Thymoquinone attenuates diabetes-induced hepatic damage in rat via regulation of oxidative/nitrosative stress, apoptosis, and inflammatory cascade with molecular docking approach.

Diabetes mellitus (DM) is a complex metabolic condition that causes organ dysfunction. The current experiment sought to determine the effect of thymoquinone (TQ) on hyperglycemia, hyperlipidemia, oxidative/nitrosative stress, inflammation, and apoptosis in diabetic rats prompted by streptozotocin (STZ) (55 mg/kg body weight i/p). The animals were allocated into control, TQ (50 mg/kg B.W. orally administered for 4 succeeding weeks), Diabetic, and Diabetic + TQ groups. This study confirmed that TQ preserves the levels of insulin, fasting blood glucose, HOMA ß-cell indices, HbA1c %, body weight, and lipid profile substantially relative to the DC group. Furthermore, hepatic antioxidant (CAT, GSH, and T-SOD) values were reduced. Conversely, the enzymatic activity of liver functions (AST, ALT, ALP, cytochrome P450, and hepatic glucose-6-phosphatase), lipid peroxidation (MDA), pro-inflammatory cytokines (IL-1ß, TNF-α, and IL-6), nitric oxide (NO) and inflammatory marker (CRP) enhanced with STZ administration, which is substantially restored after TQ treatment. Relative to the diabetic rats, TQ reestablished the hepatic architectural changes and collagen fibers. Additionally, TQ downregulated the intensity of the immunohistochemical staining of pro-apoptotic marker (caspase-3), p53, and tumor necrosis factor-alpha (TNF-α) proteins in hepatic tissues. Furthermore, TQ displayed abilities to interact and inhibit the binding site of caspase-3, interleukin-6 receptor, interleukin-1 receptor type 1, TNF receptor superfamily member 1A, and TNF receptor superfamily member 1B in rats following the molecular docking modeling. All these data re-establish the liver functions, antioxidant enzymes, anti-inflammatory markers, and anti-apoptotic proteins impacts of TQ in STZ-induced DM rats. Founded on these outcomes, the experiment proposes that TQ is a novel natural supplement with various clinical applications, including managing DM, which in turn is recommended to play a pivotal role in preventing the progression of diabetes mellitus.

Panax ginseng ameliorates hepatorenal oxidative alterations induced by commercially used cypermethrin in male rats: experimental and molecular docking approaches.

Cypermethrin (CYP) is a synthetic pyrethroid utilized as an insecticide in agriculture and various pest eradication programs. However, it induces numerous health hazards for animals and humans. Therefore, the current study used Panax ginseng root extract (ginseng) to reduce the hepatorenal damage caused by commercially used CYP. Thirty-two male Wistar albino rats were distributed into control, ginseng (300 mg/kg B.W/day), CYP (4.67 mg/kg B.W.), and Ginseng+CYP (rats received both CYP and ginseng). All treatments were administered orally for 30 consecutive days. Cypermethrin induced harmful effects on hepatic and renal tissues through a substantial decline in body weight in addition to a considerable increase in liver enzymes, functional renal markers, and cholesterol. Also, CYP significantly decreased acetylcholinesterase (AChE) activity and increased pro-inflammatory cytokines (interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α)). Moreover, a marked increase in malondialdehyde level with a significant drop in reduced glutathione level and total superoxide dismutase (T-SOD) and catalase (CAT) activities was reported in the CYP group in kidney and liver tissues. Additionally, CYP exhibited affinities to bind and inhibit AChE and antioxidant enzymes (T-SOD and CAT) in rats following the molecular docking modeling. The apparent hepatorenal oxidative damage was linked with obvious impairments in the liver and kidney histoarchitecture, immunohistochemical staining of B cell lymphoma-2 (Bcl-2), and caspase-3 proteins. Ginseng reduced CYP's oxidative alterations by repairing the metabolic functional markers, improving antioxidant status, reducing the inflammatory response, and enhancing the molecular docking evaluation. It also ameliorated the intensity of the histopathological alterations and improved the immunohistochemical staining of Bcl-2 and caspase-3 proteins in the liver and kidney tissues. Finally, concomitant oral administration of ginseng mitigated CYP-prompted hepatorenal damage through its antioxidant, anti-inflammatory, and anti-apoptotic potentials.

The Impact of Curcumin on Growth Performance, Growth-Related Gene Expression, Oxidative Stress, and Immunological Biomarkers in Broiler Chickens at Different Stocking Densities.

Curcumin's antioxidant properties reduce free radicals and may improve broiler growth. Therefore, the influence of stocking density (SD) and administration of curcumin in the diet on broiler performance was explored to clarify the impact of HSD and curcumin on the performance of growth, behavioural patterns, haematological, oxidant/antioxidant parameters, immunity markers, and the growth-related genes expression in broiler chickens. A total of 200 broiler chickens (Cobb 500, 2-weeks old) were allotted into 4 groups; SD (moderate and high) and curcumin (100 and 200 mg/kg diet)-supplemented HSD, respectively. Behavioural observations were performed. After a 28-day experimental period, tissue and blood samples were collected for analysis. Expressions of mRNA for insulin-like growth factor-1 (IGF-1), growth hormone receptor (GHR), myostatin (MSTN), and leptin in liver tissues were examined. HSD birds exhibited lower growth performance measurements, haematological parameters, circulating 3,5,3-triiodothyronine and thyroxine levels, antioxidant activities (GSH-Px, catalase, superoxide dismutase), immunoglobulins (A, G, M), and hepatic GHR and IGF-1 expression values. However, HSD birds even had an increment of serum corticosterone, malondialdehyde, pro-inflammatory cytokine (TNF-a, IL-2, IL-6) levels, hepatic leptin and MSTN expression. Moreover, HSD decreased drinking, feeding, crouching, body care, and increased standing and walking behaviour. The addition of curcumin, particularly at a 200 mg/kg diet, alleviated the effect of HSD through amending growth-related gene expression in the chickens. In conclusion, curcumin can enhance birds' growth performance, behavioural patterns, and immunity by reducing oxidative stress and up-regulating the growth-related gene expressions of broilers under stressful conditions due to a high stocking density.

Novel biomarkers for subtle myocardial involvement in type I diabetes mellitus.

BACKGROUND: Evaluation of certain biomarkers could be used to predict left ventricular (LV) and right ventricular (RV) function impairment in children with type 1 diabetes mellitus. The aim of this study was to determine the best cardiac biomarker for prediction of diabetic cardiomyopathy. METHODOLOGY: This study was designed as case-control study. A total of 55 children with type 1 diabetes mellitus (group/G1) and 55 healthy controls (G2) were subjected to echocardiography including 3D-Speckle Tracking Echocardiography and tissue Doppler imaging for assessment of RV and LV systolic and diastolic functions. As well as HbA1c, troponin I, brain natriuretic peptide (BNP), plasma cardiotrophin (CT-1), activin-A, transforming growth factor-ß, and human insulin-like growth factor binding protein-7 (IGFBP-7) measurements. RESULTS: Diabetic patients showed RV and LV systo-diastolic dysfunction compared to controls, the best predictor of LV systolic dysfunction was CT-1 (sensitivity: 69%, while IGFBP-7 was found to be the best predictor of RV systolic dysfunction (sensitivity: 63%). BNP was found to the best predictor of diastolic RV and LV dysfunction (sensitivity: 82% for both). CONCLUSION: CT-1 has proven to be a diagnostic superiority in LV systolic dysfunction whilst BNP continues to prove every day through our study and through many others that it is the chief marker of diastolic dysfunction and HFpEF. This potential accuracy and the increasing availability of BNP in the outpatient setting make it clear that it should be used as a screening test for diabetic patients.

Date palm fruit extract ameliorated pancreatic apoptosis, endocrine dysfunction and regulatory inflammatory cytokines in Streptozotocin-induced diabetes in rats.

The current work studied the mechanism(s) and ability by which date palm (Phoenix dactylifera L.) fruit extract (DPE) inspired a glucose-lowering impact in rats suffering from diabetes. Forty-eight albino rats were divided into six various experimental treatments after induction of diabetes by intraperitoneal infusion of streptozotocin (45 mg/kg bwt) as follows: normal control, DPE, diabetic control, diabetic glibenclamide (GLI), diabetic DPE, and diabetic GLI plus DPE-treated groups. In animals euthanized after 8 weeks, blood and pancreatic tissue samples were assembled to assess different biochemical and histopathological changes. The expressions of insulin, B cell lymphoma-2 (Bcl-2), and cysteine aspartate-specific protease-3 (caspase-3) in islet ß cells were also evaluated using immunohistochemical assessment. Diabetic rats exhibited hyperglycemia; increment of pancreatic malondialdehyde (lipid peroxidation biomarker), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß); and decrement of plasma insulin and pancreatic antioxidants: glutathione, superoxide dismutase, and catalase values. Also, the pancreatic islets exhibited histopathological and morphometric alternations associated with weak positive insulin and Bcl-2 immunoreactivity and strong positive caspase-3 immunoreactivity. DPE and/or GLI, an anti-diabetic drug, improved the pancreatic histoarchitecture and improved ß cell function and structure, which increased insulin levels and improved the insulin, Bcl-2, and caspase-3 immunoreactivity in diabetic rats. Nevertheless, the combined DPE and GLI therapy revealed a significant recovery and restoration of ß cells' structure and function. The date palm fruit has anti-apoptotic, anti-inflammatory, and antioxidant activities and hypoglycemic effects, which in turn play a pivotal role in avoiding the progression of diabetes mellitus. Moreover, it could potentiate the glucose-lowering activity of anti-diabetic drugs.

Platelet-rich plasma and/or sildenafil topical applications accelerate and better repair wound healing in rats through regulation of proinflammatory cytokines and collagen/TGF-ß1 pathway.

Platelet-rich plasma (PRP) composites of various cytokines and growth factors which have the potential to activate and speed the process of wound repair. Sildenafil also is a potent stimulator of angiogenesis which favors its potential effects on wound healing in several models. Existing work planned to examine the effectiveness of topical application of PRP and/or sildenafil citrate hydrogel (SCH) in a non-splinted excision skin wound model. Adult male rats were allocated into control, PRP, SCH, and PRP/SCH groups. On the 7th and 14th days, blood and tissue samples were collected for hematobiochemical, histopathological, and immunohistochemistry analyses. PRP and/or SCH topical treatments caused an enhancement of wound healing parameters, including a rapid switch from inflammatory phase to connective tissue stage evident by less systemic hematological changes and decreased values of proinflammatory cytokines (IL-6, TNF-α, and IL-1ß) and C-reactive protein (CRP) on the 7th or 14th days post-wounding. Also, tissue hydroxyproline, collagen, nitrite, and total protein contents were higher in therapeutically handled wounded rats. Histologically, PRP- and/or SCH-treated wounded rats exhibited less necrosis, inflammation, and fibrin with a higher level of granulation tissue formation on the 7th day post-wounding and abundant collagen remodeling, epithelization, and vascularization on the 14th day relative to control. Interestingly, combined PRP and SCH treatment was more efficient in wound healing scoring with less inflammation, more collagen remodeling, and more epithelization. Our findings confirm the effectiveness of PRP and/or SCH as a topical wound healing treatment, with better skin wound healing with their combination.

L-α-Phosphatidylcholine attenuates mercury-induced hepato-renal damage through suppressing oxidative stress and inflammation.

The potential ameliorative effects of L-α-phosphatidylcholine (PC) against mercuric chloride (HgCl2)-induced hematological and hepato-renal damage were investigated. Rats were randomly allocated into four groups (n = 12): control, PC (100 mg/kg bwt, intragastrically every other day for 30 consecutive days), HgCl2 (5 mg/kg bwt, intragastrically daily), and PC plus HgCl2. Hematological and hepato-renal dysfunctions were evaluated biochemically and histopathologically. Hepatic and renal oxidative/antioxidative indices were evaluated. The expression of proinflammatory cytokines (tumor necrosis factor-α and interleukin-6) was also detected by ELISA. HgCl2 significantly increased serum aminotransferases (ALT, AST), urea, and creatinine levels that are indicative of hepato-renal damage. HgCl2 also induced a significant accumulation of malondialdehyde (+ 195%) with depletion of glutathione (- 43%) levels in the liver and renal tissues. The apparent hepato-renal oxidative damage was associated with obvious organ dysfunction that was confirmed by impairments in the liver and kidney histoarchitecture. Furthermore, HgCl2 significantly attenuated the expression of proinflammatory cytokines named tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Conversely, PC treatment attenuated these effects, which improved the hematological and serum biochemical alternations, reduced the oxidative stress and proinflammatory cytokine levels, and ameliorated the intensity of the histopathological alterations in livers and kidneys of HgCl2-treated rats. It could be concluded that PC displayed potential anti-inflammatory and antioxidant activities against HgCl2-induced hepato-renal damage via suppression of proinflammatory cytokines and declining oxidative stress.

Detection of an earlier tubulopathy in diabetic nephropathy among children with normoalbuminuria.

INTRODUCTION: Diabetic nephropathy is a major cause of morbidity and mortality among young adults with type 1 diabetes mellitus (DM). Albuminuria, the gold standard for early diagnosis, cannot always detect early diabetic nephropathy. We aimed at evaluating the level of urine neutrophil gelatinase-associated lipocalin (NGAL) as a marker of tubulointerstitial damage in children and adolescents with type 1 DM in relation to the level of albuminuria and other parameters. MATERIALS AND METHODS: Fifty children with type 1 DM for more than 5 years were included in this study (mean age, 13.8 ± 4.0 years), and 18 healthy children served as controls. Patients with overt albuminuria (> 300 mg/g creatinine) or inflammatory states were excluded. Urine NGAL, microalbuminuria, and urine albumin-creatinine ratio were measured in patients and controls as well as other parameters. RESULTS: Urine NGAL was significantly higher in microalbuminuric in comparison with normoalbuminuric patients and controls, and correlated positively with urine albumin-creatinine ratio. A positive urine NGAL was observed in 12 of 38 normoalbuminuric patients (31.6%) compared to 9 of 12 microalbuminuric patients (75%). A positive correlation was reported between urine NGAL and both Hemoglobin A1c and duration of DM, but not with estimated glomerular filtration rate or hypertension. CONCLUSIONS: Diabetic children, even some normoalbuminurics, showed increased urine NGAL. This finding may support the hypothesis of a "tubular phase" of diabetic disease preceding overt diabetic nephropathy, and hence, the use of urine NGAL measurement for early evaluation of renal involvement.

CD4(+) CD25(+) cells in type 1 diabetic patients with other autoimmune manifestations.

The existence of multiple autoimmune disorders in diabetics may indicate underlying primary defects of immune regulation. The study aims at estimation of defects of CD4(+) CD25(+high) cells among diabetic children with multiple autoimmune manifestations, and identification of disease characteristics in those children. Twenty-two cases with type 1 diabetes associated with other autoimmune diseases were recruited from the Diabetic Endocrine and Metabolic Pediatric Unit (DEMPU), Cairo University along with twenty-one normal subjects matched for age and sex as a control group. Their anthropometric measurements, diabetic profiles and glycemic control were recorded. Laboratory investigations included complete blood picture, glycosylated hemoglobin, antithyroid antibodies, celiac antibody panel and inflammatory bowel disease markers when indicated. Flow cytometric analysis of T-cell subpopulation was performed using anti-CD3, anti-CD4, anti-CD8, anti-CD25 monoclonal antibodies. Three cases revealed a proportion of CD4(+) CD25(+high) below 0.1% and one case had zero counts. However, this observation did not mount to a significant statistical difference between the case and control groups neither in percentage nor absolute numbers. Significant statistical differences were observed between the case and the control groups regarding their height, weight centiles, as well as hemoglobin percentage, white cell counts and the absolute lymphocytic counts. We concluded that, derangements of CD4(+) CD25(+high) cells may exist among diabetic children with multiple autoimmune manifestations indicating defects of immune controllers.