Hala Osman El Mesallamy

Alzheimer's disease (AD) is a complex form of neurodegenerative dementia. Growing body of evidence supports the cardinal role of sirtuin1 (SIRT1) in neurodegeneration and AD development. Recently, adipose tissue‐derived mesenchymal stem cells (Ad‐MSCs) have made their mark for a wide array of regenerative medicine applications, including neurodegenerative disorders. Therefore, the present study aimed to investigate the therapeutic potential of Ad‐MSCs in AD rat model, and to explore the possible implication of SIRT1. Ad‐MSCs were isolated from rat epididymal fat pads and properly characterized. Aluminum chloride was used to induce AD in rats, and afterward, a group of AD‐induced rats received a single dose of Ad‐MSCs (2 × 10⁶cell, I.V per rat). One month after Ad‐MSCs transplantation, behavioral tests were done, brain tissues were collected, then histopathological and biochemical assessments were performed. Amyloid beta and SIRT1 levels were determined by enzyme‐linked immunosorbent assay. Whereas expression levels of neprilysin, BCL2 associated X protein,B‐cell lymphoma‐2,interleukin‐1β,interleukin‐6,and nerve growth factor in hippocampus and frontal cortex brain tissues were assessed using reverse transcriptase quantitative polymerase chain reaction. Our data demonstrated that transplantation of Ad‐MSCs alleviated cognitive impairment in AD rats. Additionally, they exhibited anti‐amyloidogenic, antiapoptotic, anti‐inflammatory, as well as neurogenic effects. Furthermore, Ad‐MSCs were found to possibly mediate their therapeutic effects, at least partially, via modulating both central and systemic SIRT1 levels. Hence, the current study portrays Ad‐MSCs as an effective therapeutic approach for AD management and opens the door for future investigations to further elucidate the role of SIRT1 and its interrelated molecular mediators in AD.

The role of different Golgi signaling proteins remains unexplored in the progression and spread of Acute myeloid leukemia (AML), whom all interact together in a way that facilitates proliferation a...

Epigenetic modifications play a pivotal role in autoimmune/inflammatory disorders and could establish a bridge between personalized medicine and disease epidemiological contexts. We sought to investigate the role of epigenetic modifications beside genetic alterations in the MEFV gene in familial Mediterranean fever (FMF). The study comprised 63 FMF patients diagnosed according to the Tel Hashomer criteria: 37 (58.7%) colchicine-responders, 26 (41.3%) non-responders, and 19 matched healthy controls. MEFV mutations were detected using a CE/IVD-labeled 4-230 FMF strip assay. DNA methylation of MEFV gene exon 2 was measured using bisulfite modification and related to pyrin level, phenotypic picture, MEFV mutations, disease severity, serum amyloid A (SAA), CRP, ESR, disease severity, and colchicine response. Our results showed that FMF patients exhibited significantly higher methylation percentage (p < 0.001) and lower pyrin levels (p < 0.001) compared to the control. The MEFV gene M694I mutation was the most commonly reported mutation (p < 0.004). High methylation percentage of the MEFV exon 2 and low pyrin concentration were correlated with disease severity, high SAA, ESR levels, H-pylori, and renal calculi. In conclusion, this study highlights the relation between high methylation percentage, reduced pyrin level, and different biomarkers in FMF, which underscores their role in the pathogenesis of FMF and could be considered as potential therapeutic targets.

Background Breast cancer (BC) is the most commonly diagnosed cancer and is considered the main cause of death in women worldwide. Metastatic BC is a state when cancerous cells spread to other tissues, including lung, bone, liver and brain. Sphingosine 1-phosphate (S1P) is emerging as a key regulator of proliferation, inflammation, vasculogenesis and resistance to apoptotic cell death. There is increasing evidence of a role of S1P receptors [e.g. sphingosine phosphate 4 (S1P4) and sphingosine kinase 1 (SK1)] in cancer, where overexpression of these proteins in estrogen receptor (ER) negative BC patients is linked to aggressive disease and poor prognosis. It has been discovered that the bioactive lipid metabolite S1P can act as a damage-associated molecular patterns (DAMP), and in vitro, it induced Nod-like receptor 3 (NLRP3) dependent activation of caspase-1 and secretion of interleukin-1b (IL-1b). Objective evaluate serum levels of S1P and NLRP3 to clarify the role of these markers in metastatic and non-metastatic BC patients and examine their potential as reliable novel diagnostic biomarkers. Methods The study involved 26 Egyptian female patients diagnosed with metastatic BC (stage 4) and 30 Egyptian female patient diagnosed with non-metastatic BC (stages 0, 1, 2 and 3). NLRP3, S1P and cancer antigen15.3 (CA 15.3) serum levels were analyzed using ELISA technique. Results The results revealed significantly lower serum levels of NLRP3 and S1P in non-metastatic and metastatic BC Egyptian patients compared to the healthy Egyptian female-control group (P < 0.001). ROC curve analysis showed that S1P has a promising good diagnostic utility in late-stage BC while NLRP3 has a moderate diagnostic utility in early and late BC. Conclusion NLRP3 and S1P could be promising novel diagnostic biomarkers of BC.

Autophagy has been demonstrated to have a beneficial effect on diabetic nephropathy (DN). Rapamycin, an inhibitor of mTOR, was shown to stimulate β-cell autophagy. However, its effects on preventing or ameliorating DN is unclear, and its effects are worth studying. As fasting is now an attractive protective strategy, we aim to compare its effect to rapamycin effects on pancreatic and renal cells. Twenty-eight adult male Wistar Albino rats were randomly divided into four groups, using streptozotocin (STZ) to induce diabetes mellitus (DM). Autophagy was induced by two ways; rapamycin or fasting. The extent of autophagy and apoptosis were investigated by measuring the level of LC3B and p53 proteins, respectively, in pancreatic and kidney tissues using Western blotting (WB) technique and imaging the renal cells under transmission electron microscope. The efflux transporter P-glycoprotein was quantified by WB as well. Rapamycin-induced autophagy occurred concurrently with apoptosis. On the other hand, fasting supported P-glycoprotein recovery and renal cell survival together with disabling β-cells apoptosis. In conclusion, this study provides a potential link between rapamycin or fasting for the cross-regulation of apoptosis and autophagy in the setting of cell stress as DN. Unlike rapamycin, fasting enhanced the active expression of ABCB1 efflux protein, providing insights on the potential ameliorative effects of fasting in DN that require further elucidation.

Background: Potassium channel tetramerization domain containing 12 (KCTD12) showed contradictory roles in many cancers, however, its role in breast cancer is unknown. Cripto-1 participates activates the Notch signaling pathway which was inhibited by KCTD12 in esophageal squamous cell carcinoma (ESCC). Uncoordinated 51-like kinase 2 (ULK2) with established roles in cancer was negatively regulated by KCTD12. Multidrug resistance protein 1 (MDR1) promotes resistance by an active transport efflux pump. KCTD12 downregulates the expression of drug-resistant proteins as ABCC4 and ABCG2 in ESCC patients. Purpose: We investigated the markers role in the early breast cancer. Methods: Sixty-five patient’s serum samples were compared with 10 controls and 15 benign ones. Results: Higher serum levels of KCTD12, Cripto-1, MDR1, and ULK2 in all malignant cases suggesting novel roles with better sensitivity and specificity along with CA15.3, where the resistant group was the highest suggesting value for de-novo breast cancer diagnosis. Conclusion: Positive correlations for KCTD12 with Cripto-1, MDR1, and ULK2 suggesting a new role of KCTD12. The cumulated ROC curves with CA15.3 revealed better sensitivity and specificity highlighting the add on of using more than one marker.

Angiogenesis is a multistep process implicated in the pathophysiology and progression of diabetic nephropathy (DN). Angiotensin-converting enzyme inhibitors (ACEI) and calcium channel blockers (CCB) have an important role in DN. We performed a randomized-controlled trial of lisinopril alone (an ACEI) or in combination with verapamil (a CCB) as a therapy for DN in type 2 diabetes mellitus (T2DM) patients with hypertension (HTN) and urinary albumin creatinine ratio (UACR) (30–300 mg/g) also to evaluate their effect on UACR, the angiogenic proteins: Angiopoietin 2 (Ang-2) and Endostatin (EST). Forty T2DM patients with microalbuminuria, aged 45–65 years were included. Patients were randomly assigned into group 1 receiving oral lisinopril and group 2 receiving oral lisinopril and verapamil once daily. After 3 months follow-up fasting blood glucose (FPG), HbA1c, lipid profile, UACR, serum urea and creatinine levels were assessed. EST and Ang-2 were measured using ELISA technique. Baseline Ang-2 and EST levels were elevated in both groups compared with controls (p<0.001). After follow-up, group 2 had significantly decreased FPG, HbA1c, UACR, EST and Ang-2 compared with their baseline levels (p<0.001 for all comparisons) and with group 1 (p<0.001). No adverse reactions were reported. Baseline EST and Ang-2 were positively correlated to UACR (r=0.753, p<0.001) (r=0.685, p<0.001). Lisinopril/verapamil combination enhanced glycemic control and kidney function via diminishing EST and Ang-2. This combination can be considered as a safe and effective approach for early stage nephropathy therapy in T2DM.

Background: The extracellular signal-regulated kinase (ERK) pathway is a key signaling pathway involved in the regulation of normal cell proliferation, survival and differentiation. However, aberrant regulations of the ERK pathway contribute to cancer and other human diseases. Objective: This study was designed to investigate the role of some ERK pathway effectors such as the connector enhancer of kinase suppressor of Ras1 (CNK1), Ephrin B1, G protein-coupled receptor 19 (GPR19) and SMAD ubiquitination regulatory factor 1 (SMURF1) in breast cancer (BC) diagnosis and metastasis risk prediction. Methods: The study involved 50 (ER(-)PR(-)Her(2+)=6, ER(+)PR(+)Her(2+)=11, ER-PR-HER2-=8, ER(+)PR(+)Her(2-)=25) newly diagnosed BC patients, 15 chemotherapy resistant BC patients, 15 benign breast tumor patients and 10 controls. All total 65 BC patients (including the chemotherapy resistant group) were subdivided into two groups: metastatic BC (17 patients), and non metastatic BC group (48 patients). CNK1, Ephrin B1, GPR19 and SMURF1 serum levels were analyzed using ELISA. Results: The study revealed significantly higher serum levels of CNK1, Ephrin B1, GPR19 and SMURF1 in all malignant groups (ER(-)PR(-)Her(2+), ER(+)PR(+)Her(2+), ER-PR-HER2-, ER(+)PR(+)Her(2-)), as well as a significant elevation in the chemotherapy resistant BC group as compared to non-resistant group (P < 0.001). They also revealed excellent value for de novo BC diagnosis and metastasis prediction. Conclusion: CNK1, Ephrin B1, GPR19 and SMURF1 may be considered as novel biomarkers for BC diagnosis and prediction of metastasis risk.