New insights into alzheimers disease pathogenesis: the involvement of neurologins in synaptic malfunction

Synaptic damage is a key hallmark of Alzheimer's disease and the best correlate with cognitive decline ante mortem. Signature protein combinations arrayed at tightly apposed pre- and post-synaptic sites characterize different types of synapse. Neuroligins are postsynaptic cell adhesion molecules that interact with neurexins across the synaptic cleft. These pairings recruit receptors, channels and signal transduction molecules to the synapse, and help mediate trans-synaptic transmission. Dysfunction in the neuroligin family can disrupt neuronal networks and leads to neurodegeneration and other diseases. The extracellular domain of neuroligins is homologous with acetylcholinesterase but lacks residues required for enzymatic activity. This domain may interact pathogenically with beta-amyloid. Here we summarize research over the last decade on the potential involvement of neuroligins in Alzheimer's disease

A role for the neurexin-neuroligin complex in Alzheimer's disease

Synaptic damage is a critical hallmark of Alzheimer's disease, and the best correlate with cognitive impairment ante mortem. Synapses, the loci of communication between neurons, are characterized by signature protein combinations arrayed at tightly apposed pre- and post-synaptic sites. The most widely studied trans-synaptic junctional complexes, which direct synaptogenesis and foster the maintenance and stability of the mature terminal, are conjunctions of presynaptic neurexins and postsynaptic neuroligins. Fluctuations in the levels of neuroligins and neurexins can sway the balance between excitatory and inhibitory neurotransmission in the brain, and could lead to damage of synapses and dendrites. This review summarizes current understanding of the roles of neurexins and neuroligins proteolytic processing in synaptic plasticity in the human brain, and outlines their possible roles in β-amyloid metabolism and function, which are central pathogenic events in Alzheimer's disease progression

Bone mass in Saudi women aged 20–40 years : the association with obesity and vitamin D deficiency

Summary: This study describes that low bone density is prevalent in premenopausal Saudi women, especially women of normal weight and vitamin D deficiency. Although BMD is higher in obese young women, this may not be beneficial later in life in conjunction with persistent vitamin D deficiency. Introduction: Not attaining peak bone mass is one crucial factor contributing to the risk of developing osteoporosis and suffering fractures in later life. The objectives of this study were to describe the normal range of bone mineral density (BMD) and bone mineral content (BMC) in premenopausal Saudi women in relation to obesity and vitamin D insufficiency. Methods: A cross-sectional study involving 312 healthy Saudi women aged 20–40. All women were clinically examined. BMD (g/cm2) and BMC (g) assessed at total body (TB), femoral neck (FN) and lumbar spine (LS) were performed using dual-energy X-ray absorptiometry (DXA). Obesity was defined as BMI ≥ 30 kg/m2 and vitamin D deficiency defined as 25(OH)D < 50 nmol/L. Results: Almost half of the studied women were obese, and the majority (86.2%) were deficient in vitamin D. Mean BMD in TB 1.060 ± 0.091, FN 0.918 ± 0.153 and LS 1.118 ± 0.123 g/cm2, while TB-BMC 2077 ± 272 g. When classified by BMI, the proportion with low bone density was 2–3 times higher among the normal weight compared to the obese women, p < 0.001. In the cohort overall, ~ 19% of these young premenopausal women had osteopenia or osteoporosis at the femoral neck, but 26% in normal weight, vitamin D deficient women. Conclusion: This study shows low bone density in premenopausal Saudi women, particularly those with normal weight. While obesity appears to confer some protection against vitamin D deficiency at this age, this is assumed to change in later life

Unveiling the Efficacy of Sesquiterpenes from Marine Sponge <i>Dactylospongia elegans</i> in Inhibiting Dihydrofolate Reductase Using Docking and Molecular Dynamic Studies

Dihydrofolate reductase (DHFR) is a crucial enzyme that maintains the levels of 5,6,7,8-tetrahydrofolate (THF) required for the biological synthesis of the building blocks of DNA, RNA, and proteins. Over-activation of DHFR results in the progression of multiple pathological conditions such as cancer, bacterial infection, and inflammation. Therefore, DHFR inhibition plays a major role in treating these illnesses. Sesquiterpenes of various types are prime metabolites derived from the marine sponge Dactylospongia elegans and have demonstrated antitumor, anti-inflammation, and antibacterial capacities. Here, we investigated the in silico potential inhibitory effects of 87 D. elegans metabolites on DHFR and predicted their ADMET properties. Compounds were prepared computationally for molecular docking into the selected crystal structure of DHFR (PDB: 1KMV). The docking scores of metabolites 34, 28, and 44 were the highest among this series (gscore values of −12.431, −11.502, and −10.62 kcal/mol, respectively), even above the co-crystallized inhibitor SRI-9662 score (−10.432 kcal/mol). The binding affinity and protein stability of these top three scored compounds were further estimated using molecular dynamic simulation. Compounds 34, 28, and 44 revealed high binding affinity to the enzyme and could be possible leads for DHFR inhibitors; however, further in vitro and in vivo investigations are required to validate their potential

Dexpanthenol improved stem cells against cisplatin-induced kidney injury by inhibition of TNF-α, TGFβ-1, β-catenin, and fibronectin pathways

Introduction: Cisplatin interacts with DNA and induces an immunological response and reactive oxygen species, which are nephrotoxic mediators. Stem cells self-renew through symmetric divisions and can develop into other cell types due to their multipotency. Dexpanthenol has been proven to protect against renal injury. Aim: This study aims to demonstrate that dexpanthenol could improve the effect of adipose-derived mesenchymal stem cells (ADMSC) against cisplatin-induced acute kidney injury. Methods: Sixty male Sprague-Dawley rats were divided into 5 groups (N = 12): control, cisplatin, cisplatin &amp; dexpanthenol, cisplatin &amp; ADMSC, and cisplatin &amp; dexpanthenol &amp; ADMSCs. On the 5th day following cisplatin injection, half the rats in each group were sacrificed, and the other half were sacrificed on the 12th day. Histopathological examination, molecular studies (IL-6, Bcl2, TGFβ-1, Caspase-3, Fibronectin, and β-catenin), antioxidants (superoxide dismutase and catalase), and renal function were all investigated. Results: In contrast to cisplatin group, the dexpanthenol and ADMSCs treatments significantly decreased renal function and oxidative stress while significantly enhancing antioxidants. Dexpanthenol improved stem cells by significantly down-regulating caspase-3, IL-6, TGF-β1, Fibronectin, and β-catenin and significantly up-regulating Bcl2 and CD34, which reversed the cisplatin effect. Conclusion: Dexpanthenol enhanced ADMSCs' ability to protect against cisplatin-induced AKI by decreasing inflammation, apoptosis, and fibrosis

Unveiling the Efficacy of Sesquiterpenes from Marine Sponge Dactylospongia elegans in Inhibiting Dihydrofolate Reductase Using Docking and Molecular Dynamic Studies

Dihydrofolate reductase (DHFR) is a crucial enzyme that maintains the levels of 5,6,7,8-tetrahydrofolate (THF) required for the biological synthesis of the building blocks of DNA, RNA, and proteins. Over-activation of DHFR results in the progression of multiple pathological conditions such as cancer, bacterial infection, and inflammation. Therefore, DHFR inhibition plays a major role in treating these illnesses. Sesquiterpenes of various types are prime metabolites derived from the marine sponge Dactylospongia elegans and have demonstrated antitumor, anti-inflammation, and antibacterial capacities. Here, we investigated the in silico potential inhibitory effects of 87 D. elegans metabolites on DHFR and predicted their ADMET properties. Compounds were prepared computationally for molecular docking into the selected crystal structure of DHFR (PDB: 1KMV). The docking scores of metabolites 34, 28, and 44 were the highest among this series (gscore values of &minus;12.431, &minus;11.502, and &minus;10.62 kcal/mol, respectively), even above the co-crystallized inhibitor SRI-9662 score (&minus;10.432 kcal/mol). The binding affinity and protein stability of these top three scored compounds were further estimated using molecular dynamic simulation. Compounds 34, 28, and 44 revealed high binding affinity to the enzyme and could be possible leads for DHFR inhibitors; however, further in vitro and in vivo investigations are required to validate their potential

Structure-Based Virtual Screening and Molecular Dynamics Simulation Assessments of Depsidones as Possible Selective Cannabinoid Receptor Type 2 Agonists

The discovery of natural drug metabolites is a leading contributor to fulfilling the sustainable development goal of finding solutions to global health challenges. Depsidones are a class of polyketides that have been separated from lichens, fungi, sponges, and plants and possess various bioactivities, including cytotoxic, antimicrobial, antimalarial, antituberculosis, acetylcholinesterase and α-glucosidase inhibition, and anti-inflammatory effects. Endocannabinoid receptors (CB1 and CB2) are G-protein-coupled receptors (GPCRs), and their activation mediates many physiological processes. CB1 is the dominant subtype in the central nervous system, while CB2 is mainly expressed in the immune system. The two receptors exhibit high heterogeneity, making developing selective ligands a great challenge. Attempts to develop CB2 selective agonists for treating inflammatory diseases and neuropathic pain have not been successful due to the high homology of the binding sites of the CB receptors. In this work, 235 depsidones from various sources were investigated for the possibility of identifying CB2-selective agonists by performing multiple docking studies, including induced fit docking and Prime/molecular mechanics–generalized Born surface area (MM-GBSA) calculations to predict the binding mode and free energy. Simplicildone J (10), lobaric acid (110), mollicellin Q (101), garcinisidone E (215), mollicellin P (100), paucinervin Q (149), and boremexin C (161) had the highest binding scores (−12.134 kcal/mol, −11.944 kcal/mol, −11.479 kcal/mol, −11.394 kcal/mol, −11.322 kcal/mol, −11.305 kcal/mol, and −11.254 kcal/mol, respectively) when screened against the CB2 receptor (PDB ID: 6KPF). The molecular dynamic simulation was performed on the compounds with the highest binding scores. The computational outcomes show that garcinisidone E (215) and paucinervin Q (149) could be substantial candidates for CB2 receptor activation and warrant further in vivo and in vitro investigations

Design, Synthesis and In-Vitro Biological Evaluation of Antofine and Tylophorine Prodrugs as Hypoxia-Targeted Anticancer Agents

Phenanthroindolizidines, such as antofine and tylophorine, are a family of natural alkaloids isolated from different species of Asclepiadaceas. They are characterized by interesting biological activities, such as pronounced cytotoxicity against different human cancerous cell lines, including multidrug-resistant examples. Nonetheless, these derivatives are associated with severe neurotoxicity and loss of in vivo activity due to the highly lipophilic nature of the alkaloids. Here, we describe the development of highly polar prodrugs of antofine and tylophorine as hypoxia-targeted prodrugs. The developed quaternary ammonium salts of phenanthroindolizidines showed high chemical and metabolic stability and are predicted to have no penetration through the blood–brain barrier. The designed prodrugs displayed decreased cytotoxicity when tested under normoxic conditions. However, their cytotoxic activity considerably increased when tested under hypoxic conditions