OPG/RANK/RANKL Axis in Egyptian Children With Acute Lymphoblastic Leukemia After Maintenance Therapy: Relationship to Bone Mineral and Vitamin D Status.

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.

New insight on the role of liraglutide in alleviating dexamethasone-induced pancreatic cytotoxicity via improving redox status, autophagy flux, and PI3K/Akt/Nrf2 signaling.

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, ß-cell function by homoeostasis model assessment (HOMA) ß index, and pancreatic redox status were assessed. Liraglutide improved blood glucose level, ß-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 ß- 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.

Modulatory effect of simvastatin on redox status, caspase-3 expression, p-protein kinase B (p-Akt), and brain-derived neurotrophic factor (BDNF) in an ethanol-induced neurodegeneration model.

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.

Redox status, inflammation, necroptosis and inflammasome as indispensable contributors to high fat diet (HFD)-induced neurodegeneration; Effect of N-acetylcysteine (NAC).

Adequate dietary intake has a crucial effect on brain health. High fat diet (HFD) rich in saturated fatty acids is linked to obesity and its complications as neurodegeneration via inducing oxidative stress and inflammation. The present study aimed to evaluate the effect of HFD on cerebral cortex in addition to shedding the light on the modulatory role of N-acetylcytsteine (NAC) and its possible underlying biochemical and molecular mechanisms. Twenty eight male Wistar rats were equally and randomly divided into four groups. Group III, and group IV were fed on HFD (45% kcal from fat) for 10 weeks. Group II and group IV were treated with NAC in a dose of 150 mg/kg body weight via intraperitoneal route. Body weight, blood glucose, serum insulin, insulin resistance index, cerebral cortex redox and inflammatory status were evaluated. Cerebral cortex receptor-interacting serine/threonine-protein kinase3 (RIPK3), mixed-lineage kinase domain-like protein (MLKL), nod like receptor protein 3 (NLRP3), interleukin (IL)-18 levels were determined by immunoassay. In addition, apoptosis-associated speck-like proteins (ASC) expression by real-time PCR; inducible nitric oxide synthase (iNOS), glial fibrillary activating protein (GFAP) and matrix metalloproteinase-9 (MMP-9) expression by immunohistochemistry were evaluated. NAC supplementation protected against HFD-induced gain of weights, hyperglycemia, and insulin resistance. Furthermore, NAC improved redox and inflammatory status; decreased levels of RIPK3, MLKL, NLRP3, IL-18; down-regulated ASC, iNOS, GFAP and MMP-9 expression; and decreased myeloperoxidase activity in cerebral cortex. NAC could protect against HFD-induced neurodegeneration via improving glycemic status and peripheral insulin resistance, disrupting oxidative stress/neuroinflammation/necroptosis/inflammasome activation axis in cerebral cortex. NAC may represent a promising strategy for conserving brain health against metabolic diseases-induced neurodegeneration.

Curcumin attenuates cytoplasmic/endoplasmic reticulum stress, apoptosis and cholinergic dysfunction in diabetic rat hippocampus.

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.

Thrombomodulin, alarmin signaling, and copeptin: cross-talk between obesity and acute ischemic stroke initiation and severity in Egyptians.

Acute ischemic stroke (AIS) is followed by a strong inflammatory response contributing to brain damage and making early diagnosis and treatment inevitable. Hence, obesity is a state of chronic inflammation with amplified oxidative stress; this study aimed to assess the role played by thrombomodulin (TM)/alarmin signaling pathway and copeptin in AIS initiation and severity in addition to the implication of abnormal body weight. The study was conducted on 50 participants; 30 were patients with AIS (15 overweight/obese and 15 normal weight), 10 were overweight/obese, and 10 were normal weight. Plasma TM, copeptin, high mobility group box1 (HMGB1), and lipocalin 2 (LCN2) levels were immunoassayed. Toll-like receptor 4 (TLR4) mRNA expression was evaluated by real-time PCR, National Institutes of Health Stroke Scale (NIHSS), carotid intima media thickness; atherogenic index and glycemic status were also assessed. TM, copeptin, HMGB1, and LCN2 levels were significantly increased in overweight/obese AIS patients and in AIS patients with NIHSS score ≥ 7 when compared to other groups (p value=, ˂ 0.001*). Receiver operating characteristic (ROC) curve elaborated HMGB-1 and LCN2 as the best biomarker for diagnosis and prediction of AIS severity, respectively. Regression analysis avails LCN2 and TM as best biomarker for AIS severity predication. In conclusion, these results highlighted detrimental role of alarmin signaling with increased adaptive response to block this pathway through TM in addition to increased copeptin level as an acute damage marker and their tight relation to WC not to BMI in AIS which clarify the implication of central adiposity.

Modulatory effects of curcumin on redox status, mitochondrial function, and caspace-3 expression during atrazin-induced toxicity.

Atrazin is currently the most widely used herbicide in agriculture with lots of adverse effects on human health. Curcumin is a polyphenol known for its antioxidant, anti-inflammatory, and anticancer properties. In the present study, the protective effect of curcumin on atrazin-intoxicated rats is evaluated. Toxicity was induced by oral administration of atrazine (400 mg/kg/day) for 3 weeks. Curcumin at a dose of 400 mg/kg/day was given simultaneously by oral route. Redox status, mitochondrial function, 8-hydroxydeoxyguanosine (8-OHdG) level by immunoassay, and caspace-3 expression by immunohistochemistry were evaluated. Curcumin showed significant cardiac protection with improvement of redox status, mitochondrial function, 8-OHdG level, caspase-3 immunoreactivity, and cardiac muscle degeneration. From this current study, it can be concluded that administration of curcumin improved atrazine-induced cardiotoxicity through its modulatory effect on redox status, mitochondrial function, and caspase-3 expression.

Saffron extract attenuates Sofosbuvir-induced retinal neurodegeneration in albino rat.

Sofosbuvir is a novel drug candidate for the treatment of hepatitis C viral infection; however, vision loss is one of its growing adverse effects. Saffron is a natural biomolecule with a high antioxidant potential that has been efficiently used in some diseases caused by oxidative stress. This study evaluated Sofosbuvir's neurodegenerative effect on the retina of albino rat and examined the potential protective role of saffron aqueous extract. Twenty-one adult male albino rats were randomly divided into three groups: Control, Sofosbuvir-treated (41.1 mg/kg /day for 6 weeks), and Sofosbuvir + Saffron co-treated groups. Retinal specimens were biochemically analyzed for malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) levels. In addition, light and transmission electron microscopic examination, as well as immunohistochemical staining for Caspase-3, COX-2, and GFAP were performed. Sofosbuvir treatment caused a significant increase in retinal MDA, IL-6, and TNF-α levels coupling with a significant decrease in retinal total antioxidant capacity level. Histopathological findings revealed disturbed retinal architecture, detached pigment epithelium, vacuolated photoreceptors, in addition to a significant decrease in the thicknesses of both outer and inner nuclear layers, and the number of ganglionic cells. Ultrastructural examination revealed extensive degenerative changes in all retinal layers. Caspase-3, COX-2, and GFAP immunohistochemical expressions were significantly increased. Meanwhile, concomitant treatment with Saffron significantly improved retinal redox status, inflammation, histological, and ultrastructural parameters. Saffron may protect the retina from the hazardous effects of Sofosbuvir. Saffron could be used as an adjuvant therapy to protect patients receiving Sofosbuvir from retinal damage.

Interplay between long non-coding RNA MALAT1 and pyroptosis in diabetic nephropathy patients.

Diabetic nephropathy (DN) the most common micro-vascular diabetic complication is the leading cause of end-stage renal disease worldwide. Diagnosis and treatment of DN in its early stage can effectively guard against its progression. Recently, pyroptosis a special type of lytic cell death and noncoding RNA were reported to have roles in early diagnosis and progression of DN. The present study aimed to evaluate the role played by long noncoding RNA (lncRNA) MALAT1, oxidative stress and pyroptosis in early detection of DN. Sixty Type 2 DM patients were included and divided according to urinary albumin-creatinine (UACR) ratio into normoalbuminuria and microalbuminuria groups beside 20 age and sex matched healthy volunteers as controls. Serum caspase 1 and interleukin 18 (IL18) levels were immunoassayed and MALAT1 expression was assessed by real-time PCR. Additionally, glycemic, redox and inflammatory status were assessed. MALAT1 expression, serum caspase1 level, IL18 level, myeloperoxidase activity, and protein carbonyl level were significantly increased in micro-albuinuria diabetic group when compared with diabetic normo-albuminuria group. Meanwhile, catalase activity was significantly decreased. Receiver operating characteristic (ROC) curve analysis revealed that IL18 had the highest sensitivity and diagnostic accuracy for detecting early microalbuminuria and incipient DN followed by caspase1and lastly MALALT1. CONCLUSION: Pyroptosis, impaired redox and altered MALAT1 expression could be an underlying mechanism for DN development. Moreover, MALAT1 expression, caspase 1 and IL 18 levels could be regarded as a potential biomarker for early prediction of DN.

Antibacterial activity and wound healing potential of Cycas thouarsii R.Br n-butanol fraction in diabetic rats supported with phytochemical profiling.

Patients with diabetes mellitus often suffer from chronic wounds due to wound healing impairment. Considering the increased prevalence of diabetes, this would predispose significant medical, economic, and social problems. These chronic wounds are frequently infected with pathogenic bacteria like Pseudomonas aeruginosa, which complicates the situation and makes the wound healing process more difficult. Therefore, there is a high need for therapeutic alternatives to the currently available treatments. Plants are vital sources of many bioactive compounds with multiple biological activities. We elucidated the wound healing possibility and antibacterial effect of Cycas thouarsii n-butanol fraction (CTBF) for the first time. Also, CTBF's phytochemical fingerprint was investigated using the LC-MS/MS technology. Interestingly, CTBF revealed antibacterial activity against P. aeruginosa isolates with minimum inhibitory concentrations range 16-128 µg/mL. Regarding the wound healing potential, we used in vivo experiment on diabetic rats. Remarkably CTBF caused a significant reduction (p 0.05) in the levels of forkhead box O1, matrix metalloproteinases 9, and chemokine (C-C motif) ligand 20. Additionally, it led to a substantial increase (p 0.05) in the level of transforming growth factor ß1. Moreover, CTBF improved the wound histological features by increasing the collagen area percentage. Regarding the immunohistochemical studies, CTBF resulted in a strong positive epidermal growth factor and a moderate positive caspase 9 immunoreaction in the epidermis and sebaceous glands of the wounds. Therefore, CTBF could be a promising source of bioactive compounds with wound healing and antibacterial activities. Finally, molecular docking was attempted using MOE software to investigate the binding mode of the major identified compounds in the matrix metalloproteinase 9 (MMP-9) receptor (PDB code: 1GKC).

Mechanistic evaluation of AMPK/SIRT1/FXR signaling axis, inflammation, and redox status in thioacetamide-induced liver cirrhosis: The role of Cichorium intybus linn (chicory)-supplemented diet.

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.