Cisplatin-induced nephrotoxicity limits its anticancer effectiveness, thus this study’s aim was t... more Cisplatin-induced nephrotoxicity limits its anticancer effectiveness, thus this study’s aim was to assess the potential modulatory effect of perindopril on cisplatin-induced nephrotoxicity and to elucidate the possible underlying mechanisms. Renal dysfunction was induced in mice by a single injection of cisplatin (10 mg kg−1, i.p.) and perindopril was administered orally (2 mg kg−1, once daily) for 5 days. Perindopril remarkably ameliorated cisplatin-induced perturbations in renal histology, renal levels of tumor necrosis factor-alpha, interleukin-6 and interleukin-10, apoptosis-regulating protein expressions (Bax and Bcl2), and partially normalized Bax to Bcl2 ratio and active caspase 3 protein expression. Conversely, perindopril had no significant effect on cisplatin-induced elevations in serum creatinine and urea, microalbuminuria, kidney to body weight ratio, lipid peroxidation marker, superoxide dismutase and catalase activities and reduced glutathione content. In conclusion, p...
In view of their expected anticonvulsant activity, some novel derivatives of 6,8-diiodo-2-methyl-... more In view of their expected anticonvulsant activity, some novel derivatives of 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones (4-14) were synthesized, evaluated for their anticonvulsant activity by the maximal electroshock-induced seizure and subcutaneous pentylenetetrazole tests. The neurotoxicity was assessed using rotorod test. All the tested compounds showed considerable anticonvulsant activity in at least one of the anticonvulsant tests. Compounds 5, 6, and 8 proved to be the most potent compounds of this series with relatively low neurotoxicity and low toxicity in the median lethal dose test when compared with the reference drugs. The obtained results showed that the most potent compounds could be useful as a template for future design, optimization, and investigation to produce more active analogs.
The lack of effective therapies for epileptic patients and the potentially harmful consequences o... more The lack of effective therapies for epileptic patients and the potentially harmful consequences of untreated seizure incidents have made epileptic disorders in humans a major health concern. Therefore, new and more potent anticonvulsant drugs are continually sought after, to combat epilepsy. On the basis of the pharmacophoric structural specifications of effective α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) antagonists with an efficient anticonvulsant activity, the present work reports the design and synthesis of two novel sets of quinoxaline derivatives. The anticonvulsant activity of the synthesized compounds was evaluated in vivo according to the pentylenetetrazol‐induced seizure protocol, and the results were compared with those of perampanel as a reference drug. Among the synthesized compounds, 24, 28, 32, and 33 showed promising activities with ED50 values of 37.50, 23.02, 29.16, and 23.86 mg/kg, respectively. Docking studies of these compounds suggested that AMPA binding could be the mechanism of action of these derivatives. Overall, the pharmacophore‐based structural optimization, in vivo and in silico docking, and druglikeness studies indicated that the designed compounds could serve as promising candidates for the development of effective anticonvulsant agents with good pharmacokinetic profiles.
Naunyn-Schmiedeberg's Archives of Pharmacology, 2020
The current study was designed to evaluate the potential abatement effect of pantoprazole against... more The current study was designed to evaluate the potential abatement effect of pantoprazole against cisplatin-induced nephrotoxicity and establishing the possible protective mechanisms. Thirty-two male mice were allocated for treatment with saline, single dose of cisplatin (10 mg/kg/i.p), pantoprazole (30 mg/kg/once daily) for 5 days or combination of pantoprazole and cisplatin for 5 days. Urine, blood, and both kidneys were collected for further evaluations. Pantoprazole significantly countermand cisplatininduced disfigurement of renal histology, kidney weight to body weight ratio, serum levels of creatinine and urea, and microalbuminuria. Furthermore, pantoprazole mostly normalized cisplatin-induced distortion of renal levels of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, interleukin-10) and renal content of apoptosis regulating protein expressions (Bax, Bcl2, and active caspase 3). In addition, pantoprazole significantly subsided cisplatin-induced distortion of renal lipid peroxidation marker (MDA), renal superoxide dismutase, and catalase activities and renal reduced glutathione content. This study provides an evidence for the protective utility of short-term pantoprazole against cisplatin-induced nephrotoxicity in mice. The protective mechanism of pantoprazole could be through diminution of cisplatin-induced inflammation, oxidative stress, and their subsequent apoptotic renal cell death via abatement of apoptosis regulating protein expressions (Bax, Bcl2, and active caspase3).
2-Methoxyestradiol (2ME), an endogenous estradiol metabolite, was developed as a novel agent base... more 2-Methoxyestradiol (2ME), an endogenous estradiol metabolite, was developed as a novel agent based on its antitumor activity and lack of toxicity. This study was designed to investigate the modulatory effect of 2ME on the antitumor effect of doxorubicin (Dox) in resistant breast tumor xenograft. Resistant MCF-7/Dox cells were implanted subcutaneously in nude mice Treatment with Dox 5 mg/kg, 2ME 30 mg/kg and their combination continued twice a week for 2 weeks. Following 28 days from starting the treatment with Dox alone, the change in tumor volume from first day of treatment was 455.6 +/- 16.2%. Combined Dox and 2ME treatment significantly reduced tumor volume to 20.8 +/- 43%. Also, combined therapy resulted in enhanced tumor apoptotic and reduced proliferative activities relative to Dox alone. The apoptotic indices were 0.13 +/- 0.03 and 0.75 +/- 0.06 in Dox alone and Dox + 2ME groups, respectively. For Dox alone group, expression of the proliferative markers PCNA and Ki67 were 0.78 +/- 0.06 and 0.63 +/- 0.18, respectively. They were significantly reduced to 0.28 +/- 0.1 and 0.12 +/- 0.1 for their corresponding combined Dox and 2ME group. Interaction analysis clearly indicated that 2ME synergies antitumor, apoptotic and anti-proliferative activity of Dox. Examining body weight, hepatic and cardiac histopathology of the different treatment groups revealed no significant signs of toxicity. These findings suggest that 2ME reverses Dox resistance, with benign side effects profile.
High blood glucose level, lipid profile disturbances and plasma homocysteine (Hcy) are important ... more High blood glucose level, lipid profile disturbances and plasma homocysteine (Hcy) are important risk factors for cardiovascular diseases in patients with type 2 diabetes. This study was conducted to evaluate and compare effects of glimepiride/metformin combination versus gliclazide/metformin combination on cardiovascular risk factors in type-2 diabetes mellitus (T2DM) patients. One hundred and eighty T2DM patients were randomly allocated for treatment with placebo (control), metformin (500 mg twice daily), glimepiride (3mg once daily), gliclazide (80 mg once daily), metformin plus glimepiride or metformin plus gliclazide for 3 months. We evaluated plasma levels of glucose (PG), glycated hemoglobin (HbA1C), Hcy, vitamin B12, folic acid and lipid profile before treatment and 3 months post treatment. Compared to metformin treated patients, glimepiride plus metformin induced significant reductions in: fasting plasma glucose, postprandial PG level, HbA1C % and Hcy level. Conversely, pla...
Background: Quinazolines and quinazolinones derivatives are well known for their important range ... more Background: Quinazolines and quinazolinones derivatives are well known for their important range of therapeutic activities. Objective: The study aims to carry out the synthesis of some derivatives of substituted fluoroquinazolinones based on structure-based design and evaluation of their antibacterial, antifungal, and anti-biofilm activities. Methods: Compounds were chemically synthesized by conventional methods. Structures were established on the basis of spectral and elemental analyses. The antimicrobial potential was tested against various microorganisms using the agar disc-diffusion method. MIC and MBC as well as anti-biofilm activity for the highly active compounds were assessed. Moreover, the computational studies were performed using Auto dock free software package (version 4.0) to explain the predicted mode of binding. Results: All derivatives (5-8), (10a-g), and (A-H) were biologically tested and showed significant antimicrobial activity comparable to the reference compound...
Naunyn-Schmiedeberg's Archives of Pharmacology, 2016
This study was aimed at investigating the antifibrotic effect of meloxicam in CCl4-induced liver ... more This study was aimed at investigating the antifibrotic effect of meloxicam in CCl4-induced liver fibrosis and elucidating its underlying mechanism. Forty male rats were equally randomized for 8-week treatment with corn oil (negative control), CCl4 (to induce liver fibrosis), and/or meloxicam. Meloxicam effectively ameliorated the CCl4-induced alterations in liver histology, liver weight to body weight ratio, liver functions, and serum markers for liver fibrosis (hyaluronic acid, laminin, and PCIII). Meloxicam significantly abrogated CCl4-induced elevation of messenger RNA (mRNA) expressions for collagen I and alpha smooth muscle actin (α-SMA) and hepatic contents of hydroxyproline, transforming growth factor beta (TGF-β), and tissue inhibitor of matrix metalloproteases (TIMP-1). Meloxicam mitigated CCl4-induced elevation in hepatic levels of nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), total nitric oxide (NO), interleukin-l beta (IL 1β), and prostaglandin E2 (PGE2). Meloxicam modulated CCl4-induced disturbance of liver cytochrome P450 subfamily 2E1 (CYP2E1) and glutathione-S-transferase (GST). The attenuation of meloxicam to liver fibrosis was associated with suppression of oxidative stress via reduction of lipid peroxides along with induction of reduced glutathione content and enhancement of superoxide dismutase, glutathione peroxidase, and catalase activities. This study provides an evidence for antifibrotic effect of meloxicam against CCl4-induced liver fibrosis in rat. The antifibrotic mechanism of meloxicam could be through decreasing NF-κB level and subsequent proinflammatory cytokine production (TNF-α, NO, IL-1 beta, and PGE2) and, hence, collagen deposition through inhibition of TIMP-1 and TGF-β. Abrogation of oxidative stress and modulation of liver-metabolizing enzymes (CYP2E1 and GST) were also involved.
The current study aimed at investigating the potential hepatoprotective property and mechanism of... more The current study aimed at investigating the potential hepatoprotective property and mechanism of meloxicam (MEL) against carbon tetrachloride (CCl 4)-induced hepatocellular damage in rats. Subcutaneous administration of CCl 4 (2 mL/kg, twice/week for 8 weeks) induced hepatocellular damage substantiated by hematoxylin and eosin staining and significant elevation in serum aspartate transaminase, alanine transaminase, and total bilirubin. In addition, CCL 4 treatment led to elevation in liver contents of lipid peroxidation marker (malondialdehyde), prostaglandin E2, active caspase 3, and Terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and reduction in the activities of superoxide dismutase, catalase, glutathione-S-transferase, and reduced glutathione in the liver tissue. Prior oral treatment with MEL (5 mg/kg, twice/week) retained the normal liver histology and significantly restored all of these parameters close to normal values. These results demonstrated the hepatoprotective utility of MEL against the CCl 4-induced liver injury which might ascribe to its antioxidant, free radical scavenging, antiapoptotic and antiinflammatory effects.
This study was undertaken to assess the possible modulatory effects and mechanisms of meloxicam, ... more This study was undertaken to assess the possible modulatory effects and mechanisms of meloxicam, a cyclooxygenase-2 inhibitor, on the antitumor activity and cardiotoxicity of doxorubicin in a mice model of mammary carcinoma. Solid tumor mass was developed in female albino mice using Ehrlich carcinoma cells. Forty mice-bearing tumor were divided randomly into four groups for treatment: with saline, meloxicam 10 mg/kg, doxorubicin 5 mg/kg and meloxicam 1 h ahead of doxorubicin, twice weekly for 2 weeks. Tumor volume was followed up and cardiac protective utility was estimated via measuring heart and serum parameters. Meloxicam expressed a non-significant increase in doxorubicin antitumor activity. Conversely, meloxicam significantly (p < 0.01) mitigated doxorubicin-induced elevation of serum cardiac enzymes [creatine kinase, lactate dehydrogenase and troponin-I]; cardiac lipid peroxidations marker; cardiac active caspase-3 content; and cardiac prostaglandin E2 content. Meloxicam si...
Beryllium chloride (BeCl 2 ) is a highly toxic substance that accumulates in different tissues af... more Beryllium chloride (BeCl 2 ) is a highly toxic substance that accumulates in different tissues after absorption. The purpose of this study was to investigate protective role of crocin against BeCl 2intoxication in rats. Male Wistar rats were used in this study and categorised into four groups (n ¼8). Group I served as normal control rats. Group II treated orally with BeCl 2 86 mg/kg b.w. for five consecutive days. This dose was equivalent to experimental LD 50 . Group III treated intraperitoneally with crocin 200 mg/kg b.w. for seven consecutive days. Group IV received crocin for seven consecutive days before BeCl 2 administration. Blood samples and liver and brain homogenates were obtained for haematological, biochemical and RT-PCR examinations. The haematocrit value, RBCs count and haemoglobin concentration were significantly decreased in BeCl 2 -treated rats. A significant increase was observed in rat liver and brain malondialdehyde level and protein carbonyls content in BeCl 2 exposed group compared to the control group, and these values were significantly declined upon administration of crocin. Lactate dehydrogenase levels in rat liver and brain significantly increased compared to the control group and was associated with significant decrease in catalase and superoxide dismutase activities. Reduced glutathione hepatic contents of BeCl 2 -treated rats were significantly decreased. There was significant decline in mRNA expression of catalase and superoxide dismutase genes in BeCl 2 -intoxicated rats compared to the normal rats. Crocin treatment prior to BeCl 2 intake resulted in significant increase in mRNA expressions of catalase and superoxide dismutase genes near to normalcy. The haematological and biochemical parameters were restored near to normal levels. Our results suggested that, BeCl 2 induced oxidation of cellular lipids and proteins and that administration of crocin reduced BeCl 2 -induced oxidative stress combined with initiation of mRNA expression of antioxidant genes.
Phthalates are abundantly produced plasticizers, and dibutyl phthalate (DBP) is the most widely u... more Phthalates are abundantly produced plasticizers, and dibutyl phthalate (DBP) is the most widely used derivative in various consumer products and medical devices. This study was conducted to further explore the potential testicular toxicity of DBP in adult rats and to elucidate the underlying mechanisms. Adult male albino rats were treated orally with DBP at doses of 0, 200, 400, or 600 mg/kg/day for 15 consecutive days. Testicular weight, sperm count, and motility were significantly decreased. Treatment with DBP decreased serum follicle-stimulating hormone and testosterone levels and testicular lactate dehydrogenase activity. DBP treatment also decreased serum total antioxidant capacity and the activities of the testicular antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione reductase. Further, DBP treatment provoked degeneration with absence of spermatogenesis and sperms and necrosis in some of seminiferous tubules. These results indicated that oxidative str...
The present study was aimed to investigate the mechanistic aspect of Aroclor 1260-induced hepatot... more The present study was aimed to investigate the mechanistic aspect of Aroclor 1260-induced hepatotoxicity and its protection by lipoic acid. The adult male Albino rats were divided into six groups. Group I served as control. Group II received lipoic acid (35 mg/kg/day). Aroclor 1260 was given to rats by oral gavage at doses 20, 40, or 60 mg/kg/day (Groups III, IV, and V, respectively). Group VI was pretreated with lipoic acid (35 mg/kg/day) 24 h before Aroclor 1260 (40 mg/kg/day). Treatment in all groups was continued for further 15 consecutive days. Serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities and total bilirubin, total cholesterol, and triglycerides were significantly increased while total protein, total albumin, and high-density lipoprotein were significantly decreased. Hydrogen peroxide production and lipid peroxidation were significantly increased while superoxide dismutase and catalase activities and redu...
Journal of Taibah University Medical Sciences, 2014
Objectives: Carbon tetrachloride (CCl4) is one of the most dangerous hepatotoxic environmental po... more Objectives: Carbon tetrachloride (CCl4) is one of the most dangerous hepatotoxic environmental pollutants thus this study aimed at investigating the potential preventive effect and mechanism of crocin against CCl4induced hepatotoxicity.
Lead is a biohazardous metal that is commonly involved in human illness including renal injury. A... more Lead is a biohazardous metal that is commonly involved in human illness including renal injury. Although it is a non-redox reactive metal, lead-induced renal injury is largely based on oxidative stress. The current work aimed at exploring the possible protective effect of γ-glutamyl cysteine (γGC) against lead-induced renal injury. Rats were allocated to normal and γGC control groups, lead-treated group, and lead and γGC-treated group. γGC alleviated lead-induced renal injury as evidenced by attenuation of histopathological aberration, amelioration of oxidative injury as demonstrated by significant reduction in lipid and protein oxidation, elevation of total antioxidant capacity, and glutathione level. The activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) was significantly elevated. γGC significantly decreased levels of the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β and the activity of the apoptotic marker caspase-3. In addition, γGC reduced kidney lead content, enhanced weight gain, and improved renal function as demonstrated by reduced serum levels of urea and creatinine. Importantly, γGC upregulated proliferating cell nuclear antigen (PCNA) expression, denoting enhanced renal regenerative capacity. Together, our findings highlight evidence for alleviating effects of γGC against lead-induced renal injury that is potentially mediated through diminution of oxidative tissue injury, reduction of inflammatory response, attenuation of apoptosis, and enhancement of renal regenerative capacity.
High blood glucose level, lipid profile disturbances and plasma homocysteine (Hcy) are important ... more High blood glucose level, lipid profile disturbances and plasma homocysteine (Hcy) are important risk factors for cardiovascular diseases in patients with type 2 diabetes. This study was conducted to evaluate and compare effects of glimepiride/metformin combination versus gliclazide/metformin combination on cardiovascular risk factors in type-2 diabetes mellitus (T2DM) patients. One hundred and eighty T2DM patients were randomly allocated for treatment with placebo (control), metformin (500mg twice daily), glimepiride (3mg once daily), gliclazide (80mg once daily), metformin plus glimepiride or metformin plus gliclazide for 3 months. We evaluated plasma levels of glucose (PG), glycated hemoglobin (HbA1C), Hcy, vitamin B12, folic acid and lipid profile before treatment and 3 months post treatment. Compared to metformin treated patients, glimepiride plus metformin induced significant reductions in: fasting plasma glucose, postprandial PG level, HbA1C % and Hcy level. Conversely, plasm...
Some novel 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones bearing sulfonamide derivative... more Some novel 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones bearing sulfonamide derivatives (4-11) were synthesized in good yields and evaluated for their possible antibacterial, anti-inflammatory activities and acute toxicity. The structures of the synthesized compounds were confirmed on the basis of their spectral data and elemental analysis. Their antibacterial activities were evaluated by the agar well diffusion method while their anti-inflammatory activities were evaluated by the carrageenan-induced hind paw edema test. All the tested compounds showed considerable antibacterial activities and high to moderate anti-inflammatory activities that last for 12 h compared to ibuprofen. All the tested compounds showed no toxic symptoms or mortality rates 24 h post-administration at tested anti-inflammatory doses. In addition, LD50 for all tested compounds was higher than that for ibuprofen implying their good safety margin. The obtained results showed that the most active compounds could be useful as a template for future design, modification and investigation to produce more active analogs.
Objectives: Carbon tetrachloride (CCl4) is one of the most dangerous hepatotoxic environmental po... more Objectives: Carbon tetrachloride (CCl4) is one of the most dangerous hepatotoxic environmental pollutants thus this study aimed at investigating the potential preventive effect and mechanism of crocin against CCl4induced hepatotoxicity.
Cisplatin-induced nephrotoxicity limits its anticancer effectiveness, thus this study’s aim was t... more Cisplatin-induced nephrotoxicity limits its anticancer effectiveness, thus this study’s aim was to assess the potential modulatory effect of perindopril on cisplatin-induced nephrotoxicity and to elucidate the possible underlying mechanisms. Renal dysfunction was induced in mice by a single injection of cisplatin (10 mg kg−1, i.p.) and perindopril was administered orally (2 mg kg−1, once daily) for 5 days. Perindopril remarkably ameliorated cisplatin-induced perturbations in renal histology, renal levels of tumor necrosis factor-alpha, interleukin-6 and interleukin-10, apoptosis-regulating protein expressions (Bax and Bcl2), and partially normalized Bax to Bcl2 ratio and active caspase 3 protein expression. Conversely, perindopril had no significant effect on cisplatin-induced elevations in serum creatinine and urea, microalbuminuria, kidney to body weight ratio, lipid peroxidation marker, superoxide dismutase and catalase activities and reduced glutathione content. In conclusion, p...
In view of their expected anticonvulsant activity, some novel derivatives of 6,8-diiodo-2-methyl-... more In view of their expected anticonvulsant activity, some novel derivatives of 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones (4-14) were synthesized, evaluated for their anticonvulsant activity by the maximal electroshock-induced seizure and subcutaneous pentylenetetrazole tests. The neurotoxicity was assessed using rotorod test. All the tested compounds showed considerable anticonvulsant activity in at least one of the anticonvulsant tests. Compounds 5, 6, and 8 proved to be the most potent compounds of this series with relatively low neurotoxicity and low toxicity in the median lethal dose test when compared with the reference drugs. The obtained results showed that the most potent compounds could be useful as a template for future design, optimization, and investigation to produce more active analogs.
The lack of effective therapies for epileptic patients and the potentially harmful consequences o... more The lack of effective therapies for epileptic patients and the potentially harmful consequences of untreated seizure incidents have made epileptic disorders in humans a major health concern. Therefore, new and more potent anticonvulsant drugs are continually sought after, to combat epilepsy. On the basis of the pharmacophoric structural specifications of effective α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) antagonists with an efficient anticonvulsant activity, the present work reports the design and synthesis of two novel sets of quinoxaline derivatives. The anticonvulsant activity of the synthesized compounds was evaluated in vivo according to the pentylenetetrazol‐induced seizure protocol, and the results were compared with those of perampanel as a reference drug. Among the synthesized compounds, 24, 28, 32, and 33 showed promising activities with ED50 values of 37.50, 23.02, 29.16, and 23.86 mg/kg, respectively. Docking studies of these compounds suggested that AMPA binding could be the mechanism of action of these derivatives. Overall, the pharmacophore‐based structural optimization, in vivo and in silico docking, and druglikeness studies indicated that the designed compounds could serve as promising candidates for the development of effective anticonvulsant agents with good pharmacokinetic profiles.
Naunyn-Schmiedeberg's Archives of Pharmacology, 2020
The current study was designed to evaluate the potential abatement effect of pantoprazole against... more The current study was designed to evaluate the potential abatement effect of pantoprazole against cisplatin-induced nephrotoxicity and establishing the possible protective mechanisms. Thirty-two male mice were allocated for treatment with saline, single dose of cisplatin (10 mg/kg/i.p), pantoprazole (30 mg/kg/once daily) for 5 days or combination of pantoprazole and cisplatin for 5 days. Urine, blood, and both kidneys were collected for further evaluations. Pantoprazole significantly countermand cisplatininduced disfigurement of renal histology, kidney weight to body weight ratio, serum levels of creatinine and urea, and microalbuminuria. Furthermore, pantoprazole mostly normalized cisplatin-induced distortion of renal levels of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, interleukin-10) and renal content of apoptosis regulating protein expressions (Bax, Bcl2, and active caspase 3). In addition, pantoprazole significantly subsided cisplatin-induced distortion of renal lipid peroxidation marker (MDA), renal superoxide dismutase, and catalase activities and renal reduced glutathione content. This study provides an evidence for the protective utility of short-term pantoprazole against cisplatin-induced nephrotoxicity in mice. The protective mechanism of pantoprazole could be through diminution of cisplatin-induced inflammation, oxidative stress, and their subsequent apoptotic renal cell death via abatement of apoptosis regulating protein expressions (Bax, Bcl2, and active caspase3).
2-Methoxyestradiol (2ME), an endogenous estradiol metabolite, was developed as a novel agent base... more 2-Methoxyestradiol (2ME), an endogenous estradiol metabolite, was developed as a novel agent based on its antitumor activity and lack of toxicity. This study was designed to investigate the modulatory effect of 2ME on the antitumor effect of doxorubicin (Dox) in resistant breast tumor xenograft. Resistant MCF-7/Dox cells were implanted subcutaneously in nude mice Treatment with Dox 5 mg/kg, 2ME 30 mg/kg and their combination continued twice a week for 2 weeks. Following 28 days from starting the treatment with Dox alone, the change in tumor volume from first day of treatment was 455.6 +/- 16.2%. Combined Dox and 2ME treatment significantly reduced tumor volume to 20.8 +/- 43%. Also, combined therapy resulted in enhanced tumor apoptotic and reduced proliferative activities relative to Dox alone. The apoptotic indices were 0.13 +/- 0.03 and 0.75 +/- 0.06 in Dox alone and Dox + 2ME groups, respectively. For Dox alone group, expression of the proliferative markers PCNA and Ki67 were 0.78 +/- 0.06 and 0.63 +/- 0.18, respectively. They were significantly reduced to 0.28 +/- 0.1 and 0.12 +/- 0.1 for their corresponding combined Dox and 2ME group. Interaction analysis clearly indicated that 2ME synergies antitumor, apoptotic and anti-proliferative activity of Dox. Examining body weight, hepatic and cardiac histopathology of the different treatment groups revealed no significant signs of toxicity. These findings suggest that 2ME reverses Dox resistance, with benign side effects profile.
High blood glucose level, lipid profile disturbances and plasma homocysteine (Hcy) are important ... more High blood glucose level, lipid profile disturbances and plasma homocysteine (Hcy) are important risk factors for cardiovascular diseases in patients with type 2 diabetes. This study was conducted to evaluate and compare effects of glimepiride/metformin combination versus gliclazide/metformin combination on cardiovascular risk factors in type-2 diabetes mellitus (T2DM) patients. One hundred and eighty T2DM patients were randomly allocated for treatment with placebo (control), metformin (500 mg twice daily), glimepiride (3mg once daily), gliclazide (80 mg once daily), metformin plus glimepiride or metformin plus gliclazide for 3 months. We evaluated plasma levels of glucose (PG), glycated hemoglobin (HbA1C), Hcy, vitamin B12, folic acid and lipid profile before treatment and 3 months post treatment. Compared to metformin treated patients, glimepiride plus metformin induced significant reductions in: fasting plasma glucose, postprandial PG level, HbA1C % and Hcy level. Conversely, pla...
Background: Quinazolines and quinazolinones derivatives are well known for their important range ... more Background: Quinazolines and quinazolinones derivatives are well known for their important range of therapeutic activities. Objective: The study aims to carry out the synthesis of some derivatives of substituted fluoroquinazolinones based on structure-based design and evaluation of their antibacterial, antifungal, and anti-biofilm activities. Methods: Compounds were chemically synthesized by conventional methods. Structures were established on the basis of spectral and elemental analyses. The antimicrobial potential was tested against various microorganisms using the agar disc-diffusion method. MIC and MBC as well as anti-biofilm activity for the highly active compounds were assessed. Moreover, the computational studies were performed using Auto dock free software package (version 4.0) to explain the predicted mode of binding. Results: All derivatives (5-8), (10a-g), and (A-H) were biologically tested and showed significant antimicrobial activity comparable to the reference compound...
Naunyn-Schmiedeberg's Archives of Pharmacology, 2016
This study was aimed at investigating the antifibrotic effect of meloxicam in CCl4-induced liver ... more This study was aimed at investigating the antifibrotic effect of meloxicam in CCl4-induced liver fibrosis and elucidating its underlying mechanism. Forty male rats were equally randomized for 8-week treatment with corn oil (negative control), CCl4 (to induce liver fibrosis), and/or meloxicam. Meloxicam effectively ameliorated the CCl4-induced alterations in liver histology, liver weight to body weight ratio, liver functions, and serum markers for liver fibrosis (hyaluronic acid, laminin, and PCIII). Meloxicam significantly abrogated CCl4-induced elevation of messenger RNA (mRNA) expressions for collagen I and alpha smooth muscle actin (α-SMA) and hepatic contents of hydroxyproline, transforming growth factor beta (TGF-β), and tissue inhibitor of matrix metalloproteases (TIMP-1). Meloxicam mitigated CCl4-induced elevation in hepatic levels of nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), total nitric oxide (NO), interleukin-l beta (IL 1β), and prostaglandin E2 (PGE2). Meloxicam modulated CCl4-induced disturbance of liver cytochrome P450 subfamily 2E1 (CYP2E1) and glutathione-S-transferase (GST). The attenuation of meloxicam to liver fibrosis was associated with suppression of oxidative stress via reduction of lipid peroxides along with induction of reduced glutathione content and enhancement of superoxide dismutase, glutathione peroxidase, and catalase activities. This study provides an evidence for antifibrotic effect of meloxicam against CCl4-induced liver fibrosis in rat. The antifibrotic mechanism of meloxicam could be through decreasing NF-κB level and subsequent proinflammatory cytokine production (TNF-α, NO, IL-1 beta, and PGE2) and, hence, collagen deposition through inhibition of TIMP-1 and TGF-β. Abrogation of oxidative stress and modulation of liver-metabolizing enzymes (CYP2E1 and GST) were also involved.
The current study aimed at investigating the potential hepatoprotective property and mechanism of... more The current study aimed at investigating the potential hepatoprotective property and mechanism of meloxicam (MEL) against carbon tetrachloride (CCl 4)-induced hepatocellular damage in rats. Subcutaneous administration of CCl 4 (2 mL/kg, twice/week for 8 weeks) induced hepatocellular damage substantiated by hematoxylin and eosin staining and significant elevation in serum aspartate transaminase, alanine transaminase, and total bilirubin. In addition, CCL 4 treatment led to elevation in liver contents of lipid peroxidation marker (malondialdehyde), prostaglandin E2, active caspase 3, and Terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and reduction in the activities of superoxide dismutase, catalase, glutathione-S-transferase, and reduced glutathione in the liver tissue. Prior oral treatment with MEL (5 mg/kg, twice/week) retained the normal liver histology and significantly restored all of these parameters close to normal values. These results demonstrated the hepatoprotective utility of MEL against the CCl 4-induced liver injury which might ascribe to its antioxidant, free radical scavenging, antiapoptotic and antiinflammatory effects.
This study was undertaken to assess the possible modulatory effects and mechanisms of meloxicam, ... more This study was undertaken to assess the possible modulatory effects and mechanisms of meloxicam, a cyclooxygenase-2 inhibitor, on the antitumor activity and cardiotoxicity of doxorubicin in a mice model of mammary carcinoma. Solid tumor mass was developed in female albino mice using Ehrlich carcinoma cells. Forty mice-bearing tumor were divided randomly into four groups for treatment: with saline, meloxicam 10 mg/kg, doxorubicin 5 mg/kg and meloxicam 1 h ahead of doxorubicin, twice weekly for 2 weeks. Tumor volume was followed up and cardiac protective utility was estimated via measuring heart and serum parameters. Meloxicam expressed a non-significant increase in doxorubicin antitumor activity. Conversely, meloxicam significantly (p < 0.01) mitigated doxorubicin-induced elevation of serum cardiac enzymes [creatine kinase, lactate dehydrogenase and troponin-I]; cardiac lipid peroxidations marker; cardiac active caspase-3 content; and cardiac prostaglandin E2 content. Meloxicam si...
Beryllium chloride (BeCl 2 ) is a highly toxic substance that accumulates in different tissues af... more Beryllium chloride (BeCl 2 ) is a highly toxic substance that accumulates in different tissues after absorption. The purpose of this study was to investigate protective role of crocin against BeCl 2intoxication in rats. Male Wistar rats were used in this study and categorised into four groups (n ¼8). Group I served as normal control rats. Group II treated orally with BeCl 2 86 mg/kg b.w. for five consecutive days. This dose was equivalent to experimental LD 50 . Group III treated intraperitoneally with crocin 200 mg/kg b.w. for seven consecutive days. Group IV received crocin for seven consecutive days before BeCl 2 administration. Blood samples and liver and brain homogenates were obtained for haematological, biochemical and RT-PCR examinations. The haematocrit value, RBCs count and haemoglobin concentration were significantly decreased in BeCl 2 -treated rats. A significant increase was observed in rat liver and brain malondialdehyde level and protein carbonyls content in BeCl 2 exposed group compared to the control group, and these values were significantly declined upon administration of crocin. Lactate dehydrogenase levels in rat liver and brain significantly increased compared to the control group and was associated with significant decrease in catalase and superoxide dismutase activities. Reduced glutathione hepatic contents of BeCl 2 -treated rats were significantly decreased. There was significant decline in mRNA expression of catalase and superoxide dismutase genes in BeCl 2 -intoxicated rats compared to the normal rats. Crocin treatment prior to BeCl 2 intake resulted in significant increase in mRNA expressions of catalase and superoxide dismutase genes near to normalcy. The haematological and biochemical parameters were restored near to normal levels. Our results suggested that, BeCl 2 induced oxidation of cellular lipids and proteins and that administration of crocin reduced BeCl 2 -induced oxidative stress combined with initiation of mRNA expression of antioxidant genes.
Phthalates are abundantly produced plasticizers, and dibutyl phthalate (DBP) is the most widely u... more Phthalates are abundantly produced plasticizers, and dibutyl phthalate (DBP) is the most widely used derivative in various consumer products and medical devices. This study was conducted to further explore the potential testicular toxicity of DBP in adult rats and to elucidate the underlying mechanisms. Adult male albino rats were treated orally with DBP at doses of 0, 200, 400, or 600 mg/kg/day for 15 consecutive days. Testicular weight, sperm count, and motility were significantly decreased. Treatment with DBP decreased serum follicle-stimulating hormone and testosterone levels and testicular lactate dehydrogenase activity. DBP treatment also decreased serum total antioxidant capacity and the activities of the testicular antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione reductase. Further, DBP treatment provoked degeneration with absence of spermatogenesis and sperms and necrosis in some of seminiferous tubules. These results indicated that oxidative str...
The present study was aimed to investigate the mechanistic aspect of Aroclor 1260-induced hepatot... more The present study was aimed to investigate the mechanistic aspect of Aroclor 1260-induced hepatotoxicity and its protection by lipoic acid. The adult male Albino rats were divided into six groups. Group I served as control. Group II received lipoic acid (35 mg/kg/day). Aroclor 1260 was given to rats by oral gavage at doses 20, 40, or 60 mg/kg/day (Groups III, IV, and V, respectively). Group VI was pretreated with lipoic acid (35 mg/kg/day) 24 h before Aroclor 1260 (40 mg/kg/day). Treatment in all groups was continued for further 15 consecutive days. Serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities and total bilirubin, total cholesterol, and triglycerides were significantly increased while total protein, total albumin, and high-density lipoprotein were significantly decreased. Hydrogen peroxide production and lipid peroxidation were significantly increased while superoxide dismutase and catalase activities and redu...
Journal of Taibah University Medical Sciences, 2014
Objectives: Carbon tetrachloride (CCl4) is one of the most dangerous hepatotoxic environmental po... more Objectives: Carbon tetrachloride (CCl4) is one of the most dangerous hepatotoxic environmental pollutants thus this study aimed at investigating the potential preventive effect and mechanism of crocin against CCl4induced hepatotoxicity.
Lead is a biohazardous metal that is commonly involved in human illness including renal injury. A... more Lead is a biohazardous metal that is commonly involved in human illness including renal injury. Although it is a non-redox reactive metal, lead-induced renal injury is largely based on oxidative stress. The current work aimed at exploring the possible protective effect of γ-glutamyl cysteine (γGC) against lead-induced renal injury. Rats were allocated to normal and γGC control groups, lead-treated group, and lead and γGC-treated group. γGC alleviated lead-induced renal injury as evidenced by attenuation of histopathological aberration, amelioration of oxidative injury as demonstrated by significant reduction in lipid and protein oxidation, elevation of total antioxidant capacity, and glutathione level. The activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) was significantly elevated. γGC significantly decreased levels of the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β and the activity of the apoptotic marker caspase-3. In addition, γGC reduced kidney lead content, enhanced weight gain, and improved renal function as demonstrated by reduced serum levels of urea and creatinine. Importantly, γGC upregulated proliferating cell nuclear antigen (PCNA) expression, denoting enhanced renal regenerative capacity. Together, our findings highlight evidence for alleviating effects of γGC against lead-induced renal injury that is potentially mediated through diminution of oxidative tissue injury, reduction of inflammatory response, attenuation of apoptosis, and enhancement of renal regenerative capacity.
High blood glucose level, lipid profile disturbances and plasma homocysteine (Hcy) are important ... more High blood glucose level, lipid profile disturbances and plasma homocysteine (Hcy) are important risk factors for cardiovascular diseases in patients with type 2 diabetes. This study was conducted to evaluate and compare effects of glimepiride/metformin combination versus gliclazide/metformin combination on cardiovascular risk factors in type-2 diabetes mellitus (T2DM) patients. One hundred and eighty T2DM patients were randomly allocated for treatment with placebo (control), metformin (500mg twice daily), glimepiride (3mg once daily), gliclazide (80mg once daily), metformin plus glimepiride or metformin plus gliclazide for 3 months. We evaluated plasma levels of glucose (PG), glycated hemoglobin (HbA1C), Hcy, vitamin B12, folic acid and lipid profile before treatment and 3 months post treatment. Compared to metformin treated patients, glimepiride plus metformin induced significant reductions in: fasting plasma glucose, postprandial PG level, HbA1C % and Hcy level. Conversely, plasm...
Some novel 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones bearing sulfonamide derivative... more Some novel 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones bearing sulfonamide derivatives (4-11) were synthesized in good yields and evaluated for their possible antibacterial, anti-inflammatory activities and acute toxicity. The structures of the synthesized compounds were confirmed on the basis of their spectral data and elemental analysis. Their antibacterial activities were evaluated by the agar well diffusion method while their anti-inflammatory activities were evaluated by the carrageenan-induced hind paw edema test. All the tested compounds showed considerable antibacterial activities and high to moderate anti-inflammatory activities that last for 12 h compared to ibuprofen. All the tested compounds showed no toxic symptoms or mortality rates 24 h post-administration at tested anti-inflammatory doses. In addition, LD50 for all tested compounds was higher than that for ibuprofen implying their good safety margin. The obtained results showed that the most active compounds could be useful as a template for future design, modification and investigation to produce more active analogs.
Objectives: Carbon tetrachloride (CCl4) is one of the most dangerous hepatotoxic environmental po... more Objectives: Carbon tetrachloride (CCl4) is one of the most dangerous hepatotoxic environmental pollutants thus this study aimed at investigating the potential preventive effect and mechanism of crocin against CCl4induced hepatotoxicity.
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