👤 Yasser H A Abdel-Wahab

Arsenic trioxide (ATO) remains vital in acute promyelocytic leukemia therapy, yet its clinical use is limited by cumulative organ toxicities, particularly neurotoxicity, which compromise tolerability and outcomes. Perindopril and L‑Arginine exert cytoprotective effects through antioxidant and anti‑inflammatory mechanisms. This study evaluated their neuroprotective efficacy against ATO‑induced neurotoxicity, emphasizing mechanistic pathways. Male rats were assigned to five groups: Control, ATO‑only (7.5 mg/kg, intraperitoneally, 14 days), Perindopril (2 mg/kg, orally), L‑Arginine (200 mg/kg, orally), and combined therapy. Interventions commenced seven days prior to the ATO challenge and continued for 21 days. Body weight was documented at baseline and endpoint; survival indices were monitored. Biochemical, histopathological, and molecular evaluations examined oxidative stress, inflammatory mediators, and apoptotic signaling. ATO exposure increased malondialdehyde (MDA) and nitric oxide derivatives (NOx), while reducing glutathione (GSH), superoxide dismutase (SOD), and catalase activities. It elevated tumor necrosis factor‑α (TNF‑α), interleukin‑1β (IL‑1β), and interleukin‑6 (IL‑6), while suppressing brain‑derived neurotrophic factor (BDNF) and nuclear factor erythroid 2‑related factor 2/heme oxygenase‑1 (Nrf2/HO‑1) signaling. Upregulation of Kelch‑like ECH‑associated protein 1/Nuclear factor kappa‑light‑chain‑enhancer of activated B cells (Keap1/NF‑κB), cleaved caspase‑3, and caspase‑3, alongside downregulation of B cell lymphoma‑2 (Bcl‑2), was evident. Histopathological lesions substantiated neurotoxicity. Perindopril and L‑Arginine markedly reversed these perturbations, reinstating molecular and structural homeostasis. Their combination afforded superior neuroprotection compared with monotherapies. Both agents mitigate ATO‑induced neurotoxicity through antioxidant, anti‑inflammatory, and anti‑apoptotic mechanisms, with their co‑administration surpassing individual efficacy. The Keap‑1/Nrf2/HO‑1 axis emerges as a critical therapeutic node, underscoring the translational potential of combined intervention. Show less

The antidiabetic actions of [A14K]PGLa-AM1, an analog of peptide glycine-leucine-amide-AM1 isolated from skin secretions of the octoploid frog Xenopus amieti, were investigated in genetically diabetic-obese db/db mice. Twice daily administration of [A14K]PGLa-AM1 (75 nmol/kg body weight) for 28 days significantly (P < 0.05) decreased circulating blood glucose and HbA1c and increased plasma insulin concentrations leading to improvements in glucose tolerance. The elevated levels of triglycerides, LDL and cholesterol associated with the db/db phenotype were significantly reduced by peptide administration. Elevated plasma alanine transaminase, aspartic acid transaminase, and alkaline phosphatase activities and creatinine concentrations were also significantly decreased. Peptide treatment increased pancreatic insulin content and improved the responses of isolated islets to established insulin secretagogues. No significant changes in islet β-cell and α-cell areas were observed in [A14K]PGLa-AM1 treated mice but the loss of large and medium-size islets was prevented. Peptide administration resulted in a significant (P < 0.01) increase in islet expression of the gene encoding Pdx-1, a major transcription factor in islet cells determining β-cell survival and function, resulting in increased expression of genes involved with insulin secretion (Abcc8, Kcnj11, Slc2a2, Cacn1c) together with the genes encoding the incretin receptors Glp1r and Gipr. In addition, the elevated expression of insulin signalling genes (Slc2a4, Insr, Irs1, Akt1, Pik3ca, Ppm1b) in skeletal muscle associated with the db/db phenotype was downregulated by peptide treatment These data suggest that the anti-diabetic properties of [A14K]PGLa-AM1 are mediated by molecular changes that enhance both the secretion and action of insulin. Show less

The antidiabetic effects and mechanisms of action of an analogue of a frog skin host-defence peptide belonging to the caerulein-precursor fragment family, [S4K]CPF-AM1 were investigated in db/db mice with a genetically inherited form of degenerative diabetes-obesity. Twice-daily treatment with the peptide (75 nmol/kg body weight) for 28 days significantly decreased blood glucose (P < 0.01) and HbA1c (P < 0.05) and increased plasma insulin (P < 0.05) concentrations with no effect on body weight, energy intake, body composition or plasma lipid profile. Peptide administration improved insulin sensitivity and intraperitoneal glucose tolerance. Elevated biomarkers of liver and kidney function associated with the db/db phenotype were significantly lowered by [S4K]CPF-AM1 administration. Peptide treatment significantly (P < 0.05) increased pancreatic insulin content and improved the responses of isolated islets to established secretagogues. Elevated expression of genes associated with insulin signalling (Slc2a4, Insr, Irs1, Akt1, Pik3ca, Ppm1b) in the skeletal muscle of db/db mice were significantly downregulated by peptide treatment. Genes associated with insulin secretion (Abcc8, Kcnj11, Slc2a2, Cacn1c, Glp1r, Gipr) were significantly upregulated by treatment with [S4K]CPF-AM1. Studies with BRIN-BD1I clonal β-cells demonstrated that the peptide evoked membrane depolarisation, increased intracellular Ca2+ and cAMP and activated the protein kinase C pathway. The data indicate that the antidiabetic properties of [S4K]CPF-AM1 mice are mediated by direct insulinotropic action and by regulation of transcription of genes involved in both the secretion and action of insulin. Show less

Genomic analyses of chronic lymphocytic leukemia (CLL) identified somatic mutations and associations of clonal diversity with adverse outcomes. Clonal evolution likely has therapeutic implications but its dynamic is less well studied. We studied clonal composition and prognostic value of seven recurrently mutated driver genes using targeted next-generation sequencing in 643 CLL patients and found higher frequencies of mutations in TP53 (35 vs. 12%, p < 0.001) and SF3B1 (20 vs. 11%, p < 0.05) and increased number of (sub)clonal (p < 0.0001) mutations in treated patients. We next performed an in-depth evaluation of clonal evolution on untreated CLL patients (50 "progressors" and 17 matched "non-progressors") using a 404 gene-sequencing panel and identified novel mutated genes such as AXIN1, SDHA, SUZ12, and FOXO3. Progressors carried more mutations at initial presentation (2.5 vs. 1, p < 0.0001). Mutations in specific genes were associated with increased (SF3B1, ATM, and FBXW7) or decreased progression risk (AXIN1 and MYD88). Mutations affecting specific signaling pathways, such as Notch and MAP kinase pathway were enriched in progressive relative to non-progressive patients. These data extend earlier findings that specific genomic alterations and diversity of subclones are associated with disease progression and persistence of disease in CLL and identify novel recurrently mutated genes and associated outcomes. Show less

The insulinotropic and antihyperglycaemic properties of glucagons from the sea lamprey (Petromyzontiformes), paddlefish (Acipenseriformes) and trout (Teleostei) and oxyntomodulin from dogfish (Elasmobranchii) and ratfish (Holocephali) were compared with those of human glucagon and GLP-1 in mammalian test systems. All fish peptides produced concentration-dependent stimulation of insulin release from BRIN-BD11 rat and 1.1 B4 human clonal β-cells and isolated mouse islets. Paddlefish glucagon was the most potent and effective peptide. The insulinotropic activity of paddlefish glucagon was significantly (P < 0.01) decreased after incubating BRIN-BD11 cells with the GLP1R antagonist, exendin-4(9-39) and the GCGR antagonist [des-His Show less

Abnormal cannabidiol (Abn-CBD) and AS-1269574 are potent selective agonists for GPR55 and GPR119, respectively. The present study evaluated the actions and ability of these small-molecule agonists to counteract experimental diabetes in mice. Diabetes was induced in NIH Swiss mice by five consecutive daily intraperitoneal injections of 40 mg/(kg body weight) streptozotocin. Diabetic mice received daily oral administration of Abn-CBD or AS-1269574 (0.1 μmol/kg) or saline vehicle (0.9% wt/vol. NaCl) over 28 days. Body weight, food intake, fluid intake, plasma glucose, insulin, glucose tolerance, insulin release, lipid profile and pancreatic morphology were examined. Mechanism of action of agonists was assessed in acute studies using incretin-receptor-knockout mice. Abn-CBD and AS-1269574 decreased plasma glucose (20-26%, p < 0.05) and increased circulating insulin (47-48%, p < 0.05) by 10-28 days, compared with saline-treated diabetic controls. Food intake and polydipsia were reduced by both agonists (21-23%, p < 0.05 and 33-35%, p < 0.01, respectively). After 28 days of treatment, plasma glucagon concentrations were reduced (p < 0.01) and glucose tolerance was enhanced by 19-44% by Abn-CBD (p < 0.05 or p < 0.001) and AS-1269574 (p < 0.05 to p < 0.001). Plasma insulin responses were improved (p < 0.01) and insulin resistance was decreased (p < 0.05 or p < 0.01) in both Abn-CBD- and AS-1269574-treated groups. Triacylglycerols were decreased by 19% with Abn-CBD (p < 0.05) and 32% with AS-1269574 (p < 0.01) while total cholesterol was reduced by 17% (p < 0.01) and 15% (p < 0.05), respectively. Both agonists enhanced beta cell proliferation (p < 0.001) although islet area was unchanged. Acute studies in Gipr- and Glp1r-knockout mice revealed an important role for the glucagon-like peptide 1 (GLP-1) receptor in the actions of both agonists, with the glucose-lowering effects of Abn-CBD also partly mediated through the glucose-dependent insulinotropic peptide (GIP) receptor. These data highlight the potential for fatty acid G-protein-coupled receptor-based therapies as novel insulinotropic and glucose-lowering agents acting partly through the activation of incretin receptors. Show less

The frog skin host-defence peptide hymenochirin-1B has been shown to stimulate insulin release in vitro from isolated pancreatic islets and BRIN-BD11 clonal β-cells. This study examines the effects of 28-day administration of a more potent analogue [P5K]hymenochirin-1B ([P5K]hym-1B) (75 nmol·kg(-1) body weight) to high-fat-fed mice with obesity, glucose intolerance and insulin resistance. Treatment with [P5K]hym-1B significantly decreased plasma glucose concentrations and improved glucose tolerance, insulin secretion, insulin sensitivity and increased the magnitude of the incretin effect (difference in response to oral vs intraperitoneal glucose loads). Responses to established insulin secretagogues were greater in islets isolated from treated animals compared with saline-treated controls. [P5K]hym-1B administration significantly decreased total islet area and β- and α-cell areas, and resulted in lower concentrations of circulating triglycerides and plasma and pancreatic glucagon. Peptide treatment had no effect on food intake, body weight, indirect calorimetry or circulating concentrations of amylase and marker enzymes of liver and kidney function. RT-PCR demonstrated that the Insr (insulin receptor) gene and genes involved in insulin signalling (Slc2a4, Irs1, Pik3ca, Akt1 and Pkd1) were significantly up-regulated in skeletal muscle from animals treated with [P5K]hym-1B. Expression of the Glp1r (GLP-1 receptor) and Gipr (GIP receptor) genes was significantly elevated in islets from peptide-treated mice. These data suggest that [P5K]hym-1B shows potential for development into an agent for treating patients with type 2 diabetes. Show less

Embryonic stem (ES) cells can be differentiated into insulin-producing cells by conditioning the culture media. However, the number of insulin-expressing cells and amount of insulin released is very low. Glucose-dependent insulinotropic polypeptide (GIP) enhances the growth and differentiation of pancreatic beta-cells. This study examined the potential of the stable analogue GIP(LysPAL16) to enhance the differentiation of mouse ES cells into insulin-producing cells using a five-stage culturing strategy. Semi-quantitative PCR indicated mRNA expression of islet development markers (nestin, Pdx1, Nkx6.1, Oct4), mature pancreatic beta-cell markers (insulin, glucagon, Glut2, Sur1, Kir6.1) and the GIP receptor gene GIP-R in undifferentiated (stage 1) cells, with increasing levels in differentiated stages 4 and 5. IAPP and somatostatin genes were only expressed in differentiated stages. Immunohistochemical studies confirmed the presence of insulin, glucagon, somatostatin and IAPP in differentiated ES cells. After supplementation with GIP(LysPAL16), ES cells at stage 4 released insulin in response to secretagogues and glucose in a concentration-dependent manner, with 35-100% increases in insulin release. Cellular C-peptide content also increased by 45% at stages 4 and 5. We conclude that the stable GIP analogue enhanced differentiation of mouse ES cells towards a phenotype expressing specific beta-cell genes and releasing insulin. Show less