The protective effects of protocatechuic acid against natural and chemical toxicants: cellular and molecular mechanisms.

Protocatechuic acid (PCA) is a water-soluble polyphenol compound that is extracted from certain fruits and plants or obtained from glucose fermentation. Several in vivo and in vitro studies have determined that PCA has protective effects against the toxicity of natural and chemical toxicants. We searched these articles in PubMed, Google Scholar, and Scopus with appropriate keywords from inception up to August 2023. Forty-nine studies were found about protective effects of PCA against drug toxicity, metal toxicity, toxins, chemical toxicants, and some other miscellaneous toxicants. PCA indicates these protective effects by suppression of oxidative stress, inflammation, and apoptosis. PCA reduces reactive oxygen/nitrogen species (RONS) and enhances the level of antioxidant parameters mainly through the activation of the Nrf-2 signaling pathway. PCA also decreases the levels of inflammatory mediators via downregulating the TLR-4-mediated IKBKB/NF-κB and MAPK/Erk signaling pathways. In addition, PCA inhibits apoptosis by lowering the expression of Bax, caspase-3, and caspase-9 along with enhancing the level of the antiapoptotic protein Bcl-2. Further evaluation, especially in humans, is necessary to confirm PCA as a potential therapeutic approach to intervene in such toxicities.

Alleviation of microcystin-leucine arginine -induced hepatotoxicity: An updated overview.

OBJECTIVES: Contamination of surface waters is a major health threat for all living creatures. Some types of blue-green algae that naturally occur in fresh water, are able to produce various toxins, like Microcystins (MCs). Microcystin-leucine arginine (MC-LR) produced by Microcystis aeruginosa is the most toxic and abundant isoforms of MCs, and it causes hepatotoxicity. The present article reviews preclinical experiments examined different treatments, including herbal derivatives, dietary supplements and drugs against MC-LR hepatotoxicity. METHODS: We searched scientific databases Web of Science, Embase, Medline (PubMed), Scopus, and Google Scholar using relevant keywords to find suitable studies until November 2023. RESULTS: MC-LR through Organic anion transporting polypeptide superfamily transporters (OATPs) penetrates and accumulates in hepatocytes, and it inhibits protein phosphatases (PP1 and PP2A). Consequently, MC-LR disturbs many signaling pathways and induces oxidative stress thus damages cellular macromolecules. Some protective agents, especially plants rich in flavonoids, and natural supplements, as well as chemoprotectants were shown to diminish MC-LR hepatotoxicity. CONCLUSION: The reviewed agents through blocking the OATP transporters (nontoxic nostocyclopeptide-M1, captopril, and naringin), then inhibition of MC-LR uptake (naringin, rifampin, cyclosporin-A, silymarin and captopril), and finally at restoration of PPAse activity (silybin, quercetin, morin, naringin, rifampin, captopril, azo dyes) exert hepatoprotective effect against MC-LR.

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.

An overview on the protective effects of ellagic acid against heavy metals, drugs, and chemicals.

Ellagic acid (EA) is a polyphenol extracted from many plants. EA modulates inflammatory mediators via antioxidant mechanisms, such as catalase (CAT) activities, superoxide dismutase (SOD), enhancement, increase in glutathione (GSH), and lipid peroxidation (LPO) suppression. EA has anti-apoptotic properties that are thought to be mediated by regulating the expression of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and caspase-3. In this article, we surveyed the literature dealing with the protective effects of EA against different heavy metals, drugs, and natural toxins. The findings indicated that EA has remarkable protective properties against various toxicants. Its protective effects were mostly mediated via normalizing lipid metabolism, oxidative stress, and inflammatory mediators, for example, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1ß. The results of this study showed that EA has significant protective effects against a varied range of compounds, either chemical or natural. These effects are mainly mediated via intensifying the antioxidant defense system. However, other mechanisms such as inhibition of inflammatory responses and suppression of apoptosis are important.

Melittin as a safe compound to BALB/c mice immune system; a tiered approach immunotoxicity screening.

BACKGROUND: Maintenance of immune system integrity is a vital requirement to protect human body against pathogens/cancers. Natural compounds have long been used due to their benefits for the immune system. One of which is bee venom that contains a peptide called melittin having antimicrobial and anticancer effects. Since a limited number of studies regarding the effects of melittin on the immune system have been carried out, we aimed to evaluate the effects of melittin on BALB/c mice immune system parameters. METHODS: Female BALB /c mice were treated intraperitoneally (i.p) with 0.75 and 1.5 mg/kg doses of melittin for 14 days (5 doses per week). The negative control group received i.p normal saline whereas the positive controls received i.p 20 mg/kg cyclophosphamide (CYP). Immunological parameters such as hematological parameters, delayed-type hypersensitivity (DTH), hemagglutination titer (HA), spleen cellularity, splenocytes proliferation, as well as spleen and bone marrow histopathological assessment were evaluated. RESULTS: Our findings showed that melittin has no gross pathological effect on the spleen and bone marrow. It was also demonstrated that melittin has no any significant effect on hematological parameters. Melittin did not cause any significant changes to proliferation response of splenocytes to PHA and LPS, spleen cellularity, DTH response, as well as the production of anti-SRBC antibodies. According to our results, melittin at 0.75 and 1.5 mg/kg doses could not induce significant changes on immune parameters and as a result, melittin was found to be safe for the mice immune system.

Natural compounds against nonalcoholic fatty liver disease: A review on the involvement of the LKB1/AMPK signaling pathway.

Although various therapeutic approaches are used to manage nonalcoholic fatty liver disease (NAFLD), the best approach to NAFLD management is unclear. NAFLD is a liver disorder associated with obesity, metabolic syndrome, and diabetes mellitus. NAFLD progression can lead to cirrhosis and end-stage liver disease. Hepatic kinase B1 (LKB1) is an upstream kinase of 5'-adenosine monophosphate-activated protein kinase (AMPK), a crucial regulator in hepatic lipid metabolism. Activation of LKB1/AMPK inhibits fatty acid synthesis, increases mitochondrial ß-oxidation, decreases the expression of genes encoding lipogenic enzymes, improves nonalcoholic steatohepatitis, and suppresses NAFLD progression. One potential opening for new and safe chemicals that can tackle the NAFLD pathogenesis through the LKB1-AMPK pathway includes natural bioactive compounds. Accordingly, we summarized in vitro and in vivo studies regarding the effect of natural bioactive compounds such as a few members of the polyphenols, terpenoids, alkaloids, and some natural extracts on NAFLD through the LKB1/AMPK signaling pathway. This manuscript may shed light on the way to finding a new therapeutic agent for NAFLD management.

Osthole attenuated cytotoxicity induced by 6-OHDA in SH-SY5Y cells through inhibition of JAK/STAT and MAPK pathways.

Objectives: Natural coumarin called osthole is regarded as a medicinal herb with widespread applications in Traditional Chinese Medicine. It has various pharmacological properties, including antioxidant, anti-inflammatory, and anti-apoptotic effects. In some neurodegenerative diseases, osthole also shows neuroprotective properties. In this study, we explored how osthole protects human neuroblastoma SH-SY5Y cells from the cytotoxicity of 6-hydroxydopamine (6-OHDA). Materials and Methods: Using the MTT assay and DCFH-DA methods, respectively, the viability of the cells and the quantity of intracellular reactive oxygen species (ROS) were evaluated. Signal Transducers and Activators of Transcription (STAT), Janus Kinase (JAK), extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and caspase-3 activation levels were examined using western blotting. Results: In SH-SY5Y cells, the results showed that a 24-hour exposure to 6-OHDA (200 µM) lowered cell viability but markedly elevated ROS, p-JAK/JAK, p-STAT/STAT, p-ERK/ERK, p-JNK/JNK ratio, and caspase-3 levels. Interestingly, osthole (100 µM) pretreatment of cells for 24 hr prevented 6-OHDA-induced cytotoxicity by undoing all effects of 6-OHDA. Conclusion: In summary, our data showed that osthole protects SH-SY5Y cells against 6-OHDA-induced cytotoxicity by inhibiting ROS generation and reducing the activity of the JAK/STAT, MAPK, and apoptotic pathways.

Probabilistic risk assessment of exposure to multiple mycotoxins in consumers of packaged and unpackaged spices in Iran.

The current study assessed the risk posed to Iranian consumers by oral exposure to a mixture of ten mycotoxins in 138 packaged and unpackaged spices collected from the Iran market. Concentrations of mycotoxins in samples were quantified by liquid chromatography, tandem mass spectrometry with triple quadrupole, and ion trap. Probabilistic health risks of oral exposure to these mycotoxins for Iranians were assessed under percent tolerable daily intake (TDI) and cancer risk scenarios. Mean concentrations of mycotoxins in both packaged and unpackaged spice samples showed statistically significant variation among different spice samples. Based on a Monte Carlo simulation model, at the 50th, 80th, and 95th centiles, oral consumption of the analyzed samples poses no carcinogenic risk for exposure to aflatoxin. Moreover, in both packaged and unpackaged samples, while the percent TDIs for ochratoxin A, deoxynivalenol, zearalenone, patulin, fumonisin B1, and fumonisin B2 were below 1.0 at the 50th, 80th, and 95th centiles, the value was above 1.0 for aflatoxin B1, aflatoxin B2, aflatoxin G1, and aflatoxin G2 at each of these centiles.

Mas receptor: a potential strategy in the management of ischemic cardiovascular diseases.

MasR is a critical element in the RAS accessory pathway that protects the heart against myocardial infarction, ischemia-reperfusion injury, and pathological remodeling by counteracting the effects of AT1R. This receptor is mainly stimulated by Ang 1-7, which is a bioactive metabolite of the angiotensin produced by ACE2. MasR activation attenuates ischemia-related myocardial damage by facilitating vasorelaxation, improving cell metabolism, reducing inflammation and oxidative stress, inhibiting thrombosis, and stabilizing atherosclerotic plaque. It also prevents pathological cardiac remodeling by suppressing hypertrophy- and fibrosis-inducing signals. In addition, the potential of MasR in lowering blood pressure, improving blood glucose and lipid profiles, and weight loss has made it effective in modulating risk factors for coronary artery disease including hypertension, diabetes, dyslipidemia, and obesity. Considering these properties, the administration of MasR agonists offers a promising approach to the prevention and treatment of ischemic heart disease.Abbreviations: Acetylcholine (Ach); AMP-activated protein kinase (AMPK); Angiotensin (Ang); Angiotensin receptor (ATR); Angiotensin receptor blocker (ARB); Angiotensin-converting enzyme (ACE); Angiotensin-converting enzyme inhibitor (ACEI); Anti-PRD1-BF1-RIZ1 homologous domain containing 16 (PRDM16); bradykinin (BK); Calcineurin (CaN); cAMP-response element binding protein (CREB); Catalase (CAT); C-C Motif Chemokine Ligand 2 (CCL2); Chloride channel 3 (CIC3); c-Jun N-terminal kinases (JNK); Cluster of differentiation 36 (CD36); Cocaine- and amphetamine-regulated transcript (CART); Connective tissue growth factor (CTGF); Coronary artery disease (CAD); Creatine phosphokinase (CPK); C-X-C motif chemokine ligand 10 (CXCL10); Cystic fibrosis transmembrane conductance regulator (CFTR); Endothelial nitric oxide synthase (eNOS); Extracellular signal-regulated kinase 1/2 (ERK 1/2); Fatty acid transport protein (FATP); Fibroblast growth factor 21 (FGF21); Forkhead box protein O1 (FoxO1); Glucokinase (Gk); Glucose transporter (GLUT); Glycogen synthase kinase 3ß (GSK3ß); High density lipoprotein (HDL); High sensitive C-reactive protein (hs-CRP); Inositol trisphosphate (IP3); Interleukin (IL); Ischemic heart disease (IHD); Janus kinase (JAK); Kruppel-like factor 4 (KLF4); Lactate dehydrogenase (LDH); Left ventricular end-diastolic pressure (LVEDP); Left ventricular end-systolic pressure (LVESP); Lipoprotein lipase (LPL); L-NG-Nitro arginine methyl ester (L-NAME); Low density lipoprotein (LDL); Mammalian target of rapamycin (mTOR); Mas-related G protein-coupled receptors (Mrgpr); Matrix metalloproteinase (MMP); MAPK phosphatase-1 (MKP-1); Mitogen-activated protein kinase (MAPK); Monocyte chemoattractant protein-1 (MCP-1); NADPH oxidase (NOX); Neuropeptide FF (NPFF); Neutral endopeptidase (NEP); Nitric oxide (NO); Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB); Nuclear-factor of activated T-cells (NFAT); Pancreatic and duodenal homeobox 1 (Pdx1); Peroxisome proliferator- activated receptor γ (PPARγ); Phosphoinositide 3-kinases (PI3k); Phospholipase C (PLC); Prepro-orexin (PPO); Prolyl-endopeptidase (PEP); Prostacyclin (PGI2); Protein kinase B (Akt); Reactive oxygen species (ROS); Renin-angiotensin system (RAS); Rho-associated protein kinase (ROCK); Serum amyloid A (SAA); Signal transducer and activator of transcription (STAT); Sirtuin 1 (Sirt1); Slit guidance ligand 3 (Slit3); Smooth muscle 22α (SM22α); Sterol regulatory element-binding protein 1 (SREBP-1c); Stromal-derived factor-1a (SDF); Superoxide dismutase (SOD); Thiobarbituric acid reactive substances (TBARS); Tissue factor (TF); Toll-like receptor 4 (TLR4); Transforming growth factor ß1 (TGF-ß1); Tumor necrosis factor α (TNF-α); Uncoupling protein 1 (UCP1); Ventrolateral medulla (VLM).

The effect of melatonin on benzo(a)pyrene-induced renal toxicity in mice.

Benzo(a)pyrene is a ubiquitous environmental contaminant, which could induce renal injury. It is reported that melatonin has a protective effect against multiple organ injuries by regulating oxidative stress, apoptosis, and autophagy. The aim of this study was to estimate the melatonin effects on benzo(a)pyrene renal toxicity in mice and the possible molecular mechanisms involved in this model. Thirty male mice were allocated to five groups and treated with benzo(a)pyrene (75 mg/kg, oral gavage) and/or melatonin (10 and 20 mg/kg, intraperitoneally). The oxidative stress factors were evaluated in renal tissue. The levels of apoptotic (the Bax/Bcl-2 ratio and caspase-3) and autophagic (the LC3 II/I, Beclin-1, and Sirt1) proteins were examined using Western blot. Following the administration of benzo(a)pyrene, malondialdehyde, caspase-3 and the Bax/Bcl-2 ratio increased in renal tissue, while Sirt1, Beclin-1, and the LC3 II/I ratio diminished. Interestingly, the co-administration of 20 mg/kg melatonin along with benzo(a)pyrene reduced the oxidative stress markers, apoptotic and autophagic proteins. Collectively, melatonin exhibited a protective effect against benzo(a)pyrene-induced renal injury through the suppression of oxidative stress and apoptosis and the inhibition of Sirt1/autophagy pathway.

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.

Natural compounds regulate the PI3K/Akt/GSK3ß pathway in myocardial ischemia-reperfusion injury.

The PI3K/Akt/GSK3ß pathway is crucial in regulating cardiomyocyte growth and survival. It has been shown that activation of this pathway alleviates the negative impact of ischemia-reperfusion. Glycogen synthase kinase-3 (GSK3ß) induces apoptosis through stimulation of transcription factors, and its phosphorylation has been suggested as a new therapeutic target for myocardial ischemia-reperfusion injury (MIRI). GSK3ß regulatory role is mediated by the reperfusion injury salvage kinase (RISK) pathway, and its inhibition by Akt activation blocks mitochondrial permeability transition pore (mPTP) opening and enhances myocardial survival. The present article discusses the involvement of the PI3K/Akt/GSK3ß pathway in cardioprotective effects of natural products against MIRI.Abbreviations: Akt: protein kinase B; AMPK: AMP-activated protein kinase; ATP: adenosine triphosphate; Bad: bcl2-associated agonist of cell death; Bax: bcl2-associated x protein; Bcl-2: B-cell lymphoma 2; CK-MB: Creatine kinase-MB; CRP: C-reactive-protein; cTnI: cardiac troponin I; EGCG: Epigallocatechin-3-gallate; Enos: endothelial nitric oxide synthase; ER: endoplasmic reticulum; ERK ½: extracellular signal­regulated protein kinase ½; GSK3ß: glycogen synthase kinase-3; GSRd: Ginsenoside Rd; GSH: glutathione; GSSG: glutathione disulfide; HO-1: heme oxygenase-1; HR: hypoxia/reoxygenation; HSYA: Hydroxysafflor Yellow A; ICAM-1: Intercellular Adhesion Molecule 1; IKK-b: IκB kinase; IL: interleukin; IPoC: Ischemic postconditioning; IRI: ischemia-reperfusion injury; JNK: c-Jun N-terminal kinase; Keap1: kelch-like ECH-associated protein- 1; LDH: lactate dehydrogenase; LVEDP: left ventricular end diastolic pressure; LVP: left ventricle pressure; LVSP: left ventricular systolic pressure; MAPK: mitogen-activated protein kinase; MDA: malondialdehyde; MIRI: myocardial ischemia-reperfusion injury; MnSOD: manganese superoxide dismutase; mPTP: mitochondrial permeability transition pore; mtHKII: mitochondria-bound hexokinase II; Nrf-1: nuclear respiratory factor 1; Nrf2: nuclear factor erythroid 2-related factor; NO: nitric oxide; PGC-1α: peroxisome proliferator­activated receptor γ coactivator­1α; PI3K: phosphoinositide 3-kinases; RISK: reperfusion injury salvage kinase; ROS: reactive oxygen species; RSV: Resveratrol; SOD: superoxide dismutase; TFAM: transcription factor A mitochondrial; TNF-α: tumor necrosis factor-alpha; VEGF-B: vascular endothelial growth factor B.

The hematopoietic potential of methanolic and aqueous extracts of Portulaca oleracea in a phenylhydrazine model of anemia.

Objective: Portulaca oleracea, commonly known as Purslane, is traditionally used as a sour, diuretic, and cooling herb with hemostatic properties. The present study evaluates the antianemic effect of methanolic and aqueous extracts of P. oleracea in a phenylhydrazine model of anemia. Materials and Methods: Phenylhydrazine (60 mg/kg/day, i.p., two consecutive days) was used to induce anemia in rats. The aqueous and methanolic extracts of P. oleracea were prepared, and three methods of treatment were defined with two doses (500 and 750 mg/kg, i.p.). The hematological parameters and blood cell morphology, total and direct bilirubin, and morphology, and pathology of bone marrow were evaluated. Results: The results showed that the methanolic extract has better effects than aqueous extract in improving phenylhydrazine-induced anemia. Our results showed that administration of 500 and 750 mg/kg of P. oleracea methanolic extracts for 4 days could protect against the development of anemia caused by phenylhydrazine. Conclusion: In summary, the methanolic extracts of P. oleracea might be effective in phenylhydrazine-induced anemia.

The role of lncRNAs/miRNAs/Sirt1 axis in myocardial and cerebral injury.

In recent years, researchers have begun to realize the importance of the role of non-coding RNAs in the treatment of cancer and cardiovascular and neurological diseases. LncRNAs and miRNAs are important non-coding RNAs, which regulate gene expression and activate mRNA translation through binding to diverse target sites. Their involvement in the regulation of protein function and the modulation of physiological and pathological conditions continues to be investigated. Sirtuins, especially Sirt1, have a critical function in regulating a variety of physiological processes such as oxidative stress, inflammation, apoptosis, and autophagy. The lncRNAs/miRNAs/Sirt1 axis may be a novel regulatory mechanism, which is involved in the progression and/or prevention of numerous diseases. This review focuses on recent findings on the crosstalk between non-coding RNAs and Sirt1 in myocardial and cerebral injuries and may provide some insight into the development of novel approaches in the treatment of these disorders.Abbreviation: BMECs, brain microvascular endothelial cells; C2dat1, calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D)-associated transcript 1; EPCs, endothelial progenitor cells; FOXOs, forkhead transcription factors; GAS5, growth arrest-specific 5; HAECs, human aortic endothelial cells; HAND2-AS1, HAND2 Antisense RNA 1; HIF-1α, hypoxia-inducible factor-1α; ILF3-AS1, interleukin enhancer-binding factor 3-antisense RNA 1; KLF3-AS1, KLF3 antisense RNA 1; LncRNA, long noncoding RNA; LUADT1, Lung Adenocarcinoma Associated Transcript 1; MALAT1, Metastasis-associated lung adenocarcinoma transcript 1; miRNA, microRNA; NEAT1, nuclear enriched abundant transcript 1; NF-κB, nuclear factor kappa B; OIP5-AS1, Opa-interacting protein 5-antisense transcript 1; Sirt1-AS, Sirt1 Antisense RNA; SNHG7, small nucleolar RNA host gene 7; SNHG8, small nucleolar RNA host gene 8; SNHG12, small nucleolar RNA host gene 12; SNHG15, small nucleolar RNA host gene 15; STAT3, signal transducers and activators of transcription 3; TUG1, taurine up-regulated gene 1; VSMCs, vascular smooth muscle cells; XIST, X inactive specific transcript; ZFAS1, ZNFX1 Antisense RNA 1.

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.

Melatonin attenuates cardiopulmonary toxicity induced by benzo(a)pyrene in mice focusing on apoptosis and autophagy pathways.

Benzo(a)pyrene (BaP) is a polycyclic aromatic hydrocarbon and a serious environmental pollutant. BaP is formed by the incomplete combustion of organic matter at high temperatures. In addition, tobacco smoke and many foods, especially charbroiled food and grilled meats, contain BaP and can cause it to enter human body. Melatonin, a pineal gland hormone, has antioxidant, anti-apoptosis, and autophagy regulatory properties. The possible protective impact of melatonin on cardiopulmonary toxicity induced by BaP was investigated by examining the antioxidant effects and the apoptosis and autophagy properties of melatonin. Thirty male mice were divided into 5 groups and treated for 28 days as follows: (I) control (BaP and melatonin solvent), (II) BaP (75 mg/kg, oral gavage), (III and IV) BaP (75 mg/kg) + melatonin (10 and 20 mg/kg, intraperitoneally), (V) melatonin (20 mg/kg). The oxidative stress factors (MDA and GSH content) were assessed in the heart and lung tissues. The levels of apoptotic (Caspase-3 and the Bax/Bcl-2 ratio) and autophagic (the LC3 ӀӀ/Ӏ, Beclin-1, and Sirt1) proteins were examined by using western blot analysis. Following the administration of BaP, MDA, the Bax/Bcl-2 ratio, and the Caspase-3 proteins increased in the heart and lung tissues, while GSH, Sirt1, Beclin-1, and the LC3 II/I ratio diminished. The coadministration of melatonin along with BaP, MDA, and apoptotic proteins returned to the control values, while GSH and the autophagy proteins were enhanced in both the heart and lungs. Melatonin exhibited a protective effect against BaP-induced heart and lung injury through the suppression of oxidative stress and apoptosis and the induction of the Sirt1/autophagy pathway.

The modulation of sirtuins by natural compounds in the management of cisplatin-induced nephrotoxicity.

Cisplatin is a highly effective antitumor agent. However, its use is limited due to severe adverse effects, particularly nephrotoxicity, which occurs in approximately 30% of patients. There is a need for novel renoprotective compounds. Sirtuins play a vital role in various physiological and pathological processes such as oxidative stress, apoptosis, inflammation, and mitochondrial bioenergetics. It has been shown that sirtuins can exert a protective effect on cisplatin-induced acute kidney injury by targeting multiple signaling pathways. Besides, sirtuins not only did not reduce the anticancer effect of cisplatin but also increased it. Several natural compounds have been reported to inhibit cisplatin-mediated nephrotoxicity through sirtuin stimulation. These compounds exert their therapeutic effects on cisplatin-induced renal injury by targeting various signaling pathways including Sirt1/p53, Sirt1/NF-κb/p56, AMPK/Sirt1, Sirt1/PGC-1α, and/or by enhancing mitochondrial function.

Assessment of Carcinogenic and Non-carcinogenic Risk of Exposure to Metals via Consumption of Coffee, Tea, and Herbal Tea in Iranians.

In the current study, we assessed health risk posed to Iranian consumers through exposure to metals via oral consumption of coffee, tea, and herbal tea of various trademarks collected from Iran market. Level of As, Cd, Cr, Cu, Fe, Hg, Ni, and Pb in 243 samples was quantified by inductively coupled plasma-optical emission spectrometry (ICP-OES). The metal levels in coffee samples from different trademarks of a specific country had statistically similar levels of metals; however, metal levels differed significantly among brand names form different countries. Metal levels in tea samples differed significantly between domestic and imported products, while different trademarks of similar countries did not show significant variations in this respect. Metal level in herbal tea samples did not show significant variations among different trademarks. Nevertheless, it should be highlighted that mean concentrations of metals statistically differed among different herbal tea samples. Deterministic hazard quotients (HQs) were <1.0 for all non-carcinogenic metals and total hazard index (HI) values indicated no risk; however, probabilistic assessment calculated HI values >1. In both deterministic and probabilistic scenarios, carcinogenic metals As and Ni had an estimated incremental lifetime cancer risk (ILCR) of medium level while that of Pb indicated no cancer risk. Sensitivity analysis showed that the concentration of metals had the most significant effect on non-carcinogenic and carcinogenic risks.

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.