Publications by authors named "Nahla N Younis"

23 Publications

  • Page 1 of 1

Pachymic Acid Attenuated Doxorubicin-Induced Heart Failure by Suppressing miR-24 and Preserving Cardiac Junctophilin-2 in Rats.

Int J Mol Sci 2021 Oct 2;22(19). Epub 2021 Oct 2.

Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.

Defects in cardiac contractility and heart failure (HF) are common following doxorubicin (DOX) administration. Different miRs play a role in HF, and their targeting was suggested as a promising therapy. We aimed to target miR-24, a suppressor upstream of junctophilin-2 (JP-2), which is required to affix the sarcoplasmic reticulum to T-tubules, and hence the release of Ca in excitation-contraction coupling using pachymic acid (PA) and/or losartan (LN). HF was induced with DOX (3.5 mg/kg, i.p., six doses, twice weekly) in 24 rats. PA and LN (10 mg/kg, daily) were administered orally for four weeks starting the next day of the last DOX dose. Echocardiography, left ventricle (LV) biochemical and histological assessment and electron microscopy were conducted. DOX increased serum BNP, HW/TL, HW/BW, mitochondrial number/size and LV expression of miR-24 but decreased EF, cardiomyocyte fiber diameter, LV content of JP-2 and ryanodine receptors-2 (RyR2). Treatment with either PA or LN reversed these changes. Combined PA + LN attained better results than monotherapies. In conclusion, HF progression following DOX administration can be prevented or even delayed by targeting miR-24 and its downstream JP-2. Our results, therefore, suggest the possibility of using PA alone or as an adjuvant therapy with LN to attain better management of HF patients, especially those who developed tolerance toward LN.
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http://dx.doi.org/10.3390/ijms221910710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509247PMC
October 2021

Resveratrol Ameliorates Aortic Calcification in Ovariectomized Rats via SIRT1 Signaling.

Curr Issues Mol Biol 2021 Sep 5;43(2):1057-1071. Epub 2021 Sep 5.

Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.

Postmenopausal women are at an increased risk of vascular calcification which is defined as the pathological deposition of minerals in the vasculature, and is strongly linked with increased cardiovascular disease risk. Since estrogen-replacement therapy is associated with increased cancer risk, there is a strong need for safer therapeutic approaches. In this study we aimed to investigate the protective and therapeutic effects of the phytoestrogen resveratrol against vascular calcification in ovariectomized rats, a preclinical model of postmenopause. Furthermore, we aimed to compare the effects of resveratrol to those of estrogen and to explore the mechanisms underpinning those effects. Treatment with resveratrol or estrogen ameliorated aortic calcification in ovariectomized rats, as shown by reduced calcium deposition in the arterial wall. Mechanistically, the effects of resveratrol and estrogen were mediated via the activation of SIRT1 signaling. SIRT1 protein expression was downregulated in the aortas of ovariectomized rats, and upregulated in rats treated with resveratrol or estrogen. Moreover, resveratrol and estrogen reduced the levels of the osteogenic markers: runt-related transcription factor 2 (RUNX2), osteocalcin and alkaline phosphatase (ALP) which have been shown to play a role during vascular calcification. Additionally, the senescence markers (p53, p16 and p21) which were also reported to play a role in the pathogenesis of vascular calcification, were reduced upon treatment with resveratrol and estrogen. In conclusion, the phytoestrogen resveratrol may be a safer alternative to estrogen, as a therapeutic approach against the progression of vascular calcification during postmenopause.
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http://dx.doi.org/10.3390/cimb43020075DOI Listing
September 2021

Potential therapeutic efficacy of pachymic acid in chronic kidney disease induced in rats: role of Wnt/β-catenin/renin-angiotensin axis.

J Pharm Pharmacol 2021 Sep 21. Epub 2021 Sep 21.

Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.

Objectives: Chronic kidney disease (CKD) is a major public health problem associated with high mortality. The therapeutic effects of pachymic in CKD management and its underlying mechanisms have not been studied. Therefore, we aimed to investigate the possible inhibitory effect of PA on renal Wnt/β-catenin signalling in CKD.

Methods: CKD was induced in rats by doxorubicin (DOX; 3.5 mg/kg i.p., twice weekly for 3 weeks). Rats were treated orally with PA (10 mg/kg/day), LOS (10 mg/kg/day) or their combination (PA + LOS) for 4 weeks starting after the last dose of DOX.

Key Findings: DOX-induced renal injury was characterized by high serum cystatin-C, and urine albumin/creatinine ratio, renal content of podocin and klotho were decreased. Tumour necrosis factor-α, interleukin-6, interleukin-1β, Wnt1, active β-catenin/total β-catenin ratio and fibronectin along with mRNA expression of RENIN, ACE and AT1 were increased in renal tissues. Treatment with either PA or LOS ameliorated all DOX-induced changes. The combined treatment was more effective in improving all changes than monotherapy.

Conclusions: These results suggest a new therapeutic benefit of PA in ameliorating CKD in rats through its up-regulatory effect on renal klotho thereby preventing Wnt/β-catenin reactivation and RAS gene expression. PA/LOS combination provided an additional inhibition of Wnt/β-catenin signalling and its downstream targets.
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http://dx.doi.org/10.1093/jpp/rgab129DOI Listing
September 2021

Alleviation of fructose-induced Alzheimer's disease in rats by pioglitazone and decaffeinated green coffee bean extract.

J Food Biochem 2021 05 29;45(5):e13715. Epub 2021 Mar 29.

Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.

Increased fructose consumption is among bad nutritional habits that contribute to increased incidence of neurodegenerative diseases. We proposed that coffee, the most popular beverage worldwide, may protect against the progression of Alzheimer's disease (AD). We investigated the protective potential of decaffeinated green coffee bean extract (GCBE) and the possible potentiation of pioglitazone (PIO) effects by decaffeinated GCBE in fructose-induced AD in rats. Twenty-four rats [12-untreated and 12-pre-treated (for 4 weeks) with GCBE] consumed drinking water supplemented with 10% fructose for 18 weeks. Twelve of these rats (6-GCBE-untreated and 6-GCBE-pre-treated) were treated orally with PIO starting on the 13th week for 6 weeks. Prophylactic administration of GCBE attenuated oxidative damage (increased cortical reduced glutathione and superoxide dismutase activity), while decreased malondialdehyde. It retarded the activation of acetylcholine esterase, increased acetylcholine level in the cortex of fructose-induced AD. It also impeded the upregulation of beta-secretase-1and the accumulation of Aβ plaques that were induced by fructose drinking. With PIO therapy, GCBE showed better effects alleviating oxidative stress and Aβ extracellular plaques formation, while improving cholinergic activity, learning, and memory ability. In conclusions, the consumption of GCBE may protect against the development of AD and delay the progression of AD when given with PIO. PRACTICAL APPLICATIONS: Decaffeinated dietary supplement of green coffee bean extract attenuated the deleterious consequences of fructose-induced Alzheimer's disease in rats. It improved the antioxidant status and cortical cholinergic activity, while hindered the changes responsible for amyloid plaque formation. It also improved the impaired learning and memory. These results, if confirmed by clinical studies, may recommend the consumption of decaffeinated green coffee beans extract as dietary supplement or as a regular beverage to protect against AD in individuals with family history or early signs of AD. With pioglitazone, such dietary supplement improved pioglitazone efficacy and delayed the progression of AD.
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http://dx.doi.org/10.1111/jfbc.13715DOI Listing
May 2021

The efficacy of bone marrow-derived mesenchymal stem cells and/or erythropoietin in ameliorating kidney damage in gamma irradiated rats: Role of non-hematopoietic erythropoietin anti-apoptotic signaling.

Life Sci 2021 Jun 24;275:119388. Epub 2021 Mar 24.

Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt. Electronic address:

Radiation-induced multiple organ injury, including γ-radiation nephropathy, is the most common. Even with dose fractionation strategy, residual late side effects are inevitable. Bone marrow-derived mesenchymal stem cells (BM-MSCs) transplantation and erythropoietin (EPO) have shown to be effective in treating chronic kidney disease and associated anemia. This study aimed to evaluate the effect of BM-MSCs and/or EPO in fractionated γ-irradiation induced kidney damage in rats. Adult male Wistar rats were randomized into 2 groups; normal and 8 Gy (fractionated dose of 2 Gy for 4 days) γ-irradiated rats. Animal from both groups were subdivided to receive the following treatments: BM-MSCs (1 × 10 cells/rat, i.v - once), EPO (100 IU/kg, i.p - every other day for 30 days) or their combined treatment (BM-MSCs and EPO). γ-Irradiated rats showed a noticeable elevation in serum urea and creatinine, kidney malondialdehyde (MDA) and caspase 3 activity. They also revealed significant drop in kidney glutathione (GSH) and Bcl2 protein contents. Conspicuously, they revealed down-regulation of renal EPO signaling (EPO, EPOR, pJAK2, pPI3K and pAkt). Conversely, groups treated with BM-MSCs and/or EPO revealed significant modulation in most tested parameters and appeared to be effective in minimizing the hazard effects of radiation. In conclusion, BM-MSCs and/or EPO exhibited therapeutic potentials against nephrotoxicity induced by fractionated dose of γ-irradiation. An effect mediated by antioxidant and non-hematopoietic EPO downstream anti-apoptotic signaling (PI3K/Akt) pathway. EPO potentiate the repair capabilities of BM-MSCs making this combined treatment a promising therapeutic strategy to overcome radiotherapy-induced kidney damage.
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http://dx.doi.org/10.1016/j.lfs.2021.119388DOI Listing
June 2021

Inactivation of Wnt/β-catenin/renin angiotensin axis by tumor necrosis factor-alpha inhibitor, infliximab, ameliorates CKD induced in rats.

Biochem Pharmacol 2021 03 20;185:114426. Epub 2021 Jan 20.

Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.

Infliximab (IFX), a chimeric monoclonal antibody against tumor necrosis factor-α (TNF-α), is widely used to treat autoimmune diseases and chronic diseases associated with inflammation. TNF-α was reported to inhibit klotho, reactivate β-catenin and cause tubular cell injury in vitro. Whether the inhibition of TNF-α can regulate Wnt/β-catenin pathway via klotho in CKD in vivo is not studied yet. We aimed to investigate the impact of IFX on Wnt/β-catenin pathway in doxorubicin (DOX)-induced nephropathy. Doxorubicin (3.5 mg/kg; i.p., twice weekly for 3 weeks) increased serum cystatin-C, urine albumin/creatinine ratio (UACR), but depleted renal podocin. It markedly increased renal contents of TNF-α, interleukin-6 (IL-6), interleukin-1β (IL1β). DOX decreased the renal expression of klotho which in turn increased Wnt1, active β-catenin/total β-catenin ratio in renal tissue. Significant increase in renal gene expression of RENIN, ACE, and AT1 was observed. Moreover, renal fibronectin and collagen deposition increased in renal tissue. Treatment with either IFX (5 mg/kg, once; i.p.), losartan (LOS, 10 mg/kg/day, orally) or their combination significantly improved renal function, inhibited inflammatory cytokines and fibrosis. Renal TNF-α was negatively correlated with renal klotho. On the hand, it was positively correlated with renal Wnt1 and active β-catenin/total β-catenin ratio. The combined IFX and LOS treatment was the most effective in improving all studied parameters. In conclusion, this study proved, for the first time, the inhibitory effect of IFX on renal Wnt/β-catenin signaling in DOX-induced nephropathy in vivo by up-regulating renal klotho. Therefore, these results suggest a new role for IFX in chronic kidney disease via targeting renal Wnt/β-catenin/renin angiotensin axis.
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http://dx.doi.org/10.1016/j.bcp.2021.114426DOI Listing
March 2021

Modulation of NADPH oxidase and Nrf2/HO-1 pathway by vanillin in cisplatin-induced nephrotoxicity in rats.

J Pharm Pharmacol 2020 Nov 3;72(11):1546-1555. Epub 2020 Aug 3.

Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.

Objectives: To investigate the protective effect of vanillin in cisplatin (CP)-induced nephrotoxicity in rats and elucidate the role of nrf-2 and its downstream antioxidant molecules.

Methods: Rats received vanillin (100 mg/kg orally) for 10 constitutive days and CP (7.5 mg/kg, once, ip) on day 6 of vanillin administration.

Key Findings: Cisplatin suppressed body weight gain, increased serum urea and creatinine and renal malondialdehyde and nitric oxide while decreased renal total antioxidant capacity. Up-regulation of NADPH oxidase-4 (NOX-4) was marked in renal tissue of CP-treated rats along with down-regulation of the antioxidant genes (nuclear factor erythroid 2-related factor2 (NRF2) and haem oxygenase-1(HO-1)). Increased tumour necrosis factor-α and decreased interleukin-10 with increased myeloperoxidase activity were apparent in renal tissue of CP-treated rats along with marked tubular injury, neutrophil infiltration and increased apoptosis (caspase-3) and some degree of interstitial fibrosis. Vanillin prophylactic administration prevented the deterioration of kidney function, oxidative and nitrosative stress. It also suppressed NOX-4 and up-regulated NRF2 and HO-1 expression in renal tissue. Inflammation, apoptosis and tubular injury were also inhibited by vanillin.

Conclusions: The antioxidant mechanism by which vanillin protected against CP-induced nephrotoxicity involved the inhibition of NOX-4 along with the stimulation of Nrf2/HO-1 signalling pathway. These in turn inhibited inflammation and apoptosis.
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http://dx.doi.org/10.1111/jphp.13340DOI Listing
November 2020

Contribution of aorta glycosaminoglycans and PCSK9 to hyperlipidemia in experimental rabbits: the role of 10-dehdrogingerdione as effective modulator.

Mol Biol Rep 2019 Aug 2;46(4):3921-3928. Epub 2019 May 2.

Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.

10-Dehydrogingerdione (10-DHGD) was previously reported to possess a hypolipidemic, anti-inflammatory and anti-oxidant properties in hyperlipidemic rabbit model. In this study, we investigated a possible new role for 10-DHGD in modulating atherogenic lipid profile by targeting proprotein convertase subtilisin kexin-9 (PCSK-9). Cholesterol (0.2% w/w)-fed rabbits received either atorvastatin (20 mg/kg) or 10-DHGD (10 mg/kg) for 12 weeks along with cholesterol feeding (HCD). Lipid profile, serum PCSK-9 and macrophage migration inhibitory factor (MIF), and aorta level of tumor necrosis factor-alpha (TNF-α) and glycosaminoglycans (GAGs) were measured. HCD-fed rabbits revealed an atherogenic lipid profile along with increased serum level of PCSK-9 (p < 0.001) and increased serum MIF and aortic TNF-α and GAGs (p < 0.001). 10-DHGD administration to HCD-fed rabbits prevented this atheogenicity by modulating the release of PCSK-9, inflammation extent (serum MIF and aortic TNF-α) and GAGs. These results provide new insights on the hypolipidemic potential of 10-DHGD. The effects of 10-DHGD was superior to that of atorvastatin in most studied parameters modulating atherogenicity. 10-DHGD is found to be able to suppress the release of PCSK-9, decrease aortic expression of GAGs in cholesterol-fed rabbits and halt the inflammation extent. These effects may provide new insights on the hypolipidemic potential of 10-DHGD.
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http://dx.doi.org/10.1007/s11033-019-04836-1DOI Listing
August 2019

The modulation of PCSK-9 and GAGs by 10-dehydrogingerdione and pentoxifylline in hyperlipidemic rabbits.

Nat Prod Res 2020 Aug 22;34(16):2372-2377. Epub 2018 Dec 22.

Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.

The hypolipidemic effect of 10-DHGD was previously reported owing to its anti-inflammatory and anti-oxidant properties. We further investigated the anti-inflammatory role of 10-DHGD in modulating atherogenicity by targeting proproteinconvertasesubtilisinkexin-9 (PCSK-9). Rabbits fed high cholesterol diet (HCD) containing 0.2% w/w cholesterol for12-weeks received either 10-DHGD (10-mg/kg), pentoxifylline (PTX, 40-mg/kg) or their combination concurrently with HCD. Lipid profile, serum PCSK-9, macrophage migration inhibitory factor (MIF), aorta tumor necrosis factor- alpha (TNF-α) and glycosaminoglycans (GAGs) were measured. Atherogenicity and increased PCSK-9, MIF and TNF-α and GAGs ( < 0.001) was proved HCD-fed rabbits. The concurrent administration of 10-DHGD or PTX with HCD feeding prevented this atheogenicity by modulating the release of PCSK-9, inflammatory markers and GAGs. The combined PTX and 10-DHGD in HCD fed rabbits not only lowered hyperlipidemia, but also targeted arterial inflammation to a better extent. In conclusion PTX and 10-DHGD can prevent hyperlipidemia and associated inflammatory process modifying factors predisposing to atherosclerosis.
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http://dx.doi.org/10.1080/14786419.2018.1536134DOI Listing
August 2020

Modulation of brain insulin signaling in Alzheimer's disease: New insight on the protective role of green coffee bean extract.

Nutr Neurosci 2020 Jan 1;23(1):27-36. Epub 2018 May 1.

Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.

Alzheimer's disease (AD), a neurodegenerative disorder, involves brain insulin signaling cascades and insulin resistance (IR). Because of limited treatment options, new treatment strategies are mandatory. Green coffee bean extract (GCBE) was reported to attenuate IR and improve brain energy metabolism. We aimed to investigate the possible use of GCBE as a prophylactic strategy to delay the onset of AD or combined with pioglitazone (PIO) as a strategy to retard the progression of AD. Rats received 10% fructose in drinking water for 18 weeks to induce AD. GCBE-prophylactic group received GCBE for 22 weeks started 4 weeks prior to fructose administration. The PIO group treated with PIO for 6 weeks started on week 12 of fructose administration. The GCBE+PIO group received GCBE for 22 weeks started 4 weeks prior to fructose administration and treated with PIO for the last 6 weeks of fructose administration. Pretreatment with GCBE, either alone or combined with PIO, alleviated IR-induced AD changes. GCBE improved cognition, decreased serine phosphorylation of insulin receptor substrate, increased phosphoinositol-3 kinase (PI3K) activity and protein kinase B (Akt) gene expression, decreased glycogen synthase kinase-3β (GS3Kβ) gene expression and Tau hyperphosphorylation. GCBE exerted neuroprotective effects against IR-induced AD mediated by alleviating IR and modulating brain insulin signaling cascade.
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http://dx.doi.org/10.1080/1028415X.2018.1468535DOI Listing
January 2020

10-DHGD ameliorates cisplatin-induced nephrotoxicity in rats.

Biomed Pharmacother 2016 Oct 1;83:241-246. Epub 2016 Jul 1.

Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.

Organs subjected to chronic injuries may develop tissue fibrosis. Several factors contribute to the combat injurious stimuli to repair, heal and alleviate any disturbance. Secretion of chemokines, migration of inflammatory cells to the affected site and activation of fibroblast for production of extracellular matrix (ECM) are examples. Recently, few studies have delt with 10-dehydrogingerdione (10-DHGD), one of the active constituent of ginger extracts that has been published. This constituent proved to be potent antioxidant, anti-inflammatory, cholesterol ester transfer protein (CETP) inhibitor, indeed, a hypolipemic agent. It has been selected in the present study as a natural anti-inflammatory agent to combat inflammation, nephrotoxicity and renal fibrosis-induced by cisplatin. Renal fibrosis state demonstrated a significant increase in creatinine, urea, nuclear factor kappa (NF-kB), insulin like growth factor I (IGF-I), fibroblast growth factor-23 (FGF-23) along with a significant decrease of hepatocytes growth factor (HGF), renal glutathione (GSH) and in confirm to histopathological examination of kidney tissue. Administration of 10-DHGD orally daily for 4 weeks resulted in a significant improvement of both the biomarkers studied in addition to the histopathological profile of the renal tissues.

Conclusion: 10-DHGD exhibited a marked anti-inflammatory potential, alleviated to a great extent of nephrotoxicity and renal fibrosis induced by cisplatin.
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http://dx.doi.org/10.1016/j.biopha.2016.06.032DOI Listing
October 2016

Silymarin preconditioning protected insulin resistant rats from liver ischemia-reperfusion injury: role of endogenous H2S.

J Surg Res 2016 08 24;204(2):398-409. Epub 2016 May 24.

Department of Pharmacology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt. Electronic address:

Background: Hydrogen sulfide (H2S) can protect against hepatic ischemia-reperfusion injury (HIR). However, it is unknown whether it can protect against HIR in insulin resistance. This study investigated the protective effects of silymarin against HIR in a rat model of insulin resistance and the possible involvement of endogenous H2S.

Materials And Methods: Insulin resistance was first established using 10% fructose in drinking water for 10 weeks. HIR was conducted in fructose-fed rats treated with saline or silymarin (100 mg/kg), 15 min before HIR (30 min ischemia, followed by 1 h reperfusion). Insulin resistance and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), total nitrites (NO2(-)), and H2S were measured. Hepatic malondialdehyde (MDA), reduced glutathione (GSH), hydroxyproline, H2S synthesizing activity, and mRNA expression of cystathionine β-synthase (CBS) or cystathionine γ-lyase (CSE) were determined. Additionally, histopathological examination involved H&E, Sirius red, and caspase-3 immunostaining.

Results: Fructose-induced insulin resistance increased serum ALT, TNF-α, H2S and H2S synthesizing activity, and hepatic MDA, hydroxyproline, and CSE mRNA and decreased NO2(-) and GSH. These changes exacerbated the HIR injury in which endogenous H2S production was auxiliary increased. Silymarin preconditioning decreased ALT, AST, MDA, NO2(-), TNF-α, and TNF-α/IL-10 ratio, increased GSH, IL-10, improved hepatic architecture, and lowered caspase-3 immunostaining. Serum H2S, its hepatic synthesizing activity, and CSE and CBS mRNA expressions were all suppressed by silymarin pretreatment.

Conclusions: The increases in endogenous H2S exacerbate HIR injury, whereas silymarin preconditioning protected against HIR in insulin resistant rats via powerful antioxidant, anti-inflammatory, and antiapoptotic effects along with suppressing H2S production.
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http://dx.doi.org/10.1016/j.jss.2016.04.069DOI Listing
August 2016

The synergistic effect between vanillin and doxorubicin in ehrlich ascites carcinoma solid tumor and MCF-7 human breast cancer cell line.

Pathol Res Pract 2016 Sep 22;212(9):767-77. Epub 2016 Jun 22.

Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt. Electronic address:

Despite the remarkable anti-tumor activity of doxorubicin (DOX), its clinical application is limited due to multiple organ toxicities. Products with less side effects are therefore highly requested. The current study investigated the anti-cancer activities of vanillin against breast cancer and possible synergistic potentiation of DOX chemotherapeutic effects by vanillin. Vanillin (100mg/kg), DOX (2mg/kg) and their combination were administered i.p. to solid Ehrlich tumor-bearing mice for 21days. MCF-7 human breast cancer cell line was treated with vanillin (1 and 2mM), DOX (100μM) or their combination. Protection against DOX-induced nephrotoxicity was studied in rats that received vanillin (100mg/kg, ip) for 10days with a single dose of DOX (15mg/kg) on day 6. Vanillin exerted anticancer effects comparable to DOX and synergesticlly potentiated DOX anticancer effects both in-vivo and in-vitro. The anticancer potency of vanillin in-vivo was mediated via apoptosis and antioxidant capacity. It also offered an in-vitro growth inhibitory effect and cytotoxicity mediated by apoptosis (increased caspase-9 and Bax:Bcl-2 ratio) along with anti-metasasis effect. Vanillin protected against DOX-induced nephrotoxicity in rats. In conclusion, vanillin can be a potential lead molecule for the development of non-toxic agents for the treatment of breast cancer either alone or combined with DOX.
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http://dx.doi.org/10.1016/j.prp.2016.06.004DOI Listing
September 2016

Bone marrow-derived mesenchymal stem cells effectively regenerate fibrotic liver in bile duct ligation rat model.

Exp Biol Med (Maywood) 2016 Mar 24;241(6):581-91. Epub 2016 Jan 24.

Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.

Mesenchymal stem cells (MSCs) have attracted lots of attention for the treatment of acute liver failure and end-stage liver diseases. This study aimed at investigating the fundamental mechanism by which bone marrow-derived MSCs (BM-MSCs) induce liver regeneration of fibrotic liver in rats. Rats underwent bile duct ligation (BDL) surgery and four weeks later they were treated with either BM-MSCs (3 × 10(6) cells /rat, once, tail vein injection) or silymarin (100 mg/kg, daily, orally) for four weeks. Liver function tests and hepatic oxidative stress were determined. Hepatic injury and fibrosis were assessed by H and E, Sirus red staining and immunohistochemical expression of α-smooth muscle actin (α-SMA). Hepatocyte growth factor (HGF) and the gene expression of cytokeratin-19 (CK-19) and matrix metalloproteinase-2 (MMP-2) in liver tissue were determined. BDL induced cholestatic liver injury characterized by elevated ALT and AST activities, bilirubin and decreased albumin. The architecture damage was staged as Metavir score: F3, A3. Fibrosis increased around proliferating bile duct as indicated by sirus red staining and α-SMA immunostaining. Fibrogenesis was favored over fibrolysis and confirmed by decreased HGF with increased expression of CK-19, but decreased MMP-2 expression. BM-MSCs treatment restored deteriorated liver functions and restored the histological changes, resolved fibrosis by improving liver regenerative capabilities (P < 0.001), increases in HGF and MMP-2 mRNA and downregulating CK-19 mRNA. Sliymarin, however, induced similar but less prominent effects compared to BM-MSCs. In conclusion, liver regenerative capabilities can be stimulated by BM-MSCs via augmentation of HGF that subsequently up-regulate MMP-2 mRNA while downregulating CK-19 mRNA.
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http://dx.doi.org/10.1177/1535370215627219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950332PMC
March 2016

10-Dehydrogingerdione raises HDL-cholesterol through a CETP inhibition and wards off oxidation and inflammation in dyslipidemic rabbits.

Atherosclerosis 2013 Dec 9;231(2):334-40. Epub 2013 Oct 9.

Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt. Electronic address:

Objective: To investigate the CETP suppression by 10-dehydrogingerdione, a compound in Zingiber officinale, and its effect on the progression of atherosclerosis in dyslipidemic rabbits and the underlying oxidative and inflammatory consequences.

Methods: Twenty-four New Zealand male rabbits were fed either a normal diet or an atherogenic diet. The rabbits on the atherogenic diet received treatments of atorvastatin or 10-dehydrogingerdione and placebo concurrently (n = 6/group). Blood samples were collected after three and six weeks for biochemical analysis.

Results: 10-Dehydrogingerdione-treated rabbits showed a significant improvement in serum lipids especially HDL-C in a time-dependant manner. This effect was correlated to its ability to lower CETP. Lp(a), ox-LDL, hsCRP, homocysteine and MMP9 decreased significantly in both 10-dehydrogingerdione- and atorvastatin-treated rabbits compared with placebo (p < 0.001). Lp(a) achieved normal values by both treatments, while homocysteine did not reach normal values by either treatments. Conversely, MMP9 returned below normal values by 10-dehydrogingerdione (p < 0.001), hsCRP and ox-LDL were slightly below normal values (hsCRP: p < 0.001; ox-LDL: p < 0.001 and p < 0.05 in 10-dehydrogingerdione and atorvastatin groups, respectively). The effect achieved by 10-dehydrogingerdione was similar to that of atorvastatin on hsCRP and Lp(a). However, 10-dehydrogingerdione exerted better effect than atorvastatin on homocysteine, MMP9 (p < 0.001) and ox-LDL (p < 0.05).

Conclusions: In a rabbit dyslipidemic model, 10-dehydrogingerdione lowers LDL-C and raises HDL-C by suppressing CETP; an effect that modulates inflammatory and oxidative risk factors of CVD. These findings suggested that the naturally occurring 10-dehydrogingerdione might be a potential CETP inhibitor for the treatment of atherosclerosis and residual risk in CVD.
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http://dx.doi.org/10.1016/j.atherosclerosis.2013.09.024DOI Listing
December 2013

Pyridoxamine, an inhibitor of protein glycation, in relation to microalbuminuria and proinflammatory cytokines in experimental diabetic nephropathy.

Exp Biol Med (Maywood) 2013 Aug;238(8):881-8

Biochemistry Department, Faculty of Pharmacy, Zagazig University, Egypt.

Diabetic nephropathy (DN) is one of the major complications that develop as consequence of chronic and uncontrolled hyperglycaemia. Hyperglycaemia initiates various processes, one of which is protein glycation, leading to the formation of advanced glycation end products. Alteration of intracellular signalling, gene expression, release of proinflammatory molecules and free radicals are examples of such changes and they contribute to the initiation of diabetic complications. In the current manuscript, we studied the effect of pyridoxamine (PM) on protein glycation, oxidative stress, interleukin-1α (IL-1α), IL-6, C-reactive protein (CRP), gene expression of tumour necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) in relation to microalbuminuria and kidney functions in a model of alloxan-induced diabetic rats. We have observed that onset of microalbuminuria has preceded the gradual increase of blood sugar level in diabetic rats. In diabetic rats, gene expression of TNF-α and TGF-β1 recorded a gradual increase and marked increase was observed after one and two weeks of alloxan administration, in comparison with normal rats. PM induced significant decrease in kidney malondialdehyde content and the gene expression of TNF-α and TGF-β1, in addition to levels of serum glucose, fructosamine, urea, creatinine, IL-1α, IL-6, CRP and urine microalbumin. Histopathological examination of kidney tissues showed certain improvements as compared with diabetic control. In conclusion, our results may provide a supporting evidence for the therapeutic benefit of PM in DN.
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http://dx.doi.org/10.1177/1535370213494644DOI Listing
August 2013

Small dense LDL is more susceptible to glycation than more buoyant LDL in Type 2 diabetes.

Clin Sci (Lond) 2013 Mar;124(5):343-9

Cardiovascular Research Group, School of Biomedicine, University of Manchester, Manchester, UK.

Glycation of apoB (apolipoprotein B) of LDL (low-density lipoprotein) increases its atherogenicity. Concentrations of both serum glyc-apoB (glycated apoB) and SD-LDL (small dense LDL) (syn LDL3; D=1.044-1.063 g/ml) are increased in diabetes and are closely correlated. We studied whether SD-LDL is more susceptible to glycation in vitro than more buoyant LDL in statin- and non-statin-treated Type 2 diabetes mellitus. Serum SD-LDL apoB and glyc-apoB on statins was 20±2 (means±S.D.) and 3.6±0.41 compared with 47±3 and 5.89±0.68 mg/dl in those not receiving statins (P<0.001 and <0.01, respectively). There was a dose-dependent increase in glycation on incubation of LDL subfractions with glucose, which was accompanied by an increase in LPO (lipid peroxide) and electrophoretic mobility and a decrease in free amino groups. SD-LDL was more susceptible to these changes than more buoyant LDL. Both SD-LDL and more buoyant LDL from statin-treated patients were less susceptible to glycation. There were fewer free amino groups on LDL subfractions from statin-treated patients, which may contribute to this resistance. In conclusion, greater susceptibility of SD-LDL to glycation is likely to contribute to the raised levels of circulating glyc-apoB in diabetes. Statins are associated with lower levels of both SD-LDL and glyc-apoB.
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http://dx.doi.org/10.1042/CS20120304DOI Listing
March 2013

High-density lipoprotein impedes glycation of low-density lipoprotein.

Diab Vasc Dis Res 2013 Mar 13;10(2):152-60. Epub 2012 Aug 13.

Cardiovascular Research Group, School of Biomedicine, University of Manchester, UK.

Glycation of low-density lipoprotein (LDL) increases its atherogenicity, but whether high-density lipoprotein (HDL) can protect LDL against glycation is not known. LDL and HDL were isolated from 32 volunteers with serum HDL cholesterol concentrations ranging from 0.76 to 2.01 (mean = 1.36) mmol/L. Glycation of LDL was induced by incubation with 0-80 mmol/L glucose for 7 days at 37°C under nitrogen in the presence of and absence of human HDL. Glycation of LDL apolipoprotein B (apoB) doubled at glucose 50 and 80 mmol/L (both p < 0.001), and this increase was ameliorated by HDL. In the absence of glucose, 0.11 (0.01) [mean (standard error, SE)] mg apoB/mg LDL protein was glycated increasing to 0.22 (0.02) mg/mg at glucose 80 mmol/L in the absence of HDL, but remaining at 0.13 (0.01) mg/mg when autologous HDL was present. Heterologous HDL from a further study of 12 healthy participants was similarly effective in impeding LDL apoB glycation. HDL impeded not only glycation but also the lipid peroxidation, free amino group consumption and increased electrophoretic mobility of LDL which accompanied glycation. HDL from participants with higher serum paraoxonase1 (PON1) was more effective in impeding glycation and the related processes. In conclusion, HDL can impede the glucose-induced glycoxidation of LDL. PON1 may be important for this function of HDL.
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http://dx.doi.org/10.1177/1479164112454309DOI Listing
March 2013

Apolipoprotein B100 is a better treatment target than calculated LDL and non-HDL cholesterol in statin-treated patients.

Ann Clin Biochem 2011 Nov 17;48(Pt 6):566-71. Epub 2011 Oct 17.

Cardiovascular Research Group, School of Biomedicine, Core Technology Facility, 3rd Floor, University of Manchester, 46 Grafton Street, Manchester M13 9NT, UK.

Introduction: Clinical trials have shown that apolipoprotein B100 (apoB) is better than calculated low-density lipoprotein cholesterol (c-LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) as a target for statin treatment. However, there are no published reports of how well these targets are reached in patients with more severe hyperlipidaemias than represented in trials, as seen in lipid clinics.

Methods: We audited 195 patients attending a tertiary centre lipid clinic, who had been treated with a statin for more than one year. We measured total cholesterol, HDL-cholesterol (HDL-C) and triglyceride and from these calculated LDL-cholesterol (LDL-C) and non-HDL-C. We determined the average measured apoB values, at critical target values of LDL-C and non-HDL-C, by linear regression and compared them with values of apoB considered equivalent to these cholesterol indexes by expert groups. We also assessed the number of patients, both before and after treatment, in whom c-LDL-C and non-HDL-C could not be calculated due to hypertriglyceridaemia.

Results: At the LDL-C target of 2.6 mmol L(-1) and the non-HDL-C target of 3.4 mmol L(-1), the measured apoB values were significantly higher than consensus apoB target values. The difference was most marked for c-LDL-C in hypertriglyceridaemic subjects and for non-HDL-C in patients without hypertriglyceridaemia. A similar pattern was seen using centile-derived consensus values but the differences were accentuated because this approach generates lower equivalent consensus apoB values.

Conclusion: ApoB offers a more consistent treatment target independent of hypertriglyceridaemia and would obviate technical problems related to high triglycerides.
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http://dx.doi.org/10.1258/acb.2011.010277DOI Listing
November 2011

Small-dense LDL and LDL glycation in metabolic syndrome and in statin-treated and non-statin-treated type 2 diabetes.

Diab Vasc Dis Res 2010 Oct 27;7(4):289-95. Epub 2010 Sep 27.

Cardiovascular Research Group, School of Clinical & Laboratory Sciences, University of Manchester, UK.

Small-dense LDL (SD-LDL) has been particularly implicated in atherosclerosis. It has previously been reported that in non-diabetic people SD-LDL is preferentially glycated. The distribution of glycated apolipoprotein B (glyc-apoB) in lipoproteins in metabolic syndrome (MS) and in type 2 diabetes has not previously been studied. Plasma apoB and glyc-apoB were determined in different apoB-containing lipoproteins including buoyant and SD-LDL in MS (n=18) and type 2 diabetes (DM) [n=48; 12 statin-untreated (DM-S) and 36 statin-treated (DM+S)]. Plasma glyc-apoB was 5.6 ± 0.9, 3.5 ± 0.5 and 4.0 ± 0.2 mg/dl in DM-S, DM+S and MS, respectively. The glycated proportion of SD-LDL-apoB was greater than buoyant LDL in all groups. SD-LDL contributed most to plasma glyc-apoB in DM-S, because SD-LDL-apoB was higher in DM-S than in MS and DM+S (p < 0.001). Plasma glyc-apoB correlated with SD-LDL-apoB (r=0.74, p < 0.0001 in diabetes and r=0.53, p < 0.001 in MS), but not with HbA(1c). SD-LDL is preferentially glycated in type 2 diabetes and MS. Its concentration is a stronger determinant of plasma glycapoB than glycaemia. Statin-induced changes in its level may be important in decreasing apoB glycation in diabetes. These findings may explain the small effect of improving glycaemia relative to statin treatment in reducing atherosclerosis risk in type 2 diabetes and the increased risk in MS even before the onset of type 2 diabetes.
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http://dx.doi.org/10.1177/1479164110383063DOI Listing
October 2010

Gastritis induced by Helicobacter pylori infection in experimental rats.

Dig Dis Sci 2010 Oct 22;55(10):2770-7. Epub 2010 Jan 22.

Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.

Background: Gastritis, an inflammation of gastric mucosa, may be due to many pathological factors and infection, such as with Helicobacter pylori. The use of experimental models of gastritis is important to evaluate the biochemical changes and study chemotherapeutic intervention. In a previous study we demonstrated an acute gastritis model induced by iodoacetamide.

Aims: Our objective in this study was to evaluate a new gastritis model induced by H. pylori infection in experimental rats in terms of certain biomarkers in serum and mucosal tissues in addition to histopathological examination.

Methods: Gastritis was induced in 20 albino Wistar rats by H. pylori isolated from antral biopsy taken from a 49-year-old male patient endoscopically diagnosed as having H. pylori infection. Another ten rats were used as controls. Serum gastrin, pepsinogen I activity, interleukin-6 (IL-6) and gastric mucosal myeloperoxidase (MPO) activity and prostaglandin E(2) (PGE(2)) were measured. Immunostaining for inducible nitric oxide synthase (iNOS), nitrotyrosine and DNA fragmentation were used to further evaluate H. pylori-induced gastritis.

Results: Serum gastrin, IL-6, mucosal MPO activity, and PGE(2) demonstrated significant increases joined with a decreased serum pepsinogen I activity (P < 0.001). Immunohistochemistry demonstrated positive reaction for iNOS, nitrotyrosine and DNA fragmentation.

Conclusions: Helicobacter pylori-induced gastritis models demonstrated massive oxidative stress and pronounced injury in mucosal tissue. Since our model in rats reflected the clinical picture of H. pylori infection, it can be considered as a consistent model to study chemotherapeutic intervention for this type of gastritis.
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http://dx.doi.org/10.1007/s10620-009-1103-yDOI Listing
October 2010

Variation in paraoxonase-1 activity and atherosclerosis.

Curr Opin Lipidol 2009 Aug;20(4):265-74

University Department of Medicine, Central Manchester and Manchester Children's University Hospitals Foundation Trust, Manchester, UK.

Purpose Of Review: Paraoxonase-1 (PON1) is an HDL-associated protein of 354 amino acids with a molecular mass of 43 000 Da. It is synthesized in the liver, and in serum it is almost exclusively associated with HDL. PON1 has been reported to be an important contributor to the antioxidant and anti-inflammatory activities of HDL. PON1 impedes oxidative modification of LDL. PON1 serum activity is related to systemic lipid peroxidation stress and prospective cardiovascular risk. In this review, we discuss the relationship between PON1 activity and atherosclerotic diseases and various factors modulating PON1 activity including genes, age, lifestyle factors and medical conditions. Finally, evidence that pharmacological agents may affect PON1 activity is summarized.

Recent Findings: There is increasing evidence from both animal and human studies linking low PON1 activity to an increased likelihood of cardiovascular diseases. Two prospective studies reported a significantly lower incidence of major cardiovascular events in participants with the highest systemic PON1 activity, compared with those with the lowest activity.

Summary: PON1 is a potentially antiatherogenic HDL-associated enzyme that protects LDL from oxidative modification. Enhancing PON1 activity could be an important target for future pharmacological agents aimed at decreasing cardiovascular risk.
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http://dx.doi.org/10.1097/MOL.0b013e32832ec141DOI Listing
August 2009

Effect of some natural products either alone or in combination on gastritis induced in experimental rats.

Dig Dis Sci 2008 Jul 27;53(7):1774-84. Epub 2008 Mar 27.

Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.

Gastritis, an inflammatory state in gastric mucosa, can be induced experimentally in various ways. The present study considered the iodoacetamide model (Iodo). Omega-3 fatty acids (fish oil), black seed oil, and curcuminoids (natural products) in addition to omeprazole (synthetic proton-pump inhibitor) were tested. Supplementation of 0.1% iodoacetamide to drinking water of experimental rats for two consecutive weeks resulted in: (i) increased serum nitric oxide (NO) and gastrin, and decreased pepsinogen, (ii) depletion of gastric mucosal glutathione (GSH), and (iii) increased gastric mucosal lipid peroxidation (MDA), but failed to affect gastric mucosal myeloperoxidase (MPO) activity. Histological examination showed marked neutrophilic infiltration after 1 week of iodoacetamide administration and shedding of apical cell layer with pale edematous vacuolated gastric gland cells and thickening of muscularis mucosa after 2 weeks of iodoacetamide intake. Individual administration of omega-3 fatty acids 12 mg/kg, black seed oil 50 mg/kg, and curcuminoids 50 mg/kg body weight orally daily for 3 weeks decreased MDA, gastrin, and NO, and normalized mucosal GSH but failed to affect serum pepsinogen level. Combined administration of these natural products for 3 weeks normalized MPO activity, and other effects were nearly the same as with individual use. Omeprazole administration 30 mg/kg body weight orally daily for 3 weeks induced a similar response except for an observed increase in serum gastrin and pepsinogen levels.
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http://dx.doi.org/10.1007/s10620-008-0246-6DOI Listing
July 2008
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