Reno-protective effect of protocatechuic acid is independent of sex-related differences in murine model of UUO-induced kidney injury.

BACKGROUND: Obstructive nephropathy is a condition often caused by urinary tract obstruction either anatomical (e.g., tumors), mechanical (e.g., urolithiasis), or compression (e.g., pregnancy) and can progress to chronic kidney disease (CKD). Studies have shown sexual dimorphism in CKD, where males were found to have a more rapid decline in kidney function following kidney injury compared to age-matched females. Protocatechuic acid (PCA), an anti-oxidant and anti-inflammatory polyphenolic compound, has demonstrated promising effects in mitigating drug-induced kidney injuries. The current study aims to explore sexual dimorphism in kidney injury after unilateral ureteral obstruction (UUO) and assess whether PCA treatment can mitigate kidney injury in both sexes. METHODS: UUO was induced in 10-12 weeks old male and female C57BL/6J mice. Mice were categorized into four groups (n = 6-8/group); Sham, Sham plus PCA (100 mg/kg, I.P daily), UUO, and UUO plus PCA. RESULTS: After 2 weeks of induction of UUO, markers of kidney oxidative stress (TBARs), inflammation (IL-1α and IL-6), tubular injury (neutrophil gelatinase-associated lipocalin, NGAL and urinary kidney injury molecule-1, KIM-1), fibrosis (Masson's trichrome staining, collagen IV expression, MMP-2 and MMP-9) and apoptosis (TUNEL+ cells, active caspase-1 and caspase-3) were significantly elevated in both males and females relative to their sham counterparts. Males exhibited significantly greater kidney oxidative stress, inflammation, fibrosis, and apoptosis after induction of UUO when compared to females. PCA treatment significantly attenuated UUO-induced kidney injury, inflammation, fibrosis, and apoptosis in both sexes. CONCLUSION: Our findings suggest a differential gender response to UUO-induced kidney injury with males being more sensitive to UUO-induced kidney inflammation, fibrosis, and apoptosis than age-matched females. Importantly, PCA treatment reduced UUO-induced kidney injury in a sex-independent manner which might be attributed to its anti-oxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic properties.

Saroglitazar mitigated NASH-associated hepatic injury in dexamethasone-treated rats via modulating autophagy, apoptosis, and necroptosis.

This study aimed to evaluate the possible ameliorative effects of saroglitazar (SAR) on aspects of hepatic injury in dexamethasone (DEX)-induced nonalcoholic steatohepatitis (NASH) in rats. Wistar rats received SAR (2 or 4 mg/kg/day, orally) or metformin (MET, 500 mg/kg/day, orally) for one week before and concurrently with DEX administration (8 mg/kg/day, i.p., for 6 days. Control and drug control groups received vehicle or the higher dose of SAR, respectively. At the end of the experiment, an oral glucose tolerance test (OGTT) was conducted, serum hepatic function parameters and lipid profile were assessed, and hepatic histological changes were evaluated. Moreover, hepatic p-Akt/Akt ratios, malondialdehyde (MDA) content, SREBP-1, FOXO1, LC3, cleaved caspase-3, and p-MLKL protein levels were determined. Furthermore, hepatic immunohistochemical expressions of FOXO1, caspase-3, Bcl-2, LC3, and P62 were examined. SAR (mainly at 4 mg/kg/day) significantly improved Area under the OGTT curve (P < 0.0001), hepatic function parameters, lipid profile, and hepatic histopathological features in DEX-administered rats. Moreover, SAR significantly attenuated DEX-induced increases in hepatic MDA content (P < 0.05), SREBP-1 levels (P < 0.0001), and nuclear FOXO1, caspase-3, LC3, P62, and p-MLKL protein expressions (P < 0.0001). Furthermore, SAR significantly enhanced hepatic p-Akt/Akt ratio and Bcl-2 protein expression in DEX-administered rats (P < 0.0001). The higher dose of SAR showed greater hepatoprotective effects compared to its corresponding lower dose and MET in most assessments, approaching levels similar to the control group. SAR mitigated hepatic injury associated with DEX-induced NASH in rats, suggesting it might be a potential hepatoprotective drug for patients with or at high risk of NASH.

Roflumilast extenuates inflammation and oxidative stress in cadmium-induced hepatic and testicular injury in rats.

Roflumilast (ROF), a highly selective phosphodiesterase-4 inhibitor, has proven anti-inflammatory and immunomodulatory effects on the pulmonary system. However, the protective effects of ROF on cadmium (Cd)-induced hepatic and testicular injury has never been investigated. Adult male Sprague Dawley rats were acutely intoxicated with CdCl2 (3 mg/Kg, ip, qd, for 5 days). In treatment groups, ROF was administered in two doses (1.5 & 3 mg/Kg, po, qd, for 5 days) 2 h prior to CdCl2 intoxication. The results demonstrated that the therapeutic potential of ROF can extend beyond the pulmonary system. The histopathological manifestation of Cd in the liver and testes were evidently mitigated by ROF prophylaxis. This study unraveled the multi-faceted ROF protective mechanisms, these comprise (i) reviving normal liver and testicular architecture, (ii) lessen immune cell infiltration in injured tissues (iii) restoration of cellular oxidant status (GSH, SOD, NO and MDA), (iv) shielding pro-inflammatory signaling pathways (NF-κB, NLRP3, IL-1ß axis), (v) dampening endoplasmic reticulum stress (IRE-1), (vi) mitigating apoptotic injury (caspase-3), (vii) restoring the integrity of blood testes barrier (Cathepsin-D) and (viii) promoting the regenerative potentials of injured testes (SDF-1). In conclusion, ROF is a promising anti-inflammatory and anti-oxidative candidate in Cd-induced hepatic and testicular injury.

Nilotinib alleviates paraquat-induced hepatic and pulmonary injury in rats via the Nrf2/Nf-kB axis.

BACKGROUND: Paraquat (PQ, 1,1'-dimethyl-4-4'-bipyridinium dichloride) is a highly toxic quaternary ammonium herbicide widely used in agriculture. It exerts its toxic effects mainly as a result of its redox cycle via the production of superoxide anions in organisms, leading to an imbalance in the redox state of the cell causing oxidative damage and finally cell death. The aim of this study was to estimate the beneficial protective role of nilotinib (NIL) on PQ-induced hepatic and pulmonary toxicity in rats. METHODS: Male wistar rats were randomly divided into four groups, namely control, PQ (15 mg/kg), PQ plus NIL (5 mg/kg) and PQ plus NIL (10 mg/kg). NIL (5 and 10 mg/kg/day) was taken by oral syringe for five days followed by a single intra-peritoneal administration of PQ (15 mg/kg) on sixth day. RESULTS: Pretreatment with NIL relieved the histological damage in liver and lung tissues and improved hepatic biochemical markers. It significantly (p < 0.05) reduced serum levels of ALT, AST, ALP, Y-GT and total bilirubin while increased that of albumin. Meanwhile, NIL significantly (p < 0.05) reduced oxidative stress markers via reduction of malondialdhyde (MDA) and elevation of glutathione (GSH) contents in liver and lung tissues. In addition, it significantly (p < 0.05) decreased the inflammation by reducing hepatic and pulmonary tumor necrosis factor alpha (TNF-α) and nuclear transcription factor kappa B (NF-KB/p65) contents. Nilotinib also down-regulated apoptosis by reducing cysteinyl aspartate-specific proteinase-3 (caspase-3). Furthermore, it upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and microtubule-associated protein 1A/1B-light chain 3 II (LC3II) in liver and lung tissues. SIGNIFICANCE: NIL suppressed PQ-induced inflammation, oxidative stress and apoptosis in liver and lung tissues by modulating Nrf2/Nf-kB axis.

Celecoxib abrogates concanavalin A-induced hepatitis in mice: Possible involvement of Nrf2/HO-1, JNK signaling pathways and COX-2 expression.

Concanavalin A (ConA) is an established model for inducing autoimmune hepatitis (AIH) in mice, mimicking clinical features in human. The aimof the current study is to explore the possible protective effect of celecoxib, a cyclooxygenase-2 inhibitor,on immunological responses elicited in the ConA model of acute hepatitis. ConA (20 mg/kg) was administered intravenously to adult male mice for 6 h. Prior to ConA intoxication, mice in the treatedgroups received daily doses of celecoxib (30 and 60 mg/kg in CMC) for 7 days. Results revealed that administration of celecoxib 60 mg/kg for 7 days significantly protected the liver from ConA-induced liver damage revealed by significant decrease in ALT and AST serum levels. Celecoxib 30 and 60 mg/kg pretreatment enhanced oxidant/antioxidant hemostasis by significantreduction of MDA and NO content and increase hepatic GSH contents and SOD activity. In addition, celecoxib 30 and 60 mg/kg caused significant increase in hepatic nuclear factor erythroid 2-related factor 2 (Nrf2) and the stress protein heme oxygenase-1 (HO-1) levels. Moreover, celecoxib 30 and 60 mg/kg inhibited the release of proinflammatory markers including IL-1ß and TNF-α along with significant decrease in p-JNK, AKT phosphorylation ratio and caspase-3 expression. Besides, Con A was correlated to high expression of cyclooxygenase COX-2 and this increasing was improved by administration of celecoxib. These changes were in good agreement with improvement in histological deterioration. The protective effect of celecoxib was also associated with significant reduction of autophagy biomarkers (Beclin-1 and LC3II). In conclusion, celecoxib showed antioxidant, anti-inflammatory, anti-apoptotic and anti-autophagy activity against Con A-induced immune-mediated hepatitis. These effects could be produced by modulation of Nrf2/HO-1, IL-1B /p-JNK/p-AKT, JNK/caspase-3, and Beclin-1/LC3II signaling pathways.

Imatinib mitigates experimentally-induced ulcerative colitis: Possible contribution of NF-kB/JAK2/STAT3/COX2 signaling pathway.

RATIONALE: Ulcerative colitis (UC) is a chronic immune-mediated disease characterized by recurrent inflammation, damage, and alteration of the large intestine's mucosal and submucosal surfaces. The purpose of this research was to evaluate the impact of tyrosine kinase inhibitor (imatinib) on experimentally induced UC in rats via acetic acid (AA). METHODS: Male rats were randomly assigned to four groups: control, AA, AA + imatinib (10 mg/kg), and AA + imatinib (20 mg/kg). Imatinib (10 and 20 mg/kg/day) was orally supplied by oral syringe for one week before induction of UC. On the eighth day, Rats received enemas containing a 4 % solution of acetic acid to induce colitis. One day after inducing colitis, rats were euthanized and their colons were subjected to morphological, biochemical, histological, and immunohistochemical analysis. RESULTS: Imatinib pretreatment significantly decreased macroscopic and histological damage scores, decreased disease activity index as well as colon mass index. In addition, imatinib successfully lowered the levels of malondialdehyde (MDA) in colonic tissues and enhanced superoxide dismutase activity (SOD) and glutathione content (GSH). Imatinib also reduced colonic levels of inflammatory interleukins (IL-23, IL-17, IL-6), JAK2 and STAT3. Furthermore, imatinib suppressed nuclear transcription factor kappa B (NF-kB/p65) level, and COX2 expression in colonic tissues. SIGNIFICANCE: Imatinib may be a viable therapy option for UC as it halts the interaction network of NF-kB/JAK2/STAT3/COX2 signaling pathway.

Candesartan protects against unilateral peripheral limb ischemia in type-2 diabetic rats: Possible contribution of PI3K-Akt-eNOS-VEGF angiogenic signaling pathway.

Type-2 diabetes (T2DM) is known to be highly associated with increased risk for vascular complications including peripheral arterial diseases (PAD). Critical limb ischemia (CLI) is the most advanced stage of PAD. Current therapeutic options for diabetic patients experiencing vascular complications are limited to surgical revascularization with no effective pharmacotherapy available for clinical settings. This study is dedicated to evaluate the angiogenic potential of candesartan an angiotensin-II receptor blocker in an experimental model of vascular complications associating T2DM. T2DM was induced in rats through feeding with high fat diet for 6 weeks, followed by injection with streptozotocin (STZ, 30 mg/kg; i.p). After establishment of T2DM, unilateral CLI was induced through the ligation and excision of superficial femoral artery. Candesartan treatment (10 or 30 mg/kg; orally) was initiated one day post CLI and thereafter once daily for up to 14 days. T2DM rats that underwent CLI demonstrated impaired angiogenic signaling, increased inflammation and apoptosis in gastrocnemius muscle (GC). Candesartan reversed ischemic insult in T2DM rats subjected to unilateral CLI and induced reparative angiogenesis that was evident by increase in p-PI3K/PI3K, p-Akt/Akt, p-eNOS/eNOS, p-VEGFR2/VEGFR2 ratios, and VEGF levels. Candesartan treatment also increased levels of HO-1; while decreased caspase-3 apoptotic marker and levels of inflammatory markers; NF-κB and TNF-α, all of which were accompanied by preserved histological manifestations of GC muscles. Candesartan was able to combat limb ischemia under diabetic conditions which could pave the way for its therapeutic utility for diabetic patients experiencing vascular complications in clinical setting.

Saroglitazar, a dual PPAR-α/γ agonist, alleviates LPS-induced hepatic and renal injury in rats.

BACKGROUND: Lipopolysaccharide (LPS), an endotoxin within gram-negative bacteria, is associated with systemic acute inflammatory response after invading living tissues and results in sepsis. The liver and kidney are both major target organs in sepsis. Septic acute hepatic-renal injury is a serious clinical condition with high risk of morbidity and mortality. Nevertheless, effective treatment is still lacking. AIM: This study highlights saroglitazar (SAR), a dual PPAR-α/γ agonist, as a proposed prophylactic drug against LPS-induced hepatic-renal injury. MAIN METHODS: Rats were pretreated with SAR (2 and 4 mg/kg/day) for 15 days, while sepsis was induced by LPS injection (10 mg/kg) on day 15 one hour following SAR oral administration. KEY FINDINGS: SAR pretreatment could successfully mitigate LPS-induced hepatic-renal injury, evidenced by enhancement of renal and hepatic functions and a decrease of tissue pathological injury. Meanwhile, SAR alleviated LPS-induced oxidative stress; it reduced malondialdehyde (MDA) levels and ameliorated decreased levels of superoxide dismutase (SOD) and glutathione (GSH). LPS-induced elevations in hepatic and renal nuclear factor-kappa B (NF-κB), phosphorylated inhibitor of kappa B alpha (p-IκBα), interferon-beta (IFN-ß), and hepatic high mobility group box-1 (HMGB-1) contents were significantly attenuated in SAR-treated groups. SAR showed an advantageous impact against LPS-induced activation of non-canonical inflammasome and pyroptosis via a significant reduction in cysteinyl aspartate-specific proteinase-11 (Caspase-11) and gasdermin D (GSDMD) expressions. Moreover, Nucleotide-Binding Oligomerization Domain (NOD)-Like Receptor Protein 3 (NLRP3) inflammasome activation with concomitant expression and activation of caspase-1 and release of interleukin-1beta (IL-1ß) were considerably diminished following SAR pretreatment. SIGNIFICANCE: SAR could be considered a prophylactic anti-inflammatory antioxidant drug against LPS-induced liver and kidney injury.

Nilotinib alleviated acetaminophen-induced acute hepatic injury in mice through inhibiting HIF-1alpha/VEGF-signaling pathway.

The current study inspects the impact of nilotinib (Nil) on liver damage caused by acetaminophen (APAP). Adult male mice were pre-treated with nilotinib (Nil,5 and 10 mg/kg) orally once daily for 7 days followed by a single intraperitoneal administration of acetaminophen (APAP, 200 mg/kg) on the 7th day. The results indicated that nilotinib significantly decreased APAP-induced elevation of biochemical markers (ALT, AST, ALP, LDH, ɤ GT, and total bilirubin). Additionally, nilotinib significantly increased hepatic GSH and SOD content, while decreased MDA content. Nil significantly suppressed the expression of HIF-1α and VEGF. Histopathological examination of hepatic tissue from Nil-treated mice revealed that Nil reduced acetaminophen-induced necrosis.

The modulatory effect of sodium molybdate against cisplatin-induced CKD: Role of TGF-ß/Smad signaling pathway.

AIMS: Chronic kidney disease (CKD) is a global non-communicable health problem. Fibrosis is considered the base and the fate of CKD; thus, the goal of this study was to evaluate the effects of sodium molybdate on cisplatin-induced CKD model and demonstrate the possible involved mechanisms. MATERIALS AND METHODS: In cisplatin model, Wistar rats were challenged with cisplatin (1 mg/kg, i.p.) twice weekly for ten weeks. Sodium molybdate (100 and 200 mg/kg, orally) was given one-week prior cisplatin and was continued daily for the next ten weeks. KEY FINDINGS: Administration of sodium molybdate amended kidney function and significantly reduced the pathological changes in renal histopathological sections. Moreover, it modulates oxidative stress parameters by increasing the levels of SOD and GSH and decreasing the level of MDA. Likewise, in renal homogenate, sodium molybdate attenuated inflammation that was revealed by NF-κB and TNF-α levels significant reduction. Additionally, it ameliorated fibrosis that was indicated by decreased Masson's trichome staining in cortex and medulla. Immunohistochemical staining of renal sections against TGF-ß1 showed reduction of positive glomerular and tubular protein expression. Additionally, it decreased profibrotic Smad3 level and increased antifibrotic Smad7 level. SIGNIFICANCE: Administration of sodium molybdate demonstrated a hopeful suppressor effect on cisplatin-induced CKD/fibrosis in rat model. This effect may be through the inhibition pof TGF-ß/Smad signaling pathway and up-regulation of Smad7 expression leading to decreased extracellular collagen accumulation. Moreover, they could ameliorate the inflammation through NF-κB and TNF-α levels reduction, decrease in ROS, and retrieval of antioxidant defenses.

Effect of Agmatine on a mouse model of allergic airway inflammation: A comparative study.

INTRODUCTION: Asthma is a chronic lung disease that injures and constricts the airways. This study evaluates the effects of agmatine on ovalbumin (OVA)-induced allergic inflammation of the airways. METHODS: OVA sensitization by intraperitoneal injection was used to induce airway inflammation in mice on days 0 and 7; then the mice were challenged using beclomethasone (150 µg/kg, inhalation), a standard anti-asthmatic drug, from day 14 to day 16. Furthermore, agmatine (200 mg/kg) was intraperitoneally injected on day 0 and then daily for 16 days, followed by OVA challenge. The lung weight ratio, total and differential cell counts, TNF-α, interleukin-5 (IL-5) and IL-13 in bronchoalveolar lavage fluid (BALF), lung nitrite/nitrate (NO), and oxidative parameters were determined. Moreover, histopathological and immunohistochemical staining was employed. RESULTS: Injection of agmatine (200 mg/kg) for 16 days significantly attenuated inflammation of the airways. The levels of BALF inflammatory cells, TNF-α, IL-5, IL-13, lung NO, and malondialdehyde (MDA), significantly decreased with concomitant elevation of superoxide dismutase (SOD) levels. Histological and immunohistochemical analyses of mast cells paralleled to biochemical improvements. CONCLUSION: Finally, this study illustrated that agmatine attenuates the allergic inflammation of airways caused by OVA by mitigating cytokines release, NO expression, and oxidative stress.

Flavocoxid halts both intestinal and extraintestinal alterations in acetic acid-induced colitis in rats.

Ulcerative colitis (UC) is an idiopathic chronic inflammatory disorder mainly affecting the colon and rectum. The present investigation was undertaken to evaluate the potential protective effect of flavocoxid, a dual COX and LOX inhibitor, in colitis model in rats. UC was induced by instillation of 2 ml of 4% acetic acid (AA) into the colon using a pediatric catheter in rats, and flavocoxid (10 and 20 mg·kg-1) was given once daily for 7 days before induction of colitis. Rats were sacrificed; sera were collected; colons and livers were isolated and then analyzed by biochemical, macroscopic, and histopathological examination. Pretreatment with flavocoxid (10 and 20 mg·kg-1) significantly reduced serum levels of alanine transaminase (ALT) (43.7 ± 7 and 76.2 ± 7.3 vs. 288.7 ± 31.4 in AA group) and aspartate transaminase (AST) (179.5 ± 22.2 and 200.5 ± 14 vs. 392.7 ± 35.6 in AA group) (p>0.05). Also, it decreased malondialdehyde (MDA) and nitric oxide (NOx) levels in both colonic and hepatic tissues. Moreover, flavocoxid effectively elevated colonic and hepatic reduced glutathione (GSH) level and superoxide dismutase (SOD) activity when compared to AA group (p>0.05). Additionally, flavocoxid significantly decreased levels of tumor necrosis factor-α (TNF-α) (878.2 ± 13.4 and 560.1 ± 2.9 vs. 1378.1 ± 31 in AA group) in colonic tissues and (701 ± 6.9 and 442.5 ± 8.2 vs. 1501 ± 9.4 in AA group) in hepatic tissues, nuclear factor kappa B (NF-κBp65) (493.8 ± 6.8 and 368.7 ± 3.1 vs. 659.2 ± 9.4 in AA group) in colonic tissues and (358 ± 5.1 and 163.5 ± 7.8 vs. 732.5 ± 4.5 in AA group) in hepatic tissues, myeloperoxidase (MPO) (15.7 ± 0.3 and 13 ± 0.2 vs. 20.9 ± 0.5 in AA group) in colonic tissues and (20.4 ± 0.3 and 16.3 ± 0.3 vs. 23.9 ± 1.2 in AA group) in hepatic tissues, and inducible nitric oxide synthase (iNOS) (12.5 ± 0.3 and 10 ± 0.2 vs. 16 ± 0.1 in AA group) in colonic tissues and (14.1 ± 0.04 and 11.5 ± 0.08 vs. 17.8 ± 0.1 in AA group) in hepatic tissues (p>0.05). Furthermore, it down-regulated Bax and caspase-3 expression in colonic and hepatic tissues upon comparison with AA group. Collectively, flavocoxid conferred a protective impact against acetic acid-induced colitis in rats via attenuating oxidative stress, inflammation, and apoptosis.

Molsidomine alleviates acetic acid-induced colitis in rats by reducing oxidative stress, inflammation and apoptosis.

Ulcerative colitis (UC) is a subcategory of intestinal inflammatory bowel disease characterized by up-regulation of proinflammatory cytokines and oxidative stress. The current study was designed to assess the probable protective effect of the nitric oxide (NO) donor, molsidomine, in experimental colitis model in rats. Rats were haphazardly classified into four groups: control, acetic acid, acetic acid + molsidomine (1 mg/kg) and acetic acid + molsidomine (2 mg/kg). Molsidomine (1 and 2 mg/kg/day) was administered by intra-peritoneal injection for 7 days prior to induction of UC. On the 8th day, colitis was induced by intra-rectal instillation of 2 ml of (4% v/v) acetic acid in normal saline using a pediatric plastic catheter. The rats were sacrificed 1 day following colitis induction, blood samples were obtained; colons and livers were isolated then underwent macroscopic, biochemical, histopathological and immunohistochemical examination. Pretreatment with molsidomine significantly reduced disease activity index, colon mass index, colonic macroscopic and histological damage. Besides, molsidomine significantly reduced the serum levels of alanine transaminase (ALT) (58.7 ± 8.9 & 59.7 ± 8 vs 288.75 ± 31.4 in AA group) and aspartate transaminase (AST) (196.2 ± 37.4 & 204 ± 30 vs 392.7 ± 35.6 in AA group). Moreover, molsidomine effectively decreased malondialdehyde (MDA) and total nitrate/nitrite (NOx) contents, and up regulated the enzymatic activity of superoxide dismutase (SOD) and glutathione level (GSH) in colonic and hepatic tissues. With regard to anti-inflammatory mechanisms, molsidomine suppressed tumor necrosis factor-alpha (TNF-α) (792.5 ± 16.7 & 448 ± 12.1 vs 1352.5 ± 45.8 in AA group) in colonic tissues and (701 ± 19 & 442.5 ± 22.5 vs 1501 ± 26 in AA group) in hepatic tissues as well as nuclear transcription factor kappa B (NF-kB/p65) levels (416.2 ± 4.1 & 185.5 ± 14.2 vs 659.2 ± 11.5 in AA group) in colonic tissues and (358 ± 6.2 & 163.5 ± 9.6 vs 732.5 ± 5.5 in AA group) in hepatic tissues. In addition, molsidomine significantly decreased inducible nitric oxide synthase (iNOS) levels (8.1 ± 0.1 & 4.9 ± 0.1 vs 16 ± 0.1 in AA group) in colonic tissues and (8.6 ± 0.3 & 6.1 ± 0.1 vs 17.8 ± 0.1 in AA group) in hepatic tissues, and myeloperoxidase (MPO) contents (10.5 ± 0.4 & 6.6 ± 0.3 vs 20.9 ± 0.6 in AA group) in colonic tissues and (13.1 ± 0.2 & 6.3 ± 0.06 vs 23.9 ± 1.4 in AA group) in hepatic tissues at p > 0.05. Furthermore, it suppressed apoptosis by reducing expression of Caspase 3 and Bax in colonic and hepatic tissues. Therefore, molsidomine might be a promising candidate for the treatment of UC.

Canagliflozin ameliorates aortic and hepatic dysfunction in dietary-induced hypercholesterolemia in the rabbit.

AIMS: Canagliflozin is an antidiabetic agent which lowers blood glucose levels by inhibiting the glucose reabsorption machinery in the proximal tubules. There have not been conducted any study on its direct impact on hypercholesterolemia and associated vascular disorders independently of blood glucose lowering activity. MATERIALS AND METHODS: Rabbits were arranged in 3 groups: Group 1 (Control): regular rabbit chow; Group 2 (HCD): 1% cholesterol-enriched chow was given to rabbits for 4 weeks; Group 3 (HCD-CANA): 1% cholesterol-enriched chow was fed to rabbits concurrently with canagliflozin (10 mg/kg/day, orally) for 4 weeks. At the end of experiment, blood and tissue samples were obtained for biochemical, histological, immunohistochemical, and vascular reactivity assessment. KEY FINDINGS: When statistically compared to Control (P < 0.05), HCD showed a significant increase in the serum triglycerides, low-density lipoprotein, total cholesterol, C-reactive protein, alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase. Furthermore, a significant decrease was seen in both liver and aortic levels of glutathione peroxidase and superoxide dismutase concurrently with a significant elevation in malondialdehyde levels. Aortic levels of nitrate/nitrite ratio were significantly elevated. Acetylcholine-induced relaxation was impaired as the Emax decreased significantly in aortae. Moreover, a significant increase was seen in the level of aortic intima/media ratio. Canagliflozin treatment significantly improved vascular function, lipid profile and inflammation and reduced liver injury. SIGNIFICANCE: Our data suggest that SGLT-2 inhibition via canagliflozin not only possesses an antihyperglycemic activity, but also improves hypercholesterolemia, vascular and liver function in dietary-induced hypercholesterolemia in the rabbit.

Impact of protocatechuic acid on high fat diet-induced metabolic syndrome sequelae in rats.

The study aimed to assess the possible protective impact of protocatechuic acid (PCA) on high fat diet (HFD)-induced metabolic syndrome (Mets) sequelae in rats. Forty-two male Sprague-Dawley (SD) rats were randomly grouped as follows: CTR group; PCA group; HFD group; HFD-PCA group and HFD-MET group. Rats were fed on standard diet or HFD for 14 weeks. HFD-fed rats exhibited significant decreases in food intake and adiponectin (ADP) level; yet, body weight and anthropometrical parameters were significantly increased. Moreover, insulin sensitivity was impaired as indicated by significant elevation in glucose AUC during oral glucose tolerance test (OGTT), fasting serum glucose, fasting serum insulin and homeostasis model assessment of insulin resistance (HOMA-IR) index. Furthermore, chronic HFD feeding elicited significant increases in serum lipid profile and free fatty acids (FFAs) with concomitant hepatic steatosis. Additionally, serum C-reactive protein (CRP), interleukin 1b (Il-1b) and monocyte chemoattractant protein 1(MCP-1) levels were increased. Also, HFD-fed rats exhibited an increase in MDA level, while superoxide dismutase (SOD) and glutathione (GSH) activities were decreased. Moreover, the insulin-signaling pathway was markedly impaired in soleus muscles as indicated by a decrease in insulin-induced AKT phosphorylation. Histopathologically, adipose tissues showed significant increase in adipocyte size. Also, flow cytometry analysis of adipose tissue confirmed a significant increase in the percentage of number of CD68+ cells. PCA administration succeeded to attenuate HFD-induced obesity, insulin resistance, oxidative stress and inflammation. In conclusion, PCA administration could protect against HFD-induced Mets, possibly via its hypoglycemic, insulin-sensitizing, anti-oxidant and anti-inflammatory effects.

The HIV reverse transcriptase Inhibitor Tenofovir suppressed DMH/HFD-induced colorectal cancer in Wistar rats.

Colon rectal cancer (CRC) is the second commonest malignancy in developed countries and a significant cause of mortality. Tenofovir reportedly reduces the risk of hepatocellular carcinoma and interferes with cell cycle and cell proliferation. The current study investigated the potential antitumor effect of tenofovir against experimentally induced CRC. CRC was induced by 1,2-dimethylhydrazine (DMH, 20 mg/kg, once a week) and high-fat diet (HFD) in Wistar rats. Rats received tenofovir at a dose of 25 or 50 mg/kg (i.p.) for 24 weeks. Tenofovir-25 failed to significantly decrease the total number of dysplasia, adenoma and adenocarcinoma and to improve histopathological changes; however, tenofovir-50 resulted in no tumors seen in the colon lumen and a significant decrease in the total number of dysplasia and no adenoma or adenocarcinoma observed compared to DMH/HFD group. Tenofovir-25 failed to attenuate DMH/HFD-induced cell proliferation, whereas tenofovir-50 significantly decreased cell proliferation revealed by the decreased PCNA expression. Tenofovir-25 also failed to attenuate DMH/HFD-induced oxidative stress, whereas tenofovir-50 significantly attenuated oxidative stress as indicated by the decreased MDA concentration and SOD activity along with the increased GSH concentrations. Moreover, tenofovir-50 decreased Bcl-2 and cyclin D1 expressions in colon tissues compared with DMH/HFD group. Tenofovir-50 also significantly decreased INF-ɤ concentration in colon tissues. These findings suggest that the high dose of tenofovir (50 mg/kg) has antitumor potential against DMH/HFD-induced CRC, which might be mediated through the inhibition of cell proliferation, oxidative stress, and inflammation.

The protective effect of protocatechuic acid on hepatotoxicity induced by cisplatin in mice.

Cisplatin is one of the most potent anti-cancer drugs used for the treatment of various solid tumors, yet it has several side effects that may limit its clinical use. Hepatotoxicity is one of the most serious side effects as it may lead to liver failure. Several mechanisms including oxidative stress, inflammation, and apoptosis have been examined in cisplatin-induced hepatotoxicity. Protocatechuic acid (Proto) which is naturally occurring phenolic acid has shown different biological activity as antioxidant, anti-inflammatory, and anti-apoptotic. In this study, we investigate the protective effect of Proto at two doses 100 and 150 mg/kg on hepatotoxicity induced by a single injection of 10 mg/kg cisplatin in female albino mice. The present study demonstrates for the first time that Proto administration (100 and 150 mg/Kg) significantly attenuates cisplatin-induced changes in liver function [increase serum albumin and decrease liver injury markers ALT, AST, GGT, and bilirubin]. This was associated with marked hepatic antioxidant effects [decrease MDA and NO levels, increase GSH and SOD activity]. Moreover, Proto reduced cisplatin-induced apoptosis in the liver through decreasing caspase-3, annexin-V, and BAX. Both doses suppressed cisplatin-induced expression of iNOS and NF-ᴋB p65 subunit and pro-inflammatory cytokines (IL-6 and TNF-α). Also, Proto improved histopathological examination of the liver. The present findings reveal that the antioxidant, anti-inflammatory, and anti-apoptotic effects of Proto are the main mechanisms by which Proto can ameliorate cisplatin-induced liver injury.

Protocatechuic acid improves hepatic insulin resistance and restores vascular oxidative status in type-2 diabetic rats.

This work explored influences of protocatechuic acid (PCA) on type 2 diabetes (T2D)-associated hepatic insulin resistance and other metabolic, hepatic and vascular irregularities using the rat model of high fat diet (HFD)+high fructose+low dose streptozotocin (STZ). Twenty-four male Wister rats were used. Twelve rats were ad libitum supplied with HFD and high fructose drinking water (25 % w/v) for 60 days. On day 30, they received a single injection of STZ (35 mg/kg, i.p). On day 32, they were divided into two subgroups (n = 6/each): T2D + PCA, received PCA (100 mg/kg/day, orally) and T2D, received PCA vehicle till the end of experiment. Rats provided with regular diet and fructose-free drinking water, with or without PCA treatment, served as PCA and control groups (n = 6/each), respectively. PCA treatment significantly reduced the elevated levels of fasting glycemia and insulin, AUCOGTT, AUCITT, and HOMA-IR index, while it boosted HOMA-ß and insulinogenic index values in T2D rats. PCA ameliorated serum lipid levels and hepatic function parameters and mitigated hepatosteatosis in T2D rats. Mechanistically, PCA mitigated hepatic lipid peroxidation and restored reduced glutathione (GSH) and superoxide dismutase (SOD) to near-normal levels. Moreover, PCA enhanced hepatic protein levels of P-AKTser473 and hepatic mRNA expression of insulin receptor substrate 1 (IRS1), phosphatidylinositol 3 kinase (PI3K)-p85 and AKT2. Furthermore, PCA ameliorated aortic oxidative stress in T2D rats, possibly via reducing serum levels of advanced glycation end products (AGEs) and diminishing vascular expression of RAGE and NOX4 mRNA. Collectively, PCA may improve hepatic insulin resistance and vascular oxidative status by modulating IRS1/PI3K/AKT2 and AGE-RAGE-NOX4 pathways, respectively.

Anti-apoptotic effect of vinpocetine on cisplatin-induced hepatotoxicity in mice: The role of Annexin-V, Caspase-3, and Bax.

Hepatic damage is one of the most common complications related to cisplatin (Cis) use. Recently, liver protection lines are being discovered to avoid hepatic cell death as a result of oxidative, inflammatory, and apoptotic disturbance. Limited data reported the hepatoprotective effect of vinpocetine (Vin) in acute liver injury models. This study was designed to determine the potential protective effect of Vin (10-30 mg/kg, orally) against Cis-induced liver injury (10 mg/kg, IP) in mice. Vin administration for 1 week before Cis injection until the end of the experiment. On the 6th day after Cis injection, mice were anesthetized, blood and tissue samples were collected. Hepatic function, histological changes, oxidative stress, inflammation, and apoptotic markers were investigated. Vin administration ameliorated liver injury as indicated by decreased liver injury parameters; serum aminotransferases, ALK-P, GGT, and bilirubin, restored the anti-oxidant status by decrease MDA and NOx , and increased GSH and SOD, inhibited inflammation (IL-6, TNF-α, NFκB-p65, and iNOS) and apoptosis (Annexin-V, Bax, and Caspase-3) parameters. Vin confers dose-dependent protection against Cis-induced liver injury. The hepatoprotective effect of Vin involved anti-oxidative, anti-inflammatory, and anti-apoptotic activities.