Walaa Arafa Keshk

Policies to maximize peak bone mass in survivor’s children of acute lymphoblastic leukemia (ALL) have been recognized as a priority area for research. The present study aimed to evaluate the relationship between osteoprotegerin (OPG)/receptor activator of nuclear factor kappa-B (RANK)/RANK ligand (RANKL) axis, vitamin D status, and serum magnesium in ALL survivors. Sixty ALL survivors treated with chemotherapy and 60 age and sex-matched controls were included. Vitamin D and parathyroid hormone, RANK, RANKL, and OPG levels were immunoassayed, in addition to serum calcium, phosphorus, magnesium levels, and alkaline phosphatase activity assessment. Furthermore, standard anthropometric measurement, history of fractures since treatment and clinical assessment were recorded. History of bone fractures after the start of therapy was detected in 17 ALL subjects (28.33%). Significantly lower vitamin D, magnesium, calcium, and OPG levels, meanwhile, significantly higher serum parathyroid hormone, RANK, and RANKL levels were detected in survivors compared with the control group. Vitamin D level was significantly positively correlated with magnesium, calcium, and OPG levels. Meanwhile, negatively correlated with RANK and RANKL levels. ALL survivors had a high prevalence of impaired vitamin D status, decreased Mg, and altered OPG/RANK/RANKL axis with impaired bone remodeling. The results herein may open the door for new interventional actions in ALL survivors to protect against bone resorption.

Chronic glucocorticoids therapy is commonly complicated by steroid diabetes, although the underlying mechanisms are still elusive. Liraglutide, a glucagon-like peptide-1, was initially found to induce glycemic control and recently it was found to have many pleotropic effects; however, its role in pancreas remains unknown. The present study aims to estimate the protective role of liraglutide on dexamethasone-induced pancreatic cytotoxicity and hyperglycemia, highlighting the possible underlying biochemical, molecular, and cellular mechanisms. Twenty-eight male Wistar rats were involved in this study and were randomly divided into four groups. Group III and IV were treated with 1 mg/kg dexamethasone daily for 10 days. Group II and IV were treated with liraglutide in a dose of 0.8 mg/kg per day for 2 weeks. Pancreatic caspase-9, nuclear factor erythroid 2–related factor 2 (Nrf2), phospho-protein kinase-B (pAkt), and sequestrome 1 (p62) levels were assessed by immunoassay. Moreover, phosphoinositide 3-kinase (PI3K) expression by real-time PCR, microtubule-associated protein light chain 3 (LC3B) expression by immunohistochemistry, glycemic status, β-cell function by homoeostasis model assessment (HOMA) β index, and pancreatic redox status were assessed. Liraglutide improved blood glucose level, β-cell function, pancreatic caspase-9 level, redox status, and autophagy. Additionally, it increased pancreatic PI3K, pAkt, and Nrf2 levels. Moreover, preservation of pancreatic histological and the ultrastructural morphological features of β- and α-cells were observed. In conclusion, liraglutide protected against dexamethasone-induced pancreatic injury and hyperglycemia and decelerated the progression towards steroid diabetes via activating PI3K/Akt/Nrf2 signaling and autophagy flux pathways.

Neurodegenerative diseases are a common cause of morbidity and mortality worldwide, with oxidative stress, inflammation, and protein aggregation representing the main underlying mechanisms that ultimately lead to cell death. Ethanol has shown strong neurodegenerative consequences in experimental animal brains. Statins are a class of lipid-lowering drugs with many pleotropic effects. Therefore, the aim of the present study was to explore the modulatory effect of simvastatin (10 mg·kg^–1·day^–1) before and after the development of neurodegeneration (for 55 and 25 days, respectively) on redox state, caspase-3 expression, p-protein kinase B (p-Akt), and brain-derived neurotrophic factor (BDNF) in ethanol-induced (15% ethanol solution for 55 days) neurodegeneration. Seventy female Albino Swiss mice were included and randomly divided into five groups: C, control group; E, ethanol group; ES, group treated with simvastatin from the first day of ethanol intake; E + S, group treated with simvastatin after neurodegeneration development; and S, simvastatin group. Administration of simvastatin from the first day improved the biochemical changes, suppressed apoptosis, and induced autophagy and neurogenesis; however, its administration after the development of neurodegeneration resulted in partial improvement. The histopathological findings confirmed the biochemical changes. In conclusion, simvastatin has a neuroprotective effect against the development of ethanol-induced neurodegeneration and its progression.

Diabetes mellitus (DM) is associated with the increased risk of the central nervous system complications as cerebrovascular disease, impaired cognition, dementia and neurodegeneration. Curcumin is a polyphenol with anti-oxidant, anti-inflammatory, anti-hyperlipidemic, and anti-cancer effects. Therefore, the present study was aimed to focus on the mechanistic insights of diabetes-induced hippocampal neurodegeneration in addition to shedding the light on the modulatory effect of curcumin. Twenty-eight male Wistar rats were randomly divided into four groups. Type I DM was induced by a single intra-peritoneal injection of streptozotocin (STZ) (65 mg/kg b.w.). Curcumin (100 mg/kg b.w.) was given to the diabetic group after the induction and for eight weeks. Hippocampal glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF-4), Bcl2 and choline acetyl transferase (ChAT) genes expression were assessed. Heat shock protein 70 (HSP70), Bcl-2-Associated X protein (Bax), Interferon-γ (INF-γ) and CCAAT-enhancer-binding protein homologous protein (CHOP) levels in the hippocampus were immunoassayed, in addition to the assessment of glycemic and redox status. Curcumin significantly improved blood glucose level, redox status, cellular stress, and decreased INF-γ and Bax levels, down-regulated GRP78 and ATF-4 expression, meanwhile, up-regulated Bcl2 and ChAT expression in hippocampus. Histological findings proved the biochemical and molecular findings. Our results support curcumin as a potential neuro-protective agent against diabetes induced hippocampal neurodegeneration.

Nephropathy is a common health issue associated with type 2 diabetes mellitus (T2DM). Treatment of diabetic nephropathy (DN) in an early stage can effectively inhibit its progression. Albuminuria is the currently accepted marker for detection of DN.This study aims to evaluate the urinary level of two novel renal tubular proteins (cyclophilin A and periostin) in patients with T2DM and among different nephropathy stages and also to validate the diagnostic accuracy of both cyclophilin A and periostin as potential markers for early prediction of DN relative to albuminuria.This cross-sectional study recruited 137 patients with T2DM, and they were divided based on their urinary albumin:creatinine ratio into T2DM with normoalbuminuria (group II), incipient T2DN with microalbuminuria (group III) and overt T2DN with macroalbuminuria (groupIV) beside 41 healthy subjects as group I. Cyclophilin A and periostin were measured in the urine using ELISA. Diagnostic accuracy of both markers was determined for prediction of DN via receiver operating characteristic curve analyses.Urinary cyclophilin A and periostin levels were significantly higher in DN groups when compared with T2DM with normoalbuminuria group. For prediction of incipient and overt DN, areas under the curve (AUCs) of periostin were 0.954, 0.997 and cyclophilin A were 0.914, 0.937, respectively. AUCs of periostin were higher than that for cyclophilin A with a significant AUC difference (p=0.022) in overt DN stage.Periostin and cyclophilin A could be regarded as a potential urinary biomarker for early prediction of DN. Periostin exhibits a higher diagnostic accuracy than urinary cyclophilin A specifically in overt DN stage.

Liver cirrhosis is a scene profitable to the advance of hepatocellular carcinoma (HCC). The current work was engrossed to weigh the potential role of Cichorium intybus linn against thioacetamide (TAA)‐induced liver cirrhosis and their probable underlying biochemical and molecular mechanisms. farnesoid‐X‐receptor (FXR) expression, proliferating cell nuclear antigen (PCNA) immunoreactivity, and activated AMP protein kinase (pAMPK), sirtuin‐1 (SIRT1), and interleukin‐6 (IL6) levels were estimated in hepatic tissue by real‐time PCR, immunohistochemistry, and immunoassay, respectively. C. intybus linn supplementation caused a significant improvement in serum liver enzymes, albumin, bilirubin levels, tissues redox status and hepatic histological features in addition to decreased IL6 level, hydroxylproline content, and PCNA immunoreactivity. On contrary, increased pAMPK/SIRT1 levels and upregulated FXR gene expression were observed. C. intybus linn could feasibly protect against TAA‐induced hepatic damage, fibrosis, and cirrhosis by relieving oxidative stress and by interruption of the inflammatory pathway via AMPK/SIRT1/FXR signaling. Practical applications No specific therapies are available until now to target the underlying mechanisms for protection against liver diseases. Herbal protection is widely available and cheap with no side effect. Cichorium intybus linn, a natural supplement, is proved in this current work to have the potential of being hepatoprotectant, antioxidant, and anti‐inflammatory agents, thus reducing the risk of hepatic cirrhosis.

β-Thalassemia, a blood disease instigated by mutations in β-globin genes or their regulatory regions. Infectious complications, immune abnormalities and iron overload related organ damage are the chief causes of morbidity and mortality. The role of inflammatory cytokines in the pathophysiology of β-thalassemia is still indistinct, so the present study aimed to evaluate immune-inflammatory and redox status in β-thalassemia and their relation to iron status, frequency/duration of blood transfusion. Seventy β-Thalassemia patients (35 β-thalassemia major; 35 β-thalassemia intermedia) and twenty age and sex-matched healthy controls were included. Interleukin4 (IL4), Interleukin10 (IL10), Interleukin 8 (IL8), and Interleukin 13 (IL13) levels were immunoassayed in addition to iron, hematological and redox status assessment. Significantly increased iron, ferritin, IL8, IL13 levels (p value ˂0.001), meanwhile, decreased IL10 level, total anti-oxidant (TAC) and iron binding capacities were observed in β-thalassemia major compared with β-thalassemia intermedia and control groups (p value ˂0.001) . IL4 level was decreased in patients group compared to control. Positive correlation was found between malondialdehyde (MDA), IL8, IL13 and iron load, transfusion frequency/duration, total leucocyte count and lymphocyte (%). Meanwhile, negative correlation was found with IL4, IL10, and TAC. Multiple blood transfusions increased iron stores which may critically impair the immune-regulatory balance with disturbed redox status and cytokine profile.