A standardized pomegranate fruit extract ameliorates thioacetamide-induced liver fibrosis in rats via AGE-RAGE-ROS signaling.

This work aimed to investigate a possible mechanism that may mediate the hepatoprotective effects of pomegranate fruit extract (PFE) against thioacetamide (THIO)-induced liver fibrosis in rats. Male Sprague Dawley rats were randomly allocated into four groups (n = 8 each): control; PFE (150 mg/kg/day, orally); THIO (200 mg/kg, i.p, 3 times a week); and THIO and PFE-treated groups. Oral PFE treatment decreased liver/body weight ratio by 12.4%, diminished serum function levels of ALT, AST, ALP, LDH, and total bilirubin, increased serum albumin, boosted hepatic GSH (by 35.6%) and SOD (by 17.5%), and significantly reduced hepatic levels of ROS, MDA, 4-HNE, AGEs, and RAGE in THIO-fibrotic rats relative to untreated THIO group. Moreover, PFE administration downregulated the hepatic levels of profibrotic TGF-ß1 (by 23.0%, P < 0.001) and TIMP-1 (by 41.5%, P < 0.001), attenuated α-SMA protein expression, decreased serum HA levels (by 41.3%), and reduced the hepatic levels of the fibrosis markers hydroxyproline (by 26.0%, P < 0.001), collagen type IV (by 44.3%, P < 0.001) and laminin (by 43.4%, P < 0.001) compared to the untreated THIO group. The histopathological examination has corroborated these findings, where PFE decreased hepatic nodule incidence, attenuated portal necroinflammation and reduced extent of fibrosis. These findings may suggest that oral PFE administration could slow the progression of hepatic fibrogenesis via reducing hepatic levels of AGEs, RAGE, ROS, TGF-ß1, and TIMP-1.

Nifuroxazide mitigates doxorubicin-induced cardiovascular injury: Insight into oxidative/NLRP3/GSDMD-mediated pyroptotic signaling modulation.

Doxorubicin (DOX) is a widely used powerful anthracycline for treatment of many varieties of malignancies; however its cumulative and dose-dependent cardio-toxicity has been limited its clinical use. In the current study, in vivo and in vitro (neonatal rat's cardiomyocytes) experiments were conducted to identify the impact of nifuroxazide (NIFU) on DOX-induced cardiomyopathy, vascular injury, and hemato-toxcity and plot the underlying regulatory mechanisms. Cardiovascular injury was induced in vivo by I.P. injection of an overall dose of DOX (21 mg/kg) administered (3.5 mg/kg) twice weekly for 21 days. NIFU (10 and 30 mg/kg) was administered orally once daily for 21 days, 1 week after DOX injection initiation. In vivo experiments confirmed NIFU to restore blood cells counts and hemoglobin concentration. Moreover, NIFU normalized the myocardial functional status as confirmed by ECG examination and myocardial injury markers; CK-MB, LDH, and AST. NIFU restored the balance between TAC and both of ROS and MDA and down-regulated the protein expression of TLR4, NF-kB, TXNIP, NLR-family pyrin domain containing 3 (NLRP3), caspase-1, IL-1ß, and GSDMD-N terminal, with inhibition of the up-stream of NLRP3 and the down-stream DOX-induced pyroptosis. The in vitro assay confirmed well preserved cardiomyocytes' architecture, amelioration of NLRP3/IL-1 ß-mediated cell pyroptosis, enhanced cell viability, and improved spontaneous beating. Moreover, NIFU normalized the disturbed aortic oxidant-antioxidant balance; enhanced eNOS- mediated endothelial relaxation, and down regulated IL-1ß expression. Thus, NIFU may be proposed to serve as a cardioprotective agent to attenuate DOX-induced cardio-toxicity and vascular injury.

Calycosin modulates NLRP3 and TXNIP-mediated pyroptotic signaling and attenuates diabetic nephropathy progression in diabetic rats; An insight.

Diabetic nephropathy [DN] is one of the most prevalent microvascular complications of diabetes mellitus [DM] and it is considered a leading cause of kidney failure. In this study calycosin, an isoflavone that constitutes the major constituent in Radix Astragali with numerous pharmacological merits was investigated as reno-protective agent against DN and also the potential underlying mechanisms were investigated. Streptozotocin (STZ) (40 mg/kg) was injected in the peritoneal cavity of male Sprague-Dawely rats to induce DM. For ten weeks, calycosin (5 and 10 mg/kg), and NAC (500 mg/kg) were orally administered and they significantly lowered blood glucose levels, but significantly increased insulin levels. Calycosin improved the deteriorated kidney functions as evidenced in retracted serum creatinine, albuminuria, blood urea nitrogen, and proteinuria levels. Meanwhile, urine creatinine clearance significantly escalated. Furthermore, biomarkers of cell injury; LDH activity, significantly declined and kidney content of NO markedly decreased as well. Inflammation, fibrosis and oxidative stress were manifested by increased serum levels of IL-1ß, renal NF-κBp65, NLRP3, TXNIP and MDA contents with declined levels of IL-10 and TAC and decreased Nrf2 expression. The above-mentioned biomarkers were significantly improved with calycosin treatment which modulated NF-κB/p65/NLRP3/TXNIP signaling, oxidative stress, inflammatory cytokines and fibrotic processes; Thus, implying a reno-protective impact. This was associated with improvement in renal histopathological and immune-histopathological parameters; H&E, Masson Trichrome and Nrf-2. Based on these findings, calycosin can be presumed to be a promising drug for hindering the development of DN through modulation of NF-κB/p65/NLRP3/TXNIP inflammasome signaling pathway.

Fasudil, a ROCK inhibitor, preserves limb integrity in a mouse model of unilateral critical limb ischemia: Possible interplay of inflammatory and angiogenic signaling pathways.

Peripheral arterial diseases (PAD) had a great attention owing to devastating consequences of disability and cardiovascular morbidity and mortality. Yet, current therapeutic options are limited to surgical revascularization with no effective pharmacotherapy available. Excessive activity of Rho-associated coiled-coil protein kinase (ROCK) is implicated with several vascular diseases, rendering ROCK inhibition as a potential therapeutic strategy for patients suffering vascular disorders. AIM: The current study was dedicated to investigating the vascular protective potential of Fasudil, a ROCK inhibitor, on an experimentally induced unilateral critical limb ischemia (CLI) model in mice and demonstrated the possible underlying mechanisms. METHODS: Unilateral CLI was induced by ligation and excision of femoral artery followed by daily i.p. injection of Fasudil (10 mg/kg or 25 mg/kg) up to two weeks post-surgery. KEY FINDINGS: Mice underwent CLI showed decreased antioxidant capacity and increased inflammatory signal, evident by elevation of ERK1/2 in both serum and GC muscles that coincided with increases in VEGFA, HIF-1α and CD34+ cells of GC muscles. CLI resulted in structural damage of GC muscle fibers, with marked apoptosis, declined proliferation and deteriorated peripheral limb function. Treatment with Fasudil restored antioxidant capacity and attenuated VEGFA, HIF-1α, CD34+ cells and inflammatory markers in ischemic limbs. Furthermore, Fasudil preserved histological integrity of ischemic GC muscles, with amelioration of apoptosis, preserved proliferation rate and improvement in peripheral limb function. SIGNIFICANCE: Fasudil could protect against experimentally induced unilateral CLI, in a dose-dependent manner, which could pave the way for future clinical application of Fasudil in patients suffering PAD.

Canagliflozin interrupts mTOR-mediated inflammatory signaling and attenuates DMBA-induced mammary cell carcinoma in rats.

BACKGROUND: Breast cancer prevalence has been globally increasing, therefore, introducing novel interventions in cancer treatment is of a significant importance. The present study was designed to investigate the anti-cancer effect of Canagliflozin (CNG) in an experimental model of DMBA-induced mammary carcinoma in female rats. METHODS: 18 female rats were divided into three experimental groups: Normal control, DMBA control, DMBA+ CNG treated group. DMBA (7.5 mg/kg) was injected subcutaneously in the mammary cells twice weekly for 4 weeks and CNG (10 mg/kg) was orally administered daily for an additional 3 weeks while DMBA control rats only received the vehicle for 3 weeks. Tumors' weight and volume were measured, BRCA-1 and TAC were quantified in serum samples, mTOR, caspase-1, NFκB, IL-1ß, NLRP3, GSDMD and MDA were quantified in tumors' homogenates. RESULTS: CNG treatment increased the BRCA-1 expression, suppressed mTOR inflammatory pathway, attenuated tumor inflammatory mediators; NLRP3, GSDMD, NFκB, IL-1ß, suppressed the oxidative stress and inhibited tumor expression of the proliferation biomarker; Ki67. CONCLUSION: CNG modulated mTOR-mediated signaling pathway and attenuated pyroptotic, inflammatory pathways, suppressed oxidative stress and eventually inhibited DMBA-induced mammary carcinoma proliferation.

Clinical and Radiographic Outcomes of Revision Total Ankle Arthroplasty Using the INBONE II Prosthesis.

BACKGROUND: The literature on the outcome of revision total ankle arthroplasty (TAA) remains limited. In this study, we aimed to report the clinical and radiographic outcomes of revision TAA at a high-volume center in the United Kingdom. METHODS: This study was a retrospective review of 28 patients who underwent 29 revision TAAs using the INBONE II Total Ankle System (Wright Medical Technology/Stryker). Demographic, radiographic, and patient-reported outcome measure data were analyzed. RESULTS: The mean duration from primary TAA to revision was 87.5 months (range, 16 to 223 months). The main indication for the revision was aseptic loosening after the primary TAA (83%). Additional procedures were required in 76% of ankles. At a mean follow-up of 40 months (range, 24 to 60 months), the infection rate was 7%, the reoperation rate was 7%, and the implant survival rate was 97%. A significant postoperative improvement in the radiographic component alignment measures was observed. The subsidence, loosening, and heterotopic ossification rates in this study were comparable with those in other reports and did not influence the clinical outcome. A significant improvement was observed in the Manchester-Oxford Foot Questionnaire (MOXFQ) in all domains and the EuroQol-5 Dimensions (EQ-5D) in 3 domains at 24 months postoperatively. CONCLUSIONS: Revision TAA using the INBONE II prosthesis was associated with good short-term survival and improvement in postoperative scores at 2 years. Maintenance of the postoperatively improved alignment was documented at the follow-up. The results of this study support the notion that revision TAA is a satisfactory option for failed primary TAA. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Hydrology, biogeochemistry and metabolism in a semi-arid mediterranean coastal wetland ecosystem.

A LOICZ Budget Model is applied to the Ichkeul Lake, a wetland ecosystem of the South Mediterranean-North African region, to evaluate its functioning in order to boost water management. The Ichkeul Lake water and nutrient budget, net ecosystem metabolism (NEM), nutrient availability, and their seasonal changes are estimated using field data. A considerable anthropogenic-driven amount of nitrogen is transferred into N2/N2O to the atmosphere during the dry season with predominance of denitrification-anammox processes. The primary production is impacted by forcing the ecosystem respiration to reduce the NEM so that the system is functioning as heterotrophic. Climate change and anthropogenic pressures are expected to exacerbate the current trends of water quality degradation, with possible negative impacts on Palearctic birds' population. Mitigation actions are possible, through the implementation of National Wetland Management Strategies that include nutrient load and water resources management.

Dose-dependent renoprotective impact of Lactoferrin against glycerol-induced rhabdomyolysis and acute kidney injury.

Acute kidney injury (AKI) is a clinical disorder with a serious impact on the quality of patients' lives. Considering its increased worldwide prevalence, investigating novel therapeutic approaches for the management of AKI has been inevitable. Lactoferrin (LF), a glycoprotein belonging to the transferrin family, is known to play an important role in regulating iron homeostasis. This study aimed to evaluate the renoprotective effect of LF (30, 100, and 300 mg/kg orally) against glycerol (GLY)-induced rhabdomyolysis (RM) in rats. RM was induced by a single intramuscular injection of GLY 50% (10 mL/kg) after 24-h water deprivation in male Sprague-Dawley rats. LF administration conferred significant dose-dependent renoprotective impact against GLY-induced RM as evidenced by the decreased renal/somatic index and the significant improvement in renal functions as confirmed by the significant increase in creatinine clearance, decrease in serum creatinine and blood urea nitrogen, and improvement in albuminuria and proteinuria. Redox homeostasis was significantly restored in a dose-dependent manner as well. Moreover, serum interleukin-1ß (IL-1ß) was significantly decreased with a parallel significant decrease in renal NOD-like receptor family pyrin domain containing 3 (NLRP3) and thioredoxin interacting protein (TXNIP), kidney injury molecule-1 (KIM-1), caspase-3 expression, nuclear factor kappa B (NF-κB), cluster of differentiation (CD68) expression, and a significant increase in renal nuclear factor erythroid 2-related factor 2 (NRF2) expression. Ultimately, LF administration was associated with a significant amelioration of GLY-induced renal necrotic and inflammatory alterations. In conclusion, the observed dose-dependent nephroprotective effect of LF can be attributed to its modulatory impact on inflammatory/apoptotic/oxidative signaling.

Indapamide Increases IRS1 Expression and Modifies Adiponectin/NLRP3/PPARγ Crosstalk in Type 2 Diabetic Rats.

The current study aimed to evaluate the anti-diabetic effects of canagliflozin (CANA) and indapamide (INDA) and their impacts as adiponectin modulators in experimentally induced type 2 diabetes mellitus (T2DM). T2DM was associated with a significant rise in blood glucose level and HbA1C%, andreduced adiponectin and insulin secretions. Moreover, the malondialdehyde (MDA) contents in both the epididymal adipocytes and soleus muscle significantly escalated, while the total antioxidant capacity (TAC) and epididymal adipocyte Nrf2 expression significantly declined. Moreover, serum TNF-α, epididymal adipocyte's NOD-like receptor protein 3, NLRP3, NF-κB and CD68 expressions markedly escalated, and serum IL-10 significantly declined. Furthermore, there was a significant escalation in PPARγ expression in epididymal adipocytes, with a significant reduction in soleus muscle's expression of IRS1. CANA and INDA treatments markedly reduced blood glucose levels, increased adiponectin and insulin secretion, enhanced anti-oxidant defenses, and reduced oxidative burden, with marked anti-inflammatory impact. Interestingly, the impact of indapamide on DM indices and oxidative and inflammatory changes was comparable to that of canagliflozin. Nevertheless, indapamide had a superior effect compared to canagliflozin on HbA1c%, expression of IRS1 and reduction of NF-κB and CD68 expressions. INDA could be effective in regulating T2DM, with underlined anti-diabetic, antioxidant, and anti-inflammatory properties. INDA increased IRS1 expression and modified adiponectin/NLRP3/PPARγ crosstalk. The impacts of INDA are comparable to those of the standard anti-diabetic drug CANA.

Diacerein versus adipoRon as adiponectin modulators in experimentally-induced end-stage type 2 diabetes mellitus in rats.

The objective of the present study is to evaluate and compare the possible anti-diabetic effects of adipoRon and diacerein in type 2 diabetes mellitus (T2DM) rats. T2DM is marked by impaired oxidative, inflammatory and metabolic signaling. Indeed, T2DM progression is associated with elevated HbA1C%, low adiponectin and insulin concentration. Moreover, in this study epididymal adipose tissue and soleus muscle MDA contents significantly escalated, while serum TAC and epididymal adipose Nrf2 significantly declined. Nevertheless, serum TNF-α, epididymal NLRP3, NF-κB, PPARγ and CD68 expression rose significantly with a parallel significant reduction in serum IL-10 and soleus muscle expression of IRS1. Both adipoRon and diacerein significantly improved adiponectin and insulin secretion with augmentation of anti-oxidant defenses and diminution of oxidative burden, with obvious anti-inflammatory consequences (p < 0.05). Thus, adipoRon and diacerein positively modulated adiponectin expression with down-regulation of NF-κB/NLRP3/PPARγ expression with subsequent improvement in glycemic control, inflammatory and oxidative signaling.

Saxagliptin defers thioacetamide-induced hepatocarcinogenesis in rats: A novel suppressive impact on Wnt/Hedgehog/Notch1 signaling.

AIM: Hepatocellular carcinoma (HCC) is a highly invasive form of hepatic cancer. It is a highly intricate disease with multiple pathophysiological mechanisms underlying its pathogenesis. MATERIALS AND METHODS: The results of the current investigation shed light on the ability of saxagliptin (SAXA) (12.5 mg/kg) to defer HCC progression in an experimental model of thioacetamide (TAA)-induced hepatocarcinogenesis. RESULTS: SAXA administration improved liver function biomarkers, with a concomitant histopathological recovery. Mechanistically, the observed hepatoprotective impact was associated with significant suppression of the hepatic content of Wnt3a, ß-catenin, Notch1, Smo, and Gli2 and enhanced expression of GSK 3ß. Nevertheless, the hepatic expression of PCNA, P53, and cyclin D1 was significantly enhanced, with a parallel increase in the tumor expression of caspase-3. Thus, it appears that SAXA significantly enhanced tumor apoptosis, with concomitant suppression of HCC proliferation. CONCLUSION: SAXA deferred experimentally-induced HCC via suppressing Wnt/Hedgehog/Notch1 Signaling, with enhanced tumor apoptosis and suppressed proliferation.

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.

CpG Islands Shape the Epigenome Landscape.

Epigenetic modifications and nucleosome positioning play an important role in modulating gene expression. However, how the patterns of epigenetic modifications and nucleosome positioning are established around promoters is not well understood. Here, we have addressed these questions in a series of genome-wide experiments coupled to a novel bioinformatic analysis approach. Our data reveal a clear correlation between CpG density, promoter activity and accumulation of active or repressive histone marks. CGI boundaries define the chromatin promoter regions that will be epigenetically modified. CpG-rich promoters are targeted by histone modifications and histone variants, while CpG-poor promoters are regulated by DNA methylation. CGIs boundaries, but not transcriptional activity, are essential determinants of H2A.Z positioning in vicinity of the promoters, suggesting that the presence of H2A.Z is not related to transcriptional control. Accordingly, H2A.Z depletion has no impact on gene expression of arrested mouse embryonic fibroblasts. Therefore, the underlying DNA sequence, the promoter CpG density and, to a lesser extent, transcriptional activity, are key factors implicated in promoter chromatin architecture.

Chrysin mitigates bleomycin-induced pulmonary fibrosis in rats through regulating inflammation, oxidative stress, and hypoxia.

Pulmonary fibrosis is a chronic condition characterized by fibroblast proliferation, and the infiltration of inflammatory cells that can initiate local tissue hypoxia. In this study the effect of chrysin (50 mg/kg/orally) in a model of bleomycin (BLM)-induced pulmonary fibrosis was studied. Chrysin managed to decrease mortality rate associated with BLM instillation and it managed to improve lung architecture and lung fibrosis by decreasing hydroxyproline content and transforming growth factor-ß1 (TGF-ß1) protein expression. Chrysin showed anti-inflammatory effect displayed by the decrease in inflammatory cells infiltrates, the decline in permeability of the alveolar/capillary barrier and the reduction in lactate dehydrogenase (LDH) activity. Chrysin demonstrated potent antioxidant effect by decreasing lipid peroxidation, increasing antioxidant defense mechanisms by increasing superoxide dismutase (SOD) activity and reduced glutathione (GSH) content. Additionally, the effect of chrysin on nitric oxide (NOx) content was assessed, where chrysin decreased NOx, increased the protein expression of endothelial nitric oxide synthase (eNOS), and decreased inducible nitric oxide synthase (iNOS) protein expression. Chrysin also succeeded in decreasing thioredoxin-interacting protein (TXNIP), the negative regulator of thioredoxin system, showing potent antioxidant effect. Finally, both tissue and bronchoalveolar lavage fluid contents of hypoxia inducible factor one alpha (HIF1α) were decreased by chrysin indicating that chrysin decreased local tissue hypoxia. In conclusion, this study exposed a possible proof that chrysin could mitigate pulmonary fibrosis induced by BLM through its anti-inflammatory, antioxidant, antifibrotic effects and its effect in alleviating hypoxia.

Modulatory role of imatinib mesylate on pancreatic ß-cells' secretory functions in an STZ rat model of diabetes mellitus.

The present study was undertaken to assess the effect of imatinib mesylate; a tyrosine kinase inhibitor and a well-known anticancer with numerous medical benefits on blood sugar levels, insulin, and glucagon secretion in an experimental model of STZ-induced diabetes mellitus. Type 1 diabetes mellitus (T1DM) was induced by a single I.P. injection of Streptozotocin (STZ) (50 mg/kg) in male Sprague-Dawley rats. Daily oral imatinib (10 mg/kg) and (20 mg/kg) for 4 weeks induced a significant attenuation in signs of DM in rats reflected in their assessed lab values. Biomarkers of cell injury, tissue necrosis, and apoptosis; caspase-3 were significantly reduced with imatinib treatment. Furthermore, pancreatic antioxidants defenses of which; superoxide dismutase (SOD) and catalase activities, reduced glutathione (GSH) concentration, and total antioxidant capacity have significantly improved with a simultaneous reduction in malondialdehyde (MDA) content. Histopathologically, imatinib treatment was associated with a minimal pancreatic injury and marked restoration of insulin content in ß-cells. Moreover, imatinib treatment revealed a significant reduction in the infiltration of macrophages in ß-cells. Imatinib's ameliorative impact on DM may be attributed to it's mediated protection and preservation of pancreatic ß-cells function and the improvement in serum insulin levels and hence the improvement of blood glucose and overall glycemic control.

Nicorandil ameliorates bleomycin-induced pulmonary fibrosis in rats through modulating eNOS, iNOS, TXNIP and HIF-1α levels.

Bleomycin (BLM) is one of the most common anti-cancer drugs used to treat numerous types of tumors. However, pulmonary toxicity is considered the most dramatic effect of BLM. Therefore, BLM has been frequently used for induction of pulmonary fibrosis. This study aimed to evaluate the effect of nicorandil on BLM-induced pulmonary fibrosis and explore the possible mechanisms. BLM was instilled intratracheally into male Sprague-Dawley rats as a single dose (5 mg/kg) and oral nicorandil was given (30 mg/kg/day) for 6 weeks after BLM challenge. At the end of experimental period, rats were sacrificed, and lung histopathology and biochemical parameters were evaluated. Nicorandil therapy attenuated lung inflammation and fibrosis elicited by BLM. Nicorandil significantly reduced total protein content, lactate dehydrogenase (LDH) activity and total and differential cell counts. Moreover, nicorandil diminished lung levels of malondialdehyde and total nitrite/nitrate, in addition to increasing lung contents of reduced glutathione and superoxide dismutase activity. Nicorandil reduced lung and bronchoalveolar lavage fluid contents of hypoxia inducible factor-1α (HIF-1α) and lung content of thioredoxin-interacting protein (TXNIP). Besides, nicorandil significantly improved histological lesions and reduced collagen deposition as well as hydroxyproline content. Immunohistochemical examination revealed that nicorandil-treated rats exhibited significant diminutions in protein expression levels of transforming growth factor beta-1(TGF-ß1) and inducible nitric oxide synthase (iNOS) and enhanced pulmonary protein expression of endothelial NOS (eNOS). In conclusion, these results illustrate the possible potential effects of nicorandil for managing pulmonary fibrosis caused by BLM.

Crocin attenuates lung inflammation and pulmonary vascular dysfunction in a rat model of bleomycin-induced pulmonary fibrosis.

Amongst the various forms of lung injury; pulmonary fibrosis remains the most intricate form with limited therapeutic options to both the patient and the physicians. Bleomycin (BLM) is a chemotherapeutic agent used for the treatment of various carcinomas; however, its therapeutic value is significantly limited by its associated pulmonary fibrosis. The current study highlights the prominent antioxidant, anti-inflammatory and anti-fibrotic effect of crocin against BLM-induced pulmonary fibrosis. Intratracheal BLM instillation induced significant biochemical, structural, functional and vascular pulmonary injury. BLM instillation increased oxidant load with quenching of antioxidant defenses together with increase inflammatory and fibrotic cytokines expression. Crocin significantly attenuated BLM-induced lung injury and its effect was comparable to the standard anti-fibrotic; halofuginone. The observed anti-inflammatory and anti-fibrotic and antioxidant impacts are thought to be embroiled in the therapeutic impacts of crocin. Down-regulation of TLR4, IL-10 expression is the major pathway involved in the observed anti-inflammatory effects and finally, down-regulation of tissue expression of TNF-α and TGF-ß1 is the major pathways implicated in the observed anti-fibrotic activities and modulation of Nrf2 and HO-1 pathways is the main mechanism involved in the observed antioxidant effects.

A comparative study of the role of crocin and sitagliptin in attenuation of STZ-induced diabetes mellitus and the associated inflammatory and apoptotic changes in pancreatic ß-islets.

Type 1 diabetes mellitus (T1DM) describes a complex group of metabolic disorders associated with elevated blood glucose levels and increased risks of complications development. Exploring new drug therapies would reduce the increased diabetes-associated morbidity and mortality and will reduce the excessive health care costs. Crocin is the major active ingredient of saffron. In the current study, DM was induced by single intraperitoneal injection of streptozocin (50 mg/kg).DM progression was associated with a significant increase in blood glucose level with reduced insulin and increased glucagon secretion. Pancreatic malondialdehyde (MDA) content significantly escalated, while superoxide dismutase (SOD) activity, reduced glutathione (GSH) concentration, catalase activity, thioredoxin level and serum total antioxidant capacity significantly declined. This was associated with a significant increase in pancreatic caspase-3 contents and pancreatic infiltration with inflammatory cells in ß-islets. Both sitagliptin and crocin significantly reduced blood glucose levels, enhanced pancreatic insulin expression and secretion and suppressed glucagon secretion with enhancement of anti-oxidant defenses and reduction of oxidative burden, with evident anti-inflammatory impacts. Interestingly, the effect of crocin on DM indices, inflammatory and apoptotic changes was comparable to that of sitagliptin; the standard oral hypoglycemic agent. Nevertheless, crocin had a superior effect compared to sitagliptin on blood sugar level, ß-islets diameter and insulin immune-reactivity. In conclusion, crocin reduced blood glucose level mainly via reduction of oxidative burden, modulation of apoptotic pathway and attenuation of pancreatic inflammation.

Serum Pentraxin 3 level as a recent biomarker of diabetic retinopathy in Egyptian patients with diabetes.

INTRODUCTION: Serum Pentraxin3 Level As A recent Biomarker Of Diabetic Retinopathy In Egyptian patients with diabetes. OBJECTIVE: To evaluate the association between elevated levels of plasma pentraxin 3 and the development and/or progression of diabetic retinopathy. SUBJECTS: and methods: This case control study was carried out in internal medicine department, outpatient clinic of internal medicine and outpatient clinic of ophthalmology, at Zagazig university Hospital, 2018. Serum PTX3 level, HsCRP, HbA1c, lipid profile, serum creatinine were determined in 20 normal subjects, 20 patients with prediabetes, 20 patients with diabetes without diabetic retinopathy (DR), 20 patients with non-proliferative diabetic retinopathy (NPDR) and 20 patients with proliferative diabetic retinopathy (PDR). RESULTS: Serum PTX3 level significantly increased in patients with DR more than patients without DR with cut off point 1150 pg/ml, sensitivity 93.3%and specificity 72%. Serum HsCRP level significantly increased in patients with DR more than patients without DR with cut off point of 7.60 pg/ml has sensitivity 93.3% and specificity 68%.. Combined use of PTX3 and HsCRP decreases sensitivity to 76.7%, but combined use increases specificity to 90%.Significant relation between poor glycemic control and development of DR and its severity as showed by HbA1c. CONCLUSION: Serum PTX3 levels mayt have significant role in the development of DR and its severity. Serum HsCRP increased with DR progression. Poor glycemic control significantly associated with high incidence of diabetic retinopathy and its severity. Longer diabetes duration is associated with progression of DR.