–6.

    Article  CAS  PubMed  Google Scholar 

  55. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264–9.

    Article  PubMed  Google Scholar 

  56. Ortona E, Locatelli SL, Pagano MT, Ascione B, Careddu G, Dupuis ML, Marconi M, Carlo-Stella C, Malorni W, Matarrese P, et al. The natural estrogen receptor beta agonist silibinin as a promising therapeutic tool in diffuse large B-cell lymphoma. Anticancer Res. 2022;42(2):767–79.

    Article  CAS  PubMed  Google Scholar 

  57. Patel N, Joseph C, Corcoran GB, Ray SD. Silymarin modulates doxorubicin-induced oxidative stress, Bcl-xL and p53 expression while preventing apoptotic and necrotic cell death in the liver. Toxicol Appl Pharmacol. 2010;245(2):143–52.

    Article  CAS  PubMed  Google Scholar 

  58. Arozal W, Suyatna FD, Juniantito V, Rosdiana DS, Amurugam S, Aulia R, Monayo ER, Siswandi R. The effects of mangiferin (Mangifera indica L.) in doxorubicin-induced cardiotoxicity in rats. Drug Res. 2015;65(11):574–80.

    CAS  Google Scholar 

  59. Rašković A, Stilinović N, Kolarović J, Vasović V, Vukmirović S, Mikov M. The protective effects of silymarin against doxorubicin-induced cardiotoxicity and hepatotoxicity in rats. Molecules (Basel). 2011;16(10):8601–13.

    Article  Google Scholar 

  60. Afsar T, Razak S, Batoo KM, Khan MR. Acacia hydaspica R. Parker prevents doxorubicin-induced cardiac injury by attenuation of oxidative stress and structural Cardiomyocyte alterations in rats. BMC Complement Altern Med. 2017; 17(1):554.

  61. Hagag AA, El Shehaby WA, El-Abasy AI, Mabrouk MM. Protective role of silymarin in early doxorubicin-induced cardiac dysfunction in children with acute lymphoblastic leukemia. Infect Disord Drug Targets. 2019;19(2):133–40.

    CAS  PubMed  Google Scholar 

  62. El-Shitany NA, El-Haggar S, El-desoky K. Silymarin prevents adriamycin-induced cardiotoxicity and nephrotoxicity in rats. Food Chem Toxicol. 2008;46(7):2422–8.

    Article  CAS  PubMed  Google Scholar 

  63. Cecen E, Dost T, Culhaci N, Karul A, Ergur B, Birincioglu M. Protective effects of silymarin against doxorubicin-induced toxicity. Asian Pac J Cancer Prev. 2011;12(10):2697–704.

    CAS  PubMed  Google Scholar 

  64. Attia GM, Elmansy RA, Algaidi SA. Silymarin decreases the expression of VEGF-A, iNOS and caspase-3 and preserves the ultrastructure of cardiac cells in doxorubicin induced cardiotoxicity in rats: a possible protective role. Int J Clin Exp Med. 2017;10(2):4158–73.

    CAS  Google Scholar 

  65. Abdelsalam HM, Samak MA, Alsemeh AE. Synergistic therapeutic effects of Vitis vinifera extract and Silymarin on experimentally induced cardiorenal injury: the pertinent role of Nrf2. Biomed Pharmacother. 2019;110:37–46.

    Article  CAS  PubMed  Google Scholar 

  66. Akinloye OA, Sulaimon LA, Adewale AO, Mubaraq T, Salami O, Abiola O. Allium vineale methanol extract attenuated oxidative stress and inflammation induced by doxorubicin in Sprague Dawley Rats. Scientific African. 2022;16:e01244.

    Article  CAS  Google Scholar 

  67. Chlopcíková S, Psotová J, Miketová P, Simánek V. Chemoprotective effect of plant phenolics against anthracycline-induced toxicity on rat cardiomyocytes. Part I. Silymarin and its flavonolignans. Phytother Res. 2004; 18(2):107–10.

  68. Chrostek L, Szmitkowski M. Enzymatic diagnosis of alcoholism-induced damage of internal organs. Psychiatr Pol. 1989;23(5–6):353–60.

    CAS  PubMed  Google Scholar 

  69. Muhammad RK, Javeria H, Rahmat AK, Jasia B, Maria S, Umbreen R. Prevention of KBr O3-induced cardiotoxicity by Sonchus asper in rat. J Med Plants Res. 2011;5(12):2514–20.

    Google Scholar 

  70. Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M, Martinelli G, Veglia F, Fiorentini C, Cipolla CM. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation. 2006;114(23):2474–81.

    Article  CAS  PubMed  Google Scholar 

  71. Reagan WJ, York M, Berridge B, Schultze E, Walker D, Pettit S. Comparison of cardiac troponin I and T, including the evaluation of an ultrasensitive assay, as indicators of doxorubicin-induced cardiotoxicity. Toxicol Pathol. 2013;41(8):1146–58.

    Article  PubMed  Google Scholar 

  72. al-Harbi MM, al-Gharably NM, al-Shabanah OA, al-Bekairi AM, Osman AM, Tawfik HN. Prevention of doxorubicin-induced myocardial and haematological toxicities in rats by the iron chelator desferrioxamine. Cancer Chemother Pharmacol. 1992; 31(3):200–4.

  73. Kim EJ, Lim KM, Kim KY, Bae ON, Noh JY, Chung SM, Shin S, Yun YP, Chung JH. Doxorubicin-induced platelet cytotoxicity: a new contributory factor for doxorubicin-mediated thrombocytopenia. J Thromb Haemost. 2009;7(7):1172–83.

    Article  CAS  PubMed  Google Scholar 

  74. Li D, Yang Y, Wang S, He X, Liu M, Bai B, Tian C, Sun R, Yu T, Chu X. Role of acetylation in doxorubicin-induced cardiotoxicity. Redox Biol. 2021;46:102089.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Hosseinzadeh L, Behravan J, Mosaffa F, Bahrami G, Bahrami A, Karimi G. Curcumin potentiates doxorubicin-induced apoptosis in H9c2 cardiac muscle cells through generation of reactive oxygen species. Food Chem Toxicol. 2011;49(5):1102–9.

    Article  CAS  PubMed  Google Scholar 

  76. He H, Luo Y, Qiao Y, Zhang Z, Yin D, Yao J, You J, He M. Curcumin attenuates doxorubicin-induced cardiotoxicity via suppressing oxidative stress and preventing mitochondrial dysfunction mediated by 14-3-3γ. Food Funct. 2018;9(8):4404–18.

    Article  CAS  PubMed  Google Scholar 

  77. Jain A, Rani V. Mode of treatment governs curcumin response on doxorubicin-induced toxicity in cardiomyoblasts. Mol Cell Biochem. 2018;442(1–2):81–96.

    Article  CAS  PubMed  Google Scholar 

  78. Sheu MT, Jhan HJ, Hsieh CM, Wang CJ, Ho HO. Efficacy of antioxidants as a Complementary and Alternative Medicine (CAM) in combination with the chemotherapeutic agent doxorubicin. Integr Cancer Ther. 2015;14(2):184–95.

    Article  CAS  PubMed  Google Scholar 

  79. Quagliariello V, Vecchione R, Coppola C, Di Cicco C, De Capua A, Piscopo G, Paciello R, Narciso V, Formisano C, Taglialatela-Scafati O, et al. Cardioprotective effects of nanoemulsions loaded with anti-inflammatory nutraceuticals against doxorubicin-induced cardiotoxicity. Nutrients. 2018;10(9):1304.

    Article  PubMed Central  PubMed  Google Scholar 

  80. Zhang Y, Li L, Xiang C, Ma Z, Ma T, Zhu S. Protective effect of melatonin against Adriamycin-induced cardiotoxicity. Exp Ther Med. 2013;5(5):1496–500.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Sadzuka Y, Nagamine M, Toyooka T, Ibuki Y, Sonobe T. Beneficial effects of curcumin on antitumor activity and adverse reactions of doxorubicin. Int J Pharm. 2012;432(1–2):42–9.

    Article  CAS  PubMed  Google Scholar 

  82. Arafa MH, Mohammad NS, Atteia HH, Abd-Elaziz HR. Protective effect of resveratrol against doxorubicin-induced cardiac toxicity and fibrosis in male experimental rats. J Physiol Biochem. 2014;70(3):701–11.

    Article  CAS  PubMed  Google Scholar 

  83. Yahyapour R, Motevaseli E, Rezaeyan A, Abdollahi H, Farhood B, Cheki M, Rezapoor S, Shabeeb D, Musa AE, Najafi M, et al. Reduction-oxidation (redox) system in radiation-induced normal tissue injury: molecular mechanisms and implications in radiation therapeutics. Clin Transl Oncol. 2018;20(8):975–88.

    Article  CAS  PubMed  Google Scholar 

  84. Hasan Kadhim A, Shamkhi Noor A, Amer AM. The effectiveness of biotin (Vitamin B7) added to the diet in improving the efficiency of productivity, and some physiological traits for broiler chickens (Ross-308) Exposed to Oxidative Stress. Arch Razi Inst. 2022;77(5):1805–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Varadhan S, Venkatachalam R, Perumal S, Ayyamkulamkara S. Evaluation of oxidative stress parameters and antioxidant status in coronary artery disease patients. Arch Razi Inst. 2022;77(2):853–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Liu MH, Shan J, Li J, Zhang Y, Lin XL. Resveratrol inhibits doxorubicin-induced cardiotoxicity via sirtuin 1 activation in H9c2 cardiomyocytes. Exp Ther Med. 2016;12(2):1113–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Tatlidede E, Sehirli O, Velioğlu-Oğünc A, Cetinel S, Yeğen BC, Yarat A, Süleymanoğlu S, Sener G. Resveratrol treatment protects against doxorubicin-induced cardiotoxicity by alleviating oxidative damage. Free Radical Res. 2009;43(3):195–205.

    Article  CAS  Google Scholar 

  88. Dolinsky VW, Rogan KJ, Sung MM, Zordoky BN, Haykowsky MJ, Young ME, Jones LW, Dyck JR. Both aerobic exercise and resveratrol supplementation attenuate doxorubicin-induced cardiac injury in mice. Am J Physiol Endocrinol Metab. 2013;305(2):E243-253.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Alanazi AM, Fadda L, Alhusaini A, Ahmad R, Hasan IH, Mahmoud AM. Liposomal resveratrol and/or carvedilol attenuate doxorubicin-induced cardiotoxicity by modulating inflammation, oxidative stress and S100A1 in rats. Antioxidants (Basel). 2020;9(2):159.

    Article  CAS  PubMed  Google Scholar 

  90. Dudka J, Gieroba R, Korga A, Burdan F, Matysiak W, Jodlowska-Jedrych B, Mandziuk S, Korobowicz E, Murias M. Different effects of resveratrol on dose-related Doxorubicin-induced heart and liver toxicity. Evidence Based Complement Altern Med. 2012;2012:606183.

    Article  Google Scholar 

  91. Al-Harthi SE, Alarabi OM, Ramadan WS, Alaama MN, Al-Kreathy HM, Damanhouri ZA, Khan LM, Osman AM. Amelioration of doxorubicin-induced cardiotoxicity by resveratrol. Mol Med Rep. 2014;10(3):1455–60.

    Article  CAS  PubMed  Google Scholar 

  92. Wang HL, Gao JP, Han YL, Xu X, Wu R, Gao Y, Cui XH. Comparative studies of polydatin and resveratrol on mutual transformation and antioxidative effect in vivo. Phytomedicine. 2015;22(5):553–9.

    Article  CAS  PubMed  Google Scholar 

  93. Mukherjee K, Venkatesh M, Venkatesh P, Saha BP, Mukherjee PK. Effect of soy phosphatidyl choline on the bioavailability and nutritional health benefits of resveratrol. Food Res Int. 2011;44(4):1088–93.

    Article  CAS  Google Scholar 

  94. Luu AZ, Chowdhury B, Al-Omran M, Teoh H, Hess DA, Verma S. Role of endothelium in doxorubicin-induced cardiomyopathy. JACC Basic Transl Sci. 2018;3(6):861–70.

    Article  PubMed Central  PubMed  Google Scholar 

  95. Münzel T, Camici GG, Maack C, Bonetti NR, Fuster V, Kovacic JC. Impact of oxidative stress on the heart and vasculature: part 2 of a 3-part series. J Am Coll Cardiol. 2017;70(2):212–29.

    Article  PubMed Central  PubMed  Google Scholar 

  96. Rezvanfar MA, Rezvanfar MA, Ahmadi A, Saadi HA, Baeeri M, Abdollahi M. Mechanistic links between oxidative/nitrosative stress and tumor necrosis factor alpha in letrozole-induced murine polycystic ovary: biochemical and pathological evidences for beneficial effect of pioglitazone. Hum Exp Toxicol. 2012;31(9):887–97.

    Article  CAS  PubMed  Google Scholar 

  97. Danz ED, Skramsted J, Henry N, Bennett JA, Keller RS. Resveratrol prevents doxorubicin cardiotoxicity through mitochondrial stabilization and the Sirt1 pathway. Free Radical Biol Med. 2009;46(12):1589–97.

    Article  Google Scholar 

  98. Dudek J, Hartmann M, Rehling P. The role of mitochondrial cardiolipin in heart function and its implication in cardiac disease. Biochim Biophys Acta. 2019;1865(4):810–21.

    Article  CAS  Google Scholar 

  99. Ichikawa Y, Ghanefar M, Bayeva M, Wu R, Khechaduri A, Naga Prasad SV, Mutharasan RK, Naik TJ, Ardehali H. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J Clin Investig. 2014;124(2):617–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  100. Syahputra RA, Harahap U, Dalimunthe A, Nasution MP, Satria D. The role of flavonoids as a cardioprotective strategy against doxorubicin-induced cardiotoxicity: a review. Molecules. 2022;27(4):1320.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  101. Surai PF. Silymarin as a natural antioxidant: an overview of the current evidence and perspectives. Antioxidants. 2015;4(1):204–47.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  102. Sheweita SA, Al-Shora S, Hassan M. Effects of benzo [a]pyrene as an environmental pollutant and two natural antioxidants on biomarkers of reproductive dysfunction in male rats. Environ Sci Pollut Res Int. 2016;23(17):17226–35.

    Article  CAS  PubMed  Google Scholar 

  103. Müzes G, Deák G, Láng I, Nékám K, Niederland V, Fehér J. Effect of silimarin (Legalon) therapy on the antioxidant defense mechanism and lipid peroxidation in alcoholic liver disease (double blind protocol). Orv Hetil. 1990;131(16):863–6.

    PubMed  Google Scholar 

  104. Ligeret H, Brault A, Vallerand D, Haddad Y, Haddad PS. Antioxidant and mitochondrial protective effects of silibinin in cold preservation-warm reperfusion liver injury. J Ethnopharmacol. 2008;115(3):507–14.

    Article  CAS  PubMed  Google Scholar 

  105. Yardım A, Kucukler S, Özdemir S, Çomaklı S, Caglayan C, Kandemir FM, Çelik H. Silymarin alleviates docetaxel-induced central and peripheral neurotoxicity by reducing oxidative stress, inflammation and apoptosis in rats. Gene. 2021;769:145239.

    Article  PubMed  Google Scholar 

  106. Ghigo A, Li M, Hirsch E. New signal transduction paradigms in anthracycline-induced cardiotoxicity. Biochimica et Biophysica Acta. 2016; 1863(7 Pt B):1916–25.

  107. Liu B, Bai QX, Chen XQ, Gao GX, Gu HT. Effect of curcumin on expression of survivin, Bcl-2 and Bax in human multiple myeloma cell line. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2007;15(4):762–6.

    CAS  PubMed  Google Scholar 

  108. Shi Y, Moon M, Dawood S, McManus B, Liu PP. Mechanisms and management of doxorubicin cardiotoxicity. Herz. 2011; 36(4):296–305.

  109. Wenningmann N, Knapp M, Ande A, Vaidya TR, Ait-Oudhia S. Insights into doxorubicin-induced cardiotoxicity: molecular mechanisms, preventive strategies, and early monitoring. Mol Pharmacol. 2019;96(2):219–32.

    Article  CAS  PubMed  Google Scholar 

  110. Shi J, Abdelwahid E, Wei L. Apoptosis in anthracycline cardiomyopathy. Curr Pediatr Rev. 2011;7(4):329–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  111. Fogli S, Nieri P, Breschi MC. The role of nitric oxide in anthracycline toxicity and prospects for pharmacologic prevention of cardiac damage. FASEB J. 2004;18(6):664–75.

    Article  CAS  PubMed  Google Scholar 

  112. Csuka O, Remenár E, Koronczay K, Doleschall Z, Németh G. Predictive value of p53, Bcl2 and bax in the radiotherapy of head and neck cancer. Pathol Oncol Res. 1997;3(3):204–10.

    Article  CAS  PubMed  Google Scholar 

  113. Haimovitz-Friedman A, Kolesnick RN, Fuks Z. Ceramide signaling in apoptosis. Br Med Bull. 1997;53(3):539–53.

    Article  CAS  PubMed  Google Scholar 

  114. Huerta S, Gao X, Dineen S, Kapur P, Saha D, Meyer J. Role of p53, Bax, p21, and DNA-PKcs in radiation sensitivity of HCT-116 cells and xenografts. Surgery. 2013;154(2):143–51.

    Article  PubMed  Google Scholar 

  115. Kim H, Yoo WS, Jung JH, Jeong BK, Woo SH, Kim JH, Kim SJ. Alpha-lipoic acid ameliorates radiation-induced lacrimal gland injury through NFAT5-dependent signaling. Int J Mol Sci. 2019;20(22):5691.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  116. Mortezaee K, Najafi M, Farhood B, Ahmadi A, Potes Y, Shabeeb D, Musa AE. Modulation of apoptosis by melatonin for improving cancer treatment efficiency: an updated review. Life Sci. 2019;228:228–41.

    Article  CAS  PubMed  Google Scholar 

  117. Moutabian H, Majdaeen M, Ghahramani-Asl R, Yadollahi M, Gharepapagh E, Ataei G, Falahatpour Z, Bagheri H, Farhood B. A systematic review of the therapeutic effects of resveratrol in combination with 5-fluorouracil during colorectal cancer treatment: with a special focus on the oxidant, apoptotic, and anti-inflammatory activities. Cancer Cell Int. 2022;22(1):142.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  118. Shoukry HS, Ammar HI, Rashed LA, Zikri MB, Shamaa AA, Abou Elfadl SG, Rub EA, Saravanan S, Dhingra S. Prophylactic supplementation of resveratrol is more effective than its therapeutic use against doxorubicin induced cardiotoxicity. PLoS ONE. 2017;12(7):e0181535.

    Article  PubMed Central  PubMed  Google Scholar 

  119. Wu R, Mei X, Wang J, Sun W, Xue T, Lin C, Xu D. Zn(ii)-Curcumin supplementation alleviates gut dysbiosis and zinc dyshomeostasis during doxorubicin-induced cardiotoxicity in rats. Food Funct. 2019;10(9):5587–604.

    Article  CAS  PubMed  Google Scholar 

  120. Yu W, Qin X, Zhang Y, Qiu P, Wang L, Zha W, Ren J. Curcumin suppresses doxorubicin-induced cardiomyocyte pyroptosis via a PI3K/Akt/mTOR-dependent manner. Cardiovasc Diagn Therapy. 2020;10(4):752–69.

    Article  Google Scholar 

  121. Hosseinzadeh L, Behravan J, Mosaffa F, Bahrami G, Bahrami AR, Karimi G. Effect of curcumin on doxorubicin-induced cytotoxicity in H9c2 cardiomyoblast cells. Iran J Basic Med Sci. 2011;14(1):49–56.

    CAS  Google Scholar 

  122. Benzer F, Kandemir FM, Ozkaraca M, Kucukler S, Caglayan C. Curcumin ameliorates doxorubicin-induced cardiotoxicity by abrogation of inflammation, apoptosis, oxidative DNA damage, and protein oxidation in rats. J Biochem Mol Toxicol. 2018;32(2):e22030.

    Article  Google Scholar 

  123. Liu MH, Lin XL, Guo DM, Zhang Y, Yuan C, Tan TP, Chen YD, Wu SJ, Ye ZF, He J. Resveratrol protects cardiomyocytes from doxorubicin-induced apoptosis through the AMPK/P53 pathway. Mol Med Rep. 2016;13(2):1281–6.

    Article  CAS  PubMed  Google Scholar 

  124. Zhang C, Feng Y, Qu S, Wei X, Zhu H, Luo Q, Liu M, Chen G, Xiao X. Resveratrol attenuates doxorubicin-induced cardiomyocyte apoptosis in mice through SIRT1-mediated deacetylation of p53. Cardiovasc Res. 2011;90(3):538–45.

    Article  CAS  PubMed  Google Scholar 

  125. Das J, Ghosh J, Manna P, Sil PC. Taurine suppresses doxorubicin-triggered oxidative stress and cardiac apoptosis in rat via up-regulation of PI3-K/Akt and inhibition of p53, p38-JNK. Biochem Pharmacol. 2011;81(7):891–909.

    Article  CAS  PubMed  Google Scholar 

  126. Sherif IO, Al-Gayyar MM. Antioxidant, anti-inflammatory and hepatoprotective effects of silymarin on hepatic dysfunction induced by sodium nitrite. Eur Cytokine Netw. 2013;24(3):114–21.

    Article  CAS  PubMed  Google Scholar 

  127. Song Z, Song M, Lee DY, Liu Y, Deaciuc IV, McClain CJ. Silymarin prevents palmitate-induced lipotoxicity in HepG2 cells: involvement of maintenance of Akt kinase activation. Basic Clin Pharmacol Toxicol. 2007;101(4):262–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  128. Kandemir FM, Kucukler S, Caglayan C, Gur C, Batil AA, Gülçin İ. Therapeutic effects of silymarin and naringin on methotrexate-induced nephrotoxicity in rats: Biochemical evaluation of anti-inflammatory, antiapoptotic, and antiautophagic properties. J Food Biochem. 2017;41(5):e12398.

    Article  Google Scholar 

  129. Aghazadeh S, Amini R, Yazdanparast R, Ghaffari SH. Anti-apoptotic and anti-inflammatory effects of Silybum marianum in treatment of experimental steatohepatitis. Exp Toxicol Pathol. 2011;63(6):569–74.

    Article  PubMed  Google Scholar 

  130. Katiyar SK, Roy AM, Baliga MS. Silymarin induces apoptosis primarily through a p53-dependent pathway involving Bcl-2/Bax, cytochrome c release, and caspase activation. Mol Cancer Ther. 2005;4(2):207–16.

    Article  CAS  PubMed  Google Scholar 

  131. Manna SK, Mukhopadhyay A, Van NT, Aggarwal BB. Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis. J Immunol. 1999;163(12):6800–9.

    Article  CAS  PubMed  Google Scholar 

  132. Vyas D, Laput G, Vyas AK. Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis. Onco Targets Ther. 2014;7:1015–23.

    Article  PubMed Central  PubMed  Google Scholar 

  133. Farhood B, Mortezaee K, Goradel NH, Khanlarkhani N, Salehi E, Nashtaei MS, Najafi M, Sahebkar A. Curcumin as an anti-inflammatory agent: Implications to radiotherapy and chemotherapy. J Cell Physiol. 2019;234(5):5728–40.

    Article  CAS  PubMed  Google Scholar 

  134. Peng J, Fumoto S, Miyamoto H, Chen Y, Kuroda N, Nishida K. One-step formation of lipid-polyacrylic acid-calcium carbonate nanoparticles for co-delivery of doxorubicin and curcumin. J Drug Target. 2017;25(8):704–14.

    Article  CAS  PubMed  Google Scholar 

  135. Wang N, Zhang Y, Liu H, Wang A, Ren T, Gou J, Zhang Y, Yin T, He H, Tang X. Toxicity reduction and efficacy promotion of doxorubicin in the treatment of breast tumors assisted by enhanced oral absorption of curcumin-loaded lipid-polyester mixed nanoparticles. Mol Pharm. 2020;17(12):4533–47.

    Article  CAS  PubMed  Google Scholar 

  136. Trappoliere M, Caligiuri A, Schmid M, Bertolani C, Failli P, Vizzutti F, Novo E, di Manzano C, Marra F, Loguercio C, et al. Silybin, a component of sylimarin, exerts anti-inflammatory and anti-fibrogenic effects on human hepatic stellate cells. J Hepatol. 2009;50(6):1102–11.

    Article  CAS  PubMed  Google Scholar 

  137. Gharagozloo M, Velardi E, Bruscoli S, Agostini M, Di Sante M, Donato V, Amirghofran Z, Riccardi C. Silymarin suppress CD4+ T cell activation and proliferation: effects on NF-kappaB activity and IL-2 production. Pharmacol Res. 2010;61(5):405–9.

    Article  CAS  PubMed  Google Scholar 

  138. Li CC, Hsiang CY, Wu SL, Ho TY. Identification of novel mechanisms of silymarin on the carbon tetrachloride-induced liver fibrosis in mice by nuclear factor-κB bioluminescent imaging-guided transcriptomic analysis. Food Chem Toxicol. 2012;50(5):1568–75.

    Article  CAS  PubMed  Google Scholar 

  139. Jin Y, Zhao X, Zhang H, Li Q, Lu G, Zhao X. Modulatory effect of silymarin on pulmonary vascular dysfunction through HIF-1α-iNOS following rat lung ischemia-reperfusion injury. Exp Ther Med. 2016;12(2):1135–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  140. Younis NN, Shaheen MA, Mahmoud MF. Silymarin preconditioning protected insulin resistant rats from liver ischemia-reperfusion injury: role of endogenous H2S. J Surg Res. 2016;204(2):398–409.

    Article  CAS  PubMed  Google Scholar 

  141. Arafa Keshk W, Zahran SM, Katary MA, Abd-Elaziz AD. Modulatory effect of silymarin on nuclear factor-erythroid-2-related factor 2 regulated redox status, nuclear factor-κB mediated inflammation and apoptosis in experimental gastric ulcer. Chem Biol Interact. 2017;273:266–72.

    Article  CAS  PubMed  Google Scholar 

  142. Akbari-Kordkheyli V, Abbaszadeh-Goudarzi K, Nejati-Laskokalayeh M, Zarpou S, Khonakdar-Tarsi A. The protective effects of silymarin on ischemia-reperfusion injuries: a mechanistic review. Iran J Basic Med Sci. 2019;22(9):968–76.

    PubMed Central  PubMed  Google Scholar 

  143. Ramasamy K, Agarwal R. Multitargeted therapy of cancer by silymarin. Cancer Lett. 2008;269(2):352–62.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  144. Khazaei R, Seidavi A, Bouyeh M. A review on the mechanisms of the effect of silymarin in milk thistle (Silybum marianum) on some laboratory animals. Vet Med Sci. 2022;8(1):289–301.

    Article  CAS  PubMed  Google Scholar 

  145. Soleimani V, Delghandi PS, Moallem SA, Karimi G. Safety and toxicity of silymarin, the major constituent of milk thistle extract: an updated review. Phytother Res. 2019;33(6):1627–38.

    Article  CAS  PubMed  Google Scholar 

  146. Bijak M. Silybin, a major bioactive component of milk thistle (Silybum marianum L. Gaernt.)-chemistry, bioavailability, and metabolism. Molecules. 2017; 22(11):1942.

  147. Gillessen A, Schmidt HH. Silymarin as supportive treatment in liver diseases: a narrative review. Adv Ther. 2020;37(4):1279–301.

    Article  PubMed Central  PubMed  Google Scholar 

  148. Amawi H, Hussein NA, Karthikeyan C, Manivannan E, Wisner A, Williams FE, Samuel T, Trivedi P, Ashby CR Jr, Tiwari AK. HM015k, a novel silybin derivative, multi-targets metastatic ovarian cancer cells and is safe in zebrafish toxicity Studies. Front Pharmacol. 2017;8:498.

    Article  PubMed Central  PubMed  Google Scholar 

  149. Kosina P, Kren V, Gebhardt R, Grambal F, Ulrichová J, Walterová D. Antioxidant properties of silybin glycosides. Phytother Res. 2002;16(Suppl 1):S33-39.

    Article  CAS  PubMed  Google Scholar 

  150. Dobiasová S, Řehořová K, Kučerová D, Biedermann D, Káňová K, Petrásková L, Koucká K, Václavíková R, Valentová K, Ruml T, et al. Multidrug resistance modulation activity of silybin derivatives and their anti-inflammatory potential. Antioxidants. 2020;9(5):455.

    Article  PubMed Central  PubMed  Google Scholar 

  151. Kubisch J, Sedmera P, Halada P. Chemoenzymatic preparation of oligoglycosides of silybin, the flavonolignan from Silybum marianum. Heterocycles. 2001;54(2):901–15.

    Article  CAS  Google Scholar 

  152. Skottová N, Švagera Z, Vecera R, Urbánek K, Jegorov A, Simánek V. Pharmacokinetic study of iodine-labeled silibinins in rat. Pharmacol Res. 2001; 44(3):247–53.

  153. Plísková M, Vondrácek J, Kren V, Gazák R, Sedmera P, Walterová D, Psotová J, Simánek V, Machala M. Effects of silymarin flavonolignans and synthetic silybin derivatives on estrogen and aryl hydrocarbon receptor activation. Toxicology. 2005;215(1–2):80–9.

    Article  PubMed  Google Scholar 

  154. Roubalová L, Dinkova-Kostova AT, Biedermann D, Křen V, Ulrichová J, Vrba J. Flavonolignan 2,3-dehydrosilydianin activates Nrf2 and upregulates NAD(P)H:quinone oxidoreductase 1 in Hepa1c1c7 cells. Fitoterapia. 2017;119:115–20.

    Article  PubMed Central  PubMed  Google Scholar 

  155. Pyszková M, Biler M, Biedermann D, Valentová K, Kuzma M, Vrba J, Ulrichová J, Sokolová R, Mojović M, Popović-Bijelić A, et al. Flavonolignan 2,3-dehydroderivatives: preparation, antiradical and cytoprotective activity. Free Radical Biol Med. 2016;90:114–25.

    Article  Google Scholar 

  156. Yang LX, Huang KX, Li HB, Gong JX, Wang F, Feng YB, Tao QF, Wu YH, Li XK, Wu XM, et al. Design, synthesis, and examination of neuron protective properties of alkenylated and amidated dehydro-silybin derivatives. J Med Chem. 2009;52(23):7732–52.

    Article  CAS  PubMed  Google Scholar 

  157. Rajnochová Svobodová A, Gabrielová E, Ulrichová J, Zálešák B, Biedermann D, Vostálová J. A pilot study of the UVA-photoprotective potential of dehydrosilybin, isosilybin, silychristin, and silydianin on human dermal fibroblasts. Arch Dermatol Res. 2019;311(6):477–90.

    Article  PubMed  Google Scholar 

  158. Drouet S, Doussot J, Garros L, Mathiron D, Bassard S, Favre-Réguillon A, Molinié R, Lainé É, Hano C. Selective synthesis of 3-O-palmitoyl-silybin, a new-to-nature flavonolignan with increased protective action against oxidative damages in lipophilic media. Molecules. 2018;23(10):2594.

    Article  PubMed Central  PubMed  Google Scholar 

  159. Di Costanzo A, Angelico R. Formulation strategies for enhancing the bioavailability of silymarin: the state of the art. Molecules. 2019;24(11):2155.

    Article  PubMed Central  PubMed  Google Scholar 

  160. He J, Hou S, Lu W, Zhu L, Feng J. Preparation, pharmacokinetics and body distribution of silymarin-loaded solid lipid nanoparticles after oral administration. J Biomed Nanotechnol. 2007;3(2):195–202.

    Article  CAS  Google Scholar 

  161. Yousaf AM, Malik UR, Shahzad Y, Mahmood T, Hussain T. Silymarin-laden PVP-PEG polymeric composite for enhanced aqueous solubility and dissolution rate: preparation and in vitro characterization. J Pharmaceut Anal. 2019;9(1):34–9.

    Google Scholar 

  162. Ibrahim AH, Rosqvist E, Smått JH, Ibrahim HM, Ismael HR, Afouna MI, Samy AM, Rosenholm JM. Formulation and optimization of lyophilized nanosuspension tablets to improve the physicochemical properties and provide immediate release of silymarin. Int J Pharm. 2019;563:217–27.

    Article  CAS  PubMed  Google Scholar 

  163. Yang G, Zhao Y, Feng N, Zhang Y, Liu Y, Dang B. Improved dissolution and bioavailability of silymarin delivered by a solid dispersion prepared using supercritical fluids. Asian J Pharm Sci. 2015;10(3):194–202.

    Article  Google Scholar 

  164. Nasr SS, Nasra MMA, Hazzah HA, Abdallah OY. Mesoporous silica nanoparticles, a safe option for silymarin delivery: preparation, characterization, and in vivo evaluation. Drug Deliv Transl Res. 2019;9(5):968–79.

    Article  CAS  PubMed  Google Scholar 

  165. Nagi A, Iqbal B, Kumar S, Sharma S, Ali J, Baboota S. Quality by design based silymarin nanoemulsion for enhancement of oral bioavailability. J Drug Del Sci Technol. 2017;40:35–44.

    Article  CAS  Google Scholar 

  166. Adhikari M, Arora R. Nano-silymarin provides protection against γ-radiation-induced oxidative stress in cultured human embryonic kidney cells. Mutat Res Genet Toxicol Environ Mutagen. 2015;792:1–11.

    Article  CAS  PubMed  Google Scholar 

  167. Azadpour M, Farajollahi MM, Dariushnejad H, Varzi AM, Varezardi A, Barati M. Effects of synthetic silymarin-PLGA nanoparticles on M2 polarization and inflammatory cytokines in LPS-treated murine peritoneal macrophages. Iran J Basic Med Sci. 2021;24(10):1446–54.

    PubMed Central  PubMed  Google Scholar 

  168. Mombeini M, Saki G, Khorsandi L, Bavarsad N. Effects of silymarin-loaded nanoparticles on HT-29 human colon cancer cells. Medicina. 2018;54(1):1.

    Article  PubMed Central  PubMed  Google Scholar 

  169. El-Far M, Salah N, Essam A, Abd El-Azim AO, El-Sherbiny IM. Silymarin nanoformulation as potential anticancer agent in experimental Ehrlich ascites carcinoma-bearing animals. Nanomedicine. 2018;13(15):1858–65.

    Article  Google Scholar 

  170. Hosseini S, Rezaei S, Moghaddam MRN, Elyasi S, Karimi G. Evaluation of oral nano-silymarin formulation efficacy on prevention of radiotherapy induced mucositis: a randomized, double-blinded, placebo-controlled clinical trial. PharmaNutrition. 2021;15:100253.

    Article  CAS  Google Scholar 

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MS, MMK, and ATJ gave the idea and drafted the manuscript. SKO, ZA, FA, ZHJ, and AAR–C performed the literature search and drafted figures. BF edited the manuscript and supervised the whole study. All authors read and approved the manuscript.

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Singh, M., Kadhim, M.M., Turki Jalil, A. et al. A systematic review of the protective effects of silymarin/silibinin against doxorubicin-induced cardiotoxicity. Cancer Cell Int 23, 88 (2023). https://doi.org/10.1186/s12935-023-02936-4

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