Publications by authors named "Nada H Eisa"

17 Publications

  • Page 1 of 1

Quinacrine Ameliorates Cisplatin-Induced Renal Toxicity via Modulation of Sirtuin-1 Pathway.

Int J Mol Sci 2021 Oct 1;22(19). Epub 2021 Oct 1.

Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

Renal toxicity is a serious side effect that hinders the use of cisplatin, a commonly used and effective chemotherapeutic agent. Meanwhile, quinacrine is an FDA approved drug that has been stated for its anti-inflammatory effect. Thus, we investigated the ameliorative effect of quinacrine against cisplatin-induced renal toxicity. Single intraperitoneal (i.p.) 10 mg/kg cisplatin administration induced renal injury in rats. Our results showed that 10 mg/kg/day quinacrine decreased the mortality rate of rats from 46.15% (cisplatin group) to 12.5%, and significantly decreased renal tissue fibrosis, relative kidney to body weight ratio, serum creatinine and urea levels compared with the cisplatin group. Indeed, quinacrine significantly decreased renal malondialdehyde concentration and increased renal total antioxidant capacity, compared with the cisplatin group. Furthermore, quinacrine caused significant upregulation of renal sirtuin-1 (SIRT-1) with significant downregulation of intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-α (TNF-α). Moreover, quinacrine significantly blocked cisplatin-induced apoptosis, which was made evident by downregulating renal apoptotic proteins (BAX and p53) and upregulating the renal anti-apoptotic protein BCL2, compared with the cisplatin group. In conclusion, this study demonstrates, for the first time, that quinacrine alleviates cisplatin-induced renal toxicity via upregulating SIRT-1, downregulating inflammatory markers (ICAM-1 and TNF-α), reducing oxidative stress, and inhibiting apoptosis.
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http://dx.doi.org/10.3390/ijms221910660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508772PMC
October 2021

Ingestion of mannose ameliorates thioacetamide-induced intrahepatic oxidative stress, inflammation and fibrosis in rats.

Life Sci 2021 Oct 9:120040. Epub 2021 Oct 9.

Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address:

Background And Aims: The monosaccharide mannose has gained recent interest for its beneficial effect against certain inflammatory disorders. Nevertheless, the influence of mannose on experimentally-induced liver fibrosis and the ensued inflammation is still not fully clear to date.

Main Methods: The current study investigated the outcomes of treating rats with mannose (0.2 ml of 20% w/v, oral gavage) 30 min before the twice weekly intoxication with thioacetamide (TAA) (200 mg/kg, intraperitoneal) for a total period of 8 weeks.

Key Findings: The data indicated that mannose markedly dampened TAA-induced liver fibrosis, as indicated by lowering the fibrotic bridges shown by Masson's trichrome staining. This effect was consistent with reducing TAA-induced hepatocellular injury, as evidenced biochemically (serum ALT and AST activities) and pathologically (necroinflammation score). These hepatoprotective effects mediated by mannose were attributed to i) reversing TAA-induced rise in malondialdehyde (MDA) and decrease in reduced glutathione (GSH) expressions in the liver, ii) limiting TAA-induced release of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), iii) impairing TAA-induced activation of hepatic stellate cells by downregulating α-smooth muscle actin expression (α-SMA) and, and importantly, iv) dampening TAA-induced fibrogenesis driven by transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF).

Significance: Mannose may be an auspicious candidate for preventing oxidative stress, inflammation and fibrogenesis in the liver.
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http://dx.doi.org/10.1016/j.lfs.2021.120040DOI Listing
October 2021

Anti-inflammatory/anti-apoptotic impact of betulin attenuates experimentally induced ulcerative colitis: An insight into TLR4/NF-kB/caspase signalling modulation.

Environ Toxicol Pharmacol 2021 Sep 28;88:103750. Epub 2021 Sep 28.

Department of Pharmacology, Faculty of Pharmacy, Horus University-Egypt, New Damietta, 34518, Egypt.

Ulcerative colitis (UC) is an inflammatory bowel disease with limited therapeutic management approaches. The present study evaluated the potential therapeutic impact of betulin on acetic acid (AA)-induced UC in rats. UC was induced by intracolonic instillation of AA (3% v/v). Rats were treated with betulin (8 mg/kg, I.P., once daily) four days post AA instillation and for 14 consecutive days. Betulin attenuated AA-induced UC as evidenced by retracted macroscopic scores, serum CRP titre and LDH activity, attenuated histopathological hallmarks of UC including mucosal necrosis, haemorrhage, congestion and inflammatory cells infiltration. Moreover, betulin dampened UC-associated colonic inflammatory load with modulation of TLR4/NF-kB axis and reduction in colonic inflammatory cytokines; TNF-α, IL1β and IL-6. Nevertheless, betulin suppressed colonic apoptosis with reduced colonic caspase-3 and caspase-8 expression. The current findings confirm a beneficial therapeutic impact of betulin against UC. The prospective underlying mechanisms include down-regulation of TLR4/NF-κB and the subsequent downstream signalling pathways.
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http://dx.doi.org/10.1016/j.etap.2021.103750DOI Listing
September 2021

Diacerein ameliorates testosterone-induced benign prostatic hyperplasia in rats: Effect on oxidative stress, inflammation and apoptosis.

Int Immunopharmacol 2021 Aug 24;100:108082. Epub 2021 Aug 24.

Biochemistry Department, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia. Electronic address:

Benign prostatic hypertrophy (BPH) is a serious medical condition among elderly male population. BPH pathogenesis has been linked to inflammation, cellular proliferation, oxidative stress and apoptosis. Diacerein (DIA) is a FDA approved anthraquinone drug that is used to treat joint diseases such as osteoarthritis. DIA has been studied for its potent anti-inflammatory and antioxidant effects, yet its role in managing BPH has not been investigated. In this study, DIA administration for two weeks at 50 mg/kg in testosterone-induced BPH rats significantly reduced prostate weight and index. Moreover, prostatic biochemical and structural features in BPH rats were significantly improved upon DIA treatment. Mechanistically, DIA treatment associated prostatic anti-hyperplastic effects were linked to downregulation of Nrf-2/HO-1 axis, downregulation of inflammatory TNF-a, IL-1β, IL-6, downregulation of the cell proliferative marker PCNA and upregulation of caspase-3 levels. In addition, DIA treatment upregulated prostatic antioxidant GSH, the enzymatic SOD and CAT activities and reduced prostatic lipid peroxidation levels. Altogether, the present study provides evidence that DIA treatment might limit BPH progression via its potent anti-oxidant, anti-inflammatory, anti-proliferative and apoptosis inducing effects.
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http://dx.doi.org/10.1016/j.intimp.2021.108082DOI Listing
August 2021

Age-associated changes in microRNAs affect the differentiation potential of human mesenchymal stem cells: Novel role of miR-29b-1-5p expression.

Bone 2021 Dec 14;153:116154. Epub 2021 Aug 14.

Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29403, United States of America; Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403, United States of America; Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States of America; Center for Healthy Aging, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States of America. Electronic address:

Age-associated osteoporosis is widely accepted as involving the disruption of osteogenic stem cell populations and their functioning. Maintenance of the local bone marrow (BM) microenvironment is critical for regulating proliferation and differentiation of the multipotent BM mesenchymal stromal/stem cell (BMSC) population with age. The potential role of microRNAs (miRNAs) in modulating BMSCs and the BM microenvironment has recently gained attention. However, miRNAs expressed in rapidly isolated BMSCs that are naïve to the non-physiologic standard tissue culture conditions and reflect a more accurate in vivo profile have not yet been reported. Here we directly isolated CD271 positive (+) BMSCs within hours from human surgical BM aspirates without culturing and performed microarray analysis to identify the age-associated changes in BMSC miRNA expression. One hundred and two miRNAs showed differential expression with aging. Target prediction and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the up-regulated miRNAs targeting genes in bone development pathways were considerably enriched. Among the differentially up-regulated miRNAs the novel passenger strand miR-29b-1-5p was abundantly expressed as a mature functional miRNA with aging. This suggests a critical arm-switching mechanism regulates the expression of the miR-29b-1-5p/3p pair shifting the normally degraded arm, miR-29b-1-5p, to be the dominantly expressed miRNA of the pair in aging. The normal guide strand miR-29b-1-3p is known to act as a pro-osteogenic miRNA. On the other hand, overexpression of the passenger strand miR-29b-1-5p in culture-expanded CD271+ BMSCs significantly down-regulated the expression of stromal cell-derived factor 1 (CXCL12)/ C-X-C chemokine receptor type 4 (SDF-1(CXCL12)/CXCR4) axis and other osteogenic genes including bone morphogenetic protein-2 (BMP-2) and runt-related transcription factor 2 (RUNX2). In contrast, blocking of miR-29b-1-5p function using an antagomir inhibitor up-regulated expression of BMP-2 and RUNX2 genes. Functional assays confirmed that miR-29b-1-5p negatively regulates BMSC osteogenesis in vitro. These novel findings provide evidence of a pathogenic anti-osteogenic role for miR-29b-1-5p and other miRNAs in age-related defects in osteogenesis and bone regeneration.
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http://dx.doi.org/10.1016/j.bone.2021.116154DOI Listing
December 2021

Betulin alleviates cisplatin-induced hepatic injury in rats: Targeting apoptosis and Nek7-independent NLRP3 inflammasome pathways.

Int Immunopharmacol 2021 Oct 1;99:107925. Epub 2021 Jul 1.

Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address:

Cisplatin is a chemotherapeutic agent that induces multiorgan toxicity side effect due to induction of inflammation, apoptosis and disruption of intracellular antioxidant pathways. Betulin is a natural triterpenoid that has been shown to counteract cisplatin-induced nephrotoxicity. In this study, we investigated the ameliorative effect of betulin against cisplatin-promoted hepatotoxicity in rats. Moreover, we studied the molecular mechanism underlying betulin's effect. Single intraperitoneal injection (i.p.) of 10 mg/kg of cisplatin, was used to induce acute liver injury in rats. To assess betulin effect, a dose of 8 mg/kg (i.p.) was daily administered for 10 days. Betulin significantly improved serum Aspartate transaminase (AST), Alanine transaminase (ALT), albumin and total bilirubin levels in comparison with cisplatin group. Histopathologically, betulin restored cisplatin-deteriorated liver structural features and hepatic fibrosis. Mechanistically, betulin reduced hepatic oxidative stress as indicated by increased total antioxidant capacity and decreased malondialdehyde levels compared to cisplatin group. In addition, betulin reduced hepatic inflammation via significant inhibition of NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome, caspase-1 and interleukin-1β (IL-1β) levels. Intriguingly, betulin did not affect the expression levels of the mitotic kinase NIMA-related kinase 7 (Nek7), an NLRP3 interacting/activating protein. Last, Betulin induced anti-apoptotic effects as denoted by significant downregulation of P53 and Bax apoptotic proteins, upregulation of the anti-apoptotic protein, BCL2 and reduction of caspases 8, -9 and -3. This study is the first to provide evidence that betulin might be beneficial as a safe therapeutic approach to manage cisplatin-induced hepatotoxicity via targeting inflammatory and apoptotic pathways.
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http://dx.doi.org/10.1016/j.intimp.2021.107925DOI Listing
October 2021

Phenethyl isothiocyanate attenuates diabetic nephropathy via modulation of glycative/oxidative/inflammatory signaling in diabetic rats.

Biomed Pharmacother 2021 Oct 29;142:111666. Epub 2021 Jun 29.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. Electronic address:

Diabetic nephropathy (DN) is a diabetic complication characterized by disruption of renal microvasculature, reactive oxygen species accumulation and increased inflammation, all of which contribute to renal injury. Phenethyl isothiocyanate (PEITC) is a naturally occurring isothiocyanate well known for its antioxidant and anti-inflammatory effects, yet its reno-preventive effects against DN has not been investigated. The current study looked into the in vivo reno-protective effects of PEITC in STZ-induced DN in rats. PEITC (3, 10 and 30 mg/kg) was administered orally for 8 weeks post DM establishment. PEITC treatment significantly improved kidney and liver functions, renal histopathological features, tissue fibrosis, macrophage infiltration and blood glucose levels compared to DN control. Mechanistically, PEITC treatment alleviated DN-induced renal damage via modulating glycation and oxidative stresses and inflammatory response. As such, PEITC activated glyoxalase 1 (GLO1) that induced a retraction in renal tissue expression of advanced glycation end products (AGEs) and its receptor (RAGE). PEITC activated nuclear erythroid 2-related factor 2 (Nrf2) and increased expression of its downstream targets, hemeoxygenase-1 (HO-1) and gamma glutamate-cysteine (γ-GCS). Additionally, PEITC treatment decreased the expression of Nrf2 repressor protein, keap1. The anti-inflammatory effect of PEITC was driven, at least in part, via reducing the NLRP3 inflammasome activation as indicated by down regulation of NLRP3, TXNIP, capsase-1 and IL-1β, TNF-alpha and IL-6. In conclusion; PEITC attenuated DN progression in a dose dependent manner mainly via interruption of AGE/RAGE and NLPR3/TXNIP/NrF2 crosstalk.
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http://dx.doi.org/10.1016/j.biopha.2021.111666DOI Listing
October 2021

Kynurenine Promotes RANKL-Induced Osteoclastogenesis In Vitro by Activating the Aryl Hydrocarbon Receptor Pathway.

Int J Mol Sci 2020 Oct 26;21(21). Epub 2020 Oct 26.

Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29403, USA.

There is increasing evidence of the involvement of the tryptophan metabolite kynurenine (KYN) in disrupting osteogenesis and contributing to aging-related bone loss. Here, we show that KYN has an effect on bone resorption by increasing osteoclastogenesis. We have previously reported that in vivo treatment with KYN significantly increased osteoclast number lining bone surfaces. Here, we report the direct effect of KYN on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis in Raw 264.7 macrophage cells, and we propose a potential mechanism for these KYN-mediated effects. We show that KYN/RANKL treatment results in enhancement of RANKL-induced osteoclast differentiation. KYN drives upregulation and activation of the key osteoclast transcription factors, c-fos and NFATc1 resulting in an increase in the number of multinucleated TRAP+ osteoclasts, and in hydroxyapatite bone resorptive activity. Mechanistically, the KYN receptor, aryl hydrocarbon receptor (AhR), plays an important role in the induction of osteoclastogenesis. We show that blocking AhR signaling using an AhR antagonist, or AhR siRNA, downregulates the KYN/RANKL-mediated increase in c-fos and NFATc1 and inhibits the formation of multinucleated TRAP + osteoclasts. Altogether, this work highlights that the novelty of the KYN and AhR pathways might have a potential role in helping to regulate osteoclast function with age and supports pursuing additional research to determine if they are potential therapeutic targets for the prevention or treatment of osteoporosis.
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http://dx.doi.org/10.3390/ijms21217931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662708PMC
October 2020

Chemo-preventive effect of crocin against experimentally-induced hepatocarcinogenesis via regulation of apoptotic and Nrf2 signaling pathways.

Environ Toxicol Pharmacol 2020 Nov 14;80:103494. Epub 2020 Sep 14.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, 35516, Mansoura, Egypt. Electronic address:

The results of the current study investigated the chemo-preventive effect of crocin against hepatocarcinogenesis in rats with particular focus on the evaluation of the modulatory impact of crocin on apoptotic and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways. Thioacetamide (TAA) (200 mg/kg, I.P.) was used for experimental induction of hepatocarcinogenesis in rats. Crocin administration significantly attenuated TAA-induced cancerous lesions with concomitant attenuation of impaired liver functions. This was associated with significant enhancement in hepatic Nrf2 and heme oxygenase-1 (HO-1) expression with parallel suppression in Keap-1 expression. Inline, crocin induced a significant improvement in hepatic oxidative status with enhanced antioxidant batteries. Crocin administration significantly suppressed the hepatic content of c-Jun N-terminal kinase (c-JNK) with significant upregulation in TNF-related apoptosis-inducing ligand (TRAIL) and caspase-8 protein expression as well as p53 gene expression; biomarkers of apoptosis. Moreover, hepatic expression of the apoptotic BAX significantly increased and the anti-apoptotic Bcl-2 significantly decreased in the liver specimen; biomarkers of intrinsic apoptosis. In conclusion; crocin attenuates experimentally induced hepato-carcinogenesis via modulation of oxidative/apoptotic signaling. Namely, crocin induced hepatic expression of Nrf2 with downstream modulation of endogenous HO-1 and Keap-1 signaling with modulation of various key players of apoptosis including; c-JNK, p53, TRAIL, caspase-8, BAX, and Bcl-2.
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http://dx.doi.org/10.1016/j.etap.2020.103494DOI Listing
November 2020

Age-related increase of kynurenine enhances miR29b-1-5p to decrease both CXCL12 signaling and the epigenetic enzyme Hdac3 in bone marrow stromal cells.

Bone Rep 2020 Jun 23;12:100270. Epub 2020 Apr 23.

Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29403, United States of America.

Mechanisms leading to age-related reductions in bone formation and subsequent osteoporosis are still incompletely understood. We recently demonstrated that kynurenine (KYN), a tryptophan metabolite, accumulates in serum of aged mice and induces bone loss. Here, we report on novel mechanisms underlying KYN's detrimental effect on bone aging. We show that KYN is increased with aging in murine bone marrow mesenchymal stem cells (BMSCs). KYN reduces bone formation via modulating levels of CXCL12 and its receptors as well as histone deacetylase 3 (Hdac3). BMSCs responded to KYN by significantly decreasing mRNA expression levels of CXCL12 and its cognate receptors, CXCR4 and ACKR3, as well as downregulating osteogenic gene RUNX2 expression, resulting in a significant inhibition in BMSCs osteogenic differentiation. KYN's effects on these targets occur by increasing regulatory miRNAs that target osteogenesis, specifically miR29b-1-5p. Thus, KYN significantly upregulated the anti-osteogenic miRNA miR29b-1-5p in BMSCs, mimicking the up-regulation of miR-29b-1-5p in human and murine BMSCs with age. Direct inhibition of miR29b-1-5p by antagomirs rescued CXCL12 protein levels downregulated by KYN, while a miR29b-1-5p mimic further decreased CXCL12 levels. KYN also significantly downregulated mRNA levels of Hdac3, a target of miR-29b-1-5p, as well as its cofactor NCoR1. KYN is a ligand for the aryl hydrocarbon receptor (AhR). We hypothesized that AhR mediates KYN's effects in BMSCs. Indeed, AhR inhibitors (CH-223191 and 3',4'-dimethoxyflavone [DMF]) partially rescued secreted CXCL12 protein levels in BMSCs treated with KYN. Importantly, we found that treatment with CXCL12, or transfection with an miR29b-1-5p antagomir, downregulated the AhR mRNA level, while transfection with miR29b-1-5p mimic significantly upregulated its level. Further, CXCL12 treatment downregulated IDO, an enzyme responsible for generating KYN. Our findings reveal novel molecular pathways involved in KYN's age-associated effects in the bone microenvironment that may be useful translational targets for treating osteoporosis.
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http://dx.doi.org/10.1016/j.bonr.2020.100270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210406PMC
June 2020

What doesn't kill you makes you stranger: Dipeptidyl peptidase-4 (CD26) proteolysis differentially modulates the activity of many peptide hormones and cytokines generating novel cryptic bioactive ligands.

Pharmacol Ther 2019 06 10;198:90-108. Epub 2019 Feb 10.

Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29403, United States; Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403, United States; Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States; Department of Orthopaedic Surgery, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States; Center for Healthy Aging, Medical College of Georgia, Augusta University, Augusta, GA, 30912, United States. Electronic address:

Dipeptidyl peptidase 4 (DPP4) is an exopeptidase found either on cell surfaces where it is highly regulated in terms of its expression and surface availability (CD26) or in a free/circulating soluble constitutively available and intrinsically active form. It is responsible for proteolytic cleavage of many peptide substrates. In this review we discuss the idea that DPP4-cleaved peptides are not necessarily inactivated, but rather can possess either a modified receptor selectivity, modified bioactivity, new antagonistic activity, or even a novel activity relative to the intact parent ligand. We examine in detail five different major DPP4 substrates: glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), peptide tyrosine-tyrosine (PYY), and neuropeptide Y (NPY), and stromal derived factor 1 (SDF-1 aka CXCL12). We note that discussion of the cleaved forms of these five peptides are underrepresented in the research literature, and are both poorly investigated and poorly understood, representing a serious research literature gap. We believe they are understudied and misinterpreted as inactive due to several factors. This includes lack of accurate and specific quantification methods, sample collection techniques that are inherently inaccurate and inappropriate, and a general perception that DPP4 cleavage inactivates its ligand substrates. Increasing evidence points towards many DPP4-cleaved ligands having their own bioactivity. For example, GLP-1 can work through a different receptor than GLP-1R, DPP4-cleaved GIP can function as a GIP receptor antagonist at high doses, and DPP4-cleaved PYY, NPY, and CXCL12 can have different receptor selectivity, or can bind novel, previously unrecognized receptors to their intact ligands, resulting in altered signaling and functionality. We believe that more rigorous research in this area could lead to a better understanding of DPP4's role and the biological importance of the generation of novel cryptic ligands. This will also significantly impact our understanding of the clinical effects and side effects of DPP4-inhibitors as a class of anti-diabetic drugs that potentially have an expanding clinical relevance. This will be specifically relevant in targeting DPP4 substrate ligands involved in a variety of other major clinical acute and chronic injury/disease areas including inflammation, immunology, cardiology, stroke, musculoskeletal disease and injury, as well as cancer biology and tissue maintenance in aging.
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http://dx.doi.org/10.1016/j.pharmthera.2019.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883480PMC
June 2019

The co-chaperone UNC45A is essential for the expression of mitotic kinase NEK7 and tumorigenesis.

J Biol Chem 2019 04 8;294(14):5246-5260. Epub 2019 Feb 8.

From the Georgia Cancer Center,

Cumulative evidence suggests that the heat shock protein 90 (Hsp90) co-chaperone UNC-45 myosin chaperone A (UNC45A) contributes to tumorigenesis and that its expression in cancer cells correlates with proliferation and metastasis of solid tumors. However, the molecular mechanism by which UNC45A regulates cancer cell proliferation remains largely unknown. Here, using siRNA-mediated gene silencing and various human cells, we report that UNC45A is essential for breast cancer cell growth, but is dispensable for normal cell proliferation. Immunofluorescence microscopy, along with gene microarray and RT-quantitative PCR analyses, revealed that UNC45A localizes to the cancer cell nucleus, where it up-regulates the transcriptional activity of the glucocorticoid receptor and thereby promotes expression of the mitotic kinase NIMA-related kinase 7 (NEK7). We observed that UNC45A-deficient cancer cells exhibit extensive pericentrosomal material disorganization, as well as defects in centrosomal separation and mitotic chromosome alignment. Consequently, these cells stalled in metaphase and cytokinesis and ultimately underwent mitotic catastrophe, phenotypes that were rescued by heterologous NEK7 expression. Our results identify a key role for the co-chaperone UNC45A in cell proliferation and provide insight into the regulatory mechanism. We propose that UNC45A represents a promising new therapeutic target to inhibit cancer cell growth in solid tumor types.
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http://dx.doi.org/10.1074/jbc.RA118.006597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462532PMC
April 2019

Synthesis of the seco-Limonoid BCD Ring System Identifies a Hsp90 Chaperon Machinery (p23) Inhibitor.

Chemistry 2019 Jan 20;25(6):1451-1455. Epub 2018 Dec 20.

School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, 4072, Queensland, Australia.

D-Ring-seco-limonoids (tetranortriterpenoids), such as gedunin and xylogranin B display anti-cancer activity, acting via inhibition of Hsp90 and/or associated chaperon machinery (e.g., p23). Despite this, these natural products have received relatively little attention, both in terms of an enabling synthetic approach (which would allow access to derivatives), and as a consequence their structure-activity relationship (SAR). Disclosed herein is a generally applicable synthetic route to the BCD ring system of the seco-D-ring double bond containing limonoids. Furthermore, cell based assays revealed the first skeletal fragment that exhibited inhibition of the p23 enzyme at a level which was equipotent to that of gedunin, despite being much less structurally complex.
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http://dx.doi.org/10.1002/chem.201805420DOI Listing
January 2019

Triggers Apoptosis, Combats Oxidative Stress and Inhibits Growth of Ehrlich Ascites Carcinoma Mouse Model.

Iran J Pharm Res 2018 ;17(4):1328-1338

Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

The aim of this study is to investigate the antitumor activity and possible molecular mechanism of () against Ehrlich ascites carcinoma and . , ascetic fluid volume, body weight, serum malondialdehyde (MDA) level and total antioxidant capacity (TAC) were determined using Ehrlich ascites carcinoma (EAC) bearing mice. MTT assay was used. RT-PCR was used to investigate role of in apoptosis by analyzing the expression of Bax, caspase-9, and Bcl-2 genes. The effect of on caspase-9 enzyme activity was also tested. and/or Doxorubicin (Dox) treatment significantly suppressed EAC growth as compared to EAC/oil control mice. treatment showed a dose-dependent inhibition of EAC cells as indicated by MTT assay. We found that significant increase in MDA level and decrease in TAC caused by Dox treatment were significantly reduced by combination with treatment. Bax, caspase-9 genes' expression and caspase-9 enzymatic activity were significantly increased, while Bcl-2 gene expression was significantly decreased in treated mice. may act as a promising anticancer agent either alone or more effectively in combination with Dox through apoptotic cell death induction.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269550PMC
January 2018

Phenethyl isothiocyanate potentiates anti-tumour effect of doxorubicin through Akt-dependent pathway.

Cell Biochem Funct 2015 Dec 8;33(8):541-51. Epub 2015 Nov 8.

Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.

The present study aims to investigate the in vivo and in vitro anti-tumour properties of phenethyl isothiocyanate (PEITC) alone and in combination with doxorubicin (Dox). The anti-tumour activity was evaluated in vitro by MTT assay using cultured human breast cancer cell line (MCF-7) and human hepatoma cell line (HepG-2) cell lines. In vivo, Ehrlich solid tumour model was used. Tumour volume, weight and antioxidant parameters were determined. Immunohistochemistry analysis for active (cleaved) caspase-3 was also performed. We tested the effect of PEITC treatment on pAkt/Akt ratio, NF-κB p65 DNA binding activity and caspase-9 enzyme activity in both MCF-7 and HepG-2 cell lines. Effect of PEITC treatment on cell migration was assessed by wound healing assay. PEITC and/or Dox treatment significantly inhibited solid tumour volume and tumour weight when compared with control mice. PEITC treatment significantly reduced oxidative stress caused by Dox treatment as indicated by significant increase in total antioxidant capacity and decrease in malondialdehyde level. Microscopic examination of tumour tissues showed a significant increase in active (cleaved) caspase-3 expression in PEITC and/or Dox treated groups. PEITC showed a dose-dependent inhibition of MCF-7 and HepG-2 cellular viability. PEITC inhibited Akt and NF-κB activation and increased caspase-9 activity in a dose-dependent manner. PEITC treatment effectively inhibited both MCF-7 and HepG-2 cell migration. We can conclude that PEITC acts via multiple molecular targets to elicit anti-carcinogenic activity. PEITC/Dox combination therapy might be a potential novel strategy, which may benefit patients with breast and liver cancers.
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http://dx.doi.org/10.1002/cbf.3153DOI Listing
December 2015

Galectin-3 and matrix metalloproteinase-9: Perspective in management of hepatocellular carcinoma.

J Oncol Pharm Pract 2015 Oct 24;21(5):323-30. Epub 2014 Apr 24.

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

Aim: Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the seventh in women. HCC varies widely in incidence through the world, with rising incidence in Egypt. This study aimed to estimate the serum levels of matrix metalloproteinase-9 (MMP-9) and its substrate galectin-3 in order to evaluate their diagnostic accuracy and their relation to HCC-related clinical features.

Methods: For this purpose, serum levels of these biochemical markers were assessed in 50 HCC patients, 30 cirrhotic patients in addition to 10 healthy subjects as a control group using enzyme linked immune-sorbent assay (ELISA).

Results: In the present study, circulating level of galectin-3, MMP-9 increased significantly in HCC as compared to the control group (P = 0.044 and 0.04, respectively). However, no significant difference was observed between cirrhotic and HCC patients (P = 0.231 and 0.193, respectively). Our study found that HCC patients with metastatic spread had a significant elevation of both serum galectin-3 and MMP-9 levels (P = 0.028 and <0.0001, respectively). In addition, galectin-3 level significantly increased in HCC patients with poor prognosis suffering from portal vein invasion (P = 0.014). Moreover, MMP-9 increased significantly with increasing stage of Barcelona-Clinic Liver Cancer Group diagnostic and treatment strategy (P = 0.01).

Conclusion: MMP-9 and galectin-3 could be used as a guide for prognosis of HCC since they may play a role in HCC progression and metastasis. However, they are not useful markers for HCC diagnosis.
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http://dx.doi.org/10.1177/1078155214532698DOI Listing
October 2015

Nitric Oxide is a Potential Diagnostic Marker for Hepatocellular Carcinoma.

Sci Pharm 2013 Jul-Sep;81(3):763-75. Epub 2013 Aug 8.

Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the seventh most common in women. This cancer varies widely in incidence throughout the world, with rising incidence in Egypt. HCC is considered the second most frequent cause of cancer incidence and mortality among men in Egypt. This study aimed to estimate the serum levels of nitric oxide (NO) and glutathione reductase in order to evaluate their role as oxidative status markers in HCC development and progression. For this purpose, serum levels of these parameters were assessed in 50 HCC patients, and 30 cirrhotic patients in addition to 15 healthy subjects as a control group. In the present study, glutathione reductase activity showed a significant increase in HCC as compared to the control group (P= 0.019). On the other hand, no significant difference was observed between the cirrhotic and HCC patients (P= 0.492). Serum NO was significantly higher in patients with HCC than in cirrhotic patients (P= 0.001) or the control group (P= 0.001), with a sensitivity of (74%) and specificity of (88.89%) at a cut-off level of 614.1 μmol/l. While AFP, alpha-fetoprotein, at a cutoff level of 200 ng/ml had a sensitivity of (52%), the specificity was (100%). Indeed, nitric oxide was high in 62.5% of AFP-negative HCC patients. In conclusion, glutathione reductase has no role in HCC diagnosis. However, nitric oxide is a potential diagnostic marker for HCC. The simultaneous determination of serum nitric oxide and AFP gave significant improvement in the detection of HCC patients compared to that of AFP alone.
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http://dx.doi.org/10.3797/scipharm.1307-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791938PMC
October 2013
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