Enhanced upregulation of SIRT1 via pioglitazone and ligustrazine confers protection against ethanol-induced gastric ulcer in rats.

Gastric ulcer is a disturbing disease that impacts many people worldwide. Pioglitazone (Piog), a thiazolidinedione, and ligustrazine (Ligu), a natural component of Ligusticum chuanxiong possess gastroprotective properties. However, the underlying mechanism is not well elucidated. The present study aimed to investigate the gastroprotective effects of Piog (15 mg/kg, p.o.), Ligu (15 mg/kg, p.o.), and their combination against ethanol-induced gastric ulcer in rats. Omeprazole (10 mg/kg) was used as a standard. Pre-treatment for 7 days with Piog, Ligu, and (Piog+Ligu) effectively alleviated ethanol-predisposed oxidative stress and inflammation through restoring HO-1, GSH, and SOD tissue levels and decreasing elevated MDA, TNF-α, ICAM, I-NOS, and IL-1ß contents. Moreover, Piog, Ligu, and (Piog+Ligu) markedly inhibited the ethanol-induced increase of gastric NF-KB and BAX. In contrast, this pre-treatment regimen significantly accelerated protein expression of SIRT1, Nrf2, and Bcl-2, along with autophagic proteins, ATG5 and Beclin. Interestingly, macroscopic, histopathological examination and mucin content were in harmony with previous results, where pre-treatment with Piog, Ligu, and (Piog+Ligu) showed a declined mucosal injury as evidenced by the remarkable decrease of the ulcer area percentage by 62.3%, 38.7%, and 91.2%, respectively, compared to the ethanol-ulcerated group. In conclusion, Piog and Ligu exhibited remarkable gastroprotective properties. Our study was the first to show that Piog, Ligu, and (Piog+Ligu) ameliorated oxidative stress, inflammation, and apoptosis and accelerated the autophagic process via the upregulation of the upstream SIRT1 protein. It is worth mentioning that future studies are needed to pave the way for the clinical use of Piog and Ligu as gastro-protective agents.

Sertraline Pre-Treatment Attenuates Hemorrhagic Transformation Induced in Rats after Cerebral Ischemia Reperfusion via Down Regulation of Neuronal CD163: Involvement of M1/M2 Polarization Interchange and Inhibiting Autophagy.

Cerebral ischemia reperfusion (I/R) is one of the neurovascular diseases which leads to severe brain deterioration. Haemorrhagic transformation (HT) is the main complication of ischemic stroke. It exacerbates by reperfusion, causing a more deleterious effect on the brain and death. The current study explored the protective effect of sertraline (Sert) against cerebral I/R in rats by inhibiting HT, together with the molecular pathways involved in this effect. Forty-eight wister male rats were divided into 4 groups: Sham, Sert + Sham, I/R, and Sert + I/R. The ischemic model was induced by bilateral occlusion of the common carotid artery for 20 min, then reperfusion for 24 h. Sertraline (20 mg/kg, p.o.) was administrated for 14 days before exposure to ischemia. Pre-treatment with Sert led to a significant attenuation of oxidative stress and inflammation. In addition, Sert attenuated phosphorylation of extracellular regulated kinases and nuclear factor kappa-p65 expression, consequently modulating microglial polarisation to M2 phenotype. Moreover, Sert prevented the hemorrhagic transformation of ischemic stroke as indicated by the notable decrease in neuronal expression of CD163, activity of Heme oxygenase-2 and matrix metalloproteinase-2 and 9 levels. In the same context, Sert decreased levels of autophagy and apoptotic markers. Furthermore, histological examination, Toluidine blue, and Prussian blue stain aligned with the results. In conclusion, Sert protected against cerebral I/R damage by attenuating oxidative stress, inflammation, autophagy, and apoptotic process. It is worth mentioning that our study was the first to show that Sert inhibited hemorrhagic transformation. The protective effect of sertraline against injury induced by cerebral ischemia reperfusion via inhibiting Hemorrhagic transformation.

Linagliptin and secoisolariciresinol diglucoside attenuate hyperlipidemia and cardiac hypertrophy induced by a high-methionine diet in rats via suppression of hyperhomocysteinemia-induced endoplasmic reticulum stress.

Background: Cardiac hypertrophy (CH) is one of the contributing causes of morbidity and mortality. Hyperhomocysteinemia (HHcy) is one of the diseases which may predispose hyperlipidemia and CH. Linagliptin (Lina) and secoisolariciresinol diglucoside (SDG) are known to alleviate a variety of illnesses by reducing oxidative stress and inflammation. Aim: This study aimed to study the effect of HHcy on cardiac tissues, with a special focus on endoplasmic reticulum (ER) stress as a mainstay pathophysiological pathway. In addition, our study examined the protective effect of Lina, SDG, and their combination against HHcy-induced hyperlipidemia and CH in rats. Methods: Seventy-five male Sprague-Dawley rats were randomly divided into five groups, and for 60 days, the following regimen was administered: Group I: rats received distilled water; Group II: rats received methionine (MET) (2 g/kg/day, p.o.); groups III and IV: rats received Lina (3 mg/kg/day, p.o.) and SDG (20 mg/kg/day, p.o.), respectively, followed by MET (2 g/kg/day, p.o.); Group V: rats received Lina and SDG, followed by MET (2 g/kg/day, p.o.). Results: Pretreatment with Lina, SDG, and their combination showed a significant decrease in serum levels of HHcy and an improved lipid profile compared to the MET group. Moreover, both drugs improved cardiac injury, as evidenced by the substantial improvement in ECG parameters, morphological features of the cardiac muscle, and reduced serum levels of cardiac markers. Additionally, Lina and SDG significantly attenuated cardiac oxidative stress, inflammation, and apoptosis. Furthermore, Lina, SDG, and their combination remarkably downregulated the enhanced expression of endoplasmic reticulum (ER) stress markers, GRP78, PERK, ATF-4, CHOP, NF-κB, and SREBP1c compared to the MET-group. Conclusion: Lina and SDG showed cardioprotective effects against HHcy-induced heart hypertrophy and hyperlipidemia in rats.

Liraglutide ameliorates gentamicin-induced acute kidney injury in rats via PGC-1α- mediated mitochondrial biogenesis: Involvement of PKA/CREB and Notch/Hes-1 signaling pathways.

Acute kidney injury (AKI) is a challenging side effect which may clinically impede the use of gentamicin (GM). The present study explored the impact of liraglutide (Lir) on GM-induced kidney injury in rats. Lir (0.2 and 0.4 mg/kg, s.c) was given for 10 days (a dose/day) starting 3 days before giving GM (100 mg/kg, i.p) once daily for 7 days. Interestingly, Lir notably ameliorated GM-induced elevated levels of renal injury markers; urea and creatinine. Moreover, Lir remarkably mitigated malondialdehyde (MDA) level and elevated glutathione (GSH) level as well as superoxide dismutase (SOD) activity. Also, Lir pre-treatment notably diminished inflammatory markers levels; interleukin-1ß (IL-1ß), tumor necrosis factor alpha (TNF-α), vascular cell adhesion molecule (VCAM), monocyte chemoattractant protein 1 (MCP-1) and interferon gamma (INF-γ). In addition, Lir significantly replenished expression of Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α), Protein kinase A (PKA), cAMP response element-binding protein (CREB), nuclear Nuclear factor erythroid 2-related factor 2 (Nrf2), heme Oxygenase-1 (HO-1), B-cell lymphoma 2 (Bcl-2), and remarkably attenuated expression of Notch homolog 1 (Notch1), Hairy and enhancer of split-1 (Hes-1), Bcl-2-associated X (Bax), cleaved caspase 3 and nuclear Nuclear factor Kappa B (NF-κB (p65)). The nephroprotective activity of Lir was further confirmed by histopathological examination as well as transmission electron microscopy (TEM). In conclusion Lir achieved its nephroprotective effects through the amelioration of oxidative stress, inflammatory and apoptotic manifestations. It is worth-mentioning that the current study is the first to focus on the involvement of mitochondrial biogenesis and its upstream regulators, PKA/CREB and Notch/Hes-1 signaling pathways in the nephroprotective potentials of Lir. The attenuation of the aforementioned injurious aspects is partially attributed to the improvement of the mitochondrial status as demonstrated by elevated PGC-1α expression via acceleration of PKA/CREB and abatement of Notch/Hes-1 signaling pathways.

Repositioning itraconazole for amelioration of bleomycin-induced pulmonary fibrosis: Targeting HMGB1/TLR4 Axis, NLRP3 inflammasome/NF-κB signaling, and autophagy.

BACKGROUND AND AIMS: Bleomycin (BLM) is one of the antitumor medications that had proven efficacy in the treatment of a wide range of malignant conditions. Pulmonary fibrosis which is frequently encountered during the course of bleomycin therapy may significantly reduce the potential efficacy of bleomycin in cancer therapy. This study tested the hypothesis that itraconazole may have mitigating effects on BLM-induced pulmonary fibrosis and tried to delineate the potential mechanisms of these effects. MATERIALS AND METHODS: In a rat model of pulmonary fibrosis elicited by BLM, the effect of different doses of itraconazole was explored at the biochemical, histopathological, and electron microscopic levels. KEY FINDINGS: Itraconazole, in a dose-dependent manner, exhibited significant effects on the pro-oxidant/antioxidant balance, the inflammatory consequences, high-mobility group box 1/toll-like receptor-4 Axis, autophagy and nuclear factor kappa B/Nod-like receptor protein 3 inflammasome signaling and alleviated the histopathological, immunohistochemical, and electron microscopic perturbations induced by BLM in the pulmonary tissues. SIGNIFICANCE: In view of the afore-mentioned data, itraconazole may be a promising drug that efficiently mitigates the deleterious effects of BLM on the pulmonary tissues.

Polydatin combats methotrexate-induced pulmonary fibrosis in rats: Involvement of biochemical and histopathological assessment.

Polydatin (PD) is a polyphenolic compound found naturally in many fruits such as grapes. It has anti-oxidant and anti-inflammatory activities that are of paramount importance for its pharmacological actions. This study aimed to explore possible protective effects of PD against methotrexate (MTX)-induced pulmonary fibrosis in rats. A single oral dose of MTX (14 mg/kg) per week for 2 weeks caused a significant decrease in glutathione (GSH) content with a marked increase in transforming growth factor-beta (TGF-ß), alpha-smooth muscle actin (α-SMA), pulmonary content of malondialdehyde (MDA), interleukin-1ß (IL-1ß), Hydroxyproline, tumor necrosis factor-alpha (TNF-α), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) as compared with the control group. Contrarily, daily administration of PD (25, 50, and 100 mg/kg, p.o.) for 14 days concomitantly with MTX ameliorated MTX-induced pulmonary fibrosis as indicated by mitigation of the previously mentioned biochemical parameters and histopathological changes in a dose-dependent manner. In conclusion, the protective effect of PD against pulmonary fibrosis induced by MTX in rats might be attributed to its anti-oxidant, anti-inflammatory as well as anti-fibrotic effects.

Ethyl pyruvate attenuates isoproterenol-induced myocardial infarction in rats: Insight to TNF-α-mediated apoptotic and necroptotic signaling interplay.

The current study investigated the prophylactic effect of ethyl pyruvate (EP) in Isoproterenol (ISO) - induced myocardial infarction (MI). Ethyl pyruvate (EP) was given at a dose of 100 mg/kg i.p for 7 days, while isoproterenol (ISO) was administered at a dose of 10 mg/kg s.c. on the 6th and 7th days to induce MI. All parameters were assessed 24 and 48 h following treatment. Interestingly, EP pre-treatment significantly improved ISO-induced hemodynamic alterations and remarkably ameliorated serum levels of cardiac injury markers, Cardiac Troponin I (cTnI) and Cardiac Creatine Kinase (CK-MB). Also, EP notably suppressed levels of oxidative stress markers, total antioxidants (TAO) and malondialdehyde (MDA) as compared to ISO-treated group. Cardioprotective effects of EP were confirmed by histopathological examination. Moreover, EP remarkably attenuated ISO-induced elevation in Tumor Necrosis Factor Alpha (TNF-α) and Nuclear factor kappa-B p65 (NF-κB) expression, along with Interleukin-6 (IL-6), Monocyte chemoattractant protein 1 (MCP-1) and Inducible nitric oxide synthase (i-NOS) levels. Also, EP significantly diminished expression of apoptotic markers; caspase 8, cleaved caspase 3 and apoptotic regulator; cellular FLICE-like inhibitory protein (cFLIP). Finally, EP notably mitigated necroptotic mediators, phosphorylated receptor-interacting serine/threonine protein kinase 1 and 3 (p-RIPK1 and p-RIPK3), phosphorylated mixed lineage kinase domain-like protein (p-MLKL) and heat shock protein 70 (HSP 70) expression as compared to the ISO-treated group. Our study was the first to investigate the effect of EP on the necroptotic signaling. Taken together, EP conferred its cardioprotective effect against ISO-induced MI partially through mitigation of TNF-α and its downstream inflammatory, apoptotic and necroptotic signaling pathways.

Diallyl sulfide alleviates cyclophosphamide-induced nephropathic encephalopathy in rats.

Diallyl sulfide (DAS) is a garlic-derived organosulfur compound. The current study was planned to evaluate the protecting effects of DAS against cyclophosphamide (CP)-induced nephropathic encephalopathy. DAS (100 mg/kg) was orally administered for 4 days, 60 min after the last dose, rats were injected with CP (150 mg/kg). DAS treatment before CP significantly decreased serum urea, creatinine, sodium, potassium, calcium, blood urea nitrogen (BUN), C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and tumor necrosis factor-alpha (TNF-α) compared with CP-treated rats. DAS treatment decreased malondialdehyde (MDA) and increased superoxide dismutase (SOD) and reduced glutathione (GSH) levels in the renal tissues and significantly attenuated the elevated neurotransmitters N-methyl-D-aspartate/adenosine triphosphate (NMDA), γ-aminobutyric acid (GABA) levels and remarkably restored neuronal nitric oxide (NO) level and nitric oxide synthase (nNOS) activity in the brain compared to CP-treated rats. DAS for 4 consecutive days before CP showed moderate positive immunohistochemically expression of the glial fibrillary acidic protein (GFAP) in the brain and kidney tissues comparable to CP-treated rats. DAS afforded renal and neuroprotection against CP-induced nephropathic encephalopathy due to its capacity to ameliorates the afore-mentioned biochemical parameters which were supported by histopathological and immunohistochemically examination.

Diallyl sulfide ameliorates carbon tetrachloride-induced hepatotoxicity in rats via suppressing stress-activated MAPK signaling pathways.

The underlined effects of diallyl sulfide (DAS) against CCL4 -induced oxidative, inflammatory, and apoptotic acute hepatic damage were assessed. Administration of DAS (50, 100, and 200 mg/kg) along with CCL 4 effectively mitigated serum aspartate aminotransferase, alanine aminotransferase activities, MDA, TNF-α, IL-1ß, and MCP-1 levels, as well as significantly restored HO-1, GSH levels and SOD activity in liver tissues compared with those in rats treated with CCL 4 . Moreover, DAS inhibited CCL 4 -induced increase of liver NF-κB (p65), Bax, p38 MAPK, and JNK protein expression. In addition, DAS accelerated protein expression of Nrf2 and Bcl-2. The hepatoprotective properties of DAS were further confirmed by the reduced severity of hepatic damage as demonstrated by histopathological findings. In conclusion, DAS achieved its protective potential against CCL4-induced hepatotoxicity through antiapoptotic activity, as well as the synchronized modulation of NF-κB and Nrf2 for the favor of antioxidant/anti-inflammatory effects via suppression of the upstream stress-activated MAPKs pathways.

The growth inhibitory effect of gambogic acid on pancreatic cancer cells.

Pancreatic cancer, the fourth most common cause of cancer-related deaths, is one of the most aggressive and devastating human malignancies with increasing incidence worldwide. To date, surgical resection is the only potentially curative therapy available for pancreatic cancer patients. Early diagnosis of pancreatic tumors is difficult, and hence, nearly 80% of patients cannot receive surgical resection. Natural products have always been a vital source for novel compounds for cancer treatment. The naturally occurring prenylated xanthone, gambogic acid, has been previously shown to exert potent anticancer, anti-inflammatory, apoptotic, antiangiogenic, and antioxidant activities. However, to our knowledge, there have been no specific studies showing its effect on the whole-genome expression in pancreatic cancer cells. Here, the anticancer activity of gambogic acid toward a panel of pancreatic cancer cells with different differentiation stages has been evaluated. Additionally, a whole-genome transcription profiling study was performed in order to identify possible candidate players modulating the antitumor effect of gambogic acid on pancreatic cancer cells. Expression analysis results showed that the pancreatic adenocarcinoma signaling pathway was specifically affected upon gambogic acid treatment. Moreover, the growth inhibitory effect of gambogic acid on pancreatic cancer cells was modulated through up-regulation of DDIT3, DUSP1, and DUSP5 and down-regulation of ALDOA, TOP2A, and ATG4B. The present work is a starting point for the generation of hypotheses on significantly regulated candidate key player genes and for a detailed dissection of the potential role of each individual gene for the activity of gambogic acid on pancreatic cancer.

Anticancer potentiality of lignan rich fraction of six Flaxseed cultivars.

The objective of our study is to highlight the therapeutic effect and mechanism of action by which purified Flaxseed hydrolysate (PFH) which is a lignan rich fraction exerts its anticancer activity on a human breast cancer cell line (T47D) and in mice bearing tumor. HPLC analysis of PFH of six flaxseed cultivars had shown that PFH of the cultivar Giza 9 (PFH-G9) contains the highest concentration of SDG (81.64 mg/g). The in vitro cytotoxic potentiality of PFH's of six flaxseed cultivars was screened against a panel of human cancer cell lines. PFH -G9 showed the most significant cytotoxic activity against ER-receptor positive breast cell lines MCF7 and T47D with IC50 13.8 and 15.8 µg/ml, respectively. Moreover, PFH-G9 reduced the expression of the metastasis marker, 1-α, metalloproteinases and vascular endothelial growth factor (VEGF), one of the most potent stimulators of angiogenesis, while it increased the caspase-3 dependent apoptosis. Our study also showed that dietary intake of 10% of Giza 9 Flaxseeds (FS), fixed oil (FSO) or Flax meal (FSM) twice daily for 3 weeks in mice-bearing solid Ehrlich ascites carcinoma (EAC) resulted in reducing the tumor volume, the expression of estrogen, insulin growth factor, progesterone, VEGF and MMP-2, but enhanced expression of caspase-3.

Diallyl sulfide alleviates cisplatin-induced nephrotoxicity in rats via suppressing NF-κB downstream inflammatory proteins and p53/Puma signalling pathway.

Despite being a potent anticancer drug, nephrotoxicity is an adverse effect which renders the clinical use of cisplatin (Cis) limited. The protective role of diallyl sulfide (DAS); a naturally occurring organo-sulfide, present in garlic, in cisplatin-induced nephrotoxicity has been reported earlier. However, the mechanism through which DAS exerts its nephroprotective activity remains elusive. The aim of the current study was to elucidate the possible mechanisms underlying the reno-protective effect of DAS in cisplatin-induced nephrotoxicity in rats. DAS was given at 2 dose levels; 50 and 100 mg/kg, orally for 4 consecutive days, starting 1 hour after administration of single dose of cisplatin (3.5 mg/kg, intraperitoneally [i.p.]). The Cis-induced elevation in serum urea and creatinine, degree of histopathological alterations was significantly ameliorated in cisplatin groups co-treated with DAS. In addition, DAS significantly restored Cis-depleted glutathione (GSH) content and superoxide dismutase (SOD) activity and attenuated Cis-elevated Malondialdehyde (MDA) level. Also, DAS significantly reduced Cis-increased renal expression of nuclear factor kappa B (NF-κB) and subsequent pro-inflammatory mediators; tumour necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS) in kidney tissues. Moreover, co-treatment with DAS significantly inhibited Cis-increased caspase-8 and -9 levels. Additionally, DAS significantly mitigated Cis-induced protein expression of p53, Puma, and Bax while, it significantly restored Cis-reduced protein expression of Bcl-xL compared to the Cis group. In conclusion, these results demonstrate that DAS ameliorates cisplatin-induced nephrotoxicity in rats through enhancement of antioxidant defense, reduction of inflammatory cytokine tissue levels as well as inhibition of apoptosis via p53/Puma signalling pathway.

Ameliorative Effect of Coenzyme Q10 and/or Candesartan on Carboplatin-Induced Nephrotoxicity: Roles of Apoptosis, Transforming Growth Factor-Β1, Nuclear Factor Kappa-B And The Nrf2/HO-1 Pathway

Background: Carboplatin is a drug that is used for treatment of many types of cancer. However, it may produce serious nephrotoxicity. Candesartan is angiotensin II receptor antagonist employed mainly for control of hypertension. Coenzyme Q10 (CoQ10) is a fat-soluble substance which was proven to have potent antioxidant and anti-inflammatory properties. Aim: Our aim was to study the effects of candesartan and/or CoQ10 on carboplatin-induced nephrotoxicity in mice. Methods: Sixty mice were divided into 6 equal groups: Control untreated; carboplatin; carboplatin + candesartan; carboplatin + CoQ10; carboplatin + carboxymethyl cellulose; and carboplatin + candesartan + CoQ10 group. Kidney weight/body weight ratio, blood urea, serum creatinine, creatinine clearance, urinary N-acetyl beta-D-glucosaminidase (NAG), gamma glutamyl transpeptidase (GGT) and the urinary albumin excretion rate (UAER) were determined. Renal tissue catalase (CAT), glutathione reductase (GR), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 (HO-1), transforming growth factor beta-1 (TGF-ß1), tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) were also determined, along with mitochondrial complex I activity. In addition, portions of the kidney were subjected to histopathological and immunohistochemical examination. Results: Candesartan and/or CoQ10 induced significant improvement of renal and mitochondrial functions with significant increase in tissue CAT, GR, Nrf2 and HO-1 content associated with significant decrease in the kidney weight/body weight ratio, tissue TGF-ß1, TNF-α and IL-6 and alleviation of the histopathological and immunohistochemical changes as compared to carboplatin alone group. These effects were more significant in candesartan/CoQ10 combination group compared to either candesartan or CoQ10 alone. Conclusion: Candesartan/CoQ10 combination might represent a beneficial therapeutic modality for amelioration of carboplatin-induced nephrotoxicity.

Targeting proinflammatory cytokines, oxidative stress, TGF-ß1 and STAT-3 by rosuvastatin and ubiquinone to ameliorate trastuzumab cardiotoxicity.

The aim of this study was to assess the possible modulatory effects of rosuvastatin and/or ubiquinone on trastuzumab (TRZ)-induced cardiotoxicity in mice. One hundred and twenty mice were divided into six equal groups as follows: control group; TRZ group; TRZ+carboxymethyl cellulose group; TRZ+rosuvastatin group; TRZ+Ubiquinone group and TRZ+rosuvastatin+Ubiquinone group. Serum creatine kinase (CK-MB), lactate dehydrogenase (LDH), troponin I and N-terminal pro-B-type natriuretic peptide (NT-pro BNP) were measured. Also, tissue malondialdehyde (MDA), catalase (CAT), glutathione peroxidase (GPx), interleukin 6 (IL-6), transforming growth factor beta 1 (TGF-ß1) and signal transducers and activators of transcription-3 (STAT-3) were determined. Also, echocardiography was performed. Parts of the heart were subjected to histopathological, immunohistochemical and electron microscopic examination. Administration of rosuvastatin and/or ubiquinone to TRZ-treated mice induced significant increase in tissue GPx, CAT and STAT-3 with significant decrease in serum CK-MB, LDH, troponin I, NT-pro BNP, tissue MDA, TGF-ß1 and IL-6 and improved the histopathological, immunohistochemical, echocardiographic and electron microscopic changes compared to the group that received TRZ alone. These changes were significant in rosuvastatin/ubiquinone combination group compared to the use of each of these drugs alone. In conclusion, rosuvastatin/ubiquinone combination may represent a new therapeutic modality to ameliorate TRZ-induced cardiotoxicity.

Ameliorative potential of fluoxetine/raloxifene combination on experimentally induced breast cancer.

Breast cancer is one of the most common types of malignancies in females worldwide. Targeting the estrogen receptors alone with raloxifene (RAL) reduces the incidence of estrogen receptor positive tumors. Fluoxetine (FLX) is one of selective serotonin reuptake inhibitors that was proven to have anticancer properties. Our aim was to detect the effects of RAL/FLX combination on experimentally induced breast cancer. Eighty female Wistar rats were divided into four equal groups: 7,12-Dimethyl Benzanthracene (DMBA) induced breast cancer group, DMBA+RAL, DMBA+FLX and DMBA+RAL+FLX. Tumor volume, tissue malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and transforming growth factor beta1 (TGF-ß1) were determined in the tumor tissues. Parts of the tumor were subjected to histopathological examination. RAL or FLX alone or in combination induced significant increase in tumor CAT and SOD with significant decrease in tumor volume, tissue MDA, TNF-α, IL-6 and TGF-ß1 and alleviated the histopathological and immunohistochemical changes compared to DMBA group. In conclusion, RAL/FLX combination had a better effect than each of RAL or FLX alone against DMBA-induced breast cancer in rats which may represent a new therapeutic modality for management of breast cancer.

Anti-cancer and cardioprotective effects of indol-3-carbinol in doxorubicin-treated mice.

Doxorubicin (DOX) is a broad-spectrum antitumor antibiotic used in treatment of cancer. Its effect may be complicated by increased risk of cardiotoxicity. It was suggested that natural compounds with anticancer properties can be used in combination with DOX to decrease its dose and side effects. Indole-3-carbinol (I3C) is one of the phytochemicals that was shown to have anti-cancer effect. Our aim was to detect the possible chemosensitizing effects of I3C in DOX-induced cytotoxicity and the possible cardioprotective effects of I3C in DOX-induced cardiotoxicity. One hundred mice were divided into five equal groups: Control untreated group, solid Ehrlich carcinoma (SEC), SEC + DOX, SEC + I3C, SEC + DOX + I3C. Tumor volume, serum creatinine kinase and lactate dehydrogenase were measured. Also, tissue malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), sphingosine kinase-1 (SphK1) activity and interleukin-6 (IL-6) were determined. Parts of the tumor and cardiac tissues were subjected to histopathological examination. DOX or I3C alone or in combination induced significant increase in tumor CAT and SOD with significant decrease in tumor volume, tumor MDA, SphK1 activity and IL-6 and alleviated the histopathological changes with significant increase in the apoptotic index and significant decrease in tissue bcl2 compared to SEC group. Also, DOX induced cardiotoxicity which was ameliorated by I3C. In conclusion, DOX/I3C combination had a better effect than each of DOX or I3C alone against SEC in mice with marked improvement of the cardiotoxicity induced by DOX.

Chemopreventive and therapeutic potentials of thymoquinone in HepG2 cells: mechanistic perspectives.

Liver cancer is the fifth commonest malignancy worldwide and the third leading cause of death. Identifying novel curative and preventive therapy may improve its prognosis. In this study, thymoquinone (TQ), the most active biological ingredient of Nigella sativa Linn, was investigated for its antitumor activity. Mechanistic perspectives underlying this antitumor activity were explored by testing its effect on cell cycle, apoptosis, and angiogenesis. In addition, the chemopreventive effect of TQ was carried out by measuring its effect on phase I CYP1A1 and phase II glutathione S-transferase (GST) drug-metabolizing enzymes. The results of the present study revealed the effectiveness of TQ as an antitumor agent against different types of cancer including brain, colon, cervix and liver at both a time- and concentration-dependent manner. In HepG2 cells, it induced G2/M phase cell cycle arrest and a concentration-dependent increase in the percentage of apoptotic cells with an increase in the ratio of Bax/BCL-2. Moreover, the expression of mRNA and protein level of vascular endothelial growth factor decreased as the concentration of TQ increased. Our data showed a significant inhibition of induced phase I CYP1A1 enzyme, and elevation in the content of glutathione and activity of phase II enzyme GST, in HepG2 cells. Our results provide support for the beneficial use of TQ as a therapeutic and chemopreventive agent against liver cancer.