Eman Said

Tranilast ameliorates cyclophosphamide-induced lung injury and nephrotoxicity

The world-wide increase in cancer incidence imposes a corresponding significant increase in the use of chemotherapeutic agents. Nephrotoxicity is a side effect frequently encountered with cyclophosphamide (CP), which is also well-known to cause acute and chronic lung toxicities. The current study focuses on the evaluation of the potential protective efficacy of tranilast against acute and subacute CP-induced lung and kidney injuries in male Swiss Albino mice. Intraperitoneal CP significantly impaired oxidant/anti-oxidant balance and increased inflammatory cell count in bronchoalveolar lavage fluid, serum creatinine, blood urea nitrogen (BUN), tumor necrosis factor-α (TNF-α) and lactate dehydrogenase (LDH) levels, with significant impairment of lung and kidney architectures. Tranilast taken orally for 8 and 14 days significantly enhanced mice anti-oxidant defense mechanisms; it increased lung and kidney SOD activity, GSH content and reduced lipid peroxidation. Tranilast significantly reduced serum creatinine and BUN. Furthermore, it decreased accumulation of inflammatory cells in the lungs. Serum TNF-α, LDH, total lung and kidney protein contents significantly declined as well. Histopathological examination revealed concomitant significant tissue recovery. Such results show a significant protective potential of tranilast against deleterious lung and kidney damage induced by CP, probably by enhancing host antioxidant defense mechanism, decreasing cytotoxicity, and decreasing expression of inflammatory cytokines.

Modulation of thioacetamide-induced liver fibrosis/cirrhosis by sildenafil treatment.

Sildenafil citrate is a phosphodiesterase-5 inhibitor, approved for the treatment of erectile dysfunction. It enhances nitric-oxide-induced vasodilatation and it promotes angiogenesis. A relationship between angiogenesis and hepatic fibrosis has long been speculated, where the 2 are believed to progress together. In this study, the ability of sildenafil (10 mg·(kg body mass)(-1), orally, once daily) to prevent and also reverse liver fibrosis/cirrhosis experimentally induced by thioacetamide injection (200 mg·kg(-1), intraperitoneal (i.p.), 3 times·week(-1)) in male Sprague-Dawley rats has been investigated. Sildenafil administration, either to prevent or to reverse liver fibrosis/cirrhosis significantly improved the estimated hepatic functions, reduced hepatic hydroxyproline and, in turn, hepatic collagen content, as well as reducing serum levels of the pro-fibrogenic mediator transforming growth factor β1. In co-ordination with such improvement, fibrosis grades declined and fibrosis retracted. Herein, the observed results provide evidence for the potential therapeutic efficacy of sildenafil as an antifibrotic agent.

Tranilast ameliorates impaired hepatic functions in Schistosoma mansoni-infected mice

The ability of tranilast, a mast cell stabilizer and anti-transforming growth factorβ (TGFβ) to improve impaired hepatic functions in Schistosoma mansoni (S. mansoni)-infected mice, was investigated, providing the first evidence on the ability of tranilast to improve hepatic impairment due to schistosomal infection. Tranilast had significant beneficial effects against progression of hepatic fibrosis in S. mansoni-infected mice treated with praziquantel and those untreated. Different aspects of drug activity were investigated. Its effect on serum liver functions was evaluated by estimating: alanine aminotransferase, aspartate aminotransferase, total bilirubin, alkaline phosphatase and albumin. Its effect on the extent of liver fibrosis, through estimation of hepatic hydroxyproline and hepatic collagen content in liver hydrolysates, was also evaluated. Also, the expression of profibrogenic mediators, such as serum TGFβ1, was estimated. Finally, the effect on S. mansoni infection itself was studied, via histopathological examination of liver specimens stained with both hematoxylin–eosin and Masson’s trichome stains. Tranilast ameliorated the harmful effects of S. mansoni infection on the liver. Such action was manifested in its significant ability to improve impaired hepatic functions, reduce histopathological changes, lower hepatic collagen content and finally reduce serum TGFβ1 levels. The beneficial effect of tranilast may be in part due to its ability to reduce the production of profibrogenic mediators in the infected animals by improving the host immune response or by interfering with critical steps in the fibrogenic cascade.

Crocin modulates IL-4/IL-13 signaling and ameliorates experimentally induced allergic airway asthma in a murine model

Abstract Allergic asthma is a chronic respiratory disease with a prevalent T helper (Th2)‐mediated immune reaction. Crocin, the major bioactive constituent of saffron, has been reported in multiple studies to have numerous pharmacological activities, including prominent anti‐oxidant activities. In the current study, the anti‐asthmatic potential of crocin was evaluated. Adult male Swiss Albino mice were administered 10 mg of ovalbumin (OVA) mixed with 1 mg of aluminum hydroxide intraperitoneally on days 0 and 7 and were administered crocin (25 mg/kg) orally daily for 16 days. Asthma progression was associated with significant increase in the lung/body weight index, inflammatory cell counts in bronchoalveolar lavage fluid (BALF), lung total protein content, and serious index of lung permeability, indicating pulmonary edema with accumulation of serous fluids within the lungs. Serum lactate dehydrogenase (LDH) activity and lung malondialdehyde (MDA) content were significantly increased, while lung superoxide dismutase (SOD) activity, reduced glutathione (GSH) levels, and serum and lung catalase activities were significantly decreased. These changes reflect significant pulmonary inflammation with concomitant disturbance of oxidant/antioxidant homeostasis. Moreover, tumor necrosis factor (TNF)‐&agr;, interleukin (IL)‐4, and IL‐13 contents in the lung were also significantly high after OVA sensitization. Crocin treatment significantly alleviated the OVA‐induced allergic asthma‐associated alterations in inflammatory and oxidative stress biomarkers. Crocin enhanced anti‐oxidant defenses, reduced the incidence of oxidative stress, and restored pro‐inflammatory cytokines to normal levels. Histopathological analysis showed significant lung improvement in crocin‐treated mice. In conclusion, crocin showed a significant protective effect against allergic asthma progression, which was associated with down‐regulation of inflammatory cytokine expression and restoration of oxidant/antioxidant homeostasis. HighlightsCrocin ameliorates allergic asthma‐induced pulmonary damage.Crocin decreases inflammatory cells recruitment and edema.Crocin decreases pulmonary MDA and increases SOD, GSH and catalase.Crocin modulates IL‐4/IL‐13 signaling.Crocin reduces lung TNF‐&agr; content.

Cytoprotective potential of tiron and methyl palmitate against acetaminophen-induced acute liver injury

Acute liver injury is a debilitating disorder associated with loss of synthetic and detoxifying functions of the liver. This investigation was designed to assess cytoprotective efficacy of daily oral tiron (300 mg/kg) and daily oral methyl palmitate (300 mg/kg) against acetaminophen-induced acute liver injury. Rats were orally pretreated with either tiron or methyl palmitate at doses (300 mg/kg) for 7 days prior to oral acetaminophen (3 g/kg). Biochemical assay of markers of hepatotoxicity indices and oxidative stress was undertaken. Expression of inflammatory cytokine IL-6 was also evaluated. Histopathological examination of liver specimens was carried out as well. Both methyl palmitate and tiron significantly reversed the acetaminophen-induced elevation of biochemical markers (ALT, AST, and ALP) with restoration of SOD levels. Serum albumin levels and GSH liver contents increased, but in a nonsignificant manner. Moreover, methyl palmitate and tiron significantly decreased the level of serum LDH and serum IL-6 levels. Histopathology revealed that tiron markedly reduced the extent of acetaminophen-induced necrosis and methyl palmitate moderately decreased the necrosis in liver tissue. Methyl palmitate (300 mg/kg) and tiron (300 mg/kg) demonstrated promising hepatoprotective effects against acetaminophen-induced acute liver injury via modulation of inflammatory response and alleviation of the oxidative stress, allowing the preservation of hepatic functions.

Nifuroxazide, a STAT3 inhibitor, mitigates inflammatory burden and protects against diabetes-induced nephropathy in rats

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus. Moreover,it is amongst the most common causes of end-stage renal failure. Inflammation is a crucial player in both development and progression of DN. JAK2/STA3 is a pleotropic cascade reported to regulate diverse inflammatory events. Previous studies reported involvement of JAK2/STA3 signal transduction pathway in diabetes-associated renal injury. In the current study, the inhibitory effect of nifuroxazide (25 mg/kg/day, orally) against inflammatory condition associating diabetic kidney progression in rats was evaluated. The underlying hypothesis is mainly via the inhibitory effect of nifuroxazide on STAT3 signaling. Results revealed that nifuroxazide effectively inhibited STAT3 activation in diabetic male rats, improved glomerular filtration function, protected against diabetes-induced histopathological and ultramicroscopic structural alterations. Further, nifuroxazide treatment significantly reduced renal macrophage infiltration and fibrosis and decreased mRNA and protein levels of TNF-α and IL-18 in diabetic renal tissue. The current findings shed the light on nifuroxazides efficacy as an alternative anti-inflammatory therapy to hinder the development and progression of DN in diabetic patients mainly via STAT3 inhibition.

Crocin mediated amelioration of oxidative burden and inflammatory cascade suppresses diabetic nephropathy progression in diabetic rats

Diabetic Nephropathy (DN) is one of the main complications associated with diabetes mellitus. Persistently elevated blood glucose level drives histopathological changes in renal tissues that hinder normal kidney functions. In the current study, crocin; the main bioactive constituent of Crocus sativus was investigated as a reno-protective agent against DN by virtue of its numerous pharmacological activities. Diabetes was induced in male Sprague-Dawely rats through intravenous injection of streptozocin (STZ) (50 mg/kg), DN was confirmed eight weeks post diabetes induction. Daily oral crocin for eight weeks (20 mg/kg) significantly reduced blood glucose level with a significant increase in insulin level. Moreover, crocin improved impaired kidney functions as manifested in reduction of serum creatinine levels, blood urea nitrogen and proteinuria with concomitant increase in urinary creatinine clearance. Furthermore, biomarkers of cell injury and tissue necrosis like LDH activity was significantly reduced, kidney content of NOS significantly declined likewise. In addition, renal antioxidants such as SOD, GSH and serum catalase activity significantly increased with concomitant reduction of kidney MDA; biomarker of oxidative load. Kidney content of toll-like receptors 4 and IL-6 significantly declined with simultaneous suppression of nuclear factor kappa-B (NF-κB/p65) protein expression and immuno-staining in rat renal cortex. Furthermore, crocin inhibited progression of renal fibrosis as seen with reduction of renal hydroxyproline and collagen content, TGF-β immuno-staining and Massons Trichrome positive tissue. Histopathologically, crocin pretreatment was associated with minimal renal damage with fewer fibrotic lesions. There was a concomitant restoration of renal tubules integrity with preservation of glomerular space area. In conclusion, crocins ameliorative impact on DN may be attributed to its free radicals scavenging properties, its ability to enhance host antioxidant defense system and its ability to inhibit inflammatory and fibrotic cascades activation.

Tadalafil reduces airway hyperactivity and protects against lung and respiratory airways dysfunction in a rat model of silicosis

Silicosis is a crippling respiratory disorder characterized by massive lung inflammation and fibrosis. The current study provides evidence on the protective potential of tadalafil; a specific phosphodiesterase-5 (PDE-5) inhibitor against experimentally-induced pulmonary silicosis in rats. Silicosis was induced by intranasal instillation of crystalline silica (50mg/rat). Halofuginone hydrobromide; a standard collagen-1 synthesis inhibitor was selected as a reference anti-fibrotic. Daily oral administration of tadalafil (1mg/kg) for 8weeks significantly ameliorated silica-induced pulmonary damage. BALF content of inflammatory cells, lung total protein, MDA, nitrite/nitrate, tumor necrosis factor α (TNFα), transforming growth factor β1 (TGFβ1) and collagen contents significantly declined with concomitant reduction in serum LDH activity; confirming reduction of silica-induced oxidative stress and inflammation. Meanwhile, lung SOD activity and GSH content significantly increased; confirming restoration of anti-oxidant defenses. Immunohistochemical analysis of lung TGFβ1 expression was correlated with observed biochemical improvements. There was a significant decline in thickness of the walls of the blood vessels and in macrophages and alveolar septal expression of TGFβ1 paralleled with reduction in collagen and extracellular matrix (ECM) components deposition. Ultimately, biochemical and histopathological improvements were accompanied by restoration of normal respiratory functions and reduction in airway hyperactivity and responses to both of carbachol and 5-HT. In conclusion; down-regulation of inflammatory and fibrogenic cytokines expression, restoration of oxidants/antioxidant hemostasis, antioxidant boost and promotion of angiogenesis are implicated in the observed protective effect of tadalafil.

Nephroprotective effect of saxagliptin against gentamicin-induced nephrotoxicity, emphasis on anti-oxidant, anti-inflammatory and anti-apoptic effects

&NA; Nephrotoxicity is a serious adverse effect frequently encountered with aminoglycosides administration. Given the value of aminoglycosides in management of serious infections, nephro‐protection is highly recommended. The current study investigated the nephro‐protective effect of saxagliptin (SAXA) (12.5 mg/kg, I.P.) against gentamicin (GEN)‐induced nephrotoxicity in rats. SAXA administration for 14 days conferred significant nephro‐protection against GEN‐induced nephrotoxicity manifested in decreased kidney/somatic index, enhanced cytoprotection and significant decrease in serum LDH activity together with functional renal improvement; significant increase in creatinine clearance with significant reduction in serum creatinine, BUN, proteinuria and albuminuria. Oxidant/antioxidants hemostasis was significantly improved with SAXA treatment with significant reduction in kidney MDA content and enhancement of GSH concentration and catalase activity. Moreover, kidney content of NO significantly declined with significant decline in kidney tumor necrosis factor&agr; (TNF&agr;), vascular adhesion molecule‐1 (VCAM‐1) and caspase‐3 content. Ultimately, SAXA administration was associated with significant attenuation of GEN‐induced necrotic and inflammatory changes. In conclusion; the modulatory effect of SAXA on inflammatory cytokines, its anti‐apoptic properties, ameliorative impact on oxidative load and positive impact on host antioxidant defenses accounts for the observed nephro‐protective impact.

Crocin Reverses Unilateral Renal Ischemia Reperfusion Injury-Induced Augmentation of Oxidative Stress and Toll like receptor-4 Activity

Renal Ischemia (RI) usually develops as a secondary manifestation of hypertension, various cardiovascular disorders and renal transplantation. It exerts hypoxic oxidative stress to kidneys, together with stimulation of several immune-mediated inflammatory cascades. Such events eventually damage renal tubules and glomeruli, driving acute kidney injury (AKI) and ultimately, renal failure. Crocin; the main bioactive constituent of Crocus sativus extract has been reported to demonstrate numerous pharmacological merits. In the current study, unilateral renal ischemia reperfusion injury (URIRI) was induced in rats by unilateral clamping of the left renal pedicle for 45 min followed by 24 h of reperfusion. Daily pre-treatment with crocin (20 mg/kg, orally) for 7 days, significantly improved all signs of renal injury. Biochemically, kidney functions; including serum creatinine (Sr Cr), blood urea nitrogen (BUN), proteinuria and creatinine clearance (Cr Cl) significantly improved. Inflammatory biomarkers; serum lactate dehydrogenase (LDH) and kidney nitric oxide (Nos) contents significantly declined. Oxidant/antioxidant balance was significantly restored; manifested in recovery of renal superoxide dismutase (SOD) activity, glutathione (GSH) concentration, malondialdehyde (MDA) content and restoration of serum catalase activity. Kidney contents of inflammatory cytokine interleukin-6 (IL6) and toll-like receptors 4 (TLR4) significantly declined as well. Histopathologically, crocin pretreatment resulted in signs of improvement with minimal renal lesions with significant decrease in renal inflammatory cells count. In conclusion, crocin induced restoration of normal kidney functions is mediated through multiple mechanisms including mainly attenuation of oxidative stress and inflammation via down-regulation of renal TLR4 and IL6 expression.