Molecular mechanisms involved in therapeutic effects of natural compounds against cisplatin-induced cardiotoxicity: a review.

Cisplatin is a widely used chemotherapeutic agent for the treatment of various cancers. However, the clinical use of cisplatin is limited by its cardiotoxic side effects. The primary mechanisms implicated in this cardiotoxicity include mitochondrial dysfunction, oxidative stress, inflammation, and apoptotic. Numerous natural compounds (NCs) have been introduced as promising protective factors against cisplatin-mediated cardiac damage. The current review summarized the potential of various NCs as cardioprotective agents at the molecular levels. These compounds exhibited potent antioxidant and anti-inflammatory effects by interaction with the PI3K/AKT, AMPK, Nrf2, NF-κB, and NLRP3/caspase-1/GSDMD pathways. Generally, the modulation of these signaling pathways by NCs represents a promising strategy for improving the therapeutic index of cisplatin by reducing its cardiac side effects.

Melatonin attenuates liver injury in arsenic-treated rats: The potential role of the Nrf2/HO-1, apoptosis, and miR-34a/Sirt1/autophagy pathways.

Arsenic is a toxic metalloid found in the environment in different organic and inorganic forms. Molecular mechanisms implicated in arsenic hepatotoxicity are complex but include oxidative stress, apoptosis, and autophagy. The current study focused on the potential protective capacity of melatonin against arsenic-induced hepatotoxicity. Thirty-six male Wistar rats were allocated into control, arsenic (15 mg/kg; orally), arsenic (15 mg/kg) plus melatonin (10, 20, and 30 mg/kg; intraperitoneally), and melatonin alone (30 mg/kg) groups for 28 days. After the treatment period, the serum sample was separated to measure liver enzymes (AST and ALT). The liver tissue was removed and then histological alterations, oxidative stress markers, antioxidant capacity, the levels of Nrf2 and HO-1, apoptosis (Bcl-2, survivin, Mcl1, Bax, and caspase-3), and autophagy (Sirt1, Beclin-1, and LC3 II/I ratio) proteins, as well as the expression level of miR-34a, were evaluated on this tissue. Arsenic exposure resulted in the enhancement of serum AST, ALT, and substantial histological damage in the liver. Increased levels of malondialdehyde, a lipid peroxidation marker, and decreased levels of physiological antioxidants including glutathione, superoxide dismutase, and catalase were indicators of arsenic-induced oxidative damage. The levels of Nrf2, HO-1, and antiapoptotic proteins diminished, while proapoptotic and autophagy proteins were elevated in the arsenic group concomitant with a low level of hepatic miR-34a. The co-treatment of melatonin and arsenic reversed the changes caused by arsenic. These findings showed that melatonin reduced the hepatic damage induced by arsenic due to its antioxidant and antiapoptotic properties as well as its regulatory effect on the miR-34a/Sirt1/autophagy pathway.

Cardioprotective effect of naringin against the ischemia/reperfusion injury of aged rats.

Aging is known as a main risk factor in the development of cardiovascular diseases. Naringin (NRG) is a flavonoid compound derived from citrus fruits. It possesses a wide spectrum of pharmacological properties, including antioxidant anti-inflammatory, and cardioprotective. This investigation aimed to assess the cardioprotective effect of NRG against the ischemia/reperfusion (I/R) injury in aged rats. In this study, D-galactose (D-GAL) at the dose of 150 mg/kg/day for 8 weeks was used to induce aging in rats. Rats were orally gavaged with NRG (40 or 100 mg/kg/day), in co-treatment with D-GAL, for 8 weeks. The Langendorff isolated heart was used to evaluate the effect of NRG on I/R injury in aged rats. NRG treatment diminished myocardial hypertrophy and maximum contracture level in aged animals. During the pre-ischemic phase, reduced heart rate was normalized by NRG. The effects of D-GAL on the left ventricular end diastolic pressure (LVDP), the rate pressure product (RPP), and the minimum and maximum rate of left ventricular pressure (±dp/dt) improved by NRG treatment in the perfusion period. NRG also enhanced post-ischemic recovery of cardiac functional parameters (± dp/dt, and RPP) in isolated hearts. An increase in serum levels of the lactate dehydrogenase (LDH), the creatine kinase-MB (CK-MB), and the tumor necrosis factor-alpha (TNF-α) were reversed by NRG in aged rats. It also normalized the D-GAL-decreased the superoxide dismutase (SOD) activity in the heart tissue. NRG treatment alleviated cardiac injury in aged hearts under conditions of I/R. NRG may improve aging-induced cardiac dysfunction through anti-oxidative and anti-inflammatory mechanisms.

Molecular mechanisms involved in doxorubicin-induced cardiotoxicity: A bibliometrics analysis by VOSviewer.

Doxorubicin is a potent chemotherapeutic agent that can cause cardiotoxicity. Many documents (more than 14,000) have been published in the area of doxorubicin-induced cardiotoxicity (DIC) since 1970. A comprehensive bibliographic analysis of author keywords was used to describe better and understand the molecular mechanisms involved in DIC. The objective was to consider the state of the author keywords of research on the molecular mechanisms involved in DIC based on a bibliometrics study of articles published over the past fifty years. A bibliometrics analysis was conducted using VOSviewer with data collected from the Web of Science Core Collection database of over 14,000 documents (from 1970 to July 19, 2023). Using scientific publications retrieved about DIC, author keywords were assessed at the scientific field level. The current study showed that the annual number of DIC-related publications has increased over the past 50 years. The Journal of Clinical Oncology is the leading journal in this field. The top cited DIC document was published in 2004. The top keywords with high frequency were "doxorubicin," "cardiotoxicity," and "adriamycin." According to the results of this study, the most common mechanisms involved in DIC were as follows oxidative stress, apoptosis, inflammation, autophagy, mitophagy, endoplasmic reticulum stress, pyroptosis, and ferroptosis. The highest occurrences of regulators-related author keywords were "AKT," "Sirt1," and "AMPK." Based on the findings, oxidative stress, apoptosis, inflammation, autophagy, mitophagy, endoplasmic reticulum stress, pyroptosis, and ferroptosis were hot research mechanisms of DIC from 1970 to July 19, 2023.

The Role of mTOR in Doxorubicin-Altered Cardiac Metabolism: A Promising Therapeutic Target of Natural Compounds.

Doxorubicin (DOX) is commonly used for the treatment of various types of cancer, however can cause serious side effects, including cardiotoxicity. The mechanisms involved in DOX-induced cardiac damage are complex and not yet fully understood. One mechanism is the disruption of cardiac metabolism, which can impair cardiac function. The mammalian target of rapamycin (mTOR) is a key regulator of cardiac energy metabolism, and dysregulation of mTOR signaling has been implicated in DOX-induced cardiac dysfunction. Natural compounds (NCs) have been shown to improve cardiac function in vivo and in vitro models of DOX-induced cardiotoxicity. This review article explores the protective effects of NCs against DOX-induced cardiac injury, with a focus on their regulation of mTOR signaling pathways. Generally, the modulation of mTOR signaling by NCs represents a promising strategy for decreasing the cardiotoxic effects of DOX.

Melatonin ameliorates arsenic-induced cardiotoxicity through the regulation of the Sirt1/Nrf2 pathway in rats.

Chronic arsenic (As) exposure, mainly as a result of drinking contaminated water, is associated with cardiovascular diseases. Mitochondrial dysfunction, oxidative stress, inflammation, apoptosis, and autophagy have been suggested as the molecular etiology of As cardiotoxicity. Melatonin (Mel) is a powerful antioxidant. Mel improves diabetic cardiomyopathy, cardiac remodeling, and heart failure. Following pre-treatment with Mel (10, 20, or 30 mg/kg/day i.p.), rats were orally gavaged with As (15 mg/kg/day) for 28 days. Electrocardiographic findings showed that Mel decreased the As-mediated QT interval prolongation. The effects of As on cardiac levels of glutathione (GSH) and malondialdehyde (MDA) were reversed by Mel pretreatment. Mel also modulated the Sirt1 and Nrf2 expressions promoted by As. Mel down-regulated autophagy markers such as Beclin-1 expression and the LC3-II/I ratio. Moreover, the cardiac expression of cleaved-caspase-3 and Bax/Bcl-2 ratio was decreased by Mel pretreatment. Reduced expression of miR-34a and miR-144 by As were reversed by Mel. The histopathological changes of cardiac injury associated with As exposure was moderated by Mel. Mel may improve As-induced cardiac dysfunction through anti-oxidative, anti-apoptotic, and anti-autophagic mechanisms.

Mechanisms of Arsenic Exposure-Induced Hypertension and Atherosclerosis: an Updated Overview.

Arsenic is an abundant element in the earth's crust. In the environment and within the human body, this toxic element can be found in both organic and inorganic forms. Chronic exposure to arsenic can predispose humans to cardiovascular diseases including hypertension, stroke, atherosclerosis, and blackfoot disease. Oxidative damage induced by reactive oxygen species is a major player in arsenic-induced toxicity, and it can affect genes expression, inflammatory responses, and/or nitric oxide homeostasis. Exposure to arsenic in drinking water can lead to vascular endothelial dysfunction which is reflected by an imbalance between vascular relaxation and contraction. Arsenic has been shown to inactivate endothelial nitric oxide synthase leading to a reduction of the generation and bioavailability of nitric oxide. Ultimately, these effects increase the risk of vascular diseases such as hypertension and atherosclerosis. The present article reviews how arsenic exposure contributes to hypertension and atherosclerosis development.

MicroRNAs target the PI3K/Akt/p53 and the Sirt1/Nrf2 signaling pathways in doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is used as a chemotherapeutic agent in the treatment of solid tumors. Irreversible cardiotoxicity is the major limitation in the clinical use of DOX. Several microRNAs (miRNAs) with diversified functions are identified that participate in exacerbating or suppressing DOX-induced cardiac damage. The miRNAs are small noncoding regulatory RNAs that modify the expression of the native genes. Studies have demonstrated that miRNAs by modifying the expression of proteins such as PTEN, Akt, and survivin can affect DOX-induced cardiac apoptosis. Moreover, miRNAs can modulate cardiac oxidative stress in DOX treatment through the posttranscriptional regulation of Sirt1, p66shc, and Nrf2 expressions. This manuscript has reviewed the regulation of the PI3K/Akt/p53 and the Sirt1/Nrf2 pathways by miRNAs in DOX-induced cardiotoxicity.

Probabilistic risk assessment of exposure to multiple metals and pesticides through consumption of fruit juice samples collected from Iranian market.

The current study assessed the risk posed to Iranian consumers by oral exposure to a mixture of 20 pesticides and six metals in 96 fruit juice (FJ) samples (3 batches × 4 brands × 8 types of FJs) collected from Iran market. Concentrations of metals and pesticides in FJs were quantified by inductively coupled plasma-optical emission spectrometry (ICP-OES) and chromatography-mass spectrometry (GC-MS), respectively. The mean concentration of all pesticides was below the maximum residue limits (MRLs) set by the European Union (EU). The calculated target hazard quotients (THQs) and total hazard index (HI) were <1.0 for all pesticides residue, indicating no risk. For the carcinogenic metals (As, Ni, and Pb), estimated incremental lifetime cancer risks (ILCRs) at the 50th and 95th centiles were respectively 4.25 × 10-5 and 5.30 × 10-5 (for As), 2.85 × 10-5 and 3.71 × 10-5 (for Ni), and 2.84 × 10-8, and 3.97 × 10-8 (for Pb), indicating no risk. At the 50th and 95th centiles, HI for non-carcinogenic metals (Cd, Hg, and Cr) was <1.0, indicating no risk. Based on sensitivity analyses of the input variables, the concentration of metals and pesticides, and the FJs ingestion rate had significant influential impacts on the calculated THQ and HI.

Sorting nexins as a promising therapeutic target for cardiovascular disorders: An updated overview.

Sorting nexins (SNXs) are involved in sorting the protein cargo within the endolysosomal system. Recently, several studies have shown the role of SNXs in cardiovascular pathology. SNXs exert both physiologic and pathologic functions in the cardiovascular system by regulating protein sorting and trafficking, maintaining protein homeostasis, and participating in multiple signaling pathways. SNX deficiency results in blood pressure response to dopamine 5 receptor [D5R] stimulation. SNX knockout protected against atherosclerosis lesions by suppressing foam cell formation. Moreover, SNXs can act as endogenous anti-arrhythmic agents via maintenance of calcium homeostasis. Overexpression SNXs also can reduce cardiac fibrosis in atrial fibrillation. The SNX-STAT3 interaction in cardiac cells promoted heart failure. SNXs may have the potential to act as a pharmacological target against specific cardiovascular diseases.

The effects of ginger and its constituents in the prevention of metabolic syndrome: A review.

Metabolic syndrome is a multifactorial disorder characterized by hyperglycemia, hyperlipidemia, obesity, and hypertension risk factors. Moreover, metabolic syndrome is the most ordinary risk factor for cardiovascular disease (CVD). Numerous chemical drugs are being synthesized to heal metabolic risk factors. Still, due to their abundant side effects, herbal medicines have a vital role in the treatment of these abnormalities. Ginger (Zingiber officinale Roscoe, Zingiberaceae) plant has been traditionally used in medicine to treat disorders, including CVD. The unique ginger properties are attributed to the presence of [6]-gingerol, [8]-gingerol, [10]-gingerol, and [6]-shogaol, which through different mechanisms can be beneficial in metabolic syndrome. Ginger has a beneficial role in metabolic syndrome treatment due to its hypotensive, anti-obesity, hypoglycemic, and hypolipidemic effects. It can significantly reduce atherosclerotic lesion areas, VLDL and LDL cholesterol levels, and elevate adenosine deaminase activity in platelet and lymphocytes. Also, it promotes ATP/ADP hydrolysis. In the current article review, the critical properties of ginger and its constituents' effects on the metabolic syndrome with a special focus on different molecular and cellular mechanisms have been discussed. This article also suggests that ginger may be introduced as a therapeutic or preventive agent against metabolic syndrome after randomized clinical trials.

The therapeutic effects of berberine against different diseases: A review on the involvement of the endoplasmic reticulum stress.

Various factors interfere with the endoplasmic reticulum (ER) function, which is involved in protein folding and calcium homeostasis. ER dysfunction referred to as ER stress triggers cell death by apoptosis and inflammation. Berberine (BBR) is an alkaloid extracted from the family Berberidacea. It has shown multiple pharmacological activities, including anti-inflammatory, antioxidative, anti-apoptotic, antiproliferative, and antihypertensive. It has been reported that BBR can decrease apoptosis and inflammation following different pathological conditions, which might be mediated by targeting ER stress pathways. In this manuscript, we reviewed the protective potential of BBR against several diseases, such as metabolic disorders, cancer, intestinal diseases, cardiovascular, liver, kidney, and central nervous system diseases, in both in vivo and in vitro studies.

Protective effect of berberine against LPS-induced injury in the intestine: a review.

Sepsis is a systemic inflammatory condition caused by an unbalanced immunological response to infection, which affects numerous organs, including the intestines. Lipopolysaccharide (LPS; also known as endotoxin), a substance found in Gram-negative bacteria, plays a major role in sepsis and is mostly responsible for the disease's morbidity and mortality. Berberine is an isoquinoline alkaloid found in a variety of plant species that has anti-inflammatory properties. For many years, berberine has been used to treat intestinal inflammation and infection. Berberine has been reported to reduce LPS-induced intestinal damage. The potential pathways through which berberine protects against LPS-induced intestinal damage by inhibiting NF-κB, suppressing MAPK, modulating ApoM/S1P pathway, inhibiting COX-2, modulating Wnt/Beta-Catenin signaling pathway, and/or increasing ZIP14 expression are reviewed.Abbreviations: LPS, lipopolysaccharide; TLR, Toll-like receptor; MD-2, myeloid differentiation factor 2; CD14, cluster of differentiation 14; LBP, lipopolysaccharide-binding protein; MYD88, myeloid differentiation primary response 88; NF-κB, nuclear factor kappa light-chain enhancer of activated B cells; MAPK, mitogen-activated protein kinase; IL, interleukin; TNFα, tumor necrosis factor-alpha; Caco-2, cyanocobalamin uptake by human colon adenocarcinoma cell line; MLCK, myosin light-chain kinase; TJ, tight junction; IκBα, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; IBS, irritable bowel syndrome; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase (JNK; GVB, gut-vascular barrier; ApoM, apolipoprotein M; S1P, sphingosine-1-phosphate; VE-cadherin, vascular endothelial cadherin; AJ, adherens junction; PV1, plasmalemma vesicle-associated protein-1; HDL, high-density lipoprotein; Wnt, wingless-related integration site; Fzd, 7-span transmembrane protein Frizzled; LRP, low-density lipoprotein receptor-related protein; TEER, transendothelial/transepithelial electrical resistance; COX-2, cyclooxygenase-2; iNOS, inducible nitric oxide synthase; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor-binding protein; ZIP, Zrt-Irt-like protein; PPAR, peroxisome proliferator-activated receptors; p-PPAR, phosphorylated-peroxisome proliferator-activated receptors; ATF, activating transcription factors; SOD, superoxide dismutase; GSH-Px, glutathione peroxidase; SARA, subacute ruminal acidosis; IPEC-J2, porcine intestinal epithelial cells; ALI, acute lung injury; ARDS, acute respiratory distress syndrome.

The protective effect of chemical and natural compounds against vincristine-induced peripheral neuropathy (VIPN).

Vincristine, an alkaloid extracted from Catharanthus rosea, is a class of chemotherapy drugs that act by altering the function of the microtubules and by inhibiting mitosis. Despite its widespread application, a major adverse effect of vincristine that limits treatment duration is the occurrence of peripheral neuropathy (PN). PN presents with several symptoms including numbness, painful sensation, tingling, and muscle weakness. Vincristine-induced PN involves impaired calcium homeostasis, an increase of reactive oxygen species (ROS), and the upregulation of tumor necrosis factor-alpha (TNF-α), and interleukin 1 beta (IL-1ß) expression. Several potential approaches to attenuate the vincristine-induced PN including the concomitant administration of chemicals with vincristine have been reported. These chemicals have a variety of pharmaceutical properties including anti-inflammation, antioxidant, and inhibition of calcium channels and calcineurin signaling pathways and increased expression of nerve growth factor (NGF). This review summarized several of these compounds and the mechanisms of action that could lead to effective options in improving vincristine-induced peripheral neuropathy (VIPN).

Targeting PPARs Signaling Pathways in Cardiotoxicity by Natural Compounds.

Cardiotoxicity can be a complication of both drugs and a variety of other chemicals that affects morbidity, quality of life, and even mortality. The accumulation of lipids and inflammation have been implicated in the development of cardiotoxicity. The peroxisome proliferator-activated receptors (PPARs), a family of transcription factors, have a role in controlling the cardiac expression of genes involved in lipid and glucose metabolism and the inflammatory response. The different PPAR isoforms, PPARα, PPARγ, and PPARß/δ, have a role in multiple functions in cardiac tissue. The protective nature of several naturally occurring chemicals (NCs) against cardiotoxicity by targeting PPARα and PPARγ has been reported. The literature related to the ability of several NCs to modulate cardiotoxicity through targeting the AMP-activated protein kinase (AMPK)/the PPARγ coactivator-1 alpha (PGC-1α)/PPARα, the PPARα/the nuclear factor-kappa B (NF-κB), and the PPARγ/the nuclear factor-erythroid 2 related factors 2 (Nrf2)/the heme oxygenase-1 (HO-1)/NF-κB signaling pathways are reviewed.

The modulation of SIRT1 and SIRT3 by natural compounds as a therapeutic target in doxorubicin-induced cardiotoxicity: A review.

Doxorubicin (DOX) is a potent antitumor agent with a broad spectrum of activity; however, irreversible cardiotoxicity resulting from DOX treatment is a major issue that limits its therapeutic use. Sirtuins (SIRTs) play an essential role in several physiological and pathological processes including oxidative stress, apoptosis, and inflammation. It has been reported that SIRT1 and SIRT3 can act as a protective molecular against DOX-induced myocardial injury through targeting numerous signaling pathways. Several natural compounds (NCs), such as resveratrol, sesamin, and berberine, with antioxidative, anti-inflammation, and antiapoptotic effects were evaluated for their potential to suppress the cardiotoxicity induced by DOX via targeting SIRT1 and SIRT3. Numerous NCs exerted their therapeutic effects on DOX-mediated cardiac damage via targeting different signaling pathways, including SIRT1/LKB1/AMPK, SIRT1/PGC-1α, SIRT1/NLRP3, and SIRT3/FoxO. SIRT3 also ameliorates cardiotoxicity by enhancing mitochondrial fusion.

Natural and chemical compounds as protective agents against cardiac lipotoxicity.

Cardiac lipotoxicity results from the deleterious effects of excess lipid deposition in cardiomyocytes. Lipotoxic cardiomyopathy involves cardiac lipid overload leading to changes in myocardial structure and function. Cardiac dysfunction has been associated with cardiac lipotoxicity through abnormal lipid metabolism. Lipid accumulation, especially saturated free fatty acids (SFFAs), in cardiac cells can cause cardiomyocyte distress and subsequent myocardial contractile dysfunction. Reducing the excess FAs supply or promoting FA storage is beneficial for cardiac function, especially under a lipotoxic condition. The protective effects of several compounds against lipotoxicity progression in the heart have been investigated. A variety of mechanisms has been suggested to prevent or treat cardiac lipotoxicity, including improvement of calcium homeostasis, lipid metabolism, and mitochondrial dysfunction. Known targets and signaling pathways involving a select group of chemicals that interfere with cardiac lipotoxicity pathogenesis are reviewed.

The role of ferroptosis in organ toxicity.

Ferroptosis, an iron-dependent form of programmed cell death, is characterized by iron overload, increased reactive oxygen species (ROS) generation, and depletion of glutathione (GSH) and lipid peroxidation. Lipophilic antioxidants and iron chelators can prevent ferroptosis. GSH-dependent glutathione peroxidase 4 (GPX4) prevents lipid ROS accumulation. Ferroptosis is thought to be initiated through GPX4 inactivation. Moreover, mitochondrial iron overload derived from the degradation of ferritin is involved in increasing ROS generation. Ferroptosis has been suggested to explain the mechanism of action of organ toxicity induced by several drugs and chemicals. Inhibition of ferroptosis may provide novel therapeutic opportunities for treatment and even prevention of such organ toxicities.

Inflammation suppression in doxorubicin-induced cardiotoxicity: natural compounds as therapeutic options.

Doxorubicin (DOX) is a potent chemotherapeutic agent; however, the accompanying cardiotoxicity is a significant complication of the usefulness of treatment with DOX. Multiple mechanisms have been suggested for this often fatal side effect, one of which is inflammation. Several pathways with different targets have been reported to result in DOX-induced heart inflammation. Some natural occurring compounds (NCs) have been reported to interact with the DOX-induced cardiotoxicity through targeting one or more of several pathways, including the Nrf2/NF-kB, TLR-4/NF-kB, MAPK/NF-kB, and NLRP3 inflammasome pathways. This article reviews several of these pathways and the potential protective effect of some NCs against the cardiac inflammation induced by DOX.

Possible protective effect of resolvin D1 on inflammation in atrial fibrillation: involvement of ER stress mediated the NLRP3 inflammasome pathway.

Atrial fibrillation (AF) is the most common type of cardiac rhythm disturbance. At the cellular level, excessive ROS generation during AF is associated with ER stress, which induces an inflammatory response by activating the unfolded protein response (UPR) pathway and the nuclear factor-kappa B (NF-kB) signaling pathway. Activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome has been linked to the pathogenesis of AF through NF-kB activation and inflammatory cytokine secretion. It has been shown that NLRP3 inflammasome activation by endoplasmic reticulum (ER) stress is dependent on NF-kB activation. The anti-inflammatory role of resolvin D1 (RvD1), a pro-resolving mediator derived from omega-3 fatty acids, has demonstrated that the NF-κB/NLRP3 inflammasome pathway in different tissues is attenuated after treatment with RvD1. However, the mechanism of the anti-inflammatory activity of RvD1 in AF has not been clarified. This review suggests that RvD1 may inhibit ER stress-induced NLRP3 inflammasome through suppressing NF-κB in cardiac tissue and, thus ameliorate AF.